New England Journal of Medicine
Vol 358:784-793, February 21, 2008, Number 8
The Effect of Aprotinin on Outcome after Coronary-Artery Bypass Grafting
Andrew D. Shaw, M.B., Mark Stafford-Smith, M.D., William D. White, M.P.H., Barbara Phillips-Bute, Ph.D.,
Madhav Swaminathan, M.D., Carmelo Milano, M.D., Ian J. Welsby, M.B., Solomon Aronson, M.D., Joseph P. Mathew, M.D., Eric D.
Peterson, M.D., M.P.H., and Mark F. Newman, M.D.
Aprotinin has recently been associated with adverse outcomes in patients undergoing cardiac surgery. We reviewed
our experience with this agent in patients undergoing cardiac surgery at Duke University Medical Center.
We retrieved data on 10,275 consecutive patients undergoing surgical coronary revascularization at Duke between
January 1, 1996, and December 31, 2005. We fit data to a logistic-regression model predicting each patient's likelihood
of receiving aprotinin on the basis of preoperative characteristics and to models predicting long-term
survival (up to 10 years) and decline in renal function, as measured by increases in serum creatinine levels.
Results: A total of 1343 patients
(13.2%) received aprotinin [Trayslol], 6776 patients (66.8%) received
aminocaproic acid, and 2029 patients (20.0%) received no antifibrinolytic therapy [therapy to prevent thrombi]. All patients underwent coronary-artery bypass grafting, and 1181 patients
(11.5%) underwent combined coronary-artery bypass grafting and valve surgery. In the risk-adjusted model,
survival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death
of 1.32 (95% confidence interval [CI], 1.12 to 1.55) for the comparison with patients receiving no antifibrinolytic
therapy (P=0.003) and 1.27 (95% CI, 1.10 to 1.46) for the comparison with patients receiving aminocaproic
acid (P=0.004). As compared with the use of aminocaproic acid or no antifibrinolytic agent, aprotinin
use was also associated with a larger risk-adjusted increase in the serum creatinine level (P<0.001) but not
with a greater risk-adjusted incidence of dialysis (P=0.56).
Patients who received aprotinin had a higher mortality rate and larger increases in serum creatinine levels than
those who received aminocaproic acid or no antifibrinolytic agent.
From the Departments of Anesthesiology (A.D.S.,
M.S.-S., W.D.W., B.P.-B., M.S., I.J.W., S.A., J.P.M., M.F.N.) and Surgery (C.M.) and the Duke Clinical Research Institute
(E.D.P.), Duke University Medical Center, Durham, NC.
Address reprint requests to Dr. Shaw at
the Department of Anesthesiology, Duke University Medical Center, Durham, NC 27516, or at email@example.com
Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death
Volume 358:771-783, February 21, 2008, Number
Sebastian Schneeweiss, M.D., Sc.D., John D. Seeger, Pharm.D., Dr.P.H., Joan Landon, M.P.H., and Alexander
M. Walker, M.D., Dr.P.H.
Aprotinin (Trasylol) is used to mitigate bleeding during coronary-artery bypass grafting (CABG). Accumulating
evidence suggests that this practice increases mortality.
Using electronic administrative records of the Premier Perspective Comparative Database, we studied hospitalized
patients with operating-room charges for the use of aprotinin [Trayslol]
(33,517 patients) or aminocaproic acid (44,682 patients) on the day CABG was performed. We tabulated
the numbers of patients with a hospital-discharge status of death and performed three types of analyses:
a multivariable logistic-regression analysis (primary analysis); propensity-score matching in the highly selected
subcohort of patients who received full amounts of the study drug, who underwent CABG by surgeons who performed
50 or more CABG surgeries during the study period, and for whom information on 10 additional covariates
was available because the surgery occurred on hospital day 3 or later; and an instrumental-variable analysis
of data from patients whose surgeons showed a strong preference for one of the two study drugs.
In all, 1512 of the 33,517 aprotinin recipients (4.5%) and 1101 of the 44,682 aminocaproic acid recipients (2.5%)
died. After adjustment for 41 characteristics of patients and hospitals, the estimated risk of death
was 64% higher in the aprotinin group than in the aminocaproic acid group (relative risk, 1.64; 95%
confidence interval [CI], 1.50 to 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital
death in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02). The relative risk in a propensity-score–matched
analysis was 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variable analysis, the use of aprotinin
was found to be associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14 to 3.04).
Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients
of aminocaproic acid.
Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received
aminocaproic acid alone. Characteristics of neither the patients nor the surgeons explain the difference,
which persisted through several approaches to control confounding.
[This 4.5% death rate correlates with the 4.4 in the Mayo study in 05. The death rate for
those taking aspirin instead of aprotinin or amicnocaproic acid was 1.7%, which is 260 percent lower.]
From the Division of Pharmacoepidemiology and
Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (S.S.); and the Department
of Epidemiology, Harvard School of Public Health (J.D.S., A.M.W.) — all in Boston; and i3 Drug Safety, Waltham, MA (S.S.,
Address reprint requests to Dr. Schneeweiss
at the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 1620 Tremont St. (Suite 3030), Boston, MA
02120, or at firstname.lastname@example.org