Faculty Peer Reviewed
Recent publications have described a potential drug interaction between clopidogrel (Plavix®) and proton pump inhibitors (PPIs). Several retrospective studies have concluded that the use of PPIs can lower the effectiveness of clopidogrel and as a result, increase the possibility of cardiovascular events. Limited data from prospective trials have yet to show a clinical significance from this potential interaction. The Food and Drug Administration (FDA) released an early communication about the ongoing safety review of clopidogrel and omeprazole on January 26, 2009. Over the next 10 months, the FDA worked with Sanofi-Aventis/Bristol-Myers Squibb (the manufacturers of clopidogrel) to investigate this potential interaction. The follow-up report was released by the FDA on November 17, 2009, warning to avoid concomitant use of clopidogrel and omeprazole.1 Subsequently, on December 10, 2009, a large, multicenter, observational study found no conclusive evidence of a clinically relevant interaction between PPIs and clopidogrel.6
Clopidogrel is a pro-drug that is activated only after metabolism via the cytochrome P450 system (mainly with the isoenzyme CYP2C19). It carries FDA approved indications for anti-platelet therapy post- myocardial infarction (MI), post-stroke and for peripheral artery disease. The use of PPIs is mainly for stress ulcer prophylaxis, treatment of gastrointestinal bleeds and acid reduction in gastroesophageal reflux disease; however there are no specific guidelines for the use of gastroprotective agents (like PPIs) in patients receiving clopidogrel. Certain PPIs are known to inhibit liver enzymes, including CYP 2C19. This inhibition can decrease the activation of clopidogrel, lowering its efficacy and thus increasing the risk of cardiovascular events. Omeprazole is known to be one of the strongest inhibitors of CYP2C19. 2
Juurlink et al. performed a retrospective case-control study that evaluated 734 post-MI patients (matched with controls) who were discharged on clopidogrel and a PPI.3 The combination of these agents was associated with a 27% increase for readmission for MI (odds ratio 1.27) versus the controls (clopidogrel only). Another retrospective cohort study by Ho et al examined 8,205 post MI/unstable angina patients who were readmitted for acute coronary syndrome or died.4 This study found that 30% of these patients were currently on clopidogrel + PPI versus 21% who were on clopidogrel alone. It was noted in both studies, however, that patients in the clopidogrel + PPI group had more co-morbid diseases such as diabetes, heart failure and/or renal insufficiency. This illustrates the difficulties of controlling for confounding factors in retrospective studies.
Early prospective trials from TRITON-TIMI 38 did not show a clinically relevant interaction between clopidogrel and PPIs.5 The primary endpoints for this randomized study were a composite of cardiovascular death, myocardial infarction, or stroke in patients taking prasugrel vs. clopidogrel. Post-hoc analysis showed that 33% of enrolled patients were on a PPI at randomization. No association was found between PPI use and risk of primary endpoint in either group.
The COGENT trial was a randomized, double-blind, parallel group, phase 3 trial comparing the safety of clopidogrel + omeprazole (combination product) vs. clopidogrel alone. Despite early termination (due to sponsor bankruptcy), the early data from 3,627 patients (mean follow-up = 133 days) did not show any signs of increased cardiovascular events in the clopidogrel + omeprazole group. Although both of these prospective studies have limitations, they may offer reassurance that there is no clinically relevant interaction between clopidogrel and PPIs.
However, new pharmacokinetic data from Sanofi-Aventis/Bristol-Myers Squibb revealed a 47% reduction in anti-platelet activity when clopidogrel is given with omeprazole.1, 6 Anti-platelet activity was measured by vasodilator-stimulated phosphoprotein (VASP) phosphorylation testing. Separating the administration times (12 hours apart) did not reduce this drug interaction. As a result, the FDA issued a follow-up to the early communication on Nov. 17, 2009 warning to avoid concomitant use of clopidogrel and omeprazole. The updated labels for clopidogrel will contain details of this drug interaction.
The FDA warnings are summarized below:1
- The concomitant use of clopidogrel with omeprazole should be avoided. Patients receiving these interacting medications may not receive the full anti-platelet effect of clopidogrel.
- Separating the administration times of clopidogrel and omeprazole does not reduce this drug interaction.
- The current warnings pertain only to omeprazole and esomeprazole (the S-enantiomer of omeprazole) and other inhibitors of CYP2C19. At this time, there is insufficient data to conclude that other proton pump inhibitors interact with clopidogrel.
- Histamine 2 receptor antagonists (H2RA’s) are not known to interact with clopidogrel (except cimetidine). These agents can be used as alternatives for acid reduction.
- Health care providers are highly encouraged to ask patients about over-the-counter medications because both omeprazole and cimetidine are available commercially without a prescription.
On Dec. 10, 2009, a subsequent study performed by Rassen et al7 evaluated the potential of an increased risk of adverse cardiovascular events among patients who took clopidogrel versus those who also concomitantly used PPIs. Patients were evaluated in 3 cohorts based on geographical location and baseline characteristics were adjusted for confounding variables by applying a high-dimensional propensity score (hd-PS). Investigators evaluated the risk of primary event occurring in all PPIs together with clopidogrel and then specifically assessed omeprazole and pantoprazole with clopidogrel to evaluated aggregate versus agent specific interactions with clopidogrel. A total 18,565 (of 64,561 patients) were evaluated and those who survived 7 days after percutaneous coronary intervention and were prescribed clopidogrel were enrolled in the study. Although a slight increased risk of MI, hospitalization or death was observed in older patients on dual therapy of a PPI and clopidogrel; the risk was modest and investigators concluded there was no statistically significant PPI-clopidogrel interaction.7 The use of aspirin and over-the-counter medications such as generic omeprazole were not evaluated in the study. Additionally, this study only included those 65 years or older, so any modest increase risk of an event occurring can only be applied to older patients. The data collected for patients’ drug usage were based on pharmacy claims data which may not be a true indicator of a patient’s actual drug usage.
The potential interaction between PPIs and clopidogrel is still currently under investigation. Despite conflicting conclusions between several observational and prospective studies, health care providers are encouraged to re-evaluate concomitant use of PPIs (especially omeprazole) with clopidogrel and adhere to the FDA warnings as closely as possible.
- During the publication of this manuscript, two additional studies were published in the medical literature. The first was a retrospective cohort study using automated data from 20,956 patients hospitalized for myocardial infarction, coronary artery revascularization or unstable angina.8 The results showed a reduced incidence of gastroduodenal bleeding with clopidogrel and omeprazole with no increase in serious cardiovascular disease. The second was an observational, retrospective study that included 588 consecutive patients undergoing coronary stenting. Primary outcomes of cardiac death or nonfatal myocardial infarction were not significantly different in clopidogrel plus omeprazole group and in clopidogrel only group after 1 year.9
Peer reviewed by John Papadopoulos, B.S., Pharm D., Pharmacology Section Editor, Cinical Correlations
Image courtesy of Wikimedia Commons user Trounce
1. Food and Drug Administration. Public Health Advisory: Updated Safety Information about a drug interaction between Clopidogrel Bisulfate and Omeprazole. http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm190825.htm. Accessed on November 20, 2009
2. Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150mg clopidogrel maintenance dose: The PACA (proton pump inhibitors and clopidogrel association) prospective randomized study. J Am Coll Cardiology 2009;54:149-53
3. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713-8
4. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-44
5. O’Donoghue M, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton pump inhibitor: an analysis of two randomized trials. Lancet 2009;374:989-97
6. Gilard M, Arnaud B, Cornily JC, et al. Influence of Omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA study. J Am Coll Cardiol 2008 Jan 22;51(3):256-60
7. Rassen JA, Choudhry NK, Avorn J, et al. Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome. Circulation 2009;120:1322-2329
8. Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors. Ann Intern Med 2010;152:337-345
9. Zairis MN, Tsiaousis GZ, Patsourakos NG, et al. The impact of treatment with omeprazole on the effectiveness of clopidogrel drug therapy during the first year after successful coronary stenting. J Cardiol 2010;26(2):e54-e57.