Early Twinges over Vioxx

Cardiologist Steven Nissen, who was first to warn of the arthritis drug's risks, says despite prior concerns, we didn't have hard data

Dr. Steven Nissen was the first to raise concerns about the risks to the heart of Merck's (MRK ) pain medication, Vioxx, back in August, 2001. At that time, the renowned cardiologist with The Cleveland Clinic reported in the Journal of the American Medical Assn. that an analysis of existing research on Vioxx suggested that arthritis patients taking the drug were twice as likely to suffer heart attacks as those taking older anti-inflammatories. Vioxx works by inhibiting COX-2, an enzyme that causes pain and inflammation.

The drug first came to Nissen's attention five years ago, when the Food & Drug Administration asked him to evaluate Vioxx during the approval process. Even then he was concerned about possible cardiovascular risks. Nissen spoke with BusinessWeek Senior Writer Catherine Arnst about Merck's decision to pull the drug from the market (see BW Online, 09/30/04, "A New World of Pain for Merck"). Edited excerpts of their conversation follow:

Q: Why does Vioxx pose a risk to the heart?

A:

We don't know exactly why. We have some ideas. The platelet is a factor in blood coagulation. When you take an aspirin, it interferes the production of a substance in the blood called thromboxane that makes platelets sticky and more likely to clump up, interfering with blood flow. On the other side, there's a countervailing force: Prostacyclin, a substance that makes platelets less sticky. Aspirin reduces the thromboxane without affecting the good stuff, the prostacyclin. There's a theory that Vioxx may raise the bad stuff, the thromboxane, but doesn't raise the good stuff.

Q: Why doesn't Celebrex, Pfizer's (PFE ) COX-2 inhibitor, pose the same danger?

A:

Celebrex might work slightly differently. We haven't seen the heart risks in Celebrex, and it has been out on the market for about as long as Vioxx.

Q: Why didn't the problem with Vioxx show up during clinical trials, before it was approved?

A:

That's a big problem with drug development. In Phase 3 trials [the final stage before seeking drug approval] you only test the drug on several thousand patients for a limited period. If you have a rare but serious side effect, you may not pick that up. Statistical chance can explain [why] it didn't show up.

But this [most recent] trial was longer, the control arm was on a placebo rather than another drug, and the patients were older. If you're testing a drug on 40-year-olds, if it raises the risk of heart attack, that's not likely to show up.

Q: Should the FDA now require the same trials on Celebrex?

A:

I think Celebrex won't get a lot of additional scrutiny -- but any new [COX-2 drugs] should.

Q: Should the FDA have rejected Vioxx in the first place?

A:

No. This was an unusual enough and subtle enough signal that it would have been premature to act on it when we first noticed it. Even in August, 2001, when we published our first report on the risks, it was highly speculative. We didn't have hard data. We had some soft data and some suspicions about the mechanism of action. We could just as easily have been wrong.

Q: How should the drug-approval process be changed to avoid such problems in the future?

A:

There's potentially a solution, but it's very costly. We need a more robust post-approval surveillance system to keep track of adverse events with new drugs. The system is voluntary on the part of the drug companies now, but I would have it be mandatory. Studies have found that only between 1% to 10% of serious adverse events with drugs on the market are actually reported. So the FDA is making decisions on inadequate data now. This [would be] a very important initiative, in my opinion.

Edited by Patricia O'Connell