[HSF] More on the Traysylol saga
prasannasimha
prasannasimha at gmail.com
Fri Oct 6 18:57:40 EDT 2006
So we now have a new term "To do a Bostonian"
Prasanna
Tea Acuff wrote:
> I recommend that anyone that chooses to remain in the Boston area to publish/ practice just be nodded and smiled at. It is an information reverse black hole. Sort of like a POM in outlook for Aussies.
> Tea
>
>
> ----- Original Message ----
> From: Ben Bidstrup <benjamin.bidstrup at bigpond.com>
> To: OpenHeart-L at lists.hsforum.com
> Sent: Thursday, October 5, 2006 3:21:30 AM
> Subject: RE: [HSF] More on the Traysylol saga
>
>
> The power that Journal Editors have is such that they must be
> answerable for their actions. Heartwire commented that the stats were
> only able to be reviewed after publication. This is absolutely
> specious. For a Journal of the calibre (now in my estimate very low)
> of the NEJM not to have someone who could comment cogently on the
> propensity analysis etc. is a very unlikely thing. After all, the
> NEJM produced 2 accompanying editorials including one from an
> consultant epidemiologist who is listed as as a statistical
> consultant to the NEJM. He points out that the study "permitted the
> use of propensity-score and conventional multivariate techniques to
> control confounding and ensured that the clinical outcomes of
> interest were not obscured by misclassification due to a lack of
> clinical detail or an inaccurate administrative assignment of
> diagnostic codes. " (Hunter, D., First, gather the data. N Engl J
> Med, 2006. 354(4): p. 329-31.) Now if a statistician who has such an
> exalted post cannot indicate the weaknesses in this study, then he
> should withdraw his paper and offer an apology, to all readers of the
> journal, to the public and to patients who suffered as a result of
> the non use of aprotinin. He should also be joined in any action.
> Readers of the HSF who feel so inclined, should express their dismay
> at this turn of events and send an open email to the editors of the
> Journal and to Mr David Armstrong, (David.Armstrong at wsj.com) the
> author of the article in the Wall Street Journal (Hal's favourite
> medical source). Furthermore, you should encourage your library to
> cancel their subscription to the NEJM. The Massachusetts Medical
> Society should also be contacted.
>
>
>
>> Ani,
>> Your comments are very provocative but true. I agree with you that
>> everything that is published should be interpreted with a grain of salt.
>> In my opinion this journal has become Tabloid of medical news at times.
>> It is a shame to misuse their power to manipulate the markets and gain
>> spotlight in the general news media.
>> Chand
>>
>>
>> -----Original Message-----
>> From: openheart-l-bounces at lists.hsforum.com
>> [mailto:openheart-l-bounces at lists.hsforum.com] On Behalf Of Ani Anyanwu
>> Sent: Wednesday, October 04, 2006 7:22 AM
>> To: OpenHeart-L at lists.hsforum.com
>> Subject: Re: [HSF] More on the Traysylol saga
>>
>> Well this confirms what several of us have maintained for the last 6
>> months. I must say I was amazed at the response from the surgical
>> committee to stop using a drug based on a paper they never read - I say
>> never read because anyone who did read the paper would have immediately
>> discounted its findings because of glaring study flaws. Indeed when I
>> read the paper, I only read the methods section and because the methods
>> were so flawed, I never wasted my time reading the results or
>> discussion. Of course arguing this point was difficult because I would
>> be reminded "it was in the NEJM...".
>>
>> The morale of the surgery is not to base our practice on what is in the
>> mass media or on rumors but to study the data ourselves. Like we often
>> quote the Loop 1986 NEJM paper as evidence for benefit of IMA grafting,
>> but I bet most have never read the paper; anyone who has would agree
>> that it is anything but evidence, also a very flawed study that would
>> not be publishable today. Indeed one of my mentors maintains that there
>> is no definitive evidence that IMA is superior to VG for grafts to the
>> LAD - I must reluctantly agree he is telling the truth.
>>
>> Hopefully the only lawsuit that will come out of this will be against
>> the multimillion dollar establishment called the NEJM for misleading the
>> medical fraternity, causing harm to thousands of patients who were
>> denied the drug and causing millions of dollars of loss to Bayer.
>>
>> For people unconvinced about the dubious business of medical publishing
>> of which NEJM is at the forefront, see
>>
>> Richard Smith The highly profitable but unethical business of
>> publishing medical research
>> J. R. Soc. Med. 2006 99: 452-456.
>>
>> Ani
>> ----- Original Message -----
>> From: Tdmartin2000 at aol.com<mailto:Tdmartin2000 at aol.com>
>> To:
>> OpenHeart-L at lists.hsforum.com<mailto:OpenHeart-L at lists.hsforum.com>
>> Sent: Tuesday, October 03, 2006 11:00 PM
>> Subject: Re: [HSF] More on the Traysylol saga
>>
>>
>> FDA committee reassures on aprotinin safety
>> from Heartwire - a professional news service of WebMD
>>
>>
>> Sue Hughes
>>
>> September 27, 2006Rockville, MD - At a meeting of the US FDA
>> Cardiovascular and Renal Drugs Advisory Committee last week, the panel
>>
>> supported the overall safety and efficacy of the antifibrinolytic drug
>>
>> aprotinin (Trasylol, Bayer) if used according to its labeled
>> indication--to reduce bleeding complications in high-risk CABG
>> patients.
>>
>>
>> The September 21, 2006 meeting was held to discuss safety concerns
>> about the drug raised by two observational studies published earlier
>> this year.
>>
>>
>>
>> The first study, by Mangano et al, published in the New England
>> Journal
>> of Medicine, showed that CABG patients who received aprotinin had
>> higher
>> rates of renal failure, MI, and stroke compared with those treated
>> with
>> other drugs to prevent bleeding or with no treatment [1]. The second
>> study, by Karkouti et al, published in Transfusion, reported more
>> cases
>> of reduced kidney function in patients treated with aprotinin compared
>>
>> with another treatment to prevent bleeding, but no excess risk of
>> cardiovascular events [2].
>>
>>
>>
>> The cardiorenal committee reviewed both these studies at the meeting,
>> along with the randomized data from clinical trials supplied by Bayer.
>>
>> Chair of the committee, Dr William Hiatt (University of Colorado
>> Health
>> Sciences Center, Denver), told heartwire that the main concern about
>> increased cardiac events was seen only in the study by Mangano et al,
>> but because of questions about some of the methodologies used in this
>> study and the fact that the data from this study had not been
>> independently reviewed by the FDA, the committee could not endorse its
>>
>> findings.
>>
>>
>>
>> The suggestion of a slight reduction in renal function, however, was
>> seen in all three data sets and is probably real, Hiatt noted. "Both
>> observational studies showed an increase in renal creatinine, and this
>>
>> was also seen in some of Bayer's data, so there is a signal for some
>> reversible renal insufficiency across the data," he commented.
>>
>>
>>
>> At the end of the session, the committee voted (18 in favor, none
>> against, and one abstention) that the totality of clinical data
>> presented supports acceptable safety and efficacy for aprotinin among
>> CABG patients.
>>
>>
>>
>> Mangano study flawed?
>>
>>
>>
>> Elaborating on the concerns voiced about the Mangano study, Hiatt
>> explained that several committee members were of the opinion that
>> Mangano et al did not conduct the propensity score properly and
>> therefore the adjustment for confounding factors could have been
>> flawed.
>> Added to this, Mangano apparently refused to allow the FDA
>> unrestricted
>> access to his data, imposing restrictions on what the agency could and
>>
>> could not see. "Because there was no independent review of his data,
>> the
>> committee could not substantiate his claims," Hiatt told heartwire.
>> "Mangano et al concluded in their paper that the use of aprotinin was
>> not advised based on their data, but we could not condone this and
>> some
>> members of the panel said this was an irresponsible statement," he
>> added.
>>
>>
>>
>> Indeed, in a somewhat unusual turn of events, one member of Mangano's
>> original study group, Dr Linda Shore-Lesserson (Montefiore Medical
>> Center, Bronx, New York), spoke at the advisory committee meeting and
>> told how she had actually removed her name from the NEJM paper because
>>
>> she believed the conclusions had been overstated.
>>
>>
>>
>> Hiatt said he would like to see more data on aprotinin, but it was
>> unlikely that any more placebo-controlled trials would be conducted.
>> "More observational data are essential, but they must be analyzed
>> properly," he stressed. He added that the panel has no problems with
>> the
>> Karkouti study, which, despite also being observational, was more
>> credible than the Mangano study because transparency and independent
>> review of the primary data by the FDA were allowed to occur.
>> Other panel members agreed with this view. Dr Robert Harrington (Duke
>> University, Durham, NC) commented to heartwire: "The Karkouti study
>> was
>> well done from a methodological view, and while it did raise questions
>>
>> about an association with renal toxicity, the authors were
>> appropriately
>> cautious about their conclusions, given that it was an observational
>> study. But the Mangano study raised a lot more discussion about the
>> statistical methods used, and the panel did not like the fact that
>> Mangano had not allowed the FDA unrestricted access to his data."
>>
>>
>>
>> FDA offered "chaperoned" view of data
>>
>>
>>
>> An FDA spokesperson confirmed that the agency had been offered a
>> "chaperoned" view of the Mangano data, which in its view was
>> insufficient. Some members of the advisory committee were vocal in
>> their
>> criticism of Mangano for this, with one pointing out that "science
>> does
>> not get done by hiding your data."
>>
>>
>>
>> Harrington said the take-home message for him from the meeting was
>> that
>> aprotinin does appear to do what it is supposed to do--reduce bleeding
>>
>> in CABG patients, with the best effect in highest-risk patents. And
>> although observational data are important, possible flaws in the
>> Mangano
>> study mean that its conclusions may not be reliable. But Harrington
>> also
>> pointed out that while concerns about cardiac events had not been seen
>>
>> in Bayer's randomized trials, these studies were quite dated, and new
>> data from contemporary studies were needed.
>>
>>
>>
>> He also noted that the panel did question whether, if aprotinin is so
>> good at reducing bleeding and transfusions after CABG, why a mortality
>>
>> reduction has not been seen. And it was suggested that there were not
>> enough data at this point to be able to conclude anything about
>> mortality.
>>
>>
>>
>> Why did the NEJM publish Mangano's study?
>>
>>
>>
>> There was also much discussion as to why the New England Journal of
>> Medicine published Mangano's study, given that several statisticians
>> present at the meeting had questioned the statistical methodology
>> used,
>> and why the journal had allowed Mangano to use such emotional language
>>
>> in his discussion section. The consumer representative at the meeting
>> made the comment: "Where were all the adults at the NEJM when this
>> paper
>> was going through peer review?"
>>
>>
>>
>> Harrington said that if Mangano had written the study up as an
>> observational study with all the caveats that that entailed, it would
>> have been better accepted. "But instead, he claimed that the rigor of
>> his data collection--because he adjusted for so many
>> variables--essentially mimicked randomization. But the panel did not
>> agree with this. There is a reason why we do randomized trials,"
>> Harrington added.
>>
>>
>>
>> Another panel member, Dr Michael Lincoff (Cleveland Clinic, OH),
>> defended the journal. "It's always easy to pick up flaws in a paper in
>>
>> retrospect. The peer-review process may not have had as much
>> statistical
>> expertise as the FDA panels and invited experts. The good thing about
>> science is that it is self correcting--the truth comes out in the
>> end."
>> But Lincoff agreed that the discussion section of the Mangano paper
>> could have been toned down somewhat. "The NEJM did allow a very
>> dogmatic
>> discussion section, with some very strong comments drawn from some
>> really quite weak data," he commented to heartwire.
>>
>>
>> One of the statisticians on the panel, Dr David Demets (University of
>> Wisconsin, Madison, WI), declined to comment on the meeting other than
>>
>> to say that the discussion was "fascinating and has implications for
>> future discussions about observational data relative to safety
>> issues."
>>
>>
>>
>> Requests by heartwire for comment from Mangano received no response.
>>
>>
>>
>> Bayer notes that it is in discussion with the FDA regarding possible
>> updates to the US label for aprotinin to include additional detail
>> specifying that aprotinin should be used in patients at increased risk
>>
>> for blood loss and blood transfusion and revised guidance with regard
>> to
>> elevations in serum creatinine levels and hypersensitivity reactions.
>>
>>
>>
>> Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in
>>
>> cardiac surgery. N Engl J Med 2006; 354:353-65.
>> Karkouti K, Beattie W, Dattilo K, et al. A propensity score
>> case-control comparison of aprotinin and tranexamic acid in
>> high-transfusion-risk cardiac surgery. Transfusion 2006; 46:327-338.
>>
>>
>> The complete contents of Heartwire, a professional news service of
>> WebMD, can be found at www.theheart.org<http://www.theheart.org/>, a
>> Web site for cardiovascular
>> healthcare professionals.
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