RCT Data Suggest No Ischemic Risks in Patients Receiving Clopidogrel and Proton-Pump Inhibitor

July 08, 2015

MIAMI, FL — An updated meta-analysis has shown that individuals who took a proton-pump inhibitor (PPI) in addition to clopidogrel had a significantly increased risk of adverse cardiovascular events, including all-cause mortality, MI, acute coronary syndrome, cerebrovascular accident, stent thrombosis, and the need for revascularization[1].

The researchers, however, do not believe this to be the full story.

When the group excluded nonrandomized observational studies and restricted their analyses to eight randomized, controlled trials alone, the concomitant use of a PPI with clopidogrel was not associated with an increased risk of adverse cardiovascular events when compared with a propensity-score matched (PSM) group of patients receiving clopidogrel alone.

"The results of our study suggest that the previously reported interaction between clopidogrel and proton-pump inhibitors may be dependent on selection bias and different patient baseline characteristics, as a clinically significant effect was not observed in a randomized/propensity score matched population," report Dr Rhanderson Cardoso (University of Miami/Jackson Memorial Hospital, FL) and colleagues. Based on their analysis of the data, they believe "PPIs are a marker of increased risk rather than a direct cause of worse outcomes."

The results of the study are published online June 30, 2015 in Open Heart.

Concerns Raised 6 Years Ago

As reported by heartwire , the US Food and Drug Administration issued a warning about the potential interaction between clopidogrel and PPIs, specifically omeprazole and esomeprazole. PPIs are used to decrease the risk of upper-GI hemorrhage in patients receiving antiplatelet therapy.

The potential interaction between clopidogrel and PPIs—clopidogrel activation depends on cytochrome P450, which can be inhibited by PPIs, explain Cardoso and colleagues—has been hotly debated and studied in randomized, clinical trials, including the COGENT study. To date, the randomized clinical trials have not shown an increased risk of ischemic events among patients treated concomitantly with clopidogrel and PPIs, but observational studies have suggested an interaction.

In this updated meta-analysis, the researchers included 39 studies with 214,851 patients. Of these, 73,731 received clopidogrel and a PPI. In the main analysis, the combination of clopidogrel plus a PPI was associated with a statistically significant increase in all-cause mortality and ischemic events, including MI and acute coronary syndrome, among others, when compared with those who received clopidogrel alone. The concomitant use of PPIs with clopidogrel did result in a significant 60% reduction in GI bleeding.

In the subanalysis including only randomized controlled trials and PSM patients, the researchers identified 23,552 patients, of whom 11,770 received the combination of clopidogrel and a PPI. In this analysis, the combination was not associated with any increased risk of ischemic events or all-cause mortality. Like the main analysis, GI bleeding was significantly reduced—in this case by 76%—in those who received clopidogrel and a PPI.

Based on their findings, the researchers conclude the interaction between PPIs and clopidogrel observed in platelet aggregation studies has no clinical significance. Instead, they believe the "patients who are prescribed PPIs have a higher burden of comorbidities and thus most likely have an increased risk for adverse cardiovascular events." The group adds that physicians may "consider proton-pump inhibitors for patients receiving clopidogrel, as there is a benefit in terms of reduced gastrointestinal bleeding."

The authors declare no relevant financial relationships.

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