Lessons to learn from the COX-2 saga

Yes, FDA reforms are needed. And marketing distorts how medications are used. But one moral to the story is that all drugs have risks.

The bad news for the COX-2 pain relievers started in September 2004. Rofecoxib (Vioxx) was pulled from the market after a study testing whether the pain reliever could prevent colon polyps instead showed that it doubled heart attack and stroke risk.

In December 2004, it went from bad to worse. The FDA put its strongest "black box" warning on valdecoxib (Bextra), another COX-2 inhibitor. One study of celecoxib (Celebrex), the best seller in the class, showed that it, too, increased cardiovascular risk, although a smaller study gave it a clean bill of health. Pfizer kept Celebrex on the market, but the FDA forced the company to stop advertising it to the public.

To add to the confusion, the National Institute on Aging stopped an Alzheimer's disease study because of evidence that naproxen — the active ingredient in over-the-counter Aleve — also increased cardiovascular risk. Yet, many doctors literally couldn't believe the naproxen finding because there was no theoretical reason or experimental evidence for the drug increasing heart disease risk. In fact, like its fellow nonsteroidal anti-inflammatory drug (NSAID), aspirin, there was some reason to think it could protect against heart attacks.

By the beginning of 2005, the COX-2 headache was wearing off a bit. A consensus had developed: The evidence for cardiovascular side effects is strongest for Vioxx and Bextra, intermediate for Celebrex, and weak for naproxen.

In the spring of 2005, the FDA asked Pfizer to voluntarily withdraw Bextra from the market — and asked manufacturers of all prescription NSAIDs to include a boxed warning that highlights the potential increased risk for cardiovascular events and serious gastrointestinal bleeding associated with these drugs. Manufacturers of over-the-counter NSAIDs were also asked to change their labeling to provide more specific information about the potential risks from these drugs and to remind consumers to take these medications according to the package instructions.

Sorting out risks and benefits

Well before the COX-2 drugs were on the market, experts suspected that they might raise the risk for narrowed arteries and blood clots, a combination that would lead to heart attack and stroke. We are also reminded, usefully, that although these studies found a doubled or even tripled risk for heart attack and stroke, the risk was less than 1% to begin with and developed after the drugs were taken for a year and a half or more. Especially with so many people taking these drugs, a doubling of risk is hardly trivial. On the other hand, a small risk doubled remains a small risk.

One more consolation: The whole episode provides "teachable moments" about the risks of drugs, the limitations of discordant studies, the effects of pharmaceutical marketing, and the weaknesses of the FDA. Here are a few morals from the COX-2 story:

There's no such thing as a free lunch — or a medication free of side effects. One of the ironies is that the COX-2 inhibitors were marketed as having fewer side effects than older analgesics. Minimizing side effects is a worthy endeavor. The history of pharmacology, especially its recent chapters, could be written as a search for medications that have fewer of them. But we're not at the end of this (or any other) history. You can't take any medication without entertaining some risk of experiencing side effects.

The fuzziness in the risk-benefit math. Every medication (and medical treatment) teeters between benefit and harm. Randomized clinical trials are the best way to get objective information about where the balancing point lies. But even such "gold standard" studies leave plenty of room for debate. The results may be objective, but their interpretation is not.

Moreover, the balance of benefit and risk differs from one person to the next. The COX-2 drugs were developed to provide stomach-sparing pain relief. They haven't been shown to be more potent pain relievers than the older NSAIDs like naproxen and ibuprofen — just less likely to cause stomach trouble.

So the risks of the COX-2 drugs may outweigh the benefits for someone who has heart disease and who hasn't tried other pain relievers or nonmedical approaches (exercise and weight loss can help a lot with some types of pain).

But the benefit may outweigh the risk for a younger person without heart disease who can't tolerate the side effects of the older pain relievers and who doesn't get relief from acetaminophen (Tylenol, other brands). That's why many people were unhappy that some of these drugs were pulled from the market: Particularly for those who had taken them only after alternatives failed and who didn't have heart disease or risk factors for it.

The COX-2 inhibitors were showing real promise in reducing the development of precancerous polyps and their growth into full-blown colon cancer. In fact, the heart disease risks came to light in trials testing them for that purpose. Some cancer experts saw the risk-benefit ratio in this context as being completely in favor of the COX-2 drugs: An uncommon risk of cardiovascular problems versus the possibility of preventing the second most common cause of cancer death in far more people. Certainly some would accept an increased risk of heart disease as the price for lowering their risk of colon cancer.

"On average" needs a reality check. Randomized clinical trials give us information about the risks and benefits for the "average" person. But that average patient is a statistical abstraction, a way of neatly summarizing the outcome of a study, not a flesh-and-blood human being. Individual experiences will differ considerably.

It's clear that your genes can affect your response to a drug, but for most medications, including the COX-2 inhibitors, we don't know yet which genes are important. Nor do we have an easy, affordable way to test for them. Doctors hope that this will change as the field of pharmacogenomics (drug therapy tailored to individual genetic makeup) blossoms.

But it's not just your genes that determine how your body will respond to a given medication. Your lifestyle may also tip your personal risk-benefit equation. People whose lifestyle makes them vulnerable to heart disease may be at greater risk from a drug like Vioxx than those with a heart-healthy lifestyle.

Let buyers beware, but give them good information. There are certainly plenty of precedents for drugs staying on the market despite dangerous side effects, even in these litigious times. For example, sildenafil (Viagra) was found to interact dangerously with the nitrate drugs used for angina. Pfizer urged doctors and patients not to use Viagra and nitrates together — but kept the drug on the market. Some Vioxx users asked whether something similar might have been done for Vioxx.

But to make wise choices, patients need good, complete information. That means lucid explanations, free of medical jargon but sufficiently detailed to give them some heft. For the inquisitive layperson, it can be frustrating when health information is too general and watered down.

Many news outlets did an impressive job covering the COX-2 story. And the Internet does make it a small world: We found some very well written pieces on the Web site of the European Medicines Agency, the European Union's version of the FDA.

Marketing changes the equation. The FDA issued new guidelines in 1997 that made it easier for drug companies to advertise on television. As a result, the companies tripled their spending on direct-to-consumer advertising in the late 1990s.

Whatever one may think about this trend, it has undoubtedly shaken up American medicine. Gone are the days when doctors and medical journals stood as the learned intermediaries between patients and the pharmaceutical companies. When drugs are advertised heavily to patients — and marketed to doctors, too — there's a powerful tendency to prescribe "the latest and greatest" and often the most costly — even though older and far less expensive drugs often are just as effective.

Were it not for marketing, Vioxx might have enjoyed a nice, quiet career as a niche medication. Vioxx and the other COX-2 drugs really make sense only for two relatively small groups of people: those who don't get pain relief from the older NSAIDs, and those who do get relief but only at doses that cause stomach irritation or gastrointestinal bleeding. Because of broader use stimulated by marketing, people who stood to gain little from Vioxx were exposed to unnecessary risks.

Why can't all the studies reach the same conclusion? Different studies have come to different conclusions about the COX-2 inhibitors (and naproxen). Why the mixed messages?

Experts can argue the finer points of study design and biostatistical analysis ad infinitum, but there are some fundamental reasons that anyone can understand.

Size matters hugely in research studies. Having fewer subjects means a quicker answer but provides a less reliable estimate of both the risks and benefits. If studies seem to zig and zag, coming up with different answers, it may be because they were small.

Even a large study involving several hundred subjects is likely to miss a side effect that occurs in one in every thousand. Similarly, longer studies may pick up on problems that shorter ones will miss. And even two studies of exactly the same size and length can be at loggerheads if the subjects differ in a material way, for example, if one study has more people with heart disease risk factors.

One way to improve the situation would be to do a much better job of monitoring side effects after a drug has been approved, when many thousands of people are taking it. Right now, the FDA doesn't do that very well, and some have suggested creating a separate agency for monitoring drugs once they're on the market.

Put more tools in the FDA toolkit. Right now, the FDA has three basic choices: It can recall a drug, threaten to recall it, or order the manufacturer to change the drug's label. Some reformers think the agency needs more options. For example, the European Medicines Agency can suspend the sale of a drug for a year while its safety record is examined.

Putting restrictions on the prescribing of drugs is another possibility. Here the FDA has to tread carefully, because legally it regulates only medications and medical devices, not the practice of medicine. But it has already taken some steps in this direction. After patients protested when alosetron (Lotronex), the irritable bowel syndrome medication, was taken off the market, the FDA allowed GlaxoSmithKline to start selling it again under a program that requires a signed statement from patients that they understand the drug's risks and benefits.