Vioxx nation

COX-2 inhibitors

Jan 27th 2005
From The Economist print edition

The risks and benefits of new anti-inflammatory drugs

FOR drugs that are meant to relieve pain, COX-2 inhibitors—a new class of medicines to treat arthritis and other inflammatory diseases—are causing plenty of discomfort these days. Merck, an American drug company, withdrew Vioxx, its $3 billion-a-year blockbuster, from the market in September after clinical trials revealed it doubled the risk of heart disease. The safety of several other COX-2 inhibitors, among them Celebrex and Bextra made by Pfizer, the world's largest drug company, has also been questioned. Next month America's Food and Drug Administration (FDA) will hold a public hearing to look at the risk and benefits of these drugs.

Even the FDA is suffering serious side-effects from the controversy over COX-2 inhibitors. Last November, David Graham, one of its officials, testified before a Senate hearing on the risks of Vioxx. He alleged that the FDA had tried to suppress his research and should have acted years earlier when signs of the drug's risks first appeared. By being more interested in getting new drugs to market than scrutinising their safety, Dr Graham believed “the FDA has let the American people down, and sadly, betrayed a public trust.”

In this week's Lancet, Dr Graham has published the research that prompted his congressional comments. He and his colleagues from Vanderbilt University and Kaiser Permanente, an American managed-care company, have studied the records of 1.4m of Kaiser's members who were prescribed several different anti-inflammatory drugs between 1999 and 2001. More than 8,000 of them developed serious heart disease, leading to more than 1,500 deaths over this period.

Misfortune, however, was not evenly distributed. After accounting for age and sex, those taking Vioxx had a significantly higher chance of developing heart disease than those on Celebrex. Even naproxen, an older anti-inflammatory drug once said to protect the heart, was associated with a slightly elevated risk of heart disease. And contrary to Merck's recent study suggesting that such problems with Vioxx start to appear after a year and a half of treatment, Dr Graham's team found an elevated risk within four months of starting the drug. Extrapolating these findings to the American population at large, Dr Graham chillingly estimates that 88,000-140,000 extra cases of serious heart disease may have resulted from people taking Vioxx between 1999 and its withdrawal.

For all their bad press, the COX-2 inhibitors can help patients who suffer gastro-intestinal bleeding and other nasty complications from older anti-inflammatory drugs, because of the way these newer drugs act on particular inflammation pathways in the body. Indeed, a smaller study by Fadia Shaya and her colleagues at the University of Maryland, published in the current issue of Archives of Internal Medicine, shows no rise in the risk of heart disease among those taking COX-2 inhibitors compared with those taking the old drugs in their target population, mainly young, poor black women. As Dr Shaya points out, it is important to look at the relative risk—and what works in one population may not work in another.

The trouble with the COX-2 inhibitors is that they have been prescribed to a far wider population than may have strictly needed them. Caleb Alexander and his colleagues from the University of Chicago and Stanford University have looked at national survey data to understand when American doctors prescribe these drugs. Their findings, also published in Archives of Internal Medicine, show that much of the rapid rise of these drugs has been among those who could have taken older—and cheaper—anti-inflammatory drugs instead.

Between 1999 and 2002, they estimate that prescriptions of COX-2 inhibitors to those at lowest risk of gastro-intestinal complications (and thus in least need of the new drugs) roughly trebled. Ironically, all the direct-to-consumer advertising that aimed to bring these drugs to the masses may result in them being taken out of reach permanently.

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