In February 2001, Dr. Steven Nissen of the Cleveland Clinic was part of an advisory panel put together by the Food and Drug Administration to address mounting evidence suggesting the popular COX-2 inhibitor Vioxx could increase risk of heart disease and stroke.
The drug had been approved two years earlier and millions throughout the world were taking daily pills to reduce the pain and inflammation of arthritis and other conditions.
Nissen told his colleague and chairman of cardiovascular medicine, Dr. Eric Topol, that he was not satisfied with the explanation put forth by Merck officials, who said Vioxx wasn’t harmful to the cardiovascular system. According to Merck, comparison studies of Vioxx versus naproxen, sold as Aleve, were actually picking up on Aleve’s protective effects on the heart, rather than alleged harmful effects from Vioxx.
The Cleveland scientists, in collaboration with Dr. Debabrata Mukherjee, analyzed data from all studies on Vioxx and the other COX-2 inhibitors to see if they could find a heart attack link. And there it was. Patients on Vioxx had a fivefold increase in heart attacks and stroke, while Celebrex, the first COX-2 inhibitor, had an insignificant 0.2 higher incidence.
The findings were published in the Journal of the American Medical Association in August 2001. Since then, Topol has written editorials to get colleagues and drug regulators to pay attention.
“Merck summarily refuted and dismissed our concerns,” Topol said yesterday during a telephone interview. “It’s been a tough road. You get the sense that we are extremists.”
But yesterday, he received a call from a Merck scientist, Dr. Richard Pasternak, vice president of clinical research in cardiovascular/atherosclerosis. Pasternak told Topol he was right all along and laid out results of a new 18-month study testing the benefits of Vioxx in reducing future polyps in colon cancer patients. “He said that it was the risk of heart attack that I forecasted,” Topol said. “I felt vindicated. But it’s a shame. They could have done something years ago.”
He also blames federal drug regulators. “FDA officials have also been remiss,” he added. “They all knew. They could have defined and quantified the risk for heart disease. They could have done something.”
FDA scientists have been mounting their own study. The FDA’s D.J. Graham was working with California scientists on data from 1.4 million people in the Kaiser Permanente HMO system. Of these, 26,748 were taking Vioxx. In September, Graham presented the findings: a threefold increase in heart attacks and stroke among Vioxx patients. FDA investigators have been analyzing the data and figuring out whether to strengthen the warning, or pull the drug, when Merck called Monday to say it was withdrawing the drug.
Until a few weeks ago, Pasternak was director of preventive cardiology and cardiac rehabilitation at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School. He joined Merck earlier this month.
He acknowledged that he called Topol yesterday, but would not return a call to comment on the discussion.
Topol said that since his 2001 JAMA paper, he has watched cardiology colleagues and Merck scientists publish paper after scientific paper cutting down his findings. “They had consultants write papers,” he said. The papers appeared in reputable journals, including Circulation, the American Heart Journal, the Journal of the American College of Cardiology and the American Journal of Rheumatology. He said that a Merck-funded study earlier this year in Circulation showed a threefold increased risk for heart attack and stroke and Merck had its scientist taken off the list of authors.