[HSF] More on the Traysylol saga

Wed Oct 4 08:22:04 EDT 2006

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. 
  _______________________________________________
  OpenHeart-L mailing list

  Send postings to:
   OpenHeart-L at lists.hsforum.com<mailto:OpenHeart-L at lists.hsforum.com>

  To UNSUBSCRIBE, to CHANGE email address, or to view archives:
  http://mmp.cjp.com/mailman/listinfo/openheart-l<http://mmp.cjp.com/mailman/listinfo/openheart-l>

  All messages transmitted by the OpenHeart-L are subject to the policies and 
  disclaimers posted at:
  http://www.hsforum.com/listdisclaim<http://www.hsforum.com/listdisclaim>
  -----------------------------------------