Comment: Mortality Benefit of No-Load Clopidogrel in COMMIT: Not a Surprise

Abstract

Myocardial Infarction Trial (COMMIT) revealed a highly significant mortality benefit of 75 mg clopidogrel when added to a fibrinolytic agent and a moderate dose of aspirin in patients who present with acute myocardial infarction (1). To be precise, 119 lives were saved in the clopidogrel arm. In a comprehensive accompanying editorial, Marc Sabatine referred to the early, first-day benefit of clopidogrel as “fascinating and unexpected” (2). In fact, these findings may be predicted and at least partly explained if we consider the following facts: First, thrombolytic agents themselves profoundly inhibit platelets in both in vitro and ex vivo settings, as shown in the platelet substudy of the Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSET-2) controlled trial (3). Second, rebound platelet activation occurs not immediately, but at 3 to 6 hours after thrombolysis, matching closely with the so-called “reperfusion injury” that was observed in another platelet substudy from the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial (4). Finally, clopidogrel is a pro-drug, and it takes 3 to 4 hours to metabolize and exhibit full antiplatelet potency (5). A few practical considerations seem to be justified. Combining fibrinolytic agents with aggressive fastacting antiplatelet agents such as GPIIb/IIIa inhibitors is probably not the best strategy for treatment of myocardial infarction, which is what has been proven by negative results of the GUSTO-V and ASSENT-4 trials. In contrast, delayed moderate platelet inhibition, when platelets are indeed blocked when they are excessively active, namely later at 3 to 6 hours after thrombolysis is a better alternative and ultimately resulted in the mortality benefit observed in COMMIT. Another clinical lesson which we learned from COMMIT is that the “the more—the better” postulate may no longer be valid with regard to antiplatelet regimens and, indirectly, may stop the unjustified escalations of clopidogrel loading doses exceeding 600 mg for coronary stenting. Last, but not least, the implication is that the mortality reduction observed in COMMIT makes it even more difficult for the experimental platelet P2Y12 receptor inhibitors to replace clopidogrel as a standard addition to aspirin in the treatment and prevention of vascular disease. Indeed, the COMMIT results break the tiny hopes of the competition to overcome “clopidogrel resistance” or/and “clopidogrel-atorvastatin interactions” with the novel agents because no-load clopidogrel already saves patients with acute myocardial infarction.