Drug Interactions between aspirin / omeprazole and Plavix

GENERALLY AVOID: Coadministration with proton pump inhibitors (PPIs) may reduce the cardioprotective effects of clopidogrel. The proposed mechanism is PPI inhibition of the CYP450 2C19-mediated metabolic bioactivation of clopidogrel. This is consistent with studies that reported decreased effectiveness of clopidogrel and poorer clinical outcome in patients who have common genetic polymorphisms of CYP450 2C19 resulting in reduced or absent enzyme activity. In a population-based nested case-control study among patients aged 66 years or older who started clopidogrel after treatment of acute myocardial infarction, concomitant use of PPIs was associated with a significantly increased short-term risk of reinfarction. No association was found with more distant exposure to PPIs or with current exposure to H2-receptor antagonists. In a stratified analysis of the type of PPIs used, pantoprazole was not associated with recurrent myocardial infarction among patients receiving clopidogrel. However, the number of patients receiving pantoprazole in the study was relatively small. Compared with no treatment, the other proton pump inhibitors (lansoprazole, omeprazole, rabeprazole) were collectively associated with a 40% increase in the risk of recurrent myocardial infarction within 90 days of initial hospital discharge. In the Clopidogrel Medco Outcomes Study, a retrospective analysis of 16,690 patients taking clopidogrel for a full year following coronary stenting revealed that patients who also took a PPI (esomeprazole, lansoprazole, omeprazole, or pantoprazole) for an average of nine months experienced a 50% increase in the combined risk of hospitalization for heart attack, stroke, unstable angina, or repeat revascularization. Specifically, use of a PPI was associated with a 70% increase in the risk of heart attack or unstable angina, a 48% increase in the risk of stroke or stroke-like symptoms, and a 35% increase in the need for a repeat coronary procedure. The event rates for the individual PPIs are esomeprazole 24.9%, lansoprazole 24.3%, omeprazole 25.1%, and pantoprazole 29.2%, compared to 17.9% for the no-PPI control group. In a study of 105 consecutive high-risk coronary angioplasty patients receiving aspirin and clopidogrel, PPI users had a significantly lower antiplatelet response to clopidogrel than nonusers as measured by the VASP (vasodilator-stimulated phosphoprotein) phosphorylation assay, which provides an index of platelet reactivity to clopidogrel. No significant differences in antiplatelet response were found for users of statins, ACE inhibitors, angiotensin II receptor antagonists, and beta-blockers compared to nonusers. A subsequent study conducted by the same investigators reported similar results when omeprazole (20 mg/day) or placebo was given for seven days to 140 coronary artery stent patients receiving aspirin and clopidogrel. In contrast, a study of 300 consecutive patients with coronary artery disease undergoing PCI found that esomeprazole or pantoprazole use did not impair the response to clopidogrel as measured by VASP assay or ADP-induced platelet aggregometry. More recent studies have also found no significant effect of dexlansoprazole, lansoprazole, or pantoprazole on the pharmacokinetics or pharmacodynamics of clopidogrel, and that increasing gastric pH did not influence platelet inhibition by clopidogrel.

MANAGEMENT: Until further data are available, empiric use of proton pump inhibitors should preferably be avoided in patients treated with clopidogrel. PPIs should only be considered in high-risk patients such as those receiving dual antiplatelet therapy, those with a history of gastrointestinal bleeding or ulcers, and those receiving concomitant anticoagulant therapy, and then only after thorough assessment of risks versus benefits. If a PPI is required, dexlansoprazole, lansoprazole, or pantoprazole may be safer alternatives. Otherwise, H2-receptor antagonists or antacids should be prescribed whenever possible.

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MONITOR: Clopidogrel has been shown to potentiate the inhibition of platelet aggregation due to aspirin. Single-dose studies have not shown a prolongation of bleeding time when aspirin was added to clopidogrel; however, the risk of gastrointestinal (GI) bleeding may be increased. A large clinical trial reported that clopidogrel 75 mg/day plus aspirin 75 to 325 mg/day for up to 1 year was associated with a higher incidence of major GI bleeding (1.3% vs 0.7% with aspirin alone). These two medications are routinely used together for their additive antiplatelet, antistroke effect. The safety of chronic administration of aspirin or other salicylates with clopidogrel has not been established.

MANAGEMENT: Until further data are available, caution is recommended, especially in patients at risk of bleeding (i.e., GI ulceration), if clopidogrel is coadministered on a long-term basis with drugs that may cause GI lesions. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, red or black stools, or bloody or coffee-ground emesis. Patients should also be counseled to avoid any other over-the-counter salicylate products.

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Coadministration with proton pump inhibitors may decrease the oral bioavailability of aspirin and other salicylates. The interaction has been studied with omeprazole and aspirin, although data are conflicting. In one study, pretreatment with omeprazole (20 mg/day for 2 days) in 11 healthy volunteers led to a significant and progressively greater reduction in the mean serum salicylate level at 30, 60, and 90 minutes after administration of aspirin (650 mg single dose). The investigators suggest that acid suppression may reduce the lipophilic nature of aspirin, thereby adversely affecting its absorption from the gastrointestinal tract. Another study found no effect of omeprazole pretreatment (20 mg/day for 4 days) on plasma salicylate and aspirin levels, skin bleeding times, or antiplatelet effect of low-dose aspirin (125 mg single dose) in 14 healthy volunteers. However, these results do not exclude the possibility that omeprazole might interfere with the analgesic, antipyretic, or anti-inflammatory effects of aspirin, which has been demonstrated in rats.

Proton pump inhibitors may enhance the release rate of salicylates from enteric-coated formulations due to premature disruption of the coating and intragastric release of the drug secondary to an increase in gastric pH. In eight healthy volunteers, omeprazole pretreatment (20 mg/day for 4 days) did not affect the bioavailability of salicylate from uncoated aspirin tablets but significantly increased the absorption rate of salicylate from enteric-coated sodium salicylate tablets. The clinical significance of this interaction is unknown. Theoretically, it may increase the risk of gastric adverse effects associated with salicylates.

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