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Proton Pump Inhibitors and Clopidogrel
Abstract & Commentary
By Malcolm Robinson, MD, FACP, FACG, AGAF, Emeritus Clinical Professor of Medicine, University of Oklahoma College of Medicine, Oklahoma City. Dr. Robinson reports no financial relationship to this field of study.
Synopsis: Proton pump inhibitors given concomitantly with clopidogrel administered after acute myocardial infarction appear to diminish the beneficial effects of clopidogrel, thus increasing the risk of re-infarction.
Source: Juurlink DN, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009 Jan 28; Epub ahead of print.
Proton pump inhibitors (PPIs) have frequently been reviewed in Internal Medicine Alert. PPIs are frequently administered, especially in hospital settings and post-discharge. It has been assumed that PPIs can be safely given in a wide range of medical settings, and relatively few clinically relevant PPI-related drug-drug interactions have been reported. Since platelet activation and aggregation are central to the pathogenesis of coronary artery occlusion, drugs that impair platelet function are almost universally administered in acute coronary syndrome. The combination of aspirin (ASA) and clopidogrel is slightly, but statistically, more effective than ASA alone in this setting. A lot of clopidogrel is prescribed. Sales in the United States were $7.3 billion in 2007. Delay in the administration of clopidogrel has been associated with adverse cardiovascular outcomes in acute myocardial infarction (MI).
Clopidogrel is activated by cytochrome P450 2C19 (CYP2C19), as well as P450 3A4 from its pro-drug form to its active form, and drugs that inhibit this enzyme would be expected to reduce the antiplatelet efficacy of clopidogrel. Previous studies have indicated that omeprazole has a negative effect on clopidogrel efficacy. A relatively small series of high-risk angioplasty patients on clopidogrel along with chronic PPIs had a 300% higher risk of acute MI vs. similar patients not taking PPIs.
Since millions of patients worldwide may receive both PPIs and clopidogrel, these authors conducted a population-based nested case-control study of Ontario patients aged 66 or older who received clopidogrel between 2002 and 2007 following hospital discharge for acute MI. The subsequent "cases" in this study were patients readmitted with recurrent MI within 90 days post hospital discharge. Of 13,636 patients receiving clopidogrel following MI, 734 were readmitted with acute MIs (the cases). These were matched to patients comprising 2057 controls who were not readmitted with MIs during an identical 90-day interval.
The Ontario Public Drug program's computerized records provided fully comprehensive records of prescriptions, and separate diagnostic and procedural data came from the Canadian Institute for Health Information Discharge Abstract Database. Physician services were tracked using information from the Ontario Health Insurance Plan. Socialized medicine has its advantages (at least for this sort of research). Patients who had received clopidogrel, ticlopidine, or dipyridamole in the year before initial hospital admission were excluded. Clopidogrel prescriptions post hospital discharge were carefully tracked along with use or non-use of PPIs within 30 days or 31-90 days or 91-180 days. Factors known to be correlated with increased mortality after acute MI were also tracked and utilized in subsequent subgroup statistical comparisons (e.g., complicated diabetes, dysrhythmias, pulmonary edema, renal failure). Median overall patient age was 76 years and 55.6% of the patients were male. Almost 20% of patients had received a PPI within 30 days of discharge with 31% receiving PPIs within 90 days post-discharge.
As anticipated, cases of recurrent MI were more likely than controls (no recurrent MIs) to have had comorbidities during the index hospitalization. After extensive multivariable analysis, data revealed a significant association between readmission with MI and current PPI use. Histamine-2-receptor antagonist use showed no such association. In a stratified analysis, pantoprazole (a PPI that doesn't inhibit cytochrome CYP2C19) did not have a statistical association with recurrent MI. Attributable risk from PPI plus clopidogrel use was found to be 1.4 or a potential 40% increase in risk. The authors stated that if 40% of patients taking clopidogrel were also prescribed a PPI other than pantoprazole, 14% of all readmissions for reinfarction could be attributed to this drug-drug interaction.
The findings of this article have been widely disseminated, and the FDA has already issued a warning to physicians against concomitant prescription of clopidogrel and PPIs. Patients who take both clopidogrel and a PPI have also been urged to contact their physicians. However, the FDA wisely included the proviso that they are not yet accepting the establishment of any cause-and-effect relationship between the drug products and the emerging safety issue. Although some previous work did support the notion that PPIs might make clopidogrel less effective, others did not. The PPI manufacturers and the makers of clopidogrel have agreed to prompt performance of additional studies to clarify potential drug-drug interactions. None of the authors seem to have competing interests such as pharmaceutical industry relationships. However, they seem to have been driven by a strong belief that pantoprazole should behave differently from all other PPIs.
Although the apparent freedom of pantoprazole from any inhibition of clopidogrel efficacy initially seems attractive from the perspective of established differences in cytochrome P450 profiles, the number of patients receiving pantoprazole was relatively low. Despite a reported statistical difference between pantoprazole and the combined group of alternative PPI recipients, there is certainly substantial overlap of the PPI populations in terms of recurrent MI rates. Most significantly, there were too few patients to allow the separation of the non-pantoprazole PPIs to define individual PPI profiles.
Despite the claims of these authors to the contrary, only omeprazole and esomeprazole have clear effects on CYP2C19. Other PPIs might have a slight effect (from secondary metabolites) or no interactions at all. The authors have no way of sorting out important genetic profiles of patients in this population, and it is known that 10-20% of patients have reduced CYP2C19 activity on a genetic basis. This is especially common in persons of Asian descent. Cimetidine is known to inhibit CYP2C19. A mismatch of these genetic profiles could negate any drug effect. The absolute change in ASA antiplatelet efficacy is only 3% when clopidogrel is added, and this makes clopidogrel effects even harder to evaluate in trials unless studies are extremely large. There was some attempt to control for common CYP3A4 inhibitors (another cytochrome enzyme needed to activate clopidogrel). These include: clarithromycin, fluconazole, itraconazole (and other drugs of this class), along with diltiazem, verapamil, and chronic high-level consumption of grapefruit juice. There are a number of drugs that enhance CYP3A4 activity and therefore would be expected to increase the antiplatelet activity of clopidogrel: rifampin, carbamazepine, barbiturates, and St. John's wort.
To make any valid recommendation regarding PPI selection for concomitant therapy with clopidogrel, there must be carefully controlled studies of individual PPIs and their effects on clinical measures of clopidogrel efficacy. Such studies should be undertaken in the near future. For now, it might be wisest to avoid omeprazole and esomeprazole in the setting of acute MI managed with aspirin and clopidogrel. If physicians believe that a PPI must be given, pantoprazole may or may not be the safest choice based on the very limited available information. However, it seems likely to me that lansoprazole or rabeprazole would also be reasonable choices.
Elimination of acid suppression (best with PPIs) would definitely increase the risk of significant gastrointestinal bleeding with platelet function antagonists. As a gastroenterologist, GI hemorrhage is anathema - to be avoided at all costs. Unfortunately, I cannot reliably estimate the potential effectiveness of alternative anticoagulation methods such as low-dose heparin in the setting of acute coronary syndrome. All of us need informed guidance on the best way to utilize antiplatelet therapy while avoiding hemorrhagic complications. For now, the use of PPIs other than omeprazole and esomeprazole should be considered.
1. Horn JR, Hansten PD. Clopidogrel: Some drugs may reduce its effectiveness. Pharmacy Times 2008;April:56 (www.PharmacyTimes.com).