Objectives: To summarize the available evidence regarding whether or not a higher aspirin maintenance dose inversely affects the ticagrelor benefit observed in the US cohort of the PLATO trial. Background: In the recent PLATO trial, the daily aspirin dosages in the USA were split between 81 and 325 mg while the vast majority of dosing outside of the USA was 75 or 100 mg. The FDA conducted exhaustive analyses of the aspirin dosage in a framework of primary clinical efficacy. Considering the post hoc, not prespecified nature of such analyses as well as multiple confounding problems with biologic plausibility, sensitivity to reclassification of small numbers of cases regarding loading versus maintenance aspirin dosing, and the distribution of events in high-dose aspirin observed outside of the USA, the FDA documents clearly suggest that aspirin dosing does not explain the disparate outcome results. In addition, the Advisory Committee members found no evidence to establish a reasonable link, and they uniformly rejected the hypothesis that aspirin dose affects the heterogeneity of outcomes in PLATO. Methods: Additional evidence driven from the FDA review on aspirin dose and PLATO outcomes is reassessed. Results: The wide distribution of outcomes differing from country to country, and inconsistency in European data despite identical aspirin doses, preclude the acceptance of the hypothesis that aspirin affects PLATO outcomes in general or adversely impacts the benefit of ticagrelor in the US cohort in particular. Differences in primary site monitoring by the study sponsor in most countries versus a third-party CRO in the USA represent an alternative explanation and deserve further attention. Conclusions: There is no solid evidence that aspirin dose affects outcomes after ticagrelor. Reevaluation of the overall endpoint differences, especially focusing on mortality, driven from sponsor-monitored sites versus outcomes observed by independent CROs is neccessary. The practice of self-monitoring in pivotal indication-seeking clinical trials should be avoided in the future.
- Clinical trial
- Site monitoring
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Pharmacology (medical)