Gerald A. Faich

CONTEXT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE: To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. DESIGN: The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. SETTING: Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS: A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. INTERVENTIONS: Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (</=325 mg/d) was permitted. MAIN OUTCOME MEASURES: Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period. RESULTS: For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P =.09) and 2. 08% vs 3.54% (P =.02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P =.04) and 1.40% vs 2.91% (P =.02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P =.92) and 4.70% vs 6.00% (P =.49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use. CONCLUSIONS: In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. JAMA. 2000;284:1247-1255

The U.S. Food and Drug Administration (FDA) has long been conducting a program to monitor reported adverse drug reactions to approved drugs. The purpose of this paper is to review the rationale for monitoring adverse drug reactions, to describe the current program, and to encourage physician participation in the program. The program began in the late 1950s, after the registration by the American Medical Association of cases of aplastic anemia due to chloramphenicol.1 It expanded greatly when the 1962 revision of the Food and Drug Act required the pharmaceutical industry to report adverse drug reactions to the FDA. Since 1969, . . .

A 12-month epidemiologic study in 1979 and 1980 of all diabetic acidosis admissions to all acute care hospitals in Rhode Island detected 152 episodes occurring in 137 persons. Eleven per cent of diabetic acidosis admissions presented in coma and the overall death-to-case ratio was 9%. Newly diagnosed diabetes accounted for 20% of these episodes, while persons having multiple episodes during the year accounted for 15% of the admissions. The annual rate of diabetic acidosis was 46 per 10,000 diabetics. Highest rates of diabetic acidosis were found for the elderly, those admitted from nursing homes and those residing in one geographic area of the state. For known diabetics with an admission for acidosis, 87% were on insulin prior to admission and 81% were nonobese. Patients seldom contacted physicians prior to admission. Insulin dose or frequency was often (40%) changed in the two weeks prior to admission. Most of the known diabetic cases of acidosis had emergency admissions for diabetes in the three-year period prior to admission and few had any structured diabetic outpatient education. Infection and noncompliance were the most frequently identified precipitants of diabetic acidosis occurring in known diabetics.