Clinical InvestigationAcute Ischemic Heart DiseaseUnder-reporting of cardiovascular events in the rofecoxib Alzheimer disease studies
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.