Aprotinin Recall by Bayer

Dean B. Andropoulos, M.D., M.H.C.M.

As many of you know, Bayer has recalled all U.S. supplies of Aprotinin (Trasylol®) as of  May 15, 2008. This decision was made in response to the New England Journal of Medicine publication of the Canadian BART trial, which demonstrated a 50% increase in 30 day mortality in adult patients undergoing high risk cardiac surgery, compared to ε-aminocaproic acid or tranexamic acid. (Fergusson DA et al. NEJM 2008;358:2319; or www.nejm.org epub May 14, 2008). This was a prospective, randomized, blinded study of the three drugs, with over 2000 patients, which was stopped early by the Data Safety Monitoring Board for the study because of concerns of excess mortality. With the stopping of the study, Bayer suspended worldwide marketing of Aprotinin on November 5, 2007, but the drug was still available for use from existing hospital supplies, which were not recalled at that time. With the publication of the full BART results, Bayer has recalled all existing supplies, which are to be sent to the manufacturer. The drug cannot be purchased, and has not been formally recalled by the FDA, but the FDA supports the recall of the drug. The FDA makes the following statement:

“Under a limited use agreement, access to Trasylol is limited to investigational use of the drug according to the procedures described in a special treatment protocol. The protocol allows treatment for certain patients who are at increased risk of blood loss and transfusions during coronary artery bypass graft surgery and who have no acceptable alternative therapy. Physicians using Trasylol in this situation must also verify that the benefits of the drug clearly outweigh the risks for their patients.” Source, www.fda.gov/bbs/topics/NEWS/2008/NEW01834.html.” However, when our hospital pharmacy and research staff inquired of Bayer whether they would supply aprotinin for a newly proposed protocol specifically for use in our lung transplant patients, the company’s response was that they would not supply drug for any new protocols. Additional information is posted on the FDA website at the URL above, and also at: http://www.fda.gov/consumer/updates/trasylolstock051608.html.

In response to this Texas Children's Hospital and others have stopped use of the drug, and replaced aprotinin with other antifibrinolytic protocols. A review of antifibrinolytics is discussed below in an article by Denise Joffe, M.D.

A poll of CCAS Board Members’ institutions reveals the following antifibrinolytic protocols, replacing aprotinin at Texas Children's Hospital, Boston Children’s Hospital, Toronto Sick Children’s Hospital, Children’s Healthcare of Atlanta, and the University of Virginia. Children’s Hospital of Philadelphia and Lucille Packard Children’s Hospital at Stanford had stopped using aprotinin considerably before the recent company actions.

Institution	Drug	Load to Patient mg/kg	Load to CPB mg/kg	Infusion mg/kg/hr	Post CPB dose mg/kg	Clinical Scenarios	Reference	rFVIIa
Boston	TXA	<20 kg: 100; >20 kg 30	<20 kg: 100; >20 kg 2	< 20 kg:10;  >20 kg: 16	NA	High risk for bleeding; repeat sternotomy	Reid RW, A&A 1997;84:990; >20 kg: Dowd NP, Anesthesiology 2002;97:390	Yes, very rare
Texas	EACA	75	75	75	NA	Complex neonates, other complex cases, repeat sternotomy	Ririe, A&A 2002;94:44	Yes—rare, 90 mcg kg  x 3 doses
Toronto	TXA	<20 kg: 100; >20 kg: 50	< 20 kg: 50; >20 kg: 25	NA	20: for ongoing bleeding only	All patients		Yes—rare, massive blood loss >1 blood volume
Atlanta	TXA	100	100	10	NA	Neonates, repeat sternotomies, cyanotic pathologies	Reid RW, A&A 1997;84:990
U. Virginia	EACA	100	100	NA	100	All patients		no
Philadelphia	EACA	250	250	NA	NA	Neonates, transplants, repeat sternotomy		Yes—rare, 90 mcg kg  x 3 doses

The issue of perioperative blood loss, returning to previously utilized protocols for antifibrinolytics, apparent lack of adverse safety data for aprotinin in children, other properties of aprotinin such as its antiinflammatory properties, and the place of recombinant factor VIIa and its potential adverse effects will all be important topics of debate and discussion in the near future, and the CCAS will attempt to keep its members up to date in addressing these topics in newsletters and educational activities.