BOSTON, Massachusetts, and NEWCASTLE, New South Wales, Australia–Two drug safety studies published online ahead of print by the Journal of the American Medical Association that call into question the current passive monitoring system used by the US Food and Drug Administration (FDA) to monitor drug safety, relieve some concerns about safety of selective cyclooxygenase (COX)-2 inhibitors (coxibs) as a class, and raise surprising questions about the safety of a conventional nonsteroidal anti-inflammatory drug (NSAID).1,2 The investigators report that:
â— Rofecoxib (Vioxx®), but not other coxibs, is associated with cardiovascular and kidney risks
â— Rofecoxib risk is elevated during the first month of treatment and not only from prolonged use
â— The risk of vascular occlusion associated with diclofenac is nearly as great as that associated with rofecoxib
â— Many of the problems associated with rofecoxib could have been recognized earlier if the FDA had used an active, cumulative surveillance system
"The finding that the adverse renal effects of rofecoxib were apparent as early as 2000 did surprise us." —Eric L. Ding
Some Rofecoxib Problems Could Have Been Detected in 2000
This meta-analysis, which was the first comprehensive review of all available randomized trials on adverse renal and arrhythmia risks of COX-2 inhibitors, and one of the largest systematic reviews ever conducted, was based on examination of more than 500 trial reports. The investigators then aggregated data from 114 randomized, double-blinded trials that included more than 116,000 participants. This large sample size enabled the researchers to examine the effects of individual drugs within the general class of COX-2 inhibitors. The drugs studied included rofecoxib, celecoxib (Celebrex®), valdecoxib (BextraR), paracoxib (DynastatR), etoricoxib, and lumiracoxib.
There was significant heterogeneity of renal effects across agents, indicating no class effects. However, rofecoxib was associated with increased risk of arrhythmia compared with controls (relative risk [RR], 2.90) and with increased risk of renal events (RR,1.53). Adverse renal effects with rofecoxib increased both with greater dose and with longer duration (both, P <.05). By contrast, celecoxib was associated with a lower risk of renal dysfunction compared with controls (RR, 0.61). The authors' time-cumulative analyses indicated that the adverse risks associated with rofecoxib were evident by the end of the year 2000 for peripheral edema and hypertension and by 2004 for risk of arrhythmia.
"The finding that the adverse renal effects of rofecoxib were apparent as early as 2000 did surprise us," Mr. Ding said.
"Notably for policy and clinical decision making, our results also suggest that a time-cumulative meta-analytic approach for examining available trial safety data would have helped clarify apparent adverse effects several years earlier than the current report. The knowledge of all potential adverse effects is important and indeed time-sensitive, for physicians and patients both need complete information about risks and benefits to properly use COX-2 inhibitors and other clinical treatments. However, the current system of postmarketing surveillance has been recognized to possess a variety of shortcomings, including an overall lack of vigilance.... Of future benefit, the establishment of an independent postmarketing surveillance system based on such an active and continuous data aggregation structure would have many advantages over the current passive reporting system," the authors write.
Review of Observational Studies Confirms Rofecoxib CV Risk, Reveals Unexpected Diclofenac Risk
A second study also released early online by JAMA confirmed a dose-related risk of cardiovascular (CV) events with rofecoxib. Patricia McGettigan, PhD, and David Henry, MB, from the University of Newcastle, New South Wales, Australia, conducted a meta-analysis of observational studies to compare the risks of serious CV events (predominantly myocardial infarction) with individual NSAIDs and coxibs. The authors based their analysis on 17 case-control studies that included 86,193 cases with CV events and more than 500,000 controls, and on 6 cohort analyses that included 75,520 users of selective COX-2 inhibitors, 375,619 users of nonselective NSAIDs, and nearly 600,000 unexposed participants.
They found a dose-related risk associated with rofecoxib (RR, 1.33 with <e;25 mg/day and 2.19 with >25 mg/day). The elevated risk was apparent during the first month of treatment.
Celecoxib was not associated with an elevated risk of vascular occlusion (RR, 1.06). "Celecoxib was not associated with a similarly elevated CV risk, but it clearly has the potential to increase risk at higher doses," Dr. Henry told CIAOMed.
Among the older NSAIDs, diclofenac was associated with an elevated risk (RR, 1.40). Naproxen, piroxicam, and ibuprofen all had summary RRs close to 1.0. "In terms of [CV] risk, naproxen is the best choice," Dr. Henry said.
"The main surprise was diclofenac," Dr. Henry added. "We did not really expect to find a risk, but it was consistent over studies and high enough to warrant a reconsideration of its use in patients at risk of cardiovascular events."
Dr. Henry advised that low-risk individuals, such as those who are younger and have no CV risk factors, use the cheapest agent that works, and that individuals at increased CV risk use should use naproxen and add a proton pump inhibitor if there are gastrointestinal problems.
References
1. 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: September 12, 2006 [Epub ahead of print.]
2. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase. A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006;296. September 12, 2006. [Epub ahead of print]