Omeprazole and clopidogrel: Should clinicians be worried?
ABSTRACTThe US Food and Drug Administration has issued a warning that omeprazole (Prilosec) reduces the antiplatelet activity of clopidogrel (Plavix) by about 50%. However, the warning is based largely on ex vivo data. Preliminary results from a randomized clinical trial revealed no effect on cardiovascular outcomes when omeprazole was given with clopidogrel. We recommend that physicians continue to prescribe a proton pump inhibitor for patients receiving dual antiplatelet therapy who are at risk of gastrointestinal bleeding or have an indication for use of a proton pump inhibitor.
KEY POINTS
- Proton pump inhibitors such as omeprazole reduce the risk of gastrointestinal bleeding in patients on antiplatelet therapy after an acute coronary syndrome or percutaneous coronary intervention.
- Omeprazole diminishes the antiplatelet activity of clopidogrel by inhibiting the CYP2C19 isoenzyme.
- Although the interaction between omeprazole and clopidogrel can be demonstrated on platelet function studies, the clinical significance of this interaction is not clear.
‘COGENT’ TRIAL HALTED EARLY, BUT PRELIMINARY RESULTS AVAILABLE
The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial was the first randomized clinical study of the effect of the interaction between clopidogrel and omeprazole on cardiovascular and gastrointestinal outcomes.15 In a double-blind fashion, patients with acute coronary syndromes or undergoing percutaneous coronary interventions were randomized to receive a fixed-dose combination pill containing either clopidogrel and delayed-release omeprazole or clopidogrel alone. All patients also received aspirin.
Unfortunately, the trial was stopped early because the sponsor declared bankruptcy. However, preliminary results revealed no significant difference in cardiovascular outcomes for patients on clopidogrel and omeprazole compared with clopidogrel alone.15 Furthermore, adverse gastrointestinal events were significantly fewer in patients on clopidogrel and omeprazole.
Thus, omeprazole appears to be safe and may offer gastrointestinal protection to patients on dual antiplatelet therapy, though we need to await publication of the full results.
‘SPICE ’ TRIAL TO EVALUATE POSSIBLE MECHANISMS OF INTERACTION
The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) trial is a mechanistic study that will evaluate platelet function and genetic polymorphisms in patients on clopidogrel and aspirin after a percutaneous coronary intervention. They will be randomized to statin therapy plus different proton pump inhibitors.16 Prior concerns about an ex vivo interaction between clopidogrel and certain statins were not validated by clinical data.17
OUR RECOMMENDATIONS
Based on the current evidence, patients on aspirin and clopidogrel who have an indication for a proton pump inhibitor or who are at risk of gastrointestinal bleeding can continue or start taking a proton pump inhibitor, including omeprazole.
Switching to another proton pump inhibitor is not currently supported by any randomized clinical trial, nor is changing to a histamine H2-receptor antagonist. The effect of proton pump inhibitors other than omeprazole on clopidogrel is unclear, and it is not known if the interaction with clopidogrel is a class effect or specific to certain drugs of this class.18 On the other hand, we still have no compelling evidence of any major clinical interaction between alternative proton pump inhibitors and clopidogrel.18
Also, separating the dosing times of clopidogrel and omeprazole by 12 hours is not supported by any randomized clinical trial, and runs contrary to at least some ex vivo data.
It is important that all physicians assess the need for a proton pump inhibitor in their patients, as overuse of these drugs has been documented in certain settings.19
Clopidogrel and omeprazole share a common metabolic link via CYP2C19. Omeprazole, along with some other proton pump inhibitors, interacts with clopidogrel at the level of the CYP450 system. Platelet function studies show that platelet inhibition by clopidogrel is impaired, though the astute clinician should be aware of the wide variability associated with platelet function assays and clopidogrel.1,20 However, what may appear to be an interaction at the enzymatic level does not necessarily translate into worse clinical outcomes. Additionally, reliance on nonrandomized studies rather than on randomized clinical trials can be misleading.
