Point-of-care (POC) versus central laboratory instrumentation for

Vascular Medicine 2005; 10: 23–27
Point-of-care (POC) versus central laboratory instrumentation
for monitoring oral anticoagulation
David M Dorfmana, Ellen M Goonana, M Kay Boutiliera, Petr Jarolima, Milenko Tanasijevica
and Samuel Z Goldhaberb
Abstract: Point-of-care (POC) instruments employing fingerstick whole blood to
monitor patients treated with warfarin are a popular alternative to complex, central
laboratory coagulation analyzers utilizing citrated plasma derived from venipuncture.
We investigated the accuracy of two widely utilized POC instruments for oral
anticoagulation monitoring compared with a central laboratory instrument.
Instrument-to-instrument variation differed for the two POC instruments, which
correlated with the central laboratory instrument, but exhibited positive bias of
0.24–0.35 INR units. Positive bias increased as the INR values increased. We conclude
that clinicians should exercise caution when interpreting results generated by POC
monitors, particularly at high INR values. A high POC measurement of INR does not
necessarily warrant decreasing the warfarin dose. Instead, a predefined cut-off range
for high INR values generated by POC instruments should mandate confirmatory
testing with central laboratory instrumentation.
Key words: international normalized ratio (INR); prothrombin time (PT); warfarin
Introduction
Methods
Patients receiving warfarin and other anti-vitamin K
agents are at risk of bleeding if the oral anticoagulant
dose is too high, or thromboembolism if the oral
anticoagulant dose is too low. Proper oral anticoagulant dosing requires an accurate prothrombin time (PT)
measurement to generate an international normalized
ratio (INR). Point-of-care (POC) instruments using fingerstick whole blood are generally convenient, easy to
use, preferred by patients, and generate immediate
results, allowing more rapid adjustments of anticoagulation therapy, compared with complex, central
laboratory coagulation analyzers utilizing citrated
plasma.1
Our objective was to investigate the accuracy of two
widely utilized POC instruments by comparing the
results generated from whole blood with results
generated by a central laboratory instrument using
citrated plasma.
Patient samples
Fifty-two consecutive patients receiving warfarin for
long-term anticoagulation of atrial fibrillation, venous
thromboembolism, or mechanical prosthetic valves as
outpatients at a suburban satellite laboratory underwent venipuncture to obtain whole blood for POC
instrument measurement of INR and to generate citrated plasma for central laboratory measurement of
INR. Previously, we and others2 obtained similar
results from POC monitors employing both fingerstick
and syringe-drawn venous whole blood. The study was
conducted in accordance with institutional policies.
aDepartment of Pathology and bCardiovascular Division,
Department of Medicine, Brigham and Women’s Hospital and
Harvard Medical School, Boston, MA, USA
Address for correspondence: David M Dorfman, Department of
Pathology, Brigham and Women’s Hospital, 75 Francis Street,
Boston, MA 02115, USA. Tel: ⫹1 617 732 7581; Fax: ⫹1 617 731
4872; E-mail: [email protected]
© 2005 Edward Arnold (Publishers) Ltd
INR determination
Immediately following venipuncture, whole blood
was used to generate INR values using the CoaguChek
S monitor, international sensitivity index (ISI) ⫽ 2.0
(Roche Diagnostics, Indianapolis, IN, USA) and the
Protime Microcoagulation System monitor, ISI ⫽ 1.0
(International Technidyne Corporation [ITC], Edison,
NJ, USA). Two devices from each manufacturer were
employed simultaneously to generate INR results for
each type of POC instrument. Concurrently, INR
results were generated from citrated plasma with a
central laboratory instrument, the STA-R® coagulation
analyzer (Diagnostica-Stago, Parsippany, NJ, USA),
which utilized Neoplastine CI ⫹ PT reagent
(ISI ⫽ 1.29).
10.1191/1358863x05vm587oa
24
DM Dorfman et al
Statistical analysis
Data were analyzed utilizing MedCalc version 7.2.0.0
statistical software (www.medcalc.be) for correlation
analysis, least squares linear regression analysis, and
to generate Bland and Altman plots.3,4
Results
First, we correlated the data generated from each
pair of POC instruments (Figure 1A). INR results
generated using the two Roche CoaguChek instruments exhibited better correlation (correlation
coefficient ⫽ 0.9817, p ⬍ 0.0001) than the two
ITC instruments (correlation coefficient ⫽ 0.8801,
p ⬍ 0.0001; Table 1). We also compared the results
from the two sets of POC instruments (correlation
coefficient ⫽ 0.8968, p ⬍ 0.0001, Table 1).
Next, we compared the INR values generated by the
two sets of POC instruments with values obtained
from the central laboratory coagulation analyzer
(Figure 1B). The mean INR measured with the STA-R
central laboratory coagulation analyzer was 2.1, with
a standard deviation (SD) of 0.6 and a range from 1.0
to 3.6. The POC instruments had higher mean INR
values, 2.4 for the CoaguChek instruments and 2.5 for
the ITC instruments, both with a higher SD (of 0.9)
than the central laboratory coagulation analyzer
(Table 1). The range of INR values was greater for the
POC instruments: from 0.9 to 5.5 for the CoaguChek
instruments and from 0.8 to 5.4 for the ITC instruments (Table 1). The correlation coefficients for the
POC instruments compared with the central laboratory STA-R instrument were comparable for the two
manufacturers’ instruments: 0.9052, p ⬍ 0.0001 for
the CoaguChek instruments and 0.9067, p ⬍ 0.0001
for the ITC instruments (Table 1).
Figure 2 depicts the differences in INR measurement between the POC instruments and the central
laboratory instrument, using the method of Bland and
Altman. The mean difference between the INR results
generated with the CoaguChek instruments and the
Figure 1 (A) Comparison of CoaguChek S POC instrument INR values (left) and ITC POC instrument INR values (right)
for two different devices. The correlation coefficient for the CoaguChek S comparison is 0.9817, p ⬍ 0.0001, and for the
ITC comparison it is 0.8801, p ⬍ 0.0001 (Table 1). (B) Correlation of CoaguChek S POC instrument (left) and ITC POC
instrument (right) INR values with those generated by the STA central laboratory instrument. The correlation coefficients are 0.9052, p ⬍ 0.0001, and 0.9067, p ⬍ 0.0001, respectively (Table 1).
Vascular Medicine 2005; 10: 23–27
Point-of-care testing for oral anticoagulation 25
Table 1
Comparison of INR data from POC and central laboratory instrumentation.
Instrument
aComparison
bComparison
Mean difference versus
STA-R (central lab)
Range
Mean ⫾ SD
52
0.9–5.5
–
0.9817a, p ⬍ 0.0001,
95% CI ⫽ 0.9682–0.9895
0.11a, 2 SD ⫽ ⫺0.26 – ⫹0.47
49
0.8–5.4
–
0.14a, 2 SD ⫽ ⫺0.98 – ⫹0.70
49
0.8–5.5
–
104
0.9–5.5
2.4 ⫾ 0.9
98
0.8–5.4
2.5 ⫾ 0.9
0.8801a, p ⬍ 0.0001,
95% CI ⫽ 0.7959–0.9309
0.8968b, p ⬍ 0.0001,
95% CI ⫽ 0.8233–0.9408
0.9052, p ⬍ 0.0001,
95% CI ⫽ 0.8631–0.9349
0.9067, p ⬍ 0.0001,
95% CI ⫽ 0.8639–0.9365
Samples
CoaguChek 1
versus
CoaguChek 2
ITC 1 versus
ITC 2
CoaguChek
versus ITC
CoaguChek
1⫹2
ITC 1 ⫹ 2
Correlation coefficient
versus STA-R
(central lab)
⫹0.24, 2 SD ⫽ ⫺0.63 – ⫹1.12
⫹0.35, 2 SD ⫽ ⫺0.53 – ⫹1.23
between POC instruments from same manufacturer.
between POC instruments from different manufacturers.
Figure 2 Bland and Altman plots of INR measurements generated by the CoaguChek POC instruments (upper left)
and ITC POC instruments (lower left) compared with the STA central laboratory coagulation analyzer. Both POC
instruments exhibit a positive measurement bias compared to the central laboratory instrument. Also shown is the
regression analysis for the same data (upper and lower right), showing a positive slope for the least squares linear
regression analysis for both POC instruments, indicating that there is increasing positive bias with higher INR values
(see text).
Vascular Medicine 2005; 10: 23–27
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DM Dorfman et al
central laboratory STA-R instrument was ⫹0.24 INR
units, while the ITC instruments had a mean difference of ⫹0.35 INR units compared with the central
laboratory instrument (Table 1). For most specimens,
the CoaguChek INR results differed from the central
laboratory INR results by ⫺0.3 to ⫹0.6 INR units,
whereas the ITC INR results differed from the central
laboratory INR results by a wider margin, ranging
from ⫺0.3 to ⫹0.8 INR units. Both types of POC
instruments exhibited increasing positive bias compared with the central laboratory instrument at higher
INR values. The slope of the least squares linear
regression analysis for the CoaguChek instruments
compared with the central laboratory instrument
was ⫹0.42, p ⬍ 0.0001, and the slope for the ITC
instruments compared with the central laboratory
instrument was ⫹0.46, p ⬍ 0.0001.
anticoagulation would be able to calibrate these instruments as well as central laboratory instruments
employed for anticoagulation testing. However, even
with calibration, there is increasing deviation of POC
and central laboratory INR values with a positive bias
for POC instruments, particularly when the INR
exceeds 3.0.10,11
Based upon our findings, we have instituted a protocol in which we do not report POC INR values that
equal or exceed 4.0. In such cases, we require
venipuncture to obtain citrated plasma for INR determination by our central laboratory. Since instituting
this program, we have performed 315 POC INR measurements, with 23 results (7.3%) that were ⱖ4.0
(mean ⫾ SD ⫽ 5.2 ⫾ 1.3, range ⫽ 4.0–8.0, with
corresponding central laboratory mean ⫾ SD ⫽
3.6 ⫾ 0.7, range 2.3–5.2), which exhibited a mean
bias of ⫹1.7 INR units compared with central laboratory findings (2 SD ⫽ ⫺0.9 – ⫹4.3).
Discussion
Our principal finding is that POC measurements of
INR exhibit positive bias as INR values increase,
despite overall good correlation with central laboratory instrumentation for the entire range of INR measurements. This observation has potentially profound
clinical implications. Without awareness of positive
bias, clinicians might decrease the dose of oral anticoagulation based upon POC measurements yielding
high INRs. This could lead to an increase in thromboembolic events in cases when the POC INR measurement was spuriously high compared with the
central laboratory. Although there is overall positive
bias of INR values generated with POC versus central
laboratory instrumentation, in some instances negative
bias of INR values was also observed. Additional
studies of a larger patient sample may be helpful to
confirm these observations.
Our results are consistent with those of previous
investigators who observed positive bias of INR values in studies comparing POC versus central laboratory instrumentation.5–7 Nevertheless, few clinicians
are aware of the implications and ongoing problem of
obtaining high INRs on POC instruments compared
with central laboratory instrumentation. Anticoagulation
services rely upon accurate determinations of the INR
in order to provide appropriate adjustment of warfarin
dosing.8 In a consortium of Italian anticoagulation
clinics, with 2011 patient-years of treatment, 70
thrombotic events (3.5 per 100 patient years) were
recorded in 67 patients. The frequency of thrombotic
events increased as the INR decreased.9
The European Concerted Action on Anticoagulation
(ECAA) developed approaches for the calibration of
POC INR instruments utilizing citrated fresh plasma
or lyophilized plasma; however, this approach
does not work for all POC instruments.10,11 Ideally,
laboratories that employ POC instruments to monitor
Vascular Medicine 2005; 10: 23–27
Conclusion
INR values generated by POC monitors exhibit positive bias for INR values at the high end of the anticoagulation range. Clinicians should exercise caution
when interpreting high INR results generated by POC
monitors due to possible important discrepancies with
plasma-based methods. Insisting upon a predetermined INR cut-off value for mandatory venipuncture
and central laboratory INR determination may
potentially decrease the frequency of avoidable
thromboembolic events and improve patient safety. If
there are clinical practices in which POC testing is
used exclusively to monitor anticoagulation therapy, it
would be useful to see whether this results in higher
rates of thromboembolic complications, as we
would predict.
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