NEWCASTLE, Australia,-A pair of meta-analysis offered yet more evidence that Vioxx (rofecoxib) was the bad actor of the Cox-2 class of pain-killers—increasing both cardiovascular and renal risks.

Moreover, one of the studies raises new concerns about the cardiovascular safety of diclofenac, an older non-steroidal anti-inflammatory drug (NSAID).

Both studies—one done here and one at Harvard—were published online today in the Journal of the American Medical Association along with an editorial, by David J. Graham, M.D., M.P.H., of the FDA. Dr. Graham, who gained fame as a whistle-blower during Senate hearings on the Cox-2 drugs, said that taken together the studies confirm that Vioxx increased the risk of acute MI at low and high doses.

And the increased risk starts early, “probably with the first dose,” Dr. Graham wrote. His editorial was approved by the FDA “as an outside activity” but not as an official FDA statement.

The studies also indicated that there is an increased risk with Celebrex (celecoxib) at doses higher than 200 mg/day, but “at lower doses, the potential risk is less clear.”

Dr. Graham wrote that given these data, the safest course for physicians who treat chronic pain is to use naproxen, which can be combined with a proton pump inhibitor in patients at high risk for gastrointestinal complications. That combination is “less costly and as effective, and probably safer, than low-dose [Celebrex],” Dr. Graham wrote.

Vioxx increased the risk of cardiovascular events at both low and high doses and the increased risk was evident early, wrote Patricia McGettigan, M.D. and David Henry M.B., Ch.B., of the University of Newcastle. Their analysis included data from 23 observational studies (17 case-control and six cohort) of Cox-2 inhibitors and NSAIDs.

Among the non-selective NSAIDs the highest risk was with diclofenac, they wrote.

At 25 mg a day Vioxx was associated with a 33% increase in risk of cardiovascular events (95% confidence interval 1.00-1.79) and more than a doubling of risk for higher doses.

Diclofenac was associated with summary relative risk of 1.40 (95% CI 1.16-1.70), Drs. McGettigan and Henry reported. They concluded that Diclofenac “appears to be harmful at commonly used doses.”

The second meta-analysis by Jingjing Zhang, M.D., Ph.D., and colleagues of the Harvard School of Public Health was derived from data from 114 randomized, double-blind clinical trials that enrolled 116,094 patients.

Considering only Cox-2 inhibitors, Vioxx was the only agent associated with increased renal and arrhythmia risks, wrote Dr. Zhang and colleagues.

Compared with controls, Vioxx use almost tripled the risk of developing arrhythmia (relative risk 2.90, 95% CI 1.07-7.88) and significantly increase the risk of renal events (P≤0.05).

Celebrex, by contrast, lowered the risk of renal events by 39% (RR 0.61; 95% CI, 0.40-0.94) and lowered the risk of hypertension (RR 0.83; 95% CI,0.71-0.97) compared with controls.

The FDA-approved agents studied in the Harvard meta-analysis included Vioxx, Celebrex , and Bextra (valdecoxib). Of the three, only Celebrex remains on the market. The analysis also included data from clinical trials of three investigational Cox-2 drugs, paracoxib, etoricoxib, and lumiracoxib.

Among the findings in the study by Dr. Zhang and colleagues:

* The risk relative risk of composite renal events with Vioxx was 1.53 (95CI 1.33-1.76) and the risk increased with dose and duration (P≤0.05 for both). * Vioxx was associated with an increased risk of peripheral edema (RR, 1.43; 95% CI 1.23-1.66), hypertension (RR1.55; 95% CI 1.29-1.85) and renal dysfunction (RR 2.31; 95% CI:1.05-5.07).

Dr. Zhang and colleagues concluded that there was no evidence of a class effect for renal events and arrhythmia events across all Cox-2 inhibitors, but they cautioned that “further safety monitoring of current and emerging treatments” is warranted.

Merck withdrew Vioxx from the market in September 2004, when it said that data from a colon cancer prevention trial suggested that daily use of Vioxx for 18 months or longer increased the risk of cardiovascular events.

More recently, Merck announced that it had performed an incorrect statistical test on the data form the APPROVe (Adenomatous Polyp Prevention on Vioxx) trial, which led to the report of late risk. The Vioxx risk was apparently early, according to the most recent analysis from the company.

Pfizer withdrew Bextra from the market in early 2005 following reports that it, too, increased cardiovascular risk.

Merck recently announced that it would seek FDA approval for its investigational Cox-2 agent etoricoxib.

Dr. Graham said that Merck has submitted data to the FDA from three randomized trials that compared etoricoxib to diclofenac. In those studies, etoricoxib did not increase cardiovascular risk compared with diclofenac.

But, as Dr. McGettigan and Henry reported in their meta-analysis, diclofenac increased the risk of cardiovascular events by 40%.

“By inference, therefore, etoricoxib also must increase cardiovascular risk,” Dr. Graham wrote. “but that inference is not immediately apparent because of the way [the three randomized trials were] designed, and by the way it appears that the findings are being interpreted and positioned.”

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