Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis

Abstract

BackgroundDual antiplatelet therapy is the standard of care after coronary stent placement but increases the bleeding risk. The effects of proton pump inhibitors (PPIs) on clopidogrel metabolism have been described, but the clinical significance is not yet definitive. We aimed to do an updated meta-analysis comparing outcomes in patients receiving clopidogrel with and without PPIs.MethodsWe systematically searched PubMed, Scopus and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs) and controlled observational studies in patients taking clopidogrel stratified by concomitant PPI use. Heterogeneity was examined with the Cochran Q test and I2 statistics; p values inferior to 0.10 and I2 >25% were considered significant for heterogeneity.ResultsWe included 39 studies with a total of 214 851 patients, of whom 73 731 (34.3%) received the combination of clopidogrel and a PPI. In pooled analysis, all-cause mortality, myocardial infarction, stent thrombosis and cerebrovascular accidents were more common in patients receiving both drugs. However, among 23 552 patients from eight RCTs and propensity-matched studies, there were no significant differences in mortality or ischaemic events between groups. The use of PPIs in patients taking clopidogrel was associated with a significant reduction in the risk of gastrointestinal bleeding.ConclusionsThe results of our meta-analysis suggest that PPIs are a marker of increased cardiovascular risk in patients taking clopidogrel, rather than a direct cause of worse outcomes. The pharmacodynamic interaction between PPIs and clopidogrel most likely has no clinical significance. Furthermore, PPIs have the potential to decrease gastrointestinal bleeding in clopidogrel users.

Pretreatment with a combination of ligustrazine and berberine improves cardiac function in rats with coronary microembolization

“…The present study showed that, in addition to its antiplatelet effects, clopidogrel showed anti-inflammatory activity; this was evidenced by the decreased serum levels of TNFα, ICAM-1, and RANTES, and heart tissue expression of TNFα, ICAM-1, IL-1β, and RANTES proteins. These findings were consistent with previous studies [22][23][24][25] and indicated that the cardioprotective effects of clopidogrel observed in the present study may be, in part, attributed to these anti-inflammatory effects.…”

How May Proton Pump Inhibitors Impair Cardiovascular Health?

“…Cardoso and co-workers performed a similar meta-analysis [41] and came to similar findings as Melloni and colleagues. They emphasize that the association between adverse outcomes and concomitant PPI-clopidogrel use persists in patients taking PPIs (rabeprazole or pantoprazole).…”

Effective and safe proton pump inhibitor therapy in acid-related diseases – A position paper addressing benefits and potential harms of acid suppression

“…Further, the only prospective study (the COGENT trial) demonstrated that omeprazole significantly reduces the rate of composite GI events but did not show any increase in the composite CV events in patients at high CV risk [277]. Additionally, a recent meta-analysis [278], while confirming that the pharmacodynamic interaction between PPI and clopidogrel has no clinical significance, actually suggests that PPIs are a marker of increased CV risk in patients taking clopidogrel rather than a direct cause of worse outcomes. Nevertheless, PPIs that lack inhibition of CYP2C19 (i.e., pantoprazole or rabeprazole) might be preferred in clopidogrel users [276].…”

“…However, current evidence shows that, while concomitant use of some PPIs with clopidogrel does attenuate the antiplatelet effect of clopidogrel, this effect is unlikely to be clinically relevant [276, 278, 406, 407]. Conversely, denying PPIs to patients at GI risk would result in increased life-threatening GI bleeding [277, 408, 409].…”