P hase 3 prospective randomized trials are designed and have statistical power for the investigation of 1 major hypothesis in a predefined population using predefined clinical end points. These large outcome trials are conducted following rules and regulations specified by Good Clinical Practice and the ethical principles of the Declaration of Helsinki to maintain the highest scientific validity and ethical standards and minimize bias. Predefined, subgroup analyses are by definition

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... for evaluation of the primary and secondary events but often performed to generate hypotheses for further understanding of the effects and side effects in important subgroups. The Platelet Inhibition and Patient Outcome (PLATO) trial successfully tested its main hypothesis: that ticagrelor compared with clopidogrel would result in a lower risk of recurrent thrombotic events in a broad patient population with acute coronary syndromes. 1 An academic executive committee was responsible for the design and the medical, scientific, and operational conduct of PLATO; expert sites and investigators conducted the trial, which was monitored closely by an independent data and safety monitoring board; and all primary and secondary efficacy and safety events were adjudicated by an independent committee of expert cardiologists and neurologists blinded to assigned treatment. Two independent academic groups have full access to the PLATO database and have performed all analyses for publication. Patients with acute coronary syndromes and with a history of stroke or transient ischemic attacks (TIA) are at particularly high risk for recurrent cardiovascular events, including death and myocardial infarction, as well as bleeding complications, including an increased risk of intracranial bleeding. In this high-risk population, the balance between safety and efficacy of antithrombotic treatment is therefore particularly important. Establishing the clinical efficacy and safety of ticagrelor versus clopidogrel in patients with previous stroke or TIA was a prespecified subgroup analysis of PLATO included in the appendix of the primary trial publication. 2 Among the 18 624 patients randomized in PLATO, 1152 (6.2%) were reported as having a history of stroke or TIA by the investigators. These patients presented higher rates of the primary composite end point, myocardial infarction, death, stroke, major bleeding and intracranial bleeding as compared with those patients without previous stroke or TIA. 3 The reductions of the primary and secondary end points of ticagrelor versus clopidogrel were consistent with the overall PLATO trial results. Thus, the relative reduction of the primary end point with ticagrelor compared with clopidogrel was 13% in patients with and 16% in patients without a history of previous stroke or TIA, with no significant treatment-by-stroke history interaction test (P=0.39) after multivariable adjustment. The relative reduction of all-cause death, with ticagrelor versus clopidogrel, was 38% and 19% in patients with or without a previous history of stroke, respectively, with no significant treatment-by-stroke history interaction (P=0.98). In the subgroup of patients with a previous history of stroke, there were similar rates of stroke (3.7% versus 3.0%), hemorrhagic stroke (0.4% versus 0.4%), and fatal stroke (0.6% versus 1.2%) in the ticagrelor and clopidogrel groups. The rates of PLATO-defined major bleeding and noncoronary artery bypass graft-related major bleeding were not significantly different between patients assigned ticagrelor and clopidogrel (14.6% versus 14.9% and 5.9% versus 6.8%, respectively). Intracranial bleeding occurred infrequently and with no difference between the ticagrelor and clopidogrel groups (0.9 versus 0.7%). Consistent with the overall PLATO trial results, the subgroup analysis of the high-risk subset of patients with a history of stroke or TIA shows that more potent inhibition of platelet aggregation with the reversibly binding P2Y 12 receptor inhibitor ticagrelor reduces ischemic events with no