Registry Fails to Find Adverse PPI-Clopidogrel Interaction

ORLANDO — Patients with coronary disease who combine clopidogrel with a proton-pump inhibitor risk clinical consequences that remain unclear but are of concern, several reports indicate.

The most recent report, on 535 patients from the University of Pittsburgh who received clopidogrel and aspirin following placement of a coronary stent, showed that the combined rate of death, myocardial infarction, or need for revascularization during the year following stenting was about the same regardless of whether patients also took a proton-pump inhibitor (PPI), Dr. Jose P. Ramirez reported at the annual meeting of the American College of Cardiology.

The finding that coadministration of a PPI in patients with coronary artery disease who also required clopidogrel did not result in a significantly increased rate of adverse coronary events contrasts with findings from several other reports over the past 6 months that found a significant, adverse interaction between the two drugs. Perhaps most notable was a study published in March that reviewed more than 8,000 patients with acute coronary syndrome treated at any of 127 Veterans Affairs hospitals. The analysis found that patients treated with a PPI on top of their clopidogrel had a significant 25% increased risk of death or rehospitalization for acute coronary syndrome during a median follow-up of 17 months (JAMA 2009;301:937–44).

The possible danger from coadministration of a PPI and clopidogrel arises because clopidogrel is a prodrug the liver converts to an active form with a cytochrome P450 enzyme, 2C19. Recent findings show that all PPIs except pantoprazole inhibit 2C19 and thus blunt clopidogrel's antiplatelet efficacy.

“The reason we're seeing studies on either side of the fence is because of confounding and ascertainment bias,” said Dr. Elliot M. Antman, director of the cardiac unit at Brigham and Women's Hospital in Boston. “Every one of these studies tried to get at this by triangulating, not in a prospective, randomized study. You don't know if the patients took the [PPI] drug they were prescribed, and there may have been selection biases for patients at increased risk of bleeding” who were prescribed a PPI, he said in an interview. “Given these limitations, it's almost like the flip-flopping on drug-eluting coronary stents, bad versus good.”

The new analysis reported by Dr. Ramirez included 535 patients who received a coronary stent at the University of Pittsburgh Medical Center and were entered into the National Heart, Lung, and Blood Institute's Dynamic Registry of coronary stent recipients during 2004 and 2006. Among these patients, 138 (26%) also received prescriptions for a PPI. Their average age was 63, and a third were women. About three-quarters underwent an elective stenting procedure, and slightly more than half received a drug-eluting coronary stent.

During the year following stent placement, the combined rate of death, myocardial infarction, or need for coronary revascularization—the primary end point for this analysis—was 23% in the patients prescribed a PPI and 24% in those who did not receive a prescription, a difference that was not statistically significant, reported Dr. Ramirez, a cardiologist at the University of Pittsburgh. The results were similar among the subgroups getting drug-eluting stents and those receiving bare-metal stents. The data available did not include information on what types of PPIs were prescribed.

Given the current uncertainty about the effect of administering a PPI to patients, “I'd go back to the ACC, American Heart Association, American College of Gastroenterology statement from last October,” said Dr. Antman, who was a member of the guideline committee (Circulation 2008;118:1894–909). “We said focus use of gastrointestinal-protective medications on patients in whom the risk of gastrointestinal bleeding is high, and not use these medications in a blanket fashion in all patients.”

His second, personal suggestion was that when treatment of a patient on clopidogrel with a PPI is necessary, there is “biologic and pharmacologic reason to believe the interaction might be less significant” with pantoprazole, although Dr. Antman cautioned that he “does not want to be seen as advocating one drug over another.”

He added that “in theory,” the potential interaction with a PPI is less likely to be an issue for prasugrel, a second-generation drug similar to clopidogrel. That's because prasugrel does not require activation by a hepatic enzyme. Analysis of how prasugrel-treated patients were affected by concurrent use of PPIs is now underway in a post hoc analysis of data from the pivotal prasugrel trial, said Dr. Antman, one of the primary researchers involved in assessing the drug. A Food and Drug Administration advisory committee recommended approval of prasugrel last February, but as of mid-May, the agency had not issued its approval decision.