Risk of Upper Gastrointestinal Hemorrhage in Warfarin Users Treated With Nonselective NSAIDs or COX-2 Inhibitors

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Abstract
Warfarin is an anticoagulant commonly used for the management of patients with a variety of thromboembolic conditions1 but it is implicated in many drug-drug interactions. Some interactions alter warfarin pharmacokinetics and others involve drugs that directly influence hemostasis or gastrointestinal integrity.2,3 Nonsteroidal anti-inflammatory drugs (NSAIDs) are often coprescribed to patients receiving warfarin, potentially resulting in a significantly increased risk of upper gastrointestinal (GI) hemorrhage.4 This increased risk may be mediated through several pathways. First, many NSAIDs are substrates for the cytochrome P450 2C9 isoenzyme. Their use may interfere with the oxidative metabolism of S-warfarin, the more active enantiomer of commercially available racemic warfarin, thereby increasing the hypoprothrombinemic response to warfarin.5 Second, the nonspecific inhibition of cyclooxygenase (COX) enzymes by nonselective NSAIDs leads to significant inhibition of COX-1–generated thromboxane A 2, impairing platelet aggregation,6,7 which may be further compounded by the concomitant use of warfarin.8 Third, traditional NSAIDs can cause gastric erosion, thereby further increasing the risk of GI bleeding in patients treated with warfarin.9