- Purpose
- Typical Antiinflammatory
Vioxx
Over the past decade, few drugs have been such touchstones for controversy as the painkiller Vioxx, developed and sold by Merck. Charges that the Food & Drug Administration ignored evidence that Vioxx elevates the risk of heart attack and stroke were major factors leading to the creation of a quasi-independent board at the agency to monitor the safety of drugs after they are approved (C&EN, Feb. 21, page 10). And Merck's voluntary recall of Vioxx last September helped spur a shift at FDA toward a stance of greater caution.
Vioxx is a striking example of a drug that appeared very promising in short-term clinical trials, involving relatively few patients. But after the drug had been given to millions of people, serious problems emerged that were not evident when it was first launched.
Prior to its withdrawal, Vioxx had generated annual revenues of about $2.5 billion from sales in 80 countries. Now, Merck faces thousands of lawsuits over alleged health problems from Vioxx. But questions remain about whether the net benefits of the drug outweigh the risks for some patients. Some arthritis victims claim it is the only medicine that relieves their pain without causing ulcers.
Launched in 1999, Vioxx is a nonsteroidal anti-inflammatory drug (NSAID) that specifically inhibits the enzyme cyclooxygenase-2 (COX-2). Like the similar cyclooxygenase COX-1, COX-2 is involved in the synthesis of prostaglandins responsible for inflammation. COX-1, however, also has a protective effect on the stomach lining. Two other arthritis drugs introduced at about the same time as Vioxx--Bextra (2001) and Celebrex (1998)--also specifically block COX-2. Older NSAIDS, such as ibuprofen and naproxen, block both COX-1 and COX-2 and are responsible for stomach ulcers in some patients. FDA estimates that older NSAIDs cause 10,000-20,000 deaths from bleeding in the gastrointestinal tract every year in the U.S.
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In February, an FDA advisory committee decided that all three specific COX-2 inhibitors--Vioxx, Bextra, and Celebrex--elevate the risk of heart attack and stroke to varying degrees but that their benefits outweigh their risks for some individuals. Although it recommended against banning any of these drugs, FDA said that strong warnings should be placed on all three, advising against use in patients with heart problems. Despite this decision, Merck made no moves to try to get Vioxx back on the market. And in April, FDA decided to ask Pfizer to withdraw Bextra because, in addition to its heart attack risk, it causes serious, and potentially life-threatening, skin reactions in some patients.
Many studies conducted before Vioxx was approved indicated that it reduces the pain of arthritis without causing stomach bleeding and ulcers. For example, in one 12-week trial, 42 of 167 patients on ibuprofen developed ulcers, whereas only 7 of 186 on Vioxx developed this condition. Altogether, about 60 preapproval studies involving a total of about 5,000 subjects revealed little risk of heart attack and stroke from Vioxx.
The first strong indication that Vioxx might increase cardiovascular risk came in a study called VIGOR completed in 2000. It showed a decreased risk of gastrointestinal ulcers in 56 patients on high doses of Vioxx as compared with 121 on naproxen. But those on Vioxx suffered more heart attacks. Merck scientists, however, did not conclude from this study that Vioxx increased the heart attack rate. They said, instead, that naproxen had lowered the rate.
Recent research involving larger study groups, however, provided stronger evidence that Vioxx elevates heart attack risk. An FDA-funded retrospective analysis of 1.4 million patients showed that those taking more than 25 mg of Vioxx daily had a 3.6 times greater risk of heart problems as those on older NSAIDs such as naproxen. And patients taking 25 mg of Vioxx per day had 1.5 times the risk of cardiac events as those on older NSAIDs. In contrast, patients on Celebrex had no increased risk of cardiac events compared with those on older NSAIDs. Study author David Graham, an FDA researcher, concluded that Vioxx may have caused between 88,000 and 140,000 excess cases of serious coronary heart disease since its launch in 1999. When testifying about his research at a Senate hearing last fall, he charged that FDA is incapable of protecting the public from dangerous drugs.
In October, the British journal Lancet published a scathing editorial saying that Merck should have addressed concerns about Vioxx several years ago by conducting a well-designed clinical trial. It also claimed that FDA, after hearing early concerns about Vioxx, should have compelled Merck to conduct further evaluations of safety, but instead asked only for labeling changes.
The study that convinced Merck to withdraw Vioxx from the market was designed to test whether the drug would lower the risk of polyps in the colon, a precursor to colon cancer. The patient group receiving 25 mg of Vioxx daily for 18 months had a fourfold greater incidence of heart attack and stroke than the placebo group.
Although Vioxx has been recalled in the U.S., about a dozen Indian firms make generic versions that can be ordered over the Internet from almost any country. So despite its withdrawal from the U.S. market, Vioxx, or its equivalent, still plays a role in global medicine.—
