Vioxx

Vioxx was a big story, underappreciated in my view. Vioxx (rofecoxib) was a new NSAID (non-steroidal anti-inflammatory drug) developed by Merck and approved by the FDA in 1999.

Aspirin interferes with two forms of cyclooygenase, Cox-1 (involved with protecting the stomach lining) and COX-2 (involved with pain and inflammation). So you get relief of pain and inflammation, but also stomach bleeds, in some cases serious. with Vioxx, the goal was something that only inhibited COX-2.

There was a study comparing Vioxx and naproxen – VIGOR, (Vioxx GI Outcomes Research). They found an elevated risk of heart attacks in the VIOXX users – a fourfold increase. This was bad, since heart attacks are A. not rare, especially in the painkiller population and B. very dangerous. Merck defended their new drug through creative bullshit: they argued that naproxen had a protective effect, and that heart-attack-prone Vioxx users in the study were simply suffering from a naproxen deficiency. at the time, there was no evidence supporting that. In order for their arguments to have been valid, naproxen would have had to had a such a strong protective effect against heart attacks that it would have one of the most valuable drugs on the market, far more valuable than Vioxx… As it turns out, naproxen has an anti-clotting effect similar to aspirin, and probably a mild protective effect, like aspirin: but not a strong protective effect.

The Vigor study was submitted in February 2001. The New England Journal of Medicine, a few months later, found that the authors had failed to mention some strokes and heart attacks near the end of the trial. The authors used a cutoff for cardiovascular effects (bad news) that was earlier than the cutoff for gastrointestinal effects (good news). why? Because they were weasels, of course. There was a lot of money riding on this drug’s success.

Other people began to notice the increased heart risks – looking at data from HMOs and such. Merck fought back. There was an MD at Stanford that was concerned about Vioxx: Merck called up the dean of Stanford Medical School at home and warned him about possible loss of financial support: he told them to go fuck themselves.

Vioxx was a bad deal. Although it caused fewer stomach bleeds, it doubled heart attack rates (meta-analysis by Juni et al, Lancet November 5 2004), which increased heart attacks by about 5 x 10-3 per year, about 30-40% of which are expected to be fatal. So, on the one hand it reduced one kind of risk by about 1.0 x 10-4 per year while increasing another kind of risk by about 1.5 x 10-3.
Fifteen times and what do you get?

With those risk numbers, it is hard to imagine any subpopulation that would have a net benefit from Vioxx. Old people are more prone to bleeds, but they’re also more prone to heart attacks.

Now it is true that there were studies that showed greater efficacy: 21 such were reported by Scott S. Reuben, former chief of acute pain at Baystate medical Center in Springfield Mass. But as it turns out, he made them all up. There’s is no evidence that Merck knew about this, but it does perhaps say something about the general climate in big pharma.

Merck knew the gist of this for four years before they pulled the plug on the drug. They had their their drug reps lie about cardio risks, threatened researchers and sued journals that talked about the emerging cardio risks. Few physicians were aware of these risks, even though a close reading of the journals would have suggested it – because hardly any physicians read the journals.

Epidemiologists think that Vioxx caused something like 40,000 deaths. Ron Unz has argued that it likely caused far more than than that – but his case is without any strength. He says that the crude death rate increased from 1998 to 1999 – usually it slightly decreases from year to year – and that it decreased dramatically in 2004, when they pulled Vioxx.

You don’t want to look at national figures: you want to look at a known population of users, so that any effect is not drowned by other effects swirling around in the general population. If you want to know the effects of height on income, you look at the correlation between individual height and income, not the relation between income in tall states and income in states that are on average short. You want to disaggregate. For example, the crude death rate is strongly affected by the age structure: if there was a baby boom many years ago, such that the boomers are now entering prime heart-attack years, that wouldn’t mean that age-adjusted heart disease was getting worse – it would mean that the country was, on average, getting older.

The age-adjusted death rate did go up 0.7% from 1998 to 1999: but deaths due to heart disease actually dropped, as did strokes. COPD, septicemia, and Alzheimers deaths went up. Something may have been happening, but it doesn’t look like a Vioxx effect. Anyhow, Vioxx only showed up in the second half of 1999 in any event.

At the same time, the epidemiologists have strong evidence that Vioxx really did cause something like 40,000 extra deaths over those five years – but that’s not enough to generate a clear signal in the overall mortality rate. For that you need something big, like the Holodomor or the 1918 flu.

Moreover, although the age-adjusted death rate dropped from 832.7 in 2003 to 816.5 in 2004, a bigger drop than from 2002 to 2003 (845.3 to 832.7), it dropped to 798.8 in 2005 (a bigger drop) and 776.5 in 2006 (a still bigger drop).

It’s not unlike the Maguffin in The Fugitive: Harrison Ford finds out that Devlin MacGregor is pushing a dangerous drug, However, the reaction in the movie was very different from the actual reaction to Vioxx. In the movie, people were outraged. In real life, not so much. I don’t think that movie was unrealistic about that – rather, times have changed.

I’ve seen many libertarian types defend Vioxx. Sebastian Mallaby did so in the editorial pages of the Washington Post. But then he’s apparently a marsupial, with low encephalization: he argued that Bush pardoning Merck would somehow solve all our economic troubles.

In the 70s corporations were the bad guys, whether they were or not. Today, billionaires are your friend.