[HSF] More on the Traysylol saga

[Tdmartin2000 at aol.com]

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, a Web site for cardiovascular 
healthcare professionals.