Efficacy and safety of off-label low-dose compared with standard-dose antiplatelet agents in patients with coronary heart disease: a meta-analysis

BACKGROUND: To compare the efficacy and safety of off-label low-dose versus standard-dose antiplatelet agents in coronary heart disease (CHD) patients, focusing on the evidence gap in comparisons of low-dose versus standard-dose ticagrelor and prasugrel. METHODS: PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure and Wanfang databases were searched up to 11 May 2025 for randomised controlled trials. Study quality was assessed using the Cochrane Risk of Bias 2.0 tool. A meta-analysis was performed, with relative risk (RR) and 95% CI as the effect estimates. Subgroup analyses were performed stratified by antiplatelet agent type, ethnic region, treatment duration and CHD subtype. RESULTS: A total of 22 randomised controlled trials, involving 7486 patients, met the study criteria. Among them, 92.09% were Asian, and 63.63% of the included studies exclusively enrolled acute coronary syndrome patients. All patients received the dual antiplatelet therapy (aspirin combined with a low or standard dose of P2Y12 receptor antagonist), mainly with low-dose prasugrel and ticagrelor. Off-label low-dose antiplatelet agents significantly reduced myocardial infarction (MI) (RR 0.75, 95% CI 0.58 to 0.97) and minimal bleeding risks (RR 0.64, 95% CI 0.50 to 0.82) compared with standard doses, with comparable risks for other ischaemic and bleeding events. Compared with standard-dose clopidogrel, they significantly reduced MI risk (RR 0.71, 95% CI 0.54 to 0.93) but increased overall (RR 1.40, 95% CI 1.11 to 1.77) and minor bleeding risks (RR 1.86, 95% CI 1.02 to 3.38). Compared with standard-dose prasugrel or ticagrelor, they demonstrated comparable ischaemic risks and significantly reduced overall and minimal bleeding risks. All other subgroup analyses were consistent with the overall findings. CONCLUSION: Off-label low-dose antiplatelet therapy reduces the risks of MI and minimal bleeding. It surpassed standard-dose clopidogrel and offered lower bleeding risks than prasugrel or ticagrelor, thus representing an effective secondary prevention strategy for Asian CHD. PROSPERO REGISTRATION NUMBER: CRD42023438376.