I have used activated Factor VIIa (Novoseven) off-label about ten times since 2002 and each time I am amazed at how effective it is in stopping intractable bleeding after prolonged cardiopulmonary bypass.

The drug was approved for use in Hemophiliacs but it has found use off-label as a great hemostatic agent. Maybe the FDA should consider it’s use outside hemophiliacs.

There is data out there showing  small but possible risk for thrombembolism. Also, it seems to work better if used early in the bleeding episode.

jnkdg

I think the FDA sounded the death knell today:

FDA NEWS RELEASE

For Immediate Release: Nov. 5, 2007
Media Inquiries: Peper Long, 301-827-0599, 240-429-9205, mary.long@fda.hhs.gov

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.

jnkdg

As a cardiac anesthesiologist, I have used my share of Aprotinin and swore that it really did reduce bleeding. I was skeptical about the Mangano study but since it’s publication, accumulating data points to the fact that Aprotinin may not be that safe and that the cheaper antifibrinolytics – Aminocaproic acid and Tranexamic acid – may be as effective.

The BART Trial, being carried on in Canada is supposed to provide a good comparison of the three drugs. Below is an early release  on this study: 

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. 

• online at www.fda.gov/medwatch/report.htm
• by returning the postage-paid FDA form 3500 (available in PDF format at www.fda.gov/medwatch/getforms.htm) to 5600 Fishers Lane, Rockville, MD 20852-9787
• faxing the form to 1-800-FDA-0178
• by phone at 1-800-332-1088

Is this the end for Aprotinin?

jnkdg