By now most of the seven million people in the UK who suffer from arthritis will know that Vioxx, a new type of widely prescribed anti-inflammatory drug, has been withdrawn because it doubled the risk of a heart attack. But until this week it wasn’t clear why. Australian scientists have just reported that Vioxx and other drugs of this type — Cox-2 inhibitors — significantly raise blood pressure, which is a serious risk factor for heart disease.
Meanwhile, a team at The Johns Hopkins University has found that these drugs also cut back on one of the chemicals in the brain that can protect neurons after a stroke. These are just the latest in an extraordinary string of revelations over the past five months about the dangers of the Cox-2 drugs, which have left thousands of people worried that they may have been damaged.
The crisis began four months ago, on September 30, when Vioxx, prescribed to 400,000 people in the UK and taken by 80 million worldwide, was suddenly withdrawn by the manufacturers, Merck. At first Merck was commended for its prompt action but evidence rapidly emerged which suggested that not only had the company known about the side-effect for years but had also harassed — and in one case sued — independent researchers who raised the issue of possible dangers (see panel).
In December, The Lancet published an angry editorial which declared that “the unacceptable cardiovascular risks of Vioxx were evident as early as 2000” and condemned the “astonishing failures” in picking up these problems after the drug was launched. The article estimated that Vioxx had caused an extra 27,000 heart attacks and deaths. By the end of January, however, that figure had risen dramatically.
Another Lancet study put the number of “excess cases of serious coronary heart disease” from Vioxx at between 88,000 and 140,000. It concluded: “People taking Vioxx had a 34 per cent higher chance of coronary heart disease than those taking other NSAIDS (non-steroidal anti-inflammatory drugs, such as ibuprofen and aspirin)”.
It is findings such as these that have led lawyers both in this country and in the US to mount compensation cases against Merck.
“I’ve had two heart attacks in the past four months,” says Robert Green, 57, whose case is being handled by Leigh Day and Co, in London. He had been taking Vioxx for four years, during which time his blood pressure rose and he began to have chest pains. “I have no history of heart problems in my family. No one warned me about any danger of heart attacks. I’m not taking anything for my arthritis now and getting out of bed in the morning can be murder.”
Cox-2 inhibitors such as Vioxx were developed to overcome the gastrointestinal damage that painkillers such as aspirin and ibuprofen can cause when used in the long term. These drugs cause about 12,000 hospital admissions a year in the UK and 2,600 deaths, equivalent to the mortality rate from cervical cancer and melanoma combined.
This week the US Federal Drug Administration will be considering whether to withdraw all Cox-2 inhibitors. Already, leading American cardiologists have called for two of them — Celebrex and Bextra — to have a warning on the packaging. Celebrex, used by 600,000 people in the UK, has also been found to double or triple the risk of heart attack.
If they are withdrawn, going back to other NSAIDS isn’t really an option in the long term. A British Medical Journal (BMJ) report in December found that they were little better than a placebo at handling the pain of osteoarthritis and, because of the side-effects, recommended they should not be taken for more than a week. Developed specifically not to damage the stomach, there was never any evidence that Cox-2 drugs were more effective at reducing pain and inflammation than other NSAIDS. However, 70 per cent of the Cox-2 prescriptions were given to people without a high risk of stomach damage.
Faced with the choice of bleeding guts or heart attacks, some arthritis experts have recommended that patients choose their pain relief on the basis of their “individual risk for heart disease or stomach problems”.
However, there is another way. In recent months there has been a virtual glut of positive results for a variety of Cam (complementary and alternative) treatments. The Christmas edition of the BMJ, for instance, carried reports that two long-term favourites — magnetic bracelets and acupuncture — both performed better than a placebo. In the case of the bracelet, a placebo-controlled trial involving 194 patients found that the bracelet decreased pain by about the same amount as Cox-2 inhibitors.
Many arthritis sufferers will already have tried omega-3 oil and glucosamine, both of which have trials in their favour, although a three-month study last autumn found that glucosamine was no better than a placebo. Less familiar, but also backed by evidence from small trials, are such remedies as ginger, vitamin B3 and bromeline, a pineapple enzyme; in a recent study 59 per cent of those who used it reported an improvement.
Other more exotic options include Blue Ease cream, which contains emu oil; the Aborigines have long used the bird’s fat to relieve muscle and joint pain. The makers claim that its anti-inflammatory relief is equal to ibuprofen. Also there are a number of studies which show the effectiveness of an extract from the Devil’s Claw plant (Harpagophytum procumbens), a traditional African remedy.
Last month a double-blind study of Civamide cream — a synthetic version of capsaicin (the hot ingredient in chillies) — found a “statistically significant improvement” in pain and movement in 695 patients. Collagen hydrolysate is a form of gelatine that has been found to reduce pain and slow the rate at which joints wear away. It is little known in the UK but more widely used in Germany.
“There are few reliable clinical trials of these complementary approaches,” says Dr Madeleine Devey, a scientific adviser to the Arthritis Research Campaign. “There are other safer drugs that people can use, such as codeine and paracetamol, and many people benefit from techniques of pain management. It’s a matter of finding what works for you.”
Robert Green, waiting to hear about the heart operation he needs, is hoping desperately that he finds that combination soon.
KEEPING IT QUIET
Just how hard Merck fought to keep the link between Vioxx and heart problems under wraps was revealed by The Wall Street Journal in November.
Company e-mails showed that its researchers had been worried about the risk since 1996. An internal document intended for the sales team about how to deal with tough questions was labelled “Dodge Ball Vioxx”.
Merck also targeted academics who questioned the drug’s safety. Last month it emerged that the company forced one of its researchers to remove her name from a study involving more than 50,000 patients that linked Vioxx with heart attacks. It was published six months before the drug was withdrawn. A spokesman said Merck “never has had a policy of retaliating against scientists” but “has a right to defend its medicines against false claims”.
