Merck & Co. Inc. first developed Vioxx as a new class of arthritis medication. But it quickly landed in medicine cabinets as a treatment for everything from muscle aches to menstrual cramps, with 3.4 million prescriptions filled in Canada last year, and 84 million people taking it around the world.
Those numbers now represent the scope of unease as Merck announced yesterday that it is yanking Vioxx off the market worldwide after discovering, in a new clinical trial, that the drug increases the risk of heart attack and stroke.
"For reasons of patient safety, we felt the best course of action was to withdraw [Vioxx]" said Francois Bertrand, executive director of medical research at Merck Frosst Canada Inc.
The stock price of the U.S.-based pharmaceutical giant, the world's second-largest drug maker, fell $12.07, or 26.8 per cent, to close at an eight-year low of $33 in New York. But the revelation was hardly a complete surprise.
Just a year after the high-profile 1999 launch of Vioxx, Merck had reason to suspect its big seller might be bad for the heart. Later studies added to those suspicions.
The developments may raise questions about regulations that bring new drugs to market, further damage faith in the industry and cast doubt on whole classes of new-generation medications.
"It's kind of a reminder to go back to the basics," said Volodko Bakowsky, a rheumatologist at the QEII Health Sciences Centre in Halifax who had prescribed Vioxx, whose generic name is rofecoxib.
"This went from headlines of being a super Aspirin, to this [withdrawal] The message people are going to get now is that this drug is a horrendous danger, when they thought it had the toxicity of water. The truth is probably somewhere in between."
Arthritis patient Stuart Winick was among those trying to keep the news in perspective.
"I have been taking this drug for about five years. So I assume that if I was going to have adverse effects, I would have had them by now," said the 57-year-old real estate broker from Thornhill, Ont.
"There may be some people reacting hysterically, but there is no point," said Mr. Winick, who found the drug effective. "I would say it would be a big loss if there were no viable alternatives."
Doctors say they will likely return patients to standard anti-inflammatory drugs, such as Aspirin.
Merck had been conducting a double-blind clinical trial comparing the drug effects against a placebo in the treatment of precancerous polyps of the large bowel.
The study, involving 2,600 patients between the ages of 40 and 96, was to have lasted three years. But last week, just 18 months into the research, the company learned the risk of heart attack and stroke was double in patients taking Vioxx and halted the trial, which included 75 patients in Toronto and Montreal.
Marshall Godwin, a family doctor in Kingston, Ont., and professor of family medicine at Queen's University, said he had lately stopped prescribing Vioxx because its link to heart problems was "in the wind."
"Even elderly patients with their ears to the ground had heard about it and came in and asked to stop taking it," he said. "For me, this makes me a little cautious about the idea of always using the latest or newest drugs."
Vioxx, along with Pfizer's painkilling arthritis drug Celebrex, was approved in Canada and the United States in 1999 with great expectations. Both represented a new class of medications known as cyclo-oxygenase-2 inhibitors, which shut off the Cox-2 enzyme that contributes to pain and swelling. Known for short as Cox-2 inhibitors, these highly styled compounds earned early praise not so much for what they did as for what they did not do.
The non-steroidal anti-inflammatory medications (known as NSAIDS) previously used to treat arthritis increased the risk of ulcers or bleeding in the stomach in the long term. The Cox-2 inhibitors, which would become some of the most successful and profitable drugs in history, caused comparatively few gastrointestinal woes.
Anticipation from patients and the medical community was such that both Health Canada and the U.S. Food and Drug Administration fast-tracked the review of these medications. But Health Canada spokesperson Jirina Vlk said yesterday that giving these drugs "priority" in no way affected the "rigour" of the review.
As soon as they hit the market, sales took off. According to IMS Health Canada, a private company that tracks prescription drug sales, Vioxx, for example, was one of the 10 top-selling drugs in the country, with retail sales in pharmacies last year of $194-million.
"These [Cox-2]drugs expanded the market," said Dr. Bakowsky. "They were perceived as being so safe that they were suddenly given to people who never should have been given anti-inflammatories in the first place."
For example, although Health Canada notes that Vioxx is not authorized for pediatric use, doctors have prescribed it to young girls to treat menstrual cramps.
Yet back in 2000, just one year after Vioxx was approved, Merck learned the drug may be associated with an increased risk of cardiovascular problems. That year, it published an 8,000-patient study in the New England Journal of Medicine that had compared the gastrointestinal side effects of Vioxx to naproxen, an NSAID. Unexpectedly, the study turned up evidence that those taking Vioxx suffered significantly more cardiovascular events, such as heart or angina attacks, than those taking naproxen.
This result prompted both the FDA and Health Canada to require Merck to list the risk of cardiovascular events on its Vioxx label by 2002.
Meanwhile, this May, Canadian researchers published a study in The Lancet that found Vioxx increased the risk of hospitalization for heart failure by 80 per cent within one year of prescription.
That study reviewed the medical records of almost 45,000 Ontario patients prescribed Cox-2 inhibitors between April 2000 and March 2001 and compared the data with 100,000 people not prescribed these drugs.
David Juurlink, a scientist with the Institute of Clinical and Evaluative Sciences at Sunnybrook and Women's College Health Sciences Centre in Toronto, and a co-author of the Lancet study, said, however, that some "side effects might be hard to detect in the context of a clinical trial" before a drug is approved.
"There's no way around this," he said. "We really don't know what the adverse-effects profile is going to be until we study it in a large population."
It is unclear at this point why Vioxx increases the risk of heart disease.
But some speculate that it can contribute to high blood pressure and stays in the body longer than its competitor, Celebrex.
Dr. Juurlink, who is also a clinical pharmacologist, noted that Celebrex did not increase the risk of hospitalization for heart failure in the study and said some patients may turn to that drug.
But Dr. Bakowsky said people may want to avoid Cox-2 inhibitors after the Vioxx withdrawal: "Some people might just decide to take Tylenol."
However, Dr. Bakowsky said patients already prone to gastrointestinal side effects may also have to take a drug to prevent the secretion of acid in the stomach along with a traditional NSAID.
More than four million Canadians have arthritis and other muscoskeletal diseases, and one in five people over age 65 take Cox-2 inhibitors.
With a report from Paul Taylor