The PLATO trial: Do you believe in magic?

Abstract

The recently published and presented PLATelet Inhibition and Clinical Outcomes (PLATO) trial was a pivotal Phase III, randomized, double-blind, parallel-group, multinational, clinical study.1 The trial compared head-to-head the efficacy of the experimental antiplatelet agent ticagrelor (formerly known as AZD6140, to be marketed as Brilintaw) vs. standard care with clopidogrel. Patients (n = 18 624) with moderate to high risk acute coronary syndromes undergoing coronary intervention were randomized to ticagrelor 180 mg loading dose followed by 90 mg twice daily thereafter, or clopidogrel 300-600 mg loading dose followed by 75 mg once daily for 6-12 months. The primary endpoint was the time of the first event of death from vascular causes, myocardial infarction (MI), or stroke, and occurred in 11.7% of patients treated with clopidogrel vs. 9.8% of patients randomized to ticagrelor, representing a highly significant benefit [hazard ratio (HR)=0.84; confidence interval (CI) =0.77-0.92; P<0.001] of the experimental drug.1 Triaging these three components of the combined endpoint suggests that the difference in favour of ticagrelor was driven by the reduction of vascular death (P<0.001) and MI (P<0.005), but not stroke (P=0.22). There were significantly more fatal intracranial bleedings (11 vs. 1, P=0.02), but numerically less overall fatal bleeding (20 vs. 23) after ticagrelor. Among side effects associated with ticagrelor, dyspnoea (already recognized in the earlier studies with AZD6140, and probably caused by transitory bronchoconstriction) was the most prominent one (HR=1.84; CI=1.68-2.02; P<0.001), followed by ventricular pauses (P,0.01), and laboratory findings of increased uric acid as well as elevated creatinine (P<0.001 for both). Obviously the PLATO data will undergo detailed scrutiny and verification during the assessment by regulatory authorities; however, some considerations already seem appropriate.