Long-term Mortality and Survival
Baseline characteristics according to treatment are summarized in Table 1. Acute and chronic vascular disease was prevalent among all patients, with several imbalances noted before propensity adjustment.
Long-term Mortality and Survival
During 5 years, 223 deaths occurred among 1072 aprotinin-treated patients (20.8%), a death rate nearly two-thirds greater than control patients (128 deaths among 1009 patients, 12.7%; covariate adjusted hazard ratio [without propensity adjustment], 1.48; 95% CI, 1.19-1.85; P<.001). Rates were similar for aminocaproic acid patients (132 deaths among 834 patients, 15.8%; adjusted hazard ratio, 1.03; 95% CI, 0.80-1.33; P = .81) and for tranexamic acid patients (65 deaths among 442 patients, 14.7%; adjusted hazard ratio, 1.07; 95% CI, 0.80-1.45; P = .64). Covariate-adjusted survival analyses demonstrated significant association with death for aprotinin, but not for either aminocaproic or tranexamic acid—the latter 2 biochemically similar lysine analogs having nearly indistinguishable mortality (survival) patterns despite disparate use and approval among countries and centers. Aprotinin's association with mortality persisted among patients who survived their index hospitalization. Proportional hazards analysis using multiple covariates confirmed the survival associations.
Multivariable logistic regression confirmed these findings, which indicates that aprotinin was an independent predictor of 5-year mortality (covariate adjusted OR, 1.51; 95% CI, 1.17-1.96) without propensity adjustment, or with adjustment (C-index = 0.70; OR, 1.48; 95% CI, 1.13-1.93), as well as among those surviving their index hospitalization. In contrast, neither aminocaproic nor tranexamic acid was associated with increased 5-year mortality.
We investigated whether the occurrence of in-hospital ischemic events (cardiovascular, cerebrovascular, renal) affected our findings on mortality over the 5 years following discharge by including in-hospital nonfatal events as covariates. Findings were similar to those in Table 2, Table 3; the OR for aprotinin vs control was 1.52 (95% CI, 1.14-2.02), aminocaproic acid vs control, 1.06 (95% CI, 0.77-1.45), and tranexamic acid vs control, 1.10 (95% CI, 0.74-1.62), and with in-hospital complications significantly associated with postdischarge death, 1.41 (95% CI, 1.10-1.82).
In secondary descriptive analyses, the association of aprotinin with death was found among diverse patient risk profiles and surgical factors, and among high-risk patients identified using in-hospital and long-term risk indices.
Finally, the association between aproprotin dose and mortality was assessed using prospective dose definitions as previously reported. We found differences in the point estimates for 5-year mortality (control, low-dose aprotinin vs high-dose aprotinin): 12.7%, 22.8%, 37.9% (P<.001); in the ORs (low-dose vs control, 1.58; 95% CI, 1.14-2.20 and high-dose vs control, 2.07; 95% CI, 1.08-3.95); and in the Kaplan-Meier survival differences (control, low-dose aprotinin vs high-dose aprotinin, P<.001 [log-rank]).
Our study, assessing the long-term safety of antifibrinolytic agents, demonstrated that aprotinin—but not aminocaproic acid or tranexamic acid—is associated with an increased risk of death during the first 5 years following surgery. Importantly, aprotinin's association with death sustained comprehensive covariate challenges, remaining significant when assessed among multiple subgroups with differing risk profiles and among patients surviving their index hospitalization. The minimal associations of the lysine analogs aminocaproic acid and tranexamic acid with long-term death, along with their previously reported efficacy and safety profiles, indicate that safe and inexpensive alternatives exist. Based on our data, we therefore believe that additional concern is now warranted regarding the long-term safety of aprotinin among patients undergoing coronary artery bypass surgery.