A Painful Mistake

By Christine Gorman

IN A WORLD IN WHICH THE FORTUNE OF a pharmaceutical company can rise and fall on the strength of a handful of blockbuster drugs, Vioxx was a giant. Unveiled with great fanfare by Merck in 1999, it was part of a group of prescription medicines called COX-2 inhibitors that were supposed to be safer for treating arthritis pain than over-the-counter remedies like aspirin, ibuprofen and naproxen. Thanks to an aggressive, multimillion-dollar marketing campaign, more than 20 million Americans took Vioxx at least once. The drug racked up $2.5 billion in worldwide sales last year and accounted for 11% of Merck's revenue.

So it wasn't just big news when Merck announced last week that it was pulling Vioxx off the market; it was a bombshell that rocked financial markets and set doctors' phones ringing. A few days earlier, an independent panel had concluded that taking the drug for more than 18 months doubled the risk of suffering a heart attack or stroke. Merck had a choice: it could beef up its warning labels, or it could bite the bullet and pull its blockbuster off the market. Given the legal risks of selling a drug known to cause heart problems, Merck probably did the right thing.

The reaction on Wall Street was swift and brutal. Merck's chief executive Ray Gilmartin announced that the company's 2004 earnings could shrink as much as 20%. Its stock promptly lost $28 billion of its market value, temporarily dragging the Dow Jones industrial average down with it. The timing could not have been worse for Merck, whose sales last year grew a paltry 5%, compared with 23% in 2000, and whose big anticholesterol drug Zocor will lose patent protection in 2006, with nothing to replace it. Some analysts wondered whether the company was ripe for a merger--an idea Merck executives have steadfastly rejected. "Without a deal, Merck cannot grow," says Richard Evans, a senior analyst with Sanford C. Bernstein & Co. "In fact it may get smaller."

Worried patients peppered doctors and other health-care providers with questions of their own. Should they stop taking Vioxx right away? How long could they expect its side effects to persist? Was there another drug they could take instead? Most doctors rushed to reassure. "This is a serious issue and should be dealt with seriously," says Dr. David Wofsy, president of the American College of Rheumatology. "But for the vast majority of people who are on Vioxx or who have ever been on Vioxx, there is no harm." (More on that in a bit.)

The recall also raised long-simmering doubts about the benefits of the whole class of COX-2 inhibitors. These so-called designer drugs, which include Celebrex and a newer drug called Bextra, were supposed to offer the pain-killing power of aspirin without the damage to the stomach lining. But they were a lot more expensive than over-the-counter pain-killers (prescriptions cost as much as $2 to $3 a day), and many doctors felt the drugs were being hyped far beyond their medical value. "These agents have been the subject of absolutely intensive, unrelenting marketing," Wofsy says. Even if you don't have arthritis, you can probably hum the Celebrex jingle or Vioxx's It's a Beautiful Morning theme.

So far, none of the other COX-2 inhibitors have been tarred with Vioxx's brush. Pfizer's Celebrex has been studied the longest; some patients in three ongoing Celebrex trials have been followed for several years without any signs of cardiovascular effects. Bextra, also from Pfizer, hasn't been tested as long, but so far the data look good. Two more COX-2 inhibitors, Arcoxia (from Merck) and Prexige (from Novartis), are awaiting FDA approval. "Obviously, we now have to look more carefully at the other members of the class," says Dr. Steven Nissen, a cardiologist at the Cleveland Clinic who voiced his concerns about Vioxx several years ago.

The first hint that there might be a problem with Vioxx surfaced in 2000, just a year after the drug won FDA approval. A study that compared Vioxx with naproxen (the active ingredient in Aleve) showed that Vioxx cut gastrointestinal problems in half but increased the risk of heart attack from 0.1% to 0.4%. Those results were ambiguous, though. Was Vioxx causing the heart attacks, or was naproxen protecting the heart? Few experts fault Merck for continuing to market Vioxx on the basis of that study alone.

But the evidence didn't stop there. Subsequent studies based on reviews of large numbers of clinical records continued to show troubling indications. The final straw was a piece of research that Merck conducted. It was a particularly careful study--a randomized, double-blind trial of 2,600 patients, comparing Vioxx with a placebo--designed to determine whether Vioxx might prevent the formation of polyps in the colon. The study was scheduled to last three years, but two weeks ago, the panel of doctors and statisticians that was monitoring the trial's safety data informed Merck that the evidence of cardiovascular problems in the subjects taking Vioxx was clear--so clear that the trial should be halted immediately. The study showed that patients who took Vioxx for more than 18 months had a small but significant risk of suffering a heart attack or stroke--1.5% for Vioxx users, compared with 0.75% for the placebo group. After a weekend spent double-checking the safety panel's data and conclusions, Merck officials told the FDA that although there was no increase in the number of deaths among those who took the drug, the company was voluntarily recalling its drug.

So what should you do if you have a bottle of Vioxx in your medicine cabinet? "For younger patients who are otherwise well, I think you can afford to wait until you talk to your doctor," says Dr. Meggan Mackay, a rheumatologist at Columbia Presbyterian Medical Center in New York City. Older patients, particularly those with a history of heart disease, should stop taking the drug immediately and consult their doctor about a new treatment. But don't throw away your bottle; Merck has promised to reimburse customers for unused medication. For more information, call 1-888-36-VIOXX.

In the meantime, don't assume you necessarily have to switch to another COX-2 inhibitor. Aspirin, ibuprofen and naproxen work just as well as the prescription drugs, provided that you are not at increased risk for bleeding, peptic ulcer or other gastrointestinal problems. (See box for more details.)

Remember also that there's more to treating arthritis pain than popping a few pills. If you have osteoarthritis (the kind that is the result of wear and tear on the joints), you can also find substantial relief just by building up the muscles that surround those joints--for example, through gentle exercises like Tai Chi, yoga or walking. The point is to keep the joints moving, even if they start the day a little stiff.

More broadly, the news about Vioxx shows once again why it is so important to continue to monitor the safety of a medication even after it has been approved. Most clinical studies involve only a few thousand patients and may last less than a year--enough to catch major problems. But once a drug passes muster with the FDA, it is often prescribed for millions of people. That's when more subtle side effects may emerge. Unfortunately, so-called postapproval surveillance still tends to get short shrift.

In addition, most drug companies carefully select study participants to exclude people who have more than one disease. That makes good scientific sense, but it's not very reflective of the real world, where someone might suffer from arthritis and heart disease and stomach problems all at once. Figuring out which drugs truly are safe and effective--and under what circumstances--is bound to become more complex as the population ages and more medications are developed for chronic conditions. Vioxx may be the biggest withdrawal of a drug in years, but it won't be the last. --With reporting by Unmesh Kher/New York

With reporting by Unmesh Kher/New York