Angiographic outcomes contradict platelet data in the PLATO trial: confusion over official trial substudies

Major indication-seeking phase 3 clinical trials usually include numerous subanalyses and substudies designed to facilitate the interpretation of results, often providing putative mechanisms that might explain clinical outcomes. Such subanalyses and/or substudies may focus on socioeconomic implications, cost-effectiveness, biomarker applicability, subgroup analyses, etc. Novel antiplatelet agents may benefit from substudies aimed at elucidating the effects on platelets, while angiographic data are also essential for the adequate assessment of coronary flow. Ideally, the data yielded from substudies should correlate well with the main results of the trial. However, in the PLATO (PLATelet Inhibition and Clinical Outcomes) trial, official angiographic data (PLATO-A) contradict platelet (PLATO-P) substudy results. While the large (n = 2,616) PLATO-A concluded that coronary flow and myocardial perfusion were almost identical after ticagrelor or clopidogrel, the small (n = 24) single-center PLATO-P suggested that ticagrelor achieved a highly significantly greater antiplatelet effect compared to clopidogrel after loading in patients enrolled in the same trial and at similar time points. In contrast to PLATO-P, PLATO-A corresponds well with clinical outcomes including the early percutaneous coronary intervention 'ticagrelor death paradox' in PLATO-USA patients and the lack of an early ticagrelor benefit in the overall invasive PLATO cohort reported by the FDA. The discrepancy between PLATO-A and PLATO-P is obvious and lacks a reasonable explanation: platelet activity and coronary flow are generally inversely related, as consistently shown for other antiplatelet regimens, and should be particularly matched when assessed in the frame of the same trial.