FDA Issues Public Health Advisory for Trasylol (Full Summary)

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.

Trasylol (aprotinin injection) is the only product approved by FDA for the prevention of peri-operative blood loss and the need for blood transfusion among patients undergoing coronary artery bypass graft surgery. The drug aids the body’s ability to stop bleeding and is used to lessen the bleeding risk during this surgical procedure. This surgery is done to bypass clogged arteries.
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FDA is evaluating the studies more closely, 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. One study, published in the New England Journal of Medicine, reported that patients who received Trasylol had higher rates of serious kidney problems, heart attacks, and stroke compared to treatment with other drugs to prevent bleeding or to no treatment; the second study, reported in Transfusion, reported more cases of decreased kidney function in patients treated with Trasylol compared to another treatment to prevent bleeding. A limitation of both studies was that doctors chose which patients were to receive Trasylol or another treatment. It is possible that patients treated with Trasylol may have been sicker than other patients. The studies used complex statistical methods to adjust for possible differences in patient risk factors.

The agency also anticipates convening an advisory committee meeting in 2006 to discuss the existing data about the risks and benefits of Trasylol, and if additional safety measures need to be taken. The FDA will notify health care providers and patients in a timely manner following further scientific investigation of adverse event reports.

FDA also urges health care providers and patients to report adverse event information to FDA via the MedWatch program by phone (1800-FDA-1088), by fax (1-800-FDA-1078) or internet.

Patient Information Sheet: Aprotinin (marketed as Trasylol)

FDA ALERT [02/2006] 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.

FDA Public Health Advisory: Aprotinin Injection (marketed as Trasylol)

On January 26, 2006, The New England Journal of Medicine (NEJM) published an article by Mangano et al. reporting an association of Trasylol (aprotinin injection) with serious renal toxicity and ischemic events (myocardial infarction and stroke) in patients undergoing coronary artery bypass grafting surgery (CABG). Another publication (Transfusion, on-line edition, January 20, 2006, Karkouti, et al.) suggests an association between aprotinin administration and renal toxicity among patients undergoing cardiac surgery with cardiopulmonary bypass. FDA is evaluating these studies, along with other studies in the literature and reports submitted to the FDA through the MedWatch program, to determine if labeling changes or other actions are warranted.

While FDA is continuing its evaluation, we are providing the following recommendations to healthcare providers and patients:

* 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.

The FDA urges health care providers and patients to report adverse event information to FDA via the 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.

Questions and Answers on Aprotinin (marketed as Trasylol)

1. What is Trasylol and what is it used to treat?

Trasylol, or aprotinin, a product derived from bovine lung tissue, inhibits certain enzymes that increase the risk for bleeding. Trasylol administration aids the body’s ability to prevent bleeding.

Patients undergoing coronary artery bypass grafting (CABG) using cardiopulmonary bypass may be at risk for bleeding complications due to prior use of anticoagulants or clinical conditions that predispose to bleeding. Trasylol is used to decrease this bleeding risk.

2. What is the concern regarding Trasylol?

A January 26, 2006 report in The New England Journal of Medicine suggests that Trasylol administration may increase the risk for serious side-effects among some patients undergoing CABG. This report describes the occurrence of serious kidney damage, heart attack (myocardial infarction) and stroke among CABG patients receiving Trasylol. More patients receiving Trasylol experienced these events than patients receiving either no medications intended to decrease blood loss or other medications intended to decrease blood loss.

Another recently published study has suggested that patients receiving Trasylol may be at higher risk for kidney damage. This report (published January 20, 2006 in the on-line edition of Transfusion) used methods similar to those used in The New England Journal of Medicine study but included a smaller number of patients.

3. Did the patients who developed these serious side-effects have other possible reasons to develop these reactions?

It is not known if the patients receiving Trasylol in The New England Journal of Medicine report were sicker and thus at higher risk prior to receiving Trasylol than the patients in the other study groups. The study report authors used statistical procedures to try to adjust for this consideration. In the Transfusion report, the patients seemed to be similar in both study groups.

4. Have other studies indicated problems with Trasylol?

In addition to the previously described studies, one additional study suggested that Trasylol administration may increase the risk for clot formation within coronary artery bypass grafts. In this study, patients receiving Trasylol were compared to those receiving a placebo. The study reported an increased rate of bypass graft closure for patients receiving Trasylol.

5. What are the strengths and limitations of The New England Journal of Medicine Report when compared to other reports?

The major strength of The New England Journal of Medicine study is the collection of information from a large number of patients who were managed according to common medical practice.

The major limitation of The New England Journal of Medicine study is that patients were not randomly assigned to any of the treatments (or to no treatment) for preventing bleeding. The treating physicians determined, based on their experience and judgment, whether to administer Trasylol, another drug to prevent bleeding, or no treatment. It is possible that the treating physicians may have chosen to administer Trasylol only to the sicker patients while the less sick patients received other products or no therapy to prevent bleeding. Consequently, the study outcomes may not truly indicate Trasylol side-effects. Instead, the study outcomes may indicate the seriousness of the underlying condition of the patients chosen to receive Trasylol. It is important to note that the study investigators used statistical analyses to try to correct for this limitation.

In clinical studies where the choice to use Trasylol or not was decided by chance alone, Trasylol administration was not associated with the detection of any increase in the risks for the serious side-effects described in The New England Journal of Medicine report. These types of studies were performed in order to rigorously detect the Trasylol effects. However, these studies also have limitations; for example, the patients enrolled in the study may not truly reflect all types of patients undergoing CABG and the other cardiovascular therapies used in the studies may differ from those routinely used in medical practice. These considerations are especially important when clinical advances may rapidly change the practice of medicine.


6. Was Trasylol responsible for the serious side-effects detected in The New England Journal of Medicine report?

The report suggests that Trasylol administration was associated with the serious side-effects. However, the limitations of the reported study require that the study findings be examined more closely.

7. Based on this report, why isn’t FDA immediately removing this product from the market?

The findings from The New England Journal of Medicine report differ from the data submitted to the FDA in support of a marketing application. These other reports indicate that Trasylol has benefits that outweigh the risks associated with the product. The FDA is re-examining all these study findings in light of The New England Journal of Medicine report and other information.

8. Are other drugs available to decrease the risk for bleeding during CABG?

No other products are approved by FDA for use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing CABG with cardiopulmonary bypass. However, other products have been used by physicians in order to try to prevent bleeding during CABG. As described in The New England Journal of Medicine report, these other products include aminocaproic acid and tranexamic acid.

9. What actions will FDA take regarding these reports?

FDA is continuing to evaluate these reports, assessing other reports and working with the Trasylol manufacturer in order to determine if product labeling changes or other actions are necessary.

10. What information was known about serious side-effects prior to Trasylol approval?

In pre-marketing clinical studies, Trasylol was administered to approximately 2,000 patients undergoing CABG with cardiopulmonary bypass. In these studies, approximately 1,000 patients received a placebo instead of Trasylol. These studies found that Trasylol decreased the need for blood cell transfusion. The studies did not detect an increased risk for serious kidney or heart side-effects. Certain pre-marketing clinical studies showed that some patients may experience allergic-type reactions to Trasylol, especially patients who receive more than one Trasylol administration. These reactions, including hypersensitivity reactions and anaphylaxis, were rare among patients who received a single Trasylol administration (package insert provides more information about Trasylol.

Information for Healthcare Professionals: Aprotinin (marketed as Trasylol)

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.

To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch program and complete a form on line at http://www.fda.gov/medwatch/report/hcp.htm or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.

Considerations:

Physicians should consider the following:

* 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.

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:

o a renal event (dialysis or increase in creatinine), p = 0.006
o either myocardial infarction or heart failure, p = 0.01
o 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.

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.