Toronto, ON - The addition of a proton-pump inhibitor (PPI) to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in acute-MI patients significantly increases the risk of recurrent infarction, a new study has shown [1]. The findings support suspicions that the drug combination diminishes the beneficial effect of the antiplatelet therapy and increases the risk of future events, say researchers.

"Effectively, we're taking a patient who should be getting a benefit from clopidogrel, they have the genetic makeup that allows them to get the benefit, but we're turning them into the equivalent of someone who cannot activate clopidogrel by prescribing selected PPIs," lead investigator Dr David Juurlink (Institute for Clinical Evaluative Science, Toronto, ON) told heartwire. "We're doing this unintentionally, and we're doing it on a massive scale, and we're doing it, quite frankly, without any appreciation of what we're doing."

The study, published online January 28, 2009 in the Canadian Medical Association Journal, showed that while selected PPIs seem to "turn off" the body's natural process of converting clopidogrel into its active form, pantoprazole (Protonix, Wyeth Pharmaceuticals), which does not interfere with clopidogrel's conversion, was not associated with an increased risk of reinfarction.

FDA now has eye on possible interaction

Earlier this week, the Food and Administration (FDA) announced that it was working with Bristol-Myers Squibb and Sanofi-Aventis, the makers of clopidogrel, to further study the effectiveness of the drug in patients taking other medications, particularly PPIs, and in those with genetic variants linked with clopidogrel resistance.

Clopidogrel is a prodrug converted in the liver to its active form by cytochrome P450 isoenzymes, with P450 2C19 playing a particularly important role. Speaking with heartwire, Juurlink said there is evidence suggesting that various PPIs can inhibit P450 2C19, which would alter the effectiveness of clopidogrel and potentially lead to an increased risk of adverse cardiovascular outcomes.

To assess the potential effects of the drug interaction, researchers identified more than 13 000 patients prescribed clopidogrel following an acute MI. Of these, 734 patients were readmitted with MI and 2057 served as event-free controls matched based on age, PCI, and risk score.

Among patients currently prescribed a PPI along with clopidogrel, the risk of reinfarction within 90 days was 27% greater than among those taking clopidogrel only. The risk is limited to those currently taking a PPI and did not extend to pantoprazole, a drug that does not interfere with the conversion of clopidogrel to its active form.

Juurlink noted that recent guidelines issued by the American Heart Association, American College of Cardiology, and American College of Gastroenterology call for PPI therapy for a majority of patients taking aspirin after MI, including all patients 60 years and older.

"This is important, because patients taking clopidogrel are almost always taking aspirin," he said. "As a result, we're going to end up with millions of people who are taking the combination of clopidogrel and a proton pump inhibitor, and our results suggest that if this is not done with some caution, thousands, perhaps tens of thousands, of recurrent heart attacks could result."

Still, the news is not all bad for patients who need to turn off gastric acid, as they can take an older drug, such as an H2 blocker like Zantac or Pepcid, or pantoprazole, he added.

Speaking with heartwire, Dr Dan Roden (Vanderbilt University School of Medicine, Nashville, TN), who was not part of the Canadian analysis, said that the interaction between clopidogrel and PPIs was addressed by several abstracts presented at the most recent AHA meeting.
 
"I think it's evident there are people out there in which this is a big deal," he said. "The basic science is there, and the fact that CYP 2C19 affects cardiovascular outcomes is also there, so it's not rocket science to think there are patients being treated with clopidogrel with the expectation they're going to be better, but they're not because they're also getting a drug that inhibits its bioactivation."
 
Despite the results from this and other studies, Roden said a randomized trial would still be the best way to prove a clinically significant interaction and to estimate its severity, although he doubts one will be ever done.
 
"I believe the results, but this isn't a very strong paper to prove it," he added. "The problem here is whether the increased MI rates observed are a result of the drug interaction or because sicker patients tend to end up on proton-pump inhibitors. The finding that the most potent CYP 2C19 inhibitor has the greatest effect makes one think this is a real result."

Last week it was announced that Cogentus Pharmaceuticals (Palo Alto, CA) halted its COGENT 1 trial, a 4000-patient study testing a single-pill combination of clopidogrel and omeprazole to reduce the incidence of GI side effects. The company has filed for bankruptcy.