(Circulation. 2001;103:643.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Prognostic Significance of Thrombocytopenia During Hirudin and Heparin Therapy in Acute Coronary Syndrome Without ST Elevation
Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) Study
From the Preventive Cardiology and Therapeutics Program (J.W.E., S.S.A., S.R.M., C.Y., S.Y.), Department of Medicine (S.S.A., S.R.M., J.I.W., S.Y.), and Hamilton Civic Hospital Research Centre (J.I.W.), McMaster University, Hamilton, Canada.
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Abstract |
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Background—The development of thrombocytopenia in acute coronary syndromes (ACS) appears to be associated with adverse clinical outcomes. Unfractionated heparin is a recognized cause of thrombocytopenia, but the incidence, predictors, and prognostic significance of thrombocytopenia during hirudin therapy in ACS have not been reported.
Methods and Results—Patients with ACS without ST elevation were randomized in a double-blind manner to receive a 72-hour intravenous infusion of unfractionated heparin or hirudin. Platelet counts were measured at baseline and within 24 hours of completion of study drug. The overall incidence of thrombocytopenia (<100x109/L) was 1% and was similar in unfractionated heparin– and hirudin-treated patients (P=0.42). Thrombocytopenia during study drug infusion was an independent predictor of 7-day outcomes, including death (OR, 6.7; 95% CI, 1.9 to 25); the composite of death, myocardial infarction, and recurrent ischemia (OR, 2.0; 95% CI, 1.0 to 1.5); revascularization (OR, 4.0; 95% CI, 2.2 to 7.1); and major bleeding (OR, 8.3; 95% CI, 3.4 to 17.7). Among patients who developed thrombocytopenia, hirudin (OR, 5.4; 95% CI, 2.6 to 11.3) but not unfractionated heparin (OR, 2.0; 95% CI, 0.3 to 14.4) therapy was associated with a significantly increased risk of major bleeding.
Conclusions—Early-onset thrombocytopenia in patients with ACS without ST elevation is strongly associated with adverse clinical outcomes, including death, ischemic events, and bleeding. The excess of major bleeding in hirudin-treated patients who develop thrombocytopenia suggests that thrombocytopenia may contribute to the increased risk of bleeding observed with hirudin.
Key Words: platelets • heparin • hirudin • angina • myocardial infarction
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Introduction |
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There is emerging evidence that the development of thrombocytopenia in patients with acute coronary syndromes is associated with an increased risk of adverse clinical outcomes, including death, myocardial infarction, and major hemorrhage.1 2 3 4 5 Drugs are an important cause of thrombocytopenia in this patient population, particularly with the advent of the new antithrombotic agents used to prevent recurrent ischemia. Unfractionated heparin, the cornerstone of treatment for patients with unstable angina, can cause immune and nonimmune thrombocytopenia.6 The more common nonimmune thrombocytopenia is a self-limiting disorder and is of no known clinical significance. In contrast, immune thrombocytopenia, so-called heparin-induced thrombocytopenia, is a more serious problem because it can be associated with thrombosis.6
Recently, hirudin has been introduced as a substitute for unfractionated heparin in patients with acute coronary syndromes. Hirudin was initially isolated from the saliva of the medicinal leech but is now available through recombinant DNA technology. A potent and specific inhibitor of thrombin, hirudin binds directly with thrombin and, unlike unfractionated heparin, inhibits fibrin-bound and circulating thrombin equally well.7 Because fibrin-bound thrombin is an important trigger of thrombus growth, its inhibition by hirudin may explain why this agent is superior to unfractionated heparin for the prevention of reinfarction and cardiovascular death during the early phase in patients with unstable angina or non–Q-wave myocardial infarction. However, the risk of major bleeding with hirudin is greater than with unfractionated heparin in patients with acute coronary syndromes.8 9 It is currently unknown whether thrombocytopenia contributes to this bleeding risk.
To address this issue, we report the incidence, baseline predictors, and prognostic significance of thrombocytopenia in the Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) study, a trial that randomized patients with unstable angina or non-Q-wave myocardial infarction to receive either intravenous unfractionated heparin or hirudin. We compared the incidence of thrombocytopenia with the 2 drugs and examined whether thrombocytopenia may contribute to the increased incidence of major hemorrhage reported with hirudin.
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Methods |
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Patients
The OASIS-2 study was an international, double-blind, randomized trial of 10 141 patients with acute coronary syndromes without ST elevation randomized to intravenous unfractionated heparin or hirudin. The inclusion and exclusion criteria, study interventions, and primary efficacy outcomes have been previously published.8 Briefly, patients were eligible for inclusion in this study if they were within 12 hours of onset of chest pain suspected to be due to unstable angina or myocardial infarction without ST-segment elevation. Patients with contraindications to unfractionated heparin or hirudin, with renal impairment (ie, creatinine >175 µmol/L or >2.0 mg/dL), or judged by the local investigator to be at high risk of bleeding complications or to have significant thrombocytopenia were excluded.
Study Treatment
Patients were randomized to a double-blind,
double-dummy, 72-hour intravenous infusion of either unfractionated
heparin or hirudin. Unfractionated heparin was given as an initial
bolus of 5000 U, followed by an infusion of 15
U · kg-1 · h-1,
and hirudin was given as an initial bolus of 0.4 mg/kg followed by an
infusion of 0.15
mg · kg-1 · h-1.
Doses of unfractionated heparin and hirudin were adjusted according to
predefined rules to maintain the activated partial thromboplastin time
between 60 and 100 seconds. Although aspirin (80 to 325 mg/d) was
recommended, the use of other nonstudy treatments was left to the
discretion of the individual investigators.
Outcomes
Data on the following outcomes were documented during
6 months of follow-up: death; new myocardial infarction, defined as
recurrent symptoms with either new ECG changes or new elevations of
enzymes; refractory angina, defined as recurrent ischemic pain lasting
5 minutes with documented new ECG changes occurring despite optimum
medical treatment and requiring an additional intervention before the
end of the next calendar day; percutaneous coronary intervention; and
CABG surgery.
The major safety outcome was major bleeding, which was
defined as bleeding that was fatal, life threatening, and permanently
or significantly disabling or required transfusion of 2 units of
blood or surgical intervention. Major bleeding was further classified
as life threatening if it was intracranial or required transfusion of
4 units of blood or surgical intervention. All other bleeding events
were classified as minor. Efficacy and safety outcomes were adjudicated
by a central committee blinded to treatment
allocation.
Platelet Counts
Platelet counts were measured at baseline and within
24 hours after completion of study drug infusion. For the purpose of
this study, thrombocytopenia was defined as a platelet count
<100x109/L and severe thrombocytopenia as
a platelet count <50x109/L. Only platelet
counts mandated by protocol were used in this
analysis.
Statistical Analysis
Continuous variables are presented as means with
their SD, and discrete variables are presented as frequency and
percents. Continuous variables were compared by use of a
t test, and categorical
variables were compared by use of a 
2
test.
A multivariable logistic regression model was used to explore the association between baseline clinical characteristics and the development of thrombocytopenia during study treatment with unfractionated heparin or hirudin. Separate models were used to explore the association between development of thrombocytopenia and efficacy and safety outcomes at 7 days (primary outcome) for the following outcomes: (1) death; (2) the composite of death, myocardial infarction, and refractory angina; (3) need for revascularization, including percutaneous coronary revascularization or CABG surgery; and (4) major bleeding during hospitalization. To assess the independent contribution of development of thrombocytopenia to these outcomes, adjustment was made for age, sex, and treatment allocation, as well as variables reported to be important prognostic factors in previous acute coronary syndrome trials4 and statistically significant baseline predictors for the development of thrombocytopenia.
Temporality of the association between the development of thrombocytopenia and clinical outcomes was further explored with the use of a separate model that included only events that occurred after the development of thrombocytopenia (ie, between the second platelet count and day 7). A potential interaction between thrombocytopenia and treatment allocation was examined by use of multiplicative interaction terms in the logistic regression model. We also examined whether there may be a graded association between absolute platelet count (>150x109/L, 100 to 150x109/L, 50 to 100x109/L, <50x109/L) at completion of study drug infusion and clinical outcome.
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Results |
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Incidence of Thrombocytopenia
Platelet counts at baseline and at the completion of study drug infusion were available in 8912 of 10141 patients (87.8%) randomized in the OASIS-2 study. Baseline characteristics were similar in patients in whom protocol-mandated platelet counts were available compared with those in whom platelet counts were not available. Meanwhile, there was an excess of early mortality in patients for whom platelet counts were not available, but this finding is not unexpected because platelet counts at the completion of treatment could include only patients who survived long enough to have the sample drawn. After patients who died early were excluded, the incidence of major adverse outcomes was similar in both groups. Patients in whom protocol-mandated platelet counts were not available are not included in subsequent analyses.
The overall incidence of thrombocytopenia
(<100x109/L) was 1% (95% CI, 0.8 to 1.2)
and was similar in unfractionated heparin– and hirudin-treated
patients (1.1% versus 0.9%,
P=0.42;
Table 1
). Severe thrombocytopenia
(<50x109/L) was uncommon in both groups
(0.02% versus 0.1%, P=0.11).
The incidence of a 20% decline in platelet count from baseline was
significantly higher in patients randomized to unfractionated heparin
than in those given hirudin (12.6% versus 10.6%,
P=0.001). After patients who
may have been exposed to unfractionated heparin during prior hospital
admissions for myocardial infarction, unstable angina, or
revascularization procedures were excluded, the incidence of
thrombocytopenia in unfractionated heparin treated patients was
1.0%.
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Baseline Characteristic in Patients With and
Without Development of Thrombocytopenia
Thrombocytopenia during study drug infusion was more
common in men than women (71.3% versus 60.2%,
P=0.04). The mean baseline
platelet count was also lower in patients who developed
thrombocytopenia during study drug infusion compared with patients who
did not develop thrombocytopenia (153x109/L
versus 229x109/L,
P<0.0001;
Table 2). The distribution of baseline and follow-up
platelet counts in patients who did and did not develop
thrombocytopenia is illustrated in
Figure 1.
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Association Between Development of
Thrombocytopenia and Clinical Outcomes
Within the first 7 days, there was a significant
association between the development of thrombocytopenia and death (OR,
5.5; 95% CI, 1.7 to 17.2;
P=0.02); the composite of
death, myocardial infarction, and refractory angina (OR, 1.9; 95% CI,
1.0 to 3.6; P=0.046); and
revascularization (OR; 2.7; 95% CI, 1.7 to 4.3;
P=0.001;
Table 3). When the analysis was confined to events that
occurred after completion of study drug infusion, thrombocytopenia
remained significantly associated with an increased risk of death (OR,
5.6; 95% CI, 1.8 to 17.5;
P=0.02). A significant
association between thrombocytopenia and death remained evident at 6
months (OR, 1.9; 95% CI, 1.1 to 3.5;
P=0.03).
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Major Bleeding
The development of thrombocytopenia was associated with
a statistically significant increase in the risk of major (OR, 5.4;
95% CI, 2.6 to 11.3;
P<0.001), life-threatening
(OR, 9.5; 95% CI, 3.5 to 26.0;
P<0.001), and fatal (OR, 33;
95% CI, 6.8 to 162) bleeding, as well as a need for transfusion (OR,
4.8; 95% CI, 2.0 to 11.5) during hospitalization. However, when
stratified according to treatment allocation, a significant increase in
any severity of bleeding was evident only in the hirudin-treated group
(Table 4).
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Logistic Regression Models
The multivariable regression model for predictors of
development of thrombocytopenia
(<100x109/L) during study drug infusion
(model A) demonstrated that treatment allocation was not a significant
predictor for the development of thrombocytopenia (OR, 1.2; 95% CI,
0.8 to 1.9; P=0.3).
Baseline platelet count remained independently associated with
development of thrombocytopenia (OR, 1.4 per
10x109/L decrease; 95% CI, 1.3 to 1.5;
P=0.0001). However,
randomization to unfractionated heparin therapy was an independent
predictor for the development of a 20% decrease in the platelet count
relative to baseline (OR, 1.5; 95% CI, 1.3 to 1.7;
P=0.0001).
After adjustment for age, sex, treatment allocation, and
baseline platelet count, development of thrombocytopenia during study
drug infusion remained independently associated with 7-day outcomes,
including death (model B); the composite of death, myocardial
infarction, and refractory angina (model C); and revascularization
(model D) (P<0.05 for
thrombocytopenia in each model;
Table 5). In an on-treatment analysis, thrombocytopenia
remained significantly associated with clinical outcome in each model
(data not shown). Thrombocytopenia also remained significantly
associated with death after exclusion of patients who underwent CABG
surgery or aortic balloon pump insertion (OR, 4.5; 95% CI, 1.05 to
19.0) or patients who did not receive antiplatelet therapy (OR, 6.6;
95% CI, 1.9 to 21.0). When separate analyses were performed with
platelet count as a continuous variable or with the analyses restricted
to events that occurred after the development of thrombocytopenia,
thrombocytopenia remained a predictor for all outcomes (data not
shown).
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Thrombocytopenia also was a strong and independent
predictor of major bleeding during hospitalization (OR, 8.3; 95% CI,
3.4 to 17.7; P=0.0001) (model
E;
Table 5
). Among patients who developed thrombocytopenia,
hirudin (OR, 5.4; 95% CI, 2.6 to 11.3) but not unfractionated heparin
(OR, 2.0; 95% CI, 0.3 to 14.4) therapy was associated with a
significantly increased risk of major bleeding. However, the model
became unstable when an interaction term for
thrombocytopenia-by-treatment allocation was included, and an
interaction between thrombocytopenia and treatment allocation could not
be confirmed. This is most likely due to the small number of major
bleeding events in heparin-treated patients. Hirudin remained
associated with a significantly increased risk of major bleeding after
exclusion of patients who developed thrombocytopenia (OR, 1.7;
95% CI, 1.2 to 2.5).
Thrombocytopenia remained independently associated with risk of major bleeding after exclusion of patients who underwent revascularization (CABG or percutaneous coronary intervention) during hospitalization (OR, 6.0; 95% CI, 2.0 to 17.4; P=0.001). Although a trend toward increased risk of major bleeding persisted when the analysis was restricted to events that occurred after the development of thrombocytopenia, the association was no longer statistically significant (OR, 1.3; 95% CI, 0.2 to 9.6; P=0.78).
There was a strong and graded association between
absolute platelet count after completion of study drug infusion
(>150x109/L, 100 to
150x109/L, 50 to
100x109/L,
<50x109/L) and clinical outcome, including
death; the composite of death, myocardial infarction, and refractory
angina; need for revascularization; and major bleeding
(Figure 2).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates a strong, consistent, independent, and graded association between the development of thrombocytopenia (platelet count <100x109/L) in patients with unstable angina and non–ST-elevation myocardial infarction and major adverse clinical outcomes, including mortality, recurrent ischemic events, need for revascularization, and major bleeding. In addition, our data suggest that clinically important thrombocytopenia is uncommon in patients treated with either short-term intravenous unfractionated heparin or hirudin therapy, with an incidence in both groups of
1%.
Treatment allocation was not a predictor of thrombocytopenia
(<100x109/L), but randomization to
unfractionated heparin therapy was an independent predictor for the
development of a 20% reduction in platelet count from baseline. The
latter observation is consistent with the known pattern of
thrombocytopenia associated with the use of unfractionated heparin.
Although heparin-induced thrombocytopenia occurs in 1% to 3% of
patients treated with unfractionated heparin, thrombocytopenia is
generally delayed for 5 to 7 days after initiation of therapy, except
in patients sensitized during previous
exposure.6 In contrast,
nonimmune thrombocytopenia is more common, occurring in up to 25% of
patients exposed to unfractionated heparin, is generally mild (platelet
count nadir, 100 to 150x109/L), occurs
early (within the first 5 to 7 days), and is self-limited, even when
unfractionated heparin therapy is
continued.6 Nonimmune
thrombocytopenia may therefore account for the increased incidence of a
mild reduction in platelet count during the first few days seen in
patients exposed to unfractionated heparin in our study.
The increased risk of bleeding with hirudin therapy was not confined to patients who developed thrombocytopenia. However, our data suggest that among patients who develop thrombocytopenia, hirudin but not unfractionated heparin therapy is associated with an increased risk of hemorrhagic complications. A possible explanation for this observation is that hirudin exerts an indirect inhibitory effect on platelets by blocking thrombin, the most potent platelet agonist. Although it is possible that by activating platelets unfractionated heparin may paradoxically lower the risk of bleeding in patients who develop thrombocytopenia,10 the small number of major bleeding events in patients treated with unfractionated heparin limited the power of our study to detect a statistically significant increase in bleeding risk in this group. In support of this concept, an interaction between treatment allocation and thrombocytopenia could not be confirmed on multivariable analysis.
The strong and graded association between thrombocytopenia and risk of nonhemorrhagic adverse outcomes demonstrated in our study remains unexplained. Platelets play a central role in the pathogenesis of acute coronary syndromes,11 and it is possible that platelet consumption results in their activation, a phenomenon that could exacerbate coronary ischemia. In support of this hypothesis is our demonstration of an association between the development of thrombocytopenia and death and a similar, although not statistically significant, association with nonfatal ischemic outcomes occurring after the development of thrombocytopenia.
The overall incidence of thrombocytopenia in this study was
only 1%, an incidence substantially lower than the 1.5% to 16.1%
others have reported in acute coronary
syndromes.1 2 3 4 5
There are a number of possible explanations. First, the other studies
included patients with various diagnoses at baseline (unstable angina,
myocardial infarction receiving thrombolytic therapy, acute coronary
syndromes undergoing percutaneous coronary intervention). Second, there
may have been differences in the incidence of prior sensitization to
unfractionated heparin among the studies. However, in the OASIS-2
study, only 20 (0.9%) of the 2108 patients who received unfractionated
heparin before randomization developed thrombocytopenia, which is
similar to the overall incidence of thrombocytopenia in unfractionated
heparin–treated patients. Third, differences in cointerventions may
account for differences in the incidence of thrombocytopenia among the
studies. To the best of our knowledge, the Platelet Glycoprotein
IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin
Therapy (PURSUIT) study4 is
the only other published report that examined the incidence of
thrombocytopenia in acute coronary syndrome without ST elevation. In
this study, >85% of patients received unfractionated heparin in
addition to being randomized to either intravenous eptifibatide or
placebo, and this may, at least in part, account for the reported 7%
incidence of thrombocytopenia. Fourth, the definition of
thrombocytopenia is not uniform, with some studies including both an
absolute decline to <100x109/L and a
relative decline of 25% from
baseline.3 4 5
However, when we include a relative decline from baseline of 50% in
our definition, the overall incidence of thrombocytopenia is 1.5% in
our study, a value still substantially lower than the 7% incidence
reported in PURSUIT.4 Fifth,
in our study, we performed only a single platelet count at the
completion of study drug infusion. In contrast, in
PURSUIT,4 serial platelet
counts were performed during the first 7 days. However, 70% to 80% of
patients who develop thrombocytopenia do so in the early hospital
phase, most commonly within the first 48 to 72
hours,4 so the timing of
platelet count determinations is unlikely to explain the difference in
the absolute incidence of thrombocytopenia described in the various
studies.
Our study has several potential limitations. First, the number of outcome events at 7 days in patients who developed thrombocytopenia is small, particularly in unfractionated heparin–treated patients, and this limits the power of our study to further explore a possible interaction between treatment allocation and thrombocytopenia on clinical outcomes. Second, platelet counts at baseline and at 72 hours were not available for all patients. However, the baseline characteristics of patients with missing data were similar to those for whom platelet counts were available, and there is no reason to expect that the pattern of association between thrombocytopenia and adverse clinical outcomes would be any different in this patient group. Third, we may have underestimated the true incidence of thrombocytopenia in our study. However, this is unlikely to have any impact on the validity of our conclusions because patients randomized to unfractionated heparin and hirudin are likely to be equally affected. Fourth, partial thromboplastin time data at the time of major bleeding in patients who developed thrombocytopenia were unavailable, precluding evaluation of the potential contributory role of excessive anticoagulation in causing major bleeding in these patients. Finally, although our study demonstrates a clear association between the development of thrombocytopenia and adverse outcomes, the possibility of confounding can never be excluded in a nonrandomized comparison.
What are the potential implications of our findings for the use of hirudin in patients with heparin-induced thrombocytopenia? Although a high incidence of antibody production to hirudin during prolonged intravenous or subcutaneous therapy has recently been reported, anti-hirudin antibodies are not associated with the development of thrombocytopenia and appear to be of limited clinical significance.12 Furthermore, there is no evidence that hirudin cross-reacts with antibodies, causing heparin-induced thrombocytopenia.13 Although we did not perform platelet aggregation studies or laboratory measures of antibody formation to unfractionated heparin or hirudin, the low incidence of clinically important thrombocytopenia associated with hirudin in our study provides no evidence to avoid the use of hirudin in patients with heparin-induced thrombocytopenia.
In conclusion, our study adds to the growing body of evidence demonstrating an association between thrombocytopenia and an increased incidence of adverse cardiovascular outcomes in patients with acute coronary syndromes. Although the strength, consistency, dose relationship, and temporality of this association are not inconsistent with the hypothesis that it may be causal,4 the design of our study cannot address the question of causality, and it remains likely that thrombocytopenia is simply a marker of adverse outcome. Prospective studies are needed to further explore whether the observed association between thrombocytopenia and adverse clinical outcomes can be modified by therapeutic interventions that prevent or correct thrombocytopenia. Meanwhile, early onset of thrombocytopenia in patients presenting with unstable angina should be considered an important predictor of adverse outcome, including bleeding, recurrent ischemic events, and death.
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Acknowledgments |
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The OASIS study was primarily funded by Hoechst Marion Roussel, Germany, with additional support from DuPont Pharmaceuticals, USA, and the Medical Research Council of Canada. Drs Eikelboom and Mehta are both recipients of Research Fellowship Awards from the Heart and Stroke Foundation of Canada. Dr Anand is the recipient of a Medical Research Council of Canada Clinician-Scientist Award. Professor Weitz is the recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada and holds a Heart and Stroke Foundation of Ontario Research Chair. Professor Yusuf is the recipient of a Medical Research Council of Canada Senior Scientist Award and holds a Heart and Stroke Foundation of Ontario Research Chair.
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Footnotes |
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Reprint requests to John Eikelboom, Preventive Cardiology and Therapeutics Program, McMaster University, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada.
Guest Editor for this article was Paul W. Armstrong, MD, University of Alberta, Alberta, Canada.
Received July 14, 2000; revision received September 14, 2000; accepted September 26, 2000.
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