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

Abstract

Summary Background Ticagrelor and prasugrel are third‐generation oral P2Y12 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 P2Y12 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 P2Y12 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 P2Y12 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 P2Y12 inhibitors also increased the risk of non‐CABG major bleeding (RR 1.18, 95% CI 1.08‐1.28). Conclusion Third‐generation P2Y12 inhibitors were associated with increased risk of GIB and non‐CABG major bleeding when compared with clopidogrel.

The risk of dyspnea in patients treated with third-generation P2Y12 inhibitors compared with clopidogrel: a meta-analysis of randomized controlled trials

“…Bleeding, as the most common side effects of thirdgeneration oral P2Y 12 inhibitors, has been well evaluated in previous studies [5][6][7]. Dyspnea was another important side effect, which was commonly reported in thirdgeneration oral P2Y 12 inhibitors users.…”

No Differences in Gastrointestinal Bleeding Risk among Clopidogrel-, Ticagrelor-, or Prasugrel-Based Dual Antiplatelet Therapy

“…Our results support the importance of gastrointestinal events because more than one in four patients treated with DAPT (29.5%) had at least one gastrointestinal event. The most common gastrointestinal event was anemia, which may have a negative effect on cardiovascular disease and has not been analyzed in previous reports [15].…”

“…Similarly, in the Study of platelet inhibition and patient outcomes (PLATO trial) [10], compared with the clopidogrel group, the ticagrelor group had a higher risk of major bleeding that was not related to coronary artery bypass graft. However, subsequent studies have yielded contradictory results, with an increased risk of bleeding with prasugrel and ticagrelor in some of them [9][10][11][12][13][14][15], but no differences between clopidogrel and these new compounds in others [16][17][18][19][20][21][22]. The main limitation of acquiring meaningful comparisons among studies and these antiplatelet agents is the variability in bleeding definitions used [23,24].…”

“…When a standardized definition is used, the differences in bleeding incidence between studies diminishes [25]. Moreover, most studies have used global bleeding as an endpoint and not specifically gastrointestinal bleeding, which is the most frequent event [15].…”

Letter: the risk of gastrointestinal bleeding in patients taking third‐generation P2Y12 inhibitors compared with clopidogrel

“…In addition, the bleeding risk assessment of each patient before using a P2Y 12 inhibitor was not mentioned. Since most previous published studies showed higher bleeding risk with ticagrelor or prasugrel, 2 this may have affected the clinical decision about P2Y 12 inhibitor selection following PCI. In fact, clopidogrel is the most common P2Y 12 inhibitor employed for acute coronary syndrome, especially in older patients and those at high risk of bleeding 5 .…”