The pharmaceutical company Merck announced the withdrawal of its non steroidal anti-inflammatory drug (NSAID) Vioxx (Rofecoxib) in September 2004 because of evidence that its use was associated with an increased risk of heart attack and stroke, writes Dr Muiris Houston, Medical Correspondent
NSAIDs are a mainstay in the treatment of osteoarthritis and rheumatoid arthritis. The older NSAIDs, such as Naproxen, blocked the effect of an enzyme, cyclooxygenase (Cox), which helps to make substances called prostaglandins. These chemicals are involved in the inflammatory process, such as that present in joints affected by arthritis.
Originally it had been thought there was only one Cox enzyme. But then a second one, called Cox-2, was discovered. And while the original Cox, now called Cox-1, has other vital functions like protecting the stomach lining, Cox-2 seemed to be present mostly during times of inflammation. An extensive research effort went into developing Cox-2 drugs, on the basis that they would relieve pain but without causing stomach ulcers.
Vioxx was one of the first Cox-2 drugs to emerge. However, in approving the drug, the different clotting effects of the Cox-1 and Cox-2 enzymes appear to have been forgotten about. Cox--2 inhibits the formation of blood clots. Therefore, if you use a drug that blocks Cox-2, the overall effect is to promote thrombosis in blood vessels.
As Dr Garrett Fitzgerald, professor of pharmacology at the University of Pennsylvania's School of Medicine, noted: "Coxibs [ Cox-2s] inhibit prostaglandin 12 formation and therefore would be expected to elevate blood pressure, accelerate plaque formation and predispose patients to an exaggerated thrombotic response."
So when evidence emerged from a large trial of 8,000 people that patients taking Vioxx were almost two-and-a-half times more likely to have a heart attack or stroke than those taking a Cox -1 inhibitor, Naproxen, it looked like the ability of Cox-2s to promote blockages in blood vessels was causing harm to patients.
Significantly, the risk seemed to emerge in people who had taken Vioxx for 18 months or longer.
Further research then pointed to problems with other Cox-2 inhibitor drugs. In one case, the risk of an adverse cardiovascular event was three-four times higher in those taking the drug for an average of 33 months at high dosage compared with those given dummy pills.
The combined data suggest an association between duration and dose of Cox-2 intake and the probability of suffering a cardiovascular problem. And while most affected patients will have been identified by now by their doctors, for anyone who experienced a heart attack, a stroke or a sudden worsening in angina while taking a Cox-2 inhibitor, there may be a link.