Safety and efficacy of clopidogrel reloading in patients on chronic clopidogrel therapy presenting with ACS - a systematic review and meta-analysis

Background Clopidogrel is a cornerstone of pharmacological therapy for patients with acute coronary syndrome (ACS). Benefits of an initial loading dose in antiplatelet-naive patients are well-established, however the role of clopidogrel reloading in patients already on chronic clopidogrel therapy remains uncertain. This strategy raises concerns about balancing potential ischemic benefits against the increased risk of bleeding. Purpose This meta-analysis aims to evaluate the safety and efficacy of clopidogrel reloading in ACS patients on chronic clopidogrel therapy. Methods A systematic search of PubMed, Embase, and Cochrane central was conducted in Feb 2025 to identify studies evaluating the efficacy and safety of clopidogrel reloading in patients on chronic clopidogrel therapy presenting with ACS vs those who did not undergo reloading. Patients not on chronic clopidogrel therapy were excluded. Outcomes assessed were in-hospital mortality and major bleeding. Statistical analysis was performed using the R software version 4.4.2. Random-effects model was applied using the restricted maximum-likelihood method to calculate risk ratios (RRs) with 95% confidence intervals (CI), and heterogeneity was quantified using I² statistics. Results Four studies were selected, including 53,655 patients (reload group: 20,813 [38.8%], non-reload group 32,824 [61.2%]). Compared to those who did not receive reloading, those who did had significantly increased risks of major bleeding (RR 1.14; 95% CI 1.071-1.20, I2=0%) and in-hospital mortality (RR 1.23; 95% CI 1.11-1.36, I2=0%). Conclusion Clopidogrel reloading in patients on chronic clopidogrel therapy presenting with ACS is associated with an increased risk of major bleeding and in-hospital mortality.