Aprotinin returns to the market or endangers public life

Release time:2017-07-18

Aprotinin was recalled to the global market due to the results of BART research. Recently, the relevant personnel of this research said that the decision of European and Canadian regulatory authorities to allow aprotinin to return to the market or the risk of endangering public life safety exists.  
The BART trial, which aims to confirm that antifibrinolytic agents can reduce the risk of massive bleeding in coronary artery bypass grafting (CABG), was terminated early by the Data Safety Monitoring Board (DSMB) in October 2007 because of the significant increase in the death events of patients in the treatment group.  
One month later, the drug manufacturer terminated its worldwide sales. However, Health Canada and the European Medicines Agency (EMA) allowed the drug to be resold in their jurisdictions in 2011 and 2012, respectively. In this regard, Dr. Paul C H é bert, the chief researcher of the BART trial, Dean A Ferguson and other colleagues said that this decision would put patients at great risk.
In an interview, Dr. Ferguson said that he still supported the BART research results, "We should be responsible for the patients and everyone involved in the trial to support the results of the trial. BART test and other accumulating evidence all suggest that antiphthalein does increase the risk of death."
Related event chain
Ferguson said that the BART test was terminated in advance within one week after receiving the DSMB warning. On the day of receiving the DSMB message, the researchers contacted the US Food and Drug Administration (FDA) and the Canadian Ministry of Health to analyze the final results and publish relevant articles. Health Canada also held a hearing "in due course". BART experimental researcher and sponsor Bayer Pharmaceuticals briefed all jurors and answered relevant questions.  
However, the Ministry of Health of Canada criticized the follow-up report on the results of the experiment and believed that the experiment was inaccurate. In this regard, Ferguson said that the project researchers have been trying to attract the attention of relevant supervision departments and the public to this result. They published an article in CMAJ magazine, detailing three key errors in the relevant reports of Health Canada.  
First, the researchers who reported the interrupted speech BART trial reclassified 75% of the primary endpoint events. In fact, H é bert et al. said that they only reclassified the data of 1.6% of the primary end points, or 38 of 2438 patients, and treated the experimental group and the control group in a "nondifferentiable form", which would not have a significant impact on the main research results.  
Second, it was reported that more than 137 patients were excluded from the trial after randomization. In this regard, H é bert et al. explained it respectively from the analysis of compliance with the protocol set and the analysis of intentionality, indicating that whether these subjects were excluded or not would not affect the main research results of the trial.  
Finally, Health Canada reported that there was a potential imbalance in baseline heparin use and/or anticoagulant testing between the experimental and control groups in this trial. A series of retrospective analyses conducted by the BART tester showed that there was no significant difference in heparin related mortality between the two groups. The researchers also objected to the improper anticoagulation in the test mentioned in the report, saying that "it is unlikely that any group in the BART test has insufficient anticoagulation".  
Ignore the issues concerned by researchers
The researchers of the BART experiment said that they had explained their data calculation results to government inspectors for many times, but no response was received. At the same time, European regulators did not fully and independently verify the information provided by Canadian regulators, and they did not directly contact the researchers of the BART test.  
H é bert and his colleagues believe that if the relevant regulatory authorities have so many doubts about the results of the BART test, the next most reasonable way should be to authorize a new large-scale clinical trial comparing aprotinin and other drugs. However, this proposal has not been approved for a long time.  
Ferguson said that before 2008, aprotinin was the most commonly used drug to reduce bleeding in cardiac surgery, but today, he believes that it has been rarely used. Aprotinin is not recommended in the blood protection guidelines for cardiothoracic surgery issued by the Society of Cardiothoracic Surgery (TTS) and the Association of Cardiovascular Anesthesiologists (SCA) in 2011.  
Ferguson believed: "Now that tranexamic acid can be selected, why is aprotinin still needed to return to the market, especially because it will increase the risk of death by 50%? Why take this risk of death when there are effective alternative drugs?" At the same time, Ferguson believed that the Ministry of Health of Canada might try to make concessions to this result, but the process was slow because its institutions were not good at handling the data of such large-scale practical trials.  
He believed that: "We have come to a patient centered era of comparative effectiveness research. Large clinical trials can most effectively evaluate safety and effectiveness, which may not be consistent with the regulatory model or framework of small placebo-controlled clinical trials." FDA also convened experts to discuss after the release of BART experimental results, and aprotinin is still off the shelf in the United States.

key word: Aprotinin returns to the market or endangers public life

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