Appropriate Use of Clopidogrel in the Older Adult
To the Editor,
I generally agreed with the analysis and conclusions of the article in the January 2010 edition of Clinical Geriatrics entitled “Appropriate Use of Clopidogrel in the Older Adult” by Dr. Ackermann.1 I have two comments:
1. I think the potential for drug-drug interactions at the cytochrome P450 2C19 enzyme should be emphasized more. Dr. Ackermann mentions the potential interaction of proton pump inhibitors (PPIs) with clopidogrel. These drugs are common in the elderly, and I doubt many primary care physicians or specialists who prescribe clopidogrel even consider this interaction. Perhaps the worst offender of PPIs is omeprazole, which is over the counter, and many patients may be taking it without their physicians’ knowledge. With clopidogrel being a prodrug needing 2C19 activity, it would render the clopidogrel less effective or perhaps useless. In this sense, the drug-drug interaction is a “silent” one—no obvious adverse drug reaction occurs. And if a patient has a cardiovascular event, it will not likely be attributed to the drug-drug interaction since patients who go on antiplatelet therapy still have cardiovascular events. In addition, other common drugs may have this interaction as well, such as fluoxetine.
2. The cost of testing for cytochrome P450 2C19 alleles is not expensive. Several labs can do this testing for $100-200, and it is reimbursable, in my experience, through most insurance and Medicare if properly justified. The study by Mega et al2 showed that carriers of one inactive allele had reduced active blood levels of active metabolite of clopidogrel, and, more importantly, had “a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI] = 1.07-2.19; P = 0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs 0.8%; hazard ratio, 3.09; 95% CI= 1.19-8.00; P = 0.02).” The results of those who would have both alleles dysfunctional likely would be worse. It is estimated that 2-6% of Caucasians have both alleles dysfunctional, as do 10-20% of Japanese and African-American persons.3 Those with one functional allele represent approximately 30% of the population. It would seem prudent to consider genetic testing before or at the time of starting clopidogrel, and then re-evaluating its usefulness once the results are returned.
Scott C. Armstrong, MD
Medical Director, Tuality Center for Geriatric Psychiatry
Forest Grove, OR
Associate Clinical Professor of Psychiatry Oregon Health & Science University, Portland
Dr. Armstrong reports no relevant financial relationships.
References
1. Ackermann R. Appropriate use of clopidogrel in the older adult. Clinical Geriatrics 2010;18(1):41-47.
2. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-362.
3. Clopidogrel (Plavix) DNA Test-CYP2C19. Genelex Website. http://www.healthanddna.com/drug-safety-dna-testing/clopidogrel.html. Accessed March 1, 2010.
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Dr. Ackermann responds:
Thank you for highlighting this important and controversial area. Let me summarize the issues: clopidogrel is metabolized by the CYP system to an active metabolite. Drugs that inhibit this metabolic pathway could therefore reduce the antiplatelet effects of clopidogrel, leading to an increase in adverse cardiovascular (CV) outcomes. Omeprazole seems to have the greatest CYP inhibition of the available PPIs, but we don’t know yet if this is a class effect or just one specific drug. On the other hand, patients taking clopidogrel, especially those also taking aspirin, have an increased risk of gastrointestinal (GI) bleeding, and PPIs can substantially reduce this risk. So here’s the rub: In patients taking dual antiplatelet therapy, PPIs (particularly omeprazole) may either be substantially harmful by decreasing cardioprotection, or substantially helpful by reducing GI bleeding. This is an important question because millions of patients take these drugs, and effects are likely to be exaggerated in frail older adults.
There is only one randomized controlled trial (RCT) that directly compares omeprazole with placebo in patients taking clopidogrel—this is the COGENT trial, which is unpublished but has been presented at a major cardiovascular meeting.1 In this trial, 3627 patients were randomized with a mean follow-up of 133 days. CV outcomes (myocardial infarction, revascularization, and all CV outcomes) were identical in the omeprazole and placebo groups, while there was about a 40% reduction in GI events in the patients taking omeprazole (P = 0.007). Unfortunately, this trial was stopped early because the sponsoring company declared bankruptcy. Other RCTs of clopidogrel that did not directly assess this area have been retrospectively analyzed with conflicting results. Observational studies have also come to opposite conclusions.2-6
The Food and Drug Administration (FDA) issued an alert in November 2009 stating that “The concomitant use of omeprazole and clopidogrel should be avoided because of the effect on clopidogrel’s active metabolite levels and anti-clotting activity. Patients at risk for heart attacks or strokes, who are given clopidogrel to prevent blood clots, may not get the full protective anti-clotting effect if they also take prescription omeprazole or the OTC form (Prilosec OTC).” 7 Some cardiology and GI professional societies strongly disagree with the FDA.
Until this controversy is resolved, clinicians caring for older adults should be aware of a potentially serious drug interaction between clopidogrel and omeprazole. Exactly what to do is unclear, but here are some options:
1. Avoid the combination unless the patient is at high risk of GI bleeding.
2. Consider other alternatives to protect against GI bleeding, such as H2 blockers or PPIs other than omeprazole.
3. If clopidogrel and omeprazole are used together, consider separating the doses (clopidogrel in the morning and omeprazole at night).
There is not enough evidence to support routine screening for individual P450 2C19 alleles at this time. We need more RCTs in a wide range of patients, including frail older adults.
Richard Ackermann, MD
Professor and Director Division of Geriatrics, Department of Family Medicine
Mercer University School of Medicine/Medical Center of Central Georgia, Macon
Dr. Ackermann reports no relevant financial relationships.
References
1. Wood S. COGENT: No CV events but significant GI benefits of PPI omeprazole. From the Transcatheter Cardiovascular Therapeutics (TCT 2009) 21st Annual Scientific Symposium, September 2009.
2. Norgard NB, Mathews KD, Wall GC. Drug-drug interaction between clopidogrel and the proton pump inhibitors. Ann Pharmacother 2009;43:1266-1274. Published Online: May 26, 2009.
3. Laine L, Hennekens C. Proton pump inhibitor and clopidogrel interaction: Fact or fiction? Am J Gastroenterol 2010;105:34-41. Published Online: November 10, 2009.
4. Liu TJ, Jackevicius CA. Drug interaction between clopidogrel and proton pump inhibitors. Pharmacotherapy 2010;30:275-289.
5. Last EJ, Sheehan AH. Review of recent evidence: Potential interaction between clopidogrel and proton pump inhibitors. Am J Health Syst Pharm 2009;66:2117-2122.
6. O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: An analysis of two randomised trials. Lancet 2009;374:989-997. Published Online: August 31, 2009.
7. U.S. Food and Drug Administration. Information for healthcare professionals: Update to the labeling of clopidogrel bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm. Accessed March 1, 2010.