How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial.
OBJECTIVE
Few data are available from prospective trials to define the hepatotoxicity of diclofenac, the most widely prescribed non-steroidal anti-inflammatory drug (NSAID) in the world. We determined the rate of laboratory and clinical adverse hepatic effects in a large double-blind trial of diclofenac.


METHODS
Patients > or = 50 years with rheumatoid arthritis or osteoarthritis were randomly assigned to diclofenac (150 mg daily) or etoricoxib (60 or 90 mg daily). Patients with hepatic disease or who reported > or = 14 alcoholic drinks weekly were excluded. Patients had visits (with liver tests) every 4 months and were contacted by phone between visits and every 6 months after discontinuation until the end of the study. Causality assessment was performed for liver-related hospitalizations, Hy's cases (serious adverse events with AST or ALT >3 x upper limit of normal (ULN) and bilirubin >2 xULN), and liver failure/transplant/death.


RESULTS
A total of 17,289 patients received diclofenac for a mean of 18 months. Liver end points with diclofenac were ALT/AST>3 xULN: 527(3.1%); ALT/AST >10 xULN: 86(0.5%); liver-related hospitalizations: 4(0.023%); Hy's cases: 2(0.012%); liver failure/death/transplant: 0. Aminotransferase elevations occurred primarily within the first 4-6 months of therapy, whereas liver-related hospitalizations occurred between 9 days and 21 months.


CONCLUSIONS
Diclofenac is commonly associated with aminotransferase elevations, generally in the first 4-6 months of therapy. Clinical liver events requiring hospitalization are relatively rare (23/100,000 patients), but may develop early or late in therapy. The markedly increased rate of aminotransferase elevation with diclofenac may not be paralleled by a proportional marked increase in clinical liver events, although clinical events potentially also may be decreased with regular monitoring in a clinical trial setting.
Laine
Loren
L
University of Southern California, Los Angeles, California 90033, USA. llaine@usc.edu
Goldkind
Lawrence
L
Curtis
Sean P
SP
Connors
Laurine G
LG
Yanqiong
Zhang
Z
Cannon
Christoper P
CP
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D056486:Chemical and Drug Induced Liver Injury; D015331:Cohort Studies; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects; D004008:Diclofenac / Q000009:adverse effects*; D004311:Double-Blind Method; D000077613:Etoricoxib; D005260:Female; D006760:Hospitalization; D006801:Humans; D008107:Liver Diseases / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000188:drug therapy*; D011725:Pyridines / Q000009:adverse effects; D012307:Risk Factors; D013450:Sulfones / Q000009:adverse effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011725:Pyridines; D013450:Sulfones; D004008:Diclofenac; D000077613:Etoricoxib