Chronotherapeutic considerations for antiplatelet therapy in cardiovascular risk prevention - A systematic review

Summary: Background: Cardiovascular physiology exhibits circadian rhythms, including a morning surge in platelet reactivity and cardiovascular events. Aligning the timing of antiplatelet therapy with these rhythms may be a simple, cost-effective approach to improve clinical efficacy. This systematic review evaluates the diurnal variability in platelet reactivity among individuals receiving aspirin, clopidogrel, ticagrelor, and prasugrel and explores the potential for timed administration to optimise platelet inhibition and other surrogate cardiovascular markers. Patients and methods: PubMed, Embase, Cochrane Central Register of Controlled Trials, and trial registries (e.g., ClinicalTrials.gov) were searched from 1980 to August 2025 for randomised controlled trials and observational studies in adults investigating morning versus evening dosing or diurnal efficacy. Results: Of 2,340 records, 25 studies were included (17 on aspirin, seven on clopidogrel, one on ticagrelor, and three overlapping with prasugrel). For aspirin, the data showed a tendency that evening administration achieved greater reductions in morning Cyclooxygenase-1 (COX-1)-dependent platelet reactivity in healthy volunteers and cardiovascular disease patients, although there were mixed effects on ambulatory blood pressure. Clopidogrel exhibited diurnal variability, with peaks in Adenosine Diphosphate (ADP)-induced aggregation occurring in the morning, while prasugrel provided more consistent inhibition than clopidogrel or ticagrelor. No studies directly compared evening versus morning dosing for P2Y12-Inhibitors, and clinical outcomes such as major adverse cardiac events were only assessed in one included study. Conclusions: While evening aspirin may enhance chronopharmacological efficacy, the available evidence is limited due to heterogeneity and variable quality. The limited number of studies on agents beyond aspirin highlights a critical research gap, with robust Randomised Controlled Trials needed to evaluate clinical benefits and inform chronotherapeutic strategies.