Clinical Significance of Thrombocytopenia During a Non–ST-Elevation Acute Coronary Syndrome
The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Experience
Background—The significance of thrombocytopenia in patients experiencing an acute coronary syndrome (ACS) has not been examined systematically. We evaluated this condition in a large non–ST-elevation ACS clinical trial, with particular interest paid to its correlation with clinical outcomes.
Methods and Results—Patients presenting without persistent ST elevation during an ACS were randomized to receive a double-blind infusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide or placebo in addition to other standard therapies including heparin and aspirin. The primary end point was death/nonfatal myocardial infarction (MI) at 30 days, whereas bleeding and stroke were the main safety outcomes. Thrombocytopenia (nadir platelet count <100×109/L or <50% of baseline) occurred in 7.0% of enrolled patients. The time to onset was a median of 4 days in both treatment arms. Patients with thrombocytopenia were older, weighed less, were more likely nonwhite, and had more cardiac risk factors. These patients experienced significantly more bleeding events: they were more than twice as likely to experience moderate/severe bleeding after adjustment for confounders. Univariably, ischemic events (stroke, MI, and death) occurred significantly (P<0.001) more frequently in patients with thrombocytopenia; multivariable regression modeling preserved this association with death/nonfatal MI at 30 days. Neither the use of heparin or eptifibatide was found to independently increase thrombocytopenic risk.
Conclusions—Although causality between thrombocytopenia and adverse clinical events could not be established definitively, thrombocytopenia was highly correlated with both bleeding and ischemic events, and the presence of this condition identified a more-at-risk patient population.
The short- and long-term consequences of coronary artery disease and its most common manifestation, the acute coronary syndrome (ACS; unstable angina and myocardial infarction [MI]), are responsible for many deaths worldwide each year.1 2 Extensive clinical research has sought to determine what therapies can improve patient outcomes with ACS, but less is known about what clinical entities are associated with worsening the already elevated risk of these patients.
Data suggest that thrombocytopenia developing during an ACS carries negative prognostic significance. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) and Thrombolysis In Myocardial Infarction (TIMI) groups have demonstrated that thrombocytopenia in patients experiencing acute ST-elevation MI is associated with significant increases in in-hospital mortality, bleeding, and total hospital stay and major and minor hemorrhage, respectively.3 4 Large ACS clinical trials have found that thrombocytopenia in patients undergoing high-risk angioplasty for an ACS correlates significantly with worse clinical outcomes, such as death and MI.5 6 7
The large subgroup of ACS patients with non–ST-elevation MI and unstable angina, however, remains relatively unstudied with respect to thrombocytopenia. The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial evaluated the clinical efficacy and safety of the platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide in this important patient population.
We examined thrombocytopenia in PURSUIT and sought to determine its incidence in this patient population, its prognostic significance, and finally, whether antiplatelet therapy through GP IIb/IIIa inhibition predisposes this population to develop thrombocytopenia.8
The international, multicenter PURSUIT trial9 evaluated 10 948 patients presenting with a non–ST-elevation ACS. Eligible patients had ischemic chest pain symptoms within 24 hours of enrollment and met either prespecified ECG or cardiac enzyme requirements. Patients were excluded from study participation for predisposition to bleeding, pregnancy, abnormal baseline laboratory measurements (including platelet count <100×109/L), or use of thrombolytics, other GP IIb/IIIa antagonists, or experimental drug therapies.
Patients were randomized in a double-blind fashion to receive either intravenous eptifibatide (180 μg/kg bolus plus 2 μg · kg−1 · min−1 infusion [high dose] or 180 μg/kg bolus plus 1.3 μg · kg−1 · min−1 infusion [low dose]) or intravenous placebo control for 72 to 96 hours. Early in the trial, however, safety parameters for the high dose of eptifibatide were within acceptable limits, and as specified by the protocol, the low-dose arm was discontinued, with all subsequent patients receiving the high-dose regimen or placebo.
Concomitant use of aspirin, heparin, and other medications was left to the discretion of the individual investigators. For those patients weighing <70 kg and receiving intravenous unfractionated heparin, the protocol suggested a weight-adjusted heparin-dosing nomogram.10 It was recommended that patients who weighed >70 kg receive a standard nonadjusted heparin dose (5000 U IV bolus–1000 U/h infusion). Transfusion guidelines were provided to all investigators to standardize transfusion usage.11 All decisions regarding cardiac catheterization or revascularization (PTCA or CABG) were left to the individual investigators.
Thrombocytopenia: Determination and Definition
Platelet count determinations were recommended at baseline, on a daily basis during study-drug infusion, and at the investigator’s discretion during the remainder of hospitalization. The case report form for all patients documented the baseline platelet count, ≤5 platelet measurements during study-drug infusion, and 1 nadir platelet count after study-drug infusion. Thrombocytopenia was defined as a nadir platelet count of <100×109/L or a relative reduction of the nadir platelet count to <50% of baseline.3 Severe and profound thrombocytopenia were defined as platelet nadirs <50×109/L and <20×109/L, respectively.5
Additional Platelet Information
Periodic review of the blinded PURSUIT database indicated which study patients were experiencing thrombocytopenia. A standard thrombocytopenia form was then used to collect additional information such as hematology consultations, heparin-induced antibody determinations, and a complete listing of all platelet counts with regard to those patients who were experiencing severe or profound thrombocytopenia.
PURSUIT Thrombocytopenia Population
For purposes of this analysis, only data from the high-dose eptifibatide and placebo arms of PURSUIT were analyzed. Those patients found to have severe and profound thrombocytopenia were then reviewed individually, when possible, to verify the occurrence and degree of reported thrombocytopenia.
Additionally, several different thrombocytopenic populations were initially analyzed as the PURSUIT thrombocytopenia population. Each of these 3 groups experienced a platelet nadir that fulfilled the PURSUIT definition of thrombocytopenia, but they were different in that the timing with respect to coronary bypass grafting, a procedure that was expected to be a significant confounder, was considered. The 3 groups analyzed were: (1) patients who developed thrombocytopenia and never underwent CABG; (2) those who experienced thrombocytopenia before CABG or who never underwent CABG; and (3) those who developed thrombocytopenia regardless of the presence or timing of CABG. In each of these analyses, although the actual numbers varied, the overall trends in outcome variables were similar. We therefore concluded that thrombocytopenia affected outcomes in a uniform direction regardless of the presence or timing of bypass grafting, and we elected to the use the broadly defined third definition for our final PURSUIT thrombocytopenic population.
Clinical events such as death and myocardial ischemia/MI were documented on the case report form. Those interventions and clinical events that occurred after the baseline hospitalization but within 30 days of enrollment were prospectively documented on a standard 30-day form.
The primary efficacy outcome of the present study was the combined end point of death and nonfatal MI by 30 days after randomization. This end point was adjudicated by an independent, blinded Clinical Events Committee (CEC) using prespecified diagnostic criteria.9
Safety outcomes for PURSUIT were CEC-adjudicated stroke; a calculated bleeding index, defined as [number of units of packed red blood cells transfused+(observed drop in hematocrit/3)]; and the incidence of bleeding based on the GUSTO definition of bleeding severity.12 According to these criteria, severe bleeding was defined as intracranial hemorrhage or a bleeding event that caused hemodynamic compromise and required intervention, whereas moderate bleeding events were defined as those requiring blood transfusion but not leading to hemodynamic compromise or need for an intervention.
Continuous variables are presented as medians with 25th and 75th percentiles. Categorical data are displayed as an incidence (%). Differences in baseline characteristics and clinical/safety outcomes between patients with and without thrombocytopenia were compared univariably with the median test for all reported medians and Pearson χ2 test for all reported incidences.
Because the outcomes in this patient population were multifactorial, we performed multivariable regression to isolate certain variables and assess their independent association with these outcomes. These variables are presented as ORs with 95% CIs. Four regression models were performed, 3 of which examined the contribution of thrombocytopenia to moderate/severe bleeding, the primary end point, and death alone, respectively. To assess the independent contribution of thrombocytopenia to these various outcomes, the model was adjusted for variables found to be important prognostic factors in previous ACS trials,13 all statistically significant differences in baseline characteristics, the presence of a moderate/severe bleeding event (except in the moderate/severe bleeding model), procedural interventions, and factors presumed to be important predictors of these outcomes. The fourth multivariable regression model, which attempted to predict risk factors for thrombocytopenia, was created with disproportionately represented baseline characteristics, procedural interventions, and known or presumed thrombocytopenia predictors used as covariates.
The overall incidence of thrombocytopenia was 7.0%. There was an even distribution of thrombocytopenia between the placebo- and eptifibatide-treated arms across all definitions of thrombocytopenia (Table 1⇓).
The Figure⇓ depicts the time to onset of thrombocytopenia for the overall thrombocytopenia definition and the combined severe/profound thrombocytopenia groups, respectively. In the overall thrombocytopenia population, the timing of thrombocytopenia was nearly identical in the 2 treatment arms (4 [2, 7] days for placebo versus 4 [2, 8] days for eptifibatide). In the combined severe/profound thrombocytopenia group, the curves diverged early, with eptifibatide-treated patients developing thrombocytopenia at a median of 52 (32, 81) hours after randomization and placebo-treated patients developing thrombocytopenia at a median of 126 (99, 293) hours.
Patients with thrombocytopenia were older, weighed less, and were more likely to not be white (Table 2⇓). Additionally, they had a greater number of cardiac risk factors, were more frequently diabetic, and had a greater incidence of previous MI, prior angioplasty, and history of peripheral vascular disease.
Although there was a significant (P<0.001) difference in baseline platelet count between the thrombocytopenia (212×109/L [163×109/L, 260×109/L]) and nonthrombocytopenia groups (226×109/L [192×109/L, 268×109/L]), the total decrease in platelet count from baseline, as expected, was more marked in the thrombocytopenia group (127×109/L [83×109/L, 164×109/L] versus 29×109/L [13×109/L, 51×109/L] for nonthrombocytopenia). The median absolute nadir platelet counts were 90×109/L (75×109/L, 103×109/L) and 193×109/L (161×109/L, 231×109/L) for the thrombocytopenia and nonthrombocytopenia groups, respectively.
The development of thrombocytopenia was associated with a substantially higher incidence of any bleeding event, a moderate/severe bleeding event, and the need for red blood cell or platelet transfusion at any point during baseline hospitalization (Table 3⇓). The bleeding index was also significantly higher (5.3 for thrombocytopenia versus 1.4 for nonthrombocytopenia; P<0.001).
Data at 30 days after randomization documented worse outcomes for patients with thrombocytopenia than for those without thrombocytopenia (Table 3⇑). The incidence of ischemic events (stroke, MI, death, and recurrent ischemia leading to cardiac procedure) at any point after enrollment was higher in patients with thrombocytopenia. The median length of stay in both intensive care units and during baseline hospitalization was also significantly (P<0.001) longer for patients experiencing thrombocytopenia.
Use of Antiplatelet Therapies
The use of abciximab (0.3% versus 0.2%; P=0.435), ticlopidine (7.1% versus 9.6%; P=0.041), aspirin (91.3% versus 93.6%; P=0.025), and thrombolytic therapy (2.1% versus 2.3%; P=0.656)—all drugs with known or potential antiplatelet effects—was similarly distributed between the thrombocytopenia and nonthrombocytopenia groups, respectively. Heparin, also a drug with a known thrombocytopenic effect,14 was used with more prevalence (94.3% versus 89.6%; P<0.001) and was infused for a longer period (87.0 versus 76.5 hours; P=0.021) in the thrombocytopenic group.
Eptifibatide Versus Placebo in Thrombocytopenic Patients
A comparison of clinical events in the thrombocytopenic population of PURSUIT, grouped by study drug, revealed a consistent but not statistically significant (except CABG, P=0.027) trend toward better clinical outcomes in patients with thrombocytopenia who were treated with eptifibatide (Table 4⇓). This relationship occurred in spite of an excess incidence of any bleeding (P=0.017) and severe bleeding (P=0.046) in this group. A formal statistical test for interaction in our primary end-point regression model confirmed no significant interaction between treatment group and thrombocytopenia, implying that the benefit seen in the overall PURSUIT trial occurred in the same direction and with similar magnitude for the thrombocytopenia subpopulation.
The multivariable regression model for predictors of moderate/severe bleeding (Table 5⇓) demonstrated that even after adjustment for confounders, thrombocytopenia was independently correlated with an increased bleeding risk (OR 2.0 [1.6 to 2.6]). Similarly, the model for predictors of the PURSUIT primary end point (Table 5⇓) revealed that thrombocytopenia was independently associated with an increased rate (OR 1.3 [1.0 to 1.6]) of death/nonfatal MI within 30 days of randomization, even after adjustment for a large number of confounding variables. Thrombocytopenia did not significantly increase the risk of death alone, however, in our third regression model (not shown).
Finally, a number of variables were found to correlate independently with increased risk of thrombocytopenia (Table 6⇓). Patients who underwent CABG were highly significantly predisposed to the development of thrombocytopenia (OR 12.2 [9.1 to 16.2]), as were patients with moderate to severe bleeding events and those treated with an intra-aortic balloon pump. However, the use of heparin, a therapy well known to cause thrombocytopenia,14 did not significantly predispose patients to increased thrombocytopenic risk in our model when evaluated dichotomously (heparin use: yes/no; exposure time: <5 days/≥5 days) and continuously (infusion duration). Similarly, the use of other antiplatelet therapies (ie, aspirin, ticlopidine, abciximab, thrombolytics, and eptifibatide) was not associated with a significantly increased risk of thrombocytopenia.
The data (Table 3⇑) suggest a clear correlation between thrombocytopenia and adverse clinical outcomes including serious bleeding and ischemic events. Although baseline characteristics of the thrombocytopenia population appear to predispose this population to poorer outcomes, our analysis shows that even after controlling for a number of these differences and other confounders (Table 5⇑), the isolated occurrence of thrombocytopenia remains significantly correlated with an increased incidence of moderate/severe bleeding and death/MI at 30 days. The physiology of primary hemostasis makes the finding of increased bleeding risk and need for transfusions in thrombocytopenic patients intuitive, but it is less clear why this condition correlates with ischemic events such as MI, stroke, and recurrent ischemia, because these outcomes are widely regarded as platelet-mediated events. These findings suggest that the observed platelet decline might be linked with clinically significant thrombosis. Regardless, the strength of the findings in PURSUIT, in combination with the consistently similar findings in the ST-elevation (TAMI3 and TIMI4 ), high-risk angioplasty (EPIC5 ), and broadly defined ACS populations (ESSENCE6 and GUSTO IIb7 ), is very suggestive of the prognostic importance of thrombocytopenia.
Definition of Thrombocytopenia
Although the <50% of baseline component of our definition of thrombocytopenia is not often included in analyses of thrombocytopenia, we felt its inclusion was important because these reductions indicate a degree of platelet compromise that is potentially clinically significant. Importantly, in addition to comparing baseline characteristics and safety/clinical outcomes for our definition of thrombocytopenia, Tables 2⇑ and 3⇑ also provide a breakdown of thrombocytopenia with a definition of a platelet nadir <100×109/L. These data are provided to facilitate comparison with already published data and also underscore how similar the <50% of baseline component of our population was to the traditionally defined <100×109/L portion.
Incidence of Thrombocytopenia
We observed a 7.0% overall incidence of thrombocytopenia (platelet nadir <100×109/L or relative reduction to <50% of baseline) in the non–ST-segment-elevation population of PURSUIT. This incidence is lower than that observed in the acute MI, thrombolytic-treated populations studied by the TAMI group (16.4%), which used the same definition of thrombocytopenia,3 and is higher than that in TIMI-I (4.8%), which broadly defined thrombocytopenia as a platelet nadir <150×109/L.15
In ACS clinical trials in which published data exist to define thrombocytopenia as a platelet nadir <100×109/L, the range of incidence of thrombocytopenia narrows considerably. In PURSUIT and EPIC, the incidences of this more conservatively defined thrombocytopenia were 4.9% and 3.9%, respectively.5 In GUSTO IIb,7 ESSENCE,6 the groups studied by TAMI,3 and the conservative arm of TIMI II,4 the rates of thrombocytopenia by this same definition were 1.0%, 3.0%, 7.3%, and 1.5%, respectively. The overall range of thrombocytopenia across these 6 large ACS clinical trials thus becomes 1.0% to 7.3%. When one allows for differences in baseline characteristics in the patient populations, duration and frequency of platelet monitoring, and varying incidences of procedure use among these studies, this range likely represents a reasonable estimate of the incidence of thrombocytopenia that can be expected in a given ACS clinical trial.
Timing of Thrombocytopenia
The median time to development of thrombocytopenia was 4 days. This is equivalent to the timing seen in TAMI3 but longer than that seen in the more invasively treated high-risk angioplasty population of EPIC (1.68 days for placebo versus 0.5 days for abciximab).5 Timing data are unpublished in most other studies of thrombocytopenia during an ACS, which makes it difficult to infer the universality of the observed PURSUIT median time to thrombocytopenia.
Origin of Thrombocytopenia
The treatment of patients experiencing an ACS involves a complex mixture of pharmacological and surgical interventions that together can obscure the underlying cause of a bout of thrombocytopenia. Cardiopulmonary bypass is associated with the condition because of a combination of mechanical consumption, hemodilution, platelet filtering, and qualitative platelet alteration16 ; and, as our model shows (Table 6⇑), patients who have undergone CABG are >12 times as likely to develop thrombocytopenia as patients who never underwent CABG. The use of intra-aortic assist devices, thought to cause thrombocytopenia mainly through mechanical trauma,16 was also found to more than double risk of thrombocytopenia (OR 2.2 [1.5 to 3.2]).
Several nonsurgical interventions predispose a patient to thrombocytopenia as well. One such intervention, heparin therapy, is associated with thrombocytopenia via 2 mechanisms: an immune-dependent, heparin-induced thrombocytopenia (HIT), which is mediated by antiplatelet antibodies, and a separate nonimmune mechanism.14 Consistent with this fact, univariably, we found a doubling of thrombocytopenic risk (P=0.001) in PURSUIT patients who were exposed to heparin therapy. Furthermore, the thrombocytopenia population was more likely to receive heparin and for a longer duration than were patients without thrombocytopenia. When examined univariably, however, heparin use is also confounded by procedural use, which by itself is associated with thrombocytopenia. Therefore, to assess the independent contribution of heparin to thrombocytopenia, we performed the regression model shown in Table 6⇑, attempting to control for procedures as well as other potentially confounding variables. In this model, we found that heparin was no longer associated with increased thrombocytopenic risk, regardless of whether heparin was measured as a dichotomous (heparin use: yes/no) variable or a continuous (infusion duration: hours) variable.
It is not entirely surprising that the use of heparin in our model was not significantly associated with the immune type of HIT. Typically, without recent exposure (ie, within the last 2 months), >4 days of heparin therapy is required to precipitate immune-mediated (type II) HIT.14 17 The PURSUIT population, however, had a median heparin exposure time of only 3.6 (2.3, 5.9; thrombocytopenia) days and 3.2 (2.0, 4.5; nonthrombocytopenia) days and thus would not be expected to manifest significant numbers of type II HIT. We also compared thrombocytopenic risk in patients exposed to heparin for ≥5 days with those exposed for <5 days. Again, we found no increase in the risk of developing thrombocytopenia in heparin-exposed patients, even with prolonged durations of heparin therapy (OR 1.0 [0.8,1.2]).
Type I HIT, however, is characterized by mild declines in the platelet count (10% to 20%), with nadir platelet counts that usually exceed 100×109/L and onset within 4 days of heparin exposure.14 This disorder is not thought to have clinical significance. It is possible that some patients in PURSUIT developed type I HIT.
Other medications thought or known to have antiplatelet effects were relatively evenly distributed between thrombocytopenic and nonthrombocytopenic patients. Consistent with this observation was the nonsignificant impact all of these drugs had on our model that predicted thrombocytopenia. It is possible, however, that the total numbers involved (especially with abciximab, ticlopidine, and thrombolytics) were inadequate to provide power to detect the potential contribution of these medications to risk of thrombocytopenia.
A recent meta-analysis of thrombocytopenic risk in the context of GP IIb/IIIa inhibition supports the concern that this new class of drug may predispose patients to develop thrombocytopenia.8 Our data (Table 1⇑) show a nearly identical distribution of thrombocytopenia between eptifibatide- and placebo-treated arms in all severities of thrombocytopenia except profound thrombocytopenia, and even in this group the difference did not reach statistical significance (P=0.258). However, 5 of the 7 patients in this group were treated with eptifibatide, and time to onset of thrombocytopenia in eptifibatide-treated patients with severe/profound thrombocytopenia diverges from placebo-treated patients quite early (Figure⇑), leaving room for speculation that in this small subset of patients with thrombocytopenia, eptifibatide exposure could contribute to thrombocytopenic risk. Even if this were true, however, only a very small subset of patients (0.1% of all patients treated) would be at risk of developing this condition, whereas the vast majority of non–ST-elevation ACS patients appear to be at an equal risk of developing thrombocytopenia regardless of eptifibatide exposure. This statement is substantiated by our regression model (Table 6⇑), which does not indicate any significant contribution of eptifibatide to thrombocytopenia after controlling for confounders. More importantly, in general, except perhaps for this group of patients with profound thrombocytopenia, patients with thrombocytopenia who receive eptifibatide appear to benefit from its use, just as they do in the overall PURSUIT population.9 This conclusion is implied by the consistent but small trend toward fewer adverse events (except bleeding) in the eptifibatide-treated thrombocytopenic population (Table 4⇑) and the absence of a significant treatment-by-thrombocytopenia interaction term in our primary end-point regression model.
Our analysis clearly points toward a correlation between thrombocytopenia and adverse events but cannot be interpreted to establish causation. Some events preceded the development of thrombocytopenia (eg, MI in Table 3⇑) and therefore cannot be included in a model to establish the predictive (causal) power of thrombocytopenia on negative outcomes. To establish such a model, one must include only those events that can be shown to have occurred after the onset of thrombocytopenia. Because of the nature of our timing data, only death, which by definition cannot be followed by events such as thrombocytopenia, is eligible for such a predictive model. Our regression model for predicting death (not shown) failed to demonstrate an increased incidence of death in patients with thrombocytopenia, however. Whether this observation reflects a lack of a causal role of thrombocytopenia on death or simply the low incidence of death in the trial is difficult to establish.
A second limitation of this study is the amount of platelet count data collected during baseline hospitalization. Although the case report form allowed documentation of up to 5 platelet counts during the initial 72 to 96 hours of enrollment, only 1 platelet count determination was recorded after infusion of the study drug. Consequently, it is not possible to address several important questions, such as total thrombocytopenia duration and the time course to complete platelet recovery.
Nearly 1 in 14 patients with a non–ST-elevation ACS enrolled in the PURSUIT trial experienced thrombocytopenia, defined as a platelet nadir <100×109/L or <50% of baseline. Our analysis demonstrates that this large subset of patients with unstable angina or non–Q-wave MI is at a significantly increased risk of experiencing not only serious bleeding events (moderate/severe bleeding, need for red blood cell/platelet transfusion) but clinically significant ischemic events (death, nonfatal MI, stroke, recurrent ischemia leading to a cardiac procedure) as well. Because causation could not be established between thrombocytopenia and outcomes, it would be inappropriate to infer from this analysis that prophylactic platelet transfusions should be administered to patients experiencing thrombocytopenia in an attempt to decrease their risk of morbidity and mortality. Further study is warranted, however, to refine the estimate of magnitude of the effect of thrombocytopenia on outcomes and to better examine its causes. In the meantime, daily platelet count determinations should be collected in all patients experiencing an ACS to aid in early identification of this important at-risk patient population.
This study was supported by COR Therapeutics, Inc (South San Francisco, Calif) and Schering Plough Research Institute (Kenilworth, NJ). The authors wish to thank Gail Tudor, PhD, for her thoughtful review and insights into the contents of this manuscript. Additionally, we are grateful to Penny Hodgson and John Daniel for their editorial expertise in drafting this manuscript.
This study was supported by COR Therapeutics, Inc (South San Francisco, Calif) and Schering Plough Research Institute (Kenilworth, NJ).
- Received July 22, 1998.
- Revision received March 2, 1999.
- Accepted March 29, 1999.
- Copyright © 1999 by American Heart Association
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