Merck & Co. yesterday pulled the blockbuster pain medicine Vioxx off the market, announcing that a new company-sponsored study showed the drug doubled the risk of heart attack and stroke when taken daily for more than 18 months.
The decision sent 2 million patients worldwide, most of them arthritis sufferers, scrambling to find alternatives to a drug that has been marketed heavily as a safer alternative to ibuprofen and naproxen. It spurred some to contact lawyers about potential suits over heart damage possibly caused by Vioxx. Doctors said potentially tens of thousands of patients might have suffered problems from the drug, though it is not clear whether anyone has died from it.
Merck, the world’s third-largest drug company, was reeling yesterday, as its market value dropped by more than one-quarter, or $26 billion. The company sold $2.5 billion worth of Vioxx in 2003 and advertised it heavily.
Many doctors praised Merck’s action, but questioned why the company and the Food and Drug Administration hadn’t acted sooner. Various studies over the last four years have linked Vioxx with heart problems, but the company consistently downplayed the risk, saying the studies were flawed or inconclusive.
”To a clinician, there’s been enough evidence in place to tip the balance away from using this drug,” said Dr. Jerry Avorn, an associate professor at Harvard Medical School who has studied the drug. ”The question is why was Merck so slow in mounting a clinical trial to show this. And why wasn’t the FDA on their case more vigorously.”
The company’s new study is the first to examine the drug’s impact over an extended time period. The FDA approved the drug in 1999, based on short-term studies of 5,000 patients, and did not detect any heart problems. In 2002, two years after another company-sponsored study first suggested a link between Vioxx and heart disease, Merck agreed to disclose the potential connection in detailed information provided to doctors.
Most recently, a large study commissioned by the FDA and released in August showed an increased risk of heart attacks and sudden cardiac deaths in Vioxx patients, but not in those on Celebrex.
Doctors and Merck officials said there was no evidence of a similar risk for related drugs, such as Celebrex and Bextra, collectively called Cox-2 inhibitors. Both drugs are made by Pfizer Inc.
But the acting commissioner of the FDA, Dr. Lester M. Crawford, said in a statement yesterday that the agency would monitor the other drugs. FDA officials said yesterday they had already been reviewing recent studies on Vioxx to decide if an additional warning was needed. The FDA could have but did not order the company to do additional studies.
Crawford said that all nonsteroidal pain killers, if taken chronically, can pose health risks, including stomach bleeding and liver and kidney damage. Some of the drugs are also linked to high blood pressure and swelling of the extremities. Vioxx and Celebrex have been aggressively marketed as pain pills that can reduce the risk of stomach problems, compared to ibuprofen and naproxen, over-the-counter drugs widely used for arthritis.
A Pfizer official, Dr. Gail Cawkwell, said the company knows of no study that shows an increased heart risk with Celebrex, which holds the largest share of the Cox-2 market. However, Cawkwell said they had not specifically studied heart risk or received results from tests of continual use for more than 18 months.
Merck and FDA officials advised patients taking Vioxx to contact their doctors immediately to discuss alternatives. Yesterday, local rheumatologists said they were flooded with calls from concerned patients and were switching them to other medications.
Some, such as Dr. Elinor Mody at Brigham and Women’s Hospital, said they had been prescribing Vioxx less often over the last year, since a study by Avorn and colleagues found that high doses of Vioxx were linked to as much as a 70 percent increase in heart attack risk in the first 90 days of use. Avorn, who recently published a book on the risks of prescription drugs, said the company had disputed the findings and the methodology of his study.
Yesterday, Merck said its own recent study of 2,600 patients, found a heightened risk that made them unwilling to continue selling the drug. The study, in which patients were randomly assigned to take Vioxx or a dummy pill, found that 15 of every 1,000 patients taking Vioxx suffered serious cardiovascular complications, compared with 7.5 per 1,000 on the placebo. The increase appeared only after patients had taken 25 milligrams of the drug, a typical dose, daily for 18 months, Merck officials said. There was no difference in the number of heart-related deaths.
”We believe this decision reaffirms Merck’s commitment to patient safety,” said Peter S. Kim, president of Merck Research Laboratories. Merck’s chairman, Raymond V. Gilmartin, said the company could have continued to sell the drug while warning patients about the increased risk, but decided that ”a voluntary withdrawal is the responsible course to take.”
Company officials said they moved quickly after a panel of doctors monitoring the safety of the study recommended a week ago that they halt it. The study, which began in 2000, was designed to see if the drug was useful for preventing a recurrence of colorectal polyps, but incidently revealed the heart problems. Kim said the company analyzed the heart data over the weekend, decided to pull the drug off the market, and told the FDA of its decision on Tuesday.
Merck officials said they did not know why Vioxx causes heart problems. But Dr. Eric Topol, chairman of the department of cardiovascular medicine at the Cleveland Clinic, suggested it is probably connected to the ability of Cox-2 inhibitors to suppress an enzyme that helps keep arteries healthy. He said it is likely that people who suffered heart attacks had undiagnosed heart disease when they began taking the drug.
Starting in 2001, Topol had called on Merck to specifically study the heart risk, and he later asked the FDA to place a drastic warning label on the drug. His concerns began with the 2000 Merck study that found that patients taking Vioxx had four- to five-times the risk of nonfatal heart attacks compared with patients taking naproxen. The company asserted at the time that the result was due to naproxen’s protective effect on the heart, as the firm continued to maintain yesterday.
”This is the first time we’ve seen this difference” in a rigorous study comparing Vioxx with a placebo, Kim said yesterday.
Topol said the company and the FDA had ignored warning signs. ”In 2001, the FDA should have mandated that Merck and other makers do trials in heart patients,” he said. ”The FDA didn’t, and the companies didn’t.”
Lyle Shelly of Needham said he stopped taking Vioxx two weeks ago after hearing a news report about the potential for heart trouble. Shelly, 55, suffers from rheumatoid arthritis and had taken Vioxx for more than a year without any significant side effects. But he was concerned, and his doctor switched him to Celebrex.
”I don’t have any heart problems,” Shelly said, ”but I don’t want any. I’m happy I stopped it.”