The Food and Drug Administration today issued a Public Health Advisory alerting doctors who perform heart bypass surgery, and their patients, that Trasyolol (aprotinin injection), a drug used to prevent blood loss during surgery, has been linked in two scientific publications to higher risks of serious side effects including kidney problems, heart attacks and strokes in patients who undergo artery bypass graft surgery.
"FDA is conducting a thorough evaluation of the safety profile for this drug in light of the recent publications," said Dr. Steven Galson, Director of FDA's Center for Drug Evaluation and Research. "We're working to evaluate the potential risks and determine whether there is a need for further action. In the meantime, we advise providers to carefully assess the benefits and risks of the drug for their patients."
FDA advises health care providers to be aware of the following:

• Physicians who use Trasylol should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart or central nervous system and promptly report adverse event information to Bayer, the drug manufacturer, or through the FDA Medwatch program.
• Physicians should consider limiting Trasylol use to those situations in which the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks.
• FDA is working with the manufacturer to examine the safety and benefits of Trasylol in light of the recent data and the evolving practice of medicine.
• Patients should discuss all major risks for heart bypass surgery with their healthcare providers. These include the risks for bleeding and the available ways to lessen the risk for bleeding.

• Physicians who use Trasylol should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, or central nervous system and promptly report adverse event information to Bayer, the drug manufacturer, or to the FDA MedWatch program, as described at the end of this advisory.
• Physicians should consider limiting Trasylol use to those situations where the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks.

The study reported in the NEJM was an observational study of patients undergoing CABG who received either Trasylol, one of two other drugs intended to decrease peri-operative bleeding (aminocaproic acid or tranexamic acid), or no specific drug treatment.  
A limitation of the study was that patients were not assigned at random to receive the treatments, but rather had their treatment chosen by their physician as part of their standard medical care.   Consequently, patients receiving Trasylol may have been at higher risk to begin with for these serious adverse events compared to patients receiving no treatment or treatment with another drug intended to decrease bleeding.  This possibility prevents a direct assessment of whether Trasylol altered the risk for serious adverse events.  The study investigators used statistical procedures (multivariable logistic regression and propensity-score adjustment) to try to adjust for known differences between the treatment groups.  Using these procedures, their study concluded that Trasylol was associated with more adverse outcomes.  Other findings in the study suggested that patients receiving higher Trasylol dosages were at greater risk than those receiving lower dosages.
The study reported in the on-line edition of Transfusion was also an observational study that used statistical methodology to compare outcomes from patients undergoing CABG. The patients in this study received, at physician direction, either Trasylol or another drug intended to decrease the risk for perioperative bleeding. This study suggested that Trasylol administration increased the risk for renal dysfunction. This study has some of the same limitations as the NEJM publication.
In pre-marketing clinical studies conducted among approximately 3,000 patients undergoing CABG, the risks and benefits of Trasylol were determined in clinical studies that randomized patients to either a placebo or Trasylol.  In these studies, the risks for serious renal toxicity and cardiovascular events were determined to be similar between patients receiving Trasylol and those receiving placebo.  However, in one study assessing coronary graft patency, Trasylol administration was associated with an increased risk of graft closure.  The FDA will work with the authors of the publications and the manufacturer of Trasylol to carefully evaluate the risks and benefits associated with use of Trasylol in CABG.  The FDA anticipates the public presentation of the recently reported information and other data at an advisory committee in the near future.  The FDA will notify health care providers and patients in a timely fashion as new information becomes available.

FDA Requests Marketing Suspension of Trasylol

The U.S. Food and Drug Administration (FDA) today announced that, at the agency's request, Bayer Pharmaceuticals Corp. has agreed to a marketing suspension of Trasylol, a drug used to control bleeding during heart surgery, pending detailed review of preliminary results from a Canadian study that suggested an increased risk for death.
FDA requested the suspension in the interest of patient safety based on the serious nature of the outcomes suggested in the preliminary data. FDA has not yet received full study data but expects to act quickly with Bayer, the study's researchers at the Ottawa Health Research Institute, and other regulatory agencies to undertake a thorough analysis of data to better understand the risks and benefits of Trasylol.
There are not many treatment options for patients at risk for excessive bleeding during cardiac surgery. Thus, FDA is working with Bayer to phase Trasylol out of the marketplace in a way that does not cause shortages of other drugs used for this purpose.
Until FDA can review the data from the terminated study it is not possible to determine and identify a population of patients undergoing cardiac surgery for which the benefits of Trasylol outweigh the risks. Understanding that individual doctors may identify specific cases where benefit outweighs risk, FDA is committed to exploring ways for those doctors to have continued, limited access to Trasylol.
Two weeks ago, FDA was notified that researchers with the Ottawa Health Institute stopped a study on Trasylol because the drug appeared to increase the risk for death compared to two other antifibrinolytic drugs used in the study. Antifibrinolytic drugs help slow the breakdown of blood clots and subsequent excessive bleeding. The preliminary data from this terminated study also suggested that fewer patients receiving the drug experienced serious bleeding events.
On Oct. 26, FDA issued an Early Communication about an Ongoing Safety Review of Trasylol in response to the Canadian study's termination. In 2006, FDA revised the labeling for Trasylol to strengthen its safety warning and limit its approved usage to patients at an increased risk for blood loss and blood transfusion during coronary bypass graft surgery.
Early Communication about an Ongoing Safety Review
Aprotinin Injection (marketed as Trasylol)
This information reflects FDA’s current analysis of available data concerning these drugs. Posting this information does not mean that FDA has concluded there is a causal relationship between the drug products and the emerging safety issue.  Nor does it mean that FDA is advising health care professionals to discontinue prescribing these products. FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action. FDA intends to update this document when additional information or analyses become available.

On October 19, 2007, FDA was notified of the Data Safety Monitoring Board’s (DSMB) recommendation to stop patient enrollment in the aprotinin (marketed as Trasylol by Bayer, Inc.) treatment group arm of the:  Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study.  The preliminary findings suggest that, compared to the antifibrinolytic drugs, epsilon-aminocaproic acid and tranexamic acid, aprotinin increases the risk of death. 
The BART study was designed to test the hypothesis that aprotinin was superior to epsilon-aminocaproic acid and tranexamic acid in decreasing the occurrence of massive bleeding associated with cardiac surgery.  The study had planned to enroll approximately 3,000 adult Canadian patients who were to undergo various types of cardiac surgery that placed them at high risk for bleeding. 
Information from the interim analyses performed by the DSMB is limited, but FDA has been informed that:

• the 30- day mortality in the aprotinin group nearly had reached conventional statistical significance at the interim analysis, when compared to either epsilon-aminocaproic acid or tranexamic acid;

• a trend toward increased mortality in the aprotinin group had been observed throughout the study;

• the use of aprotinin was associated with less serious bleeding than either of the comparator drugs; however, more deaths due to hemorrhage had been observed among patients receiving aprotinin;

• the DSMB concluded that continued enrollment of patients into the aprotinin group was unlikely to significantly change the study findings.

Additional data collection and analyses must be performed to more thoroughly assess the findings from the BART study.  However, these preliminary data support the findings from observational studies that also suggested increased risks for mortality when aprotinin was compared to other antifibrinolytic drugs.  These observational studies were discussed at a September 12, 2007, joint meeting of the Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committees.  
In light of the preliminary BART study findings, FDA anticipates re-evaluation of the overall risks and benefits of Trasylol. This re-evaluation may result in the need to revise the labeling or other regulatory actions.  Until this process has been completed, healthcare providers who are considering use of Trasylol should be aware of the risks and benefits described in the labeling for Trasylol and the accumulating data suggesting Trasylol administration increases the risk for death compared to other antifibrinolytic drugs. 
Trasylol is currently approved 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 (CABG) surgery who are at an increased risk for blood loss and blood transfusion.
This early communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs.  FDA will work with the sponsor of the BART study and the manufacturer of Trasylol to fully evaluate the risks and benefits associated with the use of Trasylol.  As soon as this process is complete, FDA will communicate the conclusions and recommendations to the public. 
The FDA urges healthcare professionals to promptly report serious and unexpected adverse reactions associated with Trasylol to Bayer or to the FDA MedWatch reporting program, as described below. 

FDA Revises Labeling for Trasylol (Aprotinin Injection) to Strengthen Safety Warnings and Limit Usage of Drug to Specific Situations

The U.S. Food and Drug Administration (FDA) today approved revised labeling for Trasylol (aprotinin injection) to strengthen its safety warnings and to limit its approved usage to specific situations.  Trasylol is given to patients before heart surgery to reduce bleeding and the need for blood transfusions.  Trasylol is marketed by Bayer Pharmaceuticals Corporation, Leverkusen, Germany.
"The purpose of the label change is to inform physicians and patients about the risks associated with Trasylol and to ensure they understand the new warnings and use the product as directed by the label," said Steven Galson, M.D., MPH, Director of FDA's Center for Drug Evaluation and Research.
The new labeling specifies that Trasylol should only be given to patients who are at an increased risk for blood loss and blood transfusion in the setting of coronary bypass graft surgery (a procedure used to improve blood flow to the heart) when patients undergo cardiopulmonary bypass (a procedure that allows a machine to take over the heart's functions when it is stopped during surgery).  The changes also include a warning that Trasylol increases the possible risk for kidney damage, and suggest ways to manage and reduce the patient's risk for hypersensitivity (exaggerated immune) reactions.
The labeling changes follow an FDA-conducted review of safety information that FDA became aware of after the product was introduced to the market.  FDA began this safety review of Trasylol in January 2006.  The review was triggered by the results of two published research studies.  One study reported an increase in the possibility of kidney failure, heart attack and stroke in patients treated with Trasylol compared to those treated with other drugs.  The other study reported an increase in the possibility of kidney damage compared to other drugs, but did not show an increased risk of heart attack or stroke.  On February 8, 2006, FDA issued a Public Health Advisory regarding these new findings with Trasylol.  On September 21, 2006, FDA held a public meeting of the Cardiovascular and Renal Drugs Advisory Committee to discuss the safety and overall risk-benefit profile for Trasylol.  At that meeting, the committee discussed the findings from the two published observational studies, a Bayer worldwide safety review, and the FDA review of its own post-marketing database, and made recommendations for labeling changes.  The labeling changes for Trasylol are based upon the recommendations of that advisory committee.
FDA announced on September 29, 2006, that Bayer informed the agency of an additional safety study on September 27, 2006.  The preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes.  The FDA review of this additional Trasylol safety information is continuing and it may result in other actions, including additional changes to the labeling.  For additional information about Trasylol, see www.fda.gov/cder/drug/infopage/aprotinin/default.htm.
Information for Healthcare Professionals
Aprotinin Injection (marketed as Trasylol)

FDA ALERT [2/2006, Updated 9/2006 and 12/2006]: This Alert highlights important revisions to the full prescribing information for Trasylol.  The new labeling for Trasylol (December 2006) has a more focused indication for use, a new Warning about renal dysfunction, a revised Warning about anaphylactic reactions, and a new Contraindication.  Trasylol is now indicated only for prophylactic use to reduce peri-operative blood loss and the need for blood transfusion in patients who are at an increased risk for blood loss and blood transfusion undergoing cardiopulmonary bypass in the course of coronary artery bypass grafting (CABG) surgery.  Trasylol should be administered only in the operative setting where cardiopulmonary bypass can be started quickly.  Trasylol should not be administered to any patient with a known or suspected exposure to aprotinin within the past 12 months. 
FDA is evaluating additional recently submitted epidemiological safety study data (discussed below), in the context of all other safety and efficacy information available on aprotinin.  This review may result in other actions, including additional changes to the full prescribing information (product labeling).
This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.

To report any serious adverse events associated with the use of this drug, please contact the FDA MedWatch program using the contact information at the bottom of this sheet.
The new labeling for Trasylol has a more focused indication, a new Warning about renal dysfunction, a revised Warning about anaphylactic reactions, and a new Contraindication.  The new labeling changes are summarized here:
Indication and Usage—more limited and focused
Trasylol is now indicated for use only in patients who are at increased risk for blood loss and blood transfusion in association with cardiopulmonary bypass in the course of coronary artery bypass grafting. It should be administered only in the operative setting where cardiopulmonary bypass can be rapidly initiated.
A new Warning about renal dysfunction
Trasylol administration increases the risk for renal dysfunction and may increase the need for dialysis in the perioperative period.
Stronger Warnings about anaphylactic reactions including a new Contraindication for previous aprotinin exposure
Anaphylactic reactions, including fatal reactions, are one of the important risks associated with Trasylol administration.  As a consequence of the higher risk for anaphylactic reactions, administration of Trasylol to patients with a known or suspected exposure during the past 12 months is contraindicated.

Recommendations and Considerations for physicians:

• Consistent with clinical practice guidelines for patients undergoing CABG surgery, when administering Trasylol, carefully monitor your patient for the occurrence of toxicity, particularly to the kidneys, heart, or central nervous system. 

• Limit Trasylol use to those situations where the clinical benefit of reduced blood loss is essential to medical management of the patient and the benefit outweighs the potential risks.

• Promptly report serious and unexpected adverse events associated with Trasylol to the drug manufacturer (Bayer), or to the FDA MedWatch program, as described at the end of this information sheet.

• Monitor patients closely for anaphylactic reactions, even when administering a test dose of Trasylol.  Anaphylactic reactions occur more frequently in patients who have been exposed previously to Trasylol or to other aprotinin-containing products (for example, fibrin glues such as Tissucol or Tisseel).  The most frequently reported sign of hypersensitivity is hypotension.

Information for the patient:  
When a decision to treat a patient with Trasylol has been made, physicians and other healthcare professionals should discuss the following with the patient:

• Because the patient has a higher chance for blood loss and blood transfusion during their upcoming cardiopulmonary bypass during their CABG surgery, they may receive Trasylol during their operation.

• The factors that increase the patient’s chance for serious complications include previous treatment with Trasylol (especially within the past 12 months), prior heart surgery, known drug allergies, or known kidney disease.

• Previous treatment with Trasylol increases the chance of experiencing an anaphylactic allergic reaction, which can happen suddenly and can be life threatening or cause death.   

• Trasylol can increase the patient’s chance of serious kidney problems that could lead to a need for kidney dialysis after surgery.  Treatment with Trasylol can also lead to kidney failure. 

Data Summary:
Two articles published in January 2006 reported the results of two new safety studies of Trasylol, which indicated a higher risk of death and serious and/or life-threatening renal and cardiac adverse events following treatment with Trasylol. 
Results from a study published in the New England Journal of Medicine
A January 26, 2006, article published in the New England Journal of Medicine (NEJM) described the findings from an observational study of 4,374 patients (1,295 treated with Trasylol) scheduled for CABG surgery at multiple centers in multiple countries.  Baseline and outcome data were prospectively collected from patients who were prescribed either no preventive drug therapy for blood loss or one of three drugs intended to prevent blood loss (Trasylol, aminocaproic acid or tranexamic acid).  The choice of treatment drug (or no treatment) was at physician discretion, rather than through random assignment. Aminocaproic acid and tranexamic acid are anti-fibrinolytic drugs approved by the FDA for indications other than prevention of blood loss in the CABG surgery setting.
In this study, imbalances in measured baseline characteristics suggested that Trasylol-treated patients may have been sicker at baseline than patients receiving other treatments. To adjust for these imbalances, the study authors used complex statistical methodology involving propensity scores. The study classified patients as primary (the surgery was elective and involved only coronary artery revascularization or angioplasty, with no history of cardiac or vascular surgery) or complex (all other patients). 
Compared to those receiving no preventive drug therapy and after propensity adjustment, primary patients receiving Trasylol had a higher risk for dialysis or creatinine increase; myocardial infarction or heart failure; or stroke, encephalopathy or coma.  Compared to those receiving no preventive drug therapy and after propensity adjustment, complex patients receiving Trasylol had a higher risk for dialysis or creatinine increase, but not for heart complications, stroke, encephalopathy or coma.  Risks for adverse renal events increased with the administered Trasylol dose.  All three drug therapies (Trasylol, aminocaproic acid or tranexamic acid) were reported to reduce blood loss to similar extents.
New Study Results from Transfusion
A January 20, 2006, Transfusion (on-line edition) publication described the findings from an
observational prospective study of 898 patients (449 treated with Trasylol) undergoing CABG surgery with cardiopulmonary bypass at a single center.  These patients were selected from a larger group of 10,870 based on their propensity scores that adjusted for imbalances in measured baseline characteristics.  Study patients received either Trasylol or tranexamic acid; the choice of treatment drug was made by the patient’s treating physician drug rather than through random assignment.   Measured baseline characteristics were similar between the two patient groups in the study.  The rate of renal dysfunction was higher among patients receiving Trasylol than among patients receiving tranexamic acid, especially in those with existing renal dysfunction.   The two patient study groups had similar rates of other adverse events and of red blood cell transfusion.
Premarketing Studies
The premarketing clinical studies supporting Trasylol safety and efficacy enrolled a total of
approximately 3,000 patients (2,002 treated with Trasylol). The studies, including six placebo-controlled trials, consistently showed that Trasylol decreased peri-operative blood loss and the
need for blood transfusion. The risks for serious renal and cardiovascular adverse events and
deaths were similar between patients receiving Trasylol and those receiving placebo. One study
of approximately 800 subjects showed that patients receiving Trasylol had higher rates of
coronary graft occlusion than patients receiving a placebo; however, this altered coronary
patency was not associated with differences in myocardial infarction and mortality risk between
the two study groups. The major pre-market safety signal was a risk for anaphylaxis, especially
among subjects re-exposed to Trasylol. The Trasylol label carries a black box warning relating
to anaphylaxis.
Post-marketing Spontaneous Reports
Two hundred ninety-one cases of hypersensitivity possibly associated with Trasylol, including 52 cases with fatal outcomes, have been reported to Bayer.  A test dose was administered in 139 of the 291 cases.  A hypersensitivity reaction occurred with the test dose alone in 81 cases, including 19 fatal cases.  Additionally, the test dose did not elicit a reaction among 38 cases (9 fatal) of anaphylaxis that occurred with a therapeutic dose.   
A new study, reported to FDA on September 27, 2006
Following a September 21, 2006 discussion of the two published observational studies and other information at an FDA Cardiovascular and Renal Drugs Advisory Committee meeting, Bayer Pharmaceuticals informed FDA of another observational study they had performed using a contract research organization.  Existing hospital data from 67,000 records of patients undergoing coronary artery bypass graft surgery were examined.  30,000 of the patients were treated with Trasylol and 37,000 were treated with alternate products.  Using complex epidemiological and statistical methods, the report suggested that patients receiving Trasylol were at increased risk for death, kidney failure, congestive heart failure and stroke. \

FDA Statement Regarding New Trasylol Data

Since January, 2006, the Food and Drug Administration (FDA) has been conducting a safety review of Trasylol (aprotinin injection). The review was triggered by the results of two published research studies: one that reported an increase in the chance of kidney failure, heart attack and stroke in patients treated with Trasylol compared to those treated with other similar drugs, and the other that reported an increase in kidney dysfunction compared to another drug.  On September 21, 2006, FDA held a public meeting of the Cardiovascular and Renal Drugs Advisory Committee to discuss the safety and overall risk-benefit profile for Trasylol.  At that meeting, the committee discussed the findings from the two published observational studies, the Bayer worldwide safety review, and the FDA review of its own post-marketing database. 
On September 27, 2006, Bayer Pharmaceuticals told FDA that it had conducted an additional safety study of Trasylol.  The preliminary findings from this new observational study of patients from a hospital database reported that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes.  FDA was not aware of these new data when it held the September 21, 2006, Advisory Committee meeting on Trasylol safety.  FDA is actively evaluating these new data and their implications for appropriate use of the drug.
While FDA conducts its evaluation of this new safety study, we recommend the following to healthcare providers:

• Physicians who use Trasylol should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, or brain, and promptly report observed adverse event information to Bayer Pharmaceuticals, the drug manufacturer, or to the FDA MedWatch program, by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), or by the Internet at http://www.fda.gov/medwatch/index.html.
• Physicians should consider limiting Trasylol use to those situations where the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks.

FDA ALERT [9/2006]
We have received results from another study of the possible harms from treatment with Trasylol. We are evaluating this study and will update this Alert when we are finished with the evaluation.

FDA ALERT [2/2006]    A new study suggests that Trasylol may increase the chance for serious side effects such as kidney failure, heart attack, and stroke in some patients. 
Another new study suggests that Trasylol may increase the chance for kidney failure.
These side effects have not been seen in other studies with Trasylol.
The FDA is looking at the results from these two new studies and will provide more information as it becomes known.
This information reflects FDA’s preliminary analysis of data concerning this drug.  FDA is considering, but has not reached a final conclusion about, this information.  FDA intends to update this sheet when additional information or analyses become available.

This is a summary of the most important information about Trasylol.  For details, talk to your healthcare professional.

What Is Trasylol?

Trasylol is a medicine given before heart surgery to reduce bleeding and the need for blood transfusions.  Trasylol is made from tissue taken from cows.
What Are The Risks?
The following are the major potential risks and side effects of Trasylol therapy. However, this list is not complete.
Serious Allergic Reaction (Anaphylactic Reaction) This is a rare but serious allergic reaction that happens suddenly and can be life threatening or cause death.  Patients who have had Trasylol in the past have a higher chance for anaphylactic reactions with a new dose of Trasylol.
What Should I Tell My Healthcare Professional?
If you are scheduled to have heart surgery, ask your doctor if he or she intends to use Trasylol.  Tell your healthcare professional if you:

• Have had Trasylol in the past
• Have had heart surgery
• Are allergic to any medicines
• Have kidney disease
• Are pregnant, trying to become pregnant, or are breast-feeding
• Are taking other medicines.  Know the medicines you take. Keep a list of them with you to show your healthcare professional.

Questions? Call Drug Information, 1-888-INFO-FDA (automated) or 301-827-4570
Information for Healthcare Professionals
Aprotinin (marketed as Trasylol)

FDA ALERT [9/2006]:
We are updating this Alert to note that the Cardiovascular and Renal Drugs Advisory Committee met on September 21, 2006 and discussed Trasylol safety information. At that meeting, the Committee reviewed the two observational epidemiological studies described below, the Bayer worldwide safety review and the FDA review of its own post-marketing database, which included a summary of post-marketing reports to FDA about potential life threatening anaphylactic allergic reactions following administration of aprotinin injection (summarized below).
On September 27, 2006 Bayer Pharmaceuticals told FDA that it had conducted an additional safety study of Trasylol. The preliminary findings from this new observational study of patients from a hospital database reported that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes. FDA was not aware of these new data when it held the September 21, 2006, Advisory Committee meeting on the safety of Trasylol. FDA is actively evaluating these new data along with other published reports and the pre-marketing clinical studies and will update this alert when we have completed our review. Meanwhile, our recommended considerations remain as below.
In the Bayer study, existing hospital data from 67,000 records of patients undergoing coronary artery bypass graft surgery were examined. 30,000 of the patients were treated with aprotinin (Trasylol) and 37,000 were treated with alternative products. This study used complex epidemiological and statistical methods to examine the relationship of aprotinin to a variety of health outcomes.

FDA ALERT [2/2006]:
FDA is issuing this alert to provide notice of two recently published studies reporting serious renal and cardiovascular toxicity following Trasylol administration to patients undergoing coronary artery bypass grafting surgery (CABG).  An observational study published on January 26, 2006 in The New England Journal of Medicine (NEJM), reported that Trasylol may be associated with increased risk of cardiovascular events (myocardial infarction or heart failure), cerebrovascular events such as stroke, encephalopathy or coma and renal dysfunction or failure.  Another publication (Transfusion, on-line edition, January 20, 2006) has reported that Trasylol administration may increase the risk for renal toxicity (dysfunction or failure).  Neither study was randomized, and both compared Trasylol to products that are not FDA approved for use in the management of cardiac surgery patients.

FDA is evaluating these observational studies in the context of the pre-marketing clinical studies supporting the safety and efficacy of Trasylol and the post-marketing reports submitted to the MedWatch program.
This information reflects FDA’s preliminary analysis of data concerning this drug.  FDA is considering, but has not reached a final conclusion about, this information.  FDA intends to update this sheet when additional information or analyses become available.

• Consistent with clinical practice guidelines for patients undergoing CABG, physicians who use Trasylol should carefully monitor for the occurrence of toxicity, particularly to the kidneys, heart, or central nervous system.

• Physicians should consider limiting Trasylol use to those situations where the clinical benefit of reduced blood loss is essential to medical management of the patient and the benefit outweighs the potential risks.
   
• Physicians should promptly report serious and unexpected adverse events associated with Trasylol to the drug manufacturer (Bayer), or to the FDA MedWatch program, as described at the end of this alert advisory.
• Physicians should monitor patients closely for anaphylactic reactions, even when administering a test dose of Trayslol. Anaphylactic reactions occur more frequently in patients who have been exposed previously to aprotinin-containing products (for example, Trasylol, and fibrin glues such as Tissucol or Tisseel). The most frequently reported sign of hypersensitivity is hypotension.

Data Summary:
Trasylol is indicated "for prophylactic use to reduce peri-operative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery." 
New Study Results from the NEJM
A January 26, 2006 NEJM publication described the findings from an observational study of 4,374 patients (1,295 treated with Trasylol) scheduled for CABG at multiple centers in multiple countries.  Baseline and outcome data were prospectively collected from patients who were prescribed either no preventive drug therapy for blood loss or one of three drugs intended to prevent blood loss (Trasylol, aminocaproic acid or tranexamic acid).  Patients were not randomized to these treatments.  Instead, the choice of study drug (or no treatment) was at physician discretion.  Aminocaproic acid and tranexamic acid are anti-fibrinolytic drugs approved by the FDA for indications other than prevention of blood loss in the CABG setting.  The following information provides the major findings from the NEJM publication.

• Certain imbalances in baseline characteristics suggest that Trasylol-treated patients may have been sicker at baseline than patients receiving other treatments.  To adjust for imbalances in baseline characteristics, the study authors used complex statistical methodology involving propensity scores.  The study classified patients as primary (the surgery was elective and involved only coronary artery revascularization or angioplasty, with no history of cardiac or vascular surgery) or complex (all other patients). 

• After propensity adjustment, primary patients receiving Trasylol had increased risk for the following outcomes when compared to patients who received no preventive drug therapy:

• a renal event (dialysis or increase in creatinine), p = 0.006
• either myocardial infarction or heart failure, p = 0.01
• stroke, encephalopathy, or coma, p = 0.02

• After propensity adjustment, complex patients receiving Trasylol had an increased risk for a renal event (dialysis or increase in creatinine, p = 0.004) compared to patients who received no preventive drug therapy.  Myocardial infarction, heart failure and stroke risk were not increased among these patients.

• Risks for adverse renal events increased with the administered Trasylol dose.

• All three drug therapies (Trasylol, aminocaproic acid or tranexamic acid) were reported to reduce blood loss to similar extents. 

New Study Results from Transfusion
A January 20, 2006 Transfusion (on-line edition) publication described the findings from an observational study of 898 patients (449 treated with Trasylol) undergoing CABG with cardiopulmonary bypass at a single center.  Baseline and outcome data were obtained from a prospectively developed database for these patients.  Patients received either Trasylol or tranexamic acid.  Patients were not randomized to these treatments.  Instead, the choice of study drug was at physician discretion.  The 898 patients studied were a subset of a larger group of 10,870 patients selected on the basis of propensity scores to adjust for imbalances in measured baseline characteristics.  Major findings from the Transfusion publication were:

• In general, the measured baseline characteristics were similar between the two patient groups in the study.

• The rate of renal dysfunction was higher among patients receiving Trasylol than among patients receiving tranexamic acid.  The association between Trasylol and renal dysfunction was especially evident in patients with existing renal dysfunction.

• The rates of other adverse events were similar between the two study groups.

• The rate of red blood cell transfusion was similar for the two patient groups.

Premarketing Studies
The premarketing clinical studies supporting Trasylol safety and efficacy enrolled a total of approximately 3,000 patients (2,002 treated with Trasylol).  The studies, including six placebo-controlled trails, consistently showed that Trasylol decreased peri-operative blood loss and the need for blood transfusion.  The risks for serious renal and cardiovascular adverse events and deaths were similar between patients receiving Trasylol and those receiving placebo.  One study of approximately 800 subjects showed that patients receiving Trasylol had higher rates of coronary graft occlusion than patients receiving a placebo; however, this altered coronary patency was not associated with differences in myocardial infarction and mortality risk between the two study groups.  The major pre-market safety signal was a risk for anaphylaxis, especially among subjects re-exposed to Trasylol.  The Trasylol label carries a black box warning relating to anaphylaxis.
Post-marketing Spontaneous Reports
Two hundred ninety-one cases of hypersensitivity possibly associated with Trasylol, including 52 cases with fatal outcomes, have been reported to Bayer. A test dose was administered in 139 of the 291 cases. A hypersensitivity reaction occurred with the test dose alone in 81 cases, including 19 fatal cases. Additionally, the test dose did not illicit a reaction among 38 cases (9 fatal) of anaphylaxis that occurred with a therapeutic dose.
Implications:
The FDA will work with the authors of the reports and the manufacturer of Trasylol to evaluate the risks and benefits associated with use of Trasylol among patients undergoing cardiopulmonary bypass for CABG surgery.  The FDA will notify health care providers and patients in a timely fashion as new information becomes available.  Physicians should carefully monitor patients for the occurrence of toxicity and promptly report toxicity to Bayer, the Trasylol manufacturer, or to the FDA MedWatch program.
FDA Public Health Advisory
Aprotinin Injection (marketed as Trasylol) 

Since January, 2006, FDA has been conducting a safety review of Trasylol (aprotinin injection). The review was triggered by the results of two published research studies: one that reported an increase in the chance of kidney failure, heart attack and stroke in patients treated with Trasylol compared to those treated with other similar drugs, and the other that reported an increase in kidney dysfunction compared to another drug.  On September 21, 2006, FDA held a public meeting of the Cardiovascular and Renal Drugs Advisory Committee to discuss the safety and overall risk-benefit profile for Trasylol.  At that meeting, the committee discussed the findings from the two published observational studies, the Bayer worldwide safety review, and the FDA review of its own post-marketing database. 
On September 27, 2006, Bayer Pharmaceuticals told FDA that it had conducted an additional safety study of Trasylol.  The preliminary findings from this new observational study of patients from a hospital database reported that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes.  FDA was not aware of these new data when it held the September 21, 2006, Advisory Committee meeting on Trasylol safety.  FDA is actively evaluating these new data and their implications for appropriate use of the drug.
While FDA conducts its evaluation of this new safety study, we recommend the following to healthcare providers:

• Physicians who use Trasylol should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, or brain, and promptly report observed adverse event information to Bayer Pharmaceuticals, the drug manufacturer, or to the FDA MedWatch program, by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), or by the Internet at http://www.fda.gov/medwatch/index.html.
• Physicians should consider limiting Trasylol use to those situations where the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks.

These recommendations are similar to those provided in a February 8, 2006, FDA Public Health Advisory and information sheets for health care professionals and patients which were based on the published studies mentioned above. See http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm.  
Trasylol works to slow or prevent bleeding, and is used to reduce blood loss and the need for blood transfusion during some types of heart surgeries.  Trasylol is made from the lung tissue of cattle. 
In the published studies and the recently supplied Bayer study, patients were not assigned at random to receive various treatments, but rather had their treatment chosen by their physician as part of their standard medical care.  Consequently, in these safety studies, patients receiving Trasylol may have had a higher chance for serious complications to begin with as compared to patients receiving no treatment or treatment with another drug intended to decrease bleeding.  This possibility complicates the assessment of whether the available studies show that Trasylol treatment, rather than other factors, increased the chance for serious kidney or heart complications.
The new study was done for Bayer by a contract research organization.  Existing hospital data from 67,000 records of patients undergoing coronary artery bypass graft surgery were examined.  30,000 of the patients were treated with Trayslol and 37,000 were treated with alternate products.  Using complex epidemiological and statistical methods, the report suggested that patients receiving Trasylol were at increased risk for death, kidney failure, congestive heart failure and stroke. 

Trasylol health risks:  kidney failure, heart attack, stroke, and death
Trasylol FDA Info
Trasylol medical information