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.

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37 Responses to Vioxx

  1. Ron Pavellas says:

    Thank you for this. As a Naproxen user, I am gratified never even to have heard of Vioxx. But your presentation has value above and beyond my petty concerns. You are protecting good science, or at least proper method.

  2. Great post. Physicians certainly don’t read journals, with the exception of the odd paper that a drug rep wrote for them.

    • dearieme says:

      I suspect that physicians learn from an old classmate who, while tipsy at a conference, spoke – insofar as he can remember – to somebody who attended a session in which it was said – if he understood aright – that something-or-other was good for patients.

  3. JoachimStrobel says:

    The Contergan case in Germany beats all that by far. A sleeping pill that caused birth defect, happened around 1960. Doctors saw that and first recommended to increase the number of nursing facilities for the handicapped. The US saw the problems before and never allowed the pill in the US. The company got eventually sued but never sentenced, they bailed out through a minor cash compensation. The last decade they market the same pill in Brazil where the same birth defects surface. They did put a sticker on the box saying that the pill not for pregnant women. Many women took it thinking it prevents pregnancy. The company still sells lifestyle cosmetics and I probably get sued spelling out their name.

    • amac78 says:

      Contergan, known as Thalidomide in the U.S.

    • Janet says:

      Oddly enough, thalidomide actually is approved by the FDA– originally (1998) for the treatment of leprosy, later for combination therapy for myeloma also. Several new analogs to thalidomide are either approved or going through the approvals process too.

      • gcochran9 says:

        Problem was chirality contamination.

        • JoachimStrobel says:

          The company in question was never convicted because their defense could prove that their was no known mechanism that would explain how the said defects were caused. Nobody disputed the correlation of Contergan vs birth defects but that did not help as the defense was making the point that it had to be Contergan plus smoking/alcohol/general unhealthieness/voting for the wrong party/not being married/voting for the communist…

      • JoachimStrobel says:

        Contergan was brought into Brazil as treatment for leprosy. With the said consequences, that 40 years after the disaster in Germany, the same birth defects were seen again in Brazil.

  4. pyrrhus says:

    Not “evidence based” medicine, but “finance based” medicine….Monsanto is following the same path…

    • Michael says:

      Good point. This aspect of Big Pharma will come as a surprise to Jayman, for example. Probably not enough data to suggest billion dollar companies have an agenda.

  5. Economic Sophisms says:

    I remember as an undergrad in 2009, (when my brain was colonized by the libertarian mind-virus,) getting into an argument with a medical doctor of some sort who was auditing a Bayesian statistics course I was in. He said that the pharmaceutical industry was rotten to the core and doctoring all sorts of studies, or spinning results. I just knew that couldn’t be true because free markets. I’m glad to be virus free today.

    Not sure what you do with this Vioxx episode, from a policy standpoint, but it makes me think of a Finnish saying: “If sauna, vodka or tar won’t cure you, you’re going to die”

    • Ron Pavellas says:

      Finns know stuff

    • gcochran9 says:

      Well, before you completely give up on your libertarian notions about free markets and medicine, what about all the progress coming out of nutritional and herbal supplements – under far milder regulation?

      That’s a joke, son.

    • gcochran9 says:

      Want to talk about that mind virus? Symptoms, prognosis, paths of infection? Clearly not an STD.

      • Economic Sophisms says:

        There’s probably a Gay Germ Theory joke here somewhere, but I don’t know if Libertarians are even that lucky.

    • SMack says:

      Libertarians believe many stupid things (open borders, the “mass incarceration” narrative, de-militarize the police, unions ruined Detroit, school choice will fix it, etc), but the thing you mentioned – “pharma fraud can’t be true because free markets” – isn’t one of them.

      Libertarian economic thought does not deny the possibility of Vioxx-style fraud, especially not in a mixed economy. In fact it predicts such fraud, since the lure of monopoly rent (the patent) combined with massive drug subsidies (Medicare, employer-based health insurance, etc.) makes it possible to earn very large excess returns. Nothing surprising about a person or a firm cheating in an attempt to capture those returns.

      Don’t unfairly compare an undergraduate dorm-room version of libertarianism with the adult version of whatever you believe now. Because every school of thought is cursed with sophomoric disciples who like to reduce the galaxy down to a slogan. God knows HBD is so afflicted, as any visit to the comment section at Chateau Heartiste or OD or AR readily shows.

      • Economic Sophisms says:

        You want to tell me Friedman or Rothbard wouldn’t have argued against the Vioxx case if they’d been alive/healthy? Do a search on “Vioxx” and “libertarian” and you’ll find all sorts of articles from the usual outlets tying themselves in mental knots coming up with arguments for why it isn’t a big deal and the FDA is still just like the NKVD, if you really think about.

        • gcochran9 says:

          When you think about it, mandating seatbelts is just like the Gulag.

          I like to think that when people make this kind of argument, they’re getting paid. Like at CATO. If they did it for free, I would lose all respect.

        • SMack says:

          Arguing against the Vioxx ban (which they do), or even against the existence of the FDA (which they also do), is not the same as arguing “pharma fraud can’t happen because muh free markets” (which they don’t).

          The third thing is the one you attributed to libertarians. Still wrongly.

  6. bleh says:

    The boy who cried wolf.

    Frequent mendacious excesses of Class Action bar (enabled by the legal/court system) and ham-fisted politicized regulatory interventions) in the area of product liability have inured the US media and population to real statistical dangers and malfeasance. The automotive “sudden acceleration” witch hunts against Audi and Toyota are well-known and straightforward examples of the problem.

    Silicone breast implants are a more relevant example*. The statistical and medical claims are hard for the average media consumer, or journalist, to parse. The salience of the purported problem and the degree of scandal-signalling by the legal system, political actors, or media are not reliable indicators of the underlying reality, severity, and skullduggery.

    Silicone breast implants were probably the largest medical product or drug media/legal conflagration and settlement prior to Vioxx and the most well-publicized since Thalidomide.

    http://www.nytimes.com/1994/03/24/us/3-companies-in-landmark-accord-on-lawsuits-over-breast-implants.html

    All of which turned out to be predicated on a medical theory that was bunk:

    http://www.ncbi.nlm.nih.gov/books/NBK44778/

    ” novel syndrome or disease associated with silicone breast implants has been proposed. Evidence for this proposed disease rests on case reports and is insufficient or flawed. The disease definition includes, as a precondition, the presence of silicone breast implants, so it cannot be studied as an independent health problem. The committee finds that the diagnosis of this condition could depend on the presence of a number of symptoms that are nonspecific and common in the general population. Thus, there does not appear to be even suggestive evidence for the existence of a novel syndrome in women with breast implants. In fact, epidemiological evidence suggests that there is no novel syndrome.”

    http://www.nationalacademies.org/hmd/Reports/1999/Safety-of-Silicone-Breast-Implants.aspx

    “there is extensive presence of, and wide exposure of citizens of developed countries to silicones in foods, cosmetics, lubricants for machinery, hypodermic syringes and other products, insulators and a wide array of consumer products;

    “a review of the toxicology studies of silicones and other substances known to be in breast implants does not provide a basis for health concerns”; and

    “because there are more than 1.5 million adult women of all ages in the United States with silicone breast implants, some of these women would be expected to develop connective tissue diseases, cancer, neurological diseases or other systemic complaints or conditions. Evidence suggests that such diseases or conditions are no more common in women with breast implants than in women without implants.”

  7. Dima Klondt says:

    Right. I always found it curious that celecoxib (Celebrex) was was not taken off the market. Given that it and rofecoxib target the exact same thing and promote heart attacks by apparently the same mechanism. Could of course be that Vioxx increases the harm by some side effect (the structures are sufficiently different for that) but in my mind could equally be that Celebrex was not tested as rigorously.

    • gcochran9 says:

      At least one study shows that the risks for Celebrex are lower than For Vioxx, although Celebrex does have cardiovascular risks. Looks as if all the NSAIDs do, other than aspirin.

  8. benespen says:

    In Europe, there was a recent case of Mediator (benfluorex). That drug caused somewhere between 500 and 2000 deaths until it was completely withdrawn from the market in 2009. The political fallout from that caused the French equivalent of the FDA, AFSSAPS. to be dissolved and replaced with an entirely new agency.

    From dealing with the successor agency, ANSM, I can report that pour encourager les autres does indeed work.

  9. ironrailsironweights says:

    Acetominophen is perfectly legal and extremely popular even though a dosage just slightly in excess of the maximum recommended dosage can be deadly. Someone with a blinding headache can easily make dosage mistakes.

    Peter

    • Danny says:

      That’s Bullshit.

      I’ve often taken several times the maximum recommended dosage without any ill effects.
      Paracetamol is actually one of the best and safest painkillers all around.
      The biggest problem is probably its bad image so stupid women try to commit suicide using a few packs which gets them into the hospital and upps the stats but not much more.

      Also many countries use it to try to kill off their opiate users, but that doesn’t make it a bad medication.

      • Rosenmops says:

        “I’ve often taken several times the maximum recommended dosage without any ill effects.”

        I hope your liver is doing ok.

  10. Rosenmops says:

    I took Vioxx every day for several years. (I have rheumatoid arthritis) . I guess I was lucky not to have a heart attack. Vioxx really did work a lot better than Naproxen, for me.
    .

    • That’s an interesting question then: Was the relatively marginal increase in heartattacks outweighed by the benefit of increased pain control? And if so, is it your right to make the call?

      • gcochran9 says:

        There’s no evidence that there was any improvement in pain control. One anecdote means nada. There were a number of favorable efficacy studies authored by Scott S. Reuben, but he made up all the data.

        Since the molecular mechanism, inhibition of COX-2, is the same as other NSAIDs, there’s no reason to suspect that Vioxx is especially effective in pain control.

        Lastly, if I’m not mistaken, heart attacks hurt a lot.

        I see other people do this – imagine facts (which happen not to be facts) that would support their ideology. I bet you have to do this a lot.

        • Is that a sufficient reason to rule out experimental results on pain control? I am not as knowledgeable as you on this topic, but isn’t your mechanistic argument on its inhibition being the same as other NSAIDs comparable to opiods such as morphine/oxycodone/fentanyl, for which we know there are meaningful differences in experimental perception of pain control?

          Either way, I don’t dispute you are likely correct. I’m no markets ideologue, despite a formal economics training.

          Most libertarian market ideologies have the tacit assumption of “all humans are equally intelligent and able to reason through choices equally,” which is where I (and I think you) get annoyed.

          • gcochran9 says:

            The different NSAIDs are not chemically identical and so there could be differences in pain control – but I don’t of any real evidence that VIOXX was better. I do know of some unreal evidence, faked. Anecdotal evidence? I’ve heard a couple of claims, but nothing more than that.

            I am tired of libertarian types (not just them) invoking evidence that ought to exist.

            Sure, libertarians assume an odd and false kind of mental uniformity (again, not just them), but I don’t think that’s their only serious problem.

  11. Brian says:

    Late to the party, as usual, but for what it’s worth: as a poison control guy I’ve probably written more death reports for acetaminophen OD’s than for any other drug. Deliberate suicide, idiotic misuse, innocent accident, you name it. Its ubiquitousness is most of the story, but not all. A lot of it is ignorance of the potential lethality, but mainly it is the toxidrome’s insidiousness: often there are no significant symptoms until your liver starts shutting down. Aspirin toxicity will make you wish you were dead (usually) well before you are beyond medical help, so many will seek medical attention in time. But many a teen aged tantrum or drunken pity party starring acetaminophen has no consequences for 24h or more, and when the heavy duty N/V starts they are facing a liver transplant or a gruesome slo-mo death. That said, I’ve also seen old alcoholics/narcotic abusers who have taken a couple of dozen Lortab a day for years with no liver sx other than cirrhosis. Or, to put it medically: “you can’t kill bad grass.”

    • Peter Gerdes says:

      I once looked up the dosages for harmful acetaminophen/alcohol interactions. They are actually much higher than one might think for substantial effects.

  12. Peter Gerdes says:

    Vioxx and other COX-2 inhibitors can be taken at higher doses than unspecific COX inhibitors. There are patients who simply can’t take enough aspirin to sufficiently suppress inflammation but can take enough COX-2 inhibitors even though their COX-2 inhibitor dosage is still low enough to avoid most of the increased heart attack risk (of course the lower dosage you take the less increase in heart attacks).

    This is why COX-2 inhibitors stay on the market and should continue to do so.

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