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Clopidogrel Plus Proton-Pump Inhibitors
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, Chief of Cardiology, University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer. This article originally appeared in the April 2009 issue of Clinical Cardiology Alert. It was edited by Ethan J. Weiss, MD. Dr. Weiss is Assistant Professor of Medicine, Division of Cardiology and CVRI, University of California, San Francisco; he reports no financial relationships relevant to this field of study.
Source: Ho PM, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301:937-944.
Since the risk of gastrointestinal bleeding is increased when clopidogrel is added to aspirin therapy in patients with acute coronary syndromes (ACS), many prescribe proton-pump inhibitors (PPIs) to reduce this risk. However, mechanistic studies suggest that PPIs may reduce the effectiveness of clopidogrel. Thus, Ho et al used a Veterans Affairs national cohort to compare rates of mortality and rehospitalization for ACS between patients taking clopidogrel alone vs. clopidogrel plus PPIs. This was a retrospective cohort study of all patients with ACS discharged from any VA hospital beginning in 2003 and ending in 2006 who were prescribed clopidogrel and who filled the prescription; pharmacy refill data was used to see if the patient was on PPIs over the course of the study. Of the 8,205 identified patients on clopidogrel, 64% were given PPIs. The latter patients were older and had more co-morbidities. During a median follow-up of 521 days, 21% were re-admitted for ACS without PPIs vs. 30% on PPIs (OR 1.25, 95% CI 1.11-1.41). Also, mortality was significantly higher in the clopidogrel plus PPI group (20% vs. 17%, p = 0.001). Among those prescribed a PPI, 60% were given omeprazole and 37% were prescribed more than one PPI. Use of PPIs without clopidogrel in ACS patients was not associated with increased adverse outcomes. Ho et al concluded that the use of clopidogrel plus PPIs after discharge for ACS was associated with an increased risk of adverse outcomes vs. patients on clopidogrel alone.
The strength of this longitudinal observational study was that drug use was assessed over the duration of follow up, not just at hospital discharge, thus strengthening the conclusion that concomitant PPI and clopidogrel use after ACS leads to increased subsequent coronary events. Sensitivity analyses in this study also showed a consistent effect across subgroups. The most common event was re-hospitalization for ACS, which substantiates the mechanistic theory that PPIs affect clopidogrel's effectiveness as a platelet aggregation inhibitor. The presumed mechanism is that both drugs are metabolized by the liver CYP2C19 cytochrome P450 isoenzyme; mechanistic studies have demonstrated this drug interaction. Poly-morphisms of the CYP2C19 gene have also shown reduced effectiveness of clopidogrel and increased cardiovascular events. Although platelet aggregation studies were not done in this large observational study, the results certainly make sense based upon what we know about these drugs.
Until more definitive studies are done, it would seem prudent to not use PPIs prophylactically for dual anti-platelet therapy but reserve it for those with other important indications. Alternatively, one could use hydrogen-blocking drugs, which do not use the P450 system, or pantoprazole, which also does not use the P450 system. Another confounding issue is that omeprazole is now available over the counter, so patients will need to be advised about indiscriminant use of this drug. Finally, if the new thienopyridine prasugrel is approved by the FDA, it may avoid this issue because it does not use the P450 system.