Review: In patients having PCI, high-dose clopidogrel reduces major cardiac events vs standard-dose clopidogrel

Question In patients having percutaneous coronary intervention (PCI), what are the effects of high-dose maintenance clopidogrel compared with standard-dose clopidogrel on major adverse cardiac events? Review scope Included English-language studies compared 4 weeks of high-dose maintenance clopidogrel (150 mg) with standard-dose maintenance clopidogrel (75 mg) in patients having PCI. Outcomes were a composite of major adverse cardiac events (cardiovascular [CV] death, nonfatal myocardial infarction [MI], definite or probable stent thrombosis, target vessel revascularization, or stroke), components of the composite outcome, and major or minor bleeding. Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane Library (all to Sep 2014), and reference lists were searched for randomized controlled trials (RCTs). 17 RCTs (n =4822, treatment duration 28 d to 12 mo) met selection criteria. 7 RCTs (n =2879) included patients with high platelet reactivity (HPR) while receiving clopidogrel. 13 RCTs had low risk for bias, and 4 had high risk for bias. Main results High-dose clopidogrel reduced a composite of major adverse cardiac events compared with standard-dose clopidogrel (Table). High-dose clopidogrel reduced stent thrombosis and revascularization but not CV death or nonfatal MI (Table). In trials that included patients with HPR, high-dose clopidogrel reduced cardiac events (relative risk reduction [RRR] 44%, 95% CI 22 to 60) and did not increase bleeding (RRR 22%, CI 17 to 48). Conclusion In patients having percutaneous coronary intervention, high-dose maintenance clopidogrel for 4 weeks reduced major adverse cardiovascular events compared with standard-dose maintenance clopidogrel. High-dose vs standard-dose maintenance clopidogrel in patients having percutaneous coronary intervention* Outcomes Number of trials (n) Weighted event rates At 28 d to 12 mo High dose Standard dose RRR (95% CI) NNT (CI) MACE 17 (4822) 2.9% 5.4% 47% (28 to 60) 40 (31 to 67) Cardiovascular death 9 (4306) 0.9% 1.4% 39% (8 to 66) NS Myocardial infarction 11 (4433) 1.4% 2.1% 33% (3 to 56) NS Stent thrombosis 9 (4198) 0.7% 1.6% 57% (22 to 77) 113 (83 to 293) Revascularization 7 (1567) 1.6% 4.1% 61% (25 to 79) 40 (31 to 97) Bleeding 10 (4052) 3.0% 3.7% 19% (12 to 43) NS *MACE = major adverse cardiovascular events; NS = not significant; other abbreviations defined in Glossary. Weighted event rates, RRR, NNT, and CI calculated from control event rates and odds ratio in article using a fixed-effect model. Composite of cardiovascular death, nonfatal myocardial infarction, definite or probable stent thrombosis, target vessel revascularization, or stroke. Commentary The meta-analysis by Ma and colleagues examined a controversial issue in a field plagued by small, underpowered RCTs and subgroup comparisons. The Gauging Responsiveness with A VerifyNow assayImpact on Thrombosis And Safety (GRAVITAS) trial, the largest and highest-quality RCT to date, compared high- with standard-dose clopidogrel for 6 months in 2214 patients who received drug-eluting stents and had HPR on clopidogrel (1). In this highest of risk groups, the trial found no improvement in a composite of death, MI, or stent thrombosis or the individual outcome components. Given the low numbers of outcome events overall and in each study included in the review, the modest benefit shown in the meta-analysis is largely driven by target lesion revascularization. Based on the current evidence and variable quality and bias of included studies, it is difficult to argue for blanket changes in practice, particularly to more complex step-up/-down regimens that could cause medication confusion and noncompliance. Availability of more potent P2Y12 antagonists may render this a moot question. For example, in patients with HPR receiving clopidogrel, ticagrelor overcame platelet nonresponsiveness (2); whether it translates to fewer clinical events at acceptable risk for bleeding must be shown in adequately powered RCTs. For now, given the overall superiority of ticagrelor compared with clopidogrel in both the acute coronary syndrome (3) and stable coronary disease (4), ticagrelor may be more reasonable than a step-up/-down clopidogrel regimen for patients considered too high risk for standard-dose clopidogrel.