Cox drugs 1/3

JAMA -- Abstract: Adverse Effects of Cyclooxygenase 2
Inhibitors on Renal and Arrhythmia Events:
Meta-analysis of Randomized Trials,
September 12, 2006, Zhang et al. 0 (2006): 296.13.jrv60015

Early Release Article, posted September 12, 2006


Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and
Arrhythmia Events
Meta-analysis of Randomized Trials
Jingjing Zhang, MD, PhD; Eric L. Ding, BA; Yiqing Song, MD, ScD
JAMA. 2006;296:(doi:10.1001/jama.296.13.jrv60015).
Context Adverse effects of selective cyclooxygenase 2 (COX-2)
inhibitors on renal events and arrhythmia have been controversial,
with suggestions of a class effect.

Objective: To quantitatively evaluate adverse risks of renal events
(renal dysfunction, hypertension, and peripheral edema) and
arrhythmia events and to explore drug class effects and temporal
trends of apparent effects of the COX-2 inhibitors: rofecoxib,
celecoxib, valdecoxib, parecoxib, etoricoxib, and lumiracoxib.

Data Sources: A systematic search of EMBASE and MEDLINE (through
June 2006), bibliographies, US Food and Drug Administration reports,
and pharmaceutical industry clinical trial databases.

Study Selection: From relevant reports, 114 randomized double-blind
clinical trials were included.

Data Extraction: Information on publication year, participant
characteristics, trial duration, drug, control, dose, and events
were extracted using a standardized protocol.

Data Synthesis: Results were pooled via random-effects models and
meta-regressions. Of 116 094 participants from 114 trial reports
including 127 trial populations (40 rofecoxib, 37 celecoxib, 29
valdecoxib + parecoxib, 15 etoricoxib, and 6 lumiracoxib), there
were a total of 6394 composite renal events (2670 peripheral edema,
3489 hypertension, 235 renal dysfunction) and 286 arrhythmia events.
Results indicated significant heterogeneity of renal effects across
agents (P for interaction = .02), indicating no class effect.
Compared with controls, rofecoxib was associated with increased risk
of arrhythmia (relative risk [RR], 2.90; 95% confidence interval
[CI], 1.07-7.88) and composite renal events (RR, 1.53; 95% CI,
1.33-1.76); adverse renal effects increased with greater dose and
duration (both P.05). For all individual renal end points, rofecoxib
was associated with increased risk of peripheral edema (RR, 1.43;
95% CI, 1.23-1.66), hypertension (RR, 1.55; 95% CI, 1.29-1.85), and
renal dysfunction (RR, 2.31; 95% CI, 1.05-5.07). In contrast,
celecoxib was associated with lower risk of both renal dysfunction
(RR, 0.61; 95% CI, 0.40-0.94) and hypertension (RR, 0.83; 95% CI,
0.71-0.97) compared with controls. Other agents were not
significantly associated with risk. Time-cumulative analyses
indicated that for rofecoxib the adverse risks for peripheral edema
and hypertension were evident by the end of year 2000 and for risk
of arrhythmia by 2004.

CONCLUSIONS In this comprehensive analysis of 114 randomized trials
with 116 094 participants, rofecoxib was associated with increased
renal and arrhythmia risks. A COX-2 inhibitor class effect was not
evident. Future safety monitoring is warranted and may benefit from
an active and continuous cumulative surveillance system.
Published online: September 12, 2006
(doi:10.1001/jama.296.13.jrv60015).

Author Affiliations: Renal Division (Dr Zhang) and Division of
Preventive Medicine (Mr Ding and Dr Song), Brigham and Women's
Hospital and Harvard Medical School, Boston, Mass; Departments of
Epidemiology and Nutrition (Mr Ding), Harvard School of Public
Health, Boston, Mass.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

COX-2 Inhibitors, Other NSAIDs, and Cardiovascular Risk:
The Seduction of Common Sense
Graham
JAMA 2006;0:296.13.jed60058-4.


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