The efficacy and safety of the prasugrel, ticagrelor, and clopidogrel dual antiplatelet therapies following an acute coronary syndrome: A systematic review and Bayesian network meta-analysis

Background The dual-antiplatelet therapies (DAPT) of clopidogrel, prasugrel, or ticagrelor in concomitant use with acetylsalicylic acid are the contemporary treatment regimens for acute coronary syndromes (ACS). Systematic comparative effectiveness and safety analyses currently lack clinically meaningful interpretations of the summarized evidence. Methods We systematically searched MEDLINE, EMBASE, CENTRAL, and [clinicaltrials.gov][1] for randomized controlled trials (RCTs) that reported on either the efficacy or safety between clopidogrel, prasugrel, or ticagrelor DAPTs in ACS patients. The primary efficacy endpoint was a composite of all-cause mortality, a recurrent non-fatal myocardial infarction, or non-fatal stroke. The primary safety endpoint was study-reported major bleeding events. A Bayesian network meta-analysis was performed using a generalized linear model logit transformation with a log-transformation of ‘time’ for varying lengths of study follow-up. Studies published in either English or French with a minimum of 6 months of follow-up and a “low” rating from the Cochrane risk of bias assessment tool were included in the main analyses. Fixed and random effects models fit was assessed by the deviance information criterion (DIC) and node-splitting methods were used to assess the consistency of direct and indirect network evidence. An HR >0.9 and <1.11 were set as our clinically important thresholds, and represented the range of practical equivalence (ROPE). Results From a total of 15,232 articles identified, 138 were selected for full-text review. From a total of 29 identified RCT’s, 17 trials, representing 57,814 subjects, were identified as a “low” risk of bias and were included in the final Bayesian network meta-analysis. Compared to clopidogrel, prasugrel and ticagrelor reduced major acute coronary events (MACE) endpoints by a median of 13% (Hazard ratio [HR]PC, 0.87; 95% credible interval [95% CrI]: 0.74, 1.06) and 5% (HRTC, 0.95; 95% CrI: 0.81, 1.14), respectively. The HR posterior distributions estimated that prasugrel had a 67.5% chance of producing a clinically meaningful – greater than 10% (HR<0.9) – decrease in the risk of MACE outcomes, while ticagrelor only had a 22.4% chance of exceeding the clinically important threshold. The primary safety outcome found prasugrel (HRPC, 1.23; 95% CrI: 1.04, 1.40) and ticagrelor (HRTC, 1.07; 95% CrI: 0.99, 1.17) DAPTs to be associated with a median increase in events relative to clopidogrel. This translates to a probability of a clinically meaningful increase (HR>1.11) in major bleeding of 83.7% for prasugrel and 67.7% for ticagrelor, when compared to clopidogrel. Conclusion When compared with ACS patients assigned to clopidogrel, prasugrel and ticagrelor were associated with moderate and modest probabilities respectively in clinically meaningful MACE reductions. Prasugrel and ticagrelor had high and modest probabilities respectively of clinically meaningful increases in bleeding. Despite guideline recommendations, the net clinical benefit for these drugs compared to clopidogrel appears uncertain. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement nil ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: As the study material consisted only of previously published material IRB and/or ethics committee approvals were not required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: https://clinicaltrials.gov