The need for additional studies to assess the potential for increased cardiovascular events with Merck's Vioxx was cited in FDA's original review of the COX-2 inhibitor.

FDA documents for Vioxx' initial approval note that "with the available data, it is impossible to answer with complete certainty whether the risk of cardiovascular and thromboembolic events is increased in patients on rofecoxib," the medical review states. "A larger database will be needed to answer this and other safety comparison questions."

"It is difficult to reach meaningful conclusions when the number of events is relatively small and the length of exposure and doses of rofecoxib used were different among studies," the documents state.

A trend towards an increased incidence of CV events in longer trials was detected, "but it is always expected to have some increase in the incidence of adverse events with longer time of observation."

Medical reviewers noted that CV adverse events were the most frequent serious adverse events in the full range of clinical studies contained in the original NDA. Most patients had CV risk factors. Events were most frequent in studies lasting longer than six months.

Merck withdrew Vioxx from the market Sept. 30 after a higher risk of CV events was definitively seen in a three-year colon polyps study. The CV risk signal was observed after 18 months of treatment (¹ Also see "FDA Has One Month To Mull Approval Of Merck's Arcoxia Following Vioxx Withdrawal" - Pink Sheet, 30 September, 2004.).

The same day that Vioxx was withdrawn from the market, FDA said that the original Vioxx safety database of 5,000 patients did not show an increased risk of heart attack or stroke.

"Analysis of the clinical database indicates that there is an unequivocal association between [Vioxx] and the occurrence of cardiovascular and renal adverse events in a finite number of exposed individuals," an April 30, 1999 consult from FDA's Division of Cardio-Renal Drug Products states.

While serious CV AEs occurred at a higher rate with Vioxx 50 mg (the highest labeled dose) than other NSAIDs at recommended doses, "whether that will translate into clinically significant differences in vascular-renal morbidity cannot be determined from the current osteoarthritis clinical database," cardio-renal reviewer Juan Carlos Pelayo, MD, added.

Reviewers ultimately concluded that Vioxx's safety profile was in line with non-specific NSAIDs.

Overall, the agency deemed rofecoxib generally safe and effective for short-term management of acute pain and dysmenorrhea and for the signs & symptoms of osteoarthritis. No post-marketing studies were requested.

A precaution about cardiovascular risk was added to labeling on April 11, 2002, based on a four- to five-fold increase in CV events for Vioxx patients versus naproxen patients seen in Merck's Vioxx Gastrointestinal Outcomes Research (VIGOR) study.

Review documents from the April 2002 approval, which also added a rheumatoid arthritis indication, echo many of the concerns raised in the original review. The medical review characterizes the potential CV risk as "a major unresolved issue."

"There is still concern for the question of cardiovascular thrombotic risks associated with the use of rofecoxib compared to naproxen or placebo, which cannot be definitively addressed by the studies to date," medical reviewers Joel Schiffenbauer, MD, and Lourdes Villalba, MD, said. "The existing published studies and databases reviewed are not conclusive."

The 2002 medical review also raises "the theoretical concern that rofecoxib may [be] pro-thrombotic based on its COX-2 specificity." Merck submitted a meta-analysis in support of its contention that an apparent signal seen in VIGOR was due to the cardioprotective nature of naproxen, thus reducing the risk of CV events.

"However, this analysis does not provide adequately robust data that a prospective randomized trial would," the review maintains. "The size and duration of submitted studies as well as the absence of meaningful comparisons to non-naproxen NSAIDs limits the conclusions from this meta-analysis."

FDA issued a March 2003 warning letter to curtail Merck's claims that VIGOR did not reflect a negative effect of Vioxx. The agency's ad division maintained that Vioxx promotions minimized the product's CV risk.

The original medical review also acknowledges the "theoretical concern that patients chronically treated with a COX-2 selective inhibitor may be at higher risk for thromboembolic cardiovascular adverse experiences than patients treated with COX-1/COX-2 inhibitors (conventional NSAIDs), due to the lack of effect of COX-1 inhibition on platelet function."

An article in the Aug. 22, 2001 Journal of the American Medical Association suggested there was a potential CV safety problem with COX-2s as a class. Pfizer's CLASS study, which was added to the Celebrex label June 7, 2002, verified the product's CV safety.

However, FDA's review of Pfizer's Bextra reflected rising concerns at the agency; reviewers requested a cardiovascular safety analysis of high risk patients. Bextra (valdecoxib) was approved Nov. 16, 2001. Labeling does not address cardiovascular risk.

Merck's follow-on COX-2 inhibitor Arcoxia is pending at FDA with an Oct. 30 user fee date, giving the agency a month to consider how the new information about Vioxx will influence Arcoxia's approval (² Also see "FDA Will Require Additional Long-Term Data For COX-2 Inhibitors" - Pink Sheet, 30 September, 2004.).

[Editor's note: Further analysis of the history of cardiovascular safety concerns with the COX-2 class will appear in the October issue of ³ Pharmaceutical Approvals Monthly. For a sample copy, contact customer service at 800-332-2181.]

- Mary Jo Laffler

Vioxx Cardiovascular Safety Raised Concerns During Original NDA Review

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