Further information: Medical Treatment of Unstable Angina, Acute Non–ST-Elevation Myocardial Infarction, and Coronary Artery Spasm (see p937) and Percutaneous Coronary Intervention for Unstable Coronary Artery Disease (see p1005) from Cardiovascular Medicine, 3rd Edn*

In August of 2009, a summary of an article published in JAMA [1] was posted on this website [2].  The article addressed the possibility of adverse effects occurring in patients who used clopidogrel and proton pump inhibitors (PPIs) together, with the primary concern being that the effectiveness of clopidogrel could be reduced, leaving patients at risk of thrombotic events.  During the American Heart Association 2009 Scientific Sessions in Orlando, FL, November 14–18, 2009, the Food and Drug Administration (FDA) issued a new public-health warning [3] that reinforced the concern regarding adverse reactions.  Several clinical investigators who were interviewed in Orlando expressed surprise over the FDA’s newly issued warning, citing several randomized trials whose results had not shown an indication of adversity.  The statement by the FDA recommended that patients taking clopidogrel should consult their healthcare provider before also taking a PPI, such as omeprazole.  An article [4] and editorial [5] recently published in Circulation are abstracted and cited here and add additional information to the controversy.

In view of the controversy surrounding the safety issues for patients using clopidogrel and a PPI together, investigators conducted a retrospective study [4] conducted from three large databases in order to address study design issues in an effort to determine whether a higher rate of adverse outcomes occurred in patients taking clopidogrel and PPIs versus patients taking clopidogrel alone.  Included in the current study were patients enrolled in the following programs: the Provincial Healthcare System funded by the British Columbia government; the Pharmaceutical Assistance Contract for the Elderly in Pennsylvania; and the Pharmaceutical Assistance to the Aged and Disabled in New Jersey.  In all, there were 64,561 patients of 65 years of age and over in the  cohort who underwent percutaneous coronary intervention or hospitalization for acute coronary syndrome between 2001 and 2005, and the results of the study showed a modest increase in risk of hospitalization or death from myocardial infarction (MI), but with wide confidence intervals and no substantial or statistically significant clopidogrel-PPI interaction, leading the authors to believe that the studies using conventional adjustment may not have adequately accounted for confounding in this treatment group.  In this study, the investigators employed a more extensive confounding adjustment and verified that after adjustment, the PPI users were not significantly more likely to be at increased risk for MI or death, and not likely to exceed a 20% risk increase.

In an editorial [5] that accompanied this article, the author studied the entire body of evidence and concluded that while he believed there was no doubt that a pharmacological interaction existed, the issue was not one of clinical relevance.  The majority of patients are not threatened by the interaction.  However, there are unidentifiable patients who would be adversely affected by the combined use of clopidogrel and a PPI because of their genetic profiles, other currently taken drugs, or with other comorbidities, and therefore, until further information can be obtained, caution in prescribing the use of the two drugs together should be exercised.

[1] Ho M, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary symptoms. JAMA 2009;301:937-44

[2] Risk of Adverse Outcomes Associated with Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following ACS. http://cardiovascular-medicine.com/?p=178

[3] Food and Drug Administration. Public-health advisory: Updated safety information about a drug interaction between clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed at Prilosec and Prilosec OTC). http://www.fda.gov/Drugs/drugsafety/publichealthadvisories/ucm190825.htm November 17, 2009

[4] Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009;120:2322-29

[5] Juurlink DN. Proton pump inhibitors and clopidogrel: putting the interaction in perspective. Circulation 2009;120:2310-12