(Circulation. 1999;99:751-756.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Automated Heparin-Delivery System to Control Activated Partial Thromboplastin Time
Evaluation in Normal Volunteers
From the Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass (C.P.C.); Clin-Pharma Research Ltd, Birsfelden, Switzerland (J.D., C.H.K.); University of Alabama, Birmingham, Ala (T.J.); and Gensia Automedics, Inc, San Diego, Calif (K.C., C.P.V.).
Correspondence to Christopher P. Cannon, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail ccannon{at}rics.bwh.harvard.edu
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Abstract |
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Background—Unfractionated heparin is used widely; however, control of the level of anticoagulation remains its greatest problem, with fewer than 35% of patients having activated partial thromboplastin times (aPTTs) within a range of 55 to 85 seconds in recent trials.
Methods and Results—We developed and tested a prototype of an automated heparin control system (AutoHep) in which a computer-based titration algorithm adjusted the heparin infusion to reach a target aPTT. In 1 study, 12 healthy male subjects received an intravenous infusion of heparin with the rate determined by AutoHep and were randomized to receive an initial bolus or no bolus of heparin preceding the infusion. A second study evaluated the automated blood sampling system in 12 subjects. Of the 344 end-point aPTT measurements, 78% were within ±10 seconds of the target (prespecified primary end point), and 89% were within a ±15-second range. The time to achieve a target aPTT was 93 minutes without and 150 minutes with an initial heparin bolus. The total percentage of time within the target range ±15 seconds was 46 of 48 hours (96%). The automatic blood sampling system successfully obtained 96% of all scheduled samples.
Conclusions—These results suggest that the AutoHep system has the potential to significantly improve aPTT control of intravenous heparin compared with current clinical practice.
Key Words: heparin • coagulation • anticoagulants
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Introduction |
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Unfractionated heparin therapy is used in the care of >4 million patients annually worldwide with arterial and venous thromboembolic disease states. Numerous studies have shown that the level of systemic anticoagulation is a major determinant of clinical outcome,1 2 3 leading to the use of activated partial thromboplastin time (aPTT) to monitor the anticoagulant response of heparin. Because of the complex pharmacokinetics and pharmacodynamics of heparin, wide patient variability in anticoagulant response, and time delays between obtaining the blood sample and reporting aPTT results,4 it is difficult to establish and maintain the therapeutic level of anticoagulation for each patient. Despite numerous efforts to improve the delivery of heparin, including heparin administration nomograms,5 use of bedside aPTT devices,4 and use of weight-adjusted6 and computer-based algorithms,7 recent trials have achieved only 30% to 35% of aPTTs that were within a 30-second target range.8 9 In an attempt to improve heparin control, we developed and tested a prototype of the AutoHep system, which automatically acquires a venous blood sample, performs an aPTT measurement, and adjusts the heparin infusion rate to achieve an operator-selected aPTT target.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Heparin Control Study
After Ethics Committee approval and each subjects' written informed consent were obtained, 12 healthy male volunteers (age, 20 to 49 years) were randomly assigned to 1 of 2 treatment groups: automated heparin system infusion after an initial bolus of 50 U/kg IV heparin (bolus group) or infusion without a loading dose of heparin (no bolus). Two intravenous catheters were placed: 1 connected to the infusion pump (IMED PC-1) for administration of the heparin solution (50 U/mL, Elkins-Sinn), and the other in the contralateral arm for collection of blood samples, with a constant saline infusion to maintain catheter patency. aPTT measurements were performed with a calibrated point-of-care instrument (Boehringer Mannheim CoaguChek Plus).4 Heparin infusion continued for 48 hours. The system targeted an aPTT of 1.5 times the baseline value for 40 hours and 2.0 times the baseline for the final 8 hours.
Safety features of the system included audible and visible alerts or alarms for problems with either the intravenous pumps or the control algorithm (eg, air in intravenous line, intravenous catheter occlusion, or aPTT measurement outside the expected range). Heparin delivery continued if there were "alert" messages but was automatically stopped by the device if an alarm occurred. The system was programmed so that the maximum instantaneous heparin infusion rate was <5000 U/h and maximum hourly cumulative heparin dose was <2000 U to avoid any potential "overdosing" of heparin.
Control Algorithm
The initial infusion calculations were based on a
pharmacodynamic model relating the aPTT response to drug infusion. The
aPTT response (R) to heparin is described as R=log aPTT-log
aPTTbaseline, which may be expressed as
aPTT=10RaPTTbaseline. The
change in log APTT is proportional to the heparin concentration (H).
The rate of change in heparin concentration is as follows:
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is the elimination rate constant,
Vm and Km are
parameters reflecting the saturable mechanism of
elimination of heparin, u is the heparin infusion rate, and
Vd is the apparent volume of distribution
(approximately equal to the blood volume). Because R=mH, the time rate
of change of the response may be written as follows:
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) consists of the
following:
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Blood samples for "end-point" aPTTs were drawn at protocol-specified intervals (0, 20, and 40 minutes; 1, 3, and 6 hours; every 3 hours thereafter, except at 27 and 33 hours; and 30 minutes and 1, 2, and 4 hours after infusion for a total of 22 samples over 52 hours) for replicate aPTT measurements to establish system performance. None of the protocol-scheduled aPTT measurements was used for feedback purposes.
Blood Sampling Study
After Ethics Committee approval and each subjects' written
informed consent were obtained, a second group of 12 normal volunteers
(50 to 60 years of age) had a single venous catheter placed and
received heparin for 60 hours with infusion rates based on a standard
nomogram. In the prototype, a computer-controlled sampling pump adjusts
the blood withdrawal rate on the basis of pressure measurements derived
from a strain beam on the sample tubing. A pneumatic tourniquet is
automatically inflated during the sample draw. Control of a saline pump
allows flushing of the heparin before sample withdrawal and flushing of
the blood from the sample line at the end of the sample cycle. At each
of the 14 scheduled time points, replicate whole-blood aPTT
measurements were obtained from these device-withdrawn samples and from
manually obtained venous samples from the contralateral arm.
End Points
Data samples considered evaluable were those acquired during
heparin infusion and after the first transition from baseline (1 hour)
or washout of bolus administration (3 hours). Thus, of 525 end-point
aPTTs, 181 were not included in the evaluable data set because 13 were
at baseline, 72 were during the postbolus washout, and 96 were after
heparin infusion. The primary performance variables were
the percentage of end-point aPTT values in the target range (target
level, ±10, ±15, or ±20 seconds). Performance of the blood
sampling device was the percentage of successfully completed sample
cycles. If a sample cycle failed, the system could retry once.
Comparisons of continuous data were made with Student's t
test. Data are presented as mean±SD and as median with
range.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Heparin Control Study
An example of a single patient test is shown in Figure 1
, which gives the measured and
pharmacodynamically modeled aPTT values and the heparin infusion rate.
Although total dose and mean infusion rate of heparin appeared to be
lower in the nonbolus group (Table 1), no statistically significant
differences were detected. For nonbolus subjects, the algorithm
delivered an initial rapid infusion of heparin (average, 644 U over 20
minutes) to quickly achieve the selected target. The average number of
aPTT measurements requested by the control algorithm over the 48-hour
period was 
9; they were evenly distributed over the infusion
period.
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Table 2 demonstrates that the target aPTT
values of 1.5 and 2.0 times control were achieved in both the bolus and
nonbolus groups. Table 3 summarizes the
percent aPTT samples within ±10, ±15, and ±20 seconds of the
selected aPTT target. For all subjects, 78% of measurements were
within 10 seconds, 89% were within 15 seconds, and 94% were within 20
seconds of the target.
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By use of the pharmacodynamic model–estimated aPTT trajectories, the
average time to target for bolus subjects was 150 minutes (range, 93 to
275 minutes), whereas for nonbolus subjects, this interval was reduced
to 93 minutes (range, 15 to 190 minutes). Thus, by the 6-hour time
point, 100% of patients were within the target range (Figure 2, top). These results can be compared
with the data on aPTT control in the intravenous heparin
group of the ESSENCE trial (Figure 2, bottom).
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The average deviation from target for all scheduled time points was
usually <5 seconds and is graphically presented in Figure 3 for bolus and nonbolus subjects,
respectively. During the period after the initial washout, only 9 of
326 aPTT values (3.5%) exceeded 80 seconds, and only 4 (1.2%)
exceeded 90 seconds. The replicate whole-blood aPTT assays yielded very
consistent results, with r=0.98 and a slope of
0.986.
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Pharmacodynamic Analysis
Table 4 shows that the initial
pharmacodynamic model parameters10 and those
for the subjects in this study were similar. The
performance analysis based on the pharmacodynamic
modeling showed that patients remained within a ±15-second range 98%
of the time (Table 5). No adverse events
were reported as device related, and no bleeding events occurred.
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Blood Sampling Study
In the blood sampling study, the system successfully withdrew 161
of 168 samples (96%). All 7 of the unsuccessful sample cycles occurred
when the subjects were not receiving intravenous heparin.
Coefficients of variation for automatic (5.5%) and manually (5.1%)
obtained aPTT measurements showed no difference (P=0.4).
Correlation of aPTT values (r=0.95) from automatic and
manual sampling methods also showed excellent agreement. One subject in
this study (which evaluated the blood sampling device and used standard
nomogram-titrated heparin) developed an isolated heme-positive
stool.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Although heparin has been used for >50 years in the management of patients with acute coronary syndromes and venous thromboembolism, control of the anticoagulation level has been its greatest challenge. Numerous studies have shown that when aPTT values are above the target range, bleeding is more frequent, as are, surprisingly, recurrent infarction and mortality.1 2 3 If aPTT values are too low, recurrent thrombotic events are more common.1 2 3 Accordingly, numerous attempts to improve control of the anticoagulation level with heparin, including the use of standardized nomograms,5 weight-adjusted dosing,6 bedside aPTT monitoring,4 and all 3 together,9 have failed to make a major improvement (Figure 4
). Only 30% to 35% of patients were in
the target 30-second range a full 24 hours after titration of heparin
in TIMI 9B8 and in a randomized trial of both bedside
monitoring and weight-adjusted heparin dosing.9 We also
analyzed aPTT values in 209 patients in TIMI IIIB who were
found after randomization to have normal coronary arteries,
thus approximating the present study population: Only 35%
of aPTT values were within the 30-second target of 45 to 75
seconds.
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Automated Heparin Control System
In this study, the prototype automated heparin control system
achieved 89% of aPTT values within a 30-second range. This corresponds
to subjects being within the target range for 46 hours of the 48-hour
treatment period. The target aPTT was achieved in only 90 to 150
minutes both initially and when the new target was selected. This was
achieved by the computerized algorithm that required on average 9 aPTT
samples over the 48-hour period. The automated venous blood sampling
succeeded in acquiring blood sample in 96% of the attempts overall and
in 100% of attempts when the subjects were receiving heparin.
Subjects receiving an initial bolus of heparin appeared to have better
aPTT control during the infusion period (Figure 3
). One reason
may have been that during washout of the bolus dose, with the large
excursion in anticoagulant status, the aPTT values may have allowed
better identification of the pharmacodynamic model in the individual
subject, thus resulting in improved overall performance.
Ultimately, the AutoHep system will automatically acquire blood samples for aPTT assays and calculate the optimal heparin delivery to achieve an operator-specified target. The time required by nurses and physicians would be reduced to the initial setup and response to any alarms (which were infrequent [<5%] in this initial study). The costs of the device and cartridges are planned to be equivalent to current costs of laboratory-based aPTT monitoring of unfractionated heparin or of low-molecular-weight heparin. With further refinements in the device and inclusion of patient demographic factors in the configuration of the control algorithm, the performance of the system may be improved further. Most importantly, however, a very stable anticoagulant effect from unfractionated heparin, a very inexpensive medication, can be achieved, which may translate into improved clinical outcomes. This hypothesis needs to be tested by use of an integrated version of the AutoHep system in future clinical trials.
In conclusion, this initial testing of the AutoHep system achieved nearly 90% of aPTTs within a target range of ±15 seconds, which can be compared with current clinical practice in which typically only 30% to 40% of aPTTs are within range. If these results can be duplicated with the integrated device in patients, it will represent a major advancement in the use of heparin.
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Footnotes |
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Dr Jannett has been a consultant for and received research funding from Gensia Automedics.
Received September 24, 1998; revision received October 20, 1998; accepted October 26, 1998.
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References |
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13. Mungall D, Floyd R. Bayesian forecasting of APTT response to continuously infused heparin with and without warfarin administration. J Clin Pharmacol. 1989;29:1043–1047.We developed and tested a prototype of an automated heparin control system (AutoHep) in which a computer-based titration algorithm adjusted the heparin infusion to reach a target activated partial thromboplastin time (aPTT). Twelve healthy male subjects received intravenous infusion of heparin with the rate determined by AutoHep. Of the 344 end-point aPTT measurements, 78% were within ±10 seconds of the target (prespecified primary end point), and 89% were within a ±15-second range. These results suggest that the AutoHep system has the potential to significantly improve aPTT control of intravenous heparin compared with current clinical practice.[Medline] [Order article via Infotrieve]
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