Risk of Hospitalization for Upper Gastrointestinal Tract Bleeding Associated With Ketorolac, Other Nonsteroidal Anti-inflammatory Drugs, Calcium Antagonists, and Other Antihypertensive Drugs

Abstract

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause substantial morbidity and mortality from upper gastrointestinal tract disease. Ketorolac tromethamine has been singled out as an NSAID with a distinct gastrotoxicity profile. Calcium channel blockers, a class of antihypertensive drugs, have also been found to increase the risk of gastrointestinal tract bleeding. METHODS: We identified 1505 patients hospitalized because of upper gastrointestinal tract bleeding and/or perforation, and we randomly sampled 20,000 controls in the source population. RESULTS: The adjusted relative risk (RR) for upper gastrointestinal tract bleeding and/or perforation in NSAID users compared with nonusers was 4.4 (95% confidence interval [CI], 3.7-5.3). The risk increased with higher daily doses. Ketorolac presented the highest risk (RR, 24.7; 95% CI, 9.6-63.5) and piroxicam ranked second (RR, 9.5; 95% CI, 6.5-13.8). Ketorolac was 5 times more gastrotoxic than all other NSAIDs (RR, 5.5; 95% CI, 2.1-14.4). The excess risk with ketorolac was observed with both oral and intramuscular administration and was already present during the first week of therapy. Among the various antihypertensive drug classes, beta-blockers were associated with the lowest relative risk (RR, 1.0; 95% CI, 0.7-1.4), and current use of calcium channel blockers with the highest (RR, 1.7; 95% CI, 1.3-2.1). The association with calcium channel blockers declined when adjusting for various markers of comorbidity (RR, 1.4; 95% CI, 1.1-1.8). Past use of calcium channel blockers was also associated with an increased risk (RR, 1.5; 95% CI, 1.3-1.8). CONCLUSIONS: The excess risk of major upper gastrointestinal tract complications associated with outpatient use of ketorolac suggests an unfavorable risk-benefit assessment compared with other NSAIDs. More data are required to reduce the uncertainty about the apparent small increased risk of upper gastrointestinal tract bleeding in patients using calcium channel blockers.