The PLATO trial reveals further opportunities to improve outcomes in patients with acute coronary syndrome

Acute coronary syndrome (ACS) and its complications are caused by ruptures of atherosclerotic plaques leading to aggregation of platelets and the formation of thrombi at the lesion or an implanted coronary stent. Before the era of early routine coronary stenting, platelet inhibition with aspirin was shown to reduce the risk of myocardial infarction (MI) and improve survival in this setting. In the current era of routine early percutaneous coronary intervention (PCI) further attenuation of platelet aggregation by either P2Y12-receptor inhibition with thienopyridines or glycoprotein 2b/3a inhibitors has provided further reduction of the risk of MI but without any accompanying decrease in mortality (1–4). This disconnect might be explained by a reduction mainly of procedure-related MIs with no consequences for long-term mortality (5) and by an increase in major bleeding associated with raised long-term mortality (6). The PLATelet Inhibition and Clinical Outcomes (PLATO) trial compared the new directly and reversibly acting P2Y12 inhibitor ticagrelor with clopidogrel in 18,624 patients with ST-elevation or moderate-high risk non-ST-elevation ACS recruited in 862 sites and 43 countries (7). In patients assigned to ticagrelor there was a reduction in the primary outcome composite of cardiovascular death, MI, and stroke from 11.7% to 9.8% per year compared to clopidogrel (p<0.001). Ticagrelor also reduced spontaneous and procedure related MI and stent thrombosis as well as cardiovascular and total mortality (7). These benefits were consistent across a spectrum of patients with ACS as evidenced in a series of predefined additional subanalyses from the PLATO trial (8–14). The PLATO trial has therefore shown ticagrelor’s ability to further improve survival beyond the currently recommended treatment strategies in a broad spectrum of patients with ACS most likely because of its capacity to further reduce spontaneous as well as procedure related MI and stent thrombosis without increasing the overall risk of bleeding or other potentially fatal adverse events (7). In a viewpoint article in this journal (15) there is extensive speculation on various aspects of the PLATO trial conduct and posthoc dissection of results and inappropriate cross-trial comparisons far outside sound scientific methodology. As the responsible academic investigators we can confidently state that PLATO successfully tested its main hypothesis by incorporating all features of large outcome clinical trials that provide minimal bias and the highest scientific validity, integrity and ethical standards: it was randomised, double-blind, and multicentre; it followed Good Clinical Practice (GCP) and the ethical principles of the Declaration of Helsinki; it was coordinated by highly respected academic research organisations with decades of experience with conducting phase III clinical trials; an academic executive committee comprising international experts in acute coronary syndromes were responsible for the design and the medical, scientific, and operational conduct of PLATO; sites experienced in conducting clinical trials with clinicians expert in treating ACS participated; an independent data and safety monitoring board followed the trial closely during its conduct; an independent committee of expert cardiologists and neurologists blinded to assigned treatment Correspondence to: Dr. Lars Wallentin Uppsala Clinical Research Center University Hospital, 75185 Uppsala, Sweden E-mail: [email protected]