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Review | Clinician's Corner

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(13):1619-1632. doi:10.1001/jama.296.13.jrv60015.
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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.

Conclusions Published online September 12, 2006 (doi:10.1001/jama.296.13.jrv60015).

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Figure 1. Trial Selection Process
Graphic Jump Location

COX indicates cyclooxygenase.

Figure 2. Time-Cumulative Analysis of Rofecoxib and Risk of Renal and Arrhythmia Events
Graphic Jump Location

*Sensitivity analyses of the 9 trials with 20 300 participants (10 126 drug, 10 174 control group) and 15 arrhythmia events (13 drug, 2 control group) without half-integer correction using sparse-events exact methods: Fisher exact test P =.004, and Mantel-Haenszel pooled relative risk 6.52 (95% CI, 1.48-28.8; P=.004).



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