SAN BRUNO, Calif., Feb. 6 -- Trasylol (aprotinin), a drug designed to limit operative blood loss, was associated with a 48% increase in risk of dying within five years of coronary artery bypass surgery, researchers here reported.
In a multi-center, observational study of 3,876 bypass patients, the five-year mortality rate was 20.8% of the patients given Trasylol, versus 15.8% for those treated with aminocaproic acid and 14.7% for those who received Cyklokapron (tranexamic acid), said Dennis T. Mangano, Ph.D., M.D., of the Ischemia Research and Education Foundation here.
These results, published in the Feb. 7 issue of the Journal of the American Medical Association, mark the second analysis of data from the same international registry that linked Trasylol with increased mortality. The first analysis reported that Trasylol increased perioperative risk of death, acute renal failure, myocardial infarction, stroke, and encephalopathy.
Dr. Mangano concluded that taken together there was now evidence of both perioperative and long term risk. "Therefore, continued use of aprotinin in this population does not appear prudent, given that safer alternatives-aminiocaproic acid and tranexamic acid-are available," he added.
The patients were treated at 62 international centers from Nov. 11, 1996 to Dec. 7, 2006. The researchers assessed survival at six weeks after the index hospitalization, six months, and annually for five years following surgery.
Among the findings:
- 1,072 patients received Trayslol, 834 received aminocaproic acid, and 442 received Cyklokapron.
- At five years there were 223 deaths in Trayslol group, 132 in the aminocaproic acid arm and 65 in the Cyklokapron group.
- The five-year hazard ratio for death in the Trayslol arm was 1.48 (95% CI, 1.13-1.93, P=0.005).
In general, Farzan Filsoufi, M.D., associate professor and associate chief of cardiac Surgery at Mount Sinai Medical Center in New York, agreed with the conclusions by Dr. Mangano and colleagues, but he cautioned that as with other recent Trasylol studies, this one was limited by its observational design and lack of randomization. Dr. Filsoufi was not involved in the study.
Dr. Filsoufi's comment echoed that of T. Bruce Ferguson, Jr., M.D., of the Brody School of Medicine at East Carolina University in Greenville, N.C.
The perioperative observational study findings "seemed to conflict with findings from several dozen randomized trials, two meta-analyses, a Cochrane Collaboration summary on aprotinin use, and an evaluation by the Food and Drug Administration," Dr. Ferguson wrote in an editorial that accompanied Dr. Mangano's study.
Dr. Ferguson noted that Trasylol use "has never been uniformly standardized, but generally has been reserved for patients in whom the surgical team anticipated a higher risk for intraoperative blood loss."
The latest analysis from Dr. Mangano and colleagues included 3,876 of the 4,374 patients included in the perioperative analysis. And seven of the original 69 participating international center were dropped from the five-year analysis, a potential limitation that Dr. Mangano said reduced the cohort size by 11%. But, he said, it had little effect on the findings because "the in-hospital mortality by study group was similarly distributed among the 62 centers participating in this study versus the seven centers that did not."
Dr. Mangano said selection bias-Trasylol was likely to be have been given to patients with more complex or advanced disease-was unlikely to affect or explain the excess mortality because since data were corrected by propensity analysis. Moreover the association with Trasylol and lack of association for the other two agents persisted in among patients with risk factors for in-hospital renal, cardiovascular, and cerebrovascular events.