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From Medscape Pharmacists > Ask the Experts

How Should We Manage Drug Interactions Between

Clopidogrel and Proton-Pump Inhibitors?Jenny A. Van Amburgh, PharmD, CDE

Published: 09/22/2009

Question

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

(PPIs)?

Response from Jenny A. Van Amburgh, PharmD, CDEAssociate 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. [3-5]

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 P2Y12receptor. 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 patients 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

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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.

References

1. Top 200 Drugs of 2007. RxList, Inc. Available at: http://www.rxlist.com/script/main/hp.asp

Accessed June 1, 2009.

2. Plavix [package insert]. Bridgewater, NJ: Bristol-Meyers Squibb/Sanofi Aventis; 2009.3. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between

proton pump inhibitors and clopidogrel. CMAJ. 2009;180:713-718.Abstract

4. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of

clopidogrel associated with aspirin. J Am Coll Cardiol. 2008;51:256-260. Abstract

5. 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;301:937-944.Abstract

6. Cytochrome P450 drug interactions. Pharmacists Letter/Prescribers Letter. 2006;22:220-233.

7. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to

clopidogrel. N Engl J Med. 2009;360:354-362.Abstract

http://www.medscape.com/medline/abstract/19176635http://www.medscape.com/medline/abstract/18206732http://www.medscape.com/medline/abstract/19258584http://www.medscape.com/medline/abstract/19258584http://www.medscape.com/medline/abstract/19258584http://www.medscape.com/medline/abstract/19106084http://www.medscape.com/medline/abstract/19176635http://www.medscape.com/medline/abstract/18206732http://www.medscape.com/medline/abstract/19258584http://www.medscape.com/medline/abstract/19106084

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8. Wood S. Possible "class effect" for proton-pump inhibitors on top of clopidogrel therapy.

Medscape Pharmacists. Available at: http://www.medscape.com/viewarticle/702485?

sssdmh=dm1.490283&src=confwrap Accessed June 29, 2009.

Authors and Disclosures

Author(s)

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

Disclosure: Jenny A. Van Amburgh, PharmD, CDE, has disclosed no relevantfinancial relationships.

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