Systematic review with meta‐analysis: the risk of gastrointestinal bleeding in patients taking third‐generation P2Y₁₂ inhibitors compared with clopidogrel

Summary Background Ticagrelor and prasugrel are third‐generation oral P2Y 12 receptor antagonists with rapid onset and pronounced platelet inhibition. However, higher overall bleeding rates have been reported for these agents when compared with clopidogrel. Aim To compare the risk of gastrointestinal bleeding (GIB) among users of third‐generation P2Y 12 inhibitors with clopidogrel. Methods We systematically searched for published randomised controlled trials of ticagrelor or prasugrel versus clopidogrel until September 2018. The primary outcome was the risk of GIB among users of third‐generation P2Y 12 inhibitors when compared to clopidogrel, expressed as risk ratio (RR) and 95% confidence interval (CI). The rates of non‐coronary artery bypass graft (CABG) major bleeding, life‐threatening bleeding, fatal bleeding, and intracranial bleeding were analysed as secondary outcomes. Results Forty‐one studies were included in the analysis of non‐CABG major bleeding, of which 12 were included in the analysis of GIB including 58 678 patients. Third‐generation P2Y 12 inhibitors were associated with higher risk of GIB as compared with clopidogrel (RR 1.28, 95% CI 1.13‐1.46). The findings were consistent for upper (RR 1.32, 95% CI 1.05‐1.67) and unspecified GIB (RR 1.25, 95% CI 1.01‐1.53), but not lower GIB (RR 1.25, 95% CI 0.95‐1.65). Subgroup analysis showed higher GIB risk in prasugrel studies (RR 1.40, 95% CI 1.10‐1.77) than in ticagrelor studies (RR 1.15, 95% CI 0.94‐1.39). Third‐generation P2Y 12 inhibitors also increased the risk of non‐CABG major bleeding (RR 1.18, 95% CI 1.08‐1.28). Conclusion Third‐generation P2Y 12 inhibitors were associated with increased risk of GIB and non‐CABG major bleeding when compared with clopidogrel.