Bayer Responds to study and commentary published in Journal of American Medical Association (JAMA)
06/02 2007
Bayer has conducted a preliminary review of the observational study entitled “Mortality Associated with Aprotinin During 5 Years Following Coronary Artery Bypass Graft Surgery” by Mangano et al. as well as the editorial by T. Bruce Ferguson, Jr., MD from the East Carolina University, Greenville, scheduled for publication on February 7, 2007 in the Journal of the American Medical Association (JAMA) regarding long-term mortality rates in coronary artery bypass graft surgery patients including those treated with aprotinin.
The study published in JAMA is a follow-on to a previous observational study from the Ischemia Research and Education Foundation published in January 2006 on which Dr. Mangano was also the lead author. Bayer believes the methodological and analytical approaches used in the earlier study were not reliable and do not support the authors’ reported conclusions. This newest paper reports on a subset of the same patient population and uses methodology and analytical approaches similar to those used in the earlier publication.
One of the limitations of both of these studies is that doctors chose whether to administer aprotinin or another treatment based on the patient’s condition. Generally, sicker patients who were already at greater risk for mortality were treated with aprotinin. As noted in the editorial by Dr. Ferguson, “Aprotinin use in cardiac surgery has never been uniformly standardized, but generally has been reserved for patients in whom the surgical team anticipated a higher risk for intraoperative blood loss. This anticipation was driven by the surgical team’s perception of increased technical complexity, increased risk of adverse outcome, or both for the patient in question.” The statistical methodologies as applied by Mangano et al. in the JAMA paper did not adequately address this bias.
In addition, and applicable to both studies, major differences in clinical practice among the contributing countries have been reported in the literature. These differences have also been reported to influence outcomes. Both studies involved more than 60 sites from all over the world and these differences in clinical practice may have affected the reported findings.
Pointing out differences in the percent of patients in the different treatment groups who underwent complex surgical procedures, Dr. Ferguson comments, “Importantly, these biases, at the level of the surgical team, were not captured in the extensive patient level data collection process nor in the analysis.” Dr. Ferguson concludes, “The mechanism for this late mortality difference is not clear and causality [to aprotinin] cannot be inferred from this data set analysis.”
Patient safety is always Bayer’s highest priority. Based on this initial review, Bayer believes that the results of this study should not serve as a basis for affecting the use of aprotinin in clinical practice. Bayer will work with regulatory agencies and external experts in the field to further evaluate the findings.
Bayer discontinues Trasylol® clinical trial program in non-CABG indications
25.01.2007
Recent label changes for Trasylol® in CABG indication impact the clinical trial development in other indications
Bayer HealthCare has decided to end three ongoing clinical studies investigating the safety and efficacy of Trasylol® (aprotinin injection) on transfusion requirements and blood loss in adults undergoing: elective spinal fusion surgery, pneumonectomy or esophagectomy for cancer, and radical or total cystectomy in bladder cancer. Trasylol® is the only drug approved by the FDA and several other regulatory authorities to reduce blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery in patients who are at an increased risk for blood loss and blood transfusion.
The Trasylol® labelling that was recently approved in the U.S. and is in the approval process in the European Union and other countries, includes a recommendation that in order to manage possible anaphylactic reactions, Trasylol® should be administered only in surgical settings where cardiopulmonary bypass (CPB) can be rapidly initiated. The use of CPB is not practical in non-cardiac surgical settings.
Bayer’s decision to discontinue these trials was not made based on any safety findings in these non-CABG studies. On November 18, 2006 an independent Data Monitoring Committee (DMC) reviewed safety data on these three studies, examining data for the first 120 patients randomized. Based on their review of these safety data, the DMC concluded that “...these three clinical trials could continue as planned without modification.”
Dr. Paul Mac Carthy, Vice President, Medical Affairs Bayer Pharmaceuticals Corporation said, “We believe that Trasylol® can continue to provide important benefits for CABG surgery patients and, therefore, fills an important role for their cardiac surgeons.”
Bayer Appoints Independent Investigator to Review Trasylol® Study Issues
13.10.2006
Bayer announced today that it has appointed independent counsel to review the company’s actions in regards to disclosure of preliminary results from an observational study on Trasylol® to the U.S. Food and Drug Administration. Bayer has retained Fred F. Fielding Esq., from the law firm Wiley Rein & Fielding LLP and charged him with conducting a complete and thorough investigation into the matter and with providing recommendations to Bayer regarding subsequent actions that the company should take.
Commenting on Mr. Fielding’s appointment, Dr. Roland Hartwig, General Counsel, Bayer AG said, “Bayer has acknowledged and regrets the error it made in not sharing with the FDA information regarding this study prior to the September 21st Advisory Committee Meeting on Trasylol®. Bayer immediately initiated a full investigation into the matter and based on our investigation so far, we believe this was a serious error in judgment by two individuals. These individuals have been suspended with immediate effect. We are committed to ascertaining how and why this error occurred, and to ensure that such errors are not repeated we have now retained Mr. Fielding, an attorney of the highest reputation for integrity and independence, to carry on this investigation“.
“Bayer will cooperate fully with Mr. Fielding’s investigation“, Dr. Hartwig continued. “We also anticipate that this independent investigation could result in a specific corrective action plan, if necessary, and we are determined to take all appropriate steps to ensure that something like this does not happen again“. The company will also publish the findings when they are complete.
Fred Fisher Fielding is senior partner at Wiley Rein & Fielding a Washington, D.C. law firm. He has served the American government in a number of roles throughout his career and from 1981 to 1986 served as Counsel to the President of the United States for President Reagan. Recently he served as a member on the National Commission on Terrorist Attacks Upon the United States.
Bayer Acknowledges That New Trasylol Study Was Not Disclosed Prior to Recent FDA Cardio-Renal Advisory Committee Meeting
29.09.2006
Bayer acknowledged today that it mistakenly did not inform the U.S. Food and Drug Administration about a retrospective study commissioned by the company to analyze the effects of aprotinin, aminocaproic acid and tranexamic acid in patients undergoing coronary artery bypass graft (CABG) surgery. This data was not shared immediately with the agency because it was preliminary in nature and raised significant questions on the study population, outcomes and methodology.
Bayer believes that despite the highly preliminary nature of this data, the information should have been shared with the FDA prior to the September 21st Advisory Committee meeting held to assess the safety and efficacy of Trasylol. This was a mistake on the company’s part.
Bayer has submitted a copy of the preliminary report to the FDA and has notified other regulatory authorities. The company is now analyzing this report, answers received from the questions posed to the investigator, and additionally will work with the investigator and other experts to examine the underlying source data and fully understand the results.
Bayer is committed to patient safety. The company will continue to work closely with the FDA to address questions regarding this study and the overall safety and efficacy of Trasylolâ (aprotinin injection).
And here you find further information of the Food and Drug Administration (FDA).
Bayer and Global Regulatory Authorities Evaluating Published Reports on Trasylol
08.02.2006
Bayer will publish and mail letters to Health Care Professionals
Bayer HealthCare is working with global regulatory authorities to evaluate recent reports published in the medical literature concerning Trasylol® (aprotinin injection) and communicating guidance to physicians and the public concerning these reports. These articles report an association of aprotinin/Trasylol with an increased risk of cardiovascular events (myocardial infarction or heart failure), cerebrovascular events1 such as stroke, encephalopathy or coma, and renal dysfunction or failure1, in patients undergoing coronary artery bypass graft (CABG) surgery.
A study entitled, “The Risk Associated with Aprotinin in Cardiac Surgery” by Mangano et al., was published in the New England Journal of Medicine, (Mangano D, Tudor J, Dietzel C. N Eng J Med, 2006 (354) :353-65. www.nejm.com). A study entitled, “A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery” by Karkouti et al. has been published in the journal Transfusion (Karkouti K, Beattie W, Dattilo K, McCluskey S, Ghannam M, Hamdy A, et al., Transfusion, on-line edition, 1/20/06. www.blackwellpublishing.com/journal.asp? ref=0041-1132).
Relevant regulatory authorities have said that they will review these reports, data supplied by Bayer and the authors of the studies, other reports in the literature as well as adverse event reports submitted to health authorities through established regulatory processes, to determine if any actions are warranted. Several health authorities have or may issue guidance to physicians and patients in their respective markets. Bayer welcomes and supports both the review and evaluation of these published studies and posting of guidance to physicians and patients in various markets. Bayer has posted and will mail letters to healthcare providers outlining background information concerning this issue.
Both studies were observational studies, and as such have certain methodological limitations, e.g. imbalances in baseline characteristics of patients which could result in the aprotinin-treated group being at higher risk to begin with for developing serious adverse events. This possibility prevents a direct assessment of whether aprotinin altered the risk for serious adverse events. To try to adjust for known differences between the treatment groups, the study authors used statistical procedures such as multivariable logistic regression and propensity score adjustments.
The NEJM publication studied patients undergoing coronary artery bypass graft (CABG) surgery who received either aprotinin or one of two other drugs intended to decrease perioperative bleeding. The authors reported an association of aprotinin with an increased risk of cardiovascular events (myocardial infarction or heart failure), cerebrovascular events such as stroke, encephalopathy or coma, and renal dysfunction or failure in these patients. The Transfusion study suggested that Trasylol administration increased the risk for renal dysfunction or failure. Renal dysfunction and renal failure have previously been reported in patients receiving Trasylol and is reflected in the current approved labeling for Trasylol. The Transfusion study authors did not find an increased rate of cardiovascular or cerebrovascular events in Trasylol-treated patients and reported comparable mortality rates between the control treatment group and the Trasylol group.
While the evaluation of these published reports and other relevant data continues, Bayer and various regulatory authorities have provided or indicated that they may soon provide guidance for physicians, other health care professionals and the public. The FDA has posted an “Alert for Healthcare Professionals” and a “Public Health Advisory” concerning Trasylol on its website (www.fda.gov) along with questions and answers related to this issue. Bayer has posted this statement and a letter to Healthcare Professionals on its websites today (www.bayer.com, www.bayerhealthcare.com, www.bayerpharma.com, www.bayervital.de and www.trasylol.com). In the next days Bayer will mail its letter to healthcare providers who use the product e.g. cardiothoracic surgeons, anesthesiologists and hospital pharmacists.
Guidance from regulatory authorities, e.g. the U.S Food and Drug Administration, (FDA) includes a recommendation that physicians carefully monitor patients receiving Trasylol for the occurrence of adverse events particularly related to the kidneys, heart, or central nervous system and promptly report any events to Bayer or the relevant regulatory authorities. The guidance also suggests that while the evaluation continues, physicians should consider limiting Trasylol use to situations where the clinical benefit of reduced blood loss is essential for medical management of the patient and outweighs potential risks.
Bayer has been working and will continue to work closely with regulatory authorities in all countries where Trasylol is marketed to address questions regarding product safety. We share the company’s data on Trasylol with regulatory authorities on an ongoing basis and welcome their evaluation of these published reports. Bayer believes that Trasylol is a safe and effective treatment when used in accordance with the product labeling.
About Trasylol
Trasylol, a broad-spectrum proteinase inhibitor, modulates the systemic inflammatory response associated with cardiopulmonary bypass (CPB) in the course of CABG surgery. Approved by the FDA in 1993, Trasylol is the only product indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing CPB in the course of CABG surgery. Full prescribing and warning information is also available at www.Trasylol.com. Trasylol Prescribing Information. Accessed on November 15, 2005. Available at: http://www.trasylol.com.
The effects of Trasylol use in CPB involves a reduction of inflammatory response to surgery, reduced bleeding and decreased re-exploration for bleeding, which translates into a decreased need for allogeneic (blood donated from another individual) blood transfusions. An important part of Bayer Pharmaceuticals Specialty Pharmaceuticals portfolio, Trasylol has remained a category leader for several years. Bayer is committed to further investment in the Trasylol franchise and is actively engaged in the research and development of a recombinant version of the product. In anticipation of emerging needs of this market, Bayer is also leading in next generation product development.
Important safety considerations
Anaphylactic or anaphylactoid reactions are possible when Trasylol is administered. Hypersensitivity reactions are rare in patients with no prior exposure to aprotinin. The risk of anaphylaxis is increased in patients who are reexposed to aprotinin-containing products. The benefit of Trasylol to patients undergoing primary CABG surgery should be weighed against the risk of anaphylaxis should a second exposure to aprotinin be required (see WARNINGS and PRECAUTIONS in the Trasylol prescribing information).
• rare (<0.1%) in patients with no prior exposure to Trasylol
• 2.7% overall reaction rate upon re-exposure
• within 6 months, the incidence was 5 percent
• after 6 months, the incidence was 0.9 percent
Trasylol is generally well tolerated. In clinical trials, graft patency, myocardial infarction, renal or hepatic dysfunction and mortality were comparable to placebo.
