Did the Avandia scare harm patients, and is Steven Nissen to blame?

The recent RECORD trial did not associate the diabetes drug Avandia with cardiovascular events.

Internist Matthew Mintz, a staunch defender of the drug, argues that because of the scare, “over 100,000 type 2 diabetic patients [needed] insulin, which could have been avoided.”

Who’s to blame? Dr. Mintz blames cardiologist Steven Nissen, whose questionable meta-analysis started the debacle, and The New England Journal of Medicine for fanning the flames. He questions whether the Journal followed its own rigorous peer review process, wondering how such an important study can be published only 3 weeks after receiving it. Indeed, Dr. Mintz speculates that “had the peer review process been followed strictly, the study may never have been published, or the results would have been modified and likely gotten much less publicity.”

Now that the cat’s out of the proverbial bag, should a full investigation be done, as Dr. Mintz suggests? It’s unlikely, given how the pharmaceutical industry is vilified both in the public and in political circles. And that may be too bad, especially if the accusations against Avandia have been conclusively proved false.

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  • http://vendorMD.com VendorMD

    Is there a manipulation of literature going on by the pharmaceutical industry? We don’t know. But that is one reason every physician should learn how to interpret these studies themselves, to protect the patients.

  • Anonymous

    I can’t believe that the most important debate in the history of American healthcare is currently underway in Congress and you are discussing Avandia.

  • http://hcrenewal.blogspot.com Roy M. Poses MD

    With all due respect, I didn’t see that Dr Mintz provided any evidence to back up his claim that patients were harmed by the withdrawal of Avandia. I am sure he did not cite any studies which showed that Avandia provides clinical benefits outweighing harms, or that withdrawal of Avandia would cause clinical harms outweighing any benefits.

    Dr Mintz seemed very favorably inclined towards Avandia, and was pretty harsh in his discussion of Dr Nissen.

    So, maybe Dr Mintz ought to have disclosed his financial ties to GSK, the maker of Avandia, for example, see:
    http://cme.medscape.com/viewprogram/6294,
    an educational program supported by a grant from GSK,
    and click on “authors and disclosures” to see that Dr Mintz has served on an advisory board and the speakers’ bureau of GSK.

  • Doc99

    This story bodes ill for comparative effectiveness – garbage in truly produces garbage out.

  • http://tarl.net/tarl Tarl Neustaedter

    Comment to Anonymous – The HealthCare debate in Washington is Politics, which most of us can do more than observe and endure. It’s going to go on for a long time and be well covered by the general media. The issue with Avandia is medicine, which may well affect decisions by patients and doctors.

    I’d asked about RECORD a few posts back because of the likelyhood of having to make a decision in a year or two. My impression from reading 3rd hand reports paralleled Dr. Pho’s conclusion – which is personally helpful to me. I have a minor indication to avoid metformin, so Avandia and similar medicines might be a better choice – and I now know to discount the inevitable horror stories when they come up.

    I only wish there was a way Dr. Pho could earn money out of this service he has provided :-)

  • Marilyn Mann

    RECORD did not exonerate rosiglitazone. Note that the accompanying editorial by Ravi Retnakaran and Bernard Zinman notes that “definitive conclusions about the relation between rosiglitazone and cardiovascular disease remain elusive, owing to study limitations. Specifically, the study was open label in design and cardiovascular disease event rates were much lower than anticipated. Furthermore, the findings are inconclusive for myocardial infarction, for which a non-statistically significant increased risk was noted in the rosiglitazone group (HR 1·14, 0·80–1·63).” The editorialists go on to support the ADA/EASD consensus statement which recommends pioglitazone over rosiglitazone.
    Steve Nissen sent the following comments to Larry Husten’s CardioBrief blog:
    “The RECORD trial is a seriously flawed study. At the time the interim analysis was published, approximately 30% of patients were no longer taking Avandia. The authors fail to disclose how many patients had stopped the drug in their Lancet manuscript, but it seems like that this number approached 50%. In a safety study, withdrawal of study drug biases the trial toward showing no difference between therapies thereby concealing hazards.
    “Furthermore, in those patients with ischemic heart disease, there was as strong trend toward an excess myocardial infarction rate with Avandia treatment.
    “There are important irregularities. More of the Avandia patients received statins, a class of drugs known to reduce cardiovascular event rates in diabetics.”
    http://cardiobrief.org/2009/06/05/1828/

  • dr kvc

    I was informed that Dr Nissen was a consultant for Actos. Is that true?
    If it is, it makes all of his assessments worthless.

  • http://hcrenewal.blogspot.com Roy M. Poses MD

    To elaborate more about RECORD, although Dr Mintz claimed that the trial showed that warnings about cardiovascular side-effects from rosiglitazone were “false alarms,” I believe that argument was based on a misinterpretation of the evidence.

    In fact, RECORD had several problems that prevented it from proving that rosiglitazone does not elevate the risk of myocardial infarction (MI, or heart attack). These were:

    1. Possibly because RECORD was an “open-label,” rather than a double-blind trial, patients in the rosiglitazone group received different co-interventions than patients in the control group. In particular, about 10% more patients in the rosiglitazone group (55.2% vs 46.0%) were receiving statins at the end of the trial than were patients in the control group. There is pretty good evidence that statins reduce the risk of coronary artery disease, and hence, of MIs. Thus, thiis version of co-intervention bias may have decreased the apparent rate of MIs in the rosiglitazone group.

    2. The RECORD trial suffered from a significant loss to follow-up. For 8.9% of patients, ascertainment of cardiovascular outcomes was incomplete. Since the rate of MIs in the whole group was less than 3% over 6 years of observation, it is possible that had all these cardiovascular outcomes been ascertained, the ratio of MIs in the rosiglitazone and control groups would have turned out quite differently, either indicating less, or more risk due to rosiglitazone.

    3. The RECORD trial was too small to prove that rosiglitazone did not raise MI risk, possibly substantially. The 95% confidence interval for the risk of MI due to rosiglitazone was (0.80, 1.63). A somewhat crude way to interpret this is that the chances of rosiglitazone causing a risk of MI higher than 1.63 was less than 5%. On the other hand, the trial could not disprove that rosiglitazone raised the risk of MI by as much as 1.63 times. (Note that the point estimate of risk of MI was 1.14, meaning that the best guess of the effect of rosiglitazone on MI risk was that it raised it by 1.14 times, or 14%)

    Furthermore, the trial showed that rosiglitazone substantially raised the risk of congestive heart failure (although there had not been much previous controversy about this adverse effect).

    Thus, I believe you were wrong in saying that rosiglitazone was not associated with cardiovascular risks. Moreover, I believe Dr Mintz’s rant about an Avandia “scare” harming patients was not justified by the evidence provided by RECORD. Furthermore, I think his call for an investigation of Dr Nissen, the New England Journal of Medicine, and the FDA vis a vis rosiglitazone is way over the top.