Continued vorapaxar versus withdrawed clopidogrel both on top of low dose aspirin in patients undergoing heart surgery: A call for randomized trial.

Despite advanced techniques and improved clinical outcomes, the optimal antiplatelet strategy following coronary artery bypass grafting (CABG) is an unsolved mystery. Vorapaxar, a novel platelet thrombin receptor (PAR-1/4) blocker, is currently approved for post-myocardial infarction and peripheral artery disease indications on top of clopidogrel or/and aspirin. We here summarize the outcomes in patients after CABG for justification of a future vorapaxar trial. We comprehended the CABG outcomes after vorapaxar yielded from TRACER, TRA2P trials, and affiliated FDA reviews. The verified evidence suggests that composite of death, myocardial infarction and stroke occurred in 2.2% of vorapaxar vs. 8.1% placebo in TRA2P. These data were similar to the endpoint differences (5.9% after vorapaxar vs. 8.3% for placebo) in TRACER. The mortality reduction also consistently suggests vorapaxar advantage (1.7% vs. 2.5% in TRA2P, and 1.7% vs. 3.9% in TRACER). Notably, the post-CABG bleeding risks after vorapaxar were only slightly, but not significantly higher. Moreover, the bleeding disadvantage in the experimental arm was most likely related to overtreatment since majority of patients in both TRACER and TRA2P received triple antiplatelet therapy with aspirin, clopidogrel on top of vorapaxar. Overall, the FDA-confirmed evidence advocate for the future vorapaxar post-CABG outcome-driven trial. The head-to-head trial testing dual therapy with continued over CABG vorapaxar versus withdrawed clopidogrel, both on top of low dose aspirin is warranted. We conclude that the primary outcomes including mortality were consistently better for heart surgery patients after vorapaxar, while the excess of bleeding was mild. Continuing vorapaxar during CABG may be superior to currently recommended withdrawal antiplatelet strategies, and should be tested in an adequately powered randomized outcome-driven trial.

Inferiority of ticagrelor in the PHILO trial: Play of chance in East Asians or nightmare confirmation of PLATO-USA?

Long-awaiting PHILO trial, conducted in 2011-2012 has been submitted and published late in 2015. In contrast to overall PLATO results, but similar to PLATO-US cohort, PHILO revealed numerical inferiority of ticagrelor with regard to death, myocardial infarction, stroke, and bleeding over clopidogrel. Hence, we comprehend the PHILO results in light of the PLATO-US evidence. To assess the PHILO (n=801) outcomes, applied statistics, and trial conduct, matching them with the PLATO-US (n=1413) patients. The Asian, predominantly Japanese ticagrelor patients had worsened outcomes even when compared to the negative American cohort with regard to death (OR=1.44 (PHILO) vs. 1.17 (PLATO-US); myocardial infarction (OR=1.63 vs. 1.38); and composite primary endpoint (OR=1.60 vs. 1.27); but not for stroke (OR=1.51 vs. 1.75). Moreover, in contrast to the trend in PLATO-US (OR=1.11; CI=0.84-1.48, p=0.46), PHILO revealed significant excess of PLATO-defined composite of major and minor bleeding events (OR=1.83; CI=1.27-2.63,p=0.0014). PLATO-defined "net clinical benefit" in PHILO was also significantly (OR=1.61; CI=1.11-2.34, p=0.0145) inferior for ticagrelor. The "number needed to harm" suggests that for every 29 PHILO patients treated for 12months with ticagrelor instead of clopidogrel, one will suffer an additional major bleeding event. Finally, unexplained premature closure of PHILO just after 200-210days mean drug exposure, and short 240days mean follow-up seems deliberate and concerning with regard to unblinding. Aside from some information censoring, early trial closure, and creative statistics, Asian ticagrelor patients did consistently worse in PHILO, than even in the negative PLATO-US cohort. Especially alarming is a significant bleeding inferiority justifying a necessity for a separate outcome-driven low-dose ticagrelor trial in Asian post-PCI patients. This strategy was successfully implemented with the low-dose prasugrel in Japan. Regulatory authorities in Asia may consider conducting an independent review of PHILO dataset to ensure adequate ticagrelor safety.