Trasylol Lawsuit - Saunders & Walker Attorney Overview
On December 29, 1993, the US FDA approved Trasylol (aprotinin), a serine protease inhibitor developed by Miles, Inc., then a U.S. subsidiary of Bayer Corporation (later renamed Bayer, Inc.). Trasylol was promoted as the only product indicated for prophylactic use to reduce blood loss and the need for blood transfusions in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass grafting surgery (CABG). In its approval announcement FDA reported that two placebo controlled clinical trials conducted in the United States demonstrated that Trasylol effectively reduced blood loss and decreased the need for transfusions. FDA added that the drug should be reserved for high-risk patients since severe allergic reactions were reported among patients who received a second dose of the drug. On August 28, 1998, FDA expanded the drug’s use to all CABG patients and eliminated the high-risk limitation.
Due to continued reports of life-threatening anaphylactic allergic reactions in patients receiving the drug, especially those receiving a second dose, a black-box warning was added to Trasylol labeling. The warning was strengthened in December 2006 when additional text was added warning of the risk of anaphylaxis in patients receiving a second dose of the drug within 12 months of the initial exposure.
In an effort to reduce bleeding risks associated with on-pump CABG surgery, US cardiothoracic surgeons embraced Trasylol between 1998 and 2005. Two other antifibrinolytic drugs also can be used to reduce bleeding in CABG patients – Amicar (aminocaproic acid, Xanodyne Pharmaceuticals, New Port, Kentucky) and Cyklokapron (tranexamic acid, Pharmacia and Upjohn, Division of Pfizer, Piscataway, New Jersey). But neither enjoyed the acceptance of Trasylol since neither has specific FDA approval for use in CABG surgery, nor have they been as widely studied or accepted for this indication as Trasylol.
Describing Trasylol as a longstanding “category leader,” Bayer announced the initiation of two Phase III studies designed to extend the use of Trasylol to elective total hip and spinal fusion procedures in 2005. In the same year Bayer announced its commitment to further investment in the Trasylol franchise and plans to develop a recombinant version of the product rather than produce the drug from natural sources.
But, in early 2006, the outlook for Trasylol began a downward spiral. The January 20, 2006 online edition of Transfusion, the journal of the AABB (American Association of Blood Banks), reported results of a study that compared Trasylol with Cyklokapron. Led by Keyvan Karkouti, M.Sc., M.D., researchers from the Departments of Anesthesia, Cardiac Surgery, and Health Policy, Management, and Evaluation, University of Toronto, concluded that while the two drugs had similar hemostatic effectiveness in high-transfusion-risk cardiac surgery, Trasylol was associated with kidney dysfunction.
In the January 26, 2006 issue of The New England Journal of Medicine, Dennis T. Mangano, Ph.D., M.D., of the Ischemic Research and Education Foundation, reported the results of an observational study comparing Trasylol, Amicar, and Cyklokapron. Trasylol was associated with twice the risk of renal failure requiring dialysis in patients undergoing complex coronary-artery surgery and, in patients undergoing primary cardiac surgery, a 55-percent increase in the risk of myocardial infarction or heart failure and a 181-percent increase in the risk of stroke or encephalopathy. Neither Amicar nor Cyklokapron were associated with an increased risk of renal, cardiac, or cerebral events.
On February 8, 2006 FDA issued a Public Health Advisory alerting cardiothoracic surgeons and their patients that Trasylol had been linked to higher risks of serious side effects including kidney problems, heart attacks and strokes in patients who undergo artery bypass graft surgery. FDA indicated it was evaluating the published studies, along with other scientific literature and reports submitted to the FDA through the MedWatch program, to determine if labeling changes or other actions are warranted.
On June 19, 2006, Roanda Pretorius, M.Sc. and other investigators of the Ottawa Health Research Institute conducting Bart (Blood Conservation using Antifibrinolytics: A Randomized Trial in High-Risk Cardiac Surgery Patients) presented preliminary results for the largest randomized trial of antifibrinolytic drugs in high-risk surgery conducted to date designed to definitively determine if Trasylol was superior to Amicar and Cykokapron. A significant background point for the triple-blind randomized clinical trial involving 2970 high-risk cardiac surgical patients from 25 Canadian cardiac surgical suites was the 10-fold cost differential between Trasylol and Amicar. The researchers reported that rates for primary and secondary outcomes for Trasylol patients had exceeded initial predictions by more than two-fold. Primary outcomes included massive postoperative bleeding, massive transfusion, death due to hemorrhage, or re-operation for hemorrhage and tamponade. Secondary outcomes included the proportion of patients exposed to any blood products over 30 days, fatal and/or life-threatening clinical consequences and serious postoperative complications. The investigators then concluded that the higher rates may be explained by the inclusion of a higher risk population than initially anticipated or the lack of recent, good quality data from large patient cohorts in which to base assumptions.
FDA’s Cardiovascular and Renal Drugs Advisory Committee met on September 21, 2006 and reviewed the two observational epidemiological studies described above, together with the Bayer worldwide safety review, and the FDA review of its own post-marketing database. During the meeting Bayer failed to disclose preliminary findings from a new observational study conducted by i3, a global pharmaceutical services company, which demonstrated that use of Trasylol may increase the chance of death, serious kidney damage, congestive heart failure, and stroke compared to Amicar. On September 26, 2006 Bayer acknowledged that it mistakenly did not inform the FDA about the retrospective study which relied on a large prospective, in-hospital database encompassing 78,199 CABG patients treated between April 2003 and March 2006. Bayer explained the data were not shared immediately with the agency because they were preliminary in nature and raised significant questions on the study population, outcomes, and methodology.
This disclosure prompted the FDA to approve,on December 15, 2006, label changes to inform physicians and patients about the associated risks and to limit approved usage to specific situations, and to schedule another panel meeting on September 12, 2007. The new label warned that Trasylol increases the risk of renal dysfunction and the need for kidney dialysis in the perioperative period. Indications for use were changed once again to limit use to CABG patients who are at increased risk for blood loss and blood transfusion.
On September 12, 2007, members of FDA’s Cardiovascular and Renal Drugs Advisory Committee met in joint session with the agency's Drug Safety and Risk Management Advisory Committee to consider Trasylol’s fate. Bayer representatives, Drs. Mangano and Karkouti, and statisticians all of whom had re-analyzed and reviewed the observational data for the FDA gave presentations. After hearing all of the evidence, panel members voted 16 to 1 (with 1 abstention) that the product met safety criteria and could remain on the market. The panel voted unanimously for Bayer to conduct further studies, including randomized controlled trials, to help explain the different conclusions from the various observational studies. Members also voted 11 to 6 (with 1 abstention) against labeling changes including results from the observational studies, but the majority wanted a general statement about the concerns the data raised.
On October 19, 2007, FDA was notified of the DSMB’s (Data Safety Monitoring Board responsible for monitoring patient safety in the BART trial) recommendation to stop patient enrollment in the Trasylol treatment group because 30-day mortality had already approached statistical significance; a trend toward increased mortality continued throughout the study; and there were more Trasylol-related deaths due to hemorrhage. The increased mortality trend reflected approximately two additional deaths per 100 patients receiving Trasylol.
As a result, US, German, and Canadian regulators pushed Bayer to stop selling Trasylol to allow authorities to complete a detailed review of the BART data. Finally, on November 5, 2007, Bayer announced the temporary suspension of global sales. Bayer pledged to work with health authorities to evaluate whether BART data have any impact on the positive benefit-risk assessment for Trasylol. Once the data are evaluated, Bayer intends to reevaluate the temporary suspension. In its statement Bayer underlined its belief “that the totality of the available data continue to support a favorable risk-benefit profile for Trasylol when used according to labeling.”
More than 4.77 million patients have received the drug since it was approved in 1993. Bayer reported that approximately 110,000 U.S. patients and 87,000 patients outside of the United States received Trasylol in 2006 and estimated that 2007 worldwide sales were roughly $135 million for the nine months through September with the United States accounting for about $91 million.
Though John K. Jenkins, director of FDA’s office of new drugs defended FDA’s handling of Trasylol, citing that two advisory panels recommended the drug remain on the market, FDA does not have any estimates Trasylol-related deaths. Jenkins admitted the FDA “cannot identify a specific patient population where we believe the benefits outweigh the risks.”
Case Clinical
Bayer’s Trasylol package insert describes the intravenous drug as a natural proteinase inhibitor obtained from bovine lung. The insert also states that Trasylol is “indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.” Administration of the drug involves an initial or test dose, a loading dose, and a dose to be added while recirculating the priming fluid of the cardiopulmonary bypass circuit and a constant infusion dose.
Coronary artery bypass surgery (CABG) is widely performed in the United States, and more than 800,000 coronary artery bypass graft surgeries are performed worldwide every year. CABG is a heart surgery procedure in which a blood vessel graft is used to bypass one or more blocked coronary arteries to restore normal blood flow to the heart. The grafts are usually harvested from the patient’s own arteries and veins located in the chest, leg, or arm. Excessive bleeding is a frequent complication of this surgery. Blood loss translates into prolonged mechanical ventilation, poor wound healing, prolonged hospital stay, and multiple organ failure.
CABG is performed both with (on-pump) and without (off-pump) the heart-lung bypass machine. Trasylol is only indicated for on-pump surgery. During off-pump surgery, the surgeon uses advanced operating equipment to stabilize portions of the heart while it continues to beat, pumping blood throughout the circulatory system.
Trasylol is dangerous. If you or a loved one suffered as a result of Trasylol you should seek legal advice immediately.
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