New meta-analyses evaluate effect of COX-2 inhibitors on renal and CV events, including arrhythmia

Two recent analyses published in the Journal of the American Medical Association (JAMA) evaluating the adverse risks of cyclooxygenase-2 (COX-2) inhibitors offered continued support for the 2004 decision to remove rofecoxib from world markets. The research also demonstrated a lack of association between celecoxib and adverse cardiovascular and renal effects.

McGettigan et al conducted a meta-analysis of 23 controlled observational studies (17 case-controlled analyses included 86,193 patients; 6 cohort analyses included 75,520 users of selective COX-2 inhibitors, 375,619 users of nonselective nonsteroidal anti-inflammatory drugs [NSAIDs], and 594,720 unexposed participants). The quality of studies analyzed was evaluated using the quality assessment instrument. Case-control studies could score a maximum of 4 points in the selection and exposure categories and 2 points in the comparability category, and cohort studies could score a maximum of 4 points for selection and outcomes assessment and 2 points for cohort comparability. All studies, except for 2 abstract case-control studies, scored 7 to 8 points.

A dose-related cardiovascular risk with rofecoxib was observed; the summary relative risk (RR) with doses ≤25 mg/d was 1.33 (95% CI, 1.00–1.79), and the summary RR with doses >25 mg/d was 2.19 (95% CI, 1.64–2.91). This risk was elevated during the first month of treatment. A similar association was not made with celecoxib (RR=1.06; 95% CI, 0.91–1.23). Older NSAIDs also were evaluated, with diclofenac exhibiting the highest risk (RR=1.40; 95% CI, 1.16–1.70); other older NSAIDs, including naproxen, had summary RRs close to 1.

In the same issue of JAMA, Zhang et al evaluated risks of adverse renal events (renal dysfunction, hypertension, and peripheral edema) and arrhythmia events related to COX-2 inhibitors and examined drug class effects and temporal trends of the apparent effects of COX-2 inhibitors. The authors acknowledged their study as the first to suggest that rofecoxib could be linked to an increased risk of arrhythmia, a different effect than that observed with other COX-2 inhibitors. The meta-analysis included data from 116,094 participants pooled from 114 randomized, double-blind clinical trials. A total of 286 arrhythmia and 6,394 composite renal events were identified (2,670 peripheral edema, 3,489 hypertension, 235 renal dysfunction). The authors reported significant heterogeneity of renal effects across agents (P for interaction=.02), indicating no class effect.

Compared with controls, rofecoxib was associated with an increased risk of arrhythmia (RR=2.90; 95% CI, 1.07–7.88) and composite renal events (RR=1.53; 95% CI, 1.33–1.76), and increased adverse renal effects were associated with greater dose and duration (both P≤.05). Rofecoxib was associated with an 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). Compared with controls, celecoxib was associated with a lower risk of renal dysfunction (RR=0.61; 95% CI, 0.40–0.94) and hypertension (RR=0.83; 95% CI, 0.71–0.97) and showed no effect on arrhythmia. No significant risks were reported with other agents.

In an editorial regarding these studies, David J. Graham, MD, MPH, criticized current FDA policies, practices, and procedures, which he says "lead it to ignore potential safety problems." Dr Graham also criticized Merck, the manufacturer of rofecoxib, for failing to change rofecoxib's label after reports of a 5-fold increase in thromboembolic cardiovascular events among patients treated with 50 mg/d of rofecoxib compared with those treated with 1,000 mg/d of naproxen in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial. Graham suggested that, in light of the data presented in the 2 systematic reviews, physicians should first consider naproxen for patients who require chronic pain relief, with the addition of a proton pump inhibitor (PPI) for patients at high risk of NSAID-related gastrointestinal tract complications.

Although the authors of both studies acknowledged several limitations, they defended the validity of their conclusions and said the strengths outweighed the risks of potential flaws.

Merck issued a press release in response to the articles, which stated: "The observations published in today's Journal of the American Medical Association (JAMA), and the opinions expressed in an accompanying editorial, regarding a potential increased short-term cardiovascular thrombotic risk of Vioxx, are not supported by the current weight of the clinical trial data." With regard to the increased renal risk reported by Zhang et al, Merck added, "Since Vioxx was first marketed, the product label has included precautionary information about the risk of peripheral edema and hypertension in certain individuals, which are well-documented adverse effects associated with NSAIDs."

SOURCES McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and non-selective inhibitors of cyclooxygenase 2. JAMA. 2006;296:1633–1644.

Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA. 2006;296:1619–1632.

Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense. JAMA. 2006;296:1653–1656.

Merck & Co., Inc. Statement about COX-2 inhibitor review studies in the Journal of the American Medical Association [press release]. Whitehouse Station, NJ: Merck; September 12, 2006.