Elsevier

American Heart Journal

Volume 164, Issue 2, August 2012, Pages 186-193
American Heart Journal

Clinical Investigation
Acute Ischemic Heart Disease
Under-reporting of cardiovascular events in the rofecoxib Alzheimer disease studies

https://doi.org/10.1016/j.ahj.2012.05.002Get rights and content

Background

In September 2004, rofecoxib (Vioxx) was removed from the market after it was found to produce a near doubling of cardiovascular thrombotic (CVT) events in a placebo-controlled study. Its manufacturer stated that this was the first clear evidence of such risk and criticized previous analyses of earlier CVT risk for focusing on investigator-reported events. We studied contemporaneously adjudicated CVT events to assess the information on cardiovascular risk available while the drug was in widespread use.

Methods

Using an intention-to-treat analysis of adjudicated CVT deaths, we analyzed detailed patient-level data collected during 3 randomized placebo-controlled trials of rofecoxib versus placebo that had been designed to define the drug's possible role in the prevention or treatment of Alzheimer disease. All trials had been completed by April 2003.

Results

In the 3 studies combined, the data indicated that rofecoxib more than tripled the risk of confirmed CVT death (risk ratio = 3.57 [1.48-9.72], P = .004). This finding reached the P < .05 level of significance by June 2001.

Conclusion

Intention-to-treat analysis of placebo-controlled studies of rofecoxib for Alzheimer disease demonstrated that the drug produced a significant increase in confirmed CVT deaths nearly 40 months before it was removed from the market. By contrast, published analyses of these trials were restricted to on-treatment analyses (ending 14 days after cessation of treatment) that did not reveal this risk. Intention-to-treat analyses of clinical trial data can reveal important information about potential drug risks and should be performed routinely and reported in a timely manner.

Section snippets

Data sources

Protocol 078 was a placebo-controlled, parallel-group, 48-month, double-blind study that enrolled 1,457 patients > 65 years old with mild cognitive impairment and randomized them to treatment with 25 mg rofecoxib daily or placebo. The primary end point was the development of AD, as determined by a battery of neuropsychological tests and referred to in study documents as “conversion.” The study began in April 1998, and data collection was completed on the last patient in April 2003. Protocol 091

Results

The ITT analyses revealed a highly significant tripling or quadrupling of the CVT mortality rate in patients who had been randomized to receive rofecoxib in these studies. Considering participants in all 3 Alzheimer studies combined, there were 20 confirmed CVT deaths in the rofecoxib arm versus 6 CVT deaths in the placebo arm (RR = 3.57 [1.48-9.72], P = .004). In many of its CVT analyses, including data it discussed in rofecoxib labeling approved in April 2002, the manufacturer pooled data

Discussion

The manufacturer stated that it withdrew rofecoxib from the market in September 2004 because of new findings of increased cardiovascular risk first detected in the placebo-controlled APPROVe study, which it said were completely unanticipated. However, our analyses present evidence that the conventional ITT analyses of 3 placebo-controlled clinical trials that had been prespecified by the company would have revealed meaningful increases in CVT events with rofecoxib years earlier. These analyses

Disclosures

Conflict of interest: Drs. Avorn, Furberg, Madigan, and Mayer have served as consultants for plaintiffs in litigation against Merck & Co Inc related to rofecoxib. Dr. Avorn did this work pro bono and did not receive any compensation. Mr. Sigelman previously represented plaintiffs in litigation against Merck & Co Inc related to rofecoxib.

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    Daniel W. Sigelman is now with the Office of Policy, Office of the Commissioner, U.S. Food and Drug Administration. This paper reflects his views and should not be construed to represent FDA's views or policies.

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