How Should We Manage Drug Interactions Between Clopidogrel and Proton-Pump Inhibitors?

Jenny A. Van Amburgh, PharmD, CDE

Disclosures

September 22, 2009

Question

What is the best practice intervention for patients on both clopidogrel and proton-pump inhibitors (PPIs)?

Response from Jenny A. Van Amburgh, PharmD, CDE
Associate Clinical Professor, School of Pharmacy, Northeastern University, Boston, Massachusetts; Director of the Clinical Pharmacy Team and Residency Director, Harbor Health Services, Inc., Boston, Massachusetts

According to a 2007 survey, clopidogrel is the sixth most commonly dispensed medication in the United States.[1] Indicated to reduce the rates of antithrombotic events in patients with a recent cardiovascular event, clopidogrel plays an integral role in the care of patients after myocardial infarction, stroke, or acute coronary syndrome.[2] To reduce the risk for gastrointestinal bleeding, which can be associated with this drug, clinicians often prescribe a concomitant proton-pump inhibitor (PPI) for high-risk patients. Because of its generic availability and over-the-counter (OTC) status, omeprazole (Prilosec®, Prilosec OTC®) is one of the most widely used and accessible PPIs today.

Recent evidence suggests that certain PPIs reduce the antiplatelet effects of clopidogrel.[3,4,5] Clopidogrel, a prodrug, requires metabolism in the liver via cytochrome P450 (CYP) enzymes. Once activated, clopidogrel blocks platelet aggregation by inhibiting adenosine diphosphate at the P2Y12 receptor. PPIs, such as omeprazole and its S-enantiomer esomeprazole (Nexium®), are thought to inhibit the CYP2C19 enzyme, thus negating the antithrombotic effects of clopidogrel.[6] CYP2C19 also acts as the primary enzyme responsible for determining a patient’s pharmacodynamic response to clopidogrel.[4] The question of how to best care for patients taking both PPIs and clopidogrel remains unanswered.

Gilard and colleagues[4] conducted a randomized, double-blind, placebo-controlled study to assess the influence of omeprazole on clopidogrel efficacy. They randomly assigned 145 patients who were undergoing coronary artery stent implantation and receiving aspirin, 75 mg daily, and clopidogrel, 75 mg daily (after a 300-mg loading dose), into 2 groups. The treatment group received omeprazole, 20 mg daily for 7 days, and the control group received placebo for 7 days. Assessment of the platelet reactivity index (PRI) was the primary endpoint. A PRI less than 50% indicated a favorable response to clopidogrel.

The data from 124 patients were reviewed after the 7-day course of therapy. Before treatment, the PRI was 83.2% in the control group and 83.9% in the treatment group. At study end, the PRI was 39.8% in the control group and 51.4% in the treatment group (P < .001). Patients who received gastroprotection with omeprazole were 4.31 times more likely to respond poorly to clopidogrel. The long-term implications of this interaction are uncertain but may suggest reduced cardioprotective benefits of clopidogrel.[5,7]

Although recent evidence indicates an interaction between PPIs and clopidogrel, further emphasis should be placed on the pharmacogenetic properties that influence clopidogrel metabolism. An estimated 30% of whites, 40% of blacks, and over 55% of East Asians have a CYP2C19 gene polymorphism that reduces the pharmacodynamic and pharmacokinetic response of clopidogrel.[7] With clopidogrel metabolism reduced in these patients, concomitant PPI therapy can further reduce its metabolism, predisposing patients to such adverse events as cardiovascular events and death.[7]

At the 2009 Society for Cardiovascular Angiography and Interventions meeting, investigators reported results of a retrospective cohort of over 16,700 patients who received clopidogrel (with or without PPI) after stenting.[8] Patients who received PPIs had a more than 50% higher risk for 1-year cardiovascular events compared with patients who did not receive PPIs. The findings suggest that the increased risk for cardiovascular events may be a class effect of PPIs and may not just be the result of specific agents as once perceived.

For now, healthcare providers should exercise clinical judgment and recommend that only high risk-patients (those receiving dual antiplatelet therapy, those with a history of gastrointestinal bleeding or ulcers, or those receiving concomitant anticoagulant therapy) receive PPIs in conjunction with clopidogrel. The manufacturer of clopidogrel discourages its use with omeprazole on the basis of the new evidence.[2]

If gastroprotection is deemed appropriate, consider using histamine-2 blockers such as ranitidine (Zantac®) or famotidine (Pepcid®) as first-line therapy. Clinicians should note that histamine-2 blockers may be less efficacious than PPIs for gastroprotection, but they have similar efficacy for heartburn and symptoms similar to those of gastroesophageal reflux disease.

The author wishes to acknowledge the assistance of Stefanie C. Nigro, PharmD, Pharmacy Practice Resident, Northeastern University School of Pharmacy and Harbor Health Services, Boston, Massachusetts.

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