Antiplatelet strategies in acute coronary syndromes: design and methodology of an international collaborative network meta-analysis of randomized controlled trials.

INTRODUCTION: The optimal choice of oral P2Y12 receptor inhibitors has the potential to significantly influence outcomes. We seek to compare the safety and efficacy of the three most commonly used oral P2Y12 receptor inhibitors (clopidogrel, prasugrel, and ticagrelor) in acute coronary syndromes (ACS) via a comprehensive systematic review and network meta-analysis. EVIDENCE ACQUISITION: In line with the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, we performed a comprehensive search for RCTs which compared cardiovascular and hemorrhagic outcomes after use of at least two of the distinct oral P2Y12 receptor inhibitors (i.e. clopidogrel, prasugrel, and ticagrelor). A search strategy has been designed to systematically search multiple databases, including MEDLINE with PubMed interface, The Cochrane Central Register of Controlled Trials, and Embase. In addition, key inclusion criteria will be trial size of at least 100 patients and at least 1 month of follow-up time. Several prespecified subgroups will be explored, including Asian patients, patients presenting with ST-elevation myocardial infarction, patients of advanced age, and others. EVIDENCE SYNTHESIS: Exploratory frequentist pairwise meta-analyses will be based primarily on a random-effects method, relying on relative risks (RR) for short-term outcomes and incidence rate ratios (IRR) for long-term outcomes. Inferential frequentist network meta-analysis will be based primarily on a random-effects method, relying on RR and IRR as specified above. Results will be reported as point summary of effect, 95% CI, and P values for effect, and graphically represented using forest plots. CONCLUSIONS: An international collaborative network meta-analysis has begun to comprehensively analyze the safety and efficacy of prasugrel, ticagrelor and clopidogrel, each on a background of aspirin, for management of patients with ACS. It is our hope that the rigor and breadth of the undertaking described herein will provide novel insights that will inform optimal patient care for patients with ACS treated conservatively, or undergoing revascularization.

Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

BACKGROUND: CYP2C19 loss-of-function (LOF) alleles impair clopidogrel effectiveness after percutaneous coronary intervention. The feasibility, sustainability, and clinical impact of using CYP2C19 genotype-guided dual antiplatelet therapy (DAPT) selection in practice remains unclear. METHODS: A single-center observational study was conducted in 1193 patients who underwent percutaneous coronary intervention and received DAPT after implementation of an algorithm that recommends CYP2C19 testing in high-risk patients and alternative DAPT (prasugrel or ticagrelor) in LOF allele carriers. The frequency of genotype testing and alternative DAPT selection were the primary implementation end points. Risk of major adverse cardiovascular or cerebrovascular and clinically significant bleeding events over 12 months were compared across genotype and DAPT groups by proportional hazards regression. RESULTS: CYP2C19 genotype was obtained in 868 (72.8%) patients. Alternative DAPT was prescribed in 186 (70.7%) LOF allele carriers. CYP2C19 testing (P<0.001) and alternative DAPT use in LOF allele carriers (P=0.001) varied over time. Risk for major adverse cardiovascular or cerebrovascular was significantly higher in LOF carriers prescribed clopidogrel versus alternative DAPT (adjusted hazard ratio, 4.65; 95% confidence interval, 2.22-10.0; P<0.001), whereas no significant difference was observed in those without a LOF allele (adjusted hazard ratio, 1.37; 95% confidence interval, 0.72-2.85; P=0.347). Bleeding event rates were similar across groups (log-rank P=0.816). CONCLUSIONS: Implementing CYP2C19 genotype-guided DAPT is feasible and sustainable in a real-world setting but challenging to maintain at a consistently high level of fidelity. The higher risk of major adverse cardiovascular or cerebrovascular associated with clopidogrel use in CYP2C19 LOF allele carriers suggests that use of genotype-guided DAPT in practice may improve clinical outcomes.