Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
BACKGROUND
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.


METHODS
The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000.


METHODS
Three hundred eighty-six clinical sites in the United States and Canada.


METHODS
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.


METHODS
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.


METHODS
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
Silverstein
F E
FE
Pharmacia Clinical Research and Development, 4901 Searle Pkwy, Bldg A3E, Skokie, IL 60077, USA.
Faich
G
G
Goldstein
J L
JL
Simon
L S
LS
Pincus
T
T
Whelton
A
A
Makuch
R
R
Eisen
G
G
Agrawal
N M
NM
Stenson
W F
WF
Burr
A M
AM
Zhao
W W
WW
Kent
J D
JD
Lefkowith
J B
JB
Verburg
K M
KM
Geis
G S
GS
D000368:Aged; D000704:Analysis of Variance; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001241:Aspirin / Q000009:adverse effects; D000068579:Celecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D004008:Diclofenac / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced*; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D010003:Osteoarthritis / Q000188:drug therapy; D010437:Peptic Ulcer / Q000139:chemically induced; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D011720:Pyrazoles; D013449:Sulfonamides / Q000009:adverse effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D004008:Diclofenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D001241:Aspirin; D007052:Ibuprofen