The secondary endpoints were MI, stent thrombosis, revascularization, cardiogenic death, and all-cause mortality. Heterogeneity of the 8 articles[5–9,13,26,29] reporting MI was not detected (I2 = 0%; P = .804); a fixed-effects model was used for analysis. A total of 265 of 14,816 patients (1.79%) in the PPI group, and 391 of 15,684 patients (2.49%) in the placebo group experienced an MI. The rates of MI in the PPI and placebo groups were not significantly different [OR 1.03 (95% CI 0.87–1.22); P = .724; Fig. 5].
Few meta-analyses have assessed the impact of PPIs on antiplatelet drugs, but they selected studies that included patients on aspirin or clopidogrel monotherapy or studies that did not restricted eligibility to patients with coronary heart disease.[16–19] Patients with a high risk of MACE are often given aspirin and clopidogrel combination therapy. The concomitant use of PPIs by those patients may multiply their occurrence of MACE compared with patients on aspirin or clopidogrel monotherapy and PPIs. However, meta-analyses of the outcomes of aspirin, clopidogrel, and PPIs combination therapy are lacking. This analysis found that the concomitant use of aspirin, clopidogrel, and PPIs decreased the rate of GI bleeding but increased the rates of MACE, stent thrombosis, and revascularization. There were no differences in the risks of MI, cardiogenic death, and all-cause mortality.
Previous studies found that when DAPT and PPIs were used in combination, the risks of MACE, stent thrombosis, and revascularization were increased.[7,9] PPIs inhibit gastric acid secretion, which increases the gastric pH and can alter the pharmacokinetics of aspirin. This might account for a decline in bioavailability and therapeutic effects of combination therapy with aspirin and PPIs.[10,11]
Another underlying mechanism involves interaction of metabolic pathways that requires CYP enzymes. Clopidogrel is a prodrug that undergoes CYP-dependent metabolic transformation to generate its active metabolite.[12–15] CYP2C19 is the predominant enzyme in this conversion, but CYP3A4/5, CYP2B6, and CYP1A2/1 may be involved. PPIs are also metabolized by the CYP enzyme system, but different PPIs require different isoenzymes. Omeprazole/esomeprazole is metabolized by CYP2C19 to 5-hydroxyomeprazole, which is converted to 5-hydroxyomeprazole sulfone by CYP3A4. Lansoprazole is metabolized by CYP2C19 and CYP3A4 to 5-hydroxy lansoprazole, lansoprazole sulfone, or lansoprazole sulfide. Pantoprazole is metabolized by CYP2C19 and CYP3A4 to hydroxy pantoprazole or pantoprazole sulfone. Rabeprazole is primarily metabolized nonenzymatically, and a portion is metabolized by CYP2C19.[31,32] The interaction of clopidogrel and PPIs thus involves competitive inhibition.[12–15] In patients carrying hypofunctional CYP2C19 alleles, the active metabolites of clopidogrel and platelet inhibition are significantly decreased, and combination therapy might not effectively reduce the occurrence of MACE. Patients with genetic polymorphisms involving hypofunctional CYP2C19 alleles might benefit more from DAPT–PPI combination therapy with clopidogrel and rabeprazole rather than one of the other PPIs, or from ticagrelor, a potent antiplatelet drug that is not affected by CYP2C19 polymorphisms.
The limitations of this meta-analysis included the selection of non-RCTs, which are subject to selection bias, confounding bias, and baseline differences of the experimental and control groups. Moreover, PPIs differ in the CYP isoenzymes required for metabolism[31,32] and have different levels of impact on clopidogrel activity.[13–15] But subgroup analyses of PPI–DAPT were not possible because of limited patient data. Consequently, which of the available PPIs is safer when combined with aspirin and clopidogrel could not have been determined.
Grammar consulting and writing assistance were kindly provided by Ying Liu and Xinhui Mao. Statistical consultation was kindly provided by Yun Yang, PhD.
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