Correspondence
Eptifibatide in Acute Coronary Syndromes
N Engl J Med 1999; 340:60-61January 7, 1999
- Article
To the Editor:
In the report on patients undergoing early coronary revascularization (within 72 hours) in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial (Aug. 13 issue),1 the investigators state that there was a 31 percent reduction in the incidence of the 30-day combined end point of death or nonfatal myocardial infarction in patients receiving eptifibatide as compared with those receiving placebo (11.6 percent vs. 16.7 percent, P=0.01). However, it is not immediately clear from the data presented in Table 3 that there was, in fact, a significant difference in the outcome at 30 days between these groups. Furthermore, a significant reduction in the composite end point was not reported for patients who did not undergo early revascularization. In addition, the odds ratios for death or nonfatal myocardial infarction show that infusion of eptifibatide was clearly favorable in North American patients, whereas the effect was less evident in patients in Western Europe, Latin America, and Eastern Europe, where catheterization was performed much less often. Given that 15 to 30 percent of all percutaneous-revascularization procedures are associated with an elevation of the creatine kinase MB level (often after seemingly uncomplicated procedures), one wonders whether the effect of eptifibatide on the combined end point is largely a manifestation of reducing revascularization-related creatine kinase MB leaks.2 The effect of infusion of eptifibatide in changing the natural history of acute coronary syndromes may be smaller than its effect in reducing the incidence of non–Q-wave infarction in patients treated with catheterization. Since the effect of procedural enzyme release on late morbidity and mortality is not yet fully known, it may be premature to conclude that eptifibatide has a major role in the routine treatment of patients with acute coronary syndromes who undergo early catheterization therapy.
2 ReferencesThomas Levin, M.D.
University of Chicago, Chicago, IL 606371
The PURSUIT Trial Investigators
Full Text | Web of Science | Medline2
Baim DS ,Cutlip DE ,Sharma SK , et al. Final results of the Balloon vs Optimal Atherectomy Trial (BOAT). Circulation 1998;97:322-331
Web of Science | Medline
To the Editor:
The PURSUIT investigators report the efficacy of eptifibatide in reducing the incidence of death or nonfatal myocardial infarction in patients presenting with ischemic chest pain. They report the total number of patients who received heparin or aspirin during the trial but not the numbers in the control group and in the eptifibatide group who received these medications. For the outcomes reported by the investigators, heparin and aspirin have proven efficacy, so knowing the number of patients who received these drugs in each treatment group is essential in evaluating the efficacy of eptifibatide. Certainly, in such a large trial, even a small difference in proportions will be statistically significant, but in this case, it may be clinically significant as well.
Furthermore, it would be interesting to know whether there is an additive effect of eptifibatide used with heparin or with aspirin. This cannot be known from the data as they are presented. The results of other subgroup analyses are presented, but not the results of an analysis according to concomitant therapy received during the trial.
Jodi Segal, M.D., M.P.H.
Johns Hopkins University, Baltimore, MD 21205To the Editor:
In the PURSUIT trial, the incidence of thrombocytopenia was similar in the eptifibatide and placebo groups, but the eptifibatide group had a higher incidence of profound thrombocytopenia. Thrombocytopenia was defined as a platelet count of less than 100,000 per cubic millimeter or a nadir below 50 percent of the base-line value, and profound thrombocytopenia was defined as a nadir platelet count below 20,000 per cubic millimeter. It appears that EDTA-mediated pseudothrombocytopenia due to platelet clumping was not ruled out as a cause of profound thrombocytopenia in the patients treated with eptifibatide.
The glycoprotein IIb/IIIa receptor inhibitor abciximab is known to cause EDTA-mediated pseudothrombocytopenia.1 Although the mechanism of EDTA-mediated platelet clumping is not entirely clear, the glycoprotein IIb/IIIa receptor has a key role in its pathogenesis.2,3 It is therefore possible that pseudothrombocytopenia also occurs with other glycoprotein IIb/IIIa receptor antagonists.
The recognition of pseudothrombocytopenia prevents unnecessary measures, such as platelet transfusions or discontinuation of treatment with the glycoprotein IIb/IIIa inhibitor. Whenever thrombocytopenia occurs in a patient treated with a glycoprotein IIb/IIIa inhibitor, EDTA-mediated pseudothrombocytopenia needs to be ruled out. A peripheral-blood film should be reviewed for the presence of platelet clumping, or a blood count obtained from blood drawn into a citrated tube.
3 ReferencesStephan Moll, M.D.
Humboldt Universität Charité, 13125 Berlin, Germany1
Christopoulos CG ,Machin SJ . A new type of pseudothrombocytopenia: EDTA-mediated agglutination of platelets bearing Fab fragments of a chimaeric antibody. Br J Haematol 1994;87:650-652
CrossRef | Web of Science | Medline2
Casonato A ,Bertomoro A ,Pontara E ,Dannhauser D ,Lazzaro AR ,Girolami A . EDTA dependent pseudothrombocytopenia caused by antibodies against the cytoadhesive receptor of platelet gpIIB-IIIA. J Clin Pathol 1994;47:625-630
CrossRef | Web of Science | Medline3
Schrezenmeier H ,Muller H ,Gunsilius E ,Heimpel H ,Seifried E . Anticoagulant-induced pseudothrombocytopenia and pseudoleucocytosis. Thromb Haemost 1995;73:506-513
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: In response to Dr. Levin, there was indeed a significant reduction in death or myocardial infarction at 30 days among patients who underwent percutaneous revascularization during the first 72 hours after randomization (the approximate period of infusion of the study drug) and who received eptifibatide, as compared with placebo. Since clinicians have no way of predicting whether these ischemic events will occur before or after revascularization, we sought to show the effects of the platelet inhibitor before and after percutaneous procedures were performed. In Table 3 of our article, the events shown for the post-procedure time points are all the events that occurred after the initiation of the procedure. In some cases, patients had events both before and after the procedure. The overall 30-day analysis included only the first event, but Table 3 includes all events.
Levin also notes that the estimate of the treatment effect was greatest in North America, where the rate of use of revascularization procedures was highest. Whether this observation reflects differences in patient populations, medical care (including use of medications and procedures), or a complex interaction of multiple factors is still under investigation.
Finally, Levin questions the clinical meaningfulness of post-procedure myocardial infarction, preferring the term “creatine kinase MB leaks” and arguing that the effect of these events is not yet known. He cites the Balloon versus Optimal Atherectomy Trial to support this position. This trial, however, consisted of only 989 low-risk patients, with a one-year mortality rate of 1.1 percent. At least 10 other studies, involving more than 10,000 patients, have demonstrated that post-procedure elevation of the creatine kinase MB level is associated with an increased risk of death.1 We assert that preventing such events is worthwhile for patients.
Neither heparin use nor aspirin use during the index hospitalization differed significantly between the treatment groups (89.7 percent of the patients in the eptifibatide group and 89.9 percent of those in the placebo group received heparin; 92.7 percent of the patients in the eptifibatide group and 93.2 percent of those in the placebo group received aspirin). The estimate of the effect of treatment with eptifibatide was greater for the patients who received heparin than for those who did not. This analysis is confounded by regional differences in heparin use (e.g., heparin was used in 97.2 percent of patients in North America vs. 77.3 percent of those in Latin America) and differences in the use of procedures that require heparin.
In response to Moll, there were very few patients with profound thrombocytopenia in this trial of almost 11,000 patients. The constraints of a large, simple trial2 preclude the collection of data at the level of detail required to rule out unusual events such as pseudothrombocytopenia. We agree that in evaluating patients with thrombocytopenia, a peripheral-blood smear should be reviewed for the presence of platelet clumping.
2 ReferencesRobert A. Harrington, M.D.
Duke Clinical Research Institute, Durham, NC 27705Maarten L. Simoons, M.D.
Erasmus University, 3000 DR Rotterdam, the NetherlandsEric J. Topol, M.D.
Cleveland Clinic Foundation, Cleveland, OH 441951
Califf RM ,Abdelmeguid AE ,Kuntz RE , et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998;31:241-251
CrossRef | Web of Science | Medline2
Topol EJ ,Califf RM . Answers to complex questions cannot be derived from “simple“ trials. Br Heart J 1992;68:348-351
CrossRef | Web of Science | Medline
