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Vioxx was recalled by Merck in September of 2004 and after a lot of scrutiny, Pfizer was forced to recall Bextra by the FDA last month. Both Merck and Pfizer are targets of tens of thousands of lawsuits for causing as many as 50,000 deaths in the US and as many as 140,000 personal injuries. Both companies deny that their drugs had anything to do with deaths or injuries, despite evidence like this study that there is a fundamental problem with the Cox-2 drugs.
Two randomized trials of COX-2 inhibitors — the gold standard of clinical evidence — conducted in 2004 at other institutions suggested that risk of cardiovascular disease might increase gradually during continued treatment with drugs such as Celebrex and Vioxx, even in individuals initially at low risk of the disease. (Related article: Pfizer continues to defend Bextra's safety) “The risk of heart attack and stroke became progressively evident during treatment with either Celebrex or Vioxx during the APPROVe and APC trials last year,” says Garret FitzGerald, MD, lead author of the study published online this week. FitzGerald is the Director of the Institute for Translational Medicine and Therapeutics at
Penn. The study was funded in part by the National Institutes of Health. Study co-authors Yan Cheng, Susanne Fries, Wen Liang Song, and Sandra Austin are from Penn, as well as Thomas M. Coffman from Duke University. (Related article: Vioxx more dangerous than Celebrex) These studies were designed to determine whether COX-2 inhibitors limited the development of benign growths in the large bowel of patients who-to the best of study authors’ knowledge-were at low risk of heart disease. “While the results of these trials are not conclusive, they are compatible with a gradual transformation of increased cardiovascular risk during continued dosing with either Celebrex or Vioxx,” says FitzGerald. “We need to determine how this might occur, and whether we can manage this risk by developing tests that reflect the process.” Earlier animal studies by Penn researchers and others showed that suppression of the protective fat prostacyclin, which is made by COX-2, could predispose individuals to a rise in blood pressure which, in turn, can accelerate hardening of the arteries, or atherosclerosis. COX-2 inhibitors such as older NSAIDs have been shown to raise blood pressure in people. In addition, the Penn group has shown in previous studies that shutting down prostacyclin hastens initiation and early development of atherosclerosis. (Related link: Pain relief drug guide) The current research expands on this notion. R. Daniel Rudic, PhD, and Derek Brinster, MD, and others in FitzGerald's laboratory, report that COX-2-derived prostacyclin also controls the changes that occur in the muscular lining of blood vessels in response to pressure-related changes in blood flow.
(Related article: BMJ
paper proves that Cox-2 drugs do not protect the stomach
lining)
| These findings suggest that during prolonged dosing with COX-2 inhibitors, several consequences of drug action-a rise in blood pressure, initiation, and early development of atherosclerosis, and now the architectural and functional response of blood vessels to such stress-could all interact in a reinforcing fashion to transform the risk of heart attack and stroke, even in previously healthy individuals. “We need to determine whether these mechanisms are operative in people, and if so, we should be able to develop tests which reflect this process,” says
FitzGerald. “This may allow us to detect the small number of individuals at risk of rapidly developing heart disease and stop the drugs before they run into trouble. We could also determine how quickly risk might dissipate on stopping the drugs. Certainly, the development of a rational approach to risk management will be key to giving Celebrex or other COX-2 inhibitors safely, even to healthy patients, for extended periods.” |
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