Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs.
BACKGROUND
Nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) toxic effects, such as upper GI tract perforations, symptomatic gastroduodenal ulcers, and upper GI tract bleeding (PUBs), are thought to be attributable to cyclooxygenase 1 (COX-1) inhibition. Rofecoxib specifically inhibits COX-2 and has demonstrated a low potential for causing upper GI injury.


OBJECTIVE
To compare the incidence of PUBs in patients with osteoarthritis treated with rofecoxib vs NSAIDs.


METHODS
Prespecified analysis of all 8 double-blind, randomized phase 2b/3 rofecoxib osteoarthritis trials conducted from December 1996 through March 1998, including one 6-week dose-ranging study, two 6-week efficacy studies vs ibuprofen and placebo, two 1-year efficacy studies vs diclofenac, two 6-month endoscopy studies vs ibuprofen and placebo, and one 6-week efficacy study vs nabumetone and placebo.


METHODS
Multinational sites. Participants Osteoarthritis patients (N = 5435; mean age, 63 years [range, 38-94 years]; 72.9% women).


METHODS
Rofecoxib, 12.5, 25, or 50 mg/d (n = 1209, 1603, and 545, respectively, combined) vs ibuprofen, 800 mg 3 times per day (n = 847), diclofenac, 50 mg 3 times per day (n = 590); or nabumetone, 1500 mg/d (n = 127) (combined).


METHODS
Cumulative incidence of PUBs for rofecoxib vs NSAIDs, based on survival analysis of time to first PUB diagnosis, using PUBs that met pre-specified criteria judged by a blinded, external adjudication committee.


RESULTS
The incidence of PUBs over 12 months was significantly lower with rofecoxib vs NSAIDs (12-month cumulative incidence, 1.3% vs 1.8%; P = .046; rate per 100 patient-years, 1.33 vs 2.60; relative risk, 0.51; 95% confidence interval, 0.26-1.00). The cumulative incidence of dyspeptic GI adverse experiences was also lower with rofecoxib vs NSAIDS over 6 months (23.5% vs 25.5%; P = .02), after which the incidence rates converged.


CONCLUSIONS
In a combined analysis of 8 trials of patients with osteoarthritis, treatment with rofecoxib was associated with a significantly lower incidence of PUBs than treatment with NSAIDs.
Langman
M J
MJ
Department of Medicine, University of Birmingham, England.
Jensen
D M
DM
Watson
D J
DJ
Harper
S E
SE
Zhao
P L
PL
Quan
H
H
Bolognese
J A
JA
Simon
T J
TJ
D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D002074:Butanones / Q000009:adverse effects / Q000627:therapeutic use; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D004008:Diclofenac / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced* / Q000175:diagnosis; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects / Q000627:therapeutic use; D007527:Isoenzymes; D007783:Lactones / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D000077430:Nabumetone; D010003:Osteoarthritis / Q000188:drug therapy; D010437:Peptic Ulcer / Q000139:chemically induced* / Q000175:diagnosis; D016016:Proportional Hazards Models; D011451:Prostaglandin-Endoperoxide Synthases; D016032:Randomized Controlled Trials as Topic; D013450:Sulfones
D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D013450:Sulfones; C116926:rofecoxib; D004008:Diclofenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000077430:Nabumetone; D007052:Ibuprofen