Researchers found a 100 percent increased cardiovascular risk linked to rofecoxib (Vioxx, Merck) during off-drug follow-up, confirming the results of the previous APPROVe trial, which found that the drug produced a 79 percent increased cardiovascular risk for patients administered rofecoxib, according to a letter published in the Dec. 13/27 issue of the Archives of Internal Medicine.
After the results of the APPROVe trial showed this risk, Merck withdrew rofecoxib from the shelves in September 2004. However, a study last month in AIM found that the CV risk could have been realized nearly four years prior to Merck voluntarily pulling the drug from the market.
“Implications for individuals who used rofecoxib are unclear, since it was withdrawn from the market nearly five years ago,” the authors wrote. However, long-term follow-up results have shown a CV risk even after patients stopped drug treatment.
In the letter, Joseph S. Ross, MD, and his colleagues from the Yale University School of Health in New Haven, Conn., aimed to examine whether the drug still posed a risk even after treatment was stopped. To do so, the researchers used data from study 078 (made available through Vioxx litigation by Merck), which was a randomized, double-blind trial that examined whether rofecoxib could delay Alzheimer’s progression in adults with mild cognitive impairment.
Included were patients who were administered one 25 mg/d dose of rofecoxib (723 patients) or placebo (728 patients), and the researchers used any incidence of death or CV thromboembolic adverse event as the primary endpoint.
The mean age of patients was 75 years of age and 33 percent were female. The average duration of on-drug treatment was 623 days for those administered rofecoxib and 724 days for patients on placebo.
The researchers reported that 43 percent of patients were at risk for a first CV event. During off-drug follow-up, there were 22 CV thromboembolic adverse events among the group administered rofecoxib and six among those administered placebo.
Deaths occurred in 23 patients treated with rofecoxib and nine administered placebo and CV thromboembolic adverse events or death occurred in 45 patients during off-drug follow-up—32 in 287 patient-years of patients administered rofecoxib and 13 in 234 patient-years in patients administered placebo.
However, the researchers noted that the estimates of the off-drug CV risk from study 078 are conservative because CV safety was not a primary or secondary outcome and due to the fact that all patients had cognitive impairment.
“To improve drug safety evaluation within clinical trials, periods of off-drug surveillance should be used when appropriate to ensure observation of long-term effects,” the authors concluded.