Drug combinations found to increase upper gastrointestinal bleeding risk

Gastrointestinal toxicity is the major issue limiting nonsteroidal anti-inflammatory use. The excess annual risk of upper gastrointestinal bleeding per 1,000 patients is about 1 with low-dose aspirin, about 2 with coxibs, and about 4-6 with traditional NSAIDs (ibuprofen, naproxen). However, the risk of upper gastrointestinal bleeding increases markedly with several factors, including the use of concomitant medications.

Ideally, large randomized trials comparing NSAIDs with and without a concomitant medication would inform our assessment of risk. However, few such trials are available, so we commonly rely on observational database studies, such as that of Masclee et al. These studies have the important benefit of large sample size and "real world" results, but also have potential limitations, including reliability of data (for example, accuracy of diagnostic coding) and potential bias because of unequal distribution of confounding factors between cases and controls.

Masclee et al. report significant synergy (more than additive risk) of traditional NSAIDs with corticosteroids, SSRIs, aldosterone antagonists, and antithrombotic agents other than low-dose aspirin (although risk was increased with traditional NSAIDs plus low-dose aspirin). Low-dose aspirin was synergistic with antithrombotic agents and corticosteroids, while coxibs were synergistic with low-dose aspirin and SSRIs.

The results of Masclee et al. support current North American guidelines, which suggest use of proton pump inhibitors or misoprostol for traditional NSAID users taking concomitant medications such as antithrombotics, corticosteroids, or SSRIs, and use of PPIs for low-dose-aspirin users taking antithrombotics or taking corticosteroids if greater than or equal to 60 years old. Their results also suggest further evaluation of aldosterone antagonists is warranted as another possible risk factor.

Dr. Loren Laine is professor of medicine, department of internal medicine, Yale University, New Haven, Conn. He is on the Data Safety Monitoring Boards of Eisai, BMS, and Bayer; and is a consultant for AstraZeneca.