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A Postmarketing Surveillance Study

Brian L. Strom, MD, MPH; Jesse A. Berlin, ScD; Judith L. Kinman, MA; Patricia W. Spitz, RN, MS; Sean Hennessy, PharmD; Harold Feldman, MD, MS; Stephen Kimmel, MD, MS; Jeffrey L. Carson, MD

JAMA. 1996;275(5):376-382.

Abstract
Objective.
—To evaluate the risk of gastrointestinal and operative site bleeding associated with the use of parenteral ketorolac tromethamine.

Design.
—Postmarketing surveillance inception cohort study.

Setting.
—A total of 35 hospitals throughout the Philadelphia, Pa, region, 1991 to 1993.

Patients.
—Patients administered 10272 courses of parenteral ketorolac therapy were compared with patients administered 10247 courses of a parenteral opiate who were matched to the ketorolac patients by hospital, admitting service, and date of initiation of study drug.

Main Outcome Measures.
—Medical records were reviewed for demographics, medical history, doses and duration of study drug, various aspects of the hospital course including surgery and concomitant medications, and adverse events.

Results.
—The multivariate adjusted odds ratio (OR) comparing ketorolac with opiates for gastrointestinal bleeding was 1.30 (95% confidence interval [CI], 1.11 to 1.52); for operative site bleeding, the OR was 1.02 (95% CI, 0.95 to 1.10). The OR was elevated further in subjects 75 years of age or older for both gastrointestinal bleeding (OR=1.66; 95% CI, 1.23 to 2.25) and operative site bleeding (OR=1.12; 95% CI, 0.94 to 1.35). A dose-response relationship was evident between average daily ketorolac dose and both gastrointestinal bleeding and operative site bleeding (trend test P<.001 for both). When analgesic therapy lasted 5 or fewer days, ketorolac was associated with only a small increased risk of gastrointestinal bleeding (OR=1.17; 95% CI, 0.99 to 1.30); when therapy was prolonged beyond 5 days, the OR was 2.20 (95% CI, 1.36 to 3.57). The association of ketorolac with operative site bleeding was not affected by duration of therapy.

Conclusions.
—The overall associations between ketorolac use and both gastrointestinal bleeding and operative site bleeding are small. However, the risk associated with the drug is larger and clinically important when ketorolac is used in higher doses, in older subjects, and for more than 5 days. Improving physicians' prescribing practices by limiting the dose and duration of ketorolac use, especially in the elderly, should enhance its overall risk-benefit balance.

(JAMA. 1996;275:376-382)

Author Affiliations
From the Center for Clinical Epidemiology and Biostatistics (Drs Strom, Berlin, Hennessy, Feldman, Kimmel, and Carson and Ms Kinman) and Departments of Biostatistics and Epidemiology (Drs Strom, Berlin, Feldman, and Kimmel) and Medicine (Drs Strom, Berlin, Feldman, Kimmel, and Carson), University of Pennsylvania School of Medicine, Philadelphia; World Safety Surveillance and Reporting, Syntex Development Research, Syntex (USA) Inc, Palo Alto, Calif (Ms Spitz); and Division of General Internal Medicine, Department of Medicine, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick (Dr Carson).

Footnotes
Presented at the 10th annual meeting of the International Society for Pharmacoepidemiology, Stockholm, Sweden, August 31, 1994.

Reprint requests to 824 Blockley Hall, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021 (Dr Strom).

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