Still a dilemma! Are vonoprazan and esomeprazole attenuating the antiplatelet function of clopidogrel when taken concomitantly? A systematic review and meta-analysis

Objective CYP2C19 metabolizes all three drugs—esomeprazole, vonoprazan, and clopidogrel—so it is mostly responsible for their drug interactions. Is this clinically true or just theoretical? This systematic review and meta-analysis aimed to investigate clopidogrel’s effectiveness when taken with one of these drugs concurrently. Methods PubMed, SCOPUS, Web of Science, and Cochrane CENTRAL were searched from inception to February 2023, and eligible randomized controlled trials (RCTs) were chosen. Using VerifyNow P2Y12 and light transmission aggregometry measuring, the inhibition of platelet aggregation (IPA%) was measured. IPA% was pooled in a random effect model. The Cochrane Risk of Bias 2.0 tool (ROB2) was used. Results Nine RCTs involving 550 patients were included, with only 222 healthy individuals and 96 coronary artery disease (CAD) patients randomly assigned to the intervention arm (esomeprazole or vonoprazan). The remaining participants were excluded as they were exposed to different PPIs. Among healthy subgroups, esomeprazole and vonoprazan showed a statistically significant reduction in the mean difference (MD) of IPA% compared to clopidogrel alone ((MD − 8.32; 95% confidence interval (CI) [− 14.13, − 2.51], I 2 = 54%, p -value = 0.005) and (− 21.28; CI [− 29.76, − 12.79], I 2 = 0%, p -value < 0.00001), respectively. However, the CAD subgroup of esomeprazole did not demonstrate statistical significance in IPA% (− 7.47, CI [− 19.98,5.04], I 2 = 86%, p -value = 0.24). Similarly, the poor-metabolizer genotype of the CYP2C19 subgroup for those who were taking esomeprazole was not statistically significant (0.03; CI [− 9.57, 9.63], I 2 = 0%, p -value = 1.00). Conclusion Both vonoprazan and esomeprazole reduce the antiplatelet function of clopidogrel to a certain extent. However, vonoprazan may have a more pronounced impact on attenuating clopidogrel’s antiplatelet function than esomeprazole. Esomeprazole did not significantly reduce IPA% in the poor-metabolizer genotype of CYP2C19. Further RCTs are needed for conclusive evidence on the effect of vonoprazan and esomeprazole on clopidogrel’s function. Trial registration PROSPERO CRD42023428798.