Stable Angina and If Inhibition: New Insights and

Transcription

I S S U E
82
Medicographia
Vol 27, No. 1, 2005
ISSN 0243-3397
S table A ng i n a an d If I nhibition:
N ew I nsights and A pplications
M. TENDERA, POLAND
EDITORIAL
A NEW TREATMENT APPROACH FOR PATIENTS
WITH STABLE ANGINA: SELECTIVE AND SPECIFIC
IF INHIBITION. UNE NOUVELLE APPROCHE
THÉRAPEUTIQUE DANS LE TRAITEMENT DE L’ANGOR
STABLE: L’INHIBITION SELECTIVE ET SPÉCIFIQUE
DU COURANT I F
3
D. A. WOOD,
UNITED KINGDOM
EPIDEMIOLOGY OF ANGINA PECTORIS
8
L. TAVAZZI, ITALY
CLINICAL ASSESSMENT OF PATIENTS WITH
15
STABLE ANGINA
A. T. L. ONG AND
P. W. SERRUYS,
THE NETHERLANDS
P. G. STEG, FRANCE
G. HEUSCH AND
R. SCHULZ, GERMANY
INTERVENTIONAL TREATMENTS IN PATIENTS WITH
21
STABLE ANGINA
STABLE ANGINA TREATMENT IN THE 21ST CENTURY:
WHAT IS STILL MISSING?
29
THE PATHOPHYSIOLOGICAL ROLE OF HEART RATE IN
35
ACUTE MYOCARDIAL ISCHEMIA AND THE BENEFITS OF
HEART RATE REDUCTION
A journal of
medical information
and international
communication
from Servier
J. S. BORER, USA
IF INHIBITION AS A THERAPEUTIC APPROACH IN STABLE
ANGINA: EXPERIMENTAL AND CLINICAL STUDIES
44
H. PURCELL AND K. FOX,
UNITED KINGDOM
SELECTIVE AND SPECIFIC IF INHIBITION:
51
NEW PERSPECTIVES
Contents continued overleaf...
Medicographia
Vol 27, No. 1, 2005
I S S U E
82
...Contents continued from cover page
S t a b l e A n g i n a a n d If I n h i b i t i o n :
N e w I n s i g h t s a n d A p p l i c a t i o ns
R. SEABRA-GOMES,
CONTROVERSIAL QUESTION
PORTUGAL / D. Y. HU AND DOES GENDER INFLUENCE THE MANAGEMENT OF
J. G. YANG, PR CHINA /
PATIENTS WITH STABLE ANGINA?
J. LÓPEZ-SENDÓN, SPAIN /
R. Y. KASSAB, LEBANON /
P. ERNE AND D. RADOVANOVIC, SWITZERLAND /
C. A. BERTOLASI, ARGENTINA / S. J. BRISTER,
CANADA / I. H. MUDERRISOGLU, TURKEY
J.-P. VILAINE AND
J.-L. PEGLION, FRANCE
C. A. WRIGHT,
UNITED KINGDOM
56
INTERVIEW
THE DISCOVERY OF THE IF CURRENT INHIBITOR
PROCORALAN
67
FOCUS
LIVING WITH STABLE ANGINA: HOW DOES IT IMPACT
76
ON THE DAILY LIFE OF PATIENTS AND WHAT ARE THE
TREATMENT OPTIONS?
UPDATE
A. DIAZ AND J.-C. TARDIF, CLINICAL APPLICATIONS OF EXCLUSIVE HEART RATE
CANADA
REDUCTION IN EMERGENCY CARDIOLOGY
C. RÉGNIER, FRANCE
T. GERVAIS, FRANCE
82
A TOUCH OF FRANCE
JEAN-BAPTISTE BAILLIÈRE (1797-1885)
THE PIONEERING PUBLISHER WHO PROMOTED
FRENCH MEDICINE THROUGHOUT THE WORLD
87
A TOUCH OF FRANCE
IMAGING THE WORLD. L’ILLUSTRATION:
THE BIRTH OF THE FRENCH ILLUSTRATED PRESS
97
AND THE INTRODUCTION OF PHOTOJOURNALISM IN
THE MID-19TH CENTURY
E
D I T O R I A L
A new treatment approach
for patients with stable angina:
selective and specific If inhibition
b y M . Te n d e r a , P o l a n d
T
Michal TENDERA, MD
Katowice, POLAND
Address for correspondence:
Prof Michal Tendera,
Ziolowa Street 47, 40-635
Katowice, Poland (e-mail:
[email protected])
Medicographia.
2005;27:3-7.
Editorial – Tendera
HE PREVALENCE OF ISCHEMIC HEART DISEASE IS STILL HIGH.
Despite an important reduction in mortality, mainly as a result of
improved primary and secondary prevention, there are still important unmet needs to be satisfied in the treatment of the disease. New
pharmacological agents are needed to alleviate the symptoms, increase exercise tolerance, and
improve quality of life. In this context, the novel selective and specific If inhibitor ivabradine has
been shown to provide effective and safe treatment of stable angina through exclusive heart rate
reduction.
Magnitude of the problem
Over the last two decades, age-adjusted mortality due to coronary artery disease has decreased
in most European countries.1 This is a consequence of better treatment and improved survival
in patients having experienced acute coronary events, and lower incidence of the disease, especially among younger people, resulting from more effective primary and secondary prevention
of atherosclerosis. The absolute number of coronary events remains relatively constant. This
means that in practice the burden of coronary atherosclerosis has shifted to older age groups.
Ischemic heart disease remains the leading cause of mortality and morbidity and continues to be
a major burden to public health. The true prevalence of chronic ischemic heart disease is difficult to estimate, since symptoms may not be typical and their predictive value for ischemia depends on sex and age, and—on the other hand—myocardial ischemia is not necessarily symptomatic.
Stable angina pectoris, which is a common manifestation of ischemia, is widely used to estimate the prevalence of ischemic heart disease. Angina occurs more frequently in men. Its
prevalence increases with age in both sexes, from 2% to 5% in men aged 45 to 54 years, to 11%
to 20% in those aged 65 to 74 years. In women, respective values increase from 0.5% to 1% to
10% to 14%. Above age 75, the prevalence of angina in men and women is almost equal.2 It is
estimated that in countries with high ischemic heart disease rates the total number of persons
with angina may be as high as 30 to 40 thousand per million total population.2 In a substantial
proportion of patients, angina causes an important limitation of everyday activities and impairs
quality of life. Thus, stable angina pectoris is common and may be debilitating.
Mortality in patients with stable angina is estimated at 2% to 3% per year.3,4 This means that
in the majority of patients risk of death may be only moderately increased as compared with agematched healthy subjects. However, prognosis in patients with chronic angina is not uniform.
It depends on several factors, including underlying coronary anatomy, left ventricular function,
and comorbidities. Identification of high-risk patients who can benefit from therapy aimed to
improve prognosis is of utmost importance. In low-risk patients, the main aim of treatment is
to eliminate symptoms and improve health-related quality of life.
MEDICOGRAPHIA, VOL 27, No.1, 2005
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Treatment options
Introduction of surgical and percutaneous myocardial revascularization has dramatically changed
the treatment of patients with ischemic heart disease. Revascularization offers effective relief of
symptoms, and in patients with extensive ischemia, like those with left main or three-vessel disease, also improves prognosis. Effective restoration of adequate coronary flow, either surgical or
percutaneous, does not obviate the need for medical treatment. Medical therapy is necessary to
prevent subsequent events and to treat residual or recurrent ischemia. In addition, not all patients with chronic ischemia require revascularization. Medical treatment is still recommended as first-line strategy to control symptoms.2
β-Blockers, calcium channel blocking agents, and nitrates have been the mainstay of medical therapy of chronic angina for a long time. Although these drugs can also improve oxygen supply, they predominantly act by decreasing myocardial oxygen demand. Contractility, systolic wall
tension, and heart rate are the most important determinants of oxygen demand. Heart rate is
relatively easy to change, and therefore its reduction is often targeted. In the presence of ischemia, heart rate reduction may restore the balance between myocardial oxygen supply and
demand. Slowing of heart rate not only decreases oxygen demand, but also improves myocardial
perfusion through prolongation of diastole. β-Blockers and some calcium channel blockers act,
at least in part, through this mechanism. β-Blockers are most often recommended as primary
therapy since, in addition to symptomatic relief, they have been found to reduce mortality and
reinfarction, at least in postinfarction patients.5 Heart rate is often used to determine the appropriate dosage of β-blockers. The recommended target heart rate on treatment is in the range
of 55 to 60 per minute at rest, and around 75% of that which provokes ischemia on exercise.6 In
clinical practice this target is often not reached because of adverse effects: fatigue, lethargy, insomnia, worsening claudication, or erectile dysfunction in men. In addition, β-blockers are contraindicated in some patients, including those with reversible airways obstruction, atrioventricular conduction defects, decompensated heart failure, symptomatic peripheral vascular disease,
brittle diabetes, or history of severe depression.
Some calcium channel blockers, like verapamil or diltiazem, can also slow the heart rate, but
their effect is difficult to predict, and the data on their clinical benefit are rather scanty. Therefore, there is an evident need for another class of drugs that could attain this effect administered
alone or on the top of other agents.
The concept of I f current blockade
The pacemaker (If) current plays a central role in heart rate control.7 This makes it an interesting target for pharmacological intervention. Inhibition of the If current results in heart rate
reduction, with no other effects on the heart. This bradycardic effect has a clear potential to reduce ischemia.
Ivabradine is a selective and specific If current blocker 8,9 that has been used to test this novel therapeutic concept. As opposed to β-blockers, ivabradine has no negative inotropic action.
It also has no impact on atrioventricular nodal conduction. In an experimental model, it decreased exercise-induced ECG changes to the same extent as propranolol, but was able to better
preserve systolic function in the ischemic area.10 Ivabradine was also shown to be superior to
β-blockade in the setting of myocardial stunning, where it improved contractility.11 In humans,
ivabradine significantly slows heart rate at rest and at peak exercise.12 It has been shown to be a
safe and effective antianginal and anti-ischemic agent in patients with stable angina. In a double-blind placebo-controlled study, it produced a dose-dependent prolongation of total exercise
time and time to development of ischemia.12
Heart rate reduction with ivabradine may carry additional benefits beyond relief of angina
and ischemia. Animal studies show that slow heart rate may attenuate the development of atherosclerosis.13 Long-term administration of ivabradine is associated with improvement in left ventricular function in rats with induced myocardial infarction.14 In humans, lower heart rates may
reduce the odds of plaque rupture and thus the probability of a new acute coronary event.15,16
The novel concept of treatment of chronic ischemic heart disease with the If current blocker ivabradine has proved effective in patients with angina, and holds promise in other patient
groups, like those at high risk of acute coronary events or those with compromised left ventricular systolic function. ❒
4
Editorial – Tendera
ÉD
REFERENCES
1. European Health for All Database. WHO Regional Office for
Europe, Copenhagen, Denmark; 2004.
2. Management of stable angina pectoris. Recommendations of
the Task Force of the European Society of Cardiology. Eur Heart J.
1997;18:394-413.
3. Brunelli C, Cristofani R, L’Abbate A. Long term survival in medically treated patients with ischaemic heart disease and prognostic importance of clinical and electrocardiographic data. Eur
Heart J. 1989;10:292-303.
4. Dargie HJ, Ford I, Fox KM, on behalf of the TIBET Investigators. Total Ischaemic Burden European Trial (TIBET). Eur Heart J.
1997;17:104-112.
5. The Beta-Blocker Pooling Project Research Group. The BetaBlocker Pooling Project (BBPP): subgroup findings from randomized trials in post infarction patients. Eur Heart J. 1988;9:
8-16.
6. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM
Guidelines for the management of patients with chronic stable
angina. J Am Coll Cardiol. 1999;33:2092-2190.
7. Brown HF, DiFrancesco D. Voltage-clamp investigations of
membrane currents underlying pacemaker activity in rabbit
sino-atrial node. J Physiol. 1980;308:331-351.
8. Bois P, Bescond J, Renaudon B, Lenfant J. Mode of action of
bradycardic agent S 16257 on ionic currents of rabbit sinoatrial
node cells. Br J Pharmacol. 1996;118:1051-1057.
9. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent
block of rabbit sino-atrial node If channels by ivabradine. J Gen
Physiol. 2002;120:1-13.
I T O R I A L
10. Vilaine JP, Bidouard JP, Lesage L, Reure H, Peglion JL. Antiischemic effects of ivabradine, a selective heart rate-reducing
agent, in exercise-induced myocardial ischemia in pigs. J Cardiovasc Pharmacol. 2003;42:688-696.
11. Monnet X, Colin P, Ghaleh B, Hittinger L, Giudicelli JF,
Berdeaux A. Heart rate reduction during exercise-induced myocardial ischaemia and stunning. Eur Heart J. 2004;25:579-586.
12. Borer JS, Fox K, Jaillon P, Lerebours G, for the Ivabradine Investigators Group. Antianginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina. A randomized, doubleblind, multicentered, placebo-controlled trial. Circulation. 2003;
107:817-823.
13. Beere PA, Glagov S, Zarins CK. Retarding effect of lowered
heart rate on coronary atherosclerosis. Science.1984;226:180182.
14. Mulder P, Barbier S, Chagraoui A, Richard V, et al. Long-term
heart rate reduction induced by the selective If current inhibitor
ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation. 2004;
109:1674-1679.
15. Heidland UE, Strauer BE. Left ventricular muscle mass and
elevated heart rate are associated with coronary plaque disruption. Circulation. 2001;104:1477-1482.
16. Aronow WS, Ahn C, Mercando AD, Epstein S. Association of
average heart rate on 24-hour ambulatory electrocardiograms
with incidence of new coronary events at 48-months follow-up
in 1311 patients (mean age 81 years) with heart disease and sinus
rhythm. Am J Cardiol. 1996;78:1175-1176.
Keywords: myocardial ischemia; stable angina; atherosclerosis; I f current inhibition; heart rate
reduction; prevention; ivabradine
Une nouvelle approche thérapeutique
dans le traitement de l’angor stable:
l’inhibition selective et spécifique
du courant If
L
A PRÉVALENCE DES CARDIOPATHIES ISCHÉMIQUES RESTE
élevée. Malgré une diminution importante de la mortalité, principalement du fait de l’amélioration de la prévention primaire et
secondaire, il subsiste encore des besoins à satisfaire dans le traitement de cette pathologie. Il manque de nouveaux agents pharmacologiques pour soulager les
symptômes, augmenter la tolérance à l’effort et améliorer la qualité de vie. Dans ce contexte,
l’ivabradine, un nouvel agent doué d’un effet inhibiteur sélectif et spécifique sur le courant If ,
a fait la preuve de son efficacité et de sa tolérance dans le traitement de l’angor stable, grâce
à une réduction exclusive de la fréquence cardiaque.
Amplitude du problème
Au cours des deux dernières décennies, la mortalité due à la maladie coronaire ajustée en fonction de l’âge a diminué dans la plupart des pays européens 1. Cet effet résulte des progrès thérapeutiques, de l’amélioration de la survie chez les malades atteints d’un syndrome coronaire aigu,
mais aussi de la diminution de l’incidence de la maladie, tout particulièrement chez les sujets
jeunes, du fait d’une plus grande efficacité dans la prévention primaire et secondaire de l’athéÉditorial – Tendera
5
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I T O R I A L
rosclérose. Le nombre absolu des événements coronaires reste cependant relativement constant,
ce qui veut dire, qu’en pratique, le fardeau de l’athérosclérose coronaire n’a fait que se déplacer vers les sujets plus âgés. Les cardiopathies ischémiques restent la principale cause de mortalité et de morbidité. Elles continuent de peser lourdement en santé publique. La prévalence
exacte des cardiopathies ischémiques chroniques est difficile à estimer, car leurs symptômes ne
sont pas toujours typiques et la valeur prédictive de ceux-ci quant à l’existence d’une ischémie
myocardique dépend du sexe et de l’âge. Cette dernière, d’autre part, n’est pas nécessairement
associée à des symptômes.
L’angor stable, manifestation courante de l’ischémie, est généralement utilisé pour estimer
la prévalence des cardiopathies ischémiques. Ce symptôme survient plus souvent chez l’homme.
Sa prévalence augmente avec l’âge dans les deux sexes. Elle est de 2-5 % chez l’homme âgé de
45 à 54 ans et de 11-20 % entre 65 et 74 ans. Chez la femme, les valeurs correspondantes sont
respectivement de 0,5-1,0 % et de 10-14 %. Après 75 ans, la prévalence de l’angor dans les deux
sexes est à peu près égale 2. On estime que, dans les pays où les cardiopathies ischémiques sont
fréquentes, le nombre total de sujets atteints d’un angor peut atteindre 30000 à 40000 par million d’habitants 2. Dans une proportion substantielle de cas, l’angor est à l’origine d’une limitation importante des activités quotidiennes et retentit sur la qualité de vie. Ce symptôme, qui
est donc commun, peut être débilitant.
La mortalité en cas d’angor stable est estimée à 2-3 % par an 3,4. En d’autres termes, par rapport à des sujets sains appariés selon l’âge, le risque de décès, chez la majorité des malades, ne
semble que modérément augmenté. Cependant, le pronostic de l’angor stable est loin d’être uniforme. Il dépend en fait de nombreux facteurs, dont l’anatomie coronaire, la fonction ventriculaire gauche et les comorbidités. L’identification des malades à haut risque qui vont bénéficier
le plus des traitements destinés à améliorer le pronostic est donc de la plus haute importance.
Chez les malades à faible risque, l’objectif principal du traitement est de soulager les symptômes
et d’améliorer la qualité de vie dépendant de la santé.
Options thérapeutiques
L’introduction de la revascularisation chirurgicale et percutanée a profondément modifié la prise
en charge thérapeutique des cardiopathies ischémiques. La revascularisation soulage efficacement les symptômes et, en cas d’ischémie étendue, liée, par exemple, à une atteinte du tronc de
l’artère coronaire gauche ou à des lésions tritronculaires, elle améliore aussi le pronostic. La
restauration effective d’un débit sanguin coronaire approprié, que ce soit par voie percutanée
ou chirurgicale, ne dispense pas du traitement médical. Celui-ci reste nécessaire pour prévenir
les événements ultérieurs et traiter l’ischémie résiduelle ou récidivante. De plus, tous les malades
atteints d’une ischémie chronique ne sont pas justiciables d’une revascularisation. Le traitement
médical est encore recommandé en tant que stratégie thérapeutique de première intention pour
contrôler les symptômes 2.
Les bêtabloquants, les inhibiteurs calciques et les dérivés nitrés ont longtemps été les piliers
du traitement médical de l’angor stable. Ces médicaments agissent principalement en diminuant les besoins myocardiques en oxygène, bien qu’ils soient capables d’augmenter les apports de ce dernier. La contractilité, la tension pariétale systolique et la fréquence cardiaque
sont les principaux déterminants des besoins myocardiques en oxygène. La fréquence cardiaque
est relativement facile à modifier, et, de ce fait, sa réduction est souvent ciblée. En présence d’une
ischémie, la baisse de la fréquence cardiaque peut restaurer l’équilibre entre les apports et les
besoins en oxygène. Le ralentissement de la fréquence cardiaque diminue certes les besoins en
O2 , mais il améliore aussi la perfusion myocardique en prolongeant la diastole. Les bêtabloquants et certains inhibiteurs calciques agissent, au moins en partie, selon ce mécanisme. Les
bêtabloquants sont le plus souvent recommandés en première intention, car, en plus de leur
effet symptomatique, ils sont capables de réduire la mortalité et la fréquence des infarctus récidivants, tout au moins dans le postinfarctus 5. La fréquence cardiaque est souvent utilisée pour
choisir le dosage le plus approprié de bêtabloquants. Elle soit se situer entre 55 et 60 par minute
au repos et autour de 75 % de la fréquence qui provoque une ischémie à l’effort 6. En pratique
courante, cet objectif n’est souvent pas atteint, du fait des effets indésirables : asthénie, léthargie, insomnie, aggravation d’une claudication intermittente ou dysfonctionnement érectile chez
l’homme. De plus, les bêtabloquants sont contre-indiqués chez certains malades, notamment
ceux atteints d’un bronchospasme réversible, de troubles de la conduction auriculoventriculaire, d’une insuffisance cardiaque décompensée, d’une artériopathie périphérique symptomatique, d’un diabète difficile à équilibrer ou encore en cas d’antécédents de dépression sévère.
6
Éditorial – Tendera
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Certains inhibiteurs calciques, tels le vérapamil ou le diltiazem, peuvent aussi ralentir la fréquence cardiaque, mais il est difficile de prédire leur effet, et, de plus, leur bénéfice clinique est
plutôt mal documenté. De fait, il y a besoin à l’évidence d’une autre classe thérapeutique qui
pourrait atteindre un tel effet, que le médicament soit administré seul ou en plus des autres
agents.
Le concept d’inhibition du courant If
Le courant pacemaker (I f ) joue un rôle central dans le contrôle de la fréquence cardiaque 7. De
ce fait, il constitue une cible privilégiée pour les interventions pharmacologiques. L’inhibition
du courant I f entraîne une diminution de la fréquence cardiaque qui ne s’accompagne d’aucun
autre effet sur le cœur. Cet effet bradycardisant permet potentiellement de réduire l’ischémie.
L’ivabradine est un inhibiteur sélectif et spécifique du courant I f 8,9 et a été utilisé à ce titre
pour tester ce nouveau concept thérapeutique. À la différence des bêtabloquants, l’ivabradine
n’exerce pas d’effet inotrope négatif. Elle n’a pas non plus d’impact sur la conduction nodale
auriculoventriculaire. Dans un modèle expérimental, elle est capable de diminuer les anomalies électrocardiographiques induites par l’effort, comme le fait le propranolol, mais, à la différence de celui-ci, elle permet de mieux préserver la fonction systolique dans les régions ischémiques 10. L’ivabradine s’est également révélée supérieure aux bêtabloquants dans le contexte
de la sidération myocardique où elle est capable d’améliorer la contractilité 11. Chez l’homme,
l’ivabradine ralentit significativement la fréquence cardiaque au repos comme à l’effort maximal 12. Elle a fait la preuve de son activité antiangineuse et anti-ischémique, mais aussi de sa
bonne tolérance chez les malades atteints d’un angor stable. Dans une étude contrôlée, menée
à double insu contre placebo, l’ivabradine a permis d’obtenir un allongement dose-dépendant
de la durée totale de l’effort et du délai avant la survenue d’une ischémie 12.
La réduction de la fréquence cardiaque obtenue grâce à l’ivabradine peut apporter un bénéfice additionnel qui va au-delà du soulagement de l’angor et de l’ischémie. Les études réalisées
chez l’animal montrent que le ralentissement de la fréquence cardiaque permet d’atténuer le
développement de l’athérosclérose 13. L’administration de l’ivabradine au long cours s’associe à
une amélioration de la fonction ventriculaire gauche chez les rats atteints d’un infarctus du myocarde expérimental 14. Chez l’homme, des fréquences cardiaques plus lentes pourraient réduire
le risque de rupture de plaque et ainsi la probabilité d’un nouvel événement coronaire aigu 15,16.
L’ivabradine, au travers de l’inhibition du courant I f , inaugure un concept thérapeutique
nouveau dans la prise en charge des cardiopathies ischémiques. Ce médicament a fait la preuve
de son efficacité chez les malades atteints d’angor. Il s’annonce prometteur dans d’autres groupes
de patients, notamment chez ceux ayant un risque élevé de syndrome coronaire aigu ou atteints
d’une altération de la fonction systolique ventriculaire gauche. ❒
✦
Éditorial – Tendera
7
STABLE ANGINA
AND
IF I N H I B I T I O N : N E W I N S I G H T S
AND
APPLICATIONS
David A. WOOD, MSc, FRCP
Professor, Department of Cardiovascular
Medicine, Cardiology Department
Charing Cross Hospital
London, UNITED KINGDOM
Epidemiology
of angina pectoris
by D. A. Wood, United Kingdom
oronary atherosclerosis most commonly presents in the community as angina pectoris,
followed by acute coronary syndromes (acute
myocardial infarction and unstable angina), and,
finally, as sudden cardiac death. Atherosclerosis also
affects the rest of the arterial circulation, principally the aorta and its major branches to the head and
limbs. Patients presenting with cerebral ischemia or
infarction, or symptoms of peripheral arterial disease, usually have coronary atherosclerosis as well.
For those who survive these other clinical manifestations of atherosclerosis, the commonest cause of
death is coronary heart disease (CHD).
When the acute manifestations of coronary artery
disease—sudden cardiac death and acute myocardial infarction—are considered together, then 1 in
C
A
ngina pectoris is the commonest clinical presentation of coronary atherosclerosis in the community. The incidence rate of angina in one epidemiological study in London was 122 per 100 000 population (25-74
years) per annum. Incidence increased with age and was higher in men (157)
than women (127). The prevalence of angina from the Rose Angina Questionnaire is 2.6% in men and 3.1% in women for the English population aged 16
years and over. In those aged 75 and over, 18% of men and 17% of women had
angina. The assessment of chest pain in the community by the general practitioner, without specialist investigations, can be difficult. A Rapid Access Chest
Pain Clinic is one new model of care that can provide specialist assessment of
patients presenting for the first time in the community. Such a clinic can resolve the diagnosis, risk-stratify those with angina, and prioritize for further
specialist investigation and, where appropriate, revascularization. Over the
longer term, there is considerable potential through lifestyle changes, risk factor modification, and the use of prophylactic drug therapies to reduce the risk of
progressing to myocardial infarction and death.
Medicographia. 2005;27:8-14.
(see French abstract on page 14)
Keywords: angina pectoris; atherosclerosis; coronary heart disease; sudden
cardiac death; epidemiology; therapy
2 patients with new or recurrent disease die within
30 days of their acute clinical presentation.1-4 About
69% die in the community, 29% die in hospital, and
the other 2% die within 30 days of discharge. However, when all first nonfatal and fatal symptomatic
expressions of coronary atherosclerosis are considered together — angina pectoris, acute coronary
syndromes, and sudden cardiac death — the vast
majority of patients survive their first clinical presentation, with only up to one fifth of all such incident cases due to sudden unheralded cardiac death
in the community. Therefore, considerable potential exists among those with angina and nonfatal
acute coronary syndromes to reduce subsequent
morbidity and mortality through therapeutic and
revascularization procedures and, over the longer
term, by lifestyle changes, risk factor modification,
and the use of prophylactic drug therapies such as
aspirin, β-blockers, angiotensin-converting enzyme
(ACE) inhibitors, cholesterol modification therapy,
and anticoagulation.
Incidence of CHD
The incidence of CHD — angina pectoris, acute
coronary syndromes, and sudden cardiac death—
is only available from specially conducted community surveys. The Bromley Coronary Heart Disease
Register (BCHDR) is the only contemporary community register to identify all symptomatic medSELECTED
ABBREVIATIONS AND ACRONYMS
A&E
Accident and Emergency
(Department)
BCHDR
Bromley Coronary Heart Disease
Register
CHD
coronary heart disease
EUROASPIRE EUROpean Action on Prevention
by Intervention to Reduce
Events
Address for correspondence: Prof David A. Wood, Department of Cardiovascular Medicine,
Cardiology Department, 5th Floor, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK
(e-mail: [email protected])
8
RACPC
Rapid Access Chest Pain Clinic
Epidemiology of angina pectoris – Wood
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ical presentations of CHD in one population.5 All
incident (first) presentations of exertional angina,
acute coronary syndromes, and sudden cardiac death
were registered for Bromley Health District in South
East London (population 186 053 in men and women aged 25 to 74 years) for the period 1996 to 1998
(Figures 1 and 2). Incidence rates for exertional angina, acute coronary syndromes, and sudden cardiac
death derived from this community survey are given in Table I.
IN
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AP
46%
AMI
28%
UA
13%
Men
Women
(n = 378)
(n = 242)
SCD
14%
SCD
13%
AP
41%
AP
52%
AMI
32%
UA
13%
All nonfatal cases
(n = 537)
AMI
32%
AP
53%
UA
15%
Men
Women
(n = 326)
(n = 211)
AMI
37%
AP
48%
AP
60%
UA
15%
UA
15%
Source: Bromley Coronary Heart Disease Register. AMI, acute myocardial infarction; AP, angina pectoris;
UA, unstable angina.
tients with symptoms, objective evidence of reversible ischemia, and coronary atherosclerosis at angiography. The age- and sex-specific incidence rates
for exertional angina in patients with no history of
CHD from the Bromley CHD register are shown in
Women
All
Rate (95% CI)
No.
Rate (95% CI)
Angina pectoris
157
172 (146, 201)
127
89 (74, 106)
284
122 (108, 137)
Unstable angina
48
53 (39, 70)
31
22 (15, 31)
79
34 (27, 42)
Acute myocardial
infarction
121
133 (110, 159)
53
37 (28, 49)
174
75 (64, 86)
52
57 (43, 75)
31
22 (15, 31)
83
36 (28, 44)
AMI
25%
Figure 2. Incidence (first presentation) of nonfatal cases of coronary heart disease in
men and women (<75 years) in the community.
No.
414 (374, 458)
AMI
22%
Source: Bromley Coronary Heart Disease Register. AMI, acute myocardial infarction; AP, angina pectoris;
SCD, sudden cardiac death; UA, unstable angina.
Men
378
UA
13%
Figure 1. Incidence (first presentation) of fatal and nonfatal cases of coronary heart
disease in men and women (<75 years) in the community.
Rate (95% CI)
All
P L I C AT I O N S
SCD
13%
No.
Sudden cardiac
death
AP
All cases
Incidence of angina
Angina is a symptom and therefore there is greater
potential for misdiagnosis, particularly in women
for whom chest pain is more commonly reported.
Angina incidence rates from this register inevitably
count some patients who are subsequently shown
at coronary arteriography to have normal coronary
arteries. Incidence will therefore be inflated by including such healthy people. However, refining the
diagnosis by electrocardiography (ECG), either at
rest or on exercise, will underestimate true incidence. This is because the majority of patients with
angina due to coronary atherosclerosis have normal resting ECGs, and only two thirds show changes
consistent with myocardial ischemia (ST-segment
and/or T-wave changes) on exercise, with some false
positives, particularly among women. So the true
incidence of angina lies somewhere between the
rate calculated for symptoms alone (regardless of
ECG and other findings) and that derived for pa-
A N D
(n = 620)
Chest pain
Chest pain is common in the community, and
breathlessness can be a variant symptom of angina.
The incidence rate for chest pain reported for the
first time by patients with no medical history of CHD
to medical services (a general practitioner [GP] or
an Accident and Emergency [A&E] Department) and
considered by a doctor to be potentially cardiac in
origin, was measured as part of the Bromley CHD
register (Table II, page 10). The incidence rate (95%
confidence interval [CI]) for chest pain for the age
group 25 to 74 years was 481 per 100 000 per annum
(480, 482); men 583 (582, 584) and women 379
(378, 380). As the incidence rate for angina in women is about half that of men (see below), chest pain
is a more common complaint in this group in relation to the true incidence of coronary disease.
: NE
242
170 (149, 193)
620
266 (246, 288)
Table I. Incidence (first
presentation) per 100 000
population (25-74 years) per
annum (95% confindence
interval [CI]) of coronary
heart disease in men and
women in the community
(Bromley Coronary Heart
Disease Register).
9
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Nonanginal chest pains
No.
<25
Incidence
7
8
25-34
54
35-44
: NE
W
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A N D
All incident chest pain
CI
No.
Incidence
CI
5.9, 10
7
8
5.9, 10
116
115, 117
56
120
119, 121
150
360
359, 361
170
407
406, 408
45-54
229
553
552, 554
307
742
741, 743
55-64
224
749
748, 750
392
1310
1309, 1311
65-75
190
710
714, 716
384
1445
1444, 1446
<75
854
312
310, 314
1316
481
480, 482
Table II. Number, age-specific incidence rates (95% confidence interval [CI]) of chest
pain per 100 000 population (25-74 years) per annum (the number and incidence of
patients presenting for the first time with chest pain considered to be exertional angina).
Tables III and IV. The incidence rate for exertional
angina for the age group 25 to 74 years was 122 per
100 000 per annum (108, 137). The incidence rate for
men was 172 (146, 201) and for women 89 (74, 106).
Prevalence of angina pectoris
Prevalence of angina has been estimated in population surveys using a standardized questionnaire.
The Health Survey for England6 used the Rose Angina Questionnaire and the overall prevalence (angiMEN
Exertional angina
Unstable angina
Age (y)
No. Inc.
No. Inc.
CI
CI
Acute myocardial infarction
No. Inc.
CI
AP
P L I C AT I O N S
na grade 1 and 2) in the population aged 16 years
and over was 2.6% in men and 3.1% in women. It
was higher in women than in men in all age groups
except for those aged 75 and over, where 7.3% of
men and 5.9% of women reported this symptom.
In contrast, the overall prevalence of having ever
been diagnosed by a doctor with angina was 5.3%
in men (3.2% currently) and 3.9% in women (2.5%
currently). In both sexes, prevalence increased with
age, being negligible in those aged under 35 to almost 1 in 5 in those aged 75 and over (18.3% of men
and 17.0% of women). The prevalence of angina as
assessed by the Rose Angina Questionnaire showed
a different pattern to reported doctor-diagnosed
angina: the overall prevalence was lower than for
reported doctor diagnosed angina, and women reported more symptoms than men. Also, the Rose
Angina Questionnaire gave higher estimates in
younger age groups and lower estimates in older
age groups than self-reported prevalence. These different measures of prevalent angina can have different applications. From a clinical perspective, a
doctor diagnosis is more useful because it is not just
based on symptoms, but also takes account of other clinical information such as risk factors, investigations, and a specialist opinion. Angina based on
hospital discharges and deaths has no meaning for
the community because most patients with exertional angina are never admitted to hospital at the
time they first present to medical services.
Sudden cardiac death
No. Inc.
CI
Total
No. Inc.
CI
25-34
0
0
–
0
0
–
1
4
(0.1, 24)
0
0
–
1
4
(0.1, 24)
35-44
4
19
(5, 48)
1
5
(0.1, 26)
11
52
(26, 93)
1
5
(0.1, 26)
18
80
(47, 129)
6
30
(11, 65)
65
327
(253, 417)
(68, 189)
130
45-54
26 129 (84, 189)
9
45
(20, 85)
25 124
(80, 183)
55-64
65 449 (346, 572)
14
97
(53, 162)
34 235
(163, 328)
17 117
65-74
62 520 (399, 667)
24 201 (129, 300)
50 420
(311, 553)
28 235 (156, 340)
164 1376 (1173, 1603)
25-74
157 172 (146, 201)
121 133
(110, 159)
52
378
48
53
(39, 70)
57
(43, 75)
897 (749, 1065)
414
(374, 458)
Table III. Number and age-specific incidence (Inc.) rates per 100 000/population (25-74 years) per annum (95% confidence interval [CI]) of
coronary heart disease in men in the community (12 months’ data collection). (Bromley Coronary Heart Disease Register.)
WOMEN
Exertional angina
Unstable angina
Age (y)
No. Inc.
No. Inc.
CI
CI
Acute myocardial infarction
No. Inc.
CI
Sudden cardiac death
No. Inc.
CI
Total
No. Inc.
CI
25-34
0
0
–
0
0
–
1
3
(0.1, 16)
0
0
–
1
3
35-44
2
6
(0.8, 23)
0
0
–
1
3
(0.1, 18)
1
3
(0.1, 18)
4
13
(4, 33)
45-54
17
53
(31, 85)
6
19
(7, 41)
4
13
(3, 32)
2
6
(0.8, 23)
29
91
(61, 131)
55-64
53 229 (172, 300)
11
48
(24, 85)
14
61
(33, 102)
6
26
(10, 56)
84
363
(290, 449)
65-74
55 250 (188, 326)
14
64
(35, 107)
33 150
(103, 211)
22 100
(63, 151)
124
564
(469, 627)
31
22
(15, 31)
53
31
(15, 31)
242
170
(149, 193)
25-74
127
89 (74, 106)
37
(28, 49)
22
(0.1, 16)
Table IV. Number and age-specific incidence (Inc.) rates per 100 000/population (25-74 years) per annum (95% confidence interval [CI]) of
coronary heart disease in women in the community (12 months data collection). (Bromley Coronary Heart Disease Register.)
10
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Presentation and management of
cardiac chest pain in the community
A patient seeking medical advice for chest pain can
do so through the GP or through the A&E Department. The doctor has to decide is the pain cardiac
in origin and, if so, whether it is due to an acute
coronary syndrome or exertional angina. The former requires urgent assessment in hospital whereas the latter can be managed as an outpatient. For
the GP, the diagnosis can be difficult from the history alone. Options are to perform an ECG, send the
patient to casualty, refer for an open access 12-lead
ECG (and in some hospitals open-access exercise
testing is also available), or refer for a cardiology
outpatient opinion. Community surveys of angina
suggest most patients with “stable angina” are managed by their GP, while only a small minority is referred for specialist opinion and investigations. For
those presenting directly to casualty, the doctor can
admit or refer to cardiology outpatient care or back
to the GP. The consequence in casualty is that there
are up to 25% inappropriate admissions of noncardiac chest pain to hospital with the label “chest
pain — exclude myocardial infarction” and, conversely, between 2% and 12% of patients being inappropriately discharged from hospital who turn
out to have coronary disease.7
Presentation and management of
exertional angina in the community
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Rapid Access Chest Pain Clinics
This new approach to the diagnosis and management of patients with exertional angina is now widely available in hospitals in the UK. For example, a
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RACPC in Bromley provided rapid daily assessment
of patients with chest pain, which, in the opinion of
the referring doctor, could be due to angina. All patients had presented with chest pain for the first
time, and none had a past medical history of CHD.
The RACPC was open Monday through Friday, 12
midday to 4 PM, and patients could therefore be rapidly assessed without appointment, either on the
day they presented or the next working day. Patients
considered by the GP to have unstable angina or an
evolving myocardial infarction were referred directly to the A&E Department in the usual way. Patients with chest pain who went direct to A&E without consulting their GP, and in whom an acute
coronary syndrome had been excluded, were also
referred to the RACPC for assessment of angina. Patients were reviewed by a cardiologist in training
and had a full history, clinical examination, resting
12-lead ECG, chest x-ray, and for those with angina
or possible angina, either a treadmill exercise test
(Bruce protocol) and/or a thallium scan if they were
Bromley Hospital
London (n=1602)
Newham Hospital
London (n=2160)
Referral criteria
Chest pain considered to be
exertional angina and no
history of CHD
Recent onset of chest pain
(under 4 weeks) and no
history of CHD
Acute coronary
syndromes
84 (5%)
86 (4%)
467* (29%)
540 (25%)
1051 (66%)
1490 (69%)
–
–
Angina
Criteria for referring patients with exertional angina from primary care to a hospital specialist are often not defined, and therefore there is likely to be a
large variation in practice between GPs. Some GPs
will refer patients when they first present, whereas
others will manage patients medically and only refer if symptoms cannot be adequately controlled
with medication alone, or for other reasons.
In one community study of prevalent angina, most
patients for whom GPs prescribed nitrates had not
been investigated in detail.8,9 Only 64% had had an
ECG, 7% an exercise test, and 4% a coronary angiogram. One in 5 of these patients attended a hospital medical clinic during the period of the survey,
and half of these were seen by a cardiologist. In a 7year follow-up of this group of patients, 20% were
admitted urgently with chest pain (although only
14% had a confirmed myocardial infarction), and
a further 15% were referred for a medical outpatient
appointment because of chest pain. Thirty-nine percent of patients died during this period, of whom
two thirds died from cardiovascular or unknown
causes. So, at the time of this survey, most patients
with suspected angina were treated by GPs without
specialist help. However, this picture has been radically changed by the development of Rapid Access
Chest Pain Clinics (RACPCs).7,10-12
: NE
Noncardiac chest
pain
Other
*Definite and possible angina combined.
unable to use the treadmill. The results of this service are shown in Table Va.13,14 Twenty-nine percent
of patients were considered to have exertional angina and two thirds noncardiac pain. One in 20 patients had an acute coronary syndrome despite the
advice to refer such patients directly to casualty.
These results are almost identical to those of a
RACPC at another London hospital where the patient referral criteria were almost identical.15 In the
Newham RACPC, the pain had to be of recent onset (within 4 weeks) and younger people (men <30
years and women <40 years) were discouraged.
These clinics show that the diagnosis of cardiac
chest pain can be resolved, those with coronary disease identified, and those with noncardiac pain appropriately reassured. The difficulty in sometimes
distinguishing an acute coronary syndrome from
exertional angina in the community is also illustrated by the inadvertent referral of such patients to
these clinics. Before the advent of RACPCs, such patients may have been inappropriately managed in
general practice and not received potential life-saving treatments. Although the majority of patients
seen in the RACPC did not have cardiac pain this
should not necessarily be seen as a judgment of the
GP’s ability to diagnose angina. The threshold for
Table V(a). Rapid
Assessment Chest Pain
Clinics (RACPCs).
11
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referral to a RACPC is likely to be lower than that
for referral to cardiology outpatients and therefore
more noncardiac cases will be seen.
The Bromley RACPC was set up in the context of
the Bromley CHD Register and so it was possible to
estimate the impact of the RACPC on the number of
new diagnoses of CHD in this district. The number
of new exertional angina cases increased by 57% as
a result of the RACPC. This increase in the number
of angina patients assessed in hospital is consistent
with previous reports of a low referral rate of angina patents by GPs to a specialist. When a chest pain
clinic opens there will inevitably be an increase in
the number of new cases of angina identified by the
cardiology service, who were not previously referred
for a specialist opinion.
Unlike Bromley and Newham, the referral criteria
for the chest pain clinics in Edinburgh7,10 (Table Vb)
were more acute—“acute or recent onset” or “new
Royal Infirmary
Edinburgh (n=1188)
Western General
Edinburgh (n=278)
Referral criteria
Suspected cardiac chest
pain of acute or recent
onset and no history of
CHD*
New or increasing chest pain,
or chest pain at rest, or
other chest pain of concern
in patients with or without
a history of CHD
Acute coronary
syndromes
144 (12%)
Angina
274 (23%)
89 (32%)
Noncardiac chest
pain
768† (65%)
136 (49%)
2 (–)
2 (–)
Other
51 (18%)
*Patients with suspected myocardial infarction or unstable angina referred directly for hospital
admission.
† Includes 82 patients with chest pain not otherwise specified.
Table V(b). Rapid
Assessment Chest Pain
Clinics (RACPCs).
12
or increasing or chest pain at rest”—and although
GPs were instructed to send patients with suspected acute coronary syndromes direct to casualty,
these referral criteria resulted in an up to threefold
increase in the proportion of patients referred to the
chest pain clinic with acute coronary disease. This
may have delayed life-saving treatments to such patients, as it may have taken longer to be assessed
through an outpatient chest pain clinic than through
a casualty department.
In the Edinburgh Royal Infirmary service, GPs
were asked to provide an initial diagnosis and an
indication of their preferred patient management if
the chest pain clinic was not available. An unambiguous referral diagnosis was only made in 29% of
cases. The GP diagnosis agreed with that of the
clinic physician in just one third of the 27% of cases for which the GP proposed hospital admission.
Only one fifth of patients required admission from
the chest pain clinic. Conversely, of the three quarters of patients who would have had a GP-requested outpatient review, about 1 in 10 actually required
direct admission to hospital. Thus, a positive impact of the chest pain clinic was to reduce intended admissions to hospital by 46%. However, on the
negative side, of the 144 patients with an acute
A N D
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P L I C AT I O N S
coronary syndrome (81% unstable angina), only
26% would have been hospitalized by their GP, thus
delaying admission and life-saving treatments for
the majority.7
Patients with exertional angina assessed in such
clinics all have specialist investigations—treadmill
exercise testing, radionuclear investigations, etc—
to determine the severity of coronary artery disease
and myocardial ischemia. In the Bromley clinic,
85% of patients with exertional angina went on to
have an exercise test (87%) or a thallium scan (13%).
On exercise testing there was objective evidence of
myocardial ischemia in 72% of patients and 74% of
patients who had thallium scans had a high probability of coronary artery disease. Fourty-eight percent of patients classified as high risk on the basis
of these noninvasive investigations proceeded to
coronary arteriography: 60% required revascularization either in the form of angioplasty ± stent implantation (70%) or coronary artery bypass grafting
(CABG, 30%), 23% were for medical therapy only,
and 17% had normal coronary angiograms. Overall, 29% of all patients presenting with exertional
angina required revascularization.
Therefore, rapid assessment of chest pain through
a specialized clinic has several advantages: (i) it
quickly resolves the cardiac diagnosis, identifies
those with angina, and reassures those with noncardiac pain; (ii) it prevents unnecessary hospital
admissions with chest pain; and (iii) it risk-stratifies patients for coronary arteriography and revascularization, thus prioritizing those at highest risk
for earlier intervention.
Drug therapies and revascularization
There is no evidence from randomized controlled
trials that any therapeutic drug class used to treat
the symptom angina has any survival benefit. This
includes nitrates, β-blockers, calcium channel blockers, and other agents. However, there is some trial
evidence from those studies that included patients
with angina pectoris that prophylactic aspirin and
cholesterol-lowering therapy with a statin reduces
the risk of subsequent morbidity and mortality and
can improve survival.16-20 In contrast, revascularization of selected patients with stable exertional angina, either by coronary artery surgery or coronary
angioplasty, will reduce morbidity and mortality.21-24
After initial medical/surgical management, the clinical strategy for patients presenting with exertional angina is to reduce the risk of a myocardial infarction and coronary death.
Cardiovascular prevention
and rehabilitation
Traditionally, cardiac rehabilitation has focused on
supervised exercise sessions, but this is gradually
evolving into comprehensive lifestyle programs—
smoking cessation, healthy food choices, as well as
increased physical activity — based on behavioral
models of change. Risk factor management in terms
of controlling blood pressure, lipids, and diabetes,
and the use of prophylactic drug therapies such as
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aspirin is also becoming an integral part of this approach. And finally, the psychosocial and vocational
support required to help patients lead as full a life
as possible is also provided. This evolution in the
scope of cardiac rehabilitation is now more appropriately called cardiovascular prevention and rehabilitation.
This evolving scope in cardiovascular prevention
and rehabilitation is also embracing a broader group
of coronary patients. Rehabilitation was initially offered only to patients recovering from a myocardial
infarction and those who had had cardiac surgery.
With the emphasis now on favorably influencing the
underlying causes of the disease, patients presenting with angina are now being included after their
initial medical or surgical management.
Although the evidence base for cardiovascular
prevention and rehabilitation of coronary patients
is now among the best of any aspect of clinical medicine, service provision still remains inadequate and
this means that many coronary patients still have
no access. There is also wide variation in the organization, staffing, and management of cardiac rehabilitation services. Thus, current service provision fails to meet the evidence-based guidelines for
cardiac rehabilitation. Most programs are outpatient, hospital-based, concentrating on lower-risk
patients who have had myocardial infarction, although many also include patients who have had
coronary artery surgery or angioplasty. Women are
less likely to receive cardiac rehabilitation than
men. The majority of programs are still exercisecentered, although patient education on other aspects of lifestyle and CHD is provided in most. The
risk factor management in patients with CHD in
Europe is far from optimal. Surveys of clinical practice such as EUROASPIRE I and II (EUROpean
Action on Prevention by Intervention to Reduce
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Patients with exertional angina are at high risk
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coronary death. By addressing lifestyle and other
coronary risk factors, and by prescribing aspirin,
blood pressure, and lipid-lowering therapies, the
risk of disease progression can be reduced. Yet, these
patients are not usually included in cardiovascular
prevention and rehabilitation programs, and surveys of risk factor management like EUROASPIRE
have shown that those with angina alone are least
well managed compared with patients following
myocardial infarction or revascularization.26
Summary
Assessment and management of patients presenting with exertional angina in the community needs
to be addressed in stages. First, prompt cardiac assessment of patients presenting for the first time
with chest pain is necessary, and the model of the
Rapid Access Chest Pain Clinic is one way of doing
so. It quickly identifies those with angina, riskstratifies, and prioritizes for revascularization. Second, appropriate medical and surgical management
needs to follow to alleviate symptoms and reduce
the risk of myocardial infarction and coronary death.
Third, angina patients require comprehensive lifestyle intervention, risk factor management, and appropriate use of prophylactic drug therapies over
the longer term. The object of a cardiovascular prevention and rehabilitation for angina patients is to
improve both quality and length of life. ❒
11. Duncan B, Fulton M, Morrison S, et al. Prognosis of new and
worsening angina pectoris. BMJ. 1976;1:981-985.
12. O’Toole L, Channer KS. Direct access exercise electrocardiography: a new service that improves the management of suspected ischaemic heart disease in the community [letter, comment].
Br Heart J. 1995;73:200.
13. Sutcliffe SJ, Fox KF, Wood DA. How to set up and run a Rapid
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18. Heidenreich PA, McDonald KM, Hastie T, et al. Meta-analysis
of trials comparing beta-blockers, calcium antagonists and nitrates for stable angina. JAMA. 1999;281:1927-1236.
19. Juul-Moller S, Edvardsson N, Jahmatz B, et al, for the Sweden
Angina Pectoris Aspirin Trial (SAPAT) Group. Double blind trial
of aspirin in primary prevention of myocardial infarction in patients with stable angina. Lancet. 1992;340:1421-1425.
20. Stone PH, Gibson RS, Glasser SP, et al. Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on
13
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ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group. Circulation. 1990;82:1962-1972.
21. BARI investigators. Five-year clinical and functional outcome
comparing bypass surgery and angioplasty in patients with multivessel coronary disease. A multicenter randomized trial. Writing Group for the Bypass Angioplasty Revascularization Investigation (BARI) Investigators. JAMA. 1997;277:715-721.
22. Pocock SJ, Henderson RA, Rickards AF, et al. Meta analysis
of randomised trials comparing coronary angioplasty with bypass
surgery. Lancet. 1995;346: 1184-1189.
23. Rogers WJ, Coggin CJ, Gersh BJ, et al. Ten year follow up of
quality of life in patients randomised to receive medical therapy
or coronary artery bypass graft surgery. The Coronary Artery
Surgery Study (CASS). Circulation. 1990;82:1647-1658.
: NE
W
IN
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A N D
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P L I C AT I O N S
24. The Bypass Angioplasty Revascularization Investigation
(BARI) Investigators. Comparison of coronary bypass surgery
with angioplasty in patients with multivessel disease. NEJM.
1996;335:217-225.
25. EUROASPIRE Study Group. EUROASPIRE. A European Society of Cardiology survey of secondary prevention of coronary
heart disease: principal results. Eur Heart J.1997;18;1569-1582.
26. EUROASPIRE Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15
countries. Principal results from EUROASPIRE II. Euro Heart
Survey Programme. Eur Heart J. 2001;22:554-572.
27. EUROASPIRE Study Group. Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine
countries. Lancet. 2001;357:995-1001.
ÉPIDÉMIOLOGIE
DE L’ANGINE DE POITRINE
L’
angine de poitrine est le tableau clinique le plus fréquent de l’athérosclérose coronaire en médecine générale. Une étude épidémiologique
londonienne a rapporté une fréquence de l’angine de poitrine de 122 personnes pour 100 000 dans la population générale (25-74 ans) et par an. L’incidence augmentait avec l’âge et était plus élevée chez les hommes (157) que chez
les femmes (127). Selon le Questionnaire sur l’Angine de Poitrine d’après Rose,
la prévalence de l’angine de poitrine est de 2,6 % chez les hommes et de 3,1 %
chez les femmes pour la population anglaise âgée de 16 ans et plus. Chez les personnes âgées de 75 ans et plus, 18 % des hommes et 17 % des femmes présentaient une angine de poitrine. L’évaluation de la douleur thoracique, en ville,
par le médecin généraliste, sans investigation par un spécialiste, peut être difficile. Un nouveau modèle de soins, la Consultation d’Accès Rapide pour Douleur Thoracique, permet d’obtenir l’avis d’un spécialiste pour des patients de
ville se présentant pour la première fois. Une telle consultation permet de poser le diagnostic, de stratifier le risque des patients présentant une angine de
poitrine et d’orienter en priorité vers une investigation ultérieure par un spécialiste et, le cas échéant, vers une revascularisation. À plus long terme, les changements de mode de vie, les modifications des facteurs de risque et les traitements prophylactiques représentent un potentiel prometteur pour réduire le
risque d’évolution vers l’infarctus du myocarde ou une issue fatale.
✦
14
STABLE ANGINA
AND
AND
APPLICATIONS
hronic stable angina pectoris, ie, symptomatic chronic ischemic heart disease, is a huge
public health problem. Chronic stable angina
carries a relatively good prognosis in the majority
of patients. Several studies have shown that mortality is, on average, approximately 2% to 3% per
annum, and that a further 2% to 3% patients each
year will sustain nonfatal myocardial infarction
(MI).1 There are, however, subgroups at higher risk:
patients with significant impairment of left ventricular function and those with malignant coronary
artery disease (CAD) due to the severity of the anatomical alterations of the coronary tree or the evolutionary aggressiveness of the disease. In patients
with stable angina undergoing coronary arteriography in whom the coronary angiogram was repeated
several years apart, it was found that a similar proportion of target and nontarget lesions progressed
rapidly, both of which contributed to the appearance of new symptoms.
The present-day “natural” history of stable angina has undergone a drastic change due to the complex effects of anti-ischemic, antithrombotic, antihypertensive, and lipid-lowering therapy, as well as
revascularization procedures, thus leading to a new
“management-influenced” history. Now as before,
thorough diagnostic assessment and risk stratification remain the first step in the management of
patients with suspected or known chronic ischemic
heart disease.
C
Luigi TAVAZZI, MD, FESC, FACC
Department of Cardiology
Policlinico S. Matteo, Institute
of Care and Research (IRCCS)
Pavia, ITALY
Clinical assessment
of patients
with stable angina
b y L . Ta v a z z i , I t a l y
Diagnosis
T
he clinical assessment of a patient with stable angina includes both a diagnostic process (at the onset of new symptoms) and a prognostic process. The diagnostic process is based on symptom evaluation, resting
ECG, and echocardiography, as well as exercise ECG and imaging. The sensitivity of exercise ECG is modest (<50% when diagnostic workup bias is minimized), whereas specificity is relatively higher (around 85%). Exercise imaging
has higher sensitivity, with echocardiography showing the highest discrimination. The prognostic process includes the same steps. Exercise imaging provides
important information for prognostic stratification and subsequent decisionmaking, in particular when evaluating the presence and extent of viable myocardium. Outcome studies show that this is the main clinical issue. Although
the various imaging techniques show no major differences in predicting prognostic benefit with revascularization, dramatic differences are noted in terms
of survival according to the extent of viable myocardium and the therapeutic
strategy employed. In the absence of myocardial viability, the reported mortality rate is similar whether patients are treated medically or surgically; in contrast, mortality is much lower in patients with myocardial viability undergoing revascularization, compared with medical treatment. Evidencing viable
myocardium and evaluating its extent is therefore critical to risk stratification
in patients with chronic ischemic heart disease.
Keywords: ischemic heart disease; diagnosis; prognosis; decision-making;
risk stratification; therapy; revascularization
Address for correspondence: Prof Luigi Tavazzi, Primario Divisione di Cardiologia,
Policlinico S. Matteo, Piazzale Golgi, 2, 27100 Pavia, Italy
Clinical assessment of patients with stable angina – Tavazzi
The diagnostic process begins with the evaluation
of symptoms and signs. To characterize the chest
pain, five criteria are considered: quality, location,
duration of pain, triggering factors, and factors that
relieve the pain. Based on these criteria, chest pain
can be qualified as typical angina, atypical angina,
or noncardiac chest pain.1
Typical angina is defined as substantial chest discomfort with a characteristic quality and duration,
which is provoked by exertion or emotional stress
and relieved by rest or nitroglycerin. Atypical angina meets two of the above criteria, and noncardiac
chest pain meets one or none of the typical angina
characteristics.1
When there is sufficient suspicion of heart disease
to warrant cardiac evaluation, the clinician should
make a probability estimate of the likelihood of CAD.
The likelihood of CAD varies strongly according
SELECTED
CAD
coronary artery disease
CASS
Coronary Artery Surgery Study
EMPIRE
Economics of Myocardial Perfusion
Imaging in Europe
END
Economics of Noninvasive Diagnosis
MI
myocardial infarction
PCI
percutaneous coronary intervention
SPECT
single photon emission computed
tomography
15
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to (correct) characterization of symptoms, and the
age and sex of the subject. In turn, this estimate
markedly affects the diagnostic utility of the next
step, the standard exercise test, the interpretation
of which, in terms of posttest likelihood of CAD, can
vary from 5% to 50% to 90% according to the pretest estimated likelihood.1
Resting investigations can also be of help. The
resting ECG is normal in about half of the patients
with chronic stable angina.2 A normal resting ECG
does not exclude severe CAD, but is associated with
normal left ventricular function in about 95% of
patients.3 Resting echocardiography is a useful tool
for aiding the diagnosis of CAD, for a number of
well-known reasons, such as analysis of regional
ventricular contraction and mechanical ventricular
function.
A meta-analysis of 147 published reports describing about 24 000 patients who underwent both coronary angiography and exercise testing reported a
wide variation in sensitivity and specificity of exercise testing in the diagnosis of obstructive CAD.4
Mean sensitivity and specificity were 68% and 77%,
respectively. When the analysis considered only results from the 58 studies that focused on diagnostic
tests by excluding patients with prior MI, sensitivity was 67% and specificity 72%. When the analysis
was restricted to the few studies that avoided diagnostic workup bias by including only patients who
agreed before any testing to have both exercise testing and coronary angiography, sensitivity was 50%
and specificity 90%.5,6 In a more recent study of 814
men that was carefully designed to minimize workup bias, sensitivity was 45% and specificity 85%.7
Therefore, the true diagnostic value of exercise ECG
lies in its relatively high specificity. The sensitivity
of exercise ECG is modest, generally lower than the
sensitivity of imaging procedures.
With respect to pretest likelihood, posttest likelihood of CAD decreases if the ST segment does not
shift significantly. If the ST segment shows a shift
greater than 1 mm, diagnostic probability does not
change much in patients with high pretest probability, but increases markedly in those with low
pretest probability.8 The magnitude of ST-segment
shifts is relevant in patients with low pretest probability, making the diagnosis almost certain for degrees of ST-segment depression greater than 2 mm.
Diagnostic testing is most valuable when the pretest
probability of obstructive CAD is intermediate. In
published research, the arbitrary definition of intermediate probability is between 10% and 90%1
or within 20% and 80%.8
Women and the elderly make up special groups
of patients. Exercise testing is less sensitive in women than in men and some studies have found it to
be also less specific. In a recent meta-analysis of 19
studies including 3721 women, sensitivity for diagnostic CAD was 61% and specificity 70%.9 However, according to the American College of Cardiology/
American Heart Association (ACC/AHA) Guidelines,1
current data are insufficient to justify replacing
standard exercise testing with stress imaging when
evaluating women for CAD. In many women with a
low pretest likelihood of disease, a negative exercise
16
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test result will be sufficient, and imaging procedures
are not required.10 This is mainly explained by the
fact that exercise testing has a high negative predictive power in women.
For a variety of reasons exercise testing in the elderly is more difficult to perform and to interpret.
The greater severity of coronary disease in this group
increases the sensitivity of exercise testing to about
85%, but also decreases specificity to about 70%.11
Despite these limitations, exercise testing remains
important in the elderly, because they are a highrisk group.
The next step in the diagnostic process is stress
imaging in those cases in which it can provide additional risk prediction information. This is the case
in patients with typical anginal symptoms and normal or nondiagnostic exercise ECG, those with atypical angina or absence of symptoms with a positive
exercise ECG, special subgroups of patients, such
as those unable to exercise or with uninterpretable
ECG or those with typical angina and a positive
exercise ECG where false-positive stress tests are
common (younger women).1 Stress imaging can be
performed by using echocardiography or perfusion
imaging. According to the ACC/AHA Guidelines,1
the advantages of echocardiography are: (i) higher
specificity; (ii) versatility: more extensive evaluation
of cardiac anatomy and function; (iii) greater convenience/efficacy/availability; and (iv) lower cost.
The advantages of perfusion imaging are: (i) higher
technical success rate; (ii) higher sensitivity, especially for one-vessel coronary disease; (iii) better accuracy in evaluating possible ischemia when multiple resting wall-motion abnormalities are present;
and (iv) more extensive published databases, specially regarding evaluation of prognosis.
In a meta-analysis of 44 studies12 published between 1990 and 1997 comparing the diagnostic
performance of exercise (Ex)-ECHO and Ex–single
photon emission computed tomography (SPECT),
Ex-ECHO had a sensitivity of 87% and a specificity
of 77%, while Ex-SPECT yielded a similar sensitivity of 87%, but a lower specificity of 64%. Both ExECHO and Ex-SPECT performed significantly better
than Ex-ECG testing. Ex-ECHO was associated with
significantly better discriminatory power than ExSPECT, even in subjects with known CAD.
An overview of the diagnostic performance of
stress-imaging techniques for the detection of CAD
showed a similar high sensitivity of both qualitative and quantitative perfusion techniques with a
slightly higher sensitivity for tomographic than planar images in exercise testing, and a somewhat lower sensitivity for dipyridamole scintigraphy.1 Both
exercise and dobutamine ECHO stress testing had
a similar, slightly lower, sensitivity, but a significantly higher specificity.12,13 Two further meta-analyses
were recently published. One, by a Dutch group,14
confirmed a slightly higher sensitivity, but a significantly lower specificity of nuclear imaging for the
detection of CAD. Another meta-analysis, already
mentioned, of the performance of imaging stress
testing to detect CAD in women,9 showed that the
perfusion scintigraphy technique slightly increased
the low sensitivity of ECG without consistently
STA
Exercise
test
ECG
All studies
MVD
Only Diag.
B L E
AN
G I N A
A N D
IF I N
H I B I T I O N
: NE
W
IN
S I G H T S
No. of studies
(No. of women)
Sensitivity
(95% CI)
Specificity
(95% CI)
Likelihood ratio
(+) (95% CI)
Likelihood ratio
(--) (95% CI)
19 (3,721)
2 (1.143)
11 (1.855)
0.61 (0.54-0.68)
0.69 (0.45-0.94)
0.66 (0.60-0.73)
0.70 (0.64-0.75)
0.61 (0.48-0.74)
0.72 (0.64-0.79)
2.25 (1.84-2.66)
1.79 (1.63-1.94)
2.73 (2.12-3.34)
0.55 (0.47-0.62)
0.46 (0.17-0.77)
0.46 (0.40-0.53)
Thallium
All studies
MVD
Tomography
Planar
5 (842)
3 (730)
3 (690)
2 (152)
0.78 (0.72-0.83)
0.85 (0.80-0.89)
0.78 (0.69-0.87)
0.76 (0.73-0.80)
0.64 (0.51-0.77)
0.52 (0.35-0.68)
0.58 (0.51-0.66)
0.89 (0.86-0.92)
2.87 (1.0-4.96)
2.08 (1.0-3.90)
1.89 (1.59-2.19)
6.9 (5.68-8.97)
0.36 (0.40-0.53)
0.32 (0.19-0.45)
0.38 (0.25-0.50)
0.26 (0.23-0.29)
ECHO
All studies
3 (296)
0.86 (0.75-0.96)
0.79 (0.72-0.86)
4.29 (2.93-5.65)
0.18 (0.05-0.31)
changing specificity. In this case, ECHO testing had
the best sensitivity and an acceptable specificity
(Table I).9 In women, thallium planar imaging was
more specific than tomographic imaging.
The noninvasive assessment of a subject with suspected CAD should lead to the diagnosis of ischemic
heart disease or to the exclusion of this diagnosis.
Coronary angiography should be performed mainly for therapeutic purposes. Direct referral for diagnostic CAD may be indicated in patients with chest
pain possibly attributable to myocardial ischemia
when noninvasive testing is contraindicated or unlikely to be appropriate because of illness (for instance, heart failure), disability, or physical characteristics.1
Prognosis
As for diagnosis, prognostication in chronic ischemic heart disease is based on a cascade of incremental information: symptoms and signs, resting instrumental investigations, functional noninvasive
assessment, and coronary angiography.
Several studies have examined the value of the
characteristics of pain associated with other clinical parameters for grading the severity of chronic ischemic heart disease (Table II).15-17 In general,
these scores have a greater impact on short-term
prognosis than long-term prognosis, and have greater prognostic value in patients with preserved left
ventricular function.1
The ESC guidelines provide a platform for prognostication.8 In general, the outcome is worse (and
the revascularization-related improvement greater)
in patients with worse left ventricular function, a
greater number of diseased vessels, more proximal
locations of coronary stenosis, greater severity of lesions, more severe angina, more easily provoked angina or ischemia, and greater age.
Resting ECG and ECHO can be of help for a variety of obvious reasons. A normal ECG is an indicator of good prognosis because, as already mentioned, it is associated with a normal left ventricular
(LV) function in about 95% of cases.3 Resting echocardiography is a pivotal prognostic tool. Thus, the
Coronary Artery Surgery Study (CASS) registry, as
far back as 20 years ago, showed a 12-year survival
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Table I. Weightened mean
sensitivities and likelihood
for exercise tests in women.
Abbreviations: CI, confidence
interval; diag, diagnosis; ECHO,
echocardiography; MVD, multivessel disease.
After reference 9: Kwok Y, Kim C,
Grady D, et al. Meta-analysis of
exercise testing to detect coronary
artery disease in women. Am J
Cardiol. 1999;83:660-666. Copyright © 1999, Elsevier Ltd.
rate of 73% in patients with a left ventricular ejection fraction (LVEF) ≥50% and 21% in patients with
a LVEF <35%.18
Ex-ECG is the first recommended step in the
prognostic stratification of patients who are not
taking digoxin, have a normal resting ECG, and are
able to exercise.1 The Duke treadmill score combines the most significant information provided by
exercise testing: exercise performance, symptoms,
and the electrophysiologic signs of induced myocardial ischemia (the ST-segment shift). In several
studies, the score worked well for both inpatients
and outpatients, and preliminary data suggest that
the score works equally well for men and women.19,20
Several studies have highlighted both the diagnostic and the prognostic performance of further exercise test parameters: chronotropic incompetence,
abnormal heart rate recovery, and delayed systolic
blood pressure response. However, the recent update of the ACC/AHA Guidelines for exercise testPryor et al,15 1991: Typical angina, previous
MI, age, gender, duration of symptoms, risk
factors, carotid bruit, chest pain frequency
◆ Hubbard et al,16 1993: Age, typical angina,
diabetes, prior MI
◆ Califf et al,17 1988: “Angina course,” anginal
frequency, rest ECG, ST-T wave abnormalities
◆
(Main indicators: symptoms, left ventricular function,
peripheral vascular disease, age); MI, myocardial infarction
Table II. Clinical
indicators of
severe angina.
ing indicate that further work is needed to define
their role in the risk stratification of symptomatic
patients relative to other well-validated exercise test
parameters. A study confirming the prognostic significance of abnormal heart rate recovery has been
recently published.21
The results of exercise testing may be used to
make therapeutic decisions or to proceed to additional testing. Proceeding with additional testing
usually involves imaging. An interesting comparison between Ex-ECG and Ex-ECHO testing in terms
of resulting prognostic stratification and consequent
decision-making was recently published by Marwick et al.13 The parameters compared were the
Duke treadmill score for ECG testing and the exMEDICOGRAPHIA, VOL 27, No.1, 2005
17
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Posttest risk:
A N D
Low
ExECHO
H I B I T I O N
Intermediate
: NE
W
IN
S I G H T S
High
ExECG
ExECHO
ExECG
ExECHO
ExECG
P
7%
59%
17%
23%
45%
37%
0.004
12%
35%
25%
24%
41%
30%
0.06
Catheterization
Revascularization
IF I N
Table III. Exercise (Ex)-ECG or Exercise (Ex)-ECHO in clinical practice. Risk-adjusted
rates of catheterization and revascularization.
After reference 13: Marwick TH, Shaw B, Case C, et al. Clinical and economic impact of exercise electrocardiography and exercise echocardiography in clinical practice. Eur Heart J. 2003;24:1153-1163.
Copyright © 2003, European Society of Cardiology.
tent and severity of ischemia as determined by ExECHO. The population of this observational study
included both symptomatic and asymptomatic patients either with or without known CAD. The main
results are reported in Table III.13 The exercise parameters were similar in both tests, but the risk
stratification was different. Ex-ECHO identified
more patients at low risk (51% vs 24%) and fewer
at intermediate (27% vs 51%) and high risk (22% vs
4%). Moreover, Ex-ECHO substratification of risk,
according to the presence of one or multiple ischemic regions, was more effective than the Duke
treadmill score with respect to MI-free cumulative
survival. The management decisions based on the
tests were also different. Coronary angiography was
performed much more frequently in patients classified as low posttest risk by Ex-ECG than in those
classified as such by Ex-ECHO, and the patients
classified as high risk after Ex-ECHO were catheterized more frequently than the patients classified as
Technique
Studies
(n)
Patients
(n)
Sensitivity
(%)
Specificity
(%)
Dob-ECHO
32
1090
81
80
Tl-201 RR
22
557
86
59
Tl-201 RI
11
301
88
50
MIBI
20
488
81
66
FDG-PET
20
598
93
58
Table IV. Accuracy of different viability techniques to predict recovery
after revascularization. A meta-analysis.
Abbreviations: Dob, dobutamine; ECHO, echocardiography; FDG-PET, fluorodeoxyglucose
positron emission tomography; MIBI, methoxyisobutyl isonitrile; Tl-201 RI, thallium-201
rest-imaging; Tl-201 RR, thallium-201 rest-redistribution.
After reference 14: Schinkel AFL, Bax JJ, Geleijnse ML, et al. Noninvasive evaluation of
ischemic heart disease: myocardial perfusion imaging or stress echocardiography? Eur
Heart J. 2003;24:789-800. Copyright © 2003, European Society of Cardiology.
high risk by Ex-ECG. Surprisingly enough, 35% of
patients classified as low risk by the Duke score were
revascularized vs only 30% of those classified at
high risk, whereas the percentages were 12% vs
41% in patients classified by the ECHO findings.
Overall, the main characteristics of Ex-ECHO as
prognostic tool in stable chronic angina can be
summarized as follows1: (i) it is sensitive and specific for detecting inducible myocardial ischemia;
(ii) a negative test in patients with a positive ECG
response predicts a low risk of events; (iii) presence
of inducible ischemia is independent and incremental to clinical and exercise data in predicting cardiac
events in both men and women; and (iv) both dobu18
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tamine and exercise stress ECHO have higher sensitivity than vasodilator stress ECHO tests.
Stress perfusion imaging is also largely used for
prognostic purposes in stable angina patients. The
main findings coming out from several studies can
be summarized as follows1: (i) normal poststress
thallium scans are highly predictive of a benign
prognosis; (ii) predictors of high risk are: number,
size, and location of perfusion abnormalities, amount
of thallium 201 lung uptake, poststress LV dilatation; and (iii) the combination of stress perfusion
and stress ventricular function assessment does not
increase the prognostic power with respect to each
stress test taken singly.
A comparative summary of the characteristics of
the different techniques used in patients with chronic CAD was also reported in the European Guidelines,8 which showed that Ex-ECG has a greater sensitivity in patients with multivessel disease, whereas
thallium scintigraphy, which is based on comparative perfusion in different myocardial regions, is
most sensitive in single-vessel disease. Echo stress
can be sensitive in both cases. The sensitivity of thallium scintigraphy is lower when the inferior wall of
the left ventricle is the target ventricular region.
Myocardial viability
An important clinical issue is the prognostic stratification leading to therapeutic decision-making in
patients with LV dysfunction, in particular, the detection of viable myocardium. The most frequently used techniques are dobutamine stress ECHO
and thallium reinjection or rest-redistribution. Two
meta-analyses addressed this issue. One showed a
relatively high sensitivity of the different techniques,
but the specificity of the nuclear technique in predicting the recovery of asynergic myocardium after
revascularization is much lower than that of dobutamine stress ECHO (Table IV).14 This difference in
sensitivity and specificity between the two techniques was highlighted by pooling the data of 17
studies in which a head-to-head comparison between dobutamine stress ECHO and nuclear imaging was performed.21
In another meta-analysis of 24 studies including
over 3000 patients,22 the primary goal was not the
comparison among different techniques in detecting viable myocardium, but the predictive power of
the long-term outcome of patients undergoing myocardial viability testing. The mortality was not predicted differently by thallium-perfusion imaging,
fluorodesoxyglucose metabolic imaging, or dobutamine stress ECHO. Specifically, there was no measurable difference between techniques in predicting prognostic benefit with revascularization. This
might suggest that the small differences observed
among the tested techniques in predicting recovery
of myocardial regions after revascularization impact little on late survival. In contrast, major differences were noted on survival in relation to either
the presence of viable myocardium or the therapeutic strategy. In patients without myocardial viability, the mortality rate was similar in patients treated medically or surgically. In contrast, the annual
STA
B L E
AN
G I N A
death rate was about 80% lower in patients with
myocardial viability in whom revascularization was
performed, with respect to those treated medically
(mortality rate 3% vs 16%).
These findings pose a further question: should
all patients with abnormal left ventricular kinetics
and function undergo a viability test in order to define the most appropriate therapeutic strategy or
should they be directed straight to coronary angiography? To answer this question, a prospective
multicenter observational study, the Economics of
Noninvasive Diagnosis (END) study, was performed,
which enrolled 11 372 patients and followed them
up for an average of 2.5±1.5 years.23 The study
showed a similar outcome whether patients underwent an aggressive strategy consisting in direct
cardiac catheterization or a conservative strategy
with initial stress myocardial perfusion tomography followed by coronary angiography when indicated. However, the revascularization rate was twice
as high in the direct cardiac catheterization strategy.
Interestingly, the revascularization rate was higher
in all clinical risk classes. Thus, once the coronary
angiography was performed, the decision to proceed
with revascularization was independent of the patients’ risk grading. Consequently, the cost per patient was higher in the aggressive strategy, and as
the outcome was similar, cost/effectiveness was lower. Similar results were obtained in the Economics
of Myocardial Perfusion Imaging in Europe (EMPIRE) study, which compared the cost-effectiveness
of four diagnostic strategies including or not myocardial perfusion imaging.24 The 2-year patient outcome was the same, irrespective of strategy, but the
use of imaging was associated with lower total cost
because of the performance of less angiography and
revascularization. In conclusion, it appears that the
decision to revascularize is strictly linked to the
process of risk assessment, and the performance of
coronary angiography does not necessarily translate into a different outcome.
Based on these findings, the ACC/AHA Guidelines1 recommend invasive strategy only if the patient’s prognosis on medical therapy is poor and
can be improved by revascularization. Coronary angiography is considered inappropriate when the estimated annual mortality rate is ≤1% (low risk with
noninvasive risk stratification). The same guidelines classify the low-risk patients as those with a
low-risk treadmill score (>5), normal or small myocardial perfusion defect at rest or with stress, and
normal stress echocardiographic wall motion or no
change of limited resting wall motion abnormalities during stress. This does not reflect the current
practice in hospitals with catheterization and coronary intervention facilities.
The indications for performing coronary angiography according to the European Guidelines8 are:
(i) severe angina (class 3 CCS); (ii) class I-II angina
if there is a history of MI or myocardial ischemia at
low workload; (iii) bundle-branch block with inducible myocardial ischemia; (v) revascularized patients with recurrent angina; and (v) severe ventricular asynergy and when essential for clinical or
occupational reasons.
A N D
IF I N
H I B I T I O N
: NE
W
IN
S I G H T S
A N D
AP
P L I C AT I O N S
The decision on which strategy to use, medical
or interventional, is also based on the prognostic
relevance of the anatomy of the coronary tree, as
summarized in Table V.8 The 5-year survival rate is
largely dependent on the extent and severity of the
obstruction of the coronary vessels. Longer-term
observations from the CASS registry also confirm
the prognostic significance of the rough classification of CAD in 1-, 2-, or 3-vessel disease.18 This obviously supports the interventional therapeutic
approach. However, we know that most events in
Extent of CAD (0-100) (%)
Prognostic
weight
5-year
survival rate
1-vessel disease, 75%≥ 95%
23-32
91-93
>1 vessel disease, 50% to 74%
23
93
2-vessel disease
37
88
2-vessel disease, both ≥ 95%
42
86
2-vessel disease, both ≥ 95% proximal LAD
56
79
3-vessel disease
56
79
3-vessel disease ≥ 95% in at least 1
63
73
67-74
59-67
3-vessel disease, 75%-95% proximal LAD
Table V. Risk stratification assuming medical treatment only.
Abbreviations: CAD, coronary artery disease; LAD, left anterior descending (coronary artery).
After reference 8: Management of stable angina pectoris. Recommendations of the Task Force of the
European Society of Cardiology. Eur Heart J. 1997;18:394-413. Copyright © 2003, European Society of
Cardiology.
patients with ischemic heart disease are induced by
the destabilization of angiographically irrelevant
nonobstructive coronary lesions. In spite of that,
from the prognostic point of view, the severity of the
obstructive coronary disease is important probably
because there is a correlation between the severity
and diffusion of the obstructive lesions and the aggressiveness of the atherosclerotic disease.
Patients with stable angina after revascularization represent a special and growing group of patients. Post–percutaneous coronary intervention
(PCI) restenosis and vein graft stenosis commonly induce silent ischemia. Moreover, saphenous
vein graft lesions represent a rather unstable form
of atherosclerosis prone to rapid progression and
thrombotic complications.25,26 Ex-ECG is an insensitive predictor of such events, with a sensitivity
ranging from 40% to 55%, significantly less than
with Ex-SPECT 27 or Ex-ECHO.28 Because of these
considerations and the need to document the site
of ischemia, stress imaging tests are preferred for
evaluating patients belonging in this group. Obviously, the rationale of this approach is that ischemia, whether painful or silent, worsens the prognosis. However, the prognostic benefit of controlling
silent ischemia still needs to be proven. Some new
findings seem to support this concept. For instance,
an observational study on 307 patients undergoing
stress myocardial perfusion testing after PCI showed
a much higher event rate (death and MI) in patients
with inducible myocardial ischemia than in those
without ischemia.29 Further data are scheduled to
be soon published in the literature and should shed
more light on this crucial issue. ❒
19
STA
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A N D
IF I N
H I B I T I O N
REFERENCES
1. ACC/AHA 2002 Guidelines update for the management of patients with chronic stable angina. A report of the American College of Cardiology/American Heart Association Task Force on
Practice Guidelines. www.acc.org; www.americanheart.org.
2. Connolly DC, Elveback LR, Oxman HA. Coronary heart disease
in resident of Rochester, Minnesota, IV. Prognostic value of the
resting electrocardiogram at the time of initial diagnosis of angina pectoris. Mayo Clin Proc. 1984;59:247-250.
3. Christian TF, Miller DT, Chareonthaitawee P, et al. Prevalence
of normal resting left ventricular function with normal rest electrocardiograms. Am J Cardiol. 1997;79:1295-1298.
4. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 Guidelines update for exercise testing: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing) 2002. American
College of Cardiology Web site. Available at: http://www.acc.org/
clinical/guidelines/exercise/exercise_clean.pdf. Accessed October
17, 2004.
5. Morise AP, Diamond GA. Comparison of the sensitivity and
specificity of exercise electrocardiography in biased and unbiased populations of men and women. Am Heart J.1995;130:741747.
6. Del Campo J, Do D, Umann T, et al. Comparison of computerized and standard visual criteria of exercise ECG for diagnosis of
coronary artery disease. Ann Noninv Electrocardiogr.1996;1:430442.
7. Froelicher VF, Lehmann KG, Thomas R, et al. The electrocardiographic exercise test in a population with reduced workup bias:
diagnostic performance, computerized interpretation, and multivariable prediction. Veterans Affairs Cooperative Study in health
Services (QUEXTA) Study Group. Quantitative Exercise testing
and Angiography. Ann Intern Med. 1998;128:965-974.
1997;18:394-413.
9. Kwok Y, Kim C, Grady D, et al. Meta-analysis of exercise testing
to detect coronary artery disease in women. Am J Cardiol.1999;
83:660-666.
10. Melin JA, Wijns W, Vanbutsele RJ, et al. Alternative strategies
for coronary artery disease in women: demonstration of the usefulness and efficiency of probability analysis. Circulation.1985;71:
535-542.
11. Kasser IS, Bruce RA. Comparative effects of aging and coronary heart disease on submaximal exercise. Circulation.1969;39:
759-774.
12. Fleischmann KE, Hunink MGM, Kuntz KM, et al. Exercise
echocardiography or exercise SPECT imaging? JAMA.1998;280:
913-920.
13. Marwick TH, Shaw B, Case C, et al. Clinical and economic
impact of exercise electrocardiography and exercise echocardiography in clinical practice. Eur Heart J. 2003;24:1153-1163.
14. Schinkel AFL, Bax JJ, Geleijnse ML, et al. Noninvasive evaluation of ischemic heart disease: myocardial perfusion imaging or
stress echocardiography? Eur Heart J. 2003;24:789-800.
15. Pryor DB, Shaw L, Harrell FE, et al. Estimating the likelihood
of severe coronary artery disease. Am J Med. 1991;90:553-562.
16. Hubbard BL. Prospective evaluation of a clinical and exercisetest model for the prediction of left main coronary artery disease.
Ann Intern Med. 1993;118:81-90.
17. Califf RM, Mark DB, Harrell FE, et al. Importance of clinical
measures of ischemia in the prognosis of patients with documented coronary artery disease. J Am Coll Cardiol.1988;11:20-26.
18. Mock MB, Ringqvist I, Fisher LD, et al. Survival of medically
treated patients in the Coronary Artery Surgery Study (CASS) registry. Circulation. 1982;66:562-568.
19. Mark DB, Shaw L, Harrel FE, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery
disease. N Engl J Med. 1991;325:849-53.
20. Hachamovitch R, Berman DS, Kiat H, et al. Exercise myocardial perfusion SPECT in patients without known coronary
artery disease: incremental prognostic value and use in risk stratification. Circulation. 1996;93:905-914.
: NE
W
IN
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A N D
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21. Nishime EO, Cole CR, Blackstone EH. Heart rate recovery
and treadmill exercise score as predictor of mortality in patients
referred for exercise ECG. JAMA. 2000;284;1392-1398.
22. Allman KC, Shaw LJ, Hachamovitch R, et al. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol. 2002;39:1151-1158.
23. Shaw LJ, Hachamovitch R, Berman DS, et al. The economic consequences of available diagnostic and prognostic strategies
for the evaluation of stable angina patients: an observational assessment of the value of precatheterization ischemia. Economics
of Noninvasive Diagnosis (END) Multicenter Study Group. J Am
Coll Cardiol. 1999;33:661-669.
24. Underwood SR, Godman B, Salyani S. Economics of myocardial perfusion imaging in Europe—The EMPIRE study. Eur
Heart J. 1999;20:157-166.
25. Neitzel GF, Barboriak JJ, Pintar K, et al. Atherosclerosis in
aortocoronary bypass grafts: morphologic study and risk factor
analysis 6 to 12 years after surgery. Arteriosclerosis.1986;6:594600.
26. Savage MP, Douglas JS, Fischman DL, et al. Stent placement
compared with balloon angioplasty for obstructed coronary bypass grafts. Saphenous Vein De Novo Trial Investigators. N Engl
J Med. 1997;337:740-747.
27. Ritchie JL, Bateman TM, Bonow RO, et al. Guidelines for clinical use of cardiac radionuclide imaging. Report of the American
College of Cardiology/American Heart Association Task Force on
Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Committee in Radionuclide Imaging), developed in collaboration with the American Society of Nuclear Cardiology. J Am
Coll Cardiol. 1995;25:521-547.
28. Cheitlin MD, Alpert JS, Armstrong WF, et al. ACC/AHA Guidelines for the Clinical application of Echocardiography. A report of
the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee on Clinical Application of Echocardiography). Developed in collaboration with the
American Society of Echocardiography. Circulation. 1997;95:
1686-1744.
29. Zellweger MJ, Weinbacher M, Zutter AW, et al. Long-term
outcome of patients with silent versus symptomatic ischemia six
months after percutaneous coronary intervention and stenting.
J Am Coll Cardiol. 2003;42:33-40.
ÉVALUATION CLINIQUE
DES MALADES ATTEINTS D’ANGOR STABLE
L’
évaluation clinique d’un malade atteint d’angor stable inclut non seulement un volant d’investigations diagnostiques, face à l’installation de
symptômes nouveaux, mais également un volant pronostique. Le bilan
diagnostique repose sur l’évaluation des symptômes, l’analyse des données électrocardiographiques et échocardiographiques au repos ainsi que sur l’ECG et
l’imagerie d’effort. La sensibilité de l’ECG d’effort est limitée (< 50 %), même
quand les biais diagnostiques sont réduits au minimum, alors que sa spécificité est plus élevée (environ 85 %). L’imagerie d’effort, quant à elle, possède une
sensibilité plus élevée, le meilleur pouvoir de discrimination revenant aux techniques échocardiographiques. L’évaluation pronostique fait appel aux mêmes
méthodes d’investigation. Les tests d’effort fournissent des données importantes
pour la stratification pronostique et la prise de décision, en particulier en ce qui
concerne l’estimation de la viabilité myocardique et de son étendue. Les études
d’issues montrent qu’il s’agit là du problème clinique principal. Les diverses
techniques d’imagerie ne montrent guère de différences en termes de prédiction
des bénéfices pronostiques de la revascularisation myocardique. En revanche,
des différences de survie conséquentes sont notées en fonction de la présence
de myocarde viable et des stratégies thérapeutiques utilisées. En l’absence de
viabilité myocardique, les taux de mortalité sont similaires, que le traitement
soit médical ou chirurgical. À l’opposé, en présence d’un myocarde viable, ces
taux sont nettement inférieurs en cas de revascularisation chirurgicale comparativement aux stratégies médicales. Ainsi, la mise en évidence d’un myocarde viable et l’évaluation de son étendue constituent une composante essentielle pour la stratification du risque au cours des cardiopathies ischémiques
chroniques.
✦
20
STABLE ANGINA
AND
AND
APPLICATIONS
schemic heart disease is a major global public
health problem and may present as a wide variety of clinical entities including stable and
unstable angina, acute myocardial infarction, or
sudden death. Chronic stable angina is the initial
manifestation in approximately half of patients.1,2
In the United States alone, the recent American
College of Cardiology/American Heart Association
(ACC/AHA) Guidelines estimated that 16 500 000
Americans suffer from stable angina.3 This number
excludes those who do not seek attention for chest
pain.
Ischemic heart disease is important not only because of its prevalence, but also because of its associated morbidity and mortality. It is the leading
single cause of death in the United States and is responsible for 1 of every 4.8 deaths.3 Furthermore,
annual rates of myocardial infarction in patients
with symptoms of angina are between 3% and 3.5%.
Over the last 30 years, numerous clinical trials
have been performed to address the role of interventional treatment, initially comparing coronary
artery bypass surgery (CABG) and medical therapy,
more recently, comparing percutaneous coronary
interventions (PCIs) and CABG. However, with the
rapid progress seen in pharmacotherapeutics, technique, and technology, it is important to take a fresh
look at earlier trials and compare them with the results of more contemporary studies.
This article discusses interventions that can be
used today to alter the course of stable angina to
improve prognosis and prevent myocardial ischemia and death. Risk modification and certain medications have also been shown to be beneficial following intervention.
I
▲
Andrew T. L. ONG, MBBS, FRACP
Patrick W. SERRUYS, MD, PhD, FESC, FACC
Thoraxcenter, Erasmus Medical Center
Rotterdam, THE NETHERLANDS
Interventional
treatments in patients
with stable angina
b y A . T. L . O n g a n d P. W . S e r r u y s ,
The Netherlands
schemic heart disease is a major global health problem. In the United States
alone, it accounts for 1 in 4.8 deaths. Chronic stable angina is the initial
manifestation in approximately half of the cases and is estimated to afflict
16 500 000 Americans. It is a condition for which interventional treatment often results in good symptom relief. Furthermore, revascularization improves
mortality in patients with significant left main coronary artery disease, and in
patients with three-vessel disease with left ventricular impairment. The use of
balloon angioplasty confirmed the superiority of revascularization compared
with medical therapy for symptom relief. It has since been superseded by the
proven superiority of bare metal stenting, and, following the results of recent
trials, is being replaced by drug-eluting stents. Coronary artery bypass surgery
confers no survival advantage over stenting for multivessel disease, the main
limitation of stenting being an increased need for reintervention due to restenosis. With the advent of drug-eluting stents, this limitation may soon disappear.
Irrespective of the mode of intervention, risk factor modification, such as smoking cessation, strict glycemic and blood pressure control, and aggressive pharmacotherapy with antiplatelet agents, statins, angiotensin-converting enzyme
(ACE) inhibitors, and -blockers are vital to preserve the revascularization procedure and reduce future events. New studies such as SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery)
and FREEDOM (Future Resvascularization Evaluation in patiEnts with Diabetes mellitus: Optimal management of Multivessel disease) are planned to address the contemporary role of drug-eluting stenting compared with coronary
artery bypass surgery.
I
Interventional options
Interventional options are divided into CABG and
PCIs. CABG was initially performed with saphenous vein grafts, but today involves the use of the
left internal mammary artery and, in some cases,
total arterial grafting with use of the right internal
mammary artery and gastroepiploic artery. PCIs
began with balloon angioplasty in 1977, and following landmark trials with coronary stenting (BENESTENT [BElgian-NEtherlands STENT],4 STRESS
[STent REStenosis Study]5), over 90% of PCIs performed today involve stent implantation. A large
arsenal of adjunctive devices are available and may
be utilized to facilitate stent implantation and inSELECTED
CABG
CVA
LAD
MACCE
Keywords: stable angina; coronary artery bypass surgery; percutaneous
coronary intervention; drug-eluting stent; statin; ACE inhibitor
Address for correspondence: Prof Patrick W. Serruys, MD, PhD, Thoraxcenter, Bd-406,
Dr Molewaterplein 40, 3015-GD Rotterdam, The Netherlands
Interventional treatments in patients with stable angina – Ong and Serruys
MACE
MI
PCI
PTCA
ABBREVIATIONS
coronary artery bypass grafting
cerebrovascular accident
left anterior descending (coronary artery)
major adverse cardiac and cerebrovascular
event
major adverse cardiac events
percutaneous transluminal coronary
angioplasty
21
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TRIAL
A N D
IF I N
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ACRONYMS
ACIP
ACME
ARTS
AWESOME
Asymptomatic Cardiac Ischemia Pilot
Angioplasty Compared to MEdicine
Arterial Revascularization Therapy Study
Angina With Extremely Serious Operative Mortality
Evaluation
BENESTENT BElgian-NEtherlands STENT
CASS
Coronary Artery Surgery Study
ECSS
European Coronary Surgery Study
ERACI II
Argentine Randomized Study: Coronary Angioplasty
with Stenting vs Coronary Bypass Surgery in
Multivessel Disease
EUROPA
EUropean trial on Reduction Of cardiac events with
Perindopril in stable coronary Artery disease
FIM
First-In-Man
FREEDOM
Future Revascularization Evaluation in patiEnts
with Diabetes mellitus: Optimal management of
Multivessel disease
HOPE
Heart Outcomes Prevention Evaluation
LIPS
Lescol Intervention Prevention Study
MASS
Medical, Angioplasty or Surgery Study
Post CABG
Post Coronary Artery Bypass Graft
RAVEL
RAndomized study with the sirolimus-eluting VElocity
balloon-expandable stent in the treatment of patients
with de novo native coronary artery Lesions
RESEARCH Rapamycin-Eluting Stent Evaluated At Rotterdam
Cardiology Hospital
REVERSAL Reversal of Atherosclerosis with Aggressive Lipid
lowering
RITA
Randomized Intervention Trial for Angina
SIRIUS
acronym for sirolimus (SIRolImUS)
SOLVD
Studies Of Left Ventricular Dysfunction
SoS
Surgery or Stent
STRESS
STent REStenosis Study
SYNTAX
SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery
TAXUS
a trademark for paclitaxel-eluting coronary stents
VA
Veterans Administration (cooperative study)
clude various wires with different coatings, weights,
and diameters to facilitate lesion crossing; cutting
balloons; laser therapy; atherectomy—both directional and rotational devices to enlarge the vessel
lumen; and intravascular ultrasound to image the
coronary artery from within. The most recent development has been drug-eluting stents, ie, stents
designed to release a drug that prevents restenosis,
which up until recently was the main late complication of stenting.
◆ Indication for intervention in stable angina
Based on the trials that will be discussed below,
revascularization is indicated in patients who have:
(i) significant left main coronary artery disease;
(ii) three-vessel disease, especially with abnormal
left ventricular function; (iii) two-vessel disease with
proximal left anterior descending (LAD) coronary
artery involvement; (iv) one- or two-vessel disease
with a large area of viable myocardium at risk; and
(v) for the relief of symptoms.3 For patients who are
not candidates for PCI or CABG, alternative therapies available include percutaneous or surgical laser
transmyocardial revascularization, enhanced external counterpulsation, or spinal cord stimulation.3
22
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P L I C AT I O N S
◆ Surgical revascularization versus medical therapy (Table I)
The first landmark trial was the Veterans Administration (VA) cooperative study of 686 patients
randomly assigned to surgery (n=332) or medical
(n=354) treatment for chronic stable angina.6 In a
subgroup of 91 patients with significant left main
coronary artery disease, CABG was superior to medical therapy at 42 months.7 Excluding left main
coronary artery lesions, there was no significant difference in mortality at 36 months, with 87% of the
medical group and 88% of the surgical group alive.
The randomized European Coronary Surgery
Study (ECSS) of 768 patients demonstrated a significant survival benefit of surgery over medical therapy for its total population, in patients with threevessel disease, and in patients with stenosis in the
proximal third of the LAD coronary artery constituting a component of either two- or three-vessel
disease.8 Patients with left main coronary artery
disease showed a trend to benefit with surgery. In
terms of angina and exercise performance, the surgical group did significantly better than the medical group throughout the 5 years of follow-up.
In the Coronary Artery Surgery Study (CASS) of
780 patients, no mortality differences were observed
at 5- or 10-year follow-up between the CABG or medically treated groups.9 CABG, however, improved
the quality of life as manifested by relief of chest
pain, improvement in both subjective and objective
measurements of functional status, and diminished
requirement for drug therapy.10
◆ PCI versus medical therapy (Table I)
The Angioplasty Compared to MEdicine (ACME)
study, published in 1992, was the first study to compare PCI with balloon angioplasty versus medical
therapy.11 A total of 212 patients with stable angina,
positive exercise stress test, and significant stenosis of one artery were randomized to balloon angioplasty or medical therapy. At 6 months, more patients in the PCI group were angina-free compared
with the medically treated group (64% versus 46%,
P<0.01). Mortality and myocardial infarction were
not different between the two groups.
The Randomized Intervention Trial for Angina
(RITA)-2 randomized 1018 patients with 1-3 vessel
disease to either PCI or medical treatment.12 Stent
use was only 9% in this study. At 2.7 years followup, there was no difference in mortality between
the study groups. Early intervention with PCI was
associated with greater symptomatic improvement
and exercise tolerance, especially in patients with
more severe angina.
The Asymptomatic Cardiac Ischemia Pilot (ACIP)
study randomized 558 patients who had coronary
anatomy suitable for revascularization to three
treatment strategies: angina-guided drug therapy
(n=183), angina plus ischemia–guided drug therapy (n=183), or revascularization by angioplasty or
bypass surgery (n=192).13 Two years after randomization, total mortality was 6.6% in the anginaguided strategy, 4.4% in the ischemia-guided strategy, and 1.1% in the revascularization strategy
(P<0.02). The rate of death or myocardial infarction
STA
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A N D
was 12.1% in the angina-guided strategy, 8.8% in
the ischemia-guided strategy, and 4.7% in the revascularization strategy (P<0.04). The rate of death,
myocardial infarction, or recurrent cardiac hospitalization was 41.8% in the angina-guided strategy,
38.5% in the ischemia-guided strategy, and 23.1%
in the revascularization strategy (P<0.001). Its im-
Years
enrolled
Trial
Vessels
treated
IF I N
H I B I T I O N
: NE
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AP
A N D
P L I C AT I O N S
the pivotal BENESTENT trial,4 520 patients with
stable angina and a single coronary artery lesion
were randomly assigned to either stent implantation (262 patients) or standard balloon angioplasty
(percutaneous transluminal coronary angioplasty,
PTCA) (258 patients). Over 7 months of follow-up,
the clinical and angiographic outcomes were better
Follow-up
(years)
Treatment
Patients
(n)
Mortality
(%)
Death or Freedom from
MI (%)
angina (%)
3
CABG
Medical
310
286
12
13
-
-
3.5
CABG
Medical
48
43
12*
35*
-
-
CABG vs medical therapy
VA6
1972-4
≥1
VA7
1972-4
Left main
ECSS8
1973-6
≥1
5
CABG
Medical
394
373
8*
15*
-
46*
28*
CASS 9,10
1975-9
≥1
5
CABG
Medical
390
390
3
3
-
≈60*†
≈35*†
PCI-balloon vs medical therapy
ACME 11
1987-90
1
0.5
PCI
Medical
105
107
0
0.9
4.8
3.7
64*
46*
RITA-212
1992-6
≥1
2.7 (median)
PCI
Medical
504
514
2.2
1.4
6.3*
3.3*
≈70*†
≈50*†
2
PCI/CABG
Angina-guided medical
Angina + ischemiaguided medical
183
183
6.6*
4.4*
12.1*
8.8*
-
192
1.1
4.7
-
72
70
72
1.4
2.9
0
-
82*
98*
34*
Intervention vs medical therapy
ACIP
13
MASS 14
1991-3
1988-91
≥1
Proximal
LAD
PCI
CABG
Medical
3 (mean)
*
*
*P<0.05.
† Not in text— estimated from graphs in reference.
portance is that this study is the only study to date
to demonstrate a superiority of percutaneous revascularization over medical therapy regarding the
end points of both mortality and death or myocardial infarction.
The Medical, Angioplasty or Surgery Study
(MASS)14 was the first randomized trial to compare
the three treatment strategies. It was a single-center study of 214 patients with single-vessel coronary
artery disease involving the proximal LAD coronary artery with single operators in each group.
Bypass surgery for single-vessel coronary artery disease is associated with a lower incidence of mediumterm and long-term events as well as fewer anginal symptoms than that found in the patients who
underwent angioplasty or medical therapy. In this
study, coronary angioplasty was only superior to
medical strategies in relation to the anginal status.
However, the three treatment regimens yielded a
similar incidence of acute myocardial infarction and
death.
in patients who received a stent than in those who
received standard coronary angioplasty. However,
this benefit was achieved at the cost of a significantly higher risk of vascular complications at the access site and a longer hospital stay. At 1 year, no significant differences in mortality (1.2% vs 0.8%),
stroke (0.0% vs 0.8%), myocardial infarction (5.0%
vs 4.2%), or coronary bypass graft surgery (6.9% vs
5.1%) were found between the stent and balloon
angioplasty groups, respectively. However, the requirement for a repeat angioplasty procedure was
significantly lower in the stent group (10%) than
the balloon angioplasty group (21%, P=0.001).15
In the United States, STRESS 5 mirrored the findings of BENESTENT. A total of 410 patients were
randomized to elective stent placement or balloon
angioplasty. Stent placement resulted in an improved rate of procedural success, a lower rate of
angiographically detected restenosis, a similar rate
of clinical events after 6 months, and a less frequent
need for revascularization of the original coronary
lesion.
Table I. Randomized trials
of intervention versus
medical therapy for
stable angina.
Abbreviations: CABG, coronary artery bypass grafting;
LAD, left anterior descending
coronary artery; MI, myocardial
infarction; PCI, percutaneous
coronary intervention.
Trial acronyms:
see box on page 22.
◆ PCI: stenting versus PTCA (Table II)
At the same time, the development of coronary stents
meant that a second avenue in PCI had opened. In
◆ PCI: stenting versus CABG (Table II)
The four most contemporary studies comparing
23
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PCI and surgery involve the use of coronary stenting. The Arterial Revascularization Therapy Study
(ARTS),16 Surgery or Stent (SoS) trial,17 Argentinean Randomized Study: Coronary Angioplasty With
Stenting Versus Coronary Bypass Surgery in Patients With Multiple-Vessel Disease (ERACI II),18 and
Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) trial19 enrolled patients
between 1995 and 2000. ERACI II and AWESOME
were predominantly unstable angina studies.
The ARTS trial randomized 1205 patients in 69
centers to either stenting (n=600) or coronary artery
Trial
Years
enrolled
AP
P L I C AT I O N S
SIRIUS26 randomized trials, which confirmed its
superiority over bare metal stents. Similar results
were obtained with a polymer-coated paclitaxeleluting stent (tradename, TAXUSTM), with the TAXUS-I,27 TAXUS-II,28 and TAXUS-IV29 randomized
trials. These trials involved the use of a drug-eluting stent to treat a single coronary lesion. The first
registry to publish extensively on the use of drugeluting stents in a “real-world” setting with different subgroups was the Rapamycin-Eluting Stent
Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry.30 In a report of 99 consecutive
Vessels
treated
Follow-up
(years)
Treatment
Patients
(n)
Mortality
(%)
Repeat
Angiographic Freedom
revascularization restenosis
from
(%)
(%)
angina (%)
PCI-stent versus PCI-balloon
BENESTENT 4
1991-3
1
0.7
Stent
Balloon
262
258
0.8
0.4
10.0*
20.6*
22*
32*
73
66
STRESS 5
1991-3
1
0.7
Stent
Balloon
207
203
1.5
1.5
11.2
12.4
32*
42*
79
71
PCI-stent versus CABG
SoS17
1996-9
≥2
2.7 (median)
Stent
CABG
471
493
4.5*
1.6*
20.7*
6.0*
-
66*
79*
ARTS-1 year 20
1997-8
≥2
1
Stent
CABG
600
605
2.5
2.8
21.0*
3.8*
-
79*
89*
ARTS-3 years 21
1997-8
≥2
3
Stent
CABG
600
605
3.7
4.6
26.7*
6.6*
-
72*
87*
*P<0.05.
Table II. Randomized
trials of stenting versus
balloon angioplasty or
bypass surgery.
Abbreviations: CABG, coronary artery bypass grafting;
PCI, percutaneous coronary
intervention.
Study acronyms: see box
on page 22.
bypass surgery (n=605) for the treatment of multivessel disease. At 1 and 3 years, there were no differences in mortality, myocardial infarction or CVA
between the groups.20,21 The primary end point was
a composite of freedom from death, myocardial infarction (MI), cerebrovascular accident (CVA), and
any repeat revascularization at 1 year, and was lower
in the stent group (73.8% versus 87.8%, P<0.001),
driven by an increased need for repeat revascularization in the stent group (21.0% versus 3.8%,
P<0.001). By 3 years, the incidence of repeat revascularization was 26.7% versus 6.6%, respectively
(P<0.001). Stenting was, however, more cost-effective by €2779 at the end of 1 year compared with
surgery. At 3 years this was reduced to €1798.
The SoS trial randomized 988 patients in 53 centers with symptomatic multivessel disease to either
stent-assisted PCI (n=488) or CABG (n=500) and
reported its results with a median follow-up of 2
years. The primary outcome of repeat revascularization was significantly higher in the PCI group
(21% versus 6%, P<0.0001).
◆ PCI: drug-eluting stents (Table III)
The advent of drug-eluting stents began with the
First-In-Man (FIM) study, utilizing a sirolimus-eluting stent.22 This was followed by the RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of
patients with de novo native coronary artery Lesions),23 SIRIUS (SIRolImUS),24 E-SIRIUS,25 and C-
24
patients electively treated for disease in the LAD
coronary artery plus at least one other major epicardial vessel, the overall freedom for major adverse
cardiac events (MACE) was 85.6% at 1 year.31 A larger series of 155 consecutive patients with multivessel disease treated almost exclusively with sirolimus-eluting stents reported a cumulative MACE
of 22.3% at 6 months.32 Patients in both series were
elective, with the majority treated for stable angina.
Given the promising results seen with drug-eluting stents so far, the next logical step would be to
apply the use of these stents to a cohort of patients
that current recommendations favor surgery —
three-vessel disease and left main coronary artery
stem lesions. In the United States, the National Institute of Health (NIH) is sponsoring the Future Revascularization Evaluation in patiEnts with Diabetes mellitus: Optimal management of Multivessel
disease (FREEDOM) study comparing surgery versus PCIs with drug-eluting stents for multivessel
disease, while in Europe the SYNTAX (SYNergy between percutaneous coronary intervention with
TAXus and cardiac surgery) study is in planning
comparing PCIs versus surgery for left main coronary artery stem and 3-vessel coronary artery disease.
◆ Importance of complete revascularization
The importance of complete revascularization in
the treatment of coronary artery disease was highlighted in a substudy from the ARTS trial.33 Patients
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Pharmacotherapy and
risk factor modification
following interventional treatment
◆ Statins
Lipid lowering with statins has been conclusively
shown to reduce events both as primary and as secondary prevention strategies, initially in hypercholesterolemic patients and later in patients with
normal cholesterol levels.
Quantitative coronary angiography follow-up
Patients Time
(n) (months)
A N D
AP
P L I C AT I O N S
angina or silent ischemia, median time to initiation
of therapy was 2 days following PCI, and patients
were followed-up for a median of 3.9 years. Stents
were implanted in 56% of lesions (enrollment period April 1996 to October 1998). The primary outcome of MACE, defined as a composite of death,
nonfatal myocardial infarction or reintervention
demonstrated that the fluvastatin treated group
enjoyed higher MACE-free survival (78.6% versus
73.3%, P<0.01).
In a substudy of LIPS, the investigators looked at
patients who were exclusively treated with stenting
(n=847, 50.5% of total cohort, fluvastatin [n= 417],
placebo [n = 430]).35 During 4 years of follow-up,
fluvastatin treatment decreased the risk of first adverse cardiac atherosclerotic events by 30% compared with placebo (P=0.03). When the data on revascularization were split into target and nontarget
lesion revascularization, a significantly lower in-
randomized to stenting were subdivided into two
groups—complete (n=406) or incomplete (n=170)
revascularization based on the diagnostic and procedural angiograms obtained at the core laboratory.
At 1 year, freedom from major adverse cardiac and
cerebrovascular events (MACCE) was higher in the
group that was successfully completely revascularized (76.6% versus 69.4%, P<0.05).
Study
S I G H T S
Clinical follow-up
Diameter
stenosis
(% ± SD)
Restenosis
(%)
14.7±7.0*
36.7±18.1
0*
26.6
23.6±16.4*
43.2±22.4
8.9*
36.3
24.7±14.7*
48.3±23.4
5.9*
42.3
20.5±10.3
47.8±24.5
2.3*
52.3
Time
Death
(months) (%)
Myocardial
Repeat
Any
Stent
infarction revascularization event thrombosis
(%)
(%)
(%)
(%)
SIROLIMUS
RAVEL23
Sirolimus
Bare stent
6
120
118
24
SIRIUS
Sirolimus
Bare stent
533
525
E-SIRIUS25
Sirolimus
Bare stent
175
177
C-SIRIUS26
Sirolimus
Bare stent
50
50
12
8
1.7
1.7
3.3
4.2
0*
22.9
5.8*
28.8
0
0.9
0.6
2.8
3.2
3.8*
15.8
7.1*
18.9
0.4
0.8
1.1
0.6
4.6
2.3
4.0*
20.9
8.0*
22.6
1.1
0
0
0
2
4
4
18
4
18
0
2
0
0
0
0
3
10
3
10
0
0
0
1.5
0
0
2.3
5.1
3.7
5.2
10.1*
15.9
6.9*
19.1
10.9*
22.0
9.9*
21.4
0.7
0
0
0
1.4
1.2
3.5
4.6
6.8*
16.7
10.6*
19.8
0.6
0.8
9
8
9
8
9
PACLITAXEL (polymer-coated)
TAXUS I 27
Paclitaxel
Bare stent
6
TAXUS II 28
Paclitaxel-SR
Bare stent-SR
Paclitaxel-MR
Bare stent-MR
131
136
135
137
TAXUS IV 29
Paclitaxel
Bare stent
662
652
24
13.56±11.77*
27.23±16.69
31
30
0
10
6
12
26.8±12.8*
35.1±15.1
26.8±13.1*
37.1±17.8
5.5*
20.1
8.6*
23.8
26.3±15.5*
39.8±18.5
7.9*
26.6
9
12
*P<0.05 versus control.
The Lescol Intervention Prevention Study (LIPS)
was the first randomized trial specifically designed
to investigate whether cholesterol lowering with
fluvastatin, initiated within days following successful completion of first PCI (with or without stenting) would prolong cardiac disease-free survival
compared with placebo in patients with average
(3.5-7.0 mmol/L) baseline cholesterol levels.34 This
multicenter trial enrolled 1677 patients with stable
cidence of nontarget vessel revascularization was
observed in the fluvastatin group (relative risk 0.47,
95% confidence interval 0.26 to 0.86, P=0.01). No
difference was observed in target lesion revascularization between the two groups.
The recently published randomized, multicenter
Reversal of Atherosclerosis with Aggressive Lipid
Lowering (REVERSAL) trial looked at the value of
aggressive lipid-lowering therapy with 80 mg of
Table III. Randomized
trials of drug-eluting
stents versus bare
metal stents.
Study acronyms:
see box on page 22.
25
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atorvastatin compared with 40 mg pravastatin and
by intravascular ultrasound (IVUS) analysis and
showed that for patients with coronary heart disease, intensive lipid-lowering treatment with atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin.36,37 Compared with
baseline values, patients treated with atorvastatin
had no change in atheroma burden, whereas patients treated with pravastatin showed progression
of coronary atherosclerosis.
Within the surgical cohort, the Post Coronary
Artery Bypass Graft (Post CABG) Trial, a multicenter randomized trial reported that aggressive lowering of low-density lipoprotein (LDL) cholesterol
levels to below 100 mg/dL reduced the progression
of atherosclerosis in patients who had at least two
patent saphenous vein grafts. Patients were followedup for a mean of 4.3 years.37
◆ Angiotensin-converting enzyme inhibitors
The cardiovascular protective effects of angiotensinconverting enzyme (ACE) inhibitors in patients with
chronic stable angina has been well documented
in all subgroups of patients. Initial studies demonstrated a mortality benefit in patients with severe
left ventricular dysfunction (Survival And Ventricular Enlargement [SAVE]38 and Studies Of Left
Ventricular Dysfunction [SOLVD]39). The Heart Outcomes Prevention Evaluation (HOPE) trial confirmed that the use of ramipril 10 mg per day reduced cardiovascular death, MI, or stroke (either a
composite or each individual component) in patients who were at high risk, or had vascular disease
in the absence of heart failure.40
More recently, the EUropean trial on Reduction
Of cardiac events with Perindopril in patients with
stable coronary Artery disease (EUROPA) study randomized 12 218 patients to perindopril or placebo
with a mean follow-up of 4.2 years.41 Perindopril
treatment was associated with a significant reduction in the primary end point (cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest, P=0.0003) in a broad population
of patients with stable coronary artery disease and
no evidence of overt heart failure (20% relative risk
reduction and 1.9% absolute risk reduction). Cardiovascular death, myocardial infarction, cardiac
arrest, acute coronary syndromes, and development
of heart failure were all reduced. The benefit began
to appear at 1 year and gradually and progressively
increased throughout the duration of the trial.
◆ -Blockers
β-Blocker use has been shown to be useful in the
management of hypertension, angina, in the postmyocardial infarction setting and in patients with
left ventricular dysfunction.3 Patients with chronic
stable angina post intervention may fulfill any of
the above criteria and are candidates for therapy.
26
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◆ Antiplatelet agents
Aspirin (75 to 325 mg daily) is recommended routinely in all patients with acute and chronic ischemic heart disease irrespective of symptoms.3 It
has also been shown to improve patency of vein
grafts following bypass surgery.
◆ Diabetes
Diabetes is associated with a poor outcome in patients with established coronary artery disease, even
after angiographic and other clinical characteristics
are considered. The incidence of restenosis is consistently higher in diabetic compared with nondiabetic patients, even in the era of drug-eluting stents.24,29
Current recommendations prescribe strict glycemic
control in diabetic patients with chronic stable
angina with the belief that this will provide benefits
with regard to microvascular complications and
also may reduce risk for other cardiovascular disease complications despite a paucity of data.3
◆ Smoking
Clinical data to date strongly suggest that smoking
cessation reduces the risk of cardiovascular events.3
Although no randomized clinical trials of smoking
cessation have been performed in patients with
chronic stable angina, three such trials have been
performed in a primary prevention setting and
smoking cessation was associated with a reduction
of 7% to 47% in cardiac event rates.
Conclusion
Chronic stable angina is a condition for which interventional treatment often results in good symptom relief. Revascularization improves mortality in
patients with significant left main coronary artery
disease, and in patients with three-vessel disease
with left ventricular impairment. The use of balloon
angioplasty confirmed the superiority of revascularization compared with medical therapy for symptom relief. It has since been superseded by the
proven superiority of bare metal stenting, and following the results of recent trials, is being replaced
by drug-eluting stents. CABG confers no survival
advantage over stenting for multivessel disease, the
main limitation of stenting being an increased need
for reintervention due to restenosis. With the advent of drug-eluting stents, this limitation may soon
disappear. Irrespective of the mode of intervention,
risk factor modification, such as smoking cessation,
strict glycemic and blood pressure control, and aggressive pharmacotherapy with antiplatelet agents,
statins, ACE inhibitors, and β-blockers are vital to
preserve the revascularization procedure and reduce future events. New studies such as SYNTAX
and FREEDOM are planned to address the contemporary role of drug-eluting stenting compared to
coronary artery bypass surgery. ❒
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14. Hueb WA, Bellotti G, de Oliveira SA, et al. The Medicine, Angioplasty or Surgery Study (MASS): a prospective, randomized
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15. Macaya C, Serruys PW, Ruygrok P, et al. Continued benefit of
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16. Serruys PW, Unger F, Crean PA, et al. Arterial revascularization therapy study (ARTS): a randomized trial of stenting in multivessel coronary disease versus bypass surgery. two year results.
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18. Rodriguez A, Bernardi V, Navia J, et al. Argentine Randomized
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19. Morrison DA, Sethi G, Sacks J, et al. Percutaneous coronary
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20. Serruys PW, Unger F, Sousa JE, et al. Comparison of coronaryartery bypass surgery and stenting for the treatment of multives-
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21. Legrand VM, Serruys PW, Unger F, et al. Three-year outcome
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22. Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression
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23. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for
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24. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents
versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315-1323.
25. Schofer J, Schluter M, Gershlick AH, et al. Sirolimus-eluting
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26. Schampaert E, Cohen EA, Schluter M, et al. The Canadian
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27. Grube E, Silber S, Hauptmann KE, et al. TAXUS I: six- and
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28. Colombo A, Drzewiecki J, Banning A, et al. Randomized study
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29. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl
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30. Lemos PA, Serruys PW, van Domburg RT, et al. Unrestricted
utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the “real world”: the RapamycinEluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. Circulation. 2004;109:190-195.
31. Arampatzis CA, Hoye A, Lemos PA, et al. Elective SirolimusEluting Stent Implantation for Multivessel Disease Involving Significant LAD Stenosis: One-Year Clinical Outcomes of 99 Consecutive Patients. The Rotterdam Experience. Catheter Cardiovasc
Interv. In press.
32. Orlic D, Bonizzoni E, Stankovic G, et al. Treatment of multivessel coronary artery disease with sirolimus-eluting stent implantation: immediate and mid-term results. J Am Coll Cardiol.
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33. van den Brand MJ, Rensing BJ, Morel MA, et al. The effect of
completeness of revascularization on event-free survival at one
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34. Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous
coronary intervention: a randomized controlled trial. JAMA. 2002;
287:3215-3222.
35. Saia F, de Feyter P, Serruys PW, et al. Effect of fluvastatin on
long-term outcome after coronary revascularization with stent
implantation. Am J Cardiol. 2004;93:92-95.
36. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.
JAMA. 2004;291:1071-1080.
37. The effect of aggressive lowering of low-density lipoprotein
cholesterol levels and low-dose anticoagulation on obstructive
changes in saphenous-vein coronary-artery bypass grafts. The
Post Coronary Artery Bypass Graft Trial Investigators. N Engl J
Med. 1997;336:153-162.
38. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on
mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med.
1992;327:669-677.
39. Effect of enalapril on survival in patients with reduced left
ventricular ejection fractions and congestive heart failure. The
SOLVD Investigators. N Engl J Med. 1991;325:293-302.
40. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events
in high-risk patients. The Heart Outcomes Prevention Evaluation
Study Investigators. N Engl J Med. 2000;342:145-153.
41. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease:
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(the EUROPA study). Lancet. 2003;362:782-788.
27
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TRAITEMENTS INTERVENTIONNELS
AU COURS DE L’ANGOR STABLE
L
es cardiopathies ischémiques chroniques constituent globalement un problème majeur en santé publique. Aux États-Unis, un décès sur 4,8 leur
est imputable. L’angor chronique stable est la manifestation initiale de
ces cardiopathies dans environ la moitié des cas. Ce symptôme qui affecterait
16 500 000 Américains constitue une condition dans laquelle les traitements interventionnels aboutissent souvent à de bons résultats symptomatiques. En
outre, la revascularisation diminue la mortalité quand il existe une sténose
du tronc commun de la coronaire gauche ou encore des lésions tritronculaires
sténosantes associées à une altération de la fonction ventriculaire gauche. Le
recours à l’angioplastie par ballonnet a confirmé la supériorité de la revascularisation sur le traitement médical pour ce qui est de l’effet symptomatique.
Depuis, cette technique a été supplantée par la mise en place des stents métalliques nus qui ont fait la preuve de leur supériorité. À la lueur des résultats des
études les plus récentes, ceux-ci tendent à être remplacés par les stents à élution de médicaments. Le pontage aorto-coronaire n’apporte pas d’avantage en
termes de survie par rapport aux stents en cas d’atteinte pluritronculaire, la
principale limitation de ceux-ci étant liée à la nécessité plus fréquente d’une réintervention du fait de la survenue d’une resténose. Avec l’avènement des stents
à élution médicamenteuse, cette limite pourrait rapidement disparaître. Indépendamment du mode d’intervention, la préservation des procédures de revascularisation et la prévention des complications ultérieures passent par la correction des facteurs de risque, notamment l’arrêt du tabagisme, le contrôle strict
de la glycémie et de la pression artérielle, ainsi que par le recours à une pharmacothérapie agressive reposant sur les agents antiplaquettaires, les statines,
les inhibiteurs de l’enzyme de conversion et les bêtabloquants. Des études nouvelles, telles SYNTAX (SYNergy between percutaneous coronary intervention
with TAXus and cardiac surgery) et FREEDOM (Future Resvascularization
Evaluation in patiEnts with Diabetes mellitus: Optimal management of Multivessel disease), sont programmées pour évaluer le rôle des stents à élution
de médicament, comparativement à la revascularisation par pontage aortocoronaire.
✦
28
STABLE ANGINA
AND
AND
APPLICATIONS
Philippe Gabriel STEG, MD
Cardiology, Hôpital Bichat-Claude Bernard
Assistance Publique—Hôpitaux de Paris
Paris, FRANCE
Stable angina treatment
in the 21st century:
what is still missing?
b y P. G . S t e g , F r a n c e
he goals of the treatment of angina pectoris/
stable angina are to improve prognosis (ie,
prolong life expectancy) by preventing death
and/or myocardial infarction (MI) and to improve
quality of life by treating and preventing the symptoms related to ischemia.1,2 Some of the therapies
designed to relieve myocardial ischemia may be expected to impact on the risk of death and MI. Before
reviewing the available therapies and discussing unmet needs, this paper first takes a look at the epidemiology of angina pectoris.
T
Epidemiology
The prevalence of angina pectoris is not well known
and most of the available studies are already somewhat old. In a recent overview,3 it was estimated that
the prevalence of angina ranged from 2% to 5%
among men aged 45 to 54 and 11% to 20% in men
C
linicians treating patients with stable angina now have an extensive
therapeutic armamentarium, including antianginal agents and other
treatments, which appears to provide adequate cardiovascular event prevention. In addition, the use of myocardial revascularization techniques has
tremendously expanded, mostly with the emergence and now preeminence of
percutaneous coronary intervention over surgical revascularization. Yet, despite these dramatic advances, many unmet medical needs remain in the treatment of patients with angina pectoris, and important challenges in the 21st
century will be to develop more effective treatments with fewer side effects,
confirm the improvement in clinical outcomes with antianginal therapy, better
implement evidence-based therapies, and improve secondary prevention and
lifestyle modification.
Keywords: stable angina; epidemiology; treatment; angiotensin-converting
enzyme inhibitor; -blocker; antiplatelet; statin; aspirin; percutaneous
coronary intervention; secondary prevention; evidence-based medicine
Address for correspondence: Professor Ph. Gabriel Steg, Hôpital Bichat,
46 rue Henri Huchard, 75877 Paris Cedex 18, France
Stable angina treatment in the 21st century: what is still missing? – Steg
aged 65 to 74. Figures in women of the same age
were markedly lower, ranging from 0.5% to 1% and
10% to 14%, respectively. These figures highlight
two key features of the epidemiology of angina: at
a given age, it is far more prevalent among men than
among women (except above 85 years old), and its
prevalence increases markedly with age after 40
years of age. It is estimated that 2 million people suffer from angina in the United Kingdom.
Recent studies have highlighted a major change
in the epidemiology of the disease in industrialized
countries: with the improvement in preventive measures as well as in prognosis and survival after acute
coronary events, the disease burden is shifting toward older age groups. Given the increasing age of
the population in most Western countries, this is
therefore likely to result in an increase in the overall prevalence of the disease. Indeed, recent statistics
appear to confirm this: comparison of two British
censuses of the prevalence of angina in England and
Wales, collected in 1981-1982 and 1991-1992, reSELECTED
ACTION
A Coronary disease Trial Investigating
Outcome with Nifedipine GITS
CAD
CAPRIE Clopidogrel versus Aspirin in Patients
at Risk of Ischemic Events
CARISA Combination Assessment of Ranolazine
in Stable Angina
EUROPA EUropean trial on Reduction Of cardiac
events with Perindopril in patients
with stable coronary Artery disease
HOPE
Heart Outcomes Prevention Evaluation
HPS
Heart Protection Study
IONA
Impact On Nicorandil in Angina
MI
PCI
RITA
Randomized Intervention Trial of Angina
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spectively,4 demonstrates an overall 60% increase
in the prevalence of (International Classification of
Diseases) ICD-9 code 413, with an almost doubling
of the prevalence in patients aged 75 years or more
(Figure 1).
Angina affects quality of life in all its dimensions,
as demonstrated by a classic analysis from the Randomized Intervention Treatment of Angina (RITA)
58
60%
57.3
1981/82
50%
1991/92
40%
35.4
30%
20%
31.9
25.7
+ 60%
17.2
13
10%
0%
8.1
0
0.9 0.4
15-24
25-44
0
All ages
Figure 1. Prevalence of
angina in men in England and Wales, in 19811982 and 1991-1992.
Reproduced from reference 4:
Royal College of General Practitioners, and the Department
of Health. Morbidity Statistics
from General Practice, Fourth
National Study, 1991-1992.
London: UK; Her Majesty's
Stationery Office, 1995.
45-64
65-74
75 & over
(y)
trial.5 In more than half of the patients, the severity of anginal symptoms seriously limits their everyday activities, often leading to premature retirement.3 Angina may also occur following an acute
coronary event: from the Framingham data, it is estimated that approximately half of the patients who
survive an acute MI suffer from residual angina.
The current therapeutic
armamentarium for stable angina
◆ Treatments to prevent death or MI
Most of these treatments do not have a direct antiischemic effect. There are essentially three categories of such therapies: antiplatelet agents, statins
and angiotensin-converting enzyme (ACE) inhibitors.
◆ Antiplatelet agents
They are of proven efficacy in preventing cardiac
events and death in all forms of coronary heart disease: unstable angina, acute MI, and stable angina. A collaborative analysis of trials of antiplatelet
agents showed a 22 per 1000 absolute reduction in
the risk of adverse vascular events after 2 years of
treatment in patients with stable angina.6 Thus, aspirin is widely recommended for patients with all
forms of ischemic heart disease, including patients
with stable angina, in the absence of contraindication. In patients who are intolerant or allergic to aspirin, thienopyridines—specifically, clopidogrel—
may be an alternative therapy. Although there are
no data available regarding the specific group of patients with stable angina, the Clopidogrel versus
Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial suggests that, in secondary prevention
of cardiovascular disease, this agent is at least as effective as aspirin.7
◆ Statins
There is solid evidence for a reduction in cardiovascular events with statin therapy in patients with el-
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evated cholesterol. More recently, the Heart Protection Study (HPS) demonstrated that treatment
with 40 mg of simvastatin was associated with a reduction in all-cause mortality in patients at high
risk of cardiovascular events, including patients with
“normal” lipid levels and with a substantial (odds
ratio [OR] 0.76) reduction in the risk of any vascular event in patients with all forms of coronary heart
disease. Therefore, aggressive lipid-lowering treatment should be initiated in patients with established
coronary artery disease (CAD) such as stable angina.2
◆ ACE inhibitors
ACE-inhibitor therapy is of proven efficacy for treating hypertension and heart failure. The Heart Outcomes Prevention Evaluation (HOPE) trial8 established its benefits in 9297 patients at high risk of
cardiovascular events, defined as patients: aged >55
years; with evidence of vascular disease or diabetes;
plus one other cardiovascular risk factor; and who
were not known to have a low ejection fraction or
heart failure. In that trial, total mortality was reduced by 16% from 12.2% to 10.4% (P=0.006), and
the composite primary end point of cardiovascular
death, MI, or stroke was reduced from 17.7% to
14.1% (P<0.001). This was strongly suggestive of
benefits beyond treatment of hypertension or heart
failure. The EUropean trial on Reduction Of cardiac
events with Perindopril in patients with stable coronary Artery disease (EUROPA)9 was established to
test the ability of perindopril to reduce cardiovascular death, MI, and cardiac arrest in patients with
stable CAD and no clinical evidence of heart failure. After 4.2 years of follow-up, patients randomly assigned to perindopril had a lower rate of cardiovascular death, MI, or cardiac arrest than patients
randomized to placebo (8.0% vs 9.9%, P=0.0003).
This was associated with a consistent benefit on secondary end points, notably the combined end point
of total mortality, MI, unstable angina, and cardiac
arrest (14.8 vs 17.1%, P=0.0009), which had been
the original primary end point of the study. With
respect to the primary end point of the study, approximately 50 patients must be treated for 4 years
to prevent 1 major cardiovascular event. EUROPA
confirms and extends the results seen in the HOPE
trial. In aggregate, these two trials strongly suggest
that all patients with CAD should receive perindopril 8 mg or ramipril 10 mg daily.
◆ Medical therapy to relieve ischemia and
symptoms
There are various classes of agents available to control or prevent myocardial ischemia and anginal
symptoms in patients with CAD, including β-blockers, calcium channel blockers, nitrates and nitratelike agents (eg, molsidomine), metabolic agents (eg,
trimetazidine or ranolazine), and potassium channel blockers (eg, nicorandil). It is generally estimated that these agents have a similar efficacy against
angina (judged from the number of angina crises
or the use of rapid-acting nitrates) or against ischemia (judged from the duration of exercise on a
stress test). Yet, most of these agents have not been
proven to reduce morbidity-mortality in patients
with angina, largely because of the small number
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of trials performed and because of the low background rate of events in patients with stable CAD.
◆ -Blockers
β-Blockers represent the cornerstone of anti-ischemic therapy for stable effort angina (in patients
with pure rest angina related to coronary spasm
with angiographically normal coronary arteries,
β-blockers are ineffective and may in fact exacerbate symptoms by resulting in unopposed α-receptor activation).10
The benefit of β-blockers may very well extend
beyond their ability to control anginal symptoms,
and the survival benefit of secondary prevention
with β-blockers after MI11 or in the treatment of hypertension suggests that they might be effective in
preventing recurrent episodes of instability and MI.
Finally, considering the role of the sympathetic nervous system in the triggering or facilitation of severe ventricular tachyarrythmias and sudden death,
it is logical that β-blockers may also be beneficial to
patients with stable angina by preventing ventricular arrhythmias or sudden death.
◆ Calcium blockers
As a class, calcium antagonists appear very similar to β-blockers in relieving anginal symptoms in
chronic stable angina.4 These agents have been
shown to be very effective in reducing angina in
patients with vasospastic angina. Yet, their impact
on patient outcomes has been the subject of intense
debate: some,12 but not all analyses of retrospective
case-control studies in hypertensive patients have
shown increased risks of MI with calcium antagonists, mostly with immediate or short-acting dihydropyridines. The 2002 American College of Cardiology/American Heart Association (ACC/AHA)
updated guidelines for the management of chronic
stable angina indicate that relatively short-acting
dihydropyridine calcium antagonists have the potential to enhance the risk of adverse cardiac events
and should be avoided, while long-acting calcium
antagonists, including slow-release and long-acting
dihydropyridines and nondihydropyridines are effective in relieving symptoms and should be used in
combination with β-blockers if they are not sufficient, or a substitute when they are contraindicated
or have unacceptable side effects.2 Recently, ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic
system [GITS]) has compared the long-acting GITS
formulation of nifedipine with placebo.13 This is in
contrast to previous studies that have used shortacting formulations of nifedipine. Just under 8000
patients were followed for a mean of 4.9 years —
half of whom were treated with nifedipine GITS and
half with placebo. The primary end point was major
cardiovascular event-free survival, defined as time
to occurrence of any of the following events: death
from any cause, acute MI, refractory angina, new
overt heart failure, debilitating stroke, and peripheral revascularization. Among patients allocated
to nifedipine, 310 died (1.64 per 100 patient-years)
compared with 291 people allocated to placebo
(1.53 per 100 patient-years, P=0.41). Primary end
point rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo
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(P=0.54). With nifedipine, the rate of death and any
cardiovascular event or procedure was 9.32 per 100
patient-years versus 10.50 per 100 patient-years for
placebo (P=0.0012). The difference was mainly attributable to a reduction in the soft end point of
“need for coronary angiography and interventions”
in patients assigned to nifedipine, despite an increase in peripheral revascularization. Nifedipine
had no effect on the rate of MI. Considering that this
study compares nifedipine with placebo, these data
do not make a compelling case for adding nifedipine to the treatment of patients. They suggest that
long-acting nifedipine is probably safe in the context of stable angina, but, conversely, does not have
a benefit in terms of reduction of “hard” end points.
◆ Nitrates
Nitrates are highly effective in relieving anginal
symptoms, being most frequently used as shortacting sublingual spray or tablet preparations. In
addition, transdermal or oral long-acting nitrates
also prevent ischemic episodes and anginal recurrences. Despite their unequivocal efficacy in curing
or preventing anginal attacks, no outcome studies
have been performed to demonstrate the benefit of
nitrates on clinical outcomes in stable angina. Thus,
presently, this class of agents is mostly indicated
for symptom relief and prevention, alone or in addition to β-blockers or calcium blockers.
◆ Nicorandil
Nicorandil is a potassium channel activator that
has pharmacologic properties similar to those of nitrates and appears effective in the treatment of stable angina. In addition to its anti-ischemic properties, this agent may have cardioprotective effects
related to mimicking the myocardial preconditioning effect. The Impact On Nicorandil in Angina
(IONA) trial14 has demonstrated, in patients with
stable angina, that nicorandil was associated with
a reduction in the combined end point of coronary
heart disease death, nonfatal MI, or unplanned hospitalization for cardiac chest pain after a mean follow-up of 1.6 years (15.5% vs 13.1% in the placebo
and nicorandil groups, respectively; P=0.014). The
trial did not demonstrate a reduction in mortality
or combined mortality and nonfatal MI.
◆ Metabolic agents
Trimetazidine has been shown, in several doubleblind randomized trials, to improve exercise capacity and anginal symptoms.15-18 These symptomatic
benefits are equivalent to those of propranolol19 or
nifedipine20 and additive with those of diltiazem21,22
or metoprolol.23 Ranolazine (not yet available for
clinical use in any country), was recently shown
to be effective in improving symptoms in patients
with chronic stable angina, in the recent Combination Assessment of Ranolazine in Stable Angina
(CARISA) placebo-controlled randomized trial.24,25
However, for both of these agents, no benefit on
clinical outcomes has been demonstrated yet.
Unmet medical needs
Given this host of available therapies to treat symptoms and ischemia, what is really missing in our
management of these patients?
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◆ Need for effective treatments with fewer side
effects
◆ Need for improved safety and tolerability of
antianginal agents
Current antianginal agents almost all have frequent
and sometimes severe side effects, most of which are
related to their hemodynamic impact. Even side effects considered as relatively mild (eg, headaches
with nitrates or leg edemas with calcium blockers),
although of course not life-threatening, are certainly common causes for treatment discontinuations,
and it is well known that compliance judged from
Table I. The most common
reasons why further
revascularization procedures are not possible.
Abbreviations: CABG:
coronary artery bypass grafting;
PTCA: percutaneous transluminal
coronary angioplasty.
Based on reference 28:
Holubkov R, Laskey WK,
Haviland A, et al. Angina 1 year
after percutaneous coronary
intervention: a report from the
NHLBI Dynamic Registry.
Am Heart J. 2002;144:826-833.
Copyright © 1996, Elsevier Inc.
REASONS FOR NOT PERFORMING
REVASCULARIZATION IN CHRONIC STABLE ANGINA
◆ Unsuitable anatomy
◆ Previous CABGs or PTCAs which exclude
further revascularization
◆ Lack of graft material
◆ Impaired left ventricular function in patients
with previous CABG and/or PTCA
◆ Extracardiac disease which increase peri/post
operative morbidity or mortality
◆ Age—often in combination with the aforemen-
tioned factors
the selected population participating in clinical trials overestimates what is seen in “real life” in unselected patients. The problem of side effects assumes
even greater proportions given the frequency of
“combination therapy” using several anti-ischemic
agents to prevent or control ischemic symptoms. In
that case, side effects such as hypotension, leg edema, and negative inotropy become much more frequent.
◆ Need for more effective antianginal agents
◆ Because patients sometimes have refractory angina. Apart from the issues of safety and tolerability of current antianginal agents, efficacy remains
often insufficient. Some patients are resistant to antianginal therapy and have refractory angina. This
is not an uncommon problem: although figures are
lacking to assess the size of the problem, there is no
doubt that there are patients with severe disabling
angina and CAD who are refractory to conventional forms of treatment, even used in combination. A
recent European Society of Cardiology (ESC) Joint
Study Group report26 has reviewed this issue and
detailed the potential therapeutic options in patients with refractory angina. These treatments often are largely experimental. Options include (but
are not limited to) enhanced external counterpulsation, laser myocardial revascularization, coronary
angiogenic therapy, neuromodulation techniques
(using transcutaneous electric nerve stimulation
and spinal cord stimulation), or even thoracic epidural anesthesia.
◆ Because patients may not be amenable to revascularization. There is a temptation to think that given the tremendous advances in percutaneous and
surgical myocardial revascularization, the issue of
chronic stable angina is dwindling. This is in fact
far from true. Given the increasing lifespan of pa32
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tients with established CAD, they will often experience acute coronary events, revascularization, and
stable angina, albeit at different times. Often, angina persists despite or after revascularization has
already been performed and the conundrum is
whether or not to attempt further revascularization.
There is a host of reasons to forego revascularization, listed in Table I.26 In fact, a Swedish survey of
patients referred for angiography because of severe
angina pectoris in 1994-1995 found that 6% to 9%
of patients referred for revascularization were rejected despite severe symptoms.26
◆ Because revascularization does not always abolish myocardial ischemia, anginal symptoms, or the
need for antianginal therapy. One would like to
think that after myocardial revascularization, be it
surgical or percutaneous, both anginal symptoms
and myocardial ischemia are abolished and that patients are no longer at risk of adverse cardiac events.
However, studies demonstrate the opposite, even
after successful revascularization for stable angina, a condition theoretically rather at low-risk of
acute events. Myocardial ischemia often persists after revascularization, and in the majority of cases is
silent.27 Data from the National Heart, Lung, and
Blood Institute (NHLBI) Dynamic Registry, which
enrolled 1755 consecutive percutaneous coronary
intervention (PCI) patients in 1997 (of whom 26%
with angina in the previous 6 weeks), shows that 1
year later, event rates were high, and higher among
patients with more severe angina prior to revascularization (Figure 2A).28 These data also demonstrate that the combined prevalence of angina and
events was superior to 18% (Figure 2B).28 Finally,
the use of antianginal medications was needed in
a substantial number of patients, even when they
were symptom-free: more than 60% of the patients
were on β-blockers and roughly one third of patients were taking at least one other antianginal.
Even allowing for the indication of β-blockers after
acute MI, these figures demonstrate the relatively
frequent need for antianginal therapy in patients
having undergone successful contemporary percutaneous revascularization.28 In another study using systematic myocardial perfusion assessment
following PCI, 19% of patients complained of angina after PCI and 32% had evidence of ischemia on
perfusion imaging.27 Silent ischemia impacted negatively on outcomes, but symptomatic ischemia was
associated with a very high rate (52%) of critical
events at follow-up (Figure 3).27
◆ Because antianginal therapy is more difficult in
some patient subsets. A good example is patients
with angina pectoris and congestive heart failure,
who represent a difficult group to treat. While their
prognosis is far more severe than that of same-age
patients with angina, treatment options are often
limited in this group. In the context of acute heart
failure, it is impossible to institute β-blockers or
other negative inotropic antianginal agents, and
it is usually necessary to discontinue them if they
were previously prescribed. Therefore, in that context, nitrates and nitrate-like agents are often the
only anti-ischemic therapy that can be used. In fact,
despite the overall frank clinical benefit of β-block-
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1755 consecutive PCI patients in 1997
35
30
Events (%)
30
25
21
20
15
0
18
11
10
5
H I B I T I O N
3
5
CCS I or II
: NE
Death
Death/MI
Death/MI/CABG
Death/MI/CABG/PCI
NHLBI Dynamic Registry
A
IF I N
Rates of angina + events (%)
STA
10
4
CCS III or IV
W
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NHLBI Dynamic Registry
1755 consecutive PCI patients in 1997
26% with angina in previous 6 weeks
B
50
47
40
40
39
33
33
30
18
20
19
18
10
0
CCS I or II
CCS III or IV
Figure 2. Event rates 1 year after successful percutaneous revascularization in the National Heart, Lung, and Blood Institute (NHLBI) Dynamic
Registry, as a function of the severity of anginal symptoms prior to PTCA. A: adverse cardiac event rates. B: Combined incidence of angina and
events.
Abbreviations: CABG, coronary artery bypass grafting; CCS, Canadian Cardiovascular Society (classification); MI, myocardial infarction; PCI, percutaneous coronary intervention.
Reproduced from reference 28: Holubkov R, Laskey WK, Haviland A, et al. Angina 1 year after percutaneous coronary intervention: a report from the NHLBI Dynamic Registry.
Am Heart J. 2002;144:826-833. Copyright © 1996, Elsevier Inc.
ers in chronic heart failure, patients with angina
and congestive heart failure remain undertreated
with β-blockers.29
comes with antianginal therapy
Since the extent and severity of ischemia are directly related to prognosis in patients with CAD, it
might be hoped that anti-ischemic agents would
be helpful in improving prognosis. Yet, very few trials have suggested or demonstrated a potential clinical benefit on “hard outcomes” such as death or MI
solely from antianginal agents, in the context of stable angina, largely because of the lack of placebocontrolled trials.30 There is thus a dire need for more
trials in appropriate, and particularly in older, highrisk patient populations to test and demonstrate
that outcomes can really be improved with antianginal agents.
◆ Need for better implementation of evidence-
based therapies
There is clear evidence from the recent literature
that despite the availability of effective and proven
therapies, these are not always used in “real-life”
situations. Studies have shown that “undertreatment” with evidence-based therapies is associated
with worse outcomes. Specifically, patients with
CAD clearly benefit from therapy using the “fab
four” combination of antiplatelet agents, β-blockers,
statins, and aspirin, and, recently, increased mortality has been associated with underprescription
of this combination in patients with acute coronary
syndromes.31 This has prompted efforts to improve
adherence to guidelines32 and use of evidence-based
therapies. Stable angina is one area where much remains to be done in that respect.
◆ Need for improved secondary prevention and
lifestyle modification
Apart from the use of antianginal agents, evidencebased therapies also encompass other areas such as
secondary prevention and lifestyle interventions.
Cumulative event-free survival
◆ Need for more evidence of improved clinical out-
Prognostic impact of ischemia
6 months after PCI
1.0
0.9
No ischemia
0.8
P =0.006
0.7
Silent ischemia
0.6
P <0.0001
0.5
Symptomatic
ischemia
0.4
0
0
200
400
600
800 1000 1200 1400
Time to event (days)
Figure 3. Prognostic impact of ischemia 6 months after myocardial perfusion scintigraphy. PCI, percutaneous coronary intervention.
Reproduced from reference 27: Zellweger MJ, Weinbacher M, Zutter AW, et al. Long-term outcome of
patients with silent versus symptomatic ischemia six months after percutaneous coronary intervention
and stenting. J Am Coll Cardiol. 2003;42:33-40. Copyright © 2003, American College of Cardiology
Foundation. Elsevier Inc.
Clearly, more needs to be done to address the issue
of continued smoking in patients with CAD and the
growing problems of obesity, metabolic syndrome,
and diabetes, which are harbingers of future trouble for these patients.
Conclusion
In conclusion, stable angina is frequent and impacts
on outcomes and quality of life. Many patients are
not amenable to revascularization and many suffer
from angina despite proper medical therapy. Others may have symptoms despite having had revascularization. Current medical therapy has shortcomings, mainly related to insufficient efficacy, lack
of hemodynamic tolerance, and side effects. There
is currently little proof of a direct impact of anti-ischemic therapy on clinical outcomes in the context
of stable angina. Finally, better implementation of
evidence-based medicine and improved secondary
prevention are issues “of the future” in the 21st
century. ❏
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Dynamic Registry. Am Heart J. 2002;144:826-833.
29. Steg PG, Dabbous OH, Feldman LJ, et al. Determinants and
prognostic impact of heart failure complicating acute coronary
syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation. 2004;109:494-499.
30. Hjemdahl P, Eriksson SV, Held C, Rehnqvist N. Prognosis of
patients with stable angina pectoris on antianginal drug therapy.
Am J Cardiol. 1996;77:6D-15D.
31. Mukherjee D, Fang J, Chetcuti S, Moscucci M, Kline-Rogers
E, Eagle KA. Impact of combination evidence-based medical therapy on mortality in patients with acute coronary syndromes.
Circulation. 2004;109:745-749.
32. Mehta RH, Montoye CK, Gallogly M, et al. Improving quality
of care for acute myocardial infarction: the Guidelines Applied
in Practice (GAP) Initiative. JAMA. 2002;287:1269-1276.
TRAITEMENT
DE L’ANGOR STABLE AU XXIE SIÈCLE
QUE MANQUE-T-IL ENCORE ?
:
U
n vaste arsenal thérapeutique est de nos jours disponible pour les cliniciens affrontés au traitement de l’angor stable. Celui-ci inclut des agents
anti-angineux efficaces ainsi que d’autres traitements qui semblent capables de prévenir l’apparition d’événements cardiovasculaires adverses. En
outre, l’utilisation des techniques de revascularisation myocardique a connu un
développement considérable, en particulier au travers de l’émergence – et désormais de la prééminence – des techniques d’intervention coronarienne percutanée, qui ont nettement pris le pas sur la revascularisation chirurgicale. Et
pourtant, en dépit de ces remarquables avancées, il demeure de nombreux besoins non satisfaits dans le domaine du traitement des patients souffrant d’angine de poitrine. Aussi, en ce début du XXI e siècle, de nombreux défis restent à
relever, tels que le développement de traitements plus efficaces assortis d’effets
adverses moins nombreux, la confirmation de l’amélioration des critères cliniques d’efficacité, une meilleure mise en œuvre des traitements issus de la médecine basée sur les faits (evidence-based medicine), et l’amélioration de la prévention secondaire et de l’hygiène de vie.
✦
34
AND
AND
APPLICATIONS
▲
STABLE ANGINA
Gerd HEUSCH, Prof Dr med, Dr hc
Rainer SCHULZ, Prof Dr med
Institut für Pathophysiologie
Universitätsklinikum Essen
Essen, GERMANY
The pathophysiological role of
heart rate in acute myocardial
ischemia and the benefits of
heart rate reduction
by G. Heusch and R. Schulz, Germany
T
his review characterizes in detail the quantitative relationship between
regional myocardial blood flow and regional contractile function in normal and acutely ischemic myocardium. Contrary to a common notion of
supply/demand imbalance as the underlying pathological mechanism of myocardial ischemia—perfusion and contraction are in fact reduced proportionately, ie, there is perfusion-contraction matching. Perfusion-contraction matching is also maintained when heart rate is increased, if both regional blood flow
and contractile function are normalized to the same time frame, ie, a single cardiac cycle. In normal myocardium, metabolic regulation prevails and increased
heart rate is associated with increased coronary blood flow. In contrast, in poststenotic myocardium with an exhausted dilator reserve, the reduction in diastolic duration prevails and coronary blood flow is decreased with increased
heart rate. When a poststenotic coronary vascular microcirculation is connected to less affected vascular territories through collaterals, both the metabolic
vasodilation of the more or less normal microcirculation and the reduced diastolic duration act in concert to decrease collateral perfusion pressure, and thus
collateral blood flow into the poststenotic coronary microcirculation. Increased
heart rate is usually seen during sympathetic activation such as caused by exercise and emotion and mediated by activation of -adrenoceptors. Accordingly, -blockers have been used to treat patients with stress-induced myocardial
ischemia. Mechanistic studies, however, revealed that the benefits of heart rate
reduction by -blockade are in part counterbalanced by decreased inotropic
state and unmasked -adrenergic coronary vasoconstriction. More selective
bradycardic agents have been developed that selectively decrease heart rate
without any negative inotropic action and without unmasking -adrenergic
coronary vasoconstriction. Accordingly, they improve blood flow distribution
into the ischemic myocardium, and, as a result, regional myocardial function.
Ivabradine is the only clinically available selective bradycardic agent and has
recently been demonstrated to exert anti-ischemic actions in patients with
chronic stable angina.
Keywords: heart rate; coronary blood flow; myocardial ischemia, steal
phenomenon
Address for correspondence: Prof Dr med, Dr hc Gerd Heusch, Institut für Pathophysiologie,
Universitätsklinikum Essen, Hufelandstraße 55, 45122 Essen, Germany
Heart rate reduction in acute myocardial infarction – Heusch and Schulz
ommon wisdom has it that myocardial ischemia is characterized by an imbalance between
supply and demand,1 and that increased heart
rate contributes to such imbalance by both decreasing supply and increasing demand. This view,
though not incorrect, is too simplistic, largely because it does not adequately consider the regional
nature of myocardial ischemia2 in most clinical scenarios, except cardioplegic arrest, where, however,
heart rate is of no importance.
This review will therefore start out by characterizing in detail both the supply side and the demand
side of regional myocardial ischemia and will then
proceed to analyze the impact of heart rate thereon.
Finally, the benefits resulting from pharmacological heart rate reduction will be presented and the
potential advantage of selective bradycardic agents
over β-blockers highlighted.
C
Methods for the quantitative analysis
of regional myocardial blood flow
and contractile function
◆ Myocardial blood flow (perfusion)
At the experimental level, the gold standard for the
measurement of regional myocardial blood flow is
the microsphere method.3 This technique has a spatial resolution down to below 100 mg of myocardial tissue, depending on the number of injected
microspheres.4,5 At this spatial resolution, myocardial blood flow, even during normoperfusion, displays a sizeable heterogeneity, with some areas having a mean blood flow of less than 20% and others
of more than 200%.4,6,7 This spatial heterogeneity of
myocardial blood flow is associated with a similar
heterogeneity in oxidative metabolism8-10 and protein expression.11 Whether or not contractile func-
35
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tion is similarly heterogeneous at the microregional level is entirely unclear at present (see below).12
The major limitation of the microsphere technique
is the restricted availability of radioactive or color
tracers.3,13 As a result, only a limited number of sequential measurements can be made and continuous recording of regional blood flow is impossible.
Clinically, the only available method to measure
regional myocardial blood flow quantitatively is
positron emission tomography (PET).14-16 However,
in addition to the high cost of technical requirements and the concerns relative to radiation safety
that prevent its widespread and frequent use, PET
has serious limitations. PET flow measurements
lack sufficient spatial—particularly transmural—
resolution, and the lack of respiration and/or cardiac
motion-gated measurements enhances this problem, such that the spatial resolution is approximately 1 to 2 orders of magnitude less than that of
the microsphere technique (ie, 1 to 10 g rather than
100 mg of myocardium). Also, the very few reported
normal blood flow values from healthy volunteers
vary widely, ie, from 0.68±0.16 [SD] mL • g –1• min–1 17
to 1.02±0.25 mL • g –1 • min–1 .18 As a result, in an individual patient, a major reduction in resting blood
flow may go undetected, while an only modest reduction in transmural blood flow evidenced by PET
in regions with contractile dysfunction may well
translate into a much more severe reduction in
subendocardial blood flow, the latter being the primary determinant of transmural wall function.19
Finally, PET, as the microsphere technique, permits
no continuous monitoring of myocardial blood flow,
and most studies only report data at one single time
point.
◆ Myocardial contractile function (contraction)
At the experimental level, the gold standard for the
measurement of regional contractile function is sonomicrometry of either segment shortening or wall
thickening.20-22 One major advantage of sonomicrometry, in contrast to the above flow measurement
techniques, is that it permits continuous monitoring of contractile function. Its spatial resolution,
however, is less than that of the microsphere technique, possibly by about 1 order of magnitude, although sonomicrometry can quantify differences
between base and apex 23,24 and, especially, between
subendocardial and subepicardial contractile function.19,25-27 Also, sonomicrometry measures only wall
excursion, but not wall stress.28 As severely hypokinetic and akinetic myocardium may be subjected
to sizeable wall stress, this means that the extent of
contractile function and its associated metabolic
cost are largely underestimated by sonomicrometric measurements of wall excursion only.29-31 This
consideration must be borne in mind, particularly when equating perfusion-contraction matching
with energetic supply-demand.
Clinical methods to measure regional contractile
function include echocardiography, contrast ventriculography, radionuclide ventriculography, and
magnetic resonance tomography. Like sonomicrometry, these clinical techniques fail to take into account wall stress. For obvious reasons, continuous
36
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measurements of regional contractile function, although technically possible with echocardiography, are not available.
Considering the technical limitations outlined
above, it is immediately apparent that no combination of techniques to measure regional myocardial
blood flow and function has the spatial and temporal resolution to truly quantify the time course of
their relation during the development of myocardial
ischemia.
Quantitative relationship between
perfusion and contraction in
normal and ischemic myocardium
◆ Normoperfusion
In the normal heart, increases in contractile function are associated with increased metabolism, and
increased metabolic demand is met principally by
increased myocardial blood flow and, to a lesser extent, by increased oxygen extraction.32,33 The mechanisms/mediators of such metabolic coronary dilation are still unclear 32; however, this is clearly
a situation of perfusion-contraction matching,34
where alterations in contractile function are the
cause of alterations in blood flow. Whether or not
perfusion-contraction matching holds also true at
the microregional level, ie, whether or not the substantial spatial heterogeneity of myocardial blood
flow is associated with a similar spatial heterogeneity of contractile function, is still unclear due to the
insufficient spatial resolution of current techniques
to measure contractile function.
A reverse causal relationship, ie, increases in myocardial blood flow causing increases in contractile function, does not exist in the normal beating
heart.35
◆ Acute ischemia
Upon acute coronary artery inflow reduction, contractile function in the ischemic region is rapidly
decreased.36 As soon as a steady state has developed
(2 to 3 min) enabling the measurement of regional
myocardial blood flow with the microsphere technique, a consistent relationship to the reduced regional contractile function is apparent. In 1980,
Vatner was the first to demonstrate an exponential
relationship between subendocardial blood flow and
subendocardial segment shortening.37 Subsequently, Weintraub et al characterized the relationship
between subendocardial blood flow and subendocardial segment shortening as sigmoidal38 and Gallagher et al showed that the relationship between
systolic wall thickening and subendocardial or
transmural blood flow was more or less linear (Figure 1).39,40 Whereas the shape of this flow/function
relationship has been a matter of some controversy
in the past, at present, the consistent, close perfusion-contraction matching appears more important than subtle differences in the shape of such
relationship, which may be attributable to differences in experimental conditions, segment shortening vs wall thickening, data presentation, and
statistical phenomena. The relationship between
ischemic regional myocardial blood flow and con-
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tractile function varies with the hemodynamic situation. There is a higher blood flow at any given
level of function during exercise than at rest.39 However, when myocardial blood flow is normalized, ie,
adjusted for heart rate (expressed as blood flow per
beat rather than per minute) and thus related to
the same temporal reference as contractile function, ie, one arbitrary average cardiac cycle, the relationships at rest and during exercise 39 as well as at
different levels of heart rate41,42 are superimposable.
When equating perfusion-contraction matching
in acutely ischemic myocardium with an energetic
supply-demand balance, several limitations must be
considered. On the supply side, in addition to blood
flow, changes in myocardial oxygen extraction and
anaerobic glycolytic metabolism may also contribute to supply. On the demand side, regional wall excursion may underestimate the regional metabolic demand when the ischemic myocardium still
develops wall tension, and indeed even dyskinetic
myocardium has a surprisingly high oxygen consumption.29-31,43
The mechanisms/biochemical signals that underlie the rapid development of perfusion-contraction
matching in acutely ischemic myocardium are still
entirely unclear. Endogenous nitric oxide (NO) is
not the biochemical signal for perfusion-contraction matching, but sets the level for such matching,
ie, with inhibition of NO-synthesis, regional myocardial function for any level of blood flow and oxygen consumption is reduced in anesthetized openchest 44 and sedated, chronically instrumented pigs 45
subjected to 90-min acute ischemia.
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1.00
Normalized systolic wall thickening
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1
2
3
4
5
6
0.50
0
0.50
1.00
Normalized transmural blood flow
--0.25
Figure 1. Linear relationship between normalized (as a fraction of baseline) regional
myocardial systolic wall thickening and normalized (as a fraction of that in remote
control myocardium) myocardial blood flow, ie, perfusion-contraction matching.
Reproduced from reference 40: Gallagher KP, Matsuzaki M, Koziol JA, et al. Regional myocardial perfusion and wall thickening during ischemia in conscious dogs. Am J Physiol Heart Circ Physiol. 1984;247:
H727-H738.X. Copyright © 1984, American Physiological Society.
Collateral
steal phenomenon
Transmural
steal phenomenon
Stenosis
F1
P1
Distribution of perfusion
and contraction in ischemic and
nonischemic myocardium
F2
Stenosis
P1
Epicardium
P2
F1+ F2
Endocardium
P2 Ischemia
◆ Perfusion
Whereas collaterals obviously have a cardioprotective function,46,47 they can also be the underlying
morphological substrate for an aggravation of myocardial ischemia when steal phenomena occur. In
the presence of a flow-limiting coronary stenosis,
flow into the ischemic terminal vascular bed is the
sum of coronary arterial inflow through the stenosis and of collateral inflow from adjacent nonischemic or less ischemic regions (Figure 2).48 Collateral inflow is dependent on the pressure gradient
between the origin of collaterals in the intact donor
vessels and their orifice in the ischemic recipient
vessels. When the dilator reserve of the ischemic
recipient vessels is fully exhausted and flow is therefore pressure-dependent, any dilation of the nonischemic donor terminal vascular bed during enhanced metabolic demand 49 or in response to dilator
agents50-54 will decrease the driving pressure gradient across the collaterals and, as a consequence,
collateral flow. This phenomenon has been termed
collateral steal.55 A similar situation arises with respect to the transmural distribution of myocardial
blood flow when subendocardial autoregulatory
reserve is exhausted, but some subepicardial autoregulatory reserve persists.56 The dilation of subepicardial vessels during enhanced metabolic demand
Ischemia
Figure 2. Collateral (left) and transmural (right) steal phenomena. P1= pressure at
the origin of collaterals, P2= pressure at the orifice of collaterals into the ischemic
terminal vascular bed, F1= flow through the stenosis, F2= collateral blood flow. Any
dilation of the normal terminal vascular bed will decrease P1, and, as a consequence,
the P1-P2 gradient, and finally F2.
Reproduced from reference 48: Baumgart D, Ehring T, Krajcar M, Heusch G. A proischemic action of
nisoldipine: relationship to a decrease in perfusion pressure and comparison to dipyridamole. Cardiovasc Res. 1993;27:1254-1259. Copyright © 1993, Elsevier, Ltd.
will then compromise subendocardial perfusion,57
a phenomenon termed transmural steal. A transmural steal phenomenon can be considered as the
major cause of the preferential subendocardial manifestation of myocardial ischemia and infarction. Finally, a steal situation also develops when a stenotic coronary artery perfuses parts of both the left and
right ventricle. During increased myocardial metabolic demand, redistribution from the left to the right
ventricular perfusion territory, ie, a right ventricular steal phenomenon, may occur.58 The presence of
a well-developed collateral circulation often maintains sufficient blood flow to the poststenotic myocardial at rest, but steal phenomena contribute to
the precipitation of myocardial ischemia during exercise.59-61
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◆ Contraction
In addition to regional ischemic dysfunction, outlined above, regional myocardial ischemia also impacts on the nonischemic myocardium. During
acute coronary artery occlusion in anesthetized
swine62 and in both anesthetized63 and conscious
dogs,64,65 the ischemic region is surrounded by a
narrow zone of normally perfused myocardium
with depressed systolic wall thickening or segment
shortening. This depressed contractile function in
the immediate borderzone surrounding the ischemic region is attributed to more or less well-defined
mechanical “tethering” between nonischemic and
Normoperfused
myocardium
Ischemic
myocardium
Maintained
vasodilatory reserve
Exhausted
vasodilatory reserve
➔
Number of contractions/min
Diastolic duration/beat
➔
➔
Heart rate
Stenosis severity
➔
➔
➔
Blood flow
➤
➤
➤
Contractile function
➔
➔
➤
Blood flow
➤
Steal phenomena
➤
➤
Coronary dilation
➔
➔
➤
Oxygen consumption
Figure 3. Schematic
diagram depicting the
effects of increased heart
rate on myocardial flow,
function, and oxygen
requirements.
38
➔
➤
Oxygen consumption
ischemic myocardial fibers.66 The mechanism of
such “tethering” is likely explained by the existence
of high regional wall stresses present at the border
between ischemic and dysfunctional vs normal myocardium.67 This dysfunctional borderzone leads to
overestimation of the ischemic region from a diagnostic point of view.
A dysfunctional nonischemic borderzone may not
only extend laterally from an ischemic region during complete coronary occlusion, but may also
overly the ischemic inner myocardial layers during
nontransmural ischemia. The subepicardium was
shown to become dysfunctional when ischemia is
restricted to the subendocardium and subepicardial
perfusion is normal,25,68 and outer wall dysfunction
was found to be out of proportion to the outer wall
flow reduction during treadmill exercise in dogs
with coronary stenosis.69
Whereas lateral and transmural tethering create
a nonischemic dysfunctional borderzone in the immediate vicinity of the ischemic region, more remote nonischemic regions are characterized by enhanced contractile function.70-73 Whether an increase
in remote nonischemic zone function can be considered as compensatory in that it acts to preserve
global left ventricular function70,73,74 is not completely clear, since a major proportion of nonischemic
zone hyperfunction occurs during isovolumic systole and does not contribute to ejection.71 The increase in function in the remote nonischemic zone
is associated with a moderate, presumably metabolically mediated increase in blood flow to this re-
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gion.70,75 However, the relationship between regional myocardial blood flow and function in remote,
hyperfunctioning, nonischemic myocardium has
not yet been systematically analyzed.
Effects of heart rate on perfusion
and contraction in normal and
ischemic myocardium
Increases in heart rate increase the number of cardiac cycles per time frame and thus also increase
the energy/oxygen demand per time frame (Figure 3). Also, in some species, possibly including
man, increases in heart rate increase the myocardial
inotropic state through a force-frequency effect.76
With an intact coronary circulation, metabolic vasodilation serves to increase coronary blood flow to
match the increased oxygen demand, since myocardial oxygen extraction is near-maximal at baseline and can only be increased by a small amount.
Simultaneously with increasing oxygen demand,
increases in heart rate also shorten diastolic duration and thus the time interval of the cardiac cycle
during which almost all of coronary blood flow occurs.77,78 In an intact coronary circulation, metabolic vasodilation is powerful enough to overcome the
limitation of coronary blood flow due to reduced
diastolic duration so that the increased oxygen demand is adequately matched; thus, increases in
heart rate are associated with proportionately increased myocardial oxygen consumption. However,
in the presence of severe coronary stenosis, when
the autoregulatory capacity of the coronary circulation to maintain a normal coronary blood flow at
baseline is exhausted, any further increase in heart
rate, more precisely, any further reduction in diastolic perfusion time,79 compromises coronary blood
flow to the point where it is actually reduced at
higher heart rates.
In the setting of regional myocardial ischemia, in
cases where a severely stenotic coronary artery is
connected via collaterals to an intact or less severely affected coronary artery, a typical redistribution/
steal scenario develops, as outlined above: metabolic vasodilation of the more or less intact coronary
microcirculation decreases collateral perfusion pressure, thereby decreasing collateral blood flow in the
poststenotic coronary microcirculation and precipitating ischemia.48
In addition to the steal phenomenon, the hemodynamic severity of a coronary stenosis is increased
at higher heart rates because of increased turbulence, further compromising coronary inflow.80,81
β-Adrenergic blockade in
regional myocardial ischemia
Exercise and excitement are characterized by sympathetic activation, and β-adrenergic mechanisms
contribute to myocardial ischemia through an unfavorable redistribution of coronary blood flow away
from the ischemic subendocardium, ie, through
both a collateral as well as a transmural steal mechanism (see above). β-Blockade decreases heart rate
at rest and attenuates the exercise-induced increas-
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es in heart rate, left ventricular dP/dt, and function
of the nonischemic myocardium. As a consequence,
increase in blood flow to the nonischemic myocardium and to the poststenotic subepicardium is
attenuated. However, subendocardial blood flow of
the ischemic myocardium is increased, thus resulting in improved regional myocardial function.82 The
hemodynamic severity of a dynamic coronary stenosis is reduced by β-blockade. The β-blockade–induced autoregulatory decrease in flow to nonischemic regions results in an increase in poststenotic
coronary perfusion pressure. Increased perfusion
pressure, in turn, reduces stenotic resistance, thus
ultimately improving blood flow to ischemic regions.83 The beneficial effects of β-blockade in exercise-induced myocardial ischemia are almost exclusively due to the attenuation of the increase in
heart rate. When reduction in heart rate is prevented by atrial pacing, ischemic regional myocardial
blood flow and function are even slightly reduced
as compared with the untreated situation, possibly
due to an unmasking of α-adrenergic constriction
in the ischemic coronary microcirculation.60 The
disadvantage of β-blockade in reducing the inotropic state is well appreciated; however, the importance
of α-adrenergic coronary vasoconstriction in patients with stable angina or in patients undergoing
coronary interventions84-87 has been largely neglected or underestimated so far.
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140
Heart rate = 55 beats/min
Selective bradycardic agents
in regional myocardial ischemia
115
90
65
Heart rate = 122 beats/min
40
15
--10
0
0.25
0.50
0.75
1.00
Subendocardial blood flow (mL/min/g)
140
Systolic wall thickening (%)
The finding that β-blockade not only reduces heart
rate, but also the myocardial inotropic state, and
that it unmasks α-adrenergic coronary vasoconstriction, has prompted the development of selective
bradycardic agents. Selective bradycardic agents
are chemically distinct compounds; the first drug
that was advocated in the early eighties as a selective bradycardic agent was alinidine. Alinidine’s
promotion as a selective bradycardic agent coincided with the detection of the sinoatrial pacemaker
current (If) by DiFrancesco.88,89 The If current subsequently became the target of all selective bradycardic agents, including the clonidine derivative
alinidine, the benzazepinones UL-FS 49 and ivabradine, and others.89-92 In conscious chronically instrumented dogs with a coronary stenosis, alinidine reduced heart rate both at rest and during
treadmill exercise. The ischemic contractile dysfunction that developed during exercise was attenuated, but this was at the expense of a significant
negative inotropic effect, both at rest and during
exercise.93 Also, in anesthetized pigs, alinidine decreased heart rate, caused a favorable redistribution
of myocardial blood flow into the poststenotic subendocardium, and attenuated ischemic contractile
dysfunction, but again at the expense of a negative
inotropic action.94 Alinidine has also been used in
patients with acute myocardial infarction and appeared to be safe,95 though it was without effect in
terms of myocardial salvage and arrhythmias.96
UL-FS 49 also decreased heart rate, both at rest
and during exercise, in conscious chronically in-
H I B I T I O N
strumented dogs with coronary stenosis. It improved
poststenotic subendocardial blood flow 61 and attenuated ischemic contractile dysfunction, and these
beneficial effects were achieved in the absence of
negative inotropic actions.61,97 Subsequently, the
mechanism of the beneficial action of UL-FS 49 in
acute myocardial ischemia was analyzed in more
detail and plots of contractile function vs subendocardial blood flow (Figure 4) 41 were established in
anesthetized pigs. UL-FS 49 improved regional systolic wall thickening for any given subendocardial
blood, when expressed in conventional terms as
blood flow per minute. However, when blood flow
was expressed as blood flow per cardiac cycle and
thus normalized for the same time frame as contractile function (see above), the flow/function relationships at different heart rates became superimposable, indicating that the beneficial effect of
UL-FS 49 on ischemic regional myocardial blood
flow and function was indeed entirely mediated
through heart rate reduction.41 With UL-FS 49, a
more favorable blood flow distribution into the left
ventricular subendocardium occurred not only from
the left ventricular subepicardium, but also from
Systolic wall thickening (%)
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90
65
40
15
--10
0
3
6
9
12
15
18
Subendocardial blood flow/beat (mL/g •10 --3)
Figure 4. Relation between systolic wall thickening and endocardial blood flow per
minute; function is increased for any given blood flow at 55 beats/min (black circles)
over that at 122 beats/min (red circles). When systolic wall thickening is plotted
against subendocardial blood flow per cardiac cycle, the relations at different heart
rates are superimposable.
Reproduced from reference 41: Indolfi C, Guth BD, Miura T, et al. Mechanisms of improved ischemic
regional dysfunction by bradycardia. Studies on UL-FS 49 in swine. Circulation. 1989;80:983-993.
Copyright © 1989, American Heart Association.
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Mean coronary artery diameter
8
Change from baseline (%)
6
4
2
+‡
‡
0
+‡
**
--2
**
--4
+
--6
+
+
--8
Baseline
Rest
Ex5
Ex10
Ex12
Figure 5. Increases in epicardial coronary artery diameter with increasing intensity
of exercise (Ex5, Ex10, Ex12) with placebo (circles) are only slightly attenuated with
ivabradine (triangles), whereas with propranolol (squares) epicardial coronary artery
diameter is decreased. +P<0.01 vs saline; **P<0.01 vs baseline; ‡P<0.01 vs propranolol.
Reproduced from reference 100: Simon L, Ghaleh B, Puybasset L, et al. Coronary and hemodynamic
effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp
Ther. 1995;275:659-666. Copyright © 1995, American Society for Pharmacology and Experimental
Therapeutics.
Extension phase;
all patients received
ivabradine 10 mg bid
Doseranging
phase
Change in time to
1-mm ST-segment depression (s)
80
60
40
Ivabradine 10 mg bid (n=31)
Ivabradine 5 mg bid (n=31)
Ivabradine 2.5 mg bid (n=30)
Placebo (n=28)
20
0
0
20
40
60
80
100
120
Time (days)
Figure 6. Changes in time to 1-mm ST-segment depression during exercise in patients
with chronic stable angina.
Reproduced from reference 106: Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic
effects of ivabradine, an If inhibitor, in stable angina. Circulation. 2003;107:817-823. Copyright © 2003,
American Heart Association.
the right ventricle, ie, there were reverse transmural and interventricular steal phenomena.98 Given
these beneficial effects on ischemic myocardial blood
flow and its distribution, it is not surprising that
UL-FS 49 also decreased infarct size during more
prolonged ischemia in anesthetized pigs, as did
atenolol; however, contractile function was better
preserved with UL-FS 49 than with atenolol.99 Despite its favorable anti-ischemic profile, UL-FS 49
was never further developed for clinical use.
The only currently available selective bradycardic agent approved for clinical use is ivabradine
(S 16257). In conscious chronically instrumented
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dogs, ivabradine causes a dose-dependent reduction
in heart rate at rest and during exercise, and — in
contrast to propranolol—exerts its effects without
a negative inotropic action. Furthermore, ivabradine only slightly attenuates the increase in epicardial coronary artery diameter during exercise,
whereas propranolol actually reduces epicardial
diameter, thus unmasking α-adrenergic coronary
vasoconstriction (Figure 5).100 Accordingly, ivabradine prolongs diastolic duration (thereby increasing
perfusion) and reduces myocardial oxygen consumption (demand).101,102 In chronically instrumented dogs with a coronary stenosis, ivabradine again
reduced heart rate at rest and during treadmill exercise and, as UL-FS 49, improved poststenotic subendocardial blood flow and contractile function.
These beneficial effects during exercise-induced ischemia were followed by an attenuation of postischemic contractile dysfunction, ie, stunning, and
attenuation of both ischemic and postischemic
contractile function was lost when the reduction
in heart rate was eliminated by atrial pacing. In contrast, β-blockade with atenolol also attenuated ischemic contractile dysfunction, but not postischemic stunning, and also reduced nonischemic wall
function.103,104
The attenuation of ischemic contractile dysfunction with reduced heart rate elicited by ivabradine
was confirmed in conscious pigs during treadmill
exercise. These animals also displayed less ST-segment shift, similar to the effects of propranolol, but
without the latter’s negative inotropic action.105 In
animal experimentation, ivabradine appears to fulfill all the criteria for selectively decreasing heart
rate without negative inotropic action and without
unmasking α-adrenergic coronary vasoconstriction.
Ivabradine’s detailed effects on the flow/function relationship (perfusion-contraction match) and on
infarct size during more prolonged ischemia have
not been elucidated yet.
Recently, preliminary clinical data on the effects
of ivabradine in patients with chronic stable angina
have become available. In a double-blind, placebocontrolled prospective trial, patients receiving ivabradine had prolonged time to 1-mm ST-segment
depression (Figure 6)106 and angina during exercise
testing during 3 months of use, without any rebound during drug withdrawal.106 In a rat model of
post–myocardial infarction remodeling and heart
failure, ivabradine reduced end-systolic, but not
end-diastolic LV volume, thereby increasing stroke
volume and preserving cardiac output.107 In patients
with left ventricular dysfunction, ivabradine also
reduced heart rate without any appreciable negative inotropic effect.108
In conclusion, increases in heart rate play a major role in precipitating myocardial ischemia, predominantly through unfavorable blood flow redistribution away from the ischemic subendocardium.
Accordingly, selective heart rate reduction attenuates the reduction in both regional myocardial
blood flow and contractile function. Importantly,
this dual attenuation is achieved without triggering
a negative inotropic action or unmasking α-adrenergic coronary vasoconstriction. ❏
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PHYSIOPATHOLOGIQUE DE LA FRÉQUENCE CARDIAQUE
DANS L’ISCHÉMIE MYOCARDIQUE AIGUË
ET BÉNÉFICES APPORTÉS PAR SA RÉDUCTION
C
ette synthèse débute par l’étude détaillée de la relation quantitative qui
existe entre le débit sanguin et la fonction contractile à l’échelon régional, au sein du myocarde normal et ischémique. Selon une notion commune, c’est un déséquilibre entre les apports et les besoins qui serait le principal mécanisme pathogénique à l’origine de l’ischémie myocardique. Cette
analyse détaillée montre, bien au contraire, que la perfusion et la contraction
sont en fait diminuées de manière proportionnelle, au point qu’il existe un équilibre entre l’une et l’autre. Ce couplage perfusion-contraction est également
maintenu aux fréquences cardiaques élevées, quand la fonction contractile et
le débit sanguin régional sont normalisées en fonction de la même échelle de
temps, c’est-à-dire un cycle cardiaque. Dans le myocarde normal, la régulation
du métabolisme prévaut et l’augmentation de la fréquence cardiaque s’associe
à une élévation du débit sanguin coronaire. En revanche, au sein du myocarde
irrigué par une coronaire sténosée, alors que la réserve vasodilatatrice est limitée, c’est la réduction de la durée de la diastole qui prévaut et le débit sanguin
coronaire diminue alors que la fréquence cardiaque augmente. Au sein de la
microcirculation coronaire située en aval d’une sténose mais connectée par une
circulation collatérale à un territoire vasculaire moins affecté, la conjonction
de deux facteurs va diminuer la pression dans cette dernière et, de ce fait, le
débit sanguin régional post-sténotique : d’une part, la vasodilatation métabolique au sein de la microcirculation plus ou moins normale, d’autre part, la
diminution de la durée de la diastole. Une augmentation de la fréquence cardiaque, médiée par les récepteurs -adrénergiques, est habituellement observée lors de l’activation sympathique qui survient à l’occasion d’un effort ou
d’une émotion. De ce fait, les -bloquants ont été utilisés dans le traitement de
l’ischémie myocardique liée à l’effort. Cependant, les études qui ont abordé
leurs mécanismes d’action ont révélé que les bénéfices induits par la réduction
de la fréquence cardiaque étaient, en partie, contrebalancés par un effet inotrope négatif et un démasquage de la vasoconstriction -adrénergique. Des
agents bradycardisants plus sélectifs ont été développés, qui diminuent sélectivement la fréquence cardiaque sans induire d’effet inotrope négatif et sans
démasquer la vasoconstriction -adrénergique. Ceux-ci augmentent la distribution du débit sanguin au sein du myocarde ischémique et, en conséquence,
améliorent la fonction myocardique régionale. L’ivabradine est le seul agent
bradycardisant sélectif disponible en clinique. Il a été récemment démontré
que ce médicament exerçait une action anti-ischémique chez les malades atteints d’un angor chronique stable.
✦
43
STABLE ANGINA
AND
AND
APPLICATIONS
Jeffrey S. BORER, MD
Division of Cardiovascular Pathophysiology and the
Howard Gilman Institute for Valvular Heart Diseases
Weill Medical College of Cornell University
The New York Presbyterian Hospital Weill Cornell
Medical Center, New York, NY, USA
If inhibition as
a therapeutic approach
in stable angina: experimental
and clinical studies
b y J . S . B o r e r, U S A
A
ngina pectoris, a debilitating symptom of myocardial ischemia, can result from coronary artery occlusive disease. Though importantly limited in quality of life, most people with angina can expect excellent survival. Current drug therapy completely prevents angina only in a minority of
patients, even when multidrug regimens are employed. Therefore, additional
pharmacological alternatives are desirable, employing pharmacological effects
different from those of conventional therapy. Myocardial ischemia results from
imbalance between myocardial oxygen supply and demand. Limitation of heart
rate, a primary determinant of demand, is particularly useful in angina prevention. The inward sodium-potassium–mediated I f current of sinoatrial node
cell membranes (virtually absent elsewhere in the myocardium), modulates
sinoatrial diastolic rate and, thus, heart rate. Blockade of this current reduces
heart rate. Ivabradine, a highly selective I f current blocker comprising linked
benzazepinone and benzocyclobutane rings, causes clinically useful heart rate
decrements at doses that are generally well tolerated and virtually devoid of
other cardiovascular effects; the only predictable (dose-related, ≤18% incidence
at 10 mg PO twice daily) adverse effects are visual (photopsia, stroboscopic effect, nontypical blurred vision) that usually are only mildly bothersome, fully
reversible with cessation of therapy, and not associated with retinal damage.
Clinical trials involving >4000 patients indicate that ivabradine, as monotherapy, is effective in preventing angina. Effects are seen in doses as low as 2.5 mg
twice daily; when employed at 7.5 mg or 10 mg twice daily, angina prevention
with ivabradine is equivalent to that achieved with amlodipine 10 mg daily or
atenolol 100 mg daily.
Address for correspondence: Jeffrey S. Borer, MD, 47 East 88th Street,
New York, NY 10128-1152, USA (e-mail: [email protected])
ngina pectoris due to coronary artery occlusive disease, characterized by central chest
discomfort that reproducibly develops during physical exertion and/or emotional stress and
is relieved within ≤ 20 minutes of cessation of the
inciting stress, is the most common symptom resulting from myocardial ischemia. Though angina
can be frightening to the patient and often markedly limits normal work and recreation, most patients
with angina are at relatively low imminent risk of
death or myocardial infarction from their underlying coronary disease.1,2 Therefore, prevention of angina is a legitimate primary therapeutic objective,
achievable with acceptable safety only by preventing ischemia, its cause.
Myocardial ischemia results from an imbalance of
myocardial oxygen supply and myocardial oxygen
demand. In theory, inhibition of If current should
be particularly useful in minimizing or preventing
stress-induced ischemia in patients with coronary
artery disease because If current is the primary electrophysiological basis of sinoatrial node depolarization, the frequency of which defines the heart rate.
Heart rate and blood pressure are the predominant
determinants of myocardial oxygen demand. Thus,
heart rate reduction by If inhibition should be highly effective in preventing angina.
Anti-ischemic/antianginal effects of heart rate
slowing also can result from augmentation of subendocardial blood flow. Subendocardial flow is inversely related to the resistance created by active
myocardial contraction, which occludes intramyocardial vessels. Because of the sequence of contraction and the morphology of the heart, the subendocardium is the region most vulnerable to compromised flow during systole. The interval free from
active contraction increases as heart rate slows, in-
44
If inhibition as a therapeutic approach in stable angina – Borer
Keywords: stable angina; I f current; heart rate reduction; treatment;
ivabradine
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creasing the duration of mechanical diastole. Additionally, though unlikely to affect typical effortinduced angina (a condition associated with relative stability of the atherosclerotic plaque), heart
rate slowing should minimize risk of plaque disruption (and acute ischemic events) by reducing mechanical perturbation of the plaque caused by foreshortening and twisting of large epicardial arteries
during systole.3 Counterbalancing these potentially beneficial effects, heart rate slowing limits cardiac
output at rest and cardiac output reserve; in certain
individuals, this can result in unacceptable fatigability. However, the clinical impact of these effects
cannot be predicted a priori: reduction in ischemia
may enhance exercise tolerance beyond the effect
of cardiac output limitation. Indeed, prevention of
ischemia may prevent myocardial dysfunction that
could limit output more than heart rate reduction.
Experimental and clinical data indicate that heart
rate slowing is an important part of the antianginal,
anti-ischemic effects of several commonly employed
drugs, including β-adrenergic blockers and calcium channel blockers of the verapamil and diltiazem
types. However, these drugs have pharmacological
effects in addition to heart rate slowing, including
negative inotropic activity (both β-blockers and calcium channel blockers) and peripheral vasodilatation (calcium channel blockers), the latter often associated with blood pressure reduction; in theory,
these effects can add to antianginal efficacy, but can
also cause debilitating “side effects.”
Nonpharmacological heart rate slowing was
achieved three decades ago with direct electrical
stimulation of the carotid sinus. The method was
effective in preventing angina, but the procedure
itself and discomfort associated with the use of the
implanted stimulator limited its application. Therefore, pure heart rate slowing by pharmacological
means, with agents devoid of additional, potentially
deleterious properties, has remained a goal of drug
research.
I f current blockers: experimental
and clinical pharmacology
More than three decades ago, the theoretical benefits of pure heart rate slowing led to initiation of
efforts to develop selective sinus node inhibitors
without direct effects on other cardiac electrophysiological properties or on myocardial mechanical
function or peripheral vascular tone.4 The role of the
hyperpolarization-activated mixed sodium-potassium inward (If) current in generating spontaneous
activity in cardiac pacemaker cells was first elucidated shortly thereafter 5; subsequent further characterization6,7 identified a clear target for drug-mediated heart rate slowing. The first If current blocker
tested clinically as an antianginal was UL-FS 49.
However, despite promising preclinical findings,8,9
angina prevention was not achieved with the doses
employed clinically, despite some heart rate reduction both at rest and during exercise.10,11 Additional testing, using higher and possibly more effective
doses, was not undertaken because transient ocular toxicity was observed at the initially employed
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doses.11 The adverse visual effects have been attributed to inhibition of currents in the retina similar to those in the sinoatrial node.
Though UL-FS 49 failed in clinical testing, If current inhibitors with other molecular structures
were evaluated for more favorable therapeutic-totoxic ratio. More than a decade ago, ivabradine, with
If current–blocking activity,7 was reported to have
pharmacological properties that compared favorably with UL-FS 49.12 Ivabradine, which structurally
comprises linked benzazepinone and benzocyclobutane rings, is highly selective for the If current.
Preclinical studies indicated that heart rate slowing
could be achieved with ivabradine in a dose-dependent manner without affecting myocardial contractility, peripheral vascular resistance, coronary vascular resistance, and mean arterial pressure, without
changing the myocardial oxygen delivery–to–myocardial oxygen consumption ratio.13 Ivabradine also
did not affect electrocardiographic PR and QT intervals, whereas, experimentally, UL-FS 49, less specific for If than ivabradine, caused QTc prolongation. The lack of QTc prolongation by ivabradine is
noteworthy13 because such electrophysiological alteration is a potent risk factor for clinically important ventricular arrhythmias that had marred research with early selective sinus node blockers.11 In
other preclinical studies, ivabradine minimized exercise-induced ischemia and stunning14 and, at doses causing heart rate slowing comparable to that of
the β-blocker atenolol at rest and during exercise,
ivabradine depressed myocardial relaxation modestly and less than the β-blocker,15 suggesting a potential advantage for the pure heart rate–slowing If inhibitor.
In clinical trials, at the doses most commonly
employed (5-10 mg twice daily), ivabradine has consistently demonstrated heart rate reduction at rest
and during exercise of the same magnitude as is effected by commonly employed doses of β-blocking
drugs, but without alteration in blood pressure (and
other cardiovascular functional changes) commonly seen with β-blockers. Thus, when compared with
placebo at peak exercise, ivabradine 10 mg twice
daily resulted in almost 15 beats/min lower heart
rate at trough of drug activity16; the heart rate response was dose-related, with evidence of a heart
rate–lowering effect even at the lowest dose tested
(2.5 mg twice daily) (Figure 1, page 40). When compared directly with the β-blocker atenolol, heart
rate lowering with ivabradine 10 mg twice daily was
only modestly less than that with atenolol 100 mg
daily (though antianginal effects of these doses were
similar, as discussed below).17 Despite substantial
heart rate lowering, ivabradine caused little change
in blood pressure relative to placebo, and caused
modestly less blood pressure lowering than atenolol.
I f current blockers:
antianginal efficacy and
safety from clinical trials
To date, ivabradine has been studied in controlled
clinical trials involving more than 4000 patients
with coronary artery disease and chronic stable anMEDICOGRAPHIA, VOL 27, No.1, 2005
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Change in heart rate
at rest (bpm)
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At trough of drug activity
10
At peak of drug activity
0
*
*
--10
*
*
*
--20
*
Placebo
Change in heart rate
at peak exercise (bpm)
B
S I G H T S
Ivabradine
2.5 mg bid
Ivabradine
5 mg bid
Ivabradine
10 mg bid
10
0
*
--10
*
*
*
*
--20
*
Placebo
Ivabradine
2.5 mg bid
Ivabradine
5 mg bid
Ivabradine
10 mg bid
Figure 1. Changes in heart rate (bpm, beats per minute) at rest (A) and at peak
exercise (B) in the different treatment groups during the double-blinded, doseranging phase of the ivabradine trial. Error bars, standard error of the mean.
*P<0.05 versus placebo in pairwise comparison.
Reproduced from reference 16: Borer JS, Fox K, Jaillon P, Lerebours G, for the European Ivabradine Investigators. Anti-anginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable
angina: a randomized, double-blinded, multicentered, placebo-controlled trial. Circulation. 2003;
107:817-823. Copyright © 2003, American Heart Association.
gina. Most trials have maintained active treatment
for at least 3 months (the generally accepted minimum duration of studies employed for purposes of
approval for marketing by legally constituted regulatory authorities18,19). This is the largest antianginal drug development program yet recorded. The
results of these studies support the efficacy of ivabradine for prevention of exertional angina and the
underlying ischemia; adverse effects have been acceptably mild, so that the drug is likely to be tolerable in clinical practice.
By consensus within the regulatory and research
communities, the primary evidentiary standard for
antianginal efficacy is improvement in exercise tolerance on standard treadmill or bicycle ergometric
testing.18-20 This should be supplemented by evidence of reduction in associated exercise-induced
ischemia to preclude the possibility that treatment
is “masking” angina by an analgesic effect, which
might allow patients to exercise unwittingly to severe and potentially lethal ischemia without symptomatic warning. Angina frequency with ambient
activity, as recorded in diaries, is considered adjunc46
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tive evidence, but is not dispositive because the intensity of stress inciting ambient angina in daily living cannot be determined from diary reports. Drug
effectiveness should be demonstrable at the end of
the interdose interval (“trough”), not only at the
time of maximal drug effect (“peak”).
Any standard method (exercise electrocardiography, myocardial perfusion scintigraphy, radionuclide cineangiography, stress echocardiography) can
be employed to demonstrate anti-ischemic effect,
though, in practice, this is done most easily and economically by assessing time to 0.1 mV (1 mm) STsegment depression during the standardized exercise test with and without treatment.
If current blockade with ivabradine has been evaluated for antianginal/anti-ischemic effect in comparison with placebo in the absence of any other
chronic (“background”) therapy, in comparison with
placebo on a background of amlodipine administered to patients with and without ivabradine, and
in direct comparison with atenolol and with amlodipine. The latter two studies were designed to test
“noninferiority” of ivabradine versus standard antianginal therapies. In the context of these studies,
“noninferiority” is a statistical concept aimed at determining the consistency with which, for a prespecified outcome variable, one intervention fails to
differ from another by more than an amount agreed,
a priori, to be of no clinical importance. Other definitions exist, but depend upon existence of a wellcharacterized and statistically stable magnitude of
incremental effect of the comparator therapy versus placebo known from previously reported trials;
such stable placebo-controlled “point estimates” do
not exist for antianginal drugs.18,20
◆ Placebo-controlled monotherapy
The efficacy of ivabradine was first confirmed in a
large (n=360 patients) double-blind, placebo-controlled, multicenter, multinational study (Figure 2),
in which patients were randomized to receive either
ivabradine 2.5 mg PO twice daily, 5 mg PO twice
daily, or 10 mg PO twice daily, or placebo, for 2 weeks
(“dose ranging”).16 Then, in an open-label extension,
the dose was increased to 10 mg PO twice daily for
2 to 3 months (in those who accepted continuation
and for whom local regulations permitted such extension). At the conclusion of the open-label phase,
randomized, double-blinded withdrawal to placebo
was undertaken in half the population, while the
other half was randomized to maintain treatment
with 10 mg PO twice daily. After exclusion of 103
patients who withdrew from treatment or violated
protocol constraints, results were analyzed among
the 257 patients treated according to protocol.Compared with placebo, time to limiting angina increased nominally at all doses, reaching statistical
significance at ivabradine 10 mg twice daily.16 When
responses to all doses were considered, a dose-effect relation was apparent and a between-group
comparison was statistically significant (P=0.049).
When protocol violators were included in the analysis (“intention-to-treat” population), ivabradine
remained superior to placebo at trough when 10 mg
was administered twice daily, though the difference
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Selection, washout, and run-in phase
Placebo
529 screened
129 not eligible
(101 target disease not proven; 8 unstable
CAD; 7 consent withdrawn; 13 other reasons)
400 selected
Double-blinded, dose-ranging phase
40 not included
(23 negative ETT at D0; 5 unstable CAD;
3 unstable ETT results; 2 consent withdrawn;
7 other reasons)
360 randomized
Ivabradine
2.5 mg bid
Ivabradine
5 mg bid
Ivabradine
10 mg bid
Placebo
90 included
87 completed
3 withdrawn (1 AE;
1 lack of efficacy;
1 nonmedical)
PP n=64
91 included
87 completed
4 withdrawn (1 AE;
1 lack of efficacy;
1 nonmedical;
1 major protocol
deviation)
PP n=59
88 included
85 completed
3 withdrawn (2 AE;
1 lack of efficacy)
PP n=66
91 included
90 completed
1 withdrawn (AE)
PP n=68
Open-label extension phase
Ivabradine 10 mg bid
173 included
(46 from 2.5 mg bid; 46 from 5 mg bid;
39 from 10 mg bid; and 42 from placebo group)
161 completed
12 withdrawn
(3 AE; 6 lack of efficacy; 1 nonmedical,
2 major protocol deviation)
PP n=120
Figure 2. Trial protocol
through all 4 phases of the
ivabradine trial.
Randomized withdrawal phase
157 randomized
Placebo
77 included
76 completed
1 withdrawn (nonmedical)
PP n=59
80 included
79 completed
1 withdrawn (AE)
PP n=65
reached the level of “statistical trend” (P=0.058)
rather than “significance.” During the open label
extension phase, in which all 173 participating patients received 10 mg twice daily, increased time
to angina was nominally apparent among the two
dose groups (totaling 89 patients) that had received
less than 10 mg twice daily in the dose-ranging
phase (Figure 3, page 42). During randomized withdrawal, time to limiting angina fell significantly in
patients withdrawn to placebo, but remained unchanged in patients maintained on ivabradine 10 mg
twice daily (between-group difference: P=0.018),
(Table I, page 42).16
Abbreviation: AE, adverse event;
CAD, coronary artery disease;
ETT, exercise tolerance test;
PP, per-protocol population.
Reproduced from reference 16:
Borer JS, Fox K, Jaillon P, Lerebours
G, for the European Ivabradine
Investigators. Anti-anginal and
anti-ischemic effects of ivabradine,
an If inhibitor, in stable angina: a
randomized, double-blinded, multicentered, placebo-controlled trial.
Circulation. 2003;107:817-823.
Copyright © 2003, American Heart
Association.
Time to 1-mm ST-segment depression was significantly reduced by ivabradine 5 mg bid and 10 mg
bid, and a significant dose-response relation was
seen across all doses for this effect, indicating that
angina prevention was associated with an anti-ischemic effect.16 Diary recordings and tabulation of
short-acting nitroglycerin use indicated that angina attack rate and nitroglycerin use during routine
daily living was lower at the end of the protocol than
at pretreatment baseline among patients receiving
ivabradine, and increased among those randomly
withdrawn to placebo at the end of the open-label
treatment phase, while remaining unchanged durMEDICOGRAPHIA, VOL 27, No.1, 2005
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Extension phase;
all patients received
ivabradine 10 mg bid
Doseranging
phase
A
IF I N
Change in time to
1-mm ST-segment depression (s)
80
60
40
Ivabradine 5 mg bid
Ivabradine 2.5 mg bid
Placebo
20
0
0
20
40
60
80
100
120
80
100
120
Time (days)
Change in time to
limiting angina (s)
B
60
40
20
0
0
20
40
60
Time (days)
Figure 3. Changes in time to 1-mm ST-segment depression and limiting angina in
patients receiving ivabradine 10 mg bid (n=59) or placebo (n=65) during the randomized withdrawal phase of the ivabradine trial. *P<0.05 versus ivabradine.
Reproduced from reference 16: Borer JS, Fox K, Jaillon P, Lerebours G, for the European Ivabradine
Investigators. Anti-anginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina: a
randomized, double-blinded, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823.
Parameter
Heart rate at rest (bpm)
Maximal heart rate (bpm)
Time to 1-mm ST-segment
depression (s)
Time to limiting angina (s)
Time to angina onset (s)
RPP at rest (bpm • mm Hg)
RPP at peak of exercise
(bpm • mm Hg)
Ivabradine
10 mg bid
n=59
Placebo
n=65
Betweengroup
P-value
--0.44±5.6
--1.31±7.48
4.25±59.7
13.3±8.8
12.3±8.8
--32.0±73.7
<0.001
<0.001
0.003
--0.78±48.8
2.1±59.1
--26±1207
--180±3195
--25.2±63.9
--36.05±76.7
1487±1628
1813±3331
0.018
0.002
<0.001
<0.001
*Expressed as value at end of the randomized withdrawal phase minus value at end of the openlabel extension phase.
Table I. Changes in ETT parameters, measured at trough of drug activity, during the
randomized withdrawal phase.*
Abbreviations: RPP, rate pressure product.
Reproduced from reference 16: Borer JS, Fox K, Jaillon P, Lerebours G, for the European Ivabradine
Investigators. Anti-anginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina: a
randomized, double-blinded, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823.
48
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ing the withdrawal phase among those who continued on ivabradine 10 mg twice daily.16
This trial also indicated the relative safety of ivabradine use during a 3-month treatment interval.
Adverse events were relatively few and generally
similar in frequency and distribution compared
with placebo, except for visual symptoms (photopsia, stroboscopic effect, nontypical blurred vision).
Visual symptoms were dose-related, rarely sufficiently bothersome to cause voluntary withdrawal
from the drug, and invariably reversible with drug
cessation, consistent with the absence of irreversible
retinal effects reported in preclinical studies. Visual
side effects occurred in approximately 15% of subjects at 10 mg twice daily during the dose-ranging
phase and 18% during the open-label phase.16 Since
the sinoatrial node is the target of If blocking therapy, patients with disease of this structure (eg, “sick
sinus syndrome”) were excluded from ivabradine
trials and, in the current state of our knowledge,
should not receive this drug. With this caveat and
exclusion, neither syncope nor untoward hypotension nor heart failure was associated with ivabradine
administration in the placebo-controlled trial of the
drug as monotherapy, nor in the other large clinical trials described below. Note, of course, that ivabradine would be ineffective in patients chronically in atrial fibrillation since the drug does not affect
the atrioventricular node and, therefore, cannot
modulate heart rate in these patients.
◆ Direct comparisons with approved antianginal
drugs at commonly employed doses
In 1195 patients randomized to ivabradine 7.5 mg
twice daily or amlodipine 10 mg daily, a 3-month
multicenter, multinational, double-blind study
demonstrated that ivabradine was indistinguishable from amlodipine in its effects on total exercise
duration, time to limiting angina, time to angina
onset, and time to 1-mm ST-segment depression.
Formal statistical testing of data from this as yet unpublished trial revealed ivabradine to be noninferior to amlodipine (P<0.0001 for this conclusion).21
In a 4-month double-blind study, 939 patients
were randomized, first, to ivabradine 5 mg twice
daily or atenolol 50 mg daily for 2 weeks; then, doses were uptitrated to ivabradine 7.5 mg or 10 mg
twice daily or to atenolol 100 mg daily.17 No statistically significant differences were found when various outcomes were compared among the tested
regimens at each stage, and ivabradine’s noninferiority to atenolol was significantly established at the
doses employed (P<0.0001).17 However, despite the
fact that atenolol 100 mg daily resulted in slightly
greater heart rate reduction than with either ivabradine 7.5 mg or 10 mg twice daily, ivabradine
was nominally superior to atenolol in enhancing
time to angina onset, time to limiting angina, and
total exercise duration at all doses, while time to
1-mm ST-segment depression was virtually identical among the regimens.17 This finding suggests
that pharmacological effects of β-blockers other
than heart rate slowing may impact negatively on
the pathophysiology of angina. This hypothesis remains to be rigorously tested.
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A growing body of data indicates that angina and
the underlying ischemia can be effectively minimized using selective sinoatrial node If current
blockade to slow heart rate. These data also suggest
that, when this effect is achieved with ivabradine,
effective prevention of angina is associated with acceptable safety and tolerability.
Because of the relatively high prevalence of angina within the world’s population (discussed elsewhere in this issue), the availability of a new approach to angina prevention has important public
health implications. Currently available drug therapy with single or multiple agents often fails to
completely or optimally prevent angina. Indeed, recent data indicate that a substantial majority of patients with angina receive combination antianginal
therapy involving at least two drugs, but, nonetheless, continue to experience approximately two angina attacks per week.22 Availability of a new agent,
with pharmacological effects different from currently available drugs, may enhance the rate of therapeutic success. Also, since drugs with different
pharmacological profiles are likely to differ also in
frequency, character, and distribution of adverse effects, tolerability of treatment across large populations is likely to be enhanced by availability of an
additional drug that may be tolerable when others
are not. For example, β-blockers may potentiate the
symptoms of peripheral arterial occlusive disease23
(commonly associated with coronary artery disease)
or obstructive pulmonary diseases,24 while increasing the risk of untoward events in patients with hypotension or intrinsic atrioventricular node disease,25 and possibly complicating the management
of metabolic disorders (diabetes mellitus26 or hyperlipidemia27). Certain calcium channel blockers28 (as
well as β-blockers in some settings) can precipitate
or potentiate congestive heart failure or atrioventricular node dysfunction; calcium channel blockers also frequently cause unacceptable peripheral
edema and constipation (the latter particularly in
elderly patients). The third most commonly used
group of angina-preventing drugs, long-acting nitrates,29 can be nontolerated because of associated
headaches or lightheadedness (which are, in fact,
direct results of its beneficial pharmacological effects); intermittent use of these drugs may result in
rebound angina and vasoconstriction. Albeit rarely,
nitrates have resulted in methemoglobinemia when
moderate overdoses are administered; it is even possible that nitrates may affect matrix metalloproteinase activity, potentially destabilizing atherosclerotic plaques.
These adverse effects are not expected with If current inhibition and, specifically, have not been associated with ivabradine use. Similarly, as demonstrated in preclinical studies (supplemented by as
yet unpublished experience in patients with heart
failure and with left ventricular ejection fraction
<40%), If current inhibition with ivabradine does
not suppress myocardial inotropy14,29,30 (potentially
a problem with β-blockers15,31 and certain calcium
channel blockers28), is not associated with the potentially lethal “rebound” effects seen with abrupt
cessation of short-acting β-blockers,23,32 and, as
demonstrated by the results of randomized withdrawal after 2 to 3 months of treatment, does not
result in pharmacological tolerance to its therapeutic effects when administered continually over
a protracted interval, a problem previously identified when long-acting nitrates are employed.33
Finally, in addition to symptom reduction and
consequent quality of life enhancement that can be
expected from ivabradine-mediated If current inhibition, it is possible that heart rate reduction may
improve survival. Though the latter hypothesis remains to be tested in a large clinical trial, pharmacological heart rate slowing has been associated
with mortality reduction in patients with heart failure34 and after myocardial infarction35; drug-associated cardioacceleration has been associated with
deleterious outcomes. Indeed, both actuarial data
and observational studies in cohorts with a variety
of cardiovascular and metabolic diseases, and in the
population at large, indicate a significant relation
between casually measured heart rate and survival.36 The intriguing potential for survival enhancement with ivabradine in patients with coronary artery disease and, indeed, in other settings as
well, remains to be explored. ❒
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2003;107:817-823.
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Eur Heart J. 2003;24(suppl):20. Abstract.
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20. Borer JS, moderator. Development of antilipid and anti-ischemic therapy: panel discussion. In: Borer JS, Somberg JC, eds.
Cardiovascular Drug Development: Protocol Design and Methodology. New York, NY: Marcel Dekker; 1999:197-211.
21. Ruzyllo W, Ford I, Tendera M, et al. Antianginal and anti-ischemic effects of the If current inhibitor ivabradine compared to
amlodipine as monotherapy in patients with chronic stable angina: a 3-month randomized, controlled, double-blind, multicenter trial. Eur Heart J. 2004;25:878. Abstract.
22. Pepine CJ, Abrams J, Marks RG, et al. Characteristics of a contemporary population with angina pectoris: TIDES Investigators.
Am J Cardiol. 1994;74:226-231.
23. Lewis RV, Lofthouse C. Adverse reactions with beta-adrenoceptor blocking drugs: an update. Drug Safety. 1993;9:272-279.
24. Tattersfield AE. Respiratory function in the elderly and the
effects of beta blockade. Cardiovasc Drugs Ther.1991;4(suppl 6):
1229-1232.
25. Ramahi TM. Beta blocker therapy for chronic heart failure.
Am Fam Physician. 2000;62:2267-2274.
26. Reneland R, Alvarez E, Andersson PE, et al. Induction of insulin resistance by beta blockade but not ACE-inhibition: longterm treatment with atenolol or trandolapril. J Hum Hypertens.
2000;14:175-180.
27. Krone W, Nagele H. Effects of antihypertensives on plasma
lipids and lipoprotein metabolism. Am Heart J. 1988;116:17291734.
28. Frishman WH, Sica DA. Calcium channel blockers. In: Frishman WH, Sonnenblick EH, Sica DA, eds. Cardiovascular Pharmacotherapies. 2nd ed. New York, NY: McGraw-Hill; 2003:105130.
29. Abrams J, Frishman WH. The organic nitrates and nitroprusside. In: Frishman WH, Sonnenblick EH, Sica DA, eds. Cardiovascular Pharmacotherapies. 2nd ed. New York, NY: McGrawHill; 2003:203-214.
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30. Simon L, Ghaleh B, Puybasset L, et al. Coronary and haemodynamic effects of S 16257, a new bradycardic agent, in resting
and exercising conscious dogs. J Pharm Exp Therap.1995;275:
659-666.
31. Moore N, Joannides R, Iacob M, et al. Effects of a pure bradycardic agent, S 16257, at rest and during exercise in healthy volunteers: comparison with propranolol. Br J Clin Pharm.1998;45:
188-189.
32. Egstrup K. Transient myocardial ischemia after abrupt withdrawal of antianginal therapy in chronic stable angina. Am J Cardiol. 1988;61:1219-1222.
33. Steering Committee, Transdermal Nitroglycerin Cooperative
Study. Acute and chronic antianginal efficacy in continuous twenty-four hour application of transdermal nitroglycerin. Am J Cardiol. 1991;68:1263-1270.
34. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in
heart failure. Eur Heart J. 1999;1(suppl H):H64-H69.
35. Kjekshus JK. Importance of heart rate in determining betablocker efficacy in acute and long-term myocardial intervention
trials. Am J Cardiol. 1986;57:43F-49F.
36. Singh BN. Impact of heart rate on cardiovascular disorders:
focus on chronic stable angina. In: Fox K, ed. Selective and Specific If Channel Inhibition in Cardiology. London, UK: Science
Press Ltd; 2004:25-36.
L’INHIBITION DU COURANT IF EN TANT
QU’APPROCHE THÉRAPEUTIQUE DE L’ANGOR STABLE
ÉTUDES EXPÉRIMENTALES ET CLINIQUES
:
L’
angor, qui est le symptôme le plus débilitant de l’ischémie myocardique,
peut résulter d’une maladie coronaire occlusive. Même si l’angor limite
notoirement la qualité de vie, le plus souvent les malades concernés ont
une excellente survie. Les traitements médicamenteux actuels ne préviennent
totalement les crises d’angor que chez une minorité de sujets, même quand ils
sont utilisés en association. Des alternatives pharmacologiques faisant appel
à des propriétés pharmacologiques qui diffèrent de celles mises en jeu dans les
traitements conventionnels sont donc souhaitables. L’ischémie myocardique résulte d’un déséquilibre entre les apports et les besoins en oxygène. La limitation de la fréquence cardiaque, un déterminant primaire des besoins en oxygène, s’avère particulièrement utile dans la prévention de l’angor. Le courant
entrant I f Na+ et K+-dépendant, présent au niveau des membranes cellulaires
du nœud sino-auriculaire (alors qu’il est pratiquement totalement absent au
niveau du reste du myocarde) module la fréquence diastolique sino-auriculaire,
et, de ce fait, la fréquence cardiaque. L’inhibition de ce courant réduit cette dernière. L’ivabradine, un inhibiteur hautement sélectif du courant I f , qui associe un cycle benzazépinone et un cycle benzocyclobutane, induit une diminution de la fréquence cardiaque qui s’avère cliniquement utile à des doses qui
sont en général bien tolérées et pratiquement dénuées de tout autre effet cardiovasculaire. Les seuls évènements indésirables prévisibles (dose-dépendants,
fréquence ≤18 % à la dose de 20 mg par jour en deux prises orales) sont visuels,
à type de photopsie, d’effet stroboscopique et de vision floue atypique). Ces effets, habituellement légers et peu gênants, disparaissent complètement à l’arrêt du traitement. Ils ne s’associent à aucune lésion rétinienne. Les essais cliniques qui ont inclus au total plus de 4000 malades indiquent que l’ivabradine
en monothérapie est efficace dans la prévention des crises d’angor. Cet effet est
perceptible dès les doses les plus faibles, en l’occurrence 5 mg/jour en deux
prises. Aux doses de 15 et 20 mg/jour, toujours réparties en deux prises, la prévention de l’angor est assurée avec une efficacité qui rejoint celle obtenue avec
l’amlodipine (10 mg/j) ou l’aténolol (100 mg/j).
✦
50
AND
AND
APPLICATIONS
▲
▲
STABLE ANGINA
▲
Henry PURCELL, MB, PhD
Senior Fellow in Cardiology
Royal Brompton Hospital, London
Kim FOX, MD, FRCP
Professor of Clinical Pharmacology
Royal Brompton Hospital, London
UNITED KINGDOM
Selective and specific
If inhibition: new perspectives
by H. Purcell and K. Fox,
United Kingdom
eart rate, along with preload, afterload, and
myocardial contractility, are among the major factors that regulate cardiac pump function. Heart rate is also a primary determinant of
oxygen consumption. This is particularly relevant
in patients with coronary heart disease, when increases in heart rate and reduction in oxygen supply, in tandem with decreased time for myocardial
relaxation and diastolic ventricular filling, can lead
to development of myocardial ischemia. There is an
inverse relationship between heart rate and life expectancy. The resting rate is an independent predictor of cardiovascular morbidity and mortality (see
reviews, references 1,2). This is particularly marked
in patients with unstable angina or acute myocardial infarction. A recent analysis3 looked at initial
(day 1) hospital admission and delayed (days 2-3)
heart rates in over 10 000 patients with acute coronary syndromes enrolled into a large clinical trial
H
levated heart rate at rest is associated with increased risk of cardiovascular events. Some agents may attenuate risk, eg, -blockers post-myocardial infarction. -Blockers are not tolerated by all patients and their
negative inotropic effects may increase side effects. There is much interest in
the development of sinus node inhibitors, which only lower heart rate. One such
specific bradycardic agent, ivabradine, selectively inhibits If , a primary sinoatrial node pacemaker current. Ivabradine has documented anti-ischemic and
antianginal properties and, because it is negatively chronotropic without suppressing contractility, it may have a role in the treatment of heart failure. Several trials to address this issue further are either ongoing or in the planning
stage.
E
Keywords: heart rate; -blockers; sinus node inhibitor; ivabradine
Address for correspondence: Dr Henry Purcell, Department of Cardiology, Royal Brompton Hospital,
Sydney Street, London SW3 6NP, UK (e-mail: h.purcell@)rbh.nthames.nhs.uk
Selective and specific If inhibition: new perspectives – Purcell and Fox
of an oral glycoprotein IIb/IIIa inhibitor. Findings
showed significant greater 30-day and 10-month
mortality among patients with higher initial and
delayed heart rates. A number of possible reasons
have been proposed to explain this, and why, clinically, tachycardia at rest is an adverse finding. Sinus
tachycardia can reflect overactive sympathetic activity. It can be demonstrated experimentally that
relatively high heart rates can amplify atherogenesis and endothelial dysfunction selectively in the
coronary vessels, and that low heart rates can exert
a sparing effect.
One classic experiment4 in cynomolgus monkeys
fed a high cholesterol diet for 6 months, showed
that after sinus node ablation by electrocautery, to
reduce heart rate, coronary atheroma was twice as
severe in the animals with higher heart rates who
underwent a sham surgical procedure compared
with those who had the ablation performed (55.9%
vs 26.1% stenosis in the two groups, respectively;
P<0.002). Similar findings were also seen with further work in carotid vessels. In both sets of experiments the animals did not significantly differ in
blood pressure, serum lipids, or body weight.
In a study of 56 patients who had sustained a myocardial infarction (MI) before the age of 45 years
and who underwent two coronary angiograms within a period of 4 to 7 years,5 progression of disease
was predicted independently by heart rate. When
patients were divided into high and low heart rate
groups (by median value of minimum heart rate)
coronary atherosclerosis progression was two times
higher in the high heart rate group. A further retrospective study examined the relationship between
bradycardia and the development of coronary collateral vessels on angiography in patients with obstructive coronary artery disease (CAD). Patel and
coworkers observed that a larger number of paMEDICOGRAPHIA, VOL 27, No.1, 2005
51
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EFFECT
COMMENT
◆ Bradycardia
◆ Absolute contraindication in 2nd and 3rd
(negative inotropism)
◆ Bronchospasm
Development of sinus node inhibitors
◆ Because of myocardial depression, initiate
with caution in stable heart failure. Avoid in
worsening unstable heart failure
◆ May precipitate (life-threatening) asthma.
Avoid in those with history of asthma or
COAD, or use cardioselective agent with
extreme (supervised) caution
◆ Cold extremities
◆ May be less common in agents with partial
agonism. Avoid in Raynaud’s disease
◆ Lethargy/fatigue
◆ May adversely affect compliance
◆ Nightmares/sleep
◆ May relate to lipophilicity. Possibly reduced
disturbances
◆ Inhibition of metabolic/
autonomic responses
to hypoglycemia
◆ May mask symptoms of hypoglycemia in
insulin-treated diabetics. Avoid in those with
frequent hypoglycemia or taking sulfonylureas
◆ Likely to be more common when β-blockers
sexual activity
used with thiazide diuretics. Generally not
commonly reported in monotherapy trials
Abbreviation: COAD, chronic
obstructive airways disease.
52
with hydrophilic agents, eg, atenolol
◆ Impotence/reduced
Table I. Effects that may
limit or contraindicate
use of β-blocker drugs.
P L I C AT I O N S
◆ May be exacerbated when used with potent
vasodilators
◆ Reduced contractility
AP
lowering drugs, there are differences between them,
and some 20% of patients do not respond to any
β-blocker.9 Similarly, there are well-documented
effects with this drug class, which limit their use
in terms of absolute or relative contraindications
(Table I).
degree heart block. Caution with other heart
rate–lowering agents
◆ Hypotension
A N D
tients with heart rates ≤50 beats/min had significantly greater development of collateral vessels
(decreasing the ischemic burden) compared with
control patients with heart rates ≥60 beats/min,
(P<0.001). The presence of collaterals was independent of the angina history or the use of β-blockers.
Another retrospective angiographic study6 looked
at 53 of 106 patients who underwent two coronary
angiograms within 6 months. These patients had
initially smooth stenoses, but developed plaque disruption by the time of the second angiogram. They
were compared with 53 control patients with smooth
stenoses without angiographic plaque disruption.
Logistic regression analysis identified positive associations between plaque disruption, left ventricular muscle mass >270 g, and a mean heart rate >80
beats/min, and a negative association with the use
of β-blockers. This association again indicates how
hemodynamic forces may play a critical role in the
process of plaque disruption. A further study7 has
shown that high heart rate is strongly associated
with high arterial rigidity, reduced distensibility,
and elevated pulse-wave velocity, all of which are
associated with myocardial infarction and cardiac
death.
Such studies have highlighted renewed interest
to investigate heart rate–lowering drugs. A number
of cardiovascular drugs are heart rate–reducing including, amiodarone, digoxin, diltiazem, verapamil,
and β-blockers, however not all improve prognosis. β-Blockers are one example of drugs that lower heart rate and blood pressure, and improve outcome in patients who have sustained a myocardial
infarction. These benefits appear to extend largely
to higher-risk patients.8 While β-blockers are probably the most widely prescribed of the heart rate–
While the interest in developing “specific bradycardic-agents” extends back over 50 years, the early 1970s saw the beginning of a formal research
program.10 The hypothesis was that pure bradycardic agents could selectively reduce heart rate
without affecting myocardial contractility, conduction velocity and refractoriness, or arterial blood
pressure. Drugs that act specifically to block the
pacemaker current might allow an opportunity to
see whether “isolated” heart rate reduction could
alleviate ischemia by reducing myocardial oxygen
consumption as well as by increasing the duration
of myocardial perfusion. They might also be better
tolerated and have potential to retard development
of atherosclerosis and exert antifibrillatory actions
to prevent arrhythmic death.11 A number of compounds were developed including falipamil, which
were benzolactam derivatives of verapamil. This reduced heart rate experimentally, but was shown to
produce QT prolongation, and it was therefore modified structurally to produce UL-FS 49, which was
more specific, and potent and had a longer duration
of action. While UL-FS 49 reduced heart rate to the
same extent as propranolol, and it also appeared to
be anti-ischemic, it was found to provide no additional antianginal benefit in terms of greater exercise tolerance to patients already receiving nifedipine.12 UL-FS 49 has also been shown to cause QT
prolongation and it causes dose-related ocular adverse effects, therefore it will not be developed for
clinical use in the future.
Development of ivabradine
Ivabradine has been extensively investigated in recent years. Ivabradine is a novel, selective inhibitor
of the cardiac pacemaker If current. The “funny” or
“pacemaker” If current was described in pacemaker cells of the sinoatrial node as a current slowly
activating on hyperpolarization that contributes to
generation of cardiac rhythmic activity and its control by sympathetic innervation.13 Thus, the “funny” channels play a key role in generation of spontaneous activity of pacemaker cells and mediate
autonomic control of heart rate. By increasing the
duration of spontaneous depolarization it induces
selective heart rate reduction. Ivabradine is a dextroisomer of the racemic compound that induces
in animals and humans dose-dependent heart rate
lowering, and that, because of its selectivity, has
minimal effects on other myocardial ionic currents.
The effects of ivabradine and propranolol have been
compared in a pig model of exercise-induced myocardial ischemia.14 Both agents were equipotent in
reducing heart rate at rest and limiting tachycardia on exercise. Ivabradine, unlike propranolol, did
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not reduce left ventricular contractility at rest or
during exercise and did not increase atrioventricular conduction time. Both compounds reduced exercise-induced ST segment shift in the ischemic region by about 80%, but only ivabradine preserved
systolic shortening significantly, that is, β-blockade
potentially limits the ability of the ischemic myocardium to respond to increased blood flow by increased contractile function. Further animal studies15 show that oral administration of ivabradine in
mice reduces heart rate without influencing contractility and that this negative chronotropic effect
is preserved even during significant (stress-evoked)
activation of the sympathoadrenergic system.
The degree to which reduction in heart rate and
contractility respectively contribute to the beneficial effects of β-blockers remains debated. A recent
study conducted in dogs attempted to dissociate
these two factors.16 The study compared heart rate
reduction during exercise-induced myocardial ischemia and stunning, with atenolol and ivabradine.
Stunning is prolonged, but reversible, contractile
dysfunction following acute ischemia despite the
return of normal blood flow. Atenolol was shown
to have greater effect on regional contractility (measured as a reduction in left ventricular wall thickening) when administered prior to exercise-induced
ischemia, despite causing similar heart rate reduction to ivabradine. However, when administered after exercise, ivabradine attenuated stunning and
shortened the recovery time for return to normal
contractility (an effect that disappeared when heart
rate reduction was reversed with atrial pacing), in
contrast to atenolol, which did not. The authors
suggest that selective heart rate reduction not only
provides an anti-ischemic effect, but also improves
contractility of the stunned myocardium, whereas
additional negative inotropism is protective against
ischemia, but deleterious in stunning. They argue
then that ivabradine might be better as a first choice
for angina pectoris.
Clinical studies
The antianginal, anti-ischemic efficacy and safety
of ivabradine have been assessed in a randomized,
double-blind, placebo-controlled study of 360 patients with chronic stable exertional angina.17 All of
the men and women enrolled (mean age about 58
years) had documented coronary artery disease. An
initial 2- to 7-day washout period on placebo was
followed by a 1-week, single-blind placebo-controlled
run-in period. After this, patients were randomly
assigned to placebo or ivabradine 2.5, 5, or 10 mg
twice daily for 2 weeks, followed by a voluntary 2- or
3-month open-label extension phase during which
all patients received ivabradine 10 mg twice daily to
assess safety and maintenance of efficacy. Finally,
those patients in the open-label extension were randomized to continue on ivabradine 10 mg twice
daily or to withdraw to placebo for 1 additional
week, in order to check for any rebound phenomena. Exercise tolerance tests (bicycle ergometry)
were conducted on days –7, 0, and 14 at the trough
of drug activity and day 14 at peak drug activity.
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Ivabradine was well tolerated and no rebound
phenomena were observed on drug withdrawal. A
dose response in heart rate reduction was seen at
all doses of ivabradine. Ivabradine 5 mg and 10 mg
twice daily significantly increased time to 1-mm STsegment depression (P<0.0005) and time to limiting angina on exercise. Patients continuing on ivabradine during the withdrawal period maintained
improvements in exercise parameters, whereas there
was significant deterioration with placebo. The incidence of overall side effects was low and similar
between ivabradine and placebo. There was, however, a dose-related increase in visual disturbances
(mainly photopsia) reported in 1 patient on ivabradine 2.5 and 5 mg and in 13 patients (14.8%) on ivabradine 10 mg twice daily. No visual disturbances
were reported on placebo. All visual symptoms resolved spontaneously during or after drug discontinuation.
An extensive phase 3 program of clinical studies
with ivabradine has been undertaken; this will be
reviewed in detail elsewhere in this publication.
Pivotal studies18 include a 3-month study in 1195
patients, where ivabradine 7.5 mg twice daily was
found to have similar efficacy to amlodipine 10 mg
once daily in increasing total exercise duration,
time to limiting angina, time to onset of angina, and
time to 1-mm ST-segment depression. Similarly, in
a 4-month study in 939 patients comparing ivabradine 5 mg and atenolol 50 mg daily for 4 weeks,
and then increased to 7.5 mg ivabradine or 10 mg
twice daily with atenolol 100 mg daily, results confirmed the antianginal and anti-ischemic efficacy
with all doses of ivabradine and demonstrated similar efficacy and safety with atenolol. These trials in
chronic stable angina patients show that ivabradine
significantly reduced the diary-recorded number of
anginal attacks and reduced glyceryl trinitrate consumption by more than two thirds. Antianginal efficacy was consistently demonstrated, without the
development of pharmacological tolerance or rebound.
An invasive clinical electrophysiology (EP) program has also been undertaken with ivabradine.19
Intravenous infusion of ivabradine 0.2 mg/kg in patients confirmed its heart rate–lowering properties
and the absence of relevant influence on intra-atrial, atrioventricular, or intraventricular conduction
times, and the absence of QTc prolongation. No effects on QTc or likelihood of proarrhythmia were
observed with doses of ivabradine up to 20 mg twice
daily. The compound was shown to be especially safe
in studies conducted in patients with left ventricular dysfunction.
A further study20 is under way to assess the effects
of chronic heart rate reduction with ivabradine in
the prevention of atherosclerosis progression assessed using intravascular ultrasound (IVUS).
Ivabradine in heart failure
Because of its lack of negative inotropism, ivabradine may be useful in controlling heart rate in patients with acute heart failure, treated with agents
such as dobutamine, for example.21 Ivabradine was
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investigated in a rat model of heart failure to determine the effects of long-term heart rate reduction
on left ventricular (LV) function and remodeling.22
The study showed that in the animals who had experienced long-term (90 days) heart rate reduction
following randomization to ivabradine, left ventricular function was improved relative to placebo, as
stroke volume increased-preserving cardiac output.
The investigators noted that this improvement in
LV function was probably related not only to heart
rate reduction, but also to modifications of left ventricular structure and/or myocyte properties. There
was a decrease in LV collagen density and an increase in capillary density without any modification
of LV weight, which persisted for at least 3 days after interruption of treatment with ivabradine.
One can only speculate about the mechanisms
that contribute to modification of myocardial structure and LV function. Possibly the heart rate lowering associated with ivabradine augments coronary
perfusion, thus preventing development of endothelial dysfunction associated with local hypoxia and
cytokine and free radical production. Similarly, it
is not known whether such changes occur in clinical use. However, preliminary findings from trials
suggest that myocardial contractility improves in
patients with heart failure treated with ivabradine
10 mg twice daily over 3 months.19 Trials are planned
to address this issue further.
Increased heart rate is an independent risk factor
for development of ischemic cardiac events. Heart
rate reduction with certain heart rate–lowering
drugs, notably β-blockers in the post-myocardial infarction setting, can reduce this risk significantly.
Specific bradycardic drugs, which are devoid of any
hemodynamic effects other than heart rate lowering, have been shown to have anti-ischemic and antianginal properties. Ivabradine is a new and novel
specific bradycardic agent, which acts by selectively inhibiting the pacemaker If current. It improves
exercise parameters during exercise stress in patients with angina, compared with placebo. Ivabradine has comparable antianginal effects to atenolol
and amlodipine. A large outcome study is now
planned to examine the role of ivabradine in patients with LV dysfunction. Ivabradine is well tolerated and appears to be safe when used in clinical
doses. The principal side effect, visual effects, is doserelated, and is experienced in a small percentage of
patients, and reverses with discontinuation of drug
use. Ivabradine does not appear to be proarrhythmic, and it may even improve cardiac function in
patients with ventricular compromise. In summary, selective and specific If inhibition offers a new
and exciting prospect for the future management of
patients with ischemic heart disease. ❒
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heart disease. Eur Heart J. 1991;1(suppl H):H58-H63.
2. Singh BN. Increased heart rate as a risk factor for cardiovascular disease. Eur Heart J. 2003;5(suppl G):G3-G9.
3. Kovar D, Cannon CP, Bentley JH, Charlesworth A, Rogers WJ.
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8. Laperche T, Logeart D, Cohen-Solal A, Gourgon R. Potential
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10. Frishman WH, Gabor R, Pepine C, Cavusoglu E. Heart rate
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12. Frishman WH, Pepine CJ, Weiss RJ, Baiker WM. Addition
of zatebradine, a direct sinus node inhibitor, provides no greater
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Study Group. J Am Coll Cardiol. 1995;26:305-312.
13. Bucchi A, Baruscotti M, DiFrancesco. Current-dependent
block of rabbit sino-atrial node If channels by ivabradine. J Gen
Physiol. 2002;120:1-13.
14. Vilaine JP, Bidouard JP, Lesage L, Recure H, Peglion JL. Antiischemic effects of ivabradine, a selective heart rate-reducing
agent, in exercise-induced myocardial ischemia in pigs. J Cardiovasc Pharmacol. 2003;42:688-696.
15. Du XJ, Feng X, Gao XM, Tan TP, Kirazis, Dart AM. If channel
inhibitor ivabradine lowers heart rate in mice with enhanced
sympathoadrenergic activities. Br J Pharmacol. 2004;142:107112.
16. Monnet X, Colin P, Ghaleh B, Hittinger L, Giudicelli JF,
Berdeaux A. Heart rate reduction during exercise-induced myocardial ischaemia and stunning. Eur Heart J. 2004;25:579-586.
17. Borer JS, Fox K, Jaillon P, Lerebours G. Ivabradine Investigators Group. Antianginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind,
multicentered, placebo-controlled trial. Circulation. 2003;107:
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18. Borer JS. Antianginal efficacy of the If inhibitor, Procoralan.
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19. Camm AJ. Electrophysiological assessment and clinical acceptability of Procoralan. Presentation at a Servier sponsored
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20. Tardif JC, Gregoire PL, Lallier PL, Joyal M. Chronic heart rate
reduction with ivabradine and prevention of atherosclerosis progression assessed using intravascular ultrasound. Eur Heart J.
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21. Danchin N. If current inhibition with ivabradine: further perspectives. Eur Heart J. 2003;5(suppl G):G52-G56.
22. Mulder P, Barbier S, Chagraoui A, et al. Long-term heart rate
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Conclusions
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IF
élévation de la fréquence cardiaque est associée à une augmentation du
risque d’évènements cardio-vasculaires. Certains médicaments peuvent
atténuer ce risque, c’est le cas, par exemple des bêtabloquants dans le
post-infarctus. Ces derniers ne sont pas cependant tolérés par tous les malades
et leur effet inotrope négatif peut même contribuer à leurs effets indésirables.
De ce fait, le développement de nouveaux inhibiteurs du nœud sinusal dont les
effets se limitent à la réduction de la fréquence cardiaque suscite un grand intérêt. L’un de ces agents bradycardisants spécifiques, l’ivabradine, est un inhibiteur sélectif du courant If qui est le courant pacemaker primaire du nœud
sino-auriculaire. Les effets anti-ischémiques et anti-angineux de l’ivabradine
sont bien documentés. Du fait de son effet chronotrope négatif qui s’exerce sans
que la contractilité soit altérée, ce médicament peut jouer un rôle important
dans le traitement de l’insuffisance cardiaque. Plusieurs études sont en cours
ou prévues pour étudier plus avant les propriétés de ce nouveau médicament.
L’
✦
55
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O N T R O V E R S I A L
Q
U E S T I O N
Does gender influence
the management of patients
with stable angina?
1
◆
R. Seabra-Gomes, Portugal
quick answer to this question could be:
it might, but… it shouldn’t. Women are
considered to be protected from coronary
artery disease (CAD) up to the age of menopause,
with a 10-year delay of onset of symptoms and
cardiovascular events compared with men. After
that age, the incidence of CAD in women is similar to that of men. Mortality is 2.5 to 4.5 times
lower in middle-aged women, but this difference
decreases in the elderly subjects.1 Great emphasis
has been placed over the past few years on the
misdiagnosis and undertreatment of CAD in women. In fact, the number of deaths, mostly due to
ischemic heart disease, has increased in women
in the past decade, and this trend could continue
due to the aging of the population and the epidemic-like incidence of obesity, metabolic syndrome, and diabetes, in women in particular.2
There is no reason to believe that the same risk
factors for CAD that are seen in men do not apply
to women. Smoking habits, hypertension, high
cholesterol, obesity, diabetes, metabolic syndrome,
stress, sedentary lifestyle, etc, affect both women
and men, and should all be taken into account
for cardiovascular prevention in women.3 The
real challenge is clinical diagnosis. Typical symptoms, such as chest discomfort or pain, are less
frequent and more difficult to interpret in women,
who also present with back and neck pain, indigestion, dizziness, fatigue, loss of appetite, or syncope. Our knowledge of the “female-pattern of
angina,” which is distinct from that seen in men,
is still incomplete, and this pattern may sometimes be confused with the most frequent comorbidities, particularly with increasing age.2 Clinical
decision-making is more difficult in women. In
a recent meta-analysis to detect CAD in women,
exercise testing (exercise ECG, thallium scintigraphy, and echocardiography) showed only moderate sensitivity and specificity for the diagnosis
of CAD.4 More often, even in a symptomatic woman, the coronary angiogram is considered normal.
This has led to the hypothesis that angina with
normal coronary arteries is a benign situation
and that CAD in women is a different disease, with
a more prominent microvascular component.2
However, 4-year risk-adjusted outcomes by extent of CAD in the Women’s Ischemia Syndrome
Evaluation (WISE) study 5 showed that there was
A
Ricardo SEABRA-GOMES
MD, PhD
Istituto do Coração
Av. Prof Reinaldo
dos Santos 27, 2795-563
Carnaxide
PORTUGAL
(e-mail:
[email protected])
56
a 9.4% death or myocardial infarction (MI) rate
(or about 2.7% annually) in the subgroup with
no or minimal disease on angiography. In an intravascular ultrasound (IVUS) substudy, >80%
of women with so-called “normal angiograms”
had plaque lesions and multiple lesions,2 and in
a cohort that underwent acetylcholine coronary
artery reactivity testing, women who failed to dilate had more cardiovascular events over followup, regardless of CAD severity.6 Women have ultimately poorer outcomes if they have CAD, with
1-year mortality rate about 1.5 times greater than
in men. However, most differences in mortality
for acute coronary syndromes or revascularization procedures are due to comorbid conditions
and advanced age. If we all become aware that
the risk of CAD in women is as important as in
men, if we pay more attention to symptoms and
noninvasive as well as invasive test findings, and
if we consider that both revascularization strategies (percutaneous coronary intervention [PCI]
or coronary artery bypass grafting [CABG])
should have the same indications irrespective of
gender, prognosis in women would be the same
as in men, paying special attention to the differences in comorbidities. Medical treatment remains the cornerstone of the management of stable angina. Once CAD is suspected or diagnosed,
symptoms should be treated with the established
pharmacological therapies available. According
to the individual patient’s needs and tolerance,
nitrates (I find the short-acting nitrates particularly useful for clinical diagnosis of angina-like
symptoms), -blockers, and calcium antagonists
should be used for angina, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin
receptor blockers (ARBs) (for those who are intolerant to the former) to block the multiple
deleterious effects of angiotensin II. In the EUropean trial on Reduction Of cardiac events with
Perindopril in stable coronary Artery disease
(EUROPA) trial, perindopril was equally effective
in women in reducing cardiovascular death, acute
myocardial infarction, and cardiac arrest.7 Antiplatelet therapy as well as statins should always
be part of the medical regimen. Special attention
should be paid to adequate and concomitant
control of high blood pressure (more difficult in
women), type 2 diabetes, depression, musculo-
Does gender influence the management of patients with stable angina?
CO
N T R O V E R S I A L
skeletal diseases, irritable bowel syndrome, etc.
The role of hormone replacement therapy (HRT)
for postmenopausal women seems to have been
definitively questioned and should not be used
to reduce the risk of CAD events.8 With progressively more research being performed in women, in relation to the atherosclerotic plaque, in-
flammation in the vessel wall, prognostic value
of blood markers, and the role of the microvasculature, it is increasingly clear that the management of CAD should be similar irrespective
of gender, with differences in outcomes related
to the most frequent comorbid conditions in
women. ❒
REFERENCES
1. Barrett-Connor E. Sex Differences in coronary heart disease: why are women so superior? The 1995 Ancel Keys Lecture. Circulation. 1997;95:252-264.
2. Pepine CJ. Ischemic heart disease in women: facts and
wishful thinking. J Am Coll Cardiol. 2004;43:1727-1730.
3. AHA Guidelines. Evidence-Based guidelines for cardiovascular
disease prevention in women. Circulation. 2004;109:672-693.
4. Kwok Y, Kim C, Grady D, et al. Meta-analysis of exercise
testing to detect coronary artery disease in women. Am J
Cardiol. 1999;83:660-666.
5. Sharaf BL, Shaw L, Johnson BD, et al. Any measurable
coronary artery disease identified in women presenting with
ischemic chest pain is associated with an adverse outcome.
J Am Coll Cardiol. 2004;43(suppl A):292A.
6. von Mering GO, Arant CB, Wessel TR, et al. Abnormal
coronary vasomotion as a prognostic indicator of cardiovascular events in women. Circulation. 2004;109:722-725.
7. The EUropean trial on Reduction of cardiac events with
Perindopril in stable coronary Artery disease Investigators.
Efficacy of perindopril in reduction of cardiovascular events
among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled multicentre trial
(the EUROPA study). Lancet. 2003;362:782-788.
8. Grady D, Herrington D, Bittner V, et al. Cardiovascular
Disease outcomes during 6.8 years of hormone therapy. JAMA.
2002;288:49-57.
2
◆
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E S T I O N
D. Y. Hu and J. G. Yang, PR China
hronic angina pectoris has detrimental effects on health-related quality of life, particularly in women.1 Research into gender
difference in chronic angina pectoris suggests
that women report greater functional disability
related to angina symptoms.2,3 Clinical factors
among women contributing to these gender differences include a delayed onset of disease, a
tendency to present at an older age, and a higher
prevalence of comorbidities at the time of presentation.4-6 Data from the Framingham study
showed that angina pectoris is a more common
clinical syndrome in women, contrasted with
myocardial infarction (MI) and sudden cardiac
death in men.4 This discrepancy may in part be
due to an increased rate of atypical symptoms of
angina pectoris in women compared with men.7,8
However, more women than men with chest pain
clinically indistinguishable from angina have
normal coronary arteries at arteriography.9-12 In
the CASS Registry, 50% of women compared with
17% of men with a clinical history compatible
with angina pectoris had no significant obstructive coronary artery disease (CAD).9 However, a
majority of women without obstructive CAD at
coronary angiography continue to have symptom-related disability and consume considerable
health care resources,13-16 in part because the
pathophysiology of ischemia in women is incompletely understood and gender-specific diagnostic and treatment strategies are underdeveloped.
Therefore, women may be undertreated with effective therapies or often referred for care later
than men, when their clinical status is more advanced. The higher risk of adverse outcomes associated with myocardial revascularization in
women may be due to their greater likelihood of
having severe disease.17 Whereas comorbid clinical
conditions are known to contribute to the higher
morbidity and mortality among women follow-
C
▲
Dayi HU, MD,
Jingang YANG, MD, PhD
Cardiovascular Center
Tongren Hospital, Capital
University of Medical Sciences
No. 2 Chong Nei Street
Dong Cheng District
Beijing
PR CHINA
ing revascularization procedures, adjustments for
age and other comorbid factors do not necessarily
eliminate differences in outcome.18-20 Women in
a number of reports about coronary artery bypass
graft (CABG) surgery also had lower rates of graft
patency, were less likely to receive an internal
mammary artery graft at CABG surgery, had
more frequent perioperative MI and heart failure,
less postoperative symptomatic relief, and were
more likely to require reoperation with the initial 5 years following CABG surgery.21 The major
risk appeared to be perioperative in that, at 15
years, survival following the operative hospitalization was comparable for women and men. Because the rates of risk reduction are similar in
treated men and women, there is no empiric evidence supporting different pharmacologic treatments based on gender. A cross-sectional survey
of the management of CHD in general practice
in the United Kingdom showed gender inequalities.22 Women were more likely to be obese and
have the last recorded blood pressures and serum
cholesterol values above recommended levels.
Men were more likely to take aspirin, have a
recorded diagnosis of hyperlipidemia, and be prescribed lipid-lowering drugs. Traditionally, significant coronary narrowing can be demonstrated
on angiography in patients with stable angina.
The Women’s Ischemic Syndrome Evaluation
(WISE) study showed that both men and women
have variable thresholds for ischemia and symptoms that may be typical or atypical of angina
pectoris. The pathophysiology of this variability,
as well as of ischemia without flow-limiting
stenoses, has now been confirmed to be due to
dynamic changes in coronary size that also include the microcirculation.16 These findings often
involve dysfunctional endothelium and have the
potential to limit flow, causing ischemia and related symptoms that may be somewhat different
57
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(eg, lesser in magnitude, limited to subendocardium, patchy distribution, prolonged duration)
from those seen with a large-vessel obstruction.23
Endothelial dysfunction has been linked to oxidative stress resulting from many atherosclerosis
risk factor conditions, particularly hypertension,
diabetes, and dyslipidemia,24 which are prevalent
in women. In summary, differences between the
treatments of stable angina in women compared
with men may exist. Improved understanding of
pathophysiology in women is helpful to explain
this difference. ❒
REFERENCES
1. Kimble LP, Kunik CL. Knowledge and use of sublingual
nitroglycerin and cardiac-related quality of life in patients with
chronic stable angina. J Pain Symptom Manage. 2000;19:
109-117.
2. Steingart RM, Packer M, Hamm P, et al. Sex differences in
the management of coronary artery disease. Survival and
Ventricular Enlargement Investigators. N Engl J Med. 1991;
325:226-230.
3. Pinsky JL, Jette AM, Branch LG, et al. The Framingham
Disability Study: relationship of various coronary heart disease manifestations to disability in older persons living in the
community. Am J Public Health. 1990;80:1363-1367.
4. Lerner DJ, Kannel WB. Patterns of coronary artery disease
morbidity and mortality in sexes: a 26-year follow-up of the
Framingham population. Am Heart J. 1986;111:383-390.
5. Wingard DL, Cohn BA, Kaplan GA, et al. Sex differentials
in morbidity and mortality risks examined by age and cause
in the same cohort. Am J Epidemiol. 1989;130:601-610.
6. Wenger NO. Gender, coronary artery disease, and coronary
bypass surgery. Ann Intern Med. 1990;112:557-558.
7. Goldberg RJ, O'Donnell C, Yarzebski J, et al. Sex differences
in symptom presentation associated with acute myocardial
infarction: a population-based perspective. Am Heart J. 1998;
136:189-195.
8. Pengue S, Halm M, Smith M. Women and coronary disease: Relationship between descriptors of signs and symptoms
and diagnostic and treatment course. Am J Crit Care. 1998;
7:175-182.
9. Principal Investigators of CASS and Their Associates. The
National Heart, Lung, and Blood Institute Coronary Artery
Surgery Study (CASS). Circulation. 1981;63:I1-I81.
10. Kennedy JW, Killip T, Fisher LD, et al. The clinical spectrum of coronary artery disease and its surgical and medical
management, 1974-1979: the Coronary Artery Surgery Study.
Circulation. 1982;66:III16-III23.
11. Thomas JL, Braus PA. Coronary artery disease in women:
a historical perspective. Arch Intern Med. 1998;158: 333-337.
12. Sharaf BL, Pepine CJ, Kerensky RA, et al. Detailed angiographic analysis of women with suspected ischemic chest
pain (pilot phase data from the NHLBI-sponsored Women
Ischemia Syndrome Evaluation [WISE] Study Angiographic
Core Laboratory). Am J Cardiol. 2001;87:937-941.
13. Romeo F, Rosano GM, Martuscelli E, et al. Long-term fol-
low-up of patients initially diagnosed with syndrome X. Am J
Cardiol. 1993;71:669-673.
14. Sullivan AK, Holdright DR, Wright CA, et al. Chest pain in
women: clinical, investigative, and prognostic features. BMJ.
1994;308:883-886.
15. Kaski JC, Rosano GM, Collins P, et al. Cardiac syndrome
X: clinical characteristics and left ventricular function. Longterm follow-up study. Am Coll Cardiol. 1995;25:807-814.
16. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal
subendocardial perfusion in cardiac syndrome X detected by
cardiovascular magnetic resonance imaging. N Engl J Med.
2002;346:1948-1953.
17. Jacobs AK, Kelsey SF, Brooks MM, et al. Better outcome
for women compared with men undergoing coronary revascularization: a report from the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1998;98:1279-1285.
18. Kelsey SF, James M, Holubkov R, et al. Results of percutaneous transluminal coronary angioplasty in women. 19851986 National Heart, lung, and blood Institute’s Coronary
Angioplasty Registry. Circulation. 1985;87:720-727.
19. Bell MR, Holmes DR, Berger PB, et al. The changing inhospital mortality of women undergoing percutaneous transluminal coronary angioplasty. JAMA. 1993;269:2091-2095.
20. Weintraub WS, Wenger NK, Kosinski AS, et al. Percutaneous transluminal coronary angioplasty in women compared
with men. J Am Coll Cardiol. 1994;24:81-90.
21. O’Connor GT, Morton JR, Diehl MJ, et al. Northern New
England Cardiovascular Disease Study Group. Differences between men and women in hospital mortality associated with
coronary artery bypass graft surgery. Circulation. 1993;88:
2104-2110.
22. Hippisley-Cox J, Pringle M, Crown N, et al. Sex inequalities
in ischaemic heart disease in general practice: Cross sectional
survey. BMJ. 2001;322:832-834.
23. Redberg RF, Cannon RO 3rd, Bairey Merz N, et al. Women’s
Ischemic Syndrome Evaluation: current status and future research directions: report of the National Heart, Lung and Blood
Institute workshop: October 2-4, 2002: Section 2: stable ischemia: pathophysiology and gender differences. Circulation.
2004;109:e47-e49.
24. Quyyumi AA. Endothelial function in health and disease:
new insights into the genesis of cardiovascular disease. Am J
Med. 1998;105:32S-39S.
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J. López-Sendón, Spain
t has been repeatedly documented that women with ischemic heart disease are investigated and treated less aggressively than men,1,2
although these differences have not been demonstrated in all studies.3,4 Women with ischemic
heart disease present the same complications as
men and their prognosis is similar or even worse
that that of men. Reasons for this possible bias
have been a matter of controversy and clear recommendations have been made to improve the
management of women with ischemic heart disease.5,6 Although this possible bias has been studied in different settings, including unstable angina, acute myocardial infarction, and chronic
stable ischemic heart disease, very little information has been obtained in clinical trials and
registries specifically focusing on patients with
stable angina.
I
José LÓPEZ-SENDÓN,
MD, FESC, FACC
Associate Professor
of Medicine, Universidad
Complutense, Madrid
and Chief, Coronary Care
Unit, Hospital Universitario
Gregorio Marañón
Doctor Esquerdo 4628007
Madrid, SPAIN
Is there evidence for gender bias in stable
angina?
One of the few registries in patients with stable
angina addressing this problem is the Euro Heart
Survey on Stable Angina (EuroHS-SA), recently
presented during the last Congress of the European Society of Cardiology in Munich.7 In this
multicenter survey, a total of 3900 patients, 42%
women, were enrolled in 197 centers from 27
countries. Exercise stress testing and coronary
angiography were less frequently performed in
women than in men, and this difference was significant after adjusting for confounding factors
such as age and functional class. Coronary angiography was less frequently used in women even
after adjusting for the results of the exercise stress
test. Treatment used in men and women was also
different. Women received less frequently coronary revascularization and evidence-based-therapy, including antiplatelet and lipid-lowering
drugs, but, on average, women received a greater
number of antianginal medications.
REFERENCES
1. Kostis JB, Wilson AC, O’Dowd K, et al. Sex differences in
the management and long-term outcome of acute myocardial
infarction. A statewide study. Circulation. 1994;90:1717-1730
2. Bell MR, Berger PB, Holmes DR Jr, Mullany CJ, Bailey KR,
Gersh BJ. Referral for coronary artery revascularization procedures after diagnostic coronary angiography: evidence for
gender bias? J Am Coll Cardiol. 1995;25:1650-1655.
3. Roeters van Lennep JE, Zwinderman AH, Roeters van Lennep
HW. Gender differences in diagnosis and treatment of coronary
artery disease from 1981 to 1997. No evidence for the Yentl
syndrome. Eur Heart J. 2000;21:911-918.
4. Bowker TJ, Turner RM, Wood DA, et al. A national Survey
of Acute Myocardial Infarction and Ischaemia (SAMII) in the
UK: characteristics, management and in-hospital outcome
in women compared to men in patients under 70 years. Eur
Heart J. 200021:1458-1463.
5. Antman E, Anbe DT, Armstrong PW, et al for the Task Force
on Practical Guidelines. ACC/AHA Guidelines for the management of patients with ST-elevation myocardial infarction.
A report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines. http://
Does the different management have an
impact on outcome?
This is a difficult question that could not be properly answered only with the analysis of data
from the limited number of patients included in
the few registries of stable angina. Again, in the
EuroHS-SA, 1-year outcome was similar in the
overall study population of men and women, but
women with stable angina and demonstrated
coronary artery disease presented a higher 1-year
mortality (odds ratio [OR] 1.5), almost double
prevalence of myocardial infarction, and were
less likely to report a complete control of angina
symptoms than men. These findings highlight
the importance of secondary prevention and treatment according to guidelines.
Why a gender bias?
A conscious bias is difficult to accept. Perception
of a milder disease in women (by the physician
and the patient herself), the more difficult clinical
diagnosis due to different symptoms, the older
age at symptoms presentation, and maybe lesser therapy compliance could in part explain the
differences. However, at present, there is no clear
explanation for the gender bias observed in patients with stable angina.
What can we do?
The diagnosis of coronary heart disease and its
appropriate treatment may be more difficult in
women presenting with chest pain, but this does
not justify improper diagnosis and should not prevent appropriate treatment. The causes of chest
pain should be investigated regardless of gender,
secondary prevention counseling should be given
according to guidelines,8 and treatment should
be carefully monitored for efficacy to control ischemia. Finally, clinical research should be conducted for a better understanding of the possible
reasons to explain the inappropriate treatment
offered to women with stable angina and ischemic
heart disease in general. ❒
www.americanheart.org/. Accessed 15 October 2004.
6. Braunwald E, Antman EM, Beasley JW, , et al for the task
force on practical guidelines. ACC/AHA guideline update for
the management of patients with unstable angina and non–
ST-segment elevation myocardial infarction. A report of the
American College of Cardiology/American Heart Association
task force on practice guidelines (committee on the management of patients with unstable angina). http://www.americanheart.org/. Accessed 15 October 2004.
7. Daly C. How Do Patients With Newly Presenting Stable
Angina Do in 2003? Results From the Euroheart Survey on
Stable Angina. Munich, Germany. European Congress of Cardiology. 31 August 2004.
8. Wood D, De Backer G, Faergeman O, et al for the Second
Joint Task Force of European and other Societies on Coronary
Prevention: European Society of Cardiology, European Atherosclerosis Society, European Society of Hypertension, International Society of Behavioural Medicine, European Society of
General Practice/Family Medicine, European Network. Prevention of coronary heart disease in clinical practice. Eur
Heart J. 1998;19:1434-1503.
59
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R. Y. Kassab, Lebanon
espite recent advances in the management of coronary atherosclerosis, coronary
artery disease (CAD) remains the first
cause of mortality in women in the USA and the
developed countries; it accounts for more than a
quarter of a million deaths each year in the USA.1
The mortality rate in women after the first myocardial infarction is higher than in men,2 because
of their more advanced age when the disease occurs, a higher prevalence of coronary risk factors
and other associated comorbidities, as well as the
smaller size and the higher tortuosity of their
coronary arteries. In addition, women with acute
coronary syndromes are less likely to benefit from
cardiac procedures and new treatments.3,4 Most
guidelines for the treatment of chronic stable
angina do not include specific gender-related
management.5 The class I pharmacotherapy to
prevent myocardial infarction and death and to
reduce symptoms, includes aspirin, -blockers,
long-acting nitrates, calcium antagonists (excluding short-acting dihydropyridines), angiotensinconverting enzyme (ACE) inhibitors in case of
diabetes and/or left ventricular (LV) dysfunction,
and statins if low-density lipoprotein (LDL) cholesterol is greater than 130 mg/dL, irrespective of
gender. While the use of -blockers is sometimes
limited in young and middle-aged men because
of sexual dysfunction, they should be widely prescribed in women in whom this problem does not
occur. Clopidogrel could be an alternative choice
when aspirin is contraindicated (class IIa). The
recommendations for treatment of risk factors,
as a preventive measure, are also identical in
both sexes regarding the treatment of hypertension (according to the JNC 7 guidelines), diabetes
and dyslipidemia, smoking cessation, weight reduction, and appropriate physical activity.6 Hormonal replacement therapy should be used with
care in postmenopausal women as it has been associated in many cases with increased morbidity.7,8
Class I recommendations for revascularization
with percutaneous coronary intervention (PCI) or
surgery (coronary artery bypass grafting [CABG])
are also similar in both sexes 5: CABG is recommended for patients with significant left main
coronary disease, 3-vessel disease mainly with abnormal LV function, 2-vessel disease with significant proximal left anterior descending coronary
artery (LAD) and either abnormal LV function or
demonstrable ischemia; either CABG or PCI can
be performed for patients with 1- or 2-vessel disease without involvement of proximal LAD, but
with a large area of viable myocardium, prior PCI
and recurrent stenosis with viable myocardium,
and in case of unsuccessful medical treatment
with acceptable risk. In contrast, PCI alone is recommended for patients with 2- or 3-vessel disease
with significant proximal LAD and suitable anatomy, normal LV function and no treated diabetes.
Women are less likely to be referred for cardiac
catheterization,9 but the rate of coronary revascularization (PCI, CABG) in stable angina seems
to be the same as in men during the year after
catheterization, and appears to reflect appropriate clinical decisions.10 Despite the fact that diabetes, hypertension, and hypercholesterolemia
are more frequent in women with CAD, hospital
mortality of CABG is not significantly different
from men,11 except for younger women who seem
to be at a higher risk of in-hospital death.12 On
the other hand, off-pump CABG surgery may be
better for women regarding the reduction of mortality, respiratory complications, and length-ofstay.13 Nevertheless, their outcome seems to be
impaired after emergency CABG for failed PTCA.14
Concerning PCI, the old data from the Nationwide Inpatient Sample confirm that female gender
is an independent predictor of short-term mortality and CABG after the procedure.15 However, after
the introduction of new stents with a lower profile and a higher tractability, the outcome has improved in women and became similar to men in
more recent trials.16,17 Some controversy remains,
however, regarding angiographic restenosis after
stent implantation,18,19 with a strong impact of
diabetes in most of the trials. Finally, when we
compare CABG versus stenting for angina pectoris
in women with multivessel disease in the Stent
or Surgery (SoS) trial, both procedures appear
equally effective after 1 year, although CABG was
superior at 6 months.20 In conclusion, due to
pathological comorbidities and unfavorable coronary anatomy, women with stable angina should
be treated aggressively, either medically or surgically or by PCI. Comparatively to men, the diagnosis of CAD should be improved, and genderbased educational strategies and evidence-based
guidelines for the treatment and the prevention
of the disease should be implemented.21,22 ❒
REFERENCES
1. American Heart Association. Heart Disease and Stroke
Statistics – 2003 Update. Dallas, Tex: American Heart Association; 2002.
2. Coronado BE, Griffith JL, Beshansky JR, et al. Hospital
mortality in women and men with acute cardiac ischemia:
a prospective multicenter study. J Am Coll Cardiol. 1997;29:
1490-1496.
3. Maynard C, Beshansky JR, Griffith JL, et al. Influence of
sex on the use of cardiac procedures in patients presenting to
the emergency department: a prospective multicenter study.
Circulation. 1996;94(suppl. 9):II93-II98.
4. Roger VL, Farkouh ME, Weston SA, et al. Sex differences
in the evaluation and outcome of unstable angina. JAMA.
2000;283:646-652.
5. ACC/AHA 2002 Guideline Update for the Management of
Patients With Chronic Stable Angina. J Am Coll Cardiol. 2003;
41:159-168.
6. Lee IM, Rexrode KM, Cook NR, Manson JE, Buring JE. Physical activity and coronary heart disease in women. JAMA.
2001;285:1447-1454.
7. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart
disease in post-menopausal women: Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA.
1998;280:605-613.
8. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone
D
Roland Y. KASSAB
Associate Professor of
Medicine, St-Joseph
University, and Head of
Division of Cardiology
at Hôtel-Dieu de France
Hospital, Adib Ishaac Street
Beirut
LEBANON
(e-mail:
[email protected])
60
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replacement therapy and antioxydant vitamin supplements on
coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002; 288: 2432-2440.
9. Schulman KA, Berlin JA, Harless W, et al. The effect of race
and sex on physicians’ recommendations for cardiac catheterization. N Engl J Med. 1999;340:618-626.
10. Ghali WA, Faris PD, Galbraith PD, et al. Sex differences
in access to coronary revascularization after cardiac catheterization: importance of detailed clinical data. Ann Intern Med.
2002;136:723-732.
11. Huang CH, Hsu CP, Lai ST, Weng ZC, Tsao NW, Tsai TH.
Operative results of coronary artery bypass grafting in women.
Int J Cardiol. 2004;94:61-66.
12. Vaccarino V, Abramson JL, Veledar E, Weintraub WS. Sex
differences in hospital mortality after coronary artery bypass
surgery: evidence for a higher mortality in younger women.
Circulation. 2002;105:1176-1181.
13. Brown PP, Mack MJ, Simon AW, et al. Outcomes experience with off-pump coronary artery bypass surgery in women.
Ann Thorac Surg. 2002;74:2113-2119.
14. Reinecke H, Roeder N, Schmid C, et al. Outcomes of women is impaired in patients undergoing emergency coronary
artery bypass grafting for failed PTCA. Z Kardiol. 2001;90:
729-736.
15. Watanabe CT, Maynard C, Ritchie JL. Comparison of shortterm outcomes following coronary artery stenting in men
5
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E S T I O N
versus women. Am J Cardiol. 2001;88:848-852.
16. Trabattoni D, Bartorelli AL, Montorsi P, et al. Comparison
of outcomes in women and men treated with coronary stent
implantation. Catheter Cardiovasc Interv. 2003;58:20-28.
17. Presbitero P, Carcagni A. Gender differences in the outcome of interventional cardiac procedures. Ital Heart J. 2003;
4:522-527.
18. Mehilli J, Kastrati A, Dirschinger J, Bollwein H, Neumann
FJ, Schomig A. Differences in prognostic factors and outcomes between women and men undergoing coronary artery
stenting. JAMA. 2000;284:1799-1805.
19. Mehilli J, Kastrati A, Bollwein H, et al. Gender and restenosis
after coronary artery stenting. Eur Heart J. 2003;24:1523-1530.
20. Zhang Z, Weintraub WS, Mahoney EM, et al. Relative
benefit of coronary artery bypass grafting versus stent-assisted
percutaneous coronary intervention for angina pectoris and
multivessel coronary disease in women versus men (one-year
results from the Stent or Surgery trial). Am J Cardiol. 2004;
93:404-409.
21. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based
guidelines for cardiovascular disease prevention in women.
AHA Guidelines. Circulation. 2004;109:672-693.
22. Merz NB, Bonow RO, Sopko G, et al. Women’s ischemic
syndrome evaluation. Current status and future research directions. AHA/NHLBI conference proceedings. Circulation.
2004;109:805-807.
P. Erne and D. Radovanovic, Switzerland
ender differences and their diagnostic relevance are well recognized in angina,
notably with regard to nausea, back pain,
and response to effort. But how does gender impact the management of stable angina? Coronary
artery disease (CAD) is the leading killer of women. Prevention guidelines were updated in 2004.1
Female gender is protective, conferring lower agespecific incidence rates than in men. But CAD
kills as many women as men: onset may be deferred by 10 years, but women’s eventual prognosis is poorer.2 Gender has little influence on the
relative importance of risk factors, and none in
primary prevention, whether regarding risk factor
management or lifestyle changes.3 Clinical assessment can be accurate in diagnosing significant obstructive CAD. However, women experience
angina differently from men, reporting greater
pain intensity and physical limitation, although
scoring similarly in total sensory or affective intensity.4 Noninvasive risk stratification is less accurate in women: not only does estrogen increase
the false positive rate of stress electrocardiography (ECG), but because stress ECG has only 50%
to 57% sensitivity in postmenopausal women,
stress echocardiography or myocardial scintigraphy are preferable investigations. Absence of
ST-segment deviation on ambulatory monitoring
has a higher negative predictive value in women,
although prognostic values do not differ.5 Coronary angiography is needed for accurate assessment: it excludes obstructive CAD in 20% to 40%
of women, as well as angina caused by microvascular dysfunction and the abnormal coronary
flow reserve caused by higher values in the follicular phase and acute postmenopausal estrogen
G
▲
Paul ERNE, MD
Dragana RADOVANOVIC, MD
Division of Cardiology
Kantonsspital Luzern
CH 6000 Luzern 16
and AMIS Plus Data Center
Institute of Social and
Preventive Medicine
University of Zurich
CH 8006
SWITZERLAND
administration.6 Women are at lower risk of sudden death and episodes of ventricular tachycardia
or fibrillation, but have higher resting heart rates.
They are at higher risk of QT-interval prolongation and torsades de pointes, probably due to
gender differences in ion channels and a greater
susceptibility to QT-prolonging drugs.7 Atrial fibrillation is less common in women. Estrogen does
not affect the QT interval in healthy women, but
decreases QT dispersion, perhaps explaining the
gender difference in susceptibility to ventricular
arrhythmia. The diagnosis and treatment of stable
angina are similar in both sexes, as recent guidelines show.8 However, management may be more
difficult in women: thrombolysis involves more
hemorrhage in older smaller women, and angioplasty and bypass carry greater risks. Blood viscosity may not be an independent risk factor, but
could be a marker of CAD. Women with symptomatic disease have more thromboembolic complications than men, and their platelets bind
more fibrinogen molecules, meaning that they
may require stronger and more specific platelet
inhibitors 9; aspirin resistance rates (20% at rest
and 22% during exercise) are gender-independent. Prothrombin fragment F1+2, a marker for
thrombin generation, is higher in hyperlipidemic
women than men, but responds to statins in both
sexes, as do C-reactive protein, fibrinopeptide A,
D dimer, and factor VIIa.10 Statins lower major
CAD events by ≈30% regardless of sex.11 Estrogen
enhances vasoreactivity and glucose tolerance,
while decreasing atherosclerosis, hemostasis, and
lipid and lipoprotein levels. In postmenopausal
women, it lowers low-density lipoprotein (LDL)
cholesterol, raises high-density lipoprotein (HDL)
61
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cholesterol, and lowers some coagulation factors
(fibrinogen) while increasing others (factor VII).
In observational studies, eg, the Nurses’ Health
Study and Uppsala Study, hormone replacement
therapy (HRT) lowered CAD risk. But prospective
trials, eg, the Women’s Health Initiative (WHI)12
and the Heart and Estrogen/Progestin Replacement Study (HERS),13 failed to confirm benefit,
while an initial mid-term decreased risk failed to
persist at follow-up despite a 35% reduction in
diabetes. HRT also conferred no benefit on atherosclerosis progression in angiographic CAD.14
Women have higher levels of glutathione peroxidase 1, one of several cellular antioxidant enzymes that may protect against atherosclerosis.15
However, antioxidant vitamin supplementation
combined with HRT had no benefit in postmenopausal women.16 Androgens may play an underestimated role in this regard, since hypoandrogenemia in men and hyperandrogenemia in
women are associated with increased CAD; androgens also upregulate atherosclerosis-related
genes in macrophages from males but not females. Estrogen receptor polymorphism is another factor accounting for the positive effects of
estrogens in certain subgroups: the ER.alpha
IVS1-401 C/C genotype is associated with an
increased HDL response to estrogen,17 and the
ESR 1c.454-397 C/C genotype with an increased
risk of infarction. Specific polymorphisms in eight
genes are associated with a metabolic syndrome,
with some gene associations being sex-specific.
Sex bias affects some aspects of CAD management. Women are less likely to receive aspirin or
aggressive lipid-lowering medication for secondary prevention in the primary care setting, but
there is no bias in assessment and treatment by
cardiologists or in revascularization rates.18 In
very young women, percutaneous revascularization is followed by much higher rates of vascular
complications, 1-year mortality, and q-wave infarction than in men.19 Bypass surgery is associated with more difficult recovery in women, independently of disease severity or prior health
status; in women with angina, surgery is equal
in efficacy to percutaneous stent-assisted intervention, while appearing superior in men with
multivessel disease. Overall, women with CAD
have a worse health-related quality of life outcome than men and a worse prognosis.20 Thus,
women need aggressive primary and secondary
prevention, together with appropriate prophylaxis
for subgroups with unfavorable left ventricular
hypertrophy. ❒
REFERENCES
1. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based
guidelines for cardiovascular disease prevention in women.
Circulation. 2004;109:672-693.
2. Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM,
for National Registry of Myocardial Infarction 2 Participants.
Sex-based differences in early mortality after myocardial
infarction. N Engl J Med. 1999;341:217-225.
3. Wegge JK, Roberts CK, Ngo TH, Barnard RJ. Effect of diet
and exercise intervention on inflammatory and adhesion
molecules in postmenopausal women on hormone replacement therapy and at risk for coronary artery disease. Metabolism. 2004;53:377-381.
4. Kimble LP, McGuire DB, Dunbar SB, Fazio S, De A, Weintraub WS, Strickland OS. Gender differences in pain characteristics of chronic stable angina and perceived physical limitation in patients with coronary artery disease. Pain. 2003;
101:45-53.
5. Nair CK, Khan JA, Mehta NJ, Ryschon KL, Nair RC. Gender
significance of ST-segment deviation detected by ambulatory
(Holter) monitoring. Int J Cardiol. 2004;95:153-157.
6. Hirata K, Shimada K, Watanabe H, et al. Modulation of
coronary flow velocity reserve by gender, menstrual cycle and
hormone replacement therapy. J Am Coll Cardiol. 2001;38:
1879-1884.
7. Peters RW, Gold MR. The influence of gender on arrhythmias. Cardiol Rev. 2004;12:97-105.
8. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002
guideline update for the management of patients with chronic
stable angina—summary article: a report of the American
College of Cardiology/American Heart Association Task Force
on Practice guidelines (Committee on the Management of
Patients with Chronic Stable Angina). Circulation. 2003;107:
149-158.
9. Goldschmidt-Clermont PJ, Schulman SP, Bray PF, et al.
Refining the treatment of women with unstable angina—
a randomized, double-blind, comparative safety and efficacy
evaluation of integrelin versus aspirin in the management of
unstable angina. Clin Cardiol. 1996;19:896-874.
10. Dangas G, Smith DA, Badimon JJ, et al. Gender differences in blood thrombogenicity in hyperlipidemic patients
and response to pravastatin. Am J Cardiol. 1999;84:639-643.
11. LaRosa JC. Understanding risk in hypercholesterolemia.
Clin Cardiol. 2003;26(suppl 1):3-6.
12. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al.
Effect of estrogen plus progestin on stroke in postmenopausal
women: the Women’s Health Initiative: a randomized trial.
JAMA. 2003;289:2673-2684.
13. Simon JA, Hsia J, Cauley JA, et al. Postmenopausal hormone
therapy and risk of stroke: The Heart and Estrogen-Progestin
Replacement Study (HERS). Circulation. 2001;103:638-642.
14. Hodis HN, Mack WJ, Azen SP, et al. Hormone therapy and
the progression of coronary artery atherosclerosis in postmenopausal women. N Engl J Med. 2003;349:535-545.
15. Blankenberg S, Rupprecht HJ, Bickel C, et al. Glutathione
peroxidase 1 activity and cardiovascular events in patients with
coronary artery disease. N Engl J Med. 2003;349:1605-1613.
16. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone
replacement therapy and antioxidant vitamin supplements on
coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002;288:2432-2440.
17. Herrington DM, Howard TD, Hawkins GA, et al. Estrogenreceptor polymorphisms and effects of estrogen replacement
on high density lipoprotein cholesterol in women with coronary artery disease. N Engl J Med. 2002;346:967-974.
18. Ghali WA, Faris PD, Galbraith PD et al. Sex differences in
access to coronary revascularization after cardiac catheterization: importance of detailed clinical data. Ann Intern Med.
2002;136:723-732.
19. Lansky AJ, Mehran R, Dangas G, et al. Comparison of differences in outcome after percutaneous coronary intervention
in men versus women <40 years of age. Am J Cardiol. 2004;93:
916-919.
20. Norris CM, Ghali WA, Galbraith PD, Graham MM, Jensen
LA, Knudtson ML. Women with coronary artery disease report
worse health-related quality of life outcomes compared to men.
Health Qual Life Outcomes. 2004;5:21.
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C. A. Bertolasi, Argentina
n one word, the answer is “yes.” However, it
is of greater interest to discuss the origin of
the difference. In my opinion, this is due to a
series of facts and fancies. Until a few years ago,
there was a broad consensus that coronary artery
disease (CAD) had a lower incidence and carried
a lesser risk in women than in men. It is true
that CAD takes longer to appear in women (by
approximately 10 years), but its incidence rapidly
increases up until the age of 50 or 60 years, leveling off with men at age 75. Increased smoking
and use of contraceptives over recent decades,
together with an increased incidence of obesity
and the metabolic syndrome, have favored an
earlier appearance of the disease. In the world’s
underdeveloped populations (more than 70% of
humanity), there has been a decline in infant and
juvenile mortality, and therefore more persons
reach vulnerable ages for CAD. Improvements in
factors such as malnutrition, the poor quality of
water, the lack of sanitary and hygiene facilities,
unsafe sex, and maternal and prenatal diseases
have contributed to that achievement. It should
also be recalled that myocardial ischemia symptoms in women are sometimes less characteristic
than in men (back pain, nausea, fatigue, or abdominal pain, more prolonged angina crisis and
a variable relationship with effort), thus making
the initial diagnosis more difficult. As mentioned
above, it was also thought that CAD carried a
lesser risk in women. The initial manifestation of
CAD in women is more often angina than acute
myocardial infarction or sudden death. Furthermore, precordial pain in women may be due to
various pathophysiological mechanisms not always linked to coronary atherosclerotic obstruction. For example, in women under 55, the association of angina and normal coronary arteries is
more frequent. This difference may be explained
by a range of disorders such as microcirculatory
disorders, vasospasm, alterations in the threshold
of pain, mitral valve prolapse, myocardiopathies,
panic attacks, costal chondritis, gastroesophageal
reflexes, and many other less frequent causes
(such as atrioventricular fistulae). We have also
observed hypochondriacs with totally atypical
syndromes who after two or three medical consultations “learn” to report the classic syndrome. A
well-directed interrogation is sufficient to put an
end to the apparent illness. Other gender-related
differences include the increase in smoking in
women and a greater difficulty for them to quit
the habit, and a greater difficulty to include wom-
I
Carlos A. BERTOLASI, MD
Miembro de Número
Academia Nacional de
Medicina, Consejo de
Investigación de la Ciudad
de Buenos Aires, Comité
de Ética Médica Institutos
de la Academia Nacional de
Medicina, Avda. del Libertador
2476 – 8°p. (1425), Ciudad de
Buenos Aires, ARGENTINA
(e-mail:
[email protected])
en in long-term exercise programs. Another factor
directly linked with gender is hormonal replacement therapy (HRT). The benefits of HRT (eg,
decrease in incidence of hip fracture and colorectal cancer), should be balanced against the increased risk of stroke, pulmonary embolism,
breast cancer, and, probably, CAD. The decision
to give HRT should therefore be based on a strict
individual benefit/risk evaluation, and it is advisable to prescribe HRT at the lowest dose and
for the shortest duration possible. The alleged
better evolution of CAD in women in fact disappears when populations of women with angiographically documented CAD are studied. Thus,
if the natural evolution of CAD does not differ
between men and women, treatment should be
the same: this is not the case. Although several
reasons may account for this paradox, the main
cause of this difference in treat-ment appears
to relate to the physician him/herself. Thus, for
young patients, the Bayesian approach (pretest
probability) indicates physicians have a positive
predisposition toward the diagnosis of CAD for
men, and a negative one for women. For elderly
persons, less aggressive treatment in general is
indicated, regardless of sex, in order to avoid drug
interactions and to take account of differences
in bioavailability (alterations in absorption and
metabolism, and altered receptor sensitivity).
Whatever the reason, women receive less pharmacological treatment (antiplatelet drugs and
-blockers; also, certain risk factors are harder
to treat in women). The percentage of women
who undergo invasive procedures is also smaller,
the causes again being diverse. The smaller number of angioplasties seems to be linked to a lesser prescription of angiographies; on the other
hand it has been observed that no matter how
high the number of angiographies is, the percentage of angioplasties almost always remains the
same, which may reflect the differences in intervention criteria of each region or hospital. This
highlights the difficulty in stratifying the clinical
risk. In the case of bypass surgery, the explanation might be different; involving the reluctance
to perform surgery in view of the clearly greater
risk in women (due to higher average age, smaller body surface, and smaller coronary arteries).
In conclusion, gender clearly exerts a strong influence on CAD management, due both to fact
and fancy. As fancy give way to reality, CAD in
women will increasingly be treated as seriously
as in men. ❒
63
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S. J. Brister, Canada
fter two studies 15 years ago identified differences between men and women in the
delivery of heart disease care,1,2 it became
clear that such differences also applied to diagnosis, treatment, and treatment response in angina.
The reasons are multifactorial and continue to
evolve. Elucidation must begin with a review of
the evidence.
A
Stephanie J. BRISTER, MD
Associate Professor
Department of Surgery
University of Toronto
and Division of Cardiac
Surgery, Toronto General
Hospital, 14 Eaton North
Room 214, 200 Elizabeth
Street, Toronto, Ontario
M5G 2C3, CANADA
(e-mail:
[email protected])
Clinical evaluation and referral
Chest pain is the most common presentation of
angina, but nausea, shortness of breath, and atypical pain in the back, jaw, neck, or abdomen are
more common in women.3 In premenopausal
women, chest pain, whether typical or atypical,
carries a lower risk of coronary artery disease
(CAD) than in age-matched men, but the incidence of CAD increases after menopause. Even in
acute myocardial infarction (MI), typical chest
pain is less frequent than in men. Women with
acute MI are older, with higher comorbidity (hypertension, diabetes). They also have a higher incidence of silent MI. A specific algorithm has been
devised for managing women with angina and
identifying the diagnostic tests and interpretations
appropriate to those stratified into low, moderate,
or high CAD probability based on chest pain characteristics and clinical risk factors; however, the
investigations are based on the same indications
as in men.4 Even in 2000, women—black women
in particular— were less likely to be referred for
cardiac catheterization.5 However, the most recent evidence indicates no such differences, but
only a treatment difference, with percutaneous
coronary interventions (PCI) being offered more
often to women and surgery to men.6
Medical management
MI is more often fatal in women, at both ends of
the age spectrum, possibly due to later presentation to the emergency services and lower perceived
risk by health care providers.7 Mortality remains
higher for at least 2 years post-MI 8; morbidity—
reinfarction, stroke, pulmonary edema, shock,
and cardiac rupture—is also higher.9 All conventional drug therapies for angina and MI have
well-established benefits in both genders, but are
less used in women. Conventional therapy may
also be less aggressive: despite an absence of
gender bias in lipid assessment, distribution of
lipid-lowering therapy, or proportion of patients
achieving lipid targets, women were treated less
aggressively in terms of absolute levels achieved.10
Revascularization
◆ Percutaneous coronary intervention (PCI)
PCI is less frequent in women, and registry data
have suggested poorer results11: the women had
equivalent CAD, but were older, with more risk
factors and more severe angina, resulting in high-
64
er complication and procedural mortality rates.
Some construed this as evidence of female gender
being an independent risk factor for major morbidity or mortality.12 But given comparable
clinical severity and strict criteria for referral,
catheterization and angioplasty, procedural referral rates have proven similar between the sexes,
with similar rates of reocclusion, reinfarction,
and mortality.13 PCI is equally effective in men
and women. Female sex was actually an independent predictor of improved 5-year survival in the
Bypass Angioplasty Revascularization Investigator (BARI) study.14
◆ Coronary artery bypass grafting (CABG)
The morbidity and mortality of CABG have
progressively declined, but remain 2 to 3 times
higher in women, for reasons unresolved. As with
PCI, women are older, with more comorbidity;
they undergo less frequent distal anastamosis,
left internal mammary artery grafting, complete
arterial revascularization, and off-pump surgery.15
These operative differences may significantly affect long-term outcome. Absolute hospital mortality is generally higher in women, for reasons
that could include decreased body size, comorbidity, emergency surgery, reoperation, low ejection fraction, hypertension, and poor diastolic
function,11 but also general risk factor profile,
including age. Satisfactory matching of the sexes
in such studies is complicated by the significant
preoperative differences.16 Recovery is more difficult in women, with higher inotropic requirements, longer hospital stay, and higher early rehospitalization. Although recurrence of angina
or MI appears more frequent, fewer women are
referred for repeat catheterization and/or surgery.
Yet their long-term survival equals or exceeds
that in men.17
Access to care
In the past, women had fewer noninvasive and
invasive investigations and fewer invasive interventions: a 50 000-patient survey in Ontario
found that access to PCI and CABG in women
post-angiography was half and two thirds that
of men, respectively.18 However, with increasing
recognition of CAD in women, these rates were
evening out from 1994/1995 to 1997/1998.19
Conclusion
We still do not know whether women are underinvestigated and undertreated or men overinvestigated and overtreated,20 nor whether the differences we have described are based primarily on
sex or gender, ie, biology or culture 21 (or on what
combination of the two). Researchers must continue to collect the best possible evidence, and
clinicians to offer diagnostics and therapy on a
bias-free basis. ❒
▲
CO
REFERENCES
1. Ayanian JA, Epstein AM. Differences in the use of procedures
between women and men hospitalized for coronary artery
disease. N Engl J Med. 1991;325:221-225.
2. Steingart RM, Packer M, Hamm P, et al. Sex differences in
the management of coronary artery disease. N Engl J Med.
1991;325:226-230.
3. Lerner DJ, Kannel WB. Patterns of coronary heart disease,
morbidity and mortality in the sexes. A 26 year follow-up of
the Framingham population. Am Heart J. 1986;111:383-390.
4. Isaac D, Walling D. Clinical evaluation of women with
ischemic heart disease; diagnosis and non-invasive testing.
Can J Cardiol. 2001;17(suppl D):38D-48D.
5. Gan SC, Beaver SK, Houch PM, et al. Treatment of acute
myocardial infarction and 30 day mortality among women
and men. N Engl J Med. 2000;343:8-15.
6. Raine RA, Black NA, Bowker TJ, et al. Gender differences
in the management and outcome of patients with acute coronary artery disease. J Epidemiol Community Health. 2002;
56:791-797.
7. Clarke KW, Gray D, Keating NA, et al. Do women with acute
myocardial infarction receive the same treatment as men?
BMJ. 1994;309:563-566.
8. Tofler GH, Stone PH, Muller JT, et al. Effect of gender and
race on prognosis after myocardial infarction: adverse prognosis for women particularly black women. J Am Coll Cardiol.
1987;9:473-482.
9. Greenland P. Reicher-Reiss H, Goldbourt V, et al. In-hospital
and 1 year mortality in 1,524 women after myocardial infarction. Circulation. 1991;83:484-491.
10. Corbelli JA, Corbelli JC, Bullano M, et al. Gender bias in
lipid assessment and treatment following percutaneous coronary intervention. J Gend Specif Med. 2003;6:21-26.
11. Jacobs AK. Coronary revascularization in women in 2003.
Sex revisited. Circulation. 2003;107:375-381.
12. Lansky AJ, Mehran R, Dangas G, et al. New-device angioplasty in women: clinical outcome and predictors in a 7,372
patient registry. Epidemiology. 2002;13(suppl 3):546-551.
13. Ghali WA, Fares PD, Galbraith PD, et al. Sex differences
8
◆
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E S T I O N
in access to coronary revascularization after cardiac catheterization importance of detailed clinical data. Ann Intern Med.
2002;136:723-732.
14. Jacobs AK, Kelsey SF, Brooks M, et al. Better outcome for
women undergoing coronary revascularization. A report from
the Bypass Angioplasty Revascularization Investigators (BARI).
Circulation. 1998;98:1279-1285.
15. Lawton JS, Brister SJ, Petro KR, Dullum M. Surgical revascularization in women. Unique intraoperative factors and
considerations. J Thorac Cardiovasc Surg. 2003;126:936-938.
16. Koch CG, Khandwala, F. Nussmeir N, Blackstone EH.
Gender profiling in coronary artery bypass grafting. J Thorac
Cardiovasc Surg. 2003;126:2032-2043.
17. Davis KB, Chaitman B, Ryan T, et al. Comparison of
15-year survival for men and women after initial medical or
surgical treatment for coronary artery disease: A CASS Registry Study. J Am Coll Cardiol. 1995;25:1000-1009.
18. Alter DA, Austin P, Tu JV. Use of coronary angiography,
angioplasty, and bypass surgery after acute myocardial infarction in Ontario. In: Naylor CD, Slaughter PM, eds. Cardiovascular Health and Services in Ontario: An ICES Atlas. Toronto,
Canada: Institute for Clinical Evaluative Sciences; 1999:
141-164.
19. Slaughter PM, Young W, DeBoer DP, Cohen EA, Naylor CD.
Patterns of revascularization. In: Naylor CD, Slaughter PM,
eds. Cardiovascular Health and Services in Ontario: An ICES
Atlas. Toronto, Canada: Institute for Clinical Evaluative Sciences; 1999:165-187.
20. Epstein AM, Weismer JS, Schneider EC, et al. Race and
gender disparities in rates of cardiac revascularization: do they
reflect appropriate use of procedures or problems in quality
of care? Med Care. 2003;41:1240-1255.
21. Pardue ML. The future of research on biological sex differences: challenges and opportunities. In: Committee on Understanding the Biology of Sex and Gender Differences; Wizemann
TM, Pardue ML eds. Exploring the Biological Contributions
to Human Health: Does Sex Matter? Washington, DC: National
Academies Press; 2001;173 -184.
I. H. Muderrisoglu, Turkey
oronary heart disease (CHD) remains the
leading cause of death and disability in both
men and women in the industrial world.
Although the misperception that CHD mainly affects men still prevails, cardiovascular disease and
stroke continue to kill more women each year.
It is widely known that gender differences exist
not only in terms of diagnosis (anginal symptom
characteristics, such as nausea, back pain, response to effort, etc), but also in the pathophysiology and management. New findings concerning
the role of inflammation in the pathophysiology
of atherosclerosis have revealed that the levels of
inflammatory markers correlated with the risk
of CHD. Two studies, the Women’s Health Study
(WHS) and the Physicians’ Health Study (PHS)
demonstrated that the risk of cardiovascular
events was associated with the levels of inflammation markers.1,2 Interestingly, both the median
levels of high-sensitivity C-reactive protein (hsCRP) and the absolute risk in women were slightly higher than those in men in those studies.3
Estrogen may have a major role in the increase
CRP levels. Although several trials in women taking hormone replacement therapy (HRT)—such
as HERS (Heart and Estrogen-progestin Replace-
C
I. Haldun MUDERRISOGLU,
MD, FESC
Professor of Medicine,
and Chief Department of
Cardiology, Baskent University
School of Medicine
10. sok no: 45 C blok kat: 2
06490 Bahcelievler, Ankara
TURKEY
ment Study) and ERA (Estrogen Replacement in
Atherosclerosis)—showed some positive effects
on lipid parameters, no reduction in risk of major
cardiovascular end points and death was evidenced. Although women share many of the traditional risk factors with men, gender differences
do affect some risk factors. Thus, diabetes mellitus
and high triglyceride levels are stronger risk factors in women than in men; women have higher
levels of fibrinogen; age and menopause increase
the level of homocysteine, etc.4 Aspirin, nitrates,
-blockers, and calcium channel blockers are
widely prescribed in the management of stable
angina pectoris. However, increasing age and female gender make patients less likely to be prescribed these treatments. Although there is a general underuse of antiplatelet drugs, -blockers,
and lipid-lowering medications in the treatment
of stable angina pectoris,5,6 multilevel logistic regression analysis revealed that -blockers and
antiplatelet agents were more likely to be prescribed in men compared with women. Another
trial emphasized the misdiagnosis and undertreatment of women with stable angina, and showed
that male patients were more likely to receive aspirin and heparin, and less likely to be given calMEDICOGRAPHIA, VOL 27, No.1, 2005
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cium channel blockers and angiotensin-converting
enzyme (ACE) inhibitors, compared with female
patients. The rates of narcotic and nitroglycerin
administration did not differ between both genders.7 Use of oral anticoagulants and oral antidiabetics was more common in men, while diuretics
were more frequently used in women.8 Most largescale trials report the benefits of statins in the
reduction of mortality, both in men and women,
ie, independently of gender.9 ACE inhibitors were
also prescribed similarly in both groups. A recent
large trial, the EUropean trial on Reduction Of
cardiac events with Perindopril in stable coronary
Artery disease (EUROPA), revealed no consistent
benefits for both genders in the management of
stable CHD when the ACE inhibitor perindopril
was added to their conventional therapies.10 In
both genders, a metabolic anti-ischemic agent,
trimetazidine, was demonstrated to improve treadmill exercise parameters, and may be recommended for elderly and coronary diabetic patients,
especially those with impaired left ventricular
function.11-14 Women experience vaguer symptoms,
which may account for underuse of effective therapies. Gender-related differences also exist in the
interventional management of stable angina. Al-
though early registries showed that women have
a higher complication and mortality risk than
men, in recent trials, especially in elective stenting, outcomes in women are as good as in men.
Diabetes and small vessel size worsen the outcomes of both percutaneous and surgical revascularization in women.15 Being a woman was independently associated with a lower probability to
be referred to a cardiac rehabilitation program at
discharge.16 An age and gender bias also exists
in the prescription of important secondary preventive therapies in primary care, which may lead
to increased mortality from ischemic heart disease in these groups.17 These findings demonstrate
that women who are hospitalized for CHD undergo fewer major diagnostic and therapeutic procedures than men.18 Physicians pursue a less aggressive management approach to coronary disease
in women than in men, despite greater cardiac
disability in women.19 In conclusion, physicians
should try to focus their efforts on proper diagnosis and treatment of CHD in women because
of delayed presentation and lower specificity of
symptoms and diagnostic accuracy of noninvasive testing, higher complication rate, lower use
of appropriate treatment and worse outcome. ❒
REFERENCES
1. Ridker PM, Buring JR, Shih J, et al. Prospective study of
C-reactive protein and the risk of future of cardiovascular
events among apparently healthy women. Circulation. 1998;
98:731-733.
2. Ridker PM, Cusman M, Stampfer MJ, et al. Inflammation,
aspirin, and the risk of cardiovascular disease in apparently
healthy men. N Engl J Med. 1997;336:973-979.
3. Ridker PM, Haughie P. Prospective studies of C-reactive
protein as a risk factor for cardiovascular disease. J Invest Med.
1998;46:391-395.
4. Nguyen VD, McLaughlin MA. Coronary heart disease in
women: a review of emerging cardiovascular risk factors. Mt
Sinai J Med. 2002;69:338-349.
5. Beaulieu MD, Blais R, Jacques A, Battista RN, Lebeau R,
Brophy J. Are patients suffering from stable angina receiving
optimal medical treatment? Q J Med. 2001;94:301-308.
6. EUROASPIRE II Study Group. Lifestyle and risk factor
management and use of drug therapies in coronary patients
from 15 countries. Principal results from EUROASPIRE II.
Euro Heart Survey Programme. Eur Heart J. 2001;22:554-572.
7. Rothrock SG, Brandt P, Godfrey B, Silvestri S, Pagane J. Is
there gender bias in the prehospital management of patients
with acute chest pain? Prehosp Emerg Care. 2001;5:331-334.
8. Kahan T, Wandell P. Risk factors in established coronary
heart disease: evaluation of a secondary prevention programme.
J Cardiovasc Risk. 2001;8:73-80.
9. Cheung BM, Lauder IJ, Kumana CR. Meta-analysis of large
randomized controlled trials to evaluate the impact of statins on
cardiovascular outcomes. Br J Clin Pharmacol. 2004;57:640-651.
10. The EUropean trial on Reduction Of cardiac events with
Perindopril in stable coronary Artery disease Investigators.
Efficacy of perindopril in reduction of cardiovascular events
among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicenter trial (the
EUROPA study). Lancet. 2003;362:782-788.
11. Belardinelli R, Purcaro A. Effects of trimetazidine on the
contractile response of chronically dysfunctional myocardium
to low-dose dobutamine in ischemic cardiomyopathy. Eur
Heart J. 2001;22:2164-2170.
12. Fragasso G, Piatti PM, Monti L, et al. Short- and long-term
beneficial effects of trimetazidine in patients with diabetes
and ischemic cardiomyopathy. Am Heart J. 2003;146;e18-e25.
13. Rosano GM, Wajngarten M, Sposato B, et al. Effect of
trimetazidine in elderly patients with ischaemic dilated cardiomyopathy. Eur Heart J. 2003;24:453.
14. Rosano G, Vitale C, Sposato B, et al. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study.
Cardiovasc Diabetol. 2003;2:16.
15. Lansky AJ. Outcomes of percutaneous and surgical revascularization in women. Prog Cardiovasc Dis. 2004;46:305-319.
16. Bongard V, Grenier O, Ferrières J, et al. Drug prescriptions
and referral to cardiac rehabilitation after acute coronary
events: comparison between men and women in the French
PREVENIR Survey. Int J Cardiol. 2004;93:217-223.
17. Williams D, Bennett K, Feely J. Evidence for an age and
gender bias in the secondary prevention of ischemic heart disease in primary care. Br J Clin Pharmacol. 2003;55:604-608.
18. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary
heart disease. N Engl J Med. 1991;325:221-225.
19. Steingart RM, Packer M, Hamm P, et al. Sex differences
in the management of coronary artery disease. N Engl J Med.
1991;325:226-230.
✦
66
I
N T E R V I E W
THE DISCOVERY OF THE
If CURRENT INHIBITOR PROCORALAN
I n t e r v i e w w i t h J . - P. V i l a i n e a n d J . - L . P e g l i o n
Jean-Paul VILAINE, MD
Director, Cardiovascular
Research Division
Jean-Louis PEGLION, PhD
Director, Chemistry
Division
Institut de Recherches Servier, Suresnes, FRANCE
You are the “fathers” of Procoralan, the
first selective and specific I f current
inhibitor: what line of research did you
pursue to discover this molecule?
ur research program was aimed
at selecting a truly innovative
compound designed for the treatment of
coronary artery disease, that would be
able to reduce heart rate selectively. Our
starting point was based on the fact that
O
many experimental, clinical, and epidemiological data had cast selective heart rate
reduction in a very attractive light as a
therapeutic mechanism in this disease.
The fundamental concept in the pathophysiology of myocardial ischemia in patients with coronary obstructive disease
is that the culprit is a mismatch between
myocardial oxygen demand and coronary
blood flow. Under normal conditions, the
heart tolerates a wide range of myocardial oxygen consumption variations. This
occurs for example during exercise, where
tachycardia plays a major role, through
autoregulation, by ensuring a parallel
increase in coronary blood flow, thereby
enabling the increased metabolic requirement to be met. However, in patients with
coronary artery disease, several mechanisms contribute to decreasing coronary
flow reserve: fixed coronary artery stenosis, coronary vasoconstriction, and im-
paired vasodilator capacity of the microcirculation. In these patients, most ischemic episodes are triggered by an
increase in heart rate. The decrease in
coronary reserve does not allow a large
enough increase in coronary flow to be
produced in order to meet the metabolic
stimulation caused by the increased
heart rate. As a result, an imbalance between oxygen demand and supply develops, the outcome of which is myocardial
ischemia.
Heart rate is the most important among
the major determinants of myocardial
oxygen consumption,1,2 alongside preload, afterload, and myocardial contractility; its increase is clearly the most deleterious factor of sympathetic stimulation
in the ischemic heart.3
A second important point is that coronary blood flow takes place essentially
during diastole. When the limit of coro-
✦
S
elective heart rate reduction is an attractive therapeutic
approach in patients with coronary artery disease (CAD).
Heart rate is the most important among the major determinants of myocardial oxygen consumption, and its increase is
responsible for most ischemic episodes in patients. Heart rate reduction can prevent or reduce the mismatch between myocardial
oxygen requirement and supply — which defines myocardial ischemia — by reducing myocardial oxygen consumption and by
prolonging diastolic time, thus improving myocardial perfusion.
Numerous epidemiological data suggest that increased heart rate
is an independent predictor of mortality and that the reduction
in mortality in patients with CAD or heart failure subsequent to
treatment with -blockers, some calcium channel blockers, or
amiodarone results from the heart rate–lowering actions of these
agents. Furthermore, experimental studies suggest that chronic
heart rate reduction limits atherosclerotic lesion progression and
rupture, promotes the development of coronary collaterals, improves cardiac remodeling, and has antiarrhythmic effects. These
mechanisms could contribute to the improvement in CAD prognosis resulting from heart rate reduction, over and above its antiischemic potential. The screening of a series of benzocycloalkane
derivatives led to the selection of Procoralan, the first selective
inhibitor of the depolarizing If current of the sinus node. In vitro,
this compound reduces the spontaneous beating rate of isolated
The discovery of the If current inhibitor Procoralan – Vilaine and Peglion
right rat atria and the action potential firing rate of rabbit sinus
node preparations. This effect is explained by a decrease in the
diastolic depolarization slope of the action potential and underlies the selective inhibition of the pacemaker If current. In vivo,
Procoralan induces a selective reduction in heart rate both at rest
and during exercise without any change in myocardial contractility, atrioventricular conduction, and ventricular repolarization
duration. Procoralan reduces exercise-induced myocardial ischemia in pigs to the same extent as a -blocker, while eliciting
a greater reduction in ischemic myocardial contractile dysfunction. The clinical development of Procoralan has confirmed its
selective electrophysiological and hemodynamic effect and an efficacy equipotent to that of a -blocker in preventing exercise-induced myocardial ischemia in patients with stable angina. Procoralan is also expected to have a beneficial effect on other clinical
forms of myocardial ischemia, in particular in the presence of heart
failure, as well as on the improvement of CAD prognosis.
Keywords: Procoralan; ivabradine; heart rate; sinus node;
If current; myocardial ischemia
Address for correspondence: Jean-Paul Vilaine & Jean-Louis Peglion,
Institut de Recherches Servier, 92150 Suresnes, France
(e-mail: [email protected]; [email protected])
67
IN
T E RV I E W
nary reserve is reached, ie, when no further coronary vasodilatation can occur
downstream of a coronary stenosis, myocardial perfusion becomes critically dependent on the duration of diastole, the
major phase of the regulation of heart
rate.
To sum up, lowering the heart rate and
preventing its acceleration contributes to
preventing the mismatch between myocardial oxygen need and supply, by4-8 :
(i) reducing myocardial oxygen consumption; and (ii) improving myocardial perfusion via prolongation of diastolic time.
These two hemodynamic effects have obvious beneficial implications in the various clinical forms of myocardial ischemia.
A further argument in support of the
speculation that reduction in heart rate
might be sufficient to result in a major
anti-ischemic effect came from experimental and clinical data showing that the
benefit of β-adrenergic blockade in exercise-induced myocardial ischemia was essentially due to heart rate reduction, and
could be abolished by atrial pacing.5,9
Last but not least, two major findings
emerged from many epidemiological
studies, which emphasized the deleterious effect of increased heart rate over and
above its consequences as a simple acute
and symptomatic mechanism occurring
during myocardial ischemia. Firstly, evidence pointed to sustained elevation of
heart rate as an independent predictor
of mortality, both in the general population10-15 and in patients with coronary
artery disease.16,17 Secondly, the reduction
in mortality in patients with coronary
artery disease or heart failure observed
following treatment with β-adrenergic
blockers, some calcium channel blockers,
or amiodarone, was attributed, in large
part, to the heart rate–lowering actions
of these agents.18-25
In addition to the role of increased
heart rate in myocardial ischemia, various mechanisms have been proposed to
explain the link between heart rate and
mortality, such as:
◆ An inverse relationship between heart
rate and the threshold of ventricular fibrillation in experimental models of myocardial ischemia.26,27
◆ An increase in the progression of
atherosclerotic lesions in experimental
animals28-30 and in patients31,32 with heart
rate elevation.
◆ The promotion of coronary plaque rupture by elevated heart rate.33
In contrast, chronic reduction in heart
rate can induce the development of a
beneficial coronary angiogenesis in animals34-36 as well as the development of
coronary collaterals in humans.37
68
The currently established drugs in the
treatment of coronary artery disease that
reduce heart rate, such as the β-adrenergic blockers and nondihydropyridine
calcium channel antagonists, do not exert a selective action on heart rate. These
two types of compounds reduce myocardial contractility and depress atrioventricular conduction. In addition, β-adrenergic blockers may indirectly modify
vascular tone by unmasking α-adrenergic
vasoconstriction, in particular in coronary arteries,38-40 while calcium channel
antagonists can induce hypotensive effects and reduce coronary artery perfusion pressure. These effects may be deleterious in the context of myocardial
ischemia or may give rise to contraindications in certain patients or clinical
situations.
All these reasons led us to develop a
research program to identify a compound
that would be able to reduce heart rate
selectively by directly targeting the sinus
node—the physiological pacemaker. To
be specific, this meant identifying a compound able to inhibit the If current of the
sinus node cells.
What makes the role of the I f current
in the modulation of heart rate such
a pivotal one?
he fundamental mechanism
underlying the spontaneous
electrical activity of the pacemaker cells
of the cardiac sinus node is spontaneous
diastolic depolarization. During diastole,
depolarization brings the membrane potential from its maximal value, at the end
of the repolarization of an action potential, up to the threshold where a new
action potential can develop. This phase
not only generates the spontaneous activity of the sinus node, transmitted to the
whole heart by the conduction system,
but is also the target of the autonomic
nervous system in the regulation of heart
rate. The If current has been demonstrated to be the major current underlying
this diastolic depolarization of the pacemaker cells41-43 and was shown to be directly regulated via intracellular cyclic
adenosine monophosphate (cAMP),44-48
which is the second messenger of the
autonomic nervous system. β-Adrenergic
stimulation, by elevating intracellular
cAMP, increases the If current and the
slope of diastolic depolarization, thereby
reducing the duration of the diastole and
increasing heart rate. In contrast, vagal
stimulation induces the opposite effects
and reduces heart rate by increasing diastolic duration. Therefore, direct inhibition of the If current appears as an ideal
T
target, as this is able to reduce heart rate
not only in resting conditions, but also
when heart rate is elevated, in particular
when the elevation is due to an increase
in sympathetic tone.
Now that the mechanism of action targeted has been clearly defined, could
you explain how you designed potential
candidates and describe the selection
process that culminated in the discovery
of Procoralan?
he first synthetic substance reported as being able to decrease
the sinus rate at concentrations or doses
much lower than those affecting other
myocardial or cardiovascular functions
was ST-567.49 Subsequently, AQ-A-39, a
compound with a completely different
chemical structure (Figure 1),50 was shown
to present a similar cardiovascular profile. However, in contrast to ST-567, the
reduction in cardiac frequency obtained
with AQ-A-39 was associated with a large
increase in the QT interval of the cat electrocardiogram, the mechanism of which
was explained by a direct prolongation of
the action potential duration, as observed
in intracellular recordings from electrically driven atrial and ventricular muscle of guinea pigs. With “compound 3,”
(Figure 1),51 the increase in the QT interval was smaller than with AQ-A-39, for the
same level of heart rate reduction. Finally, UL-FS 49, whose structure was very
close to that of AQ-A-39 and “compound
3,” elicited a potent decrease in sinus
rate, without concomitant negative inotropy or hypotensive effect, but still associated with an increase in action potential duration. These three compounds
possess the dimethoxy phenethylamine
moiety (Figure 1), which is present in a
great variety of drugs, in particular those
displaying a tropism for the cardiovascular system. With these three derivatives,
a progressive reduction in the increase
in action potential duration was achieved
by modifying the aromatic moiety opposite to the phenethylamine moiety (Figure 1, upper panel).
We decided to take a different approach,
and focused on modifying the phenethylamine moiety, with the aim of identifying derivatives with an enhanced selectivity for the pacemaker current versus the
channels governing the duration of the
action potential, so as to obtain compounds without any effect on action potential duration. To achieve this goal, it
was important to design chemical structures showing a high degree of rigidity,
since high rigidity often leads to high selectivity. For this purpose, we designed
T
IN
the basis of these results, S 16257, which
was later given the name Procoralan,
was chosen for further pharmacological
evaluation.
O
O
O
N
AQ-A-39
O
N
O
O
O
O
Compound 3
N
O
N
O
O
O
UL-FS 49
O
N
O
N
O
Phenethylamine
Cyclic phenethylamines
O
O
N
N
O
O
O
O
S 15544 and
S 16257 (Procoralan)
O
N
N
O
O
O
Figure 1. Chemical structures of reference substances cited in the literature (upper panel)
and prepared during the project, which led to the discovery of Procoralan (lower panel).
and synthesized cyclic analogs of the
phenethylamine moiety for introduction
into the final structures (Figure 1, lower
panel).52
The resulting compounds were then
tested for their ability to: (i) reduce the
spontaneous beating rate of rat isolated
right atria; (ii) decrease the diastolic depolarization slope of the action potential
of rabbit sinus node preparations, leading
to a reduction in their spontaneous firing rate; and (iii) slow the heart rate in
conscious rat. In addition, we evaluated
the potential effect of the most promising
compounds on the action potential duration of ventricular preparations (guineapig papillary muscle and rabbit Purkinje
fibers), driven at constant frequency, to
exclude compounds inducing inappropriate direct prolongation of the duration
of repolarization, as had been previously
shown to be the case with UL-FS 49 that
could promote arrhythmias.
A number of derivatives showed a
marked decrease in the slope of diastolic
depolarization of the action potential of
sinus node preparations, together with
a very robust reduction in the cardiac
rhythm of conscious rats, but their selectivity toward other channels differed
markedly. Depending on the nature of
the cyclic phenethylamine moiety of the
compounds, different effects on action
potential duration of ventricular preparations were observed: some derivatives
produced a dramatic prolongation in
duration; however, in contrast, S 15544,
which had the most rigid cyclic phenethylamine moiety among all the compounds
prepared in this project, only induced a
very small increase in the action potential
duration of these preparations. S 15544
is a racemic mixture of two optical isomers: we therefore subjected the camphorsulfonate salts of S 15544 to fractional recrystallization, which resolved this
mixture into S 16257 (S configuration
isomer) and S 16260 (R configuration
isomer). Both isomers were equipotent
in reducing atrial rate, but S 16257 induced an even weaker effect on action
potential duration than S 15544, a property not shared by S 16260, which elicited a dramatic increase in this effect. On
T E RV I E W
Once you had selected the “winner,”
how did you set about evaluating its
properties?
arious in vitro and in vivo experiments were used to specify
the effects and mechanism of action of
Procoralan.53
◆ In isolated right atria of rat, Procoralan
was shown to reduce the spontaneous
beating rate in a concentration-dependent manner, with a maximal effect attained after 3 hours of application of
single concentrations. Using single concentrations yielded an IC30 of 1.910- 7 M
at 3 hours (ie, the inhibitory concentration reducing the initial beating rate by
30%), in contrast to screening protocols
using cumulative concentrations applied
during 30 minutes, which yielded an
IC30 of 2.110- 6 M. The effect of Procoralan on beating rate was not modified
in the presence of atropine, indicating
that it did not act through stimulation
of muscarinic receptors. A β-adrenergic
blocking activity of Procoralan was excluded, since the reduction in basal rate
of the preparations was maintained in
the presence of increasing concentrations
of isoproterenol, without any change in
the 50% effective concentration (EC50)
of this agonist. In addition, binding studies indicated the absence of affinity of
Procoralan for β-adrenergic and muscarinic receptors.
◆ Electrophysiological studies in rabbit sinus node and ventricular preparations (guinea-pig papillary muscle and
rabbit Purkinje fibers) were carried out,
which confirmed the selective effect of
Procoralan on the sinus node (Figure 2,
page 70).54,55
◆ In rabbit sinus node preparations,
Procoralan slowed the spontaneous firing
of the action potentials in a concentration-dependent manner, with a reduction
of about 24% after 40 minutes of application of a concentration of 3.010-6 M.
This effect resulted exclusively from a
decrease in the slope of the slow diastolic
depolarization of the pacemaker cells,
without change in maximal diastolic potential or in threshold potential for action potential firing. Furthermore, Procoralan did not affect the amplitude and
the duration of the action potential.
◆ In guinea-pig papillary muscles, Procoralan induced minimal effect on action
potential duration and did not affect the
other parameters.
V
69
IN
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A
Procoralan 3 10–6 M
0
– 40
mV
100 ms
B
C
0
0
– 40
mV
– 40
mV
100 ms
100 ms
Figure 2. Change in action potential configuration in isolated rabbit sinoatrial
node tissue (A), rabbit Purkinje fiber (B), and guinea-pig papillary muscle (C) in
the presence of Procoralan 310- 6 M. Arrows show action potentials after 40 min
exposure to Procoralan.
Modified from reference 54: Thollon C, Cambarrat C, Vian J, et al. Electrophysiological effects of
S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49. Br J Pharmacol. 1994;112:37-42. Copyright ©, 1994 Nature Publishing Group.
◆ In rabbit Purkinje fibers, which were
paced at a very low frequency, making
them very sensitive to compounds that
prolong action potential duration, Procoralan induced only a weak effect on
repolarization duration.
◆ At micromolar concentrations, Procoralan was found to have no depressive
effect on: (i) the plateau phase of the action potential in these two latter preparations; (ii) the tension developed by the
papillary muscles; (iii) the contractility
of rat left atria; and (iv) the contraction
of rat aorta induced with KCK (80 mM),
indicating the absence of calcium channel antagonist activity of Procoralan.
◆ The selective inhibition of the If current underlying the effect of Procoralan
on sinus node diastolic depolarization
was established using the patch-clamp
technique.56 In single pacemaker cells
dissociated from rabbit sinus node preparations, Procoralan reduced the amplitude of the If current in a concentrationdependent and use-dependent way, with
an estimated IC50 value of 2.210- 6 M
(Figure 3).56
◆ On the other currents playing a role
in diastolic depolarization (the outward
potassium current [IKr , delayed rectifier]
and the two types of inward calcium
currents, ICa,T [transient] and ICa,L [longlasting]), Procoralan, at high concentration (10- 5 M), had no detectable effect on
the T-type calcium current and slightly
decreased the L-type calcium current
(--18.1%±0.7%), without significant usedependent blockade. Procoralan also had
no effect on the delayed outward potassium current IKr at 310-6 M though a
slight decrease was observed at higher
concentrations (--16.3%±1.2% at 10- 5 M).
◆ In vivo, the selective effect of Procoralan on heart rate was shown in different species at rest and during exercise.
◆ In conscious rats, single administration of Procoralan, by intravenous as
well as by oral route, reduced heart rate
in a dose-dependent manner without
affecting mean arterial blood pressure.
For example, maximal reduction in
heart rate was obtained 90 minutes after
(2)
100
(1)
(10)
310–6 M
I f reduction (%)
(9)
50
(8)
(2)
250 pA
10–6 M
250 ms
310–7 M
Control
(1)
0
10–8
10–7
10–6
10–5
10–4
Drug concentration (M)
Figure 3. Concentration-dependent inhibition of If current elicited by hyperpolarizing steps to --100 mV from a holding potential
of --30 mV in sinoatrial node cells isolated from rabbit heart. Examples of current traces in control and after the steady-state usedependent block of If in the presence of increasing concentrations of Procoralan (left) and concentration-dependent curve for If
inhibition (right, IC50 = 2.210 - 6 M).
Modified from reference 56: Bois P, Bescond J, Renaudon B, et al. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node
cells. Br J Pharmacol. 1996;118:1051-1057. Copyright © 1996, Nature Publishing Group.
70
IN
Vehicle
1.5 mg/kg
6 mg/kg
10
0.03
0.1
0.3
1
30
60
90
T E RV I E W
Dose
(mg/kg IV)
10
–10
*
**
–20
**
**
*
*
**
*
**
**
**
**
–30
0
1
2
3
4
5
**
Heart rate (% change)
20
0
0
–10
120
Time (min)
–20
–30
6
–40
Time (hours)
Vehicle (n=10)
–50
Figure 4. Dose-dependent reduction in heart rate (HR) after single
oral administration of Procoralan in conscious rats. Procoralan was
given at 1.5 and 6 mg/kg in separate groups (n=6 per dose). Data are
expressed as mean ± SEM, as percent change from predrug value.
Significantly different from vehicle: *P<0.05; **P<0.01.
Day 1
10
0
4
8
12
16
20
24
–20
Vehicle
Procoralan
3 mg/kg/day
30
1
30
60
90
Dose
(mg/kg IV)
10
0
120
Time (min)
–10
Day 6
0
4
Figure 6. Dose-dependent effects of Procoralan on heart rate (HR)
and QTc interval after intravenous administration in anesthetized
pigs. Data are expressed as mean ± SEM, as percent change from the
predrug value before the first administration.
Modified from reference 55: Thollon C, Bibouard JP, Cambarrat C, et al. Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)-S 16257. Eur J
Pharmacol. 1997;339:43-51. Copyright © 1997, Elsevier B. V.
10
–10
0.3
Time (hours)
–10
20
0.1
20
QTc (% change)
30
20
0.03
Procoralan (n=10)
8
12
16
20
24
Time (hours)
–20
oral administration (--11.7%±2.8% and
--18.9%±2.0% at 1.5 and 6 mg/kg, respectively) and was maintained at 6 hours
(Figure 4). Repeated once-daily oral administration of Procoralan was shown
to selectively reduce the heart rate,
measured by telemetry, once again in
rats. This effect lasted 12 hours after administration and remained unchanged
after administration of repeated doses
(Figure 5).
◆ In anesthetized pigs, Procoralan, administered at increasing intravenous
doses 30 minutes apart, reduced heart
rate in a dose-dependent manner (from
Figure 5. Reduction in
heart rate (HR) after
repeated oral administration of Procoralan
(3 mg/kg/day, n=12)
in conscious rats for 6
days. Data are expressed
as mean ± SEM, as
percent change from
predrug value.
--15.7%±3.0% at 0.1 mg/kg to --36.8%±
4.1% at 1 mg/kg).55 As anticipated from
in vitro studies, Procoralan did not induce significant prolongations in the
corrected QT interval of the electrocardiogram at any dose (Figure 6) and did
not modify the PR interval. Furthermore,
no change in arterial pressure or left
ventricular contractility was observed,
under these conditions.
In parallel with the lowering of heart
rate, Procoralan reduced myocardial oxygen consumption, in a dose-dependent
manner, without affecting the ratio of
oxygen delivery to oxygen consumption,
thus indicating the absence of a direct
effect on coronary vascular tone.
◆ In normal Yucatan micropigs, the
hemodynamic effects of Procoralan and
propranolol were compared during treadmill exercise. It was shown that Procoralan and the β-blocker propranolol, at
the same oral dose of 5 mg/kg and versus
a control treatment with the vehicles,
were equipotent in reducing basal heart
rate and exercise-induced tachycardia.
However, it was shown that only Procoralan, in contrast to propranolol, preserved the increase in contractility and
cardiac output, as well as peripheral vasodilatation (Figure 7, page 72).53
◆ In normal dogs, the coronary and
systemic hemodynamics of Procoralan
(0.5 mg/kg IV) and propranolol (1 mg/kg
IV) were analyzed at rest and during
graded treadmill exercises in comparison
with the vehicles.57 Both compounds induced similar decreases in resting heart
rate and limitations of exercise-induced
71
IN
T E RV I E W
Heart rate
Could you describe the highly sophisticated therapeutic model you developed
to study the effects of Procoralan?
LV dP/dt
200
150
**
**
**
**
**
100
mm Hg/s
Beats/min
4000
**
2000
**
**
E1
E3
**
1000
50
R CE
E1
E3
R CE
E5
**
**
3
mm Hg/L/min
L/min
4
**
E5
Total peripheral resistance
Cardiac output
5
40
**
30
**
**
E3
E5
20
2
R CE
E1
E3
R CE
E5
E1
†
90
†
60
0
30
*
*
Baseline
R
E5
E10
E12
Mean coronary resistance
0
†
–30
–60
†
†
30
–30
†
†
‡
Baseline
R
E5
E10
Heart rate
120
†
‡
E12
Figure 7. Systemic hemodynamics in conscious pigs (n=5), at rest (R), during control exercise
(CE), and exercise (E), after oral treatment with vehicle (gray curves), Procoralan (red curves),
or propranolol (green curves) (5 mg/kg). E1, E3, E5: exercises performed 1, 3, or 5 hours after
treatments, respectively. Data are expressed as mean ± SEM. Statistical analysis was performed
using a two-way analysis of variance, followed by a Newman-Keuls test. Significantly different
from vehicle: *P<0.05; **P<0.01.
150
150
Left ventricular peak dP/dt
120
90
60
†‡
30
‡
0
–30
8
†‡
Baseline
**
†
R
E5
†
†
E10
E12
Mean coronary artery diameter
6
4
2
0
–2
–4
–6
–8
‡
†‡
†‡
**
**
Baseline
R
†
†
†
E5
E10
E12
Figure 8. Percent change from baseline of heart rate, left ventricular peak dP/dt, mean coronary
resistance, and mean coronary artery diameter at rest (R) and during treadmill exercise (E) at 5,
10, and 12 km/h after intravenous administration of saline (gray curves), 0.5 mg/kg of Procoralan (red curves), and 1 mg/kg of propranolol (green curves) in conscious dogs. Significantly
different from baseline: *P<0.05; **P<0.01; significantly different from saline: †P<0.01; significantly different from propranolol: ‡ P<0.01.
After reference 57: Simon L, Ghaleh B, Puybasset L, et al. Coronary and haemodynamic effects of S 16257, a new
bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther. 1995;275:659-666. Copyright
© 1995, American Society for Pharmacology and Experimental Therapeutics.
tachycardia (Figure 8).57 In contrast to
propranolol, Procoralan induced no direct negative inotropic effect both at rest
and during exercise. After treatment with
Procoralan, during exercise, the decrease
in coronary resistance and increase in
72
e developed a model of regional myocardial ischemia
induced by treadmill exercise in Yucatan
micropigs, to mimic exercise-induced
angina in patients.58 In this model, a fixed
coronary artery stenosis of the left anterior coronary artery was achieved, which
was not severe enough to induce myocardial ischemia at rest, but sufficient to
limit the increase in coronary blood flow
during exercise and to induce regional
ischemia in the poststenotic myocardium. The animals were chronically instrumented to measure hemodynamic
parameters, and ultrasonic crystals were
implanted in the subendocardium to detect and quantify myocardial ischemia
by measuring the shift in ST-segment of
local electrocardiograms as well as myocardial contractile dysfunction (abnormal
decrease from resting values in systolic
segment shortening during exercise).
This model was used to compare the
effects of Procoralan and propranolol,
both administered orally at 5 mg/kg,
as well as that of their vehicles. With
this model, reproducible hemodynamic
changes and regional myocardial ischemia in the poststenotic myocardium
were observed under control conditions,
ie, during exercise performed before any
treatment, and during exercise after treatment with the vehicle only. Procoralan
and propranolol were shown to be equipotent in reducing heart rate at rest and
in limiting exercise-induced tachycardia
(Figure 9).58 Neither compound modified
mean arterial pressure at rest or during
exercise. Propranolol significantly reduced basal myocardial contractility and
its increase during exercise, whereas
Procoralan did not. During exercise, in
the poststenotic myocardium, both compounds reduced, to a similar extent (by
80%), the ST-segment shift on local electrocardiograms (Figure 10),58 but Procoralan resulted in a greater improvement in regional myocardial contractile
function than propranolol. Thus, after
treatment with Procoralan, the exerciseinduced decrease in systolic segment
shortening in the poststenotic myocardium was improved by 78% vs control exercise before treatment, whereas a significant decrease from resting values still
remained during exercise after treatment
with propranolol. With propranolol, the
improvement in regional myocardial contractility was only 26% in comparison
with control exercise before treatment
(Figure 10).
W
3000
coronary artery diameter remained
normal, while after treatment with propranolol, a significant reduction in the
decrease in coronary resistance and a
decrease in coronary artery diameter
were observed.
IN
Change from rest
before treatment (%)
REST
Heart rate
Procoralan Propranolol
Vehicle
–10
–20
***
***
10
–30
0
LV dP/dt
Vehicle
–10
–20
*
–30
0
Heart rate
Vehicle
–10
–20
–30
**
**
Change from exercise
EXERCISE
10
LV dP/dt
10
0
Vehicle
–10
–20
–30
–40
**
Figure 9. Comparison of the effects of Procoralan (5 mg/kg, orally), propranolol (5 mg/kg,
orally), and vehicle on heart rate and LV dP/dt in pigs at rest and during exercise 3 hours after
treatments. Data are expressed as mean ± SEM (n=5). Significantly different from vehicle:
*P<0.05, **P<0.01, ***P<0.001.
Modified from reference 58: Vilaine JP, Bidouard JP, Lesage L, et al. Anti-ischemic effects of ivabradine, a selective
heart rate reducing agent, in exercise-induced myocardial ischemia in pigs. J Cardiovasc Pharmacol. 2003;42:688696. Copyright © 2003, Lippincott Williams & Wilkins.
POSTSTENOTIC MYOCARDIUM
ST-segment shift
Regional myocardial contractility
10
0
100
Vehicle
–20
–40
– 60
–80
–100
***
***
T
0
he preclinical studies confirmed
both the pivotal role of the If
current in the regulation of heart rate and
the selective inhibition of the If current
with Procoralan, resulting in a reduction
in basal heart rate and exercise-induced
tachycardia without any modification of
other electrophysiological or hemodynamic parameters. These studies also
demonstrated that the pure heart rate
reduction obtained with Procoralan resulted in a similar limitation of exerciseinduced myocardial ischemia as with
β-adrenergic blockers, while ensuring
better preservation of regional myocardial
contractility.
The clinical development of Procoralan
confirmed these properties in patients,
showing, in particular:
◆ A selective electrophysiological effect:
Procoralan lowers the heart rate without
modifying atrioventricular and intraventricular conduction or the QT interval
of the electrocardiogram corrected for
heart rate.59
◆ A selective hemodynamic effect, in particular in patients with left ventricular
dysfunction, in whom Procoralan reduces
the heart rate while preserving left ventricular ejection fraction.60
◆ The efficacy of Procoralan in preventing exercise-induced myocardial ischemia in patients with stable angina. This
was demonstrated by two large-scale
clinical trials,61,62 which were the first to
show that selective heart rate reduction
with Procoralan results in a major protection against exercise-induced myocardial ischemia at a level comparable to
that afforded by the β-adrenergic blocker
atenolol.62
In future, we expect that the clinical
benefit of Procoralan, at present demonstrated in patients with stable angina, will
also be demonstrated in the other clinical forms of myocardial ischemia.
Procoralan could be of particular value
in ischemic heart disease with left ventricular dysfunction, by preventing the
deleterious hemodynamic effect of elevated heart rate, as well as the imbalance
between myocardial oxygen delivery and
consumption, without affecting myocardial contractility.
Regarding heart failure, the potential
therapeutic value of Procoralan was
recently illustrated in a rat model of ischemic heart failure, in which long-term
heart rate reduction was associated with
improvement in left ventricular function
and structure.63
10
Change from rest
What lessons does the discovery and
development of Procoralan hold, and
what are the prospects for the future?
T E RV I E W
**
80
60
40
20
0
Vehicle
–20
Figure 10. Comparison of the effects of Procoralan (5 mg/kg, orally), propranolol (5 mg/kg,
orally), and vehicle on ST-segment shift and regional contractility in the poststenotic myocardium during exercise performed 3 hours after treatments. Data are expressed as mean ± SEM
(n=5). Significantly different from vehicle: **P<0.01, ***P<0.001.
Modified from reference 58: Vilaine JP, Bidouard JP, Lesage L, et al. Anti-ischemic effects of ivabradine, a selective
heart rate reducing agent, in exercise-induced myocardial ischemia in pigs. J Cardiovasc Pharmacol. 2003;42:688696. Copyright © 2003, Lippincott Williams & Wilkins.
However, some of the most intriguing
prospects relate to the inhibition of the
If current per se: the cardiac If current,
which normally only occurs in pacemaker cells in the adult, has been shown to
be reexpressed in ventricular cardiomyocytes isolated from human hearts explanted because of terminal ischemic
heart failure.64 This If current is thought
to represent an arrhythmogenic mechanism, which could benefit from the action of Procoralan.
Finally, a major challenge for the future is to determine whether, as suggested by experimental studies and mentioned above, pure long-term heart rate
reduction due to If inhibition with Procoralan could improve the prognosis of
coronary artery disease by modifying the
progression of atherosclerotic lesions,
the development of coronary collaterals,
cardiac remodeling, and arrhythmogenic
mechanisms. Again, the prospects here
appear to be promising. ❒
73
IN
T E RV I E W
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IN
LA
DÉCOUVERTE DE
PROCORALAN, L’INHIBITEUR
L
e ralentissement sélectif de la fréquence cardiaque apparaît
comme une une approche thérapeutique attractive pour
le traitement des cardiopathies ischémiques. La fréquence
cardiaque représente le facteur de consommation d’oxygène myocardique le plus important et son accélération est impliquée dans
la plupart des épisodes cliniques d’ischémie myocardique. La réduction de la fréquence cardiaque peut prévenir ou réduire le
déséquilibre entre besoins et apports en oxygène myocardique, qui
définit l’ischémie myocardique, en diminuant la consommation
d’oxygène myocardique et en améliorant la perfusion myocardique par augmentation du temps de diastole. De plus, de nombreuses études épidémiologiques font apparaître que l’augmentation de la fréquence cardiaque représente un facteur indépendant
prédictif de mortalité et que la réduction de mortalité dans les
cardiopathies ischémiques ou l’insuffisance cardiaque observée
avec les bêtabloquants, certains inhibiteurs calciques ou l’amiodarone, peut être attribuée à l’effet de ces produits sur la fréquence cardiaque. Par ailleurs, des études expérimentales suggèrent que le ralentissement de la fréquence cardiaque peut limiter
la progression et la rupture des lésions d’athérosclérose, favoriser
le développement des collatérales coronaires, améliorer le remodelage cardiaque et avoir un effet antiarythmique. Ces mécanismes pourraient participer à l’amélioration du pronostic des
cardiopathies ischémiques liée à la réduction de la fréquence
DU COURANT
T E RV I E W
IF
cardiaque au-delà de son effet anti-ischémique. Le criblage d’une
série originale de composés, de structure benzocycloalkane, a
conduit à la sélection de Procoralan, premier inhibiteur sélectif
du courant dépolarisant If du nœud sinusal. In vitro, ce produit
réduit, de façon directe, la fréquence des battements spontanés
d’oreillettes droites isolées de rat et de déclenchement des potentiels d’action de préparations sino-auriculaires de lapin. Cet effet
est lié à une diminution de la pente de dépolarisation diastolique
du potentiel d’action et est sous-tendu par une inhibition sélective du courant pacemaker If du nœud sinusal. In vivo, Procoralan
réduit sélectivement la fréquence cardiaque, tant au repos qu’à
l’effort, sans modifier la contractilité myocardique, la conduction
auriculo-ventriculaire ou la durée de repolarisation ventriculaire.
Il limite de façon aussi efficace qu’un bêtabloquant l’ischémie
myocardique induite par l’exercice chez le porc, mais réduit mieux
la dysfonction myocardique contractile qui en résulte. Le développement clinique de Procoralan a confirmé la sélectivité de son
effet électrophysiologique et hémodynamique et son efficacité,
équipotente à celle d’un bêtabloquant, à prévenir l’ischémie myocardique d’effort chez des patients présentant un angor stable. Le
bénéfice thérapeutique de Procoralan est également attendu dans
les autres formes cliniques d’ischémie myocardique, en particulier avec insuffisance cardiaque, ainsi que dans l’amélioration du
pronostic des cardiopathies ischémiques.
✦
75
F
O C U S
LIVING WITH STABLE ANGINA:
HOW DOES IT IMPACT ON THE DAILY LIFE
OF PATIENTS AND WHAT ARE THE
TREATMENT OPTIONS?
by C. A. Wright, United Kingdom
What is it like living with angina?
n many cases angina leads to a life of anxiety, depression, and fear. Many patients fear that they
may die during an anginal attack and yet the
symptom is often only described as a “discomfort”
or “tightness” rather than pain. It is also interesting
to note that many studies have shown that symptomatology is not directly related to the severity of
coronary artery disease (CAD) found on angiography.1 People with angina also commonly believe
that every attack causes damage to the heart. It is
these factors that leave patients isolated and depressed, avoiding any exertion or enjoyment in life.
Data regarding the adverse impact of depression
on prognosis are accumulating with studies such
as that reported by Barefoot et al.2 In this study,
1031 patients admitted for coronary angiography
were assessed for depression on admission, with a
median follow-up of 15.2 years. The investigators
found that surgical patients had a lower mortality
I
Christine A. WRIGHT, RN
Specialist Angina Department
Royal Brompton Hospital
London, UNITED KINGDOM
than those managed medically, but that, controlling for this, the Self-Rating Depression Scale (SDS)
scores were predictive of cardiac death. A total of
51.4% of the cohort with moderate-to-severe depression died of cardiovascular causes, compared
with 42.4% of the mildly depressed group and 38%
with no depression. Those with the most depression
were found to be most at risk in the first year, showing that we need to intervene as early as possible.
This is also the time to educate the cardiac patient
on the benefits of lifestyle changes and increasing
exercise before fears and misconceptions take hold.
It is also noteworthy that the increased risk associated with depression continues after 5 years of follow-up. In this, as in other studies, the depression
score at baseline was not linked to the severity of
disease or recurrent events. The authors suggest that
possible causes of the increased risk associated with
depression are neuroendocrine function, poor compliance with medication, and increased cardiovascular risk factor profile.
✦
C
oronary artery disease (CAD) is a complex, multifactorial
disease process. Angina is a common manifestation of this
process, often leading to a life associated with unemployment, depression, anxiety, and social isolation. That is not to say
that there are no solutions to these comorbidities and, along with
the explosion of research in the pharmaceutical and technical interventions, there are many “low-tech” therapies that are effective in improving the quality of life of such patients. Imaginative,
self-help programs designed for use at home are available, and
refractory angina clinics have been introduced. Globally, we are
beginning to acknowledge that the industrial lifestyle of inactivity, convenience food, and nicotine consumption has greatly
contributed to this epidemic of atherosclerosis. Lifestyle interventions are often as challenging as the research and development,
but we should not be discouraged by the enormity of the problem.
Reduction in cigarette smoking has helped to reduce the incidence
of the disease, and legislation, such as that passed by Ireland to
ban smoking in the workplace, shows that bold initiatives can be
made. Other ideas such as introducing free fruit into schools and
designing buildings and housing estates that encourage more
76
exercise are slowly working their way into public life. The paradox of CAD is that the disease is the most common cause of mortality in the West, but the remedies to help prevention are relatively simple. CAD rates have reached epidemic proportions in the
more affluent parts of the world and are also increasing in urbanized parts of the developing world. The incidence of angina increases with age, so it is inevitable that there will be more people
to treat as we live longer. It would also be fair to say that of all the
chronic diseases afflicting the Western world, ischemic heart disease has made the most dramatic progress in treatment and prevention. This paper looks at the impact angina can have on everyday life and at some of the ways it can be ameliorated.
Keywords: stable angina; depression; lifestyle changes;
rehabilitation
Address for correspondence: Christine A. Wright, RN, Specialist Angina Department,
Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
Living with angina: impact and treatment options – Wright
FO
Depression is a modifiable risk factor and treatment helps to improve health outcomes.3 Ruo et al
studied 1024 patients with known CAD and performed psychological as well as cardiac functional
assessment. They recruited participants with previous myocardial infarction (MI), history of revascularization, and diagnosis of CAD made by a physician, and found a strong association between
depression and self-reported health status outcome
in all groups. Of the 1024 participants in their study,
20% had depression, and the depressive symptoms
were associated with overall health status, independent of cardiac function. Patients who were depressed were in the younger age-group, had lower
income, and were more likely to be female and unmarried. They were also more likely to have diabetes
mellitus, to smoke, to be obese, and to have lower
exercise capacity. The authors emphasize that more
attention should be paid to the mental health of
cardiac patients, and measures taken to treat depression.
Why does depression have an adverse effect? Does
it delay presentation for treatment? A recent study
by Dickens et al4 suggests that associated social isolation may play an important role. The authors studied people with depression before and after MI. They
found that depression preceding MI was not associated with increased morbidity or mortality, but
that having a close confidant halved the risk of having a subsequent cardiac event. These patients were
more likely to smoke and drink heavily though these
two variables were not predictive on their own. The
authors postulated that people without a close confidant may delay seeking treatment for suspected
MI and may be less likely to follow treatments once
discharged from hospital.They also emphasized that
although depression was not significantly associated with cardiac events post-MI, there was a high
prevalence of depression in the sample and that it
should be considered a risk factor when treating patients with CAD.
The main treatment options for depression in the
coronary patient are cognitive behavioral therapy
(CBT) and medication. Appels5 suggests that CBT
would be an appropriate choice if feelings of sadness, hopelessness, and negative thoughts about
the future extend beyond the diagnosis of CAD. He
does point out that CBT should be offered with caution, and not offered to those in whom depression
is a realistic response, ie, with a poor prognosis,
rather that a distortion of the reality. Antidepressant
therapy can be effective, although Appels stresses
that it should be offered as part of comprehensive
SELECTED
CAD
CHAMP
Cardiac Hospitalization Atherosclerosis Management Program
EUROASPIRE II Second EUROpean Action on
Secondary Prevention by Intervention to Reduce Events
MI
TENS
transcutaneous electrical nerve
stimulation
C U S
treatment. He postulates that many coronary patients refuse antidepressive medication for fear of
being branded as having a mental health problem.
Relaxation therapy using breathing techniques can
be a powerful tool, especially for those reluctant to
admit to, or are insensitive to, fatigue. These techniques are also useful for those patients with emotional triggers for angina. Gabbay et al6 studied 63
patients with CAD, and, using Holter monitoring,
looked at myocardial ischemia during daily life.
They found that ischemia occurred not only during
strenuous activity, but also with other triggers during low levels of exertion such as anger and smoking.
Patients with stable angina form a considerable
proportion of patients with CAD. They are often not
included in the rehabilitation programs offered to
other cardiac patients. Angina can have a deleterious impact on life, both mentally and physically.
This often leads to maladaptive behavior, resulting
in a sedentary lifestyle, physical deconditioning, and
depression. Lewin has developed the Angina Plan,7
which is a cognitive behavioral self-help program.
Health professionals, mainly nurses, take a distance
learning course in order to deliver the program. It
is designed to help alter false beliefs and anxieties
and encourage healthy lifestyle changes and more
enjoyment in life. This is done by reeducation, relaxation techniques, and individualized exercise
programs, along with risk factor management, all
supported by the health care professional. It is a
practical and effective way of reaching many people
in the community who may otherwise be neglected.
The group in York, led by Lewin, evaluated the Angina Plan7 in a randomized controlled study looking
at patients with newly diagnosed angina. They found
that compared with usual advice and consultation
given by a practice nurse, the Angina Plan significantly reduced reported angina, improved psychological well being, and increased activity levels.
Other imaginative treatment strategies have been
developed. Lorig et al8 at Stanford University looked
at 831 people suffering from at least one chronic
disease and asked them to participate in an intensive 71/2-week self-management program. The program was based on one used for arthritis management and was adapted for use in any of four chosen
chronic diseases, one of them being heart disease.
The classes included relaxation and distraction techniques, nutritional change, fatigue and sleep management, training in communication with health
professionals, and the management of fear, anger,
and depression. The participants were assessed at 1
and 2 years for health status, self-efficacy, and health
care utilization. Those that participated in the selfmanagement program showed a significant reduction in visits to hospital and GP and in health distress, and had increased self-efficacy. Interestingly,
the improvement continued at 2 years even if some
participants had more than one chronic disease with
deterioration in their symptoms.
The Chronic Disease Self-Management Program
developed by Lorig has been adapted for use in
the UK and is part of the Expert Patient Scheme
(www.expertpatients.nhs.uk). The instructors are patients, usually having one or more chronic diseases,
77
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C U S
and have attended a short training course. Similar
schemes are running in Europe and Australasia.
There are many studies that illustrate the impact
behavioral change can have on a disease process.
Ornish et al9 set out to look at the short-term effects
of stress management training in 46 patients with
CAD and randomly assigned them to an intense intervention program for 1 month and compared
them with the nonintervention group receiving
conventional care. The authors addressed characteristics of many cardiac patients, including anxiety, depression, competitiveness, and impatience, by
promoting behavioral changes through meditation,
yoga, and relaxation techniques. The intervention
group was taken to a residential, rural setting and
introduced to regular programs of behavioral management as well as adhering to a strict vegan diet,
avoiding sugar, salt, alcohol, and caffeine. The results showed that the treatment group, despite the
fact that there was no aerobic training, improved
their exercise duration by 44% on bicycle ergometry. The plasma cholesterol levels and triglycerides
dropped by significant levels, and the amount of reported angina decreased from 10.1 to 1.6 per week.
Left ventricular function was assessed using exercise radionuclide ventriculography and showed that
in the treated group the mean ejection fraction response to exercise was significantly improved, with
also some improvement in regional wall motion at
peak exercise. Although this was a short-term study,
it did show what can be done with relatively simple
interventions. It should certainly help to inform patients that change in lifestyle can lead to dramatic
improvement in health.
met. Neuroticism had a significantly deleterious effect on recovery and was the leading predictor of
cardiac invalidism. It would appear that maximum
social support should occur for about 1 month following the event with a gradual reduction over the
next few months. Health care workers should look
out for signs of neuroticism such as moodiness, poor
concentration, surges in energy, and sluggishness.
Patient educational achievement, literacy, and
socioeconomic status can also influence the prevalence of risk factors for CAD.
The likelihood of receiving appropriate treatment
has been examined by a substudy of the Second EUROpean Action on Secondary Prevention by Intervention to Reduce Events (EUROASPIRE II).12 The
investigators found that from the fifteen participating European countries, patients with known CAD
and lower educational status had higher body mass
index, blood pressure, glucose, and total cholesterol. In women, educational status did not affect
their smoking habits, but, in men, smoking was
significantly less prevalent with higher educational achievement. β-Blockers and statins were most
likely to be prescribed to those with higher educational achievement, whereas those with lower educational status were more often treated with calcium antagonists and antidiabetic drugs. In order to
reach disadvantaged groups in the community, including ethnic minorities, health providers should
look at ease of access to their clinics, both for clinic times and transport. Outreach clinics can sometimes offer a solution.
What other factors affect outcome?
The dramatic improvement in cardiac mortality in
recent years is, in part, attributable to new medication tested with well-conducted, sufficiently powered trials. Many patients dislike taking medication,
especially as the number of tablets increases. It is
important to rationalize their medication list on a
regular basis and explain the necessity for their prescription. Safety is often a concern mentioned by
patients, but we are fortunate to have numerous
studies to help support our reassurances that these
drugs are safe. Some patients respond well to hearing details of such studies and their results. Regular biochemistry monitoring can help to forestall
any potential harm and if adverse effects are mentioned, then a suitable alternative should be sought.
Most countries in Europe have guidelines for
treating conditions such as angina. A recent EuroHeart Survey13 of newly presenting stable angina
looked at prescribed medication of such patients.
It found that 81% of patients were prescribed an
antiplatelet agent, but only 48% were given a statin
and 67% were prescribed a β-blocker. This shows a
resistance to prescribing according to guidelines,
particularly as these patients may well have to wait
several months before their diagnostic tests are
complete.
A group in California looked at ways of improving secondary prevention measures in patients with
demonstrated CAD, prior to hospital discharge.14
They developed a program called CHAMP (Cardiac
Misinformation is widely available from friends,
media, and medical staff. This can lead to unnecessary anxiety and unhelpful coping strategies. Furze
et al10 investigated this phenomenon using a postal
survey of 132 patients and their friend or partner.
The interesting finding was that the peers or partner were significantly more likely to think that people with angina should take life easy, avoid exercise,
and that angina causes permanent damage to the
heart. While pressure of time is often used as a reason for not discussing secondary prevention, this
study shows that health professionals should use
every opportunity to discuss the importance of exercise, diet, and smoking cessation.
It is sometimes thought that cardiac invalidism is
caused by having overprotective support, but this
is not necessarily the case. Riegal and Dracup11 describe cardiac invalidism as low self-esteem, anxiety,
and a feeling of being highly dependent on others,
whatever the severity of the disease. The study comprised of 120 patients experiencing their first MI,
and unaware of any preexisting coronary disease.
Follow up was 1 month and 4 months post event.
The significant finding was that the group of patients who perceived themselves to be overprotected recovered sooner than those who did not.
The authors observed that cardiac invalidism
seems to develop when a patient’s needs are not
78
Medication
FO
Hospitalization Atherosclerosis Management Program). The emphasis of the program was that aspirin, cholesterol-lowering medication using lowdensity lipoprotein (LDL) as a target, β-blocker, and
angiotensin-converting enzyme (ACE)-inhibitor
therapy should be prescribed unless contraindicated. The patients also received secondary prevention
advice. The goal was that these medications and
secondary prevention advice should be administered prior to hospital discharge, emphasizing their
importance and hopefully improving compliance.
The algorithm included a 6-week, 6-month, and
1-year follow-up to check fasting lipids, exercise levels, smoking status, and compliance and adjustments to medication.
Subsequently, patients in the CHAMP program
were assessed and compared with non-CHAMP subjects. They found that hospital discharge rates for
prescribing aspirin was 78% pre CHAMP compared
with 92 % post CHAMP, β-blocker from 12% to 61%,
ACE inhibitors from 4% to 56%, and statins from
6% to 86%. These simple and cost-effective measures can be implemented with demonstrable results.
Fortunately, most cardiac medications are in a
once-daily formula, and maybe in the future several pharmacological agents will be incorporated into
one “polypill.”
How can we best help our patients?
A well-run, comprehensive rehabilitation program
is invaluable. A good example is one based in Basingstoke, UK. It offers both physical and psychological evaluation so that the course will suit the
patient as an individual. It also includes stress management, relaxation, risk factor modification, and
an exercise program. Participants can attend for up
to 6 months. The unit evaluated the outcomes of
their course and also looked at the patient characteristics.15 Of the 1902 patients recruited, they found
a 20% increase in physical fitness and a significant
reduction in anxiety and depression, particularly in
females. The commonest cause for defaulting was
depression, whereas age, gender, anxiety, and initial fitness did not affect compliance. Patients with
a primary diagnosis of angina and those with percutaneous transluminal coronary angioplasty (PTCA)
were twice as likely to default than those post MI
and post coronary artery bypass grafting (CABG).
Unfortunately, those who would most benefit from
cardiac rehabilitation are least likely to attend. The
authors recommend that this group of patients
should be identified at enrollment and particular
attention given to encourage attendance.
It is important to identify cardiac patients least
likely to use medical services so that they can be
targeted and solutions found to improve uptake.
A group of patients from the Rotherham area of
North England participated in a study looking at
barriers to uptake of health services.16 They all had
stable angina and many complex reasons for not
using services. There were practical issues such as
poor transport and inconvenient or infrequent surgery times. The episodic nature of angina led to pa-
C U S
tients delaying consultation, along with fear, denial,
a wish to self-manage, and low expectation were
other reasons for poor uptake of health services.
These barriers operate before general practitioners
get involved, and the authors suggest that one solution would be to set up community development
programs. Adherence to national guidelines helps
to reduce inequality of care.
Support from health professionals is important
when directing patients toward lifestyle changes.
This is well illustrated in a paper looking at 6-month
health outcomes of patients with angina discharged
from a chest pain service.17 The authors followed up
57 patients admitted to hospital with chest pain and
a confirmed diagnosis of CAD. Fifty-eight per cent of
the participants still had angina and 72% reported
shortness of breath; however, there was no rehabilitation program available for these patients, resulting in frequent contact with primary care services,
which was not always appropriate or effective.
Beinhart et al18 looked at treatment satisfaction
following admission with acute coronary syndrome
and found that poor physician-patient communication and angina frequency were strongly associated
with reduced satisfaction.
Although the importance of behavioral and lifestyle change is established, the provision of cardiac
rehabilitation (CR) is patchy and mainly aimed at
CABG patients. In the UK, it is estimated that of all
the people receiving CR, 33% to 56 % are post-bypass patients, 14% to 23 % are post-MI, and 6% to
10 % are post-PTCA.19 The substantial group of patients with stable angina is truly neglected.
What about the patients refractory
to interventional and
pharmaceutical intervention?
It is not always possible to control angina with intervention or maximum medical therapy. The characteristics of patients with refractory angina are
3-vessel disease with well-preserved left ventricular
function. They rarely suffer from arrhythmias, and
cardiovascular mortality is low at 3.5% to 5% per
annum, but they have debilitating angina.20 Some
centers have set up refractory angina clinics to offer
treatments using a multidisciplinary approach including cardiologists, anesthetists specializing in
pain management, psychologists, and clinical nurse
specialists. Although there is not much evidence
to support some of the interventions, the patient
should be evaluated and treated using set algorithms. Treatments such as transcutaneous electrical nerve stimulation (TENS), spinal cord stimulation, temporary or permanent sympathectomy,
and enhanced external balloon counterpulsation all
have their part to play in pain relief. Stem cell therapy to stimulate new blood vessel formation in the
myocardium is one of the hopes for the future.
It is with risk factor modification that the most
dramatic effects on mortality can be seen,21 as highlighted by a recent exploration of the effects of treatment and risk on CHD mortality in England and
Wales. This paper shows the areas of treatment that
have the most effect on mortality, namely, that apMEDICOGRAPHIA, VOL 27, No.1, 2005
79
FO
C U S
80
60
Treatment
50
Risk
40
30
be
sit
Ph y
ys
ica
l
Di
ab inac
et
t
es ivit
y
20
10
O
Total deaths prevented or postponed (%)
70
proximately 40% of the reduction in mortality was
attributable to the combined effects of modern cardiological treatments and almost 60% to reduction
in major risk factors, particularly smoking. Of great
concern, they point out that the increase in obesity, and incidence of diabetes and physical inactivity contributed to approximately 8000 additional
deaths in 2000. Looking at current trends in the
prevalence of these risk factors, this is likely to deteriorate in the future (Figure 1).21
Conclusion
It would not be unreasonable to conclude that the
incidence of angina is going to increase globally in
the foreseeable future. Groups of patients most in
need of attention, such as the depressed, socially deprived, and ethnic groups, need to identified and
strategies introduced to include them in all the resources available. A multidisciplinary approach is
the way forward so that we inspire our patients to
REFERENCES
1. Lewin B. The psychological and behavioral management of angina. J Psychom Res.1997;43:453-462.
2. Barefoot JC, Helms MJ, Mark DB, et al. Depression
and long term mortality risk in patients with coronary artery disease. Am J Cardiol. 1996;76:613-617.
3. Ruo B, Rumsfeld JS, Hlatky M, Liu HY, Browner
WS, Whooley MA. Depressive symptoms and healthrelated quality of life. JAMA. 2003;290:215-221.
4. Dickens CM, McGowan L, Percival C, et al. Lack of
a close confidant, but not depression, predicts further
cardiac events after myocardial infarction. Heart.
2004;90:518-522.
5. Appels A. Depression and coronary heart disease:
observation and questions. J Psychosom Res. 1997;
43:443-452.
6. Gabbay FH, Krantz DS, Kop WJ, Hedges SM, Klein
J, Gottdiener JS. Triggers of myocardial ischaemia
during everyday life in patients with coronary artery
disease: physical and mental activities, anger and
smoking. J Am Coll Cardiol. 1996;27:585-592
7. Lewin RJP, Furze G, Robinson J, et al. A randomized controlled trial of a self-management plan for patients with newly diagnosed angina. Br J Gen Pract.
2002;52:194-201.
8. Lorig KR, Ritter P, Stewart AL, et al. Chronic disease
80
r
la ol
tio
De n B
P
pr
iva
tio
n
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ste
ok
i
ol
e
Po
pu
Sm
Ch
M
pr
I
ev
He enti
on
ar
tf
ai
Al
l
lt
re ure
Al atm
lr
e
isk nts
fa
cto
rs
na
gi
2n
d
ns
te
er
Hy
p
–10
An
io
n
0
Figure 1. Proportional contributions
of specific treatments and risk factor
changes to coronary heart disease
(CHD) mortality reduction in England and Wales, 1981-2000: results
of a sensitivity analysis.
Symbols and abbreviations: ■ best estimate,
minimum, maximum; BP, blood pressure;
MI, myocardial infarction.
Reproduced from reference 21: Unal B,
Critchley J, Capewell S. Explaining the Decline
in coronary heart disease mortality in England
and Wales Between 1981 and 2000. Circulation.
2004;109:1101-1107. Copyright © 2004,
American Heart Association.
take control of their condition and be part of the
decision making process. Angina is a devastating
disease, the foundations of which are laid down prior to conception. Looking into the future, the emphasis must be on lifestyle modification or else our
evolutionary journey will condemn many of us to a
life of morbid obesity leading to conditions such as
CAD, a largely preventable disease.
The EU has stated that one of the objectives for
the new millennium is that every child born should
be free from avoidable cardiovascular disease until
the age of 65. This will require enormous changes in
our societies, including resisting the power of the
corporate food, drink, and leisure industry. Looking at the history of our addiction to tobacco, we can
see what can be achieved and we should not easily
abandon the ambition to improve our quality of life
no matter how enormous the task may seem. ❒
I would like to thank Caroline Daly, MB, BCh, and Henry
Purcell, MB, PhD, for their support in writing this paper.
self-management program: 2-year health status and
health care utilization outcomes. Med Care. 2001;
39:1217-1223.
9. Ornish D, Scherwitz LW, Doody RS, Kesten D,
McLanahan SM, Brown SE. Effects of stress management training and dietary changes in treating ischemic heart disease. JAMA. 1983;249:54-59.
10. Furze G, Roebuck A, Bull P, Lewin RJ, Thompson
DR. A comparison of the illness beliefs of people with
angina and their peers: a questionnaire study. BMC
Cardiovasc Disord. 2002;2:4.
11. Riegal BJ, Dracup KA. Does overprotection cause
cardiac invalidism after myocardial infarction? Heart
Lung. 1992;21:529-535.
12. Mayer O, Heidrich SJ, Cokkinos DV, De Bacquer D.
Educational level and risk profile of cardiac profile
of cardiac patients in the EUROASPIRE II substudy.
J Epidemiol Commun Health. 2004;58:47-52.
13. EuroHeart Survey of Newly Presenting Stable Angina. ESC Abstract Presentation. 2003.
14. Fonarow G, Gawlinski A, Moughrabi S, Tillisch J.
Improved treatment of coronary heart disease by implementation of a Cardiac Hospitalization Atherosclerosis Management Program (CHAMP). Am J Cardiol.
2001;87:819-822.
15. Turner SC, Bethell HJ, Evans JA, Goddard JR,
Mullee MA. Patient characteristics and outcomes of
cardiac rehabilitation. J Cardiopulm Rehabil. 2002;
22:253-260.
16. Todd AM, Read C, Lacey A, Abbott J. Barriers to uptake of services for coronary heart disease: qualitative
study. BMJ. 2001;323:1-6.
17. Smith K, Rose D, Connolly E. Investigating sixmonth health outcomes of patients with angina discharged from a chest pain service. Eur J Cardiovasc
Nurs. 2002;1:255-264.
18. Beinhart SC, Sales AE, Spertus JA, Plomondon ME,
Every NR, Rumsfeld JS. Impact of angina burden and
other factors on treatment satisfaction after acute
coronary syndromes. Am Heart J. 2003;146:646-652.
19. Bethell HJ, Turner SC, Evans JA, Rose L. Cardiac
rehabilitation in the United Kingdom. How complete
is the provision? J Cardiopulm Rehabil. 2001;21:111115.
20. DeJongste M, Tio R, Foreman R. Chronic refractory angina pectoris. Heart. 2004;90:225-230.
21. Unal B, Critchley J, Capewell S. Explaining the
Decline in coronary heart disease mortality in England and Wales Between 1981 and 2000. Circulation.
2004;109:1101-1107.
FO
C U S
VIVRE AVEC UN ANGOR STABLE :
IMPACT SUR LA VIE QUOTIDIENNE DES PATIENTS ET OPTIONS THÉRAPEUTIQUES
L
a maladie coronaire est un processus pathologique complexe et multifactoriel. L’angor en est sa manifestation la
plus commune et ce symptôme retentit souvent sur la vie
du malade, au travers du chômage, de la dépression, de l’anxiété
ou encore de l’isolement social. Cela ne veut pas dire qu’il n’y a
pas de solutions pour ces comorbidités et, en même temps que
l’explosion de la recherche dans les interventions techniques et
pharmaceutiques, sont apparus des traitements adjuvants non
pharmacologiques, néanmoins capables d’améliorer la qualité de
vie. Des programmes originaux qui relèvent de l’auto-assistance,
conçus pour être utilisés à domicile, sont désormais disponibles
et des cliniques pour l’angor réfractaire ont été créées. Globalement, nous commençons à réaliser que le mode de vie sédentaire
des sociétés industrielles, le recours aux aliments tout prêts et la
consommation de nicotine ont largement contribué à cette épidémie d’athérosclérose. Les interventions visant à modifier ce
mode de vie constituent souvent un défi qui s’apparente à celui
de la recherche et du développement, mais il ne faut pas se décourager face à l’énormité du problème. La diminution de la consommation tabagique a contribué à réduire l’incidence de la maladie
et la législation, adoptée en Irlande, qui interdit de fumer sur le
lieu de travail, montre que des initiatives audacieuses peuvent
être prises. D’autres idées font lentement leur chemin dans le domaine public, qu’il s’agisse de la mise en place de la consommation gratuite de fruits dans les établissements scolaires ou encore
de la conception d’immeubles ou de logements qui incitent à une
plus grande dépense physique. Le paradoxe de la maladie coronaire est que celle-ci représente la cause de mortalité la plus fréquente dans les pays occidentaux, alors que les remèdes destinés
à sa prévention sont relativement simples. Cette affection a pris
des proportions épidémiques dans la plupart des sociétés d’abondance du monde, mais sa fréquence augmente aussi dans les
zones urbaines des pays en voie de développement. L’incidence de
l’angor augmente avec l’âge, de sorte qu’il y aura inévitablement
de plus en plus de malades à traiter dans la mesure où nous vivons plus longtemps. Il faut aussi signaler à juste titre que, de
toutes les affections chroniques qui frappent les pays occidentaux,
les cardiopathies ischémiques sont celles qui ont connu les progrès les plus spectaculaires en termes de prévention et de traitement. Cet article envisage l’impact que peut avoir l’angor sur
la vie quotidienne et certains des moyens qui permettent de l’améliorer.
✦
81
U
P D A T E
CLINICAL APPLICATIONS
OF EXCLUSIVE HEART RATE REDUCTION
IN EMERGENCY CARDIOLOGY
b y A . D i a z a n d J . - C . Ta r d i f , C a n a d a
hysicians in intensive-care units and emergency wards are routinely faced with clinical
situations where heart rate reduction would
be desirable in unstable patients. Some of these patients are dependent on inotropic and/or vasoactive
drugs such as epinephrine, norepinephrine, and dobutamine, and most adrenergic agonists produce
tachycardia. An induced or spontaneously high heart
rate leads to both greater myocardial oxygen consumption (MVO2) and decreased myocardial perfusion, the latter by shortening the duration of diastole, which can induce or exacerbate myocardial
ischemia. Pulmonary congestion and/or hemodynamic instability often make β-blockers and other
negative chronotropic agents such as calcium-chan-
P
SELECTED
▲
Jean-Claude TARDIF, MD,
FRCPC, FACC
Ariel DIAZ, MD
Montreal Heart Institute (MHI)
Research Center, Montreal
CANADA
AV
COPD
IABP
INITIATIVE
nel blockers relatively contraindicated. A selective
heart rate–reducing agent would often represent
a more logical option than the use of β-blockers or
calcium channel blockers in these settings. In addition to its already known antianginal and anti-ischemic properties,1,2 the If channel inhibitor ivabradine (Procoralan) holds promise in cardiovascular
emergencies (Tables I & II). Its pharmacokinetic
properties, ability to selectively reduce heart rate,
and lack of deleterious hemodynamic effects, result
in several possible therapeutic applications for ivabradine in conditions such as acute heart failure
with decreased or preserved ventricular function,
shock, and inappropriate sinus tachycardia. In addition, contraindications to the use of β-blockers in
patients with acute coronary syndromes represent
other potential indications for ivabradine.
Pharmacological properties
of ivabradine
atrioventricular
chronic obstructive pulmonary disease
intra-aortic balloon pump
INternatIonal TrIAl on the Treatment
of angina with IVabradinE versus
atenolol
Ivabradine (Procoralan) is a new heart rate–reducing agent that acts by inhibiting the specific If current involved in the pacemaker activity of sinoatrial (SA)-node cells. Its N-demethylated metabolite,
✦
I
vabradine is a selective and specific If channel inhibitor with
proven antianginal and anti-ischemic properties, but without effects on blood pressure, systolic and diastolic function,
and atrioventricular (AV) node conduction. Its unique pharmacokinetic-pharmacodynamic properties, ability to selectively reduce heart rate, and lack of deleterious hemodynamic effects, result in several possible therapeutic applications for ivabradine in
conditions such as acute heart failure with decreased or preserved
ventricular function, shock, and inappropriate sinus tachycardia.
Patients with unstable angina or acute myocardial infarction
generally benefit from heart rate reduction both through a decrease in myocardial oxygen requirement and a lengthening in
the duration of diastole and myocardial perfusion. However, the
negative inotropic and hypotensive effects of -blockers contraindicate their use in patients with pulmonary congestion, low
blood pressure, or cardiogenic shock. The absence of effects on
systolic and diastolic function and blood pressure places ivabradine in a unique position to control heart rate in such unstable
patients. In addition, contraindications to the use of -blockers in
patients with acute coronary syndromes, such as bronchospasm
82
and AV block, represent other potential indications for ivabradine.
Tachycardia induced by the infusion of dobutamine or dopamine
may aggravate myocardial ischemia. Ivabradine may play a crucial role in the management of these patients, limiting unnecessary tachycardia without preventing positive inotropic effects,
hence improving myocardial perfusion and hemodynamic parameters in acute heart failure or cardiogenic shock. A wide range
of cardiovascular emergencies may benefit from the use of ivabradine, especially in clinical situations where heart rate reduction
is required, but the use of -blockers is limited by pulmonary congestion, hypotension, or other contraindications.
Keywords: heart rate; bradycardia; cardiovascular emergency;
angina; diastolic dysfunction
Address for correspondence: Jean-Claude Tardif, MD, FRCPC, FACC, Director,
MHI Center, Associate Professor of Medicine, Canadian Institutes of Health Research
Chair in Atherosclerosis, Montreal Heart Institute, 5000 Belanger Street, Montreal,
Canada H1T 1C8 (e-mail: [email protected])
Clinical applications of exclusive heart rate reduction in emergency cardiology – Diaz and Tardif
UP
S 18982, has also shown heart rate–reduction activity in animals as well as in humans. La Veille et al
reported the complete profile of the pharmacokinetic properties of ivabradine.3-7 This novel agent is
rapidly and well absorbed (tmax =0.75-1.5 hour) and
has good bioavailability (37% to 49%). Ivabradine
has extensive tissue distribution with limited protein binding. It is metabolized exclusively by cytochrome P450 3A4 to its active metabolite. The latter is eliminated by fecal and urinary pathways. The
half-life of ivabradine is 2 hours, whereas that of its
N-demethylated metabolite is 13 hours. In a study
of healthy volunteers assessing the correlation between bradycardic activity and plasma levels of the
parent compound and its metabolite, it was found
that ivabradine exerts a dose-dependent heart rate–
◆ Exclusive heart rate reduction
◆ Proven anti-ischemic and antianginal properties
◆ Absence of negative inotropic effects
◆ Preservation of left ventricular relaxation (lack
of effects on diastolic function)
◆ Preservation of blood pressure
◆ Preservation of atrioventricular and ventricular
conduction
◆ Absence of coronary vasoconstriction
◆ Absence of bronchospasm associated with
β-blockers
Table I. Advantages of ivabradine in emergency
cardiology.
◆ Unstable angina with tachycardia and congestive
heart failure
◆ Acute myocardial infarction with tachycardia
and congestive heart failure
D AT E
toriness of the atria, atrioventricular (AV) node, HisPurkinje system, and ventricles. In addition, Manz
et al studied with echocardiography the impact of
a single intravenous dose of ivabradine on left ventricular (LV) function in patients with systolic dysfunction.10 The LV ejection fraction did not significantly decrease with ivabradine (0.2%) compared
with placebo (1.7%). Other echocardiographic parameters, such as fractional shortening and stroke
volume, were also unchanged after the intravenous
administration of ivabradine.
Left ventricular relaxation is as crucial for optimal left ventricular function as is contractility. The
negative lusitropic effect of β-blockers could therefore be potentially deleterious. Colin et al11 investigated the effects of ivabradine and atenolol on LV
isovolumetric relaxation at rest and during treadmill exercise in chronically instrumented dogs. For
a similar reduction in heart rate at rest and during exercise, ivabradine, in contrast to atenolol, did
not exert any negative lusitropic effect (Figure 1,
page 84).12
Ivabradine has demonstrated a very good safety
profile in all clinical trials to date, including the
large multicenter, double-blind randomized INITIATIVE trial (INternatIonal TrIAl on the Treatment
of angina with IVabradinE versus atenolol)2 evaluating the antianginal and anti-ischemic effects of
ivabradine versus the β-blocker atenolol in 939 patients with chronic stable angina. The most frequent
adverse drug reactions have been visual symptoms,
the majority being phosphenes that were transient
and nonserious in nature. Importantly, the abrupt
discontinuation of ivabradine has not resulted in a
rebound phenomenon. Thus, these pharmacological properties of ivabradine render this drug suitable for use in cardiovascular emergencies.
◆ Acute coronary syndrome and contraindications
to β-blockers (eg, COPD)
◆ Acute diastolic heart failure
◆ Inappropriate sinus tachycardia with inotropic
agents for shock or congestive heart failure
◆ Inappropriate sinus tachycardia after cardiac
surgery
◆ Reduction of heart rate for beating heart surgery
(off-pump CABG surgery)
Table II. Indications of ivabradine in emergency
cardiology.
Abbreviations: CABG, coronary artery bypass graft; COPD, chronic
obstructive pulmonary disease.
reducing effect, to which its N-demethylated metabolite contributes.8 In this study, the maximal reductions in heart rate during exercise were 11%±4%
(10 mg) and 18%±6% (20 mg) after single oral doses (P<0.05), and 18%±4 % (10 mg) and 27%±6%
(20 mg) after repeated doses (P<0.01).8 Maximum
heart rate reduction after an intravenous bolus of
ivabradine was 19%±4%.
The electrophysiological effects of a single intravenous administration of ivabradine were studied
in patients with normal baseline electrophysiology
by Camm et al.9 They observed that an intravenous
dose of ivabradine does not prolong the corrected
QT interval (QTc) or modify conductivity and refrac-
Use of ivabradine
in acute congestive heart failure
and cardiogenic shock
Patients with unstable angina or acute myocardial
infarction generally benefit from heart rate reduction both through a decrease in myocardial oxygen
requirement and a lengthening in the duration of
diastole and myocardial perfusion. However, the
negative inotropic and hypotensive effects of βblockers contraindicate their use in patients with
pulmonary congestion, borderline blood pressure,
overt pulmonary edema, or cardiogenic shock (defined as hypotension, poor cardiac output, and evidence of tissue hypoxia in the presence of adequate
intravascular volume).12 LV systolic dysfunction
exacerbated by β-blockade may worsen myocardial
ischemia by causing pulmonary congestion and
hypoxemia and by decreasing the coronary perfusion pressure gradient, the latter by reducing systemic pressure and increasing LV filling pressure.13
Furthermore, ischemic LV dysfunction with or
without cardiogenic shock is not only characterized by systolic dysfunction, but it is also often accompanied by diastolic dysfunction.14 Because excessive tachycardia has deleterious consequences
on diastolic function, heart rate reduction is imporMEDICOGRAPHIA, VOL 27, No.1, 2005
83
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D AT E
A
LVP (mm Hg)
80
B
80
60
60
60
40
40
40
20
20
20
0
0
0
10
20
30
40
Time (ms)
C
80
0
0
10
20
Time (ms)
30
40
0
10
20
30
40
Time (ms)
Figure 1. Typical traces of the LVP (left ventricular pressure) measured during the isovolumic relaxation period vs time in a
conscious dog at baseline (A), at rest (B), and during exercise (C) at spontaneous heart rate. Data were obtained after administration of saline (gray curves), ivabradine (1 mg/kg; red curves), and atenolol (1 mg/kg; green curves). Each point was obtained
every 2 ms. Ivabradine did not alter the LVP decay either at rest or during exercise. In contrast, atenolol significantly prolonged
the LV isovolumic relaxation period both at rest and during exercise compared with control and ivabradine.
Modified from reference 12: Colin P, Glaleh B, Hittinger L, et al. Differential effects of heart rate reduction and beta-blockade on left ventricular relaxation
during exercise. Am J Physiol Heart Circ Physiol. 2002;282:H672-H679. Copyright © 2002, American Physiological Society.
tant to achieve. However, the negative lusitropic effects of β-blockers may represent another disadvantage in this setting. The absence of effects on systolic
and diastolic function and blood pressure places
ivabradine in a unique position to control heart rate
in such unstable patients.
Vasoactive and inotropic agents often need to be
initiated in patients with LV dysfunction and inadequate tissue perfusion. Dobutamine can precipitate inappropriate tachycardia and may exacerbate
hypotension in some patients. Dopamine also acts
directly on myocardial β1-adrenergic receptors and
indirectly releases norepinephrine. Tachycardia induced by the infusion of dobutamine or dopamine
may aggravate myocardial ischemia. Ivabradine may
play a crucial role in the management of these patients, limiting unnecessary tachycardia without
preventing positive inotropic effects, hence improving myocardial perfusion and hemodynamic parameters in overt heart failure or cardiogenic shock.
An optimal heart rate is also desirable in patients
with an intra-aortic balloon pump (IABP), which is
commonly used in patients with cardiogenic shock.
Systolic and diastolic ventricular dysfunction is
not only restricted to cardiogenic shock. LV function can also be abnormal in septic shock, resulting
in a continuum from isolated diastolic dysfunction
to combined diastolic and systolic failure.15 Limiting
tachycardia in ischemic patients with other causes
of shock is also a valuable potential application of
ivabradine.
Acute coronary syndromes
and contraindications to β-blockers
Although β-blockers have several side effects including depression, fatigue, sexual dysfunction, cold
extremities, and gastrointestinal disturbances, in
the emergency setting, bronchospasm and AV block
constitute the most relevant adverse reactions that
84
limit their use. While asthma or chronic obstructive pulmonary disease (COPD) represent only relative contraindications to β-blockade, some patients
clearly develop bronchospasm and wheezing with
β-blockers, which require dose reduction or abrupt
withdrawal. Such patients who require heart rate
reduction would clearly benefit from the lack of this
side effect with ivabradine. Furthermore, some patients with both an acute coronary syndrome and
COPD develop angina when treated with inhaled
β-adrenergic agonists because of the resulting
tachycardia. The heart rate reduction obtained with
ivabradine could also very helpful in this setting.
Patients with an acute coronary syndrome can
have variable degrees of AV block that develop or
are exacerbated with β-blockers. The need for selective heart rate reduction in patients with myocardial ischemia and AV-node conduction abnormalities represents another excellent indication for
ivabradine.
Acute diastolic heart failure
Treatment of diastolic dysfunction to date is largely unsatisfactory. In the absence of controlled clinical trials, the management of patients with diastolic dysfunction is based on the control of factors
that are known to exert important effects on ventricular filling, such as blood pressure, heart rate,
and myocardial ischemia.16 Although epidemiological studies have suggested that 30% to 50% of
heart failure patients have preserved LV systolic
function, the presumption that all of these patients
have isolated diastolic heart failure is probably incorrect.17 Nevertheless, Gandhi et al have reported
a series of 38 patients with acute pulmonary edema and hypertension18 in whom they evaluated LV
ejection fraction and regional function, both during the acute episode and 3 days after treatment.
Their conclusions were similar to what many physi-
UP
cians observe in their daily practice: patients with
hypertensive pulmonary edema show a normal LV
ejection fraction after treatment. This suggests that
the pulmonary edema might have been due to an
exacerbation of diastolic dysfunction.
Because limited data exist in patients with heart
failure and preserved LV ejection fraction,19 the use
of β-blockers remains largely speculative considering their negative inotropic and lusitropic effects. In contrast, ivabradine offers the unique advantage of lengthening ventricular filling time and
coronary perfusion without any other undesirable
effect on LV systolic and diastolic function in patients with acute diastolic heart failure with or without pulmonary edema.
Acute heart failure
and stenotic valvular disease
Another potentially valuable clinical application of
ivabradine in emergency cardiology is the decompensated patient with mitral stenosis. Hydraulic
laws dictate that for any given orifice size the transvalvular pressure gradient is a function of the square
of the transvalvular flow rate.20 Thus, a doubling
of flow rate quadruples the pressure gradient, and
therefore situations such as stress, exercise, or
tachycardia in patients with moderate or severe mitral stenosis cause a marked elevation of left atrial
pressure. Tachycardia shortens diastole proportionately more than systole and reduces the time available for flow across the mitral valve. In symptomatic patients with more than a mild degree of mitral
stenosis and in sinus rhythm, medication usually
begins with β-blockers.21 The rationale for this prescription is to avoid excessive tachycardia.22 However, there exists some controversy about the value
of β-blockers in this clinical situation.23 β-Blockers
may decrease resting and peak exercise heart rate,
but they have no beneficial effect on treadmill exercise time, aerobic capacity, and ventilatory performance.24,25 The exclusive heart rate–reducing agent
ivabradine may benefit patients with mitral stenosis in sinus rhythm because of its lack of effects on
blood pressure and systolic function.
The use of β-blockers is contraindicated in patients with aortic stenosis and acute heart failure.21
In such patients with severe aortic stenosis, angina,
and pulmonary congestion, pure heart rate reduction with ivabradine may allow patient stabilization
and cardiac surgery under more stable conditions.
REFERENCES
1. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind,
multicentered, placebo-controlled trial. Circulation.
2003;107:817-823.
2. Tardif J, Ford M, Tendera K. Anti-anginal and antiischemic effects of the If current inhibitor ivabradine
versus atenolol in stable angina. A 4-month randomised, double-blind, multicenter trial. Eur Heart J
Suppl. 2003;24:20. Abstract.
3. La Veille CF, Frey N, Lerebours G, Resplandy G,
Jochemsen R. Population pharmacokinetics-pharmacodynamics of a new specific bradycardic agent:
S-16257. In: Population Approach Group in Europe
(PAGE). Frankfurt; Germany; 1995.
Use of ivabradine
in the perioperative setting
The intraoperative management of patients undergoing off-pump coronary artery bypass graft
(off-pump CABG) surgery has distinctive and challenging features. Surgeons benefit from a “quiet”
surgical field and different mechanical stabilizers
are used in order to attain this important goal during off-pump CABG. During the procedure, drugs
such as β-blockers, calcium-channel antagonists,
adenosine, neostigmine, and edrophonium are used
to produce a lower heart rate. However, the surgeon
needs to manipulate the beating heart, which commonly leads to hypotension. While pharmacologically induced bradycardia is a desirable objective in
order to better stabilize the target vessel, frequent
hypotension episodes can preclude or limit the use
of β-blockers and other agents that can also lower
blood pressure during off-pump CABG. Bel et al26
tested different classes of bradycardic drugs in isolated buffer-perfused rabbit hearts. While nicorandil did not interfere with LV function, the βblocker esmolol induced marked deterioration of
systolic function. Significant heart rate reduction
was achieved with the pacemaker current inhibitor
ivabradine, which was otherwise associated with
an excellent preservation of contractility, diastolic
function, and coronary flow.26
Patients occasionally present inappropriate sinus
tachycardia in the first few days after cardiac surgery. Once causes for appropriate sinus tachycardia, such as cardiac tamponade, have been ruled out
in the postoperative setting, the use of ivabradine
may allow safe heart rate reduction27 in relatively
unstable patients or those in whom β-blockers are
relatively or absolutely contraindicated.
Conclusions
Ivabradine is a selective and specific If channel
inhibitor with proven antianginal and anti-ischemic
properties, but without effects on blood pressure,
systolic and diastolic function, and AV node conduction. It has unique pharmacokinetic-pharmacodynamic properties that allow its use in emergency
settings. A wide range of cardiovascular emergencies
may benefit from its use, especially in clinical situations where heart rate reduction is required, but
the use of β-blockers is limited by pulmonary congestion, hypotension, or other contraindications. ❒
Jochemsen R. Population pharmacokinetics-pharmacodynamics of a new specific bradycardic agent
(S 16257) and its metabolite (S 18982). Evaluation of
the drug/metabolite potency ratio. In: COST B1; 1997;
Geneva, Switzerland; 1997.
Jochemsen R. Population pharmacokinetics-pharmacodynamics of a new specific bradycardic agent
(S 16257) and its metabolite (S 18982). Evaluation of
the drug/metobolite potency ratio. In: Population Approach Group in Europe (PAGE). Glasgow, UK; 1997.
Jochemsen R. Population pharmacokinetics of a new
bradycardic agent in healthy male volunteers: influ-
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ence of food and time of administration. In: Population Approach Group in Europe (PAGE). 1996; Sandwich, UK; 1996.
7. Resplandy G, Klippert P, La Veille CF, Jochemsen
R, Merdjan H. A review of the pharmacokinetics of
S 16257 in healthy male volunteers. In: VIth European Congress of Biopharmaceutics and Pharmacokinetics 1996; Athens, Greece; 1996.
8. Ragueneau I, Laveille C, Jochemsen R, Resplandy G,
Funck-Brentano C, Jaillon P. Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a
direct sinus node inhibitor, on heart rate in healthy
volunteers. Clin Pharmacol Ther. 1998;64:192-203.
9. Camm AJ, Lau CP. Electrophysiological effects of
a single intravenous administration of ivabradine
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(S 16257) in adult patients with normal baseline electrophysiology. Drugs R D. 2003;4:83-89.
10. Manz M, Reuter M, Lauck G, Omran H, Jung W.
A single intravenous dose of ivabradine, a novel If inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology. 2003;100:149-155.
11. Colin P, Ghaleh B, Hittinger L, et al. Differential
effects of heart rate reduction and beta-blockade on
left ventricular relaxation during exercise. Am J Physiol Heart Circ Physiol. 2002;282:H672-H679.
12. Ryan TJ, Antman EM, Brooks NH, et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of
the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1999;34:890-911.
13. Hollenberg SM, Kavinsky CJ, Parrillo JE. Cardiogenic shock. Ann Intern Med. 1999;131:47-59.
14. Califf RM, Bengtson JR. Cardiogenic shock. N Engl
J Med. 1994;330:1724-1730.
15. Poelaert J, Declerck C, Vogelaers D, Colardyn F,
Visser CA. Left ventricular systolic and diastolic function in septic shock. Intensive Care Med.1997;23:553560.
LES
16. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA
guidelines for the evaluation and management of
chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/
American Heart Association Task Force on Practice
Guidelines (Committee to revise the 1995 Guidelines
for the Evaluation and Management of Heart Failure).
J Am Coll Cardiol. 2001;38:2101-2113.
17. Banerjee P, Clark AL, Nikitin N, Cleland JG. Diastolic heart failure. Paroxysmal or chronic? Eur J Heart
Fail. 2004;6:427-431.
18. Gandhi SK, Powers JC, Nomeir AM, et al. The
pathogenesis of acute pulmonary edema associated
with hypertension. N Engl J Med. 2001;344:17-22.
19. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur
Heart J. 2001;22:1527-1560.
20. Gorlin R, Gorlin SG. Hydraulic formula for calculation of the area of the stenotic mitral valve, other
cardiac valves, and central circulatory shunts. I. Am
Heart J. 1951;41:1-29.
21. Bonow RO, Carabello B, de Leon AC Jr, et al. Guidelines for the management of patients with valvular
heart disease: executive summary. A report of the
American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Commit-
tee on Management of Patients with Valvular Heart
Disease). Circulation. 1998;98:1949-1984.
22. Nakhjavan FK, Katz MR, Maranhao V, Goldberg
H. Analysis of influence of catecholamine and tachycardia during supine exercise in patients with mitral
stenosis and sinus rhythm. Br Heart J.1969;31:753761.
23. Klein HO, Sareli P, Schamroth CL, Carim Y, Epstein M, Marcus B. Effects of atenolol on exercise capacity in patients with mitral stenosis with sinus
rhythm. Am J Cardiol. 1985;56:598-601.
24. Monmeneu Menadas JV, Marin Ortuno F, Reyes
Gomis F, et al. Beta-blockade and exercise capacity in
patients with mitral stenosis in sinus rhythm. J Heart
Valve Dis. 2002;11:199-203.
25. Patel JJ, Dyer RB, Mitha AS. Beta-adrenergic
blockade does not improve effort tolerance in patients
with mitral stenosis in sinus rhythm. Eur Heart J.
1995;16:1264-1268.
26. Bel A, Perrault LP, Faris B, Mouas C, Vilaine JP,
Menasche P. Inhibition of the pacemaker current: a
bradycardic therapy for off-pump coronary operations.
Ann Thorac Surg. 1998;66:148-152.
27. Yusuf S, Camm AJ. Sinus tachyarrhythmias and
the specific bradycardic agents: a marriage made in
heaven? J Cardiovasc Pharmacol Ther. 2003;8:89-105.
APPLICATIONS CLINIQUES DE LA RÉDUCTION SÉLECTIVE DE LA FRÉQUENCE CARDIAQUE
DANS LES URGENCES CARDIOLOGIQUES
L’
ficatif sur la fonction systolique ou diastolique du ventricule
gauche ou sur la pression artérielle ; cette molécule est donc appelée à jouer un rôle privilégié dans le contrôle de la fréquence
cardiaque dans ces situations cliniques hémodynamiquement instables. En outre, d’autres contre-indications aux bêtabloquants
chez les malades atteints d’un syndrome coronaire aigu, telles un
bronchospasme ou un bloc auriculoventriculaire représentent
des indications potentielles pour l’ivabradine. La tachycardie induite par la perfusion de dobutamine ou de dopamine peut aggraver l’ischémie myocardique et, dans ce cas de figure, l’ivabradine peut jouer un rôle crucial en limitant l’augmentation inutile
de la fréquence cardiaque sans pour autant s’opposer aux effets
inotropes positifs de ces médicaments, ce qui permet d’améliorer
à la fois la perfusion myocardique et les paramètres hémodynamiques aussi bien dans l’insuffisance cardiaque aiguë que dans
le choc cardiogénique. Des urgences cardiologiques variées peuvent bénéficier de l’apport de l’ivabradine, tout particulièrement
quand elles surviennent dans des situations cliniques où la réduction de la fréquence cardiaque est requise, alors que le recours aux bêtabloquants est limité par l’existence d’une congestion pulmonaire, d’une hypotension artérielle ou d’autres contreindications.
ivabradine est un inhibiteur à la fois sélectif et spécifique
du courant If qui possède des propriétés anti-angineuses
et anti-ischémiques bien démontrées. Elle n’exerce aucun
effet sur la pression artérielle. Elle respecte, en outre, tant la fonction systolique et diastolique du ventricule gauche que la conduction auriculoventriculaire. Du fait de ses propriétés pharmacodynamiques et pharmacocinétiques uniques en leur genre, de son
aptitude à réduire sélectivement la fréquence cardiaque sans entraîner le moindre effet hémodynamique délétère, les applications thérapeutiques potentielles de l’ivabradine sont nombreuses,
dans des situations diverses telles l’insuffisance cardiaque aiguë
avec ou sans altération de la fonction ventriculaire, le choc ou
encore la tachycardie sinusale inappropriée. Chez les malades
atteints d’un angor instable ou d’un infarctus du myocarde à la
phase aiguë, la réduction de la fréquence cardiaque est en général bénéfique, car elle permet à la fois de diminuer les besoins en
oxygène du myocarde et d’allonger la durée de la diastole autant que celle de la perfusion myocardique. Cependant, du fait de
leur effet hypotenseur et de leur effet inotrope négatif, les bêtabloquants sont contre-indiqués face à un tableau de congestion
pulmonaire, d’hypotension artérielle ou encore de choc cardiogénique. L’ivabradine, pour sa part, n’exerce aucun effet signi-
✦
86
A
T
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O F
F
R A N C E
Christian RÉGNIER, MD
Praticien Attaché des Hôpitaux de Paris
Société Internationale d’Histoire de la Médecine
9, rue Bachaumont 75002 Paris, FRANCE
Jean-Baptiste Baillière
(1797-1885)
The pioneering publisher
who promoted French medicine
throughout the world
b y C . R é g n i e r, F r a n c e
I
n the field of medical and scientific books, Jean-Baptiste Baillière (1797-1885) was no ordinary publisher. His bookshop business was marked by its longevity: J.-B. Baillière lived 88 years and was a publisher for 67 of them. Then his brothers, nephews, sons, and descendents continued to run the family
business. Even if today there is no longer any family link with the founder, the firm of J.-B. Baillière
still exists, and the present company continues to publish the highly respected La Revue du Praticien
and Les Archives des Maladies du Cœur et des Vaisseaux.
However, the real claim to fame of J.-B. Baillière was the quality of the works he published. J.-B. Baillière
employed the best printers and the most skilled engravers and lithographers. He was one of the pioneers
of the publication of photographic illustrations. But even more important than the technical quality of his
publications, J.-B. Baillière’s reputation was in large part due to the eminence of the authors selected. The
great names of French medicine in the 19th century were published by J.-B. Baillière. Intransigent concerning deadlines for reception of manuscripts, stingy with the number of authors’ copies, the publisher was both feared and respected. This didn’t keep him from making friends for life, notably with Claude
Bernard, Émile Littré, Charles Daremberg, and Jean-Baptiste Bouillaud.
✦
J
ean-Baptiste Baillière survived three monarchies, two empires, three revolutions, and two republics. Steering clear of political convulsions, he was and remained both a bookseller in Paris
and publisher of medical and scientific books and journals. He devoted his life to this one aim,
and swept along in his wake sons, brothers, nephews, and grandsons. The success of J.-B. Baillière
was not only that of a shrewd and groundbreaking businessman, but also of an outstanding professional publisher who contributed to the creation of the Paris Booksellers Society, the international regulation of author copyright protection, and the organization of the profession of publisher in
France. Inspired by the excellence of French medicine at the start of the 19th century, driven by a romantic ideal of the exchange of knowledge between peoples, he developed a vast network of representatives
and family branches throughout the world. Baillière family members made their homes in England, the
Americas, Australia, Spain, and elsewhere. But, J.-B. Baillière was above all the publisher of the greatest
names in French medicine: Claude Bernard, Bichat, Bouillaud, Cabanis, Cruveilhier, Daremberg, Davaine,
Dupuytren, Esquirol, Flourens, Grisolle, Guyon, Huchard, Laennec, Laveran, Littré, Louis, Magendie,
Malgaigne, Nélaton, Portal, Rayer, Ricord, Trousseau, Velpeau, Vidal, and Villemin. The worldwide reputation of the Baillière publishing house endures to this day with such flagship medical journals as
La Revue du Praticien and Les Archives des Maladies du Cœur et des Vaisseaux.
Jean-Baptiste Baillière (1797-1885): pioneering publisher – Régnier
87
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O U C H
O F
FR
A N C E
Last but not least, perhaps the most original aspect of the Baillière publishing house was its early interest in internationalization. Aided by the then unsurpassed reputation of French medicine, and particularly that of the Paris School at the beginning of the 19th century, J.-B. Baillière rapidly distributed his
authors’ works throughout the world. Members of the family departed to England, America, Australia, and
Spain in order to become publishers themselves.
The golden legend of Jean-Baptiste Baillière
The fourth son of ten children, J.-B. Baillière was born in 1797 in Beauvais where his grandfather and
father were master drapers. The family business collapsed after the closing of the Beauvais tapestries and
after Napoleon had imposed a blockade against British goods. The young Jean-Baptiste, aged 15, was
sent to Paris where he arrived on June 3, 1812. One of his cousins introduced him to the Méquignons,
distant relations of the Baillière family, who had a bookshop
in the rue de l’École de Médecine at the heart of the what
had, ever since the Middle Ages, been the university sector,
the Quartier Latin. Hardworking, lively, and very talented,
the Méquignon’s new assistant classified books, helped at
the auctioning of old books, and rapidly learned the tricks
of the bookseller’s trade.
This was a major asset. All his life J.-B. Baillière was admired for his perfect understanding of the “market” for old
books, and for his ability to catalog collections of works on
biology and medicine bought when bookshops or medical
libraries (like that of Dr François Broussais) were sold. Physicians of the first half of the 19th century relied to a great
extent on the writings and anatomicoclinical observations
of the authors of the previous century. The fact that J.-B.
Baillière was indeed a shrewd connoisseur of books is confirmed by the catalog of his personal library.1-3
In 1818, just six years after his arrival in Paris, J.-B. Baillière opened a small bookshop at 14 rue de l’École de Médecine, a neighborhood where such shops proliferated; indeed,
his own shop moved around the same street several times.
In 1819, he met Dr Félix Séverin Ratier (1797-1866) who
had translated the 1st-century Roman physician Celsus.
Eventually, he married his sister (unfortunately, she was to
Portrait of Jean-Baptiste Baillière, in his 84th year. The coat
suffer an early death, in 1827). This connection gave him
of arms (blue background with three fleur-de-lis and an open
book) is that of the the guild of booksellers. Photo courtesy
entry to the Paris medical circle.4 Not yet having his pubof Éditions J.-B. Baillière.
lisher’s certificate, Baillière published theses and bought
collections of books. He obtained the requisite publisher’s certificate (n°1625, dated July 12, 1821), and
thus the right to publish. He rapidly launched his first work Essays on the Physical Education of Children
written by his brother-in-law, Doctor Ratier. In 1824, the Baillière catalog already boasted forty titles. Publishing success arrived rapidly with the printing of New Elements in Medico-Surgical Pathology or the
Precise Theory and Practice of Medicine and Surgery by Louis Charles Roche (1790-1895) and the elder
Joseph Sanson (1790-1841), respectively students of Joseph François Broussais (1772-1838) and Guillaume
Dupuytren (1777-1835). The work was republished four times in 25 years, and was a mainstay of medical teaching in France. Despite the serious competition of editors of medical dictionaries like Panckoucke
or Béchet, the Baillière publishing house published (or copublished) the Dictionary of Practical Medicine
and Surgery (1829), compiled by medical leading lights and dubbed “the fifteen volumes.” It was this dictionary that truly launched the reputation of the House of Baillière. Forty-seven years after the 1st edition,
Sigismond Jaccoud was given the task of completely revising the dictionary, which became the New Dictionary of Practical Medicine and Surgery. However, it was not quite as successful as the hundred-volume
dictionary of Amédée Dechambre published between 1864 and 1869 by Victor Masson. There was also the
no less celebrated Dictionary of Medicine, Surgery, Pharmacy, Minor Sciences, and Veterinary Art, with
a complex publishing history. The first 8 editions were published by Brosson, then Brosson and Chaudé,
then Chaudé. In 1845, the rights were acquired by J.-B. Baillière for the 9th edition. The editorial history
is even more complex. The first edition, compiled in 1806 by Joseph Capuron, was followed by a second
edition in 1810 by the same and Pierre-Hubert Nysten. Nysten then compiled the successive editions,
initially single-handedly, then with Émile Littré. In 1855, Émile Littré prepared an entirely revised version,
and was in charge of all successive editions until the 21st and final edition in 1908.1,4,5
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The social and professional progress of J.-B. Baillière seemed ineluctably placed under the sign of success despite the death of his wife on January 19, 1827. This same year, he became “publisher to the Royal
(then Imperial) Academy of Medicine,” and held the post until December 1871, when Baillière was “dismissed” and replaced by Masson.6
To ensure he remained in the headlines and to safeguard his reputation, he published (at a loss) the
Annals and the Bulletin of the Academy. He then began publishing specialized medical journals and reviews including the General Archives of Medicine (1823-1856), The Weekly Journal of Medicine (18281830), the Annals of Public Hygiene and Legal Medicine (1829-1856), the Journal of Medico-Surgical
Knowledge (1833-1856), and The Experience (1837-1844).7,8 These publications enjoyed a relatively large
circulation, but curiously Baillière did not know how to exploit this kind of journal and he was left behind by his eternal rival Victor Masson. Yet, these journals had the advantage of covering the whole field
Stained-glass window in the SaintSéverin church, the parish church of
the Baillière family. The stained-glass
window depicting the birth of Christ
was donated by Jean-Baptiste Baillière
in 1878 (as indicated on the scroll at
the bottom of the middle panel, see
enlargment below). Following a long
tradition dating back to the Middle Ages,
the donor features among the group of
worshippers (top right, rightmost figure,
facing the viewer, not the newborn
Child, who is none other than Georges
Baillière, Jean-Baptiste’s grandson,
bottom right). Photos by Marc Bertrand.
With kind permission from Direction des
Affaires Culturelles de la Ville de Paris.
of medical knowledge and were a good hunting ground for promising young talent.9 In 1828, after one
year of being a widower, J.-B. Baillière married Marie-Georgette Meaux Saint-Marc (1808-1859), the daughter of a rich businessman, shareholder of the Bank of France.2
In 1847, J.-B. Baillière was elected vice-president of the Booksellers Society, alongside Ambroise Firmin
Didot (1790-1876), Louis Hachette (1800-1864), and Victor Masson (1807-1879), three great names of
French publishing. Three years later, thanks to the support of his father-in-law, he occupied one of the
twelve seats of the very powerful Discount Committee of the Bank of France, thus marking the entry of
capitalistic publishing into the economic life of France. In 1864, invoking reasons of health (poor eyesight)
he abandoned his seat to his eldest son Émile.4
On the death of J.-B. Baillière, on November 8, 1885, his sons Émile (1831-1920) and Henri (1840-1905)
inherited the business. Émile had become a partner in 1856 and Henri in 1871.1,5 In his will of 28 March
1885, their father had written: “I leave a fortune much greater than I could ever have hoped, this is neither due to luck nor speculation. I owe it to my persevering work, to the intelligent and devoted support
of my wife, to order, to economy, to sound investments, and to the increase in the value of money. The
“sound investments” mainly concerned the purchase of 364 hectares of rich agricultural land in Brie
and to investments in various Paris properties, including the historic J.-B. Baillière and Sons building,
19 rue Hautefeuille, Paris 6.5
In the Baillière family, Jean-Baptiste had not been the only one to launch himself into medical publishing and succeed. In 1829, his younger brother, Germer Jules (1837-1905), inherited the estate of Mme
Auger-Méquignon and opened his own publishing business. On the death of his father, Gustave-Germer
(1837-1905), he took over the business and then in 1875 became an associate of Félix Alcan (1841-1935),
who continued alone after 1883.1,2
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The
physician
and physiologist
Claude Bernard (18131878). He received three
prizes from the Academy
(1851-1853) for his
research on the action
of the secretions of the
alimentary canal, the
pancreatic juice, and the
connection between the
liver and the nervous
system. His Introduction
to the Study of Experimental Medicine (1865)
is a scientific classic.
Photo courtesy of BIUM
(Bibliothèque InterUniversitaire de
Médecine), Paris.
A N C E
An intransigent publisher
On Sunday June 15, 1862, in his vast property of Bonfruit near Melun (South-East of Paris), J.-B. Baillière,
then aged 65, had invited several important guests to celebrate his fifty years as publisher. Among them
were Claude Bernard (1813-1878), the founder of experimental medicine; Jean-Baptiste Bouillaud (17961881), who had been Balzac’s doctor and the first to describe acute articular rheumatism, which was to
be named after him (maladie de Bouillaud); Charles Daremberg (1817-1872), who had interpreted
the texts of Galen; Émile Littré (1801-1888), translator of the works of Hippocrates; and Count
de Germiny (1799-1871), governor of the Bank of France. Also invited was Louis Hachette, who
addressed the guests and declared J.-B. Baillière to be “an intelligent and perspicacious editor and publisher, who had detected and encouraged the talents of a considerable number
of young students who later became an honor to the medical intelligentsia.” His son-inlaw, the psychologist Auguste Félix Voisin (1829-1898), added, “our friend has given disinterested and generous help in various circumstances to young doctors who today practice
with distinction in our capital, and who, demoralized and exhausted by misfortune at the
start of their career would never have overcome the obstacles without his help.”4,11
Having a prodigious memory — as he himself claimed — J.-B. Baillière had a reputation
for reliability, for the rapidity of his work, for the rigor of his corrections, for the quality of his
suppliers (paper makers, printers, lithographers), and he always selected his engravers himself.
On June 14, 1829 he wrote to Isidore Geoffroy Saint-Hilaire (1805-1861), several months before the
publication of the author’s Treatise on Teratology. “As far as the execution of drawings and lithographs
is concerned, you can be sure I attach as much importance to it as you. The draftsman will be the one you
yourself have chosen, our Mr Martin.”10 The catalog of the personal library of J.-B. Baillière contains a great
number of works dealing with publishing, as well as essays on engraving and the techniques of printing.5
However, the character of the editor sometimes appears to have been rather brusque—a letter written by
Jean Cruveilhier on August 17, 1828 suggests this: “The Sunday you have spent with me has completely
dispelled the unpleasant impression that your earlier brusque manner and immoderate expression made.”10
Letters between authors and J.-B. Baillière show that the editor sometimes obtained for them books
and articles they themselves could not find (thanks to his network of correspondents in France and
abroad)— thus remaining faithful to his trade of bookseller. On October 16, 1824, the zoologist and paleontologist Gérard Paul Deshayes (1795-1875) wrote to J.-B. Baillière: “You would do me a great service
if, while browsing through books, you could find me for 20 or 25 francs (it’s expensive) a book entitled
On the Oryctology of the Region Surrounding Brussels, by Bertin.”10 (“Oryctology” is an old name for mineralogy, geology, and paleontology all in one.) Similarly, in a letter to J.-B. Baillière dated September 3,
1866, Paul Bert (1833-1886) wrote: “I would like to know where the work by Haidenhain on the transformation of movement into animal heat was published. Perhaps in the journal of Duboys-Reymond or in
his archives? The date must be around 1865 or 1866.”10
The editorial office of the Baillière publishing
house, rue Hautefeuille, in the early 1930s.
From left to right: Albert Baillière, Pierre-Victor
Bonnet, Georges Baillière. Family archives.
The rue Hautefeuille, in the 6th arrondissement of
Paris in 1870. The Baillière library (No. 19), the
parent company, is the first shop window on the left.
© Photothèque de la Ville de Paris.
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J.-B. Baillière was uncompromising concerning deadlines: the letters written by
authors presenting their apologies for being late illustrate their apprehension.
In a letter dated September 18, 1832, at the time he was compiling his vast
Pathological Anatomy of the Human Body, Jean Cruveilhier tried to play for
time: “Your reproaches are perfectly justified, my dear Mr Baillière, I will give
you top priority until I have finished the 13th, 14th, and 15th deliveries. Please
be patient and all will be well.”10 The same apprehension is echoed by the surgeon
Joseph François Malgaigne (1806-1865) who on November 20, 1837 wrote to J.-B.
Baillière: “You sent me a preposterous letter, but I will gladly let it pass since this
delay must be as exasperating for you as it is for me (…) Your printers must be practical
jokers”10 If manuscripts were long overdue, the financial penalties were pitiless, as Isidore
Geoffroy Saint-Hilaire found to his cost in 1836 when volumes II and III of his Treatise on
Teratology were published. The son of the famous naturalist had delivered the manuscripts
three years late. He wrote to J.-B. Baillière: “I was astonished to read your demand that
I forgo my rather scanty fees of 1500 francs for the treatise, and I am sure you would not
have suggested it if you had had before your eyes copies of your letters in which you
offered me 2400 francs in 1833. My legal right now would be to make drastic cuts
in the manuscript.” Other authors tried to strike the right chord, like the famous
neurologist Charles Édouard Brown-Séquard (1817-1894) who wrote on May 19,
1856: “I am convinced that you and I have much to gain thanks to the delay in
my delivering the manuscript to you. As you know I have recently been awarded
the prize for experimental physiology and, moreover, all the principal journals
in Europe and the United States have taken an interest in my work and have
given me high praise. Thanks to this… the sales of my book will be increased
considerably.”10
Anatomic plate
(engraving) with lavish
use of color and minute
details from Névrologie
du Système Nerveux et
des Organes des Sens de
l’Homme [Neurology
of the Nervous System
and Sensory Organs of
Man] by Dr Ludovic
Hirschfeld, illustrated by
J.-B. Leveillé, published
by J.-B. Baillière in 1853.
The international penetration of French medicine
through the Baillière network
Since he planned to translate French medical texts and distribute them abroad
himself, J.-B. Baillière decided that his company had to be international. Fearing
that the books in his catalog would be pirated, he was an ardent defender of literary copyright. His international expansion was greatly assisted by the prestige
that French science enjoyed in the 19th century. On the first of June 1826, on the
occasion of the opening of his branch in London, the new bookshop published a
paragraph in English: “Thanks to the present period of peace, the advantage of facilities for communication between the nations favors the establishment of a regular correspondence between the men of science and the rapid transmission of discoveries from
one people to another.”12 J.-B. Baillière called upon the services
of his family, and sent his youngest brother to England and a
nephew to Spain; his sons departed to study the bookselling
business in Germany. On arrival in a new country (England,
Spain, United States, Australia), the Baillières exhibited an extraordinary “faculty of integration”; in less that one generation
they had become English, Spanish, American, or Australian.
Their father also established a very dense network of correspondents, which enabled him to do without agents.
A planned family dispersion
In the first half of the 19th century, J.-B. Baillière busied himself with the editorial conquest of the English- and Spanishspeaking world. It was much easier to penetrate these countries
than the Germanic ones, who had a strong editorial tradition.
In the German-speaking regions he relied instead on correspondents.
In 1826, J.-B. Baillière opened a branch in London under the
direction of his brother Hippolyte (1809-1867). On the first of
June, the two brothers published an announcement, a sort of
profession of faith in which they undertook to sell the journals
printed in France at the same price in London as in Paris, at an
Title page of the first Baillière “booksoller”
(sic) catalog published in London in 1826.
Family archives.
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J.-B. BAILLIÈRE AND THE FIRST STIRRINGS OF MEDICAL PHOTOGRAPHY
On January 17, 1839, François Arago (1786-1853) addressed
his colleagues of the Academy of Science: “M. Daguerre has developed special plates on which optical images leave a perfect
print where everything that the image contains is reproduced
down to the most minute detail with an exactitude and a sharpness that are incredible.” This date has gone down in history as
the official birth of photography. The idea of using photographs
in medical books took root quite rapidly in the minds of publishers, and J.-B. Baillière was to play a pioneering role thanks
to three reference books:
◆ An atlas, Courses in Microscopy Complementary to Medical Studies, by Alfred Donné and Léon Foucault, published by
J.-B. Baillière in 1845 (75 pages).18
◆ The celebrated Album of Pathological Photographs a companion volume to Localized Electric Shocks, by Guillaume
Duchenne de Boulogne, published in 1862 (40 pages).19
◆ Photographic Iconography of the Nerve
Centers (1873) by Jules Bernard Luys, consisting of a book (114 pages) and an atlas
(135 pages).20
◆ Microbiology
◆ The physiology of movement
The advent of photography made it possible to compensate for
the shortcomings of the human eye, which was incapable of
grasping the separate instants of a displacement or a movement.
In 1852, Doctor Guillaume Amand Duchenne (known as Duchenne de Boulogne) (1806-1875) and Adrien Tournachon (the
brother of Félix Tournachon, aka Nadar, the celebrated photograph) (1825-1903), began a series of studies on human physiognomy. Duchenne photographed his patients undergoing
“electrophysiological stimulation” and wrote: “using electrophysiological analysis and with the aid of photography, I will
demonstrate how to paint correctly the expressive lines of the
human face, which one might call the orthography of the physiognomy of movement.” Electrodes placed on the face induced
a contraction of the muscles involved in the principal expressions of the human face (the “passions”). In 1862, Duchenne entrusted J.-B. Baillière and the widow of Jules
Renouard with the publication of his famous
treatise: The Mechanism of the Human Physiognomy, or the Electrophysiological Analysis of the Expression of Passions that are
Relevant to the Practice of Plastic Arts. It
was illustrated with 74 portraits on albumen
paper. Duchenne also photographed patients
with neurological disorders and published
sixteen of the images in his Album of Pathological Photographs (22.5 29 cm) published in 1862 by Baillière. This book was one
of the first works in France to use albumen
photographs of clinical cases (11 18 cm).19
Microscopic objects were among the first to
be photographed. The technique was difficult because of problems of lighting and the
lack of contrast in microscopic objects; moreover, the question of optical convergence between the microscope and the camera obscura had not been resolved. On February
24, 1840, the hematologist Alfred Donné
(1801-1878) presented to the Academy of
Science photomicrographs taken with a so◆ Neuroanatomy
lar microscope (he had replaced the eyepiece
The neuroanatomist Jules Bernard Luys
of his microscope with a plate). Donné and
(1828-1897) is famous for his description of
his assistant, the physician Léon Foucault
the accessory band of the superior olive nu(1819-1868), had succeeding in fixing imcleus and the centromedian nucleus to which
Photographic plate of brain section, from
ages of bone tissue, dental tissue, and some
he has given his name (centre médian de
the Iconographie Photographique des
natural samples on daguerreotypes. For six Centres Nerveux – Atlas [Iconography Luys). His Photographic Iconography of the
of the Nerve Centers- Atlas] by Julesyears, the two men carried on their photoNerve Centers published in 1873 by J.-B. BailBernard Luys, published by Baillière in
micrographic studies and solved the problière and Sons consisted of an 27 35.5-cm
1873. Baillière was among the first
lem of lighting by replacing sunlight (vari- medical publishers to use photography. atlas with 70 photographs on albumen paable and thus often insufficient) with arti- Photo courtesy of BIUM (Bibliothèque per; the images were of different sizes and
Inter-Universitaire de Médecine), Paris.
ficial light obtained by the combustion of
were glued on the right-hand page while on
hydrogen in oxygen in the presence of lime. In 1844-1845, Bailthe left-hand page a lithograph gave the numbers of the titles
lière published Donné’s Courses in Microscopy, which was ac(which could be consulted in another volume). To obtain good
companied by an 45 32.5-cm atlas with 20 plates each illusprints, Luys always took care not to use chromic acid in his
trated with four images produced using the daguerreotype
anatomical preparations, since on hardening it gave a greenmethod (magnification 200 or 400). It was one of the first
ish color to the preparations and had the disadvantage of being
medical books illustrated with engravings inspired by daguerreorefractory to light. His youngest son, Georges Luys (1870-1953),
types. In it Donné described “globulins,” later called platelets,
a doctor, also took numerous photographs. The father justified
for the first time, as well as Trichomonas vaginalis. Donné paid
his illustrations of anatomical observations “because I wanted
homage to J.-B. Baillière: “because our editor showed so much
to be understood at any cost.” In 1883, he published, again with
good will and desire to make our work as perfect as possible, we
J.-B. Baillière, Research on the Structure of the Brain Memdid not hesitate to multiply the plates and show several when
brane Using the Microphotographic Method, which also conone might well have been sufficient.”18
tained photographs on albumen paper.20
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Rudolf Virchow (18211902). German pathologist
and politician who, as a
liberal member of the
Reichstag (1880-1893), was a
strong opponent of Bismarck.
Virchow was the founder of
cellular pathology, establishing that every morbid
structure contained cells
derived from previous
healthy cells. He contributed
to the study of tumors,
leukemia, and hygiene.
© Library of Congress
Prints and Photographs
Division, Washington DC,
USA; George Grantham
Bain Collection.
Jules
Bernard
Luys, French
physician (1828-1897)
who first described the
subthalamic nucleus,
known as Luys body
(see box page 92).
(Bibliothèque InterUniversitaire de
Médecine), Paris.
O U C H
O F
FR
A N C E
Title page of
Virchow’s groundbreaking work,
Cellularpathologie (1858), which
was translated
into French by
Paul Picard and
published by
J.-B. Baillière in
1861. The translation was supervised by Virchow
himself. Photo
courtesy of BIUM
(Bibliothèque
Inter-Universitaire
de Médecine),
Paris.
exchange rate of one franc for one shilling. Thus, all new publications and journals in all branches of medicine and science would be available in London within 15 days of their appearance in Paris.12 In April 1830,
the Baillière bookshop published its first catalog of books, which consisted not only of French and German translations, but also original works by English physicians and botanists; success was complete when
the bookshop was accredited by the British Museum. Having moved to 219 Regent Street in 1831, the bookshop was financially independent of the parent company in Paris. The success of the London Baillière
branch very rapidly inspired emulators in the family, and three Hippolyte sons emigrated to the United
States and Australia. In 1869, two years after the death of her husband, Madame Hippolyte Baillière sold
the London business rights to two English editors, Albert Alfred Tindall (1840-1931) and George Cox
(1828-1899); the Baillière bookshop became the Baillière, Tindall, and Cox Publishing House, known to
all British doctors.2,13
In 1848, in Madrid, Jean-Baptiste’s nephew Charles François Bailly (1825-1909), known as Carlos BaillyBaillière, translated and edited French authors for the Spanish-speaking medical students. Carlos even
founded a printing works. The Bailly-Baillière books were exported to the Spanish colonies of South America. His sons Antonio (1866-1909) and Enrique Bailly (1864-?) took over the bookshop, which finally disappeared in the torments of the Spanish civil war in 1936.2
Around 1855, J.-B. Baillière sent his eldest son, Émile (1831-1920) aged 20, to Leipzig, the metropolis of the book trade, to learn his craft and to study German printing techniques. Apprenticed to
Weigel, Émile acquired a good knowledge of the industrial organization of bookshops in Germany, and retained close links with the publishing houses in Leipzig.14 J.-B. Baillière was
the French translator and editor of Cellularpathologie (Cellular Pathology, one of the
founding texts of modern medicine) of Rudolf Virchow (1821-1902), who himself supervised the quality of the translation.
In 1851, Pierre-François Hippolyte Baillière (nicknamed “the Englishman”) sent his
sons Hippolyte Émile (1832-1876) and Charles Edmund (1834-?) to the United States;
the first became a paper manufacturer in Newark, New-Jersey, before opening a bookstore. He then founded, with his brother Charles Edmund, the Baillière-Brothers Company in New York, which published books on Broadway from 1851 to1868.13 In 1860, Ferdinand François (1838-1881), another son of Pierre François Hippolyte, opened a Baillière
bookstore in Melbourne (Australia). Three years after his arrival he was official editor to the
government of the state of Victoria. He made friends with Doctor George Beaney (1828-1891),
surgeon general of Melbourne Hospital, and published medical books and the first Australian medical journals: The Medical and Surgical Review (1863), The Australian Medical Journal, and The Melbourne
Medical Record (1873). Because of its small population, the British colony did not have enough doctors
to keep an editor busy, so Ferdinand François Baillière also published nonmedical books. Thus, in 1875,
Baillière published a book with photographs of the pictures in the Melbourne National Gallery. This work
is important in the context of 19th-century Melbourne publishing and equally important in the context
of Baillière’s work. It is one of the earliest catalogs to feature pictorial aspects of an Australian gallery collection. Diversifying even further, Ferdinand François Baillière also bought and sold surgical instruments,
scientific material, microscopes, and skeletons.2,15
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In 1862, after having completed his law studies, Henri Baillière (1840-1905), the second son of J.-B. Baillière, went to Germany to make professional contacts in Berlin. He traveled throughout Egypt in 1867
and wrote a book on his impressions of the country.16
The Baillière network throughout the world
Apart from the four branches he established in England, the United States, Australia, and Spain, which published and sold books (both medical and nonmedical) in English and Spanish, J.-B. Baillière set up a network of correspondents throughout the world who ensured the sale of his books. These correspondents
not only distributed the French authors published by J.-B. Baillière, they also served as “scouts” and proposed to the Paris publisher works by famous authors published in their own country that they would edit
and translate into French themselves. The correspondents were also much solicited by J.-B. Baillière when
seeking rare editions or books not available in France for his own authors.
Map showing
the international
development of the
Baillière publishing
houses and correspondents between
1826 and 1902.
Courtesy of Société
Française d’Histoire
de la Médecine.
The names and locations of retail bookshops in the Baillière network mentioned on page 2 of the Nysten
Dictionary of Medicine (1858 edition) were those of 107 bookshops of which 53 were in France and 54 in
12 other countries. This internationalization reflects the worldwide respect for French medicine in the middle of the 19th century. There were 16 correspondents in Italy, 10 in Belgium, 7 in Russia, 6 in Holland, 5 in
Germany, 3 in Portugal, 2 in Sweden, and one each in Havana, Mexico, Warsaw, Geneva, and Athens.17
In 1910, the House of J.-B. Baillière and Sons could claim to have more than 800 correspondents distributed throughout the world.12
Baillière today
J.-B. Baillière long resisted the urge to publish medical journals. And yet, ironically, it is through a journal that the link has been preserved between yesterday’s family-run enterprise headed by five generations of Baillières — an enterprise that weathered such momentous events as the Industrial Revolution
and several major wars, including World War I and II, during the 19th and 20th centuries—and today’s
incorporated company. This journal is the famed La Revue du Praticien—an obligatory read for all French
physicians even today—which was started in 1951 by Dr André Roux-Dessarps–Baillière, and which continued under his son Gérard (also a doctor), in collaboration with his nephew, Henri Morel d’Arleux-
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Poster
announcing
the Baillière
Symposium
“J.-B. Baillière
and Sons,
Medical Publishers” on
29 January
2005 in Paris.
(Bibliothèque
Inter-Universitaire de
Médecine),
Paris.
Front cover
of the 15 June
2004 issue of
La Revue du
Praticien, the
flagship journal published
by Baillière.
Photo courtesy
of Groupe
JB Baillière
Santé.
Baillière. Unfortunately, the family was plagued by recurrent health problems that prevented them from
carrying on their publishing activities. By a quirk of fate, and faithful to the long-established Baillière tradition of internationalization, the publishing house once again, in 1987, moved across the Channel to
London and came into British ownership… only to return to its French roots, in 1999, in Paris, under the
name Groupe JB Baillière Santé.
Publication of La Revue du Praticien continues to this day, with three different editions: the standard
edition of La Revue du Praticien destined for all physicians (indexed in the MEDLINE database and hence
accessible to all doctors throughout the world), and its two offshoots, La Revue du Praticien – Médecine
Générale, started in 1987, to reflect the newly created specialty of general medicine, and La Revue du
Praticien Gynécologie et Obstétrique, started in 1988, for gynecologists, obstetricians, midwives, etc. Another leading publication, Les Archives des Maladies du Cœur et des Vaisseaux, was also created in 1908,
and is indexed in MEDLINE. Baillière is well known for the numerous, well-attended symposia and congresses it organizes, and has developed several web sites to increase its reach to French-speaking doctors
and provide a wider international basis for its publications. ❒
This article is based on family archives selected by Mr Michel Roux-Dessarps.
REFERENCES
1. Conan P, Régnier C, Roux-Dessarps M. À propos de l’exposition “Une grande maison d’édition médicale française J.-B. Baillière et fils”, Hist Sci Med. 2003;37:407-414.
2. Baillière JB. Famille Baillière. Paris, France: Jean-Baptiste
Baillière; 1885.
3. Noblet C. Notice nécrologique de J.-B. Baillière. Chronique du
Journal Général de l’Imprimerie et de la Librairie.1885;51:225228.
4. Othmar K. L’avènement de la médecine clinique moderne en
Europe (1750-1815). Geneva, Switzerland; Georg éditeur, Montréal, Canada: Presses Universitaires de Montréal, 2001.
This author is cited by Dr Alain Ségal, President of the French History of Medicine
Society (SFHM), in the introduction to the catalog published in November 2001
on the occasion of the exhibition of works published by the Jean-Baptiste Baillière
company. This exhibition took place at the Bibliothèque Inter-Universtaire de
Médecine (BIUM) as part of the events commemorating the SFHM centennial.
5. Mollier JY. L’Argent et les Lettres. Histoire du Capitalisme
d’Édition (1888-1920). Paris, France: Fayard; 1988.
6. Baillière JB. Histoire de nos Relations avec l’Académie de Médecine (1827-1871). Paris, France: Librairie J.-B. Baillière et fils;
1872.
7. Wickersheimer E. Index Chronologique des Périodiques Médicaux de la France (1679-1856). Paris, France: Maloine; 1910.
8. Bibliothèque Impériale, Département des Imprimés. Catalogue
des Sciences Médicales, Volume 1. Paris, France: F. Didot; 1857.
9. Pluet-Despatin J, Leymarie M, Mollier JY. La Belle Époque des
Revues (1880-1914). Paris, France: Éditions de l’IMEC; 2002.
10. Private and family collections of autographs and correspondence between Jean-Baptiste Baillière and his authors.
11. Baillière J.-B. La Cinquantaine d’un Libraire. Paris, France:
Jean-Baptiste Baillière; 1862.
12. Family archives of Mrs Gérard Roux-Dessarps and Mr Michel
Roux-Dessarps.
13. Tindall DH. A Short History of Baillière Tindall. London, UK:
Baillière Tindall; 1983.
14. Baillière E. La Librairie de Leipzig—Autour du Congrès des
Éditeurs—Notes de Voyage. Bibliographie de la France.1901;27:
117-119.
15. Clark L. Aspects of the Melbourne Book Trade History: Innovation and Specialisation in the Careers of F.F. Baillière and
Margareta Webber. Melbourne, Australia: Mulini Press; 1997.
16. Baillière H. Notices Nécrologiques—Henri Baillière. Paris,
France: J.-B. Baillière et fils; 1906.
17. Nysten PH. In: Littré E, Robin C. Dictionnaire de Médecine, de Chirurgie, de Pharmacie, des Sciences Accessoires et
de l’Art Vétérinaire. 11th Ed. Paris, France: J.-B. Baillière et fils;
1858.
18. Donné A, Foucault L. Cours de Microscopie Complémentaire
aux Études Médicales. Anatomie Microscopique et Physiologie
des Fluides de l’Économie. Paris, France: Jean Baptiste Baillière;
London, UK: H. Baillière; 1845.
19. Duchenne de Boulogne G. Album de Photographies Pathologiques Complémentaire du Livre Intitulé de l’Électrisation
Localisée. Paris, France: Jean-Baptiste Baillière; Londres, UK:
Hippolyte Baillière: New York, NY; Baillière Brothers, Madrid,
Spain: C. Bailly-Baillière; 1862.
20. Luys JB. Iconographie Photographique des Centres Nerveux.
Paris, France J.-B. Baillière; 1873.
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JEAN-BAPTISTE BAILLIÈRE (1797-1885)
L’ÉDITEUR
VISIONNAIRE QUI DIFFUSA LA MÉDECINE FRANÇAISE À TRAVERS LE MONDE
J
ean-Baptiste Baillière traversa trois régimes monarchiques, deux empires, trois révolutions et
deux républiques. Pendant ce temps, se tenant à l’écart des soubresauts politiques, il fut et demeura libraire à Paris, éditeur de livres et de revues médicales et scientifiques. Il consacra sa vie
à ce seul but et entraîna dans son sillage fils, frères, neveux et petits-fils. La réussite de J.-B. Baillière n’est pas seulement celle d’un homme d’affaires avisé et novateur, c’est aussi celle d’un grand
professionnel de l’édition qui fut à l’origine de la création du Cercle de la Librairie à Paris, de la
réglementation internationale sur la propriété littéraire et de l’organisation de la profession d’éditeur en
France. Porté par l’excellence de la médecine française du début du XIXe siècle, animé par un idéal romantique d’échanges des savoirs entre les peuples, il développa un immense réseau de correspondants et
de succursales familiales à travers le monde. Des Baillière s’installèrent et firent souche en Angleterre,
dans les Amériques, en Australie, en Espagne et ailleurs. Mais J.-B. Baillière, c’est surtout l’éditeur des
plus grands noms de la médecine française comme Claude Bernard, Bichat, Bouillaud, Cabanis, Cruveilhier, Daremberg, Davaine, Dupuytren, Esquirol, Flourens, Grisolle, Guyon, Huchard, Laennec, Laveran,
Littré, Louis, Magendie, Malgaigne, Nélaton, Portal, Rayer, Ricord, Trousseau, Velpeau, Vidal, Villemin.
La réputation internationale des Éditions Baillière subsiste à ce jour, au travers de publications-phares
telles que La Revue du Praticien et Les Archives des Maladies du Cœur et des Vaisseaux.
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Thierry GERVAIS
Lecturer, Paris III University
Cinema Section, Audiovisual Department
and École des Hautes Études en
Sciences Sociales (EHESS)
Editor, Études Photographiques
(French Photographic Society [SFP])
Paris, FRANCE
Imaging the world
L’Illustration: the birth of
the French illustrated press and
the introduction of photojournalism
in the mid-19th century
b y T. G e r v a i s , F r a n c e
T
he French broadsheet press in the 1830s was a saturated market that forced editors to come
up with new solutions if they were to publish and survive. Émile de Girardin’s La Presse (1836)
maintained the format of the traditional political newspaper, but halved the subscription rates.
Three years earlier, Le Magasin Pittoresque had offered what it termed “useful” knowledge, accompanied by woodcuts. Its editor-in-chief for nine years, Édouard Charton, then visited London in the
summer of 1842 and discovered a new type of illustrated paper, The Illustrated London News. This
weekly broadsheet had thrown its news pages open to images, contending that these were more readable, and above all a better reflection of reality. On returning to Paris, Charton propounded this approach to two journalist-publishers, Jean-Baptiste Paulin and Jean-Jacques Dubochet, who were already
well-known for having produced Gil Blas (1835) and Don Quichotte (1836) in illustrated editions sold
in weekly installments— a system that not only provided publishers with ready cash, but also groomed
a readership network avid for illustrated texts.
✦
T
he illustrated news press that came into being almost simultaneously across mid-19th century
Europe was little less than a revolution. Periodicals such as Charivari in France were already
renowned for their satirical prints, but the mid-century saw the press putting topical images to more
attractive and didactic use, led by series of weeklies. In the vanguard was the Illustrated London News
(Britain, 1842), which appears to this day, followed by L’Illustration (France, 1843-1944), the Illustrierte
Zeitung (Leipzig, 1843-1940), and a host of other illustrated periodicals worldwide in the 1860s. Editorial offices fed the boom by employing teams of draftsmen and engravers, soon joined by photographers.
L’Illustration, founded by Édouard Charton, Jean-Baptiste Paulin, and Alexandre Dubochet, was an instant success, attracting tens of thousands of loyal readers with its high-quality prints, wealth of news
items, contributions from a network of correspondents, and an ever-increasing reliance on images. Prints
were created mainly from drawings, but L’Illustration lost no time in using photographs, beginning in
1848 — even if, in those first decades, they required an engraver’s input before they could be published
(half-tone mechanical reproduction came only in the 1890s). The paper offers a panorama of sociopolitical, scientific, and cultural life in the 19th century. Issues were devoured by their contemporary readership and have since become collectors’ items in book fairs and flea markets. L’Illustration was a key player in the history of the French press and a founding member of modern media-driven society.
L’Illustration and the birth of the French illustrated press – Gervais
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Creation of an illustrated newspaper
L’Illustration was founded in 1843, with Dubochet et Paulin injecting a sum of 375 000 francs (of that
time), or 150 shares at 2500 francs each. Fifty other shares were issued, bringing the total capital to 500 000
francs. For having come up with the basic idea, Charton was given two shares which he sold for 60 000 francs
in the fall of 1844. This represented an appreciation of 1200% over 18 months, and was a resounding confirmation of success. It underlines the message that between 1836 and 1844, images had begun to pay and
were attracting investors accordingly.
The first issue of L’Illustration appeared on Saturday, March 5, 1843. Despite the editors’ denial of political partisanship, the “History of the Week” section, the choice of cultural articles, and the way they were
handled all expressed, in the view of a modern historian, “the
desire to maintain the status quo, even if this was not always
conscious.” Many reports dealt with railroad construction,
printing works, telegraphy, and photography, reflecting an
era of innovation and technical progress. Travel stories from
inside France, the United States, and above all the new colony
of Algeria conveyed a message of advancing Western civilization. Book, theater, and art reviews echoed the annual
Salons and the cultural fashions of the time. As for national and international conflicts, and underlying social unrest,
these were largely downplayed, as with the Paris demonstrations of June 1848.
However, L’Illustration differed from the broadsheets affiliated to political parties by its declared apoliticism, while
maintaining a focus on the various types of current events.
The weekly was tailored to the bourgeoisie who relied on political calm for their prosperity. An annual subscription in
Paris cost 30 francs, increased in 1848 to 36 francs; in the
provinces it cost 32 francs, before also being increased to 36
francs. This was only slightly less than a daily appearing seven times more often (40 francs). A single issue cost 75 centimes, compared with 10 centimes for Le Magasin Pittoresque.
A subscription was equivalent to 210 hours of a provincial
laborer’s wage. Launching an illustrated news weekly in 1843
could only work if it was favorably received by a bourgeoisie
with solid incomes. There are several indicators of bias towards its Paris readership in L’Illustration. The “Paris Page”
addressed the capital’s inhabitants directly, the art sections
concentrated on the Paris scene, and single issues only went
on sale in Paris. The profile of the typical reader was therefore
Title page of the April 10, 1858 (No. 789) issue of L’Illustration. The
that of the Paris bourgeois and his family.
larger picture shows the inauguration of the Boulevard de Sébastopol
A rapidly introduced “Readers’ Letters” section kept the
in Paris (April 5). Engraving from photographs by M. Richebourg.
It was only through the indication “from a photograph” that readers
publishers’ fingers on the readers’ pulse. Many readers ofcould tell the difference between the origins of illustrations.
fered ideas for cover stories or help in covering local events,
© L’Illustration /Keystone.
although most offers reached the editors’ office after their
newsworthiness had expired. Readers were plainly attracted by the images that were published. Their
letters spoke of sending drawings, and donating collections of images to the weekly; they discussed the
authenticity of prints, the choice of paintings, and the kind of images they would like to see in the paper.
Such feedback only confirmed Charton, Paulin, and Dubochet in the foresightedness of their imagebased enterprise.
Images: mixing enlightenment with pleasure
In 1843, the preface to the first volume of L’Illustration, entitled “Our purpose,” described images as a
knowledge tool: “How pale, lifeless, persistently incomplete, and difficult to understand even the best of
written descriptions can be, compared with showing things as they really are! It has long been recognized that ‘what reaches the mind via the ear is less easily retained than what reaches it via the eye’.”
Irrespective of a reader’s educational level, images facilitated access to knowledge by using what the
weekly described as “this other language: […] the pencil and the engraver’s chisel.” The lines of a drawing
were considered as more accessible to human vision than the letters of a text, which require prior knowledge to be read. “L’Illustration will, from the outset, be truly what we intended it to be, a vast repository
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The “engraving room” of L’Illustration
(March 2, 1844, No. 53 issue). Teams of
engravers worked 24 hours a day to produce
the wood blocks for the generously illustrated
journal. © L’Illustration /Keystone.
describing and depicting all
the facts that contemporary
history records in its annals,
as they occur. [...] L’Illustration will, in a word, be a mirror faithfully reflecting [...]
life in 19th-century society.”
The weekly justified the use
of wood engraving as a way of
so shortening the intellectual distance between spectator
and subject that it came to reflect the news itself. Over and above the educational aspect, this use of images expressed a form of journalistic modernity that was also apparent in the editors’ textual policy. Although they did sometimes use
news items from the Havas agency, they tended to avoid official sources, placing minimal reliance on intermediaries, and turning in preference to their network of regular correspondents—readers for the most
part—and special correspondents, dispatched into the field. Reports and images had to demonstrate proximity to the event and mirror-like objectivity, enabling the paper to distance itself from the propagandist
techniques of the partisan broadsheets. However, before the task of enlightenment could begin, the illustrations first had to attract readers and get them to buy. Images may have had a didactic function, but
they also expressed the idea that there could be pleasure in acquiring knowledge. Far more than the other techniques that were mobilized to
boost the circulation—social diary, serials, famous writers—images equated newspaper reading with pleasure.
Boxwood block with
engraving of a “cockfight
in Flanders.” After a
painting by Rémi Cogghe
(oil on canvas, 1889) now
at the Musée d’Art et
d’Industrie de Roubaix.
For extra speed, several
engravers would work
on a single engraving,
each on one of the smaller blocks that made up
the final image. The
smaller blocks were then
assembled (notice the
horizontal lines and the
conspicuous vertical line).
The engraving is so fine
one hardly feels it when
running a finger along
the surface. After printing, blocks were scraped
and reused many times.
About 80 blocks are still
preserved at the offices of
L’Illustration. On the right:
the printed outcome.
Photos by Frédéric Joly.
© L’Illustration/Keystone.
Images in text
The increase in illustrated publications, whether periodicals or books,
had prompted many French engravers
to learn relief wood engraving. Imported by the English engraver Charles
Thomson in 1816, this technique came
into widespread use in the 1830s. The
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The editorial office of L’Illustration.
(March 2, 1844, No. 53 issue) with the
founders. © L’Illustration /Keystone.
demand drove a tenfold increase in the
number of engraving workshops; there
were over 200 wood engravers by 1857. In
the early 1840s the second generation of
wood engravers became sufficiently wellorganized and numerous to meet the demand without calling in English specialists. At its inception, L’Illustration worked
with just one studio: Andrew-Best-Leloir.
Unlike conventional woodcuts made in
the sense of the grain, relief engraving
against the grain used blocks sawn transversally to the trunk. Another difference was that the wood was not worked with the graver used for conventional woodcuts, but with a chisel of the kind used on metal. This technique remained just as fast, but
was more akin to metalwork, and could produce many deft shades of gray. This was a definite advantage
in artistic engraving, but also in reproducing paintings or photographs with many subtle shades. It made
it possible to copy daguerreotypes. Also, in relief engraving the wood blocks were cut at the same height as
print blocks, meaning that they did not have to be printed separately, but could be composed in a page
for printing amidst typographic characters. In expert hands, images printed perfectly with text, thus “captivating at first glance,” according to a modern commentator, “and forcing the attention of the least attentive.” The result was an acceptable quality/cost/time-to-completion ratio, encouraging publishers to think
up new objects to construct around the image and typesetters to develop a range of critical new skills.
Text as a graphic component
L’Illustration was a 16-page broadsheet. Each page comprised three equal-width columns, separated by
two vertical white-space gutters. A thicker horizontal white space separated each article from the next.
Together with the title block, these white spaces organized the divisions between type. The text was in
size 8 Garamond-like font, which was easy to read. Only on the advertisement page — the inside back
page — were fonts, emboldenings, and type sizes varied to
enliven the page presentation and attract the reader’s eye.
Images greatly lightened the mass of text and were the main
method of optimizing the transition between pages.
The flag, or paper title, was always accompanied by a fullwidth engraving and masthead showing the issue and volume numbers, date of publication, subscription charges, and
publisher’s address, all of which occupied a third of the cover page. The following texts, list of contents and usually the
“Story of the week” section were always squeezed by the accompanying image. Initially, engravings could vary in width,
but always in line with the column margins. But as the years
passed, they became freer, resulting in a less disciplined
presentation. Although this made the text harder to read, it
added to the overall graphic impact. Sometimes the text
Top: Engraving showing the church at Mesnil-surl’Estrée, about 90 km east of Paris. The village is still
famous for the printing works founded in 1689 by
Firmin-Didot (part of which can be glimpsed on the
left). The church served essentially the Firmin-Didot
workers, who among others printed L’Illustration. In
the issue of April 14, 1855, the accompanying article
indicates that the total length of paper used up each
year for L’Illustration was 3420 km, “enough to wrap
up the whole of France four times over with a strip
of paper 1.30 m in width.”
Bottom left: P. Van Rees, Resident (diplomat) in
Batavia (now Jakarta). Engraving from a photograph
by Eugène Disdéri. © L’Illustration /Keystone.
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would be reduced to just a few lines, occupying a third of a column, becoming a graphic feature in its
own right, setting off the engravings on the page. Text and images were combined to maximum effect on
the illustrated page to astonish and captivate the reader-spectator.
To optimize their print quality, all images were set on the same surface, so that once the paper was folded they would be found on pages 1, 4, 5, 8, 9, 12, 13, and 16. Articles were in an order—or, as the paper
once acknowledged, “disorder”—closely determined by the images. Layout was subject to printing constraints and dictated by the engravings. Text had to follow suit. Once set, image formats could not be
changed; wood engravings could not be enlarged or reduced to comply with spatial constraints. Text, on
Ancients or Moderns ?
Engraving showing the
draftsman Durand-Brager
capturing “on-the-spot”
a scene in the trenches
during the Crimean war
in 1855. Technical equipment required: pencil and
sketchbook, possibly a
pocket knife to sharpen the
pencil; erasor. The rifle
belongs to a soldier.
Ancients or Moderns ? Photographic print on salted
paper (17.5 16.5 cm) showing Roger Fenton, during
the Crimean war in 1855, with his celebrated “photographic van.” In the early days, it was far from obvious
that photography would become the pervasive medium
it now is. By the time photographers has set up their
(bulky) material “on-the-spot” photography more often
than not was “history!” © Library of Congress Prints
and Photographs Division, Washington DC, USA.
#LC-USZ62-2319.
the other hand, was malleable, and could be shortened or expanded. Articles could thus be divided into
parts and published according to need in several issues. Every day, the editorial offices received “detailed
reports and original drawings of all the important events that had happened during the week on the
planet.” To feed their need for news, they transformed these facts into consumable events and elevated
banal situations into picturesque engravings, practicing a version of journalism that they termed “newsism.” Images and text were selection criteria of equal weight in informing editorial choice. If a drawing
arrived too late to be engraved, the event was not mentioned. The same applied if the quality of a sketch
failed to come up to editorial expectation. Images were a structural component that defined the illustrated newspaper.
Introduction of photography
From 1848 onwards, the words “From a photograph” began to appear beside the legends to certain engravings, becoming more frequent during the 1850s and weekly from 1858 onwards. Before half-tone engraving made it possible to mix text and image directly in the page layout, photographs had to transit
through the engravers’ workshop before they could be published.
Of the images published in L’Illustration under the editorship of Paulin (1844-1859), 214 were engraved
from a silver-plate image. In eight of these cases, the legend stated that they had been engraved from a
daguerreotype. In the remainder, the wording is imprecise and the photographic technique difficult to
identify. We know which proofs were supplied by Louis Désiré Blanquart-Évrard (1802-1872, who introduced the albumen paper print process) and the botanist Louis-Alphonse de Brébisson (1798-1872): these
were paper prints. Most of the other original images were probably negatives on glass sensitized with collodion (nitrocellulose dissolved in ether). That L’Illustration used photographs at all is clearly of interest,
but 214 is a paltry tally compared with the total engravings published from 1843 and 1859, estimated at
between 19 800 and 26 400. The period between 1840 and 1870 was one of feverish experiment in photomechanical reproduction, involving some key figures in the early history of photography: the physicist
Armand Fizeau (1819-1896), Abel Niépce de Saint-Victor (1805-1870), the nephew of Nicéphore Niépce
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(one of the inventors of photography), the printer and lithographer Joseph Lemercier (1803-1887), the
artist Charles Nègre (1820-1880), the British polymath William Henry Fox Talbot (1800-1877), and perhaps above all the chemical engineer Alphonse Poitevin (1819-1882). In 1856, Charles Nègre patented a
coated steel plate method that gave good results. Honoré d’Albert, Duc de Luynes, who the same year famously offered two prizes, one for the best method of photomechanical reproduction and the other for
the best method of stabilizing prints, commissioned Nègre with the illustrations for his book Voyage
d’Exploration à la Mer Morte[…]. However, it was Poitevin who took both prizes in 1867 for his techniques
of photolithography and carbon printing. But neither was compatible with typographic characters.
Until the introduction of half-tone reproduction in 1890, photography and typography remained condemned to converge in the engraver’s workshop where a flat image was transformed into a relief engraving on a block of wood. Whether it came on metal or paper, the photographic image was first evaluated
by the editors before being dispatched to a draftsman who reproduced it on a plank of boxwood; this was
then forwarded to the engraving workshop where it acquired the requisite relief for receiving the printer’s ink. When the engraving reached the printer the day
before publication, it was switched for the lead plate that
had been keeping its place in the page layout. In other
words, photographs followed the same itinerary as any other images. The procedure was neither simpler nor shorter.
Unlike the lines of a drawing, the shades of gray were not
copied, but interpreted. In addition, the only human figures in these photographs were often no more than blurred
images, to be accepted as such, with their unscheduled presence on the scene having to be molded to the conventions
of composition.
News and credibility
L’Illustration expounded its views on depicting the personages of the time in its very first issue: “Biography offers us
a wide stage. Our wish is that before long there shall not
be a single personage in Europe [...] who has not paid our
newspaper the tribute of their portrait. All of us recognize
that we understand a man’s words and actions better once
we are acquainted with his features.” The first image published in L’Illustration was a portrait and each issue revealed the face of a public personage, man or woman. One
quarter of the 214 engravings from photographs were portraits. Of this substantial collection from a whole variety
of sources, 19 images were the work of Paris professionals,
some of whom had set up shop on the fashionable boulevards. The painter-photographer Gustave Le Gray (18201884), on the boulevard des Capucines, was the major contributor, but totalled only six portraits. In other words, the
“Jenny Lind,” from a photographic plate; L’Illustration November
22, 1850 (No. 404). Jenny Lind was a Swedish soprano who, at
overall contribution from portrait photography was minthe age of nine, entered the Swedish court theater school of
imal, and represented only a minute fraction of total stusinging. She then took lessons in Paris, where she gained great
dio output. The catalog of Eugène Disdéri (1819-1889), who
popularity. The photograph was taken during a singing tour in
America. The article states, somewhat puzzingly: “The presence
patented the carte de visite (calling card) technique, numof Jenny Lind, whom the Americans refer to as the Nightingale,
bered several thousand portraits, only three of which were
is a cause of immense rejoicing for this great people… all the
published before 1859. Other leading names did not feature
easier to impress that they must certainly be always bored.”
The illustration at the bottom shows the stampede to buy tickets
at all among the contributors, notably the Bisson broth(which were auctioned off) for the performance in New York.
ers, Louis (1814-1876) and Auguste (1826-1900), working
from the same building on the boulevard des Capucines,
and perhaps most celebrated of all, Nadar (1820-1910) in the rue Saint-Lazare. It is thus unrealistic at this
stage to talk of a business partnership between the press and portrait photography. The relationship was
not financial. L’Illustration received a batch of images every day from its correspondents for nominal
amounts: the major investment was downstream, in the chain of draftsmen, engravers, and printers who
processed the image for publication. A wood engraving, once completed, was a tradable asset in that it bypassed this chain. The engraving of Jenny Lind, published in Germany and France in 1850, was undoubtedly bought (or traded) by the L’Illustration from the Illustrierte Zeitung, which had published it a few
days earlier.
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Apart from such examples of trade in “image objects” in the early years of the illustrated press, the image as the subject of an
illustration reached the paper for no fee.
Whether amateurs or professionals, all
photographers were credited. This detail
was important for the paper, since some
legends did not credit the author. Of all the
images from this period, of whatever kind,
23 carry the byline “from a photograph.”
Where the author was known, the name was
given, not to add to reputation, but to authenticate the provenance of the imagebased information involved. Whether textual or visual, news was more reliable if it
came from the site of an event rather than
from official sources. Naming an image’s
author, even if obscure, together if possible
with the location, offered guarantees in this
regard. In some cases, only the location was
given: “from photographic proofs sent from
Saint Petersburg.” If neither name nor location could be given, it could still be published, provided it was used with the accompanying article. On the other hand, an
image with clear subject and authenticated
provenance could be published on its own,
without an accompanying article.
Top: “The Palma theater
fire,” on June 21, 1858, from
a drawing by Mr. Viringue.
Bottom: “After the Fire,”
from a photograph by
Mr. Martin. Because of
the complexity of taking
photographs, and the long
time needed to expose the
plates, photographers were
condemned to the “before
and after” of catastrophes or
events with large moving
crowds, all of which would
only come out as “blurs.”
The draftsman still reigned
supreme, but his days
were counted. July 10,
1858 (No. 802) issue.
Photographing events
Orchestrated festivities accounted for many of the images. Over one third of the engravings “from photographs” depicted “launches,” “arrivals” and “landings,” “openings” and “celebrations,” “maneuvers” and
“parades,” and “banquets” and “receptions.” For photographers, the advantage in all these events was the
absence of surprise: they were planned well in advance. Working with wetplate collodion or even a dry
method required prior organization. Forewarned photographers had the time they needed to transport
their equipment, prepare their chemistry, and select their viewpoint. The seconds required for exposure
meant choosing an angle that would minimize the impact of movement. A photographer needing to avoid
a blurred image could never approach his subject as closely as could a draftsman. Draftsmen could adopt
photographers’ solutions to the technical constraints of their medium, but a photograph could not produce as many effects as a drawing.
Engraved boxwood block showing “Dr Lippman, at the Sorbonne,” end 19th
century. Photo by Frédéric Joly. © L’Illustration /Keystone.
The cathedral of Milan, Italy, during the festivities for
the “Emperor of the French.” From a photograph by
L. Crete, photographer to the king of Sardinia. August
27, 1859 (No. 861) issue. © L’Illustration /Keystone.
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The 1843 preface, “Our purpose,” proclaimed the editors’ interest in “news items whose disaster proportions demand a pencil to reproduce them exactly for the mind.” Fifteen engravings “from a photograph”
depicted catastrophes affecting buildings and landscapes. From Florence, the Alinari brothers, founders
of the world’s oldest extant photography laboratory, sent a view of the town of San Stefano under water;
Alphonse Bernoud (1820-1875) provided nine photographs of an earthquake in Naples, while a “Mr Martin”
in the Balearic Islands sent in a picture of the ruins “of Palma theater after a fire,” (see page 103). Photographers were at their greatest disadvantage under these conditions. Such events were sudden in onset
and full of movement, thus doubly unsuited for recording on silver plate. They could be depicted only in
terms of their aftermaths—ruined buildings and
desolate landscapes—leaving the reader’s imagination to reconstruct the instants of unrecordable climactic tragedy—rumbling earthquake or
searing flames—which had brought them about.
The engravings of catastrophes from photographs
were thus pictures of non-events.
Title page of the Saturday
13th February 1897 issue
(No. 2816) of L’Illustration
depicting the “Weighing
of the President of the
100-kg Society”: in 1897,
obesity was already
making the headlines…
Photo by Frédéric Joly.
Drawing or photography?
It was, and remains, difficult to identify the technique at the origin of an uncredited illustration.
Some of the subtle features of engravings “from
photographs” are caused by problems that photographers managed to circumvent. But in addition to the technical constraints of photography,
there was also the input from draftsman and engraver that tended to make all illustrations look
the same, irrespective of their origin. These artisans reshaped the silver image, touching up adjustments and additions in pencil and crayon, and
chiseling the wealth of photographic half-tones
into close-knit hatchings. The wetplate collodion
method was more sensitive than the daguerreotype, but still did not allow photographers to take
pictures involving movement. Unless several extreme conditions could be met simultaneously, “live” photography was unusual in this period. Conventional engravings, on the other hand, had typically been “live” since the beginning of the 19th century.
When draftsmen trained in this tradition touched up photographers’ images, they only added to the confusion over the technical origin of uncredited engravings published in L’Illustration. The only sure way
of telling a photograph from a drawing was to refer to the legend. Initially, legends gave only the subject
of the image. Subsequently they added information on provenance. Just as the author’s name and location
offered credibility, so the legend certified the technical origin of the engraving—all the more usefully
in the case of photographs, since the difference was otherwise invisible.
This being the case, why did illustrated papers use photographs as an image source at all? Visually, engravings “from photographs” differed little, if at all, from those inspired by a drawing or painting. Legends stating the technical origin were not specific to photographs. They provided the same information
about author, location, and technique in the case of drawings and paintings too. To think that considerations of photographic authenticity governed image selection by the editors is a modern take, with no relevance to the thinking of the time. Engravings “from photographs” may well have represented the entry
of the new medium into the illustrated press, but their informational value did not exceed that of a drawing. In addition, we now tend to underestimate the entertainment function of the image that underpinned the entire illustrated newspaper enterprise.
According to statistics from the 1860s, the number of engravings from photographs used in L’Illustration increased to 1865, then fell to 1870, during which period wood engraving remained unchallenged
in periodical illustration. Could it be that the press had already ceased to believe that photography offered added informational value?
The editors did not choose photographs at the expense of drawings, but simply accepted them from their
image providers. Paintings, drawings, and photographs were so many variants of a single Image species,
whose function was to charm the readership. Photographs offered a manageable compromise: wood engraving took rather longer, but at no substantial additional cost. The legends too fitted in with the paper’s
general dynamic.
A T
O U C H
O F
FR
A N C E
From its first issue onwards, L’Illustration was intent on developing a new form
of journalism based on a network of regular and special correspondents. This illustrated “news-ism” set itself apart from
the conventional press by spurning official news sources. Crediting author, location and technique in their legends was
one way for the editors to proclaim the
independence of their sources, enhance
their credibility, and mask the underlying
entertainment function of their images.
News or information?
The author of the 1843 preface preferred
the term “news” to that of “information,”
and its corollary “news-ism” to that of
journalism. Although news and information were alike in that both were an assemblage of facts about someone or something, news had no sense of research or
enquiry, unlike information, which presupposed some notion of both. L’Illustration offered its images as an alternative
path to knowledge. Easier than conventional written communication, this path
was based on the premise that illustraAnd then there was color. L’Illustration was soon to treat its readers
tions were instantly intelligible. The pow- with a lavish use of color, first for engravings and lithographs, and
er accorded to images created a belief in ultimately by introducing color photography. Shown here is the covtheir impartiality, based on the relation- er of the Christmas 1896 issue of L’Illustration with a color lithograph by Mucha. Photo by Frédéric Joly. © L’Illustration /Keystone.
ship of trust established between them
and the reader. In its desire to be independent of the official sources of information, L’Illustration constructed the idea of credible “news-ism.” There was nothing inevitable about its encounter with photography. It was the product of market conditions that forced papers to expand their readership by offering
something new: the illustrated weekly. To what extent images helped to transform the press of opinion
into the press of information remains to be defined. ❒
Abridged and modified from: D’après photographie. Premiers usages de la photographie dans le journal L’Illustration
(1843-1859) [From a photograph. First uses of photography in L’Illustration (1843-1859)] by Thierry Gervais, in:
Études Photographiques. 2003;13:56-85]. Copyright © 2003, Société Française de Photographie (SFP). The author
wishes to thank SFP for their kind permission.
FURTHER READING
– Anon. [Paulin]. Les Mystères de L’Illustration. art. cit., p. 7-9.
– Notre but. L’Illustration. 1843(March 4, No. 1):1.
– Ambroise-Rendu AC. Du dessin de presse à la photographie
(1878-1914): histoire d’une mutation technique et culturelle.
Rev Hist Moderne Contemp. 1992(Jan-March):6-28.
– von Dewitz B, Lebeck R. In: Kiosk, Eine Geschichte der Fotoreportage (Exhibition Catalog). Köln, Germany: Museum Ludwig/
Agfa Foto-Historama; 2001.
– Thérenty ME, Vaillant A. 1836. L’an I de l’Ère Médiatique. Analyse Littéraire et Historique de La Presse de Girardin. Paris,
France: Nouveau Monde Éditions; 2001.
– Bacot JP. Quatre Générations de Presse Illustrée Généraliste
au XIXe siècle. University Thesis in Information and Communication Sciences. Paris, France: Université Paris III; 2003.
– Vincent-Aurenche ML. Édouard Charton et L’Invention du Magasin Pittoresque (1833-1870). University Thesis in Literature
and Arts. Lyon, France: Université Lyon II; 1999.
– Gilles Feyel. La Presse d’Information en France des Origines à
1944. Histoire Politique et Matérielle. Paris, France: Ellipses; 1999.
– Bellanger C et al. Histoire de la Presse Française de 1815 à 1871.
Paris, France: PUF; 1969;2.
– Marchandiau JN. 1843-1944. Vie et Mort d’un Journal. Toulouse, France: Bibliothèque Historique Privat; 1987.
– Watelet J. La Presse Illustrée en France, 1814-1914. Villeneuve
d’Asq, France: Presse du Septentrion; 1999.
– Kunzle D. L’Illustration, journal universel (1843-1853). Le premier magazine illustré en France. Affirmation du pouvoir de la
bourgeoisie. Les Nouvelles de L’Estampe. 1979(Jan-Feb).
– Jean Martin O, Jean Martin H. Le monde des éditeurs. In: Histoire de L’Édition Française Vol 3. Le Temps des Éditeurs du Romantisme à la Belle Époque. Paris, France: Promodis; 1985;3:
158-215.
– Melot M. Le texte et l’image. In: Histoire de L’Édition Française
Vol 3. Le Temps des Éditeurs du Romantisme à la Belle Époque.
Paris, France: Promodis; 1985;3:286-311.
– Lefebure A. Havas. Les Arcanes du Pouvoir. Paris, France: Grasset; 1982.
– Blachon R. La Gravure sur Bois au XIXe Siècle. L’Âge du Bois
Debout. Paris, France: Édition de l’Amateur; 2001.
– Aubenas A. D’Encre et de Charbon. Le Concours Photographique du Duc de Luynes 1856-1867. Paris, France: BNF; 1994.
– Weise B. Aktuelle Nachrichtenbilder “nach Photographien” in
der deutschen illustrierten Presse der zweiten Hälfte des 19. Jahrhunderts. In: Grivel C, Gunthert A, Stiegler B, eds: Die Eroberung der Bilder. Photographie in Buch und Presse, 1816-1914.
Munich, Germany: Wilhelm Fink Verlag; 2003:62-101.
– Gretton T. Différence et compétition. L’imitation et la reproduction des oeuvres d’art dans un journal illustré du XIXe siècle. In :
Majeur ou Mineur? Les Hiérarchies en Art, Nîmes, France: éd.
Jacqueline Chambon; 2000:117.
A T
O U C H
O F
FR
A N C E
LE
MONDE EN IMAGES
LA NAISSANCE DE LA PRESSE ILLUSTRÉE ET L’AVÈNEMENT DE LA PHOTOGRAPHIE
DANS LA PRESSE FRANÇAISE DANS LA SECONDE MOITIÉ DU XIXE SIÈCLE
L’ILLUSTRATION :
A
vec l’avènement quasi simultané en Europe de la presse illustrée d’actualité, la seconde moitié
du XIXe siècle fut le théâtre d’une véritable révolution dans le domaine de la presse écrite. Si la
fonction satirique de la gravure connaissait depuis longtemps un succès dans la presse, ainsi
Charivari, à partir des années 1840, des journaux proposent un usage séduisant et didactique de
l’image d’actualité. Le coup d’envoi de ce nouveau processus d’illustration dans la presse hebdomadaire fut donné par l’Illustrated London News (Angleterre, 1842 et encore publié de nos
jours), suivi l’année d’après par L’Illustration (France, 1843 jusqu’en 1944) et l’Illustrierte Zeitung (Leipzig, Allemagne, 1843 à 1940), puis par de nombreux autres journaux illustrés de par le monde dans les
années 1860. Cet essor de la presse obligea les rédactions de l’époque à employer jour et nuit de véritables
équipes de dessinateurs et de graveurs et bientôt de photographes. L’Illustration, fondée par Édouard
Charton, Jean-Baptiste Paulin et Alexandre Dubochet, connut un succès immédiat et s’attacha des dizaines
de milliers de lecteurs grâce à la qualité d’impression de ses gravures, à la richesse de ses informations,
à la collaboration d’un réseau de correspondants et à la place toujours plus grande donnée à l’image. Pour
l’essentiel les gravures sont majoritairement réalisées à partir de dessins, mais L’Illustration utilise rapidement des photographies (dès 1848), bien que celles-ci doivent passer, dans un premier temps, par les
mains d’un graveur pour être reproduites dans les pages du journal (il faudra attendre les années 1890
pour que les procédés tramés permettent de reproduire mécaniquement la photographie). La collection
de L’Illustration offre un panorama complet de la vie sociale, politique, scientifique et culturelle du XIXe
siècle. Chaque numéro était lu avec passion par les lecteurs d’alors et L’Illustration est désormais recherchée avec ardeur par les collectionneurs dans les foires aux livres et les brocantes. L’Illustration joua un
rôle essentiel dans l’histoire de la presse française et doit être envisagée comme un élément fondateur de
l’ère médiatique qui caractérise notre société contemporaine.
✦
Medicographia
A
Ser vier
publication
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for authors
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1. Ouriel K, Geary K, Green RM, Geary JE, DeWeese JA. Factors
determining survival after ruptured abdominal aneurysm. J Vasc Surg.
1990;11:493-496.
2. Darling RC, Brewster DC, Ottinger LW. Autopsy study of unoperated abdominal aortic aneurysms: the case for early resection.
Circulation. 1977;56(suppl II):II161-II164.
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