Merck agreed to pay $4.85B US in Vioxx settlements. (Daniel Hulshizer, Associated Press, file)

Red flags about the pain reliever Vioxx were present at least three years before the drug was taken off the market, U.S. researchers say.

In Monday's issue of Archives of Internal Medicine, Dr. Harlan Krumholz of Yale University School of Medicine, and his colleagues said the heart risks of Merck & Co's painkiller Vioxx could have been detected three years before the company withdrew the drug in September 2004.

The researchers were paid consultants for the plaintiffs in a lawsuit against Merck by people who had heart attacks or strokes after taking the drug.

The researchers pooled data from 30 studies on the effectiveness of the drug, compared with a placebo, that were conducted by the company between 1996 and 2004 but were not available before the lawsuit began.

The first safety concerns arose in December 2000 when 21 of the 30 studies had been completed, the researchers said. The red flag reached a statistically significant level by June 2001 — nearly 3½ years before the drug was voluntarily taken off the market because of concerns about increased risk of heart attack and stroke after long-term, high-dosage use.

At that time, there was a strong concern that patients taking Vioxx were at greater risk of or adverse events or death from cardiovascular conditions or blood clots.

Detect harm early

"Comprehensive, rigorous analysis of clinical trial data allows the earlier identification of drug risks, promoting more informed treatment decisions, protecting the public's health and perhaps saving lives," Dr. Joseph Ross, a professor of geriatrics and palliative medicine and of medicine at Mount Sinai School of Medicine, who led the review, said in a release.

An amendment to a U.S. Food and Drug Administration act now requires all trial results to be published in its database within 12 to 24 months of completion, which could give doctors and patients the information they need when determining whether to start a new drug treatment, the study's authors said.

"Our study provides insight into what should have been known about the risks of rofecoxib," they concluded, using the generic term for Vioxx.

"If we are to detect harms early and protect the public's health, while ensuring the availability of new, clinically effective therapeutics, a system must be established that makes full use of all existing evidence."

Of the 30 studies, 18 were published before September 2004, when the drug was withdrawn. Six were published after that, and six were never published.

Merck rejected the methodology and conclusions of the latest report.

"There is nothing new here. We studied Vioxx before and after it was on the market. We studied it extensively using more rigorous methods than these authors used and we didn't see any cardiovascular risk," Ron Rogers, a Merck spokesman, told Reuters.