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, they 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.

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 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.  

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.

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

IF YOU FEEL YOU HAVE INJURED AS A RESULT OF TAKING THE MEDICATION TRASYLOL, YOU SHOULD CONTACT AN ATTORNEY. FOR A FREE CASE EVALUATION, COMPLETELY FILL OUT THE FORM BELOW.  AN ATTORNEY WILL REVIEW YOUR FORM AND MAY CONTACT YOU PURSUANT TO OUR SITE'S TERMS AND CONDITIONS.

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