[HSF] Medical publishing and the NEJM
prasannasimha
prasannasimha at gmail.com
Thu Oct 5 19:58:39 EDT 2006
Ani, can you send me the paper by email ?
prasanna
Ani Anyanwu wrote:
> I recommend all to read the paper by Richard Smith - The highly profitable but unethical business of publishing medical research J. R. Soc. Med. 2006 99: 452-456.
> Smith was the editor of the British Medical Journal for over 10 years and thus is an insider in it all and by his own admission was part of the whole façade.
>
> Another must read, also by Richard Smith is "Lapses at the New England Journal of Medicine" J R Soc Med 2006;99:380-2 which talks about the irresponsible approach to publishing at the NEJM.
>
> In reference to the NEJM he says - "The Massachussetts Medical Society, the owner of the journal made $88 million from publishing in 2005. My guess is that the journal accounts for at least 75 million"
>
> Of the appointment of the editor Jeff Drazen he said "He had financial connections with 21 drug companies between 1994 and 2000"
>
> Smiths second paper was mainly in reference to the publication of the now notorious VIGOR study (randomized study of naproxen vs vioxx) which had in 2000 proclaimed safety of the cox-2 inhibitor Vioxx. Of course the rubber stamp by the NEJM was more than enough for doctors world wide to join the Vioxx bandwagon making it one of the most profitable drugs of the decade. Merck purchased 900,000 reprints of this NEJM (at a cost of up to $700,000) for worldwide distribution as the words of authority. The NEJM paper cleverly toned down or ignored the increase in MI that was seen with vioxx in this study (they interpreted data to mean Naproxen was protective on the heart rather than Vioxx being harmful). Five years later when all the damage was done and the money made, NEJM published and expression of concern about the VIGOR data. Indeed the other famous journal on which we base our practice (wall street journal) claims the NEJM editor knew about excess vioxx cardiovascular deaths (that had been excluded from the published paper) in 2001 but did not issue a correction or reinterpretation to the study (I don't know that that was ever issued till today). When the FDA in 2001 cast some concern on safety of Vioxx, NEJM rebound with a review article on Cox-2 inhibitors which reassured the safety of the drugs. As we know now, the rest is history. No more Vioxx. And it 2005 AFTER the FDA had withdrawn the drug, and after tens or hundreds had died taking vioxx, NEJM then finally issues its expression of concern about validity of the VIGOR study.
>
> He concludes "It fits with the argument that medical journals are an extension of the marketing arm of pharmaceutical companies and that the full data of trials should be published not in medical journals, where an incomplete story is advanced, but on the web". In the case of Aprotinin, the NEJM has acted against the financial interests of one company (Bayer) and thereby promoting the interest of others (such as makers of other procoagulants and blood transfusion products).
>
> In reference to cardiac surgery the NEJM has misled us in the past on aspects like off-pump surgery and arterial grafting.
>
> Like in my previous contributions, I urge surgeons that if they are to change their practice based on a single study, they should first read that paper themselves - what interests you might not be the same as what interests the publishers. I had asked before (to those who are concerned about risk of aprotinin), how many patients you had to treat to cause one to go into renal failure - nobody answered, because I suspect nobody had read the paper.
>
> Ani
>
> Conflict of Interest: I have no connections to Bayer or other pharmaceutical companies
>
>
> ----- Original Message -----
> From: Ben Bidstrup<mailto:benjamin.bidstrup at bigpond.com>
> To: OpenHeart-L at lists.hsforum.com<mailto:OpenHeart-L at lists.hsforum.com>
> Sent: Thursday, October 05, 2006 4:21 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<mailto: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>
> >[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<mailto: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<mailto:Tdmartin2000 at aol.com<mailto:Tdmartin2000 at aol.com>>
> > To:
> >OpenHeart-L at lists.hsforum.com<mailto: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/<http://www.theheart.org<http://www.theheart.org/>>, a
> >Web site for cardiovascular
> > healthcare professionals.
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>
> --
> Ben Bidstrup FRACS FRCSEd FEBCTS
> Consultant Cardiothoracic Surgeon
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