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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 846-851
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Heparin-induced thrombocytopenia with thromboembolic
complications: meta-analysis of 2 prospective trials to assess the
value of parenteral treatment with lepirudin and its
therapeutic aPTT range
Andreas Greinacher,
Petra Eichler,
Norbert Lubenow,
Harald Kwasny, and
Matthias Luz
From the Institute for Immunology and Transfusion Medicine,
Ernst-Moritz-Arndt University Greifswald; the Biometrics Department,
Aventis-Behring, Marburg; and the Clinical Operations Department,
Aventis Pharma, Frankfurt, Germany.
 |
Abstract |
This meta-analysis focuses on 2 prospective studies in patients with
heparin-induced thrombocytopenia (HIT) and thromboembolic complication
(TEC) who were treated with lepirudin (n = 113). Data were compared
with those of a historical control group (n = 91). The primary
endpoint (combined incidence of death, new TEC, and limb
amputation) occurred in 25 lepirudin-treated patients (22.1%; 95% CI,
14.5%-29.8%): 11 died (9.7%; 95% CI, 4.9%-16.8%), 7 underwent
limb amputation (6.2%; 95% CI, 2.5%-12.3%), and 12 experienced new
TEC (10.6%; 95% CI, 5.8%-18.3%). The risk was highest in the period
between diagnosis of HIT and the start of lepirudin therapy (combined
event rate per patient day 6.1%). It markedly decreased to 1.3%
during lepirudin treatment and to 0.7% in the posttreatment period.
From the start of lepirudin therapy to the end of follow-up,
lepirudin-treated patients had consistently lower incidences of the
combined endpoint than the historical control group (P = .004, log-rank test), primarily because of a reduced risk for new
TEC (P = .005). Thrombin-antithrombin levels in the
pretreatment period (median, 43.9 µg/L) decreased after the
initiation of lepirudin (at 24 hours ± 6 hours; median, 9.18 µg/L.)
During treatment with lepirudin, aPTT ratios of 1.5 to 2.5 produced
optimal clinical efficacy with a moderate risk for bleeding, aPTT
ratios lower than 1.5 were subtherapeutic, and aPTT levels greater than
2.5 were associated with high bleeding risk. Bleeding events requiring
transfusion were significantly more frequent in patients taking
lepirudin than in historical control patients (P = .02). In
conclusion, this meta-analysis provides further evidence that lepirudin
is an effective and acceptably safe treatment for patients with HIT.
(Blood. 2000;96:846-851)
© 2000 by The American Society of Hematology.
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Introduction |
Heparin-induced thrombocytopenia (HIT) is a well-known
complication of heparin therapy.1 It develops in up to 3%
of patients treated with unfractionated heparin.2
Immune-mediated HIT typically is manifested 5 to 10 days after the
start of heparin therapy; the mechanism appears to involve the
development of antibodies of the IgG class, which bind to heparin
platelet factor 4 (PF4) complexes.3,4 The interaction of
these antigen-antibody complexes with endothelial cells5-7
and platelets8,9 may contribute to the development
of new thrombi.
Thrombin plays a central role in HIT-related thromboembolic
complication (TEC). Thrombin generation is enhanced in HIT by the
concomitant activation of platelets,10 the generation of platelet microparticles,11 and the alteration of
endothelial cells.5 Immediate cessation of heparin
treatment is necessary when HIT develops. However, thrombin generation
continues even after the cessation of heparin,12,13 and
many patients require further parenteral anticoagulation because of
their underlying disease, especially if they have experienced a recent
TEC. A nonheparin anticoagulant that does not cross-react with HIT
antibodies, such as hirudin, may be appropriate for this purpose.
Hirudin is a direct inhibitor of thrombin and acts independently of
cofactors such as antithrombin14; unlike heparin, hirudin
is not inactivated by PF4 and may be more effective in the presence of
platelet-rich thrombi.15 Hirudin can also inhibit thrombin
that is bound to fibrin or fibrin-degradation
products.16,17 It should, therefore, be an ideal
anticoagulant in HIT, a syndrome triggered by intravascular platelet
activation and thrombin generation and often complicated by new TEC.
We evaluated the recombinant hirudin lepirudin (Refludan; Aventis
Pharma, Frankfurt, Germany) in patients with HIT in 2 prospective studies of similar design.12,18 At the time the studies
were conducted, no active comparator was available, and a
placebo-controlled trial was considered ethically inappropriate;
therefore, clinical outcomes of patients in the studies were compared
with those of a historical control group.
In the HAT-1 trial,18 lepirudin treatment resulted in a
statistically significant reduction of new TEC, limb amputation, or
death (combined endpoint). Although the HAT-2 trial showed a similar
trend toward fewer clinical events with lepirudin, the results did not
reach statistical significance.12 The reasons for the
different outcomes in the 2 studies are still unclear. Each study
included patients with thrombocytopenic HIT with and without TEC at
baseline. This meta-analysis was designed to evaluate the effects of
lepirudin in the patients with TEC at baseline, for whom the need for
continued parenteral anticoagulation is generally accepted. Taken
together, HAT-1 and HAT-2 provide the largest prospective data
collection published to date of such severely affected patients with
HIT. The objectives of the meta-analysis were to evaluate the clinical
outcomes of patients with HIT and TEC who were treated with lepirudin
and to compare them with the clinical outcomes of historical control
patients who did not receive lepirudin, to evaluate the therapeutic
aPTT ranges for lepirudin, and to assess potential cofactors
influencing the outcomes in these patients, such as sex, age, patient
population (surgery vs medical and others), and comedications (aspirin,
coumarin, thrombolytics).
| |
Patients and methods |
Patients
Patients administered lepirudin were selected from 2 prospective
clinical studies,12,18 and control patients were selected from a registry of patients who did not receive lepirudin (or any other
hirudin).18 The registry was established before lepirudin was available. Diagnoses for all patients (lepirudin study and historical control) were made in the same laboratory using the same
methods, and all patients were enrolled consecutively. Patients qualified for the meta-analysis if they had arterial or venous thromboembolism and a diagnosis of HIT based on clinical criteria (decrease in platelet count by 50% or more or to less than 100 × 109/L, new TEC during heparin administration, or both
conditions) and based on laboratory-confirmed HIT antibodies. The
heparin-induced platelet activation test was used to detect HIT
antibodies.19,20 Exclusion criteria were age younger than
18 years, no ongoing thrombosis, missing date of laboratory
confirmation of HIT, more than 21 days between onset of clinical
symptoms (thrombocytopenia or TEC during heparin treatment) and
laboratory confirmation of HIT, cardiopulmonary bypass, and start of
therapy more than 60 days after laboratory confirmation of HIT.
Treatment regimens
Lepirudin (Refludan; Aventis Pharma) treatment regimens used in the
2 prospective studies were as follows. In regimen A1, patients with HIT
and thrombosis were administered a 0.4 mg/kg intravenous
(IV) loading dose and then 0.15 mg/kg per hour of continuous IV
infusion, adjusted according to aPTT. In regimen A2, patients with HIT
and thrombosis who were receiving thrombolysis were administered a 0.2 mg/kg IV loading dose and then 0.1 mg/kg per hour continuous IV
infusion adjusted according to aPTT.
The aPTT was used to monitor lepirudin treatment. Based on studies in
patients without HIT,21 the therapeutic range was predefined as a 1.5- to 2.5-fold prolongation of the baseline aPTT
value. If the patient's baseline aPTT value was unavailable, the mean
of the laboratory normal range was used. As described previously,12 the lepirudin dosage was reduced in patients
with serum creatinine levels higher than 1.5 mg/dL (133 µmol/L).
Historical control patients were treated at the discretion of the
treating physician. Management decisions were made by the treating physician.
Clinical outcome
Prespecified clinical efficacy variables included new TEC, limb
amputations, and death. Patients were monitored daily for platelet
counts and for new TEC from the time of laboratory confirmation of HIT
until 14 days after the end of treatment. In the first 56 patients
thrombin-antithrombin complexes (Enzygnost; Dade-Behring, Marburg,
Germany) were assessed before treatment with lepirudin, 4, 12, 24, and
36 hours after the start of lepirudin, and then daily until the end of treatment.
Because laboratory confirmation of HIT was an absolute inclusion
criterion, there was a time delay between suspicion of HIT and start of
lepirudin treatment. To evaluate whether a clinical suspicion of HIT
would justify immediate treatment with lepirudin or whether
confirmation of the tentative diagnosis by laboratory assay should be
sought first, average combined outcome rates per patient day were
estimated for each of the following periods: before treatment, or after
laboratory confirmation of HIT and before the start of lepirudin
treatment; during lepirudin treatment; and after treatment, extending
to 2 weeks after the cessation of lepirudin treatment. Clinical safety
variables included any bleeding and bleeding requiring transfusion
during treatment.
Comparison with historical control.
Outcome data from patients in the prospective trials were compared with
those from patients in the historical control group. The primary
endpoint of the comparison was the cumulative incidence of the combined
endpoint of death, new TEC, and limb amputation. Because no lepirudin
effect could be expected during the pretreatment interval, the start of
treatment was considered the most relevant starting point for
comparison with the historical controls.
Determination of the therapeutic aPTT range for lepirudin and
identification of potential covariates affecting outcome.
To determine the therapeutic range of aPTT prolongation for lepirudin,
the association between aPTT levels and clinical outcome was assessed.
Lepirudin-treated patients were classified as having aPTT ratios that
were low (1.0 to 1.5), medium (1.5 to 2.5), or high (greater than 2.5).
Patients moved from one aPTT class to another depending on various
modifications of treatment (eg, delayed start of therapy, dose
adjustments, dose interruptions, treatment discontinuation). Risk ratio
(RR) for the combined incidence of new TEC, limb amputation, death, and
bleeding were calculated for aPTT class and were compared with the
historical control, taking into account additional potential prognostic
variables sex, age, patient population (surgery vs medical and
others), and comedication (aspirin, coumarin, thrombolytics).
Determination of the impact of lepirudin on the monitoring of
vitamin K antagonists (phenprocoumon).
The impact of lepirudin on parameters used for monitoring the extrinsic
coagulation pathway (INR or Quick value) was determined by comparing
the values up to 8 hours before the start of lepirudin, with those
obtained 4 to 8 hours after the start of lepirudin and the values 8 hours before the end of lepirudin with those obtained from 8 to 36 hours after the cessation of lepirudin. Because this was not a
prespecified parameter of the studies, we did not document the INR and,
therefore, had to use the Quick values of the different laboratories.
This did not allow an absolute comparison but only a description of
relative changes.
Statistical methods
Average combined event rates per patient day were calculated on the
basis of the endpoint events that were observed in the respective study
period. Rates in the pretreatment period were descriptively compared
with those in the treatment and posttreatment periods.
Comparison with the historical control group was conducted according to
the Kaplan-Meier method22 using a time-to-event analysis
starting with the initiation of study treatment. Cumulative incidences
of clinical events were estimated using Kaplan-Meier survival curves
and were not subjected to statistical inference. Time from start of
treatment to onset of a clinical event (defined as new TEC, limb
amputation, or death) in the lepirudin group was compared with that in
the historical control group using the log-rank test.22 In
the historical control group, the first therapeutic option chosen
within 2 days after laboratory confirmation of HIT was identified and
used to define the start of treatment.
A Cox proportional hazards model was used to reassess the therapeutic
aPTT range compared with the event rate in the historical control
group. In this model, the aPTT ratios were considered time-dependent
covariates. Other potential factors that were modeled as simple
covariates included sex, age (younger than 65 vs older than 65 years),
patient population (surgery vs medical and others), aspirin treatment,
coumarin treatment, and thrombolytic treatment.
Cumulative incidences of any bleeding and bleeding requiring
transfusion were estimated using the Kaplan-Meier method. The differences between the lepirudin and historical control groups in time
to bleeding were compared using the log-rank test.
Quick values were compared by Wilcoxon test.
| |
Results |
Lepirudin-treated patients and historical control population
Two hundred four patients were included in the meta-analysis, 113 in
the lepirudin group and 91 in the historical control group. Baseline
characteristics of all patients are summarized in Table
1. Patients in the lepirudin group were
generally younger than those in the historical control group (mean
ages, 57 vs 64 years, respectively). Each patient had an ongoing
thrombosis at study entry, but not all experienced TEC during or
shortly after heparin treatment (ie, HIT related). In the remaining
patients, spontaneous thrombosis was the indication for heparin
treatment. Of the 113 lepirudin-treated patients, 57 had platelet
counts lower than 100 × 109/L at the start of
lepirudin treatment. The number of patients with TEC during heparin
therapy was higher in the historical control group (89%) than in the
lepirudin-treated patient group (77%). There was no association
between the incidence of the combined endpoint and sex (female vs male,
RR = 0.75; 95% CI, 0.46-1.22; P = .25), age (older than 65 vs
younger than 65 years, RR = 1.07; 95% CI, 0.66-1.75; P = .78),
or patient population (medical and others vs surgery, RR = 1.0; 95%
CI, 0.61-1.65; P = ~l.0).
Efficacy
Outcomes during study periods.
Overall, 105 patients were treated according to regimen A1 for a mean
of 13.5 days (range, 0-104 days), and 8 patients were treated according
to regimen A2 for a mean of 10.6 days (range, 1-29 days). Platelet
counts normalized rapidly in most patients (Figure
1). During the entire observation period,
the primary endpoint occurred in 25 lepirudin-treated patients (22.1%;
95% CI, 14.5%-29.8%): 11 patients died (9.7%; 95% CI,
4.9%-16.8%), 7 patients underwent limb amputation (6.2%; 95% CI,
2.5%-12.3%), and 12 patients experienced a total of 23 new TEC
(10.6%; 95% CI, 5.8%-18.3%). However, venous limb gangrene did not
develop in any patient after the change to oral anticoagulation
(phenprocoumon). The risk for a clinical event was highest from the
time of diagnosis of HIT to the start of lepirudin treatment (mean, 1.7 days). The combined event rate per patient day during this pretreatment
period was 6.1%. It decreased to 1.3% during lepirudin treatment and to 0.7% in the posttreatment period (Figure
2), primarily because of a risk reduction
for new TEC (pretreatment, 6.1%; treatment period, 0.6%;
posttreatment, 0.2% per patient day). This was paralleled by a rapid
decrease in elevated thrombin-antithrombin levels from a pretreatment
median of 43.9 µg/L ± 118.3 to a median 9.18 µg/L ± 71.7 at
24 ± 6 hours and to a median 4.9 µg/L ± 27.8 on day 7 (Figure
3).
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| Fig 1.
Platelet count profile of the 113 patients with HIT and
ongoing thrombosis.
The profile shows a decrease of platelet counts with a nadir at the
time of HIT diagnosis and a rapid normalization to supranormal platelet
count levels after the cessation of heparin therapy and start of
lepirudin (day 0). The median (bold line) and the 25% and 75%
quartiles are given.
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| Fig 2.
Average rate of adverse events (death, limb amputation,
and new TEC) per patient day by study interval.
Bar width indicates the mean duration of the observation period per
patient in days (d). This shows that patients are at highest risk for
new complications from the time of diagnosis of HIT to the start of
alternative anticoagulation therapy; cessation of heparin therapy alone
is insufficient to prevent further thromboembolism; if there is a
strong clinical suspicion of HIT, the patient should be anticoagulated
with an alternative drug immediately.
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| Fig 3.
Decrease of elevated thrombin-antithrombin (TAT) levels
during lepirudin treatment.
Thrombin-antithrombin (TAT) levels as measured by ELISA were highly
elevated in patients with acute HIT and ongoing thromboembolic
complications (normal range, 1.0-4.1 µg/L), but normalized rapidly
after the start of lepirudin treatment. The 25% and 75% quartiles and
minimum and maximum values are given at the baseline (ie, up to 48 hours before the start of lepirudin), at 4 hours ± 2 hours, 12 hours ± 2 hours, 24 hours ± 6 hours, 36 hours ± 6 hours
after the start of lepirudin, and then daily. Numbers of investigated
patients at each time point are given at the top of the figure. The low
number of patients at day 3 results from an overlap because 36 hours ± 6 hours was day 3 in those patients for whom treatment started
late, at day 1, and values were counted only once. The small peak at
day 3 was induced by patients receiving concomitant thrombolysis and,
therefore, a reduced lepirudin dosage. These data underscore the
prominent role of thrombin in acute HIT, provide a rationale for the
use of a direct thrombin inhibitor in these patients, and indicate that
in acute HIT thrombin generation is highest until day 4 to 5.
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Comparison with the historical control group.
In the historical control group, 75 patients qualified for comparison.
Fourteen patients were excluded because of incomplete treatment data,
and 2 patients were excluded because of incomplete time-to-event data.
Patients were treated with danaparoid (n = 24), phenprocoumon (n = 21), others (n = 30; low-molecular-weight heparin, no
anticoagulation, acetyl salicylic acid, thrombolysis).
When outcomes between the start of active treatment and the end of the
observation period were compared, lepirudin-treated patients had
consistently lower incidences of the combined endpoint than the
historical control group (P = .004, log-rank test; Figure 4). This resulted primarily from a
reduction of new TEC (at day 35: 10.1% [95% CI, 4.4%-15.8%] vs
27.2% [95% CI, 16.6%-37.8%]; P = .005, log-rank test).
Cumulative incidences of death (day 35: 8.9% vs 17.6%) and limb
amputation (day 35: 6.5% vs 10.4%) were nominally lower in the
lepirudin group than in the historical control group, but the
differences did not reach statistical significance (Figure
5). At least 1 patient in the historical
control group lost his leg because of venous limb gangrene when heparin
treatment was discontinued and he received phenprocoumon without
overlapping parenteral anticoagulation.
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| Fig 4.
Comparison of lepirudin-treated patients and historical
control group.
Cumulative incidence of events (new TEC, limb amputation, and death)
was higher in the historical control group (scattered line) than in the
lepirudin group (solid line); P = .004. The number of patients at risk is given at the top of the figure.
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| Fig 5.
Description of combined and single endpoints in HIT
patients treated with lepirudin, or danapariod, or phenprocoumon, or
other treatments.
Incidences of the combined and single endpoints of death, limb
amputation, and new TEC at day 35 are given in percentages and
corresponding 95% confidence intervals (CI) for lepirudin-treated
patients (n = 113) and historical control patients (total, n = 75;
danaparoid, n = 24; phenprocoumon, n = 21; others, n = 30).
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Correlation between aPTT ratios and efficacy.
Medium aPTT ratios (1.5-2.5) were associated with a clinically and
statistically significant reduction in the incidence of the combined
endpoint compared with the historical control group (RR = 0.42; 95%
CI, 0.22-0.80; P = .009). Low aPTT ratios (1.0 to 1.5) were
associated with an insignificant effect (RR = 0.86; 95% CI, 0.38-1.94;
P = .72), whereas high aPTT ratios (greater than 2.5)
demonstrated no additional improvement compared with medium aPTT ratios
(RR = 0.70; 95% CI, 0.21-2.32; P = .56; Figure 6).
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| Fig 6.
Assessment of the optimal therapeutic range of lepirudin
in HIT patients with thrombosis.
Risk ratios (RR) and 95% confidence intervals for the combined
endpoint of new TEC, limb amputation, and death (black bars and solid
line) and for bleeding complications (white bars and dotted line) are
given for the lepirudin-treated patients according to aPTT classes in
comparison with the historical control population. In this Cox
proportional hazards model, the aPTT ratio was considered a
time-dependent covariate. Medium aPTT ratios (1.5-2.5) were associated
with a clinically and statistically significant reduction in the
incidence of the combined endpoint compared with the historical control
group (RR = 0.42; 95% CI, 0.22-0.80; P = .009). Low aPTT
ratios (1.0-1.5) were associated with an insignificant effect (RR = 0.86; 95% CI, 0.38-1.94; P = .72), whereas high aPTT ratios
(greater than 2.5) demonstrated no additional improvement compared with
medium aPTT ratios (RR = 0.70; 95% CI, 0.21-2.32; P = .56).
However, there was a marked increase in bleedings with high aPTT ratios
(RR = 6.03; 95% CI, 2.34-15.54; P = .0002). We, therefore,
consider aPTT ratios of 1.5 to 2.5 as the therapeutic window in
patients with HIT and acute thrombosis.
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Effect of thrombolytics, aspirin, and coumarin.
At some point during the study, but not necessarily in conjunction with
lepirudin, 29 patients received aspirin, 93 patients received coumarin,
and 27 patients received thrombolytics; for 7 patients, this
information was missing. Comedication with thrombolytics (RR = 0.38;
95% CI, 0.14-1.05; P = .06) or coumarin (RR = 0.61; 95% CI,
0.36-1.02; P = .06) showed a trend toward a reduction of the combined endpoint, whereas coadministration with aspirin was
associated with a trend toward higher event rates (RR = 1.75; 95% CI,
0.95-3.25; P = .08).
After the initiation of lepirudin therapy, the Quick value decreased
from 74.3% (±24.8% SD) to 55.6% (±19.8% SD); P =
.0005. More important, at the end of lepirudin treatment, Quick values did not change if lepirudin was discontinued (37.0% ± 15.2% vs 35.3% ± 15.5%; P = .31).
Safety
Bleeding events.
The cumulative incidence of bleeding was significantly higher in the
lepirudin-treated group than in the historical control group (at 35 days: 42.0% [95% CI, 28.9%-55.0%] vs 23.6% [95% CI, 9.3%-37.8%]; P = .001). Similarly, more lepirudin-treated
patients than historical control patients experienced bleeding that
required transfusion (at 35 days: 18.8% [95% CI, 11.6%-26.1%] vs
7.1% [95% CI, 1.1%-13.1%]; P = .02). No fatal or
intracranial bleed occurred in patients treated with lepirudin (2 intracranial bleeds occurred in the historical control group).
Correlation of aPTT ratios and bleeding events.
With low aPTT ratios, the risk for bleeding in lepirudin-treated
patients was not significantly increased in comparison with historical
control patients (RR = 1.57; 95% CI, 0.52-4.72; P = .42).
However, there was a marked increase with medium aPTT ratios (RR = 3.21; 95% CI, 1.72-6.02; P = .0003) and particularly with high
aPTT ratios (RR = 6.03; 95% CI, 2.34-15.54; P = .0002; Figure 6). None of the covariates assessed were significantly associated with
an increased bleeding risk: sex (female vs male, RR = 1.06; 95% CI,
0.61-1.85; P = .83); age (older than 65 vs younger than 65 years, RR = 1.29; 95% CI, 0.74-2.26; P = .37); patient
population (medical and others vs surgery, RR = 1.58; 95% CI,
0.91-2.73; P = .10); aspirin treatment (RR = 1.2; 95% CI,
0.56-2.55; P = .65); coumarin treatment (RR = 0.72; 95% CI,
0.40-1.30; P = .28); and thrombolytic treatment (RR = 1.77;
95% CI, 0.86-3.65; P = .20).
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Discussion |
This meta-analysis of data from 2 prospective clinical studies
presents the largest population of patients with HIT and thromboembolic complications treated with lepirudin. It provides the rationale for new
or extended recommendations for lepirudin in the treatment of patients
with HIT and TEC, and it illustrates important concepts in the
treatment of HIT in general.
The reduction in the combined endpoint of death, limb amputation, and
new TEC in lepirudin-treated patients compared with the historical
control population (Figure 4) indicates that lepirudin offers clinical
benefits for patients with HIT and ongoing thrombosis. By 35 days,
there was a 27% relative risk reduction for the combined endpoint,
with trends in the same direction for all individual endpoints (death,
9%; limb amputation, 4%; new TEC, 17%). Because this meta-analysis
is based on historically controlled studies, a bias cannot be excluded,
and results must be interpreted with caution; nevertheless, the
outcomes of lepirudin-treated patients in these studies were far better
than those reported for patients with HIT in other
studies.23,24 The number of danaparoid-treated patients (n = 24) in the historical control group is too small to allow any firm
conclusion regarding its comparability with lepirudin.
Prospectively assessed thrombin-antithrombin complexes clearly show
that HIT is associated with the massive generation of thrombin, as has
been suggested recently based on retrospective data.25 In
conjunction with the clinical findings of the meta-analysis, this
corroborates that heparin cessation alone is insufficient to prevent
further thromboembolism in acute HIT. Of the 41 clinical outcome events
reported during the study period, 14 (34.1%) occurred during the
pretreatment period, and the combined event rate per patient day was
substantially higher during the pretreatment interval (6.1%) than
during the treatment (1.3%) or posttreatment period (0.7%; Figure 2).
Differences in the combined event rates were primarily accounted for by
differences in the incidences of new TEC. Thus, if there is a strong
suspicion of HIT, a patient with a recent thrombosis should immediately
be treated with an anticoagulant other than heparin. Awaiting
laboratory confirmation of HIT before alternative anticoagulation
therapy is started would cause a significant delay for most patients
and substantially enhance the risk for the patient.
This study compares for the first time different anticoagulation
intensities in patients with HIT using the aPTT ratio. Based on our
results, we consider the aPTT ratio to have a significant impact on the
outcome of patients with HIT and thromboembolic complications. Low aPTT
ratios (1.0-1.5) were clearly subtherapeutic and had minimal effects on
clinical events and bleeding. In contrast, medium aPTT ratios (1.5 to
2.5) were associated with a pronounced reduction in the combined
endpoint rate (RR = 0.42) and a moderately increased risk for bleeding
(RR = 3.21). This increased risk for bleeding appears to be clinically
acceptable because it is outweighed by the prevention of serious
clinical events, particularly new TEC. Higher aPTT ratios did not
further reduce the combined endpoint rates, but they once more doubled
the risk for bleeding (RR = 6.03). Thus, the aPTT ratio of greater than
1.5 to 2.5 is the recommended target range (when actin FS or
neothromtin reagents are used, the ratio should be greater than
1.5-3.0).
However, even with this optimal aPTT ratio, bleeding complications were
more frequent in lepirudin-treated patients than in the historical
control population. This may reflect the limitations of the aPTT as a
monitoring tool for lepirudin treatment. Although the aPTT method of
monitoring anticoagulation is readily available and easy to use, it may
not be optimal.26,27 At higher hirudin concentrations,
causing an aPTT longer than 70 seconds, the correlation between aPTT
and free hirudin plasma levels is relatively poor.27 Pötzsch et al27 have further shown that if high
hirudin concentrations are clinically indicated (eg, during
cardiopulmonary bypass surgery), monitoring by ecarin
clotting time instead of the aPTT may be beneficial. It appears that
lepirudin has a narrow therapeutic window and a relatively high
bleeding risk even when given in clinically relevant doses in patients
with HIT. Even so, the drug remains an important therapeutic agent
given the dangerous clinical course of HIT and the apparent low risk
for fatal hemorrhage related to lepirudin use. However, patients should
be informed about the potential risk for bleeding before
anticoagulation therapy is changed to lepirudin therapy.
Various covariates such as sex, age, and patient population (medical
and others vs surgery) had no obvious impact on patient outcome.
Regarding comedication, thrombolytics may be beneficial in certain
patient groups, whereas concomitant therapy with aspirin does not
appear to be. However, measuring concomitant drug effects was not part
of the prospective study design of either trial, so these findings
should be interpreted cautiously. Specifically, the need for aspirin
could indicate that patients receiving aspirin may have a higher risk
for further complications because of other risk factors for arterial
embolism. There was no evidence to suggest that concomitant treatment
with thrombolytics or aspirin was associated with a significant
increase in the risk for bleeding complications. Therefore, until
further information is available, it seems acceptable to use
lepirudin with these medications if they are clinically indicated after
a careful individual risk/benefit assessment.
Most patients with HIT and thrombosis require prolonged
anticoagulation, usually with oral anticoagulants such as phenprocoumon or warfarin. Of the lepirudin-treated patients, 93 were changed to
phenprocoumon therapy for long-term anticoagulation. Venous limb
gangrene did not develop in any of these patients. In contrast, at
least 1 of 21 historical control patients treated with phenprocoumon lost a leg only because of venous gangrene. This indicates that lepirudin allows a safe change to oral anticoagulants in patients with
HIT and further supports the concept of Warkentin et al25 that oral anticoagulants should not be given to patients with HIT
unless parenteral anticoagulation therapy is sufficient.
At the start of treatment, lepirudin has an impact on the clotting
parameters for the extrinsic coagulation pathway (decrease of Quick
value or increase of the INR). Because of insufficient standardization
of the Quick value, however, we cannot give an exact INR range. Whereas
a change in the Quick value at the start of treatment with
lepirudin has only minor clinical relevance, the impact of lepirudin on
the monitoring parameter may be crucial once the therapeutic range for
oral anticoagulation is reached and lepirudin should be
stopped. Because we did not find evidence that the cessation of
lepirudin causes a change of the monitoring values for oral
anticoagulants, patients seem to remain in the therapeutic window.
This meta-analysis gives further evidence that lepirudin is effective
for the treatment of patients with HIT with ongoing thrombosis and that
it has an acceptable safety profile at aPTT ratios of greater than 1.5 to 2.5. It underscores the necessity of an early start of alternative
anticoagulation once the diagnosis of HIT is made, and it provides
evidence that oral anticoagulation can be started safely without the
risk of inducing venous limb gangrene during the concomitant
application of lepirudin.
| |
Acknowledgment |
We thank Mrs Uta Alpen for her secretarial assistance.
| |
Footnotes |
Submitted September 24, 1999; accepted March 16, 2000.
Supported by Aventis Pharma and Deutsche Forschungsgemeinschaft GR
1096/2-3.
Reprints: Andreas Greinacher, Institute for Immunology and
Transfusion Medicine, Ernst-Moritz-Arndt University,
Sauerbruchstrasse/Diagnostikzentrum, 17487 Greifswald, Germany; e-mail:
greinach{at}mail.uni-greifswald.de.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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502 - 506.
[Abstract]
[Full Text]
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J. Hirsh, S. S. Anand, J. L. Halperin, and V. Fuster
Guide to Anticoagulant Therapy: Heparin : A Statement for Healthcare Professionals From the American Heart Association
Arterioscler Thromb Vasc Biol,
July 1, 2001;
21
(7):
e9 - e9.
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J. Hirsh, S. S. Anand, J. L. Halperin, and V. Fuster
Guide to Anticoagulant Therapy: Heparin : A Statement for Healthcare Professionals From the American Heart Association
Circulation,
June 19, 2001;
103(24):
2994 - 3018.
[Full Text]
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A. Greinacher and N. Lubenow
Recombinant Hirudin in Clinical Practice : Focus on Lepirudin
Circulation,
March 13, 2001;
103(10):
1479 - 1484.
[Abstract]
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K. R. McCrae, J. B. Bussel, P. M. Mannucci, G. Remuzzi, and D. B. Cines
Platelets: An Update on Diagnosis and Management of Thrombocytopenic Disorders
Hematology,
January 1, 2001;
2001(1):
282 - 305.
[Abstract]
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J. A. Ginsberg, M. A. Crowther, R. H. White, and T. L. Ortel
Anticoagulation Therapy
Hematology,
January 1, 2001;
2001(1):
339 - 357.
[Abstract]
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J. Hirsh, T. E. Warkentin, S. G. Shaughnessy, S. S. Anand, J. L. Halperin, R. Raschke, C. Granger, E. M. Ohman, and J. E. Dalen
Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety
Chest,
January 1, 2001;
119
(2009):
64S - 94S.
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Top
Abstract
Introduction