New unpublished study may help tighten the noose around Avandia’s neck

A new unpublished study utilizing data from 227,571 Medicare patients is raising new questions about rosiglitazone (Avandia), which will be the subject of an extraordinary 2-day FDA advisory panel meeting in July. The study found that among elderly people taking a thiazolidinedione (TZD), the risk of stroke, heart failure, and death, as well as of composite endpoints including AMI or death, was higher in those taking rosiglitazone compared to those taking pioglitazone. The study was led by the FDA’s David Graham, a noted critic of Avandia and, earlier, Vioxx. Co-authors of the study are from the FDA, Acumen, and CMS.

“Given the lack of any proven, unique, and medically important health benefits of rosiglitazone compared to pioglitazone, there is no rationale for its continued availability on the market or its use by prescribing physicians or patients,” the authors conclude in the study’s manuscript.

The existence of the manuscript, and an associated brouhaha involving its possible suppression by some FDA officials, was reported by Ed Silverman on Pharmalot. Silverman reports that  Graham sent an email on May 28 to the FDA’s two top officials, Margaret Hamburg and Joshua Sharfstein, stating his situation.

Here is an excerpt from the email, which Silverman reprints:

“JAMA is very interested in our manuscript and we would like to submit it before next Friday, June 4. Gerald Dal Pan, my supervisor is prepared to sign the clearance form (the paper has a disclaimer and does not represent an official FDA position) but won’t unless Dr. Woodcock and Dr. Jenkins approve. He is afraid to act, even though he is the ‘clearing official.'”

However, in an update to his original post, Silverman wrote that he was told by an FDA spokeswoman that “we didn’t suppress this” and that “the manuscript could be submitted and provided authorization in time for a June 4 deadline.”

In his email Graham also notes that his “CMS co-authors are also anxious to submit the manuscript and feel that they have a duty to their customers, Medicare patients, to bring these results to public notice in a scientific journal as soon as possible. The idea of being blocked from doing this by a sister Agency is a source of concern to them and to me.”

Graham also provides the background for his concerns: “In late 2004, CDER management suppressed the publication of a study I conducted using data from Kaiser California that showed increased AMI risk with rofecoxib. This was done in an effort to downplay the seriousness of their prior poor decision-making in leaving rofecoxib on the market. So you can understand that I am very sensitive to anything that remotely smells like suppression or censorship. I am asking for your assistance in ensuring that we are able to submit our manuscript to JAMA before June 4.”

In the manuscript of the paper, Graham et al discuss the widespread use of rosiglitazone, especially in its early years, and the estimated impact of its adverse effects:

“From the start of marketing in 1999 through 2009, an estimated 82.5 million prescriptions for rosiglitazone were filled in the US, of which 38.4% were for patients age 65 years or older. The mean prescription length was 32.7 days, leading to a total exposure time of 2.8 million years in the elderly. Based on the number needed to harm, an estimated 4268 AMIs, 9231 strokes, 26735 cases of hospitalized HF, and 12708 deaths would have been averted had pioglitazone been prescribed instead of rosiglitazone (table 7). For the composite of AMI, stroke, HF, or death, the NNH was 59 person-years, with an estimated excess of 48,000 events attributable to rosiglitazone.

The authors further note that “the national impact has been undoubtedly much greater because our estimate does not account for rosiglitazone use among patients under the age of 65 years, where an estimated 61.6% of rosiglitazone use occurred through mid-2009. This would place rosiglitazone in the same category as rofecoxib with respect to magnitude and severity of population harm.”

Silverman doesn’t reveal the source of the manuscript and email. It is theoretically possible that the early release of the manuscript will jeopardize or complicate the acceptance of the study by JAMA or another medical journal.

Click here for previous CardioBrief coverage of Avandia.

Comments

  1. As an older patient who is supposed to be taking several prescription medications, I am puzzled about why doctors are so insistent that patients take so many questionable meds.

    Even more troubling is that many doctors seem to blindly trust the reports funded by Big Pharma, while they stubbornly dismiss side-effects reported by their own patients as “anecdotal.”

    The system is broken.

    Jim Purdy
    The 50 Best Health Blogs

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  1. […] Husten, at Cardiobrief, picked up on the news, and ended his post with this: It is theoretically possible that the early release of the manuscript will jeopardize or […]

  2. […] New unpublished study may help tighten the noose around Avandia’s neck […]

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