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Safety of Perioperative Aprotinin Administration During Isolated Coronary Artery Bypass Graft Surgery: Insights From the ART (Arterial Revascularization Trial)

Background There is still uncertainty about the safety of aprotinin for coronary artery bypass graft surgery. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral versus single internal thoracic artery grafting. Many of the ART patients (≈30%) received perioperative aprotinin. We investigated the association between perioperative aprotinin administration and short‐term (in‐hospital) and long‐term outcomes by performing a post hoc analysis of the ART. Methods and Results Among patients enrolled in the ART (n=3102) from 2004 to 2007, we excluded those who did not undergo surgery (n=18) and those with no information about use of perioperative aprotinin (n=9). Finally, 836 of 3076 patients (27%) received aprotinin. Propensity matching was used to select 536 pairs for final comparison. Aprotinin was also associated with an increased risk of hospital mortality (9 [1.7%] versus 1 [0.2%]; odds ratio, 9.12; 95% confidence interval [CI], 1.15–72.2; P=0.03), intra‐aortic balloon pump insertion (37 [6.9%] versus 17 [3.2%]; odds ratio, 2.26; 95% CI, 1.26–4.07; P=0.006), and acute kidney injury (102 [19.0%] versus 76 [14.2%]; odds ratio, 1.42; 95% CI, 1.03–1.97; P=0.03). Aprotinin was not associated with a lower incidence of transfusion (37 [6.9%] versus 28 [5.2%]; odds ratio, 1.34; 95% CI, 0.81–2.23; P=0.25) and reexploration (26 [4.9%] versus 19 [3.5%]; hazard ratio, 1.39; 95% CI, 0.76–2.53; P=0.28). At 5 years, all‐cause mortality was significantly increased in the aprotinin group (56 [10.6%] versus 38 [7.3%]; hazard ratio, 1.51; 95% CI, 1.0–2.28; P=0.045). Conclusions In the present post hoc ART analysis, aprotinin was associated with a significantly increased risk of early and late mortality. Clinical Trial Registration URL: http://www.isrctn.com. Unique identifier: ISRCTN46552265.

B leeding remains a major complication after coronary artery bypass graft (CABG) surgery and is associated with poorer short-and long-term outcomes. 1 Aprotinin is the most studied antifibrinolytic agent to limit blood loss in cardiac surgery. However, concerns have been expressed over its potential detrimental effect on short-term outcomes, including renal dysfunction, graft occlusion, and stroke, 2-5 as well as late mortality. 6 Aprotinin was taken off the market in November 2007 because of safety concerns expressed in 4 studies in The New England Journal of Medicine. [2][3][4][5] Ten years later, aprotinin is being reintroduced, but without any new clinical trials on safety. The regulatory authorities, including Health Canada and the European Medicines Agency, revisited the previously available data, and after highlighting several methodological limitations, they concluded that no firm assumption could be made on mortality. 7 Consequently, aprotinin is currently being reestablished into clinical practice in Europe and Canada for adult patients undergoing isolated CABG who are at high risk of major blood loss. 8 The ART (Arterial Revascularization Trial) is designed to compare 10-year survival after bilateral internal thoracic artery versus single left internal thoracic artery grafting, and an interim report at 5 years has not shown any clear difference between the 2 groups. 9 Approximately 30% of patients enrolled in the ART received perioperative aprotinin. We investigated the association between perioperative aprotinin administration and short-and long-term outcomes in patients undergoing isolated CABG by conducting a post hoc analysis on high-quality data from the ART.

Methods
The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. A post hoc analysis of the ART was conducted. This research adheres to the principles set forth in the Declaration of Helsinki. In ART, aprotinin was the only antifibrinolytic agent administered perioperatively, and its use was based on surgeon discretion/local policies. For the present analysis, among patients enrolled in the ART (n=3102) from 2004 to 2007, we excluded those who did not undergo surgery (n=18) and those with no information about use of perioperative aprotinin (n=9). Perioperative aprotinin was administered to 836 of 3076 patients (27.1%, aprotinin group) included in the present analysis. The baseline characteristics in the aprotinin and no aprotinin groups are reported in Table S1. There was a large variation in aprotinin use across different centers. Unadjusted hospital and longterm outcomes in the 2 groups are reported in Tables S2  and S3.

Patient Involvement
Because the present study represents a post hoc observational analysis of the ART, there was no patient involvement.

Trial Design
The ART was approved by the institutional review board of all participating centers, and informed consent was obtained from each participant. The protocol for the ART has been published. 10 Briefly, the ART is a 2-arm, randomized, multicenter trial conducted in 28 hospitals in 7 countries, with patients being randomized equally to single left internal thoracic artery or bilateral internal thoracic artery grafts. Eligible patients were those with multivessel coronary artery disease undergoing CABG, including urgent patients. Only emergency patients (refractory myocardial ischemia/cardiogenic shock) and those requiring single grafts or redo CABG were excluded.

Follow-Up
Questionnaires were sent to study participants by post every year after surgery. No clinic visits were planned apart from the routine clinical 6-week postoperative visit. Participants were sent stamped addressed envelopes to improve the return rates of postal questionnaires. Study coordinators contacted participants by telephone to alert them to the questionnaire's arrival and to ask them about medications, adverse events, and health services resource use.

Study Outcomes
Primary outcomes were hospital outcomes, which included hospital death, myocardial infarction (MI), cerebrovascular accident, need for repeated revascularization, postoperative atrial fibrillation, need for intra-aortic balloon pump insertion, postoperative renal replacement therapy, acute kidney injury (AKI), sternal wound infection, red blood cell transfusion, and reexploration for bleeding. We also investigated the association between perioperative aprotinin administration and 5-year mortality (including all-cause and cardiovascular mortality), nonfatal MI, cerebrovascular accident, and repeated revascularization.

Clinical Perspective
What Is New?
• Aprotinin is currently being reestablished into clinical practice in Europe and Canada for adult patients undergoing isolated coronary bypass surgery without any new clinical trials on safety in this subgroup. • The present analysis on a selected low-risk coronary bypass surgery population supports the association between aprotinin administration and adverse hospital outcomes and long-term survival.
What Are the Clinical Implications?
• On the basis of the present findings, a word of caution should be exercised by local authorities on the liberal use of aprotinin before further investigations will clarify the potential risks related to its perioperative administration.

Outcome Definitions
Death was classified into cardiovascular and noncardiovascular, where possible, using autopsy reports and death certificates. Congestive heart failure, arrhythmia or MI, pulmonary embolus, and dissection were considered cardiovascular causes of death. MI was diagnosed when 2 of the following 3 criteria were present: (1) unequivocal ECG changes, (2) elevation of cardiac enzyme(s) above twice the upper limit of normal or diagnostic troponin increases, and (3) chest pain typical for acute MI, which lasted >20 minutes. Cerebrovascular accident was defined as new neurological deficit evidenced by clinical signs of paresis, plegia, or new cognitive dysfunction, including any mental status alteration lasting >24 hours and/or evidence on computed tomographic or magnetic resonance imaging scan of a recent brain infarct (<6 months). Repeated revascularization was defined as coronary bypass surgery or percutaneous coronary intervention performed after the trial procedure. AKI was defined as a 0.3-mg/dL (≥26.5-mmol/L) creatinine increase from baseline within 48 hours of surgery. 11

Statistical Analysis
Multiple imputation (m=10) was used to address missing data ( Figure S1). The method of Rubin 12 was used to combine results from each of the imputed data sets (Amelia R package). Because use of aprotinin was not based on randomization, a propensity score (PS) was generated for each patient from a multivariable logistic regression model on the basis of baseline and intraoperative covariates as independent variables, with aprotinin versus no aprotinin as a binary dependent variable. 13 Because a large variation in aprotinin use was found among recruiting centers, individual centers were also included into the PS model to adjust for potential confounding related to different practice patterns. Pairs of patients were derived using greedy 1:1 matching, with a caliper of width of 0.2 SDs of the logit of the PS (MatchIt R package). The quality of the match was assessed by graphical visualization of PS distribution overlapping. Selected pretreatment variables in PS-matched groups were compared using the absolute standardized mean difference, with a value >0.10 taken to represent meaningful covariate imbalance. For outcomes analysis, conditional logistic and Cox regression models stratified for matched pairs with robust standard error estimation were used to investigate the treatment effect on short-and long-term outcomes, respectively. For competing risks, a model for the subdistribution hazard of the cumulative incidence function, proposed by Fine and Gray, was used 14 (riskRegression R packages). The effect of aprotinin on longterm mortality was also adjusted for medications prescribed at discharge. P<0.05 was considered statistically significant. All statistical analysis was performed using R Statistical Software (version 3.2.3; R Foundation for Statistical Computing, Vienna, Austria). Table S2 summarizes baseline characteristics of patients in the original aprotinin and no aprotinin groups. Patients who received aprotinin were more likely to be white, to be older, and to have an advanced New York Heart Association functional class. The use of aprotinin was also associated with a higher rate of preoperative dual-antiplatelet administration and use of cardiopulmonary bypass and saphenous vein grafts. Patients who did not receive aprotinin were more likely to be diabetic and to receive preoperative angiotensinconverting enzyme inhibitors/receptor blockers. There were also a few centers where the aprotinin administration rate was extremely high (eg, Edinburgh Royal Infirmary) and others where the aprotinin administration rate was extremely low (eg, Papworth Hospital and Austin Repatriation Medical Centre). PS matching selected 536 matched pairs with similar distribution of covariates and recruiting centers (all standardized mean differences, <0.10), as shown in Table 1, and comparable PS distribution ( Figure 1).

Hospital Outcomes
Hospital outcomes in the matched sample are summarized in Table 2. Hospital mortality was significantly higher in the aprotinin group (

Five-Year Outcomes
Five-year outcomes are summarized in Table 3

Discussion
The present post hoc ART analysis found that, in patients undergoing isolated CABG, aprotinin administration was associated with a higher risk of in-hospital mortality, intraaortic balloon pump insertion, and AKI. We also found a nonstatistically significant increased risk of early reintervention. At 5 years, perioperative aprotinin administration was associated with significantly higher mortality.  Aprotinin has been shown to effectively reduce blood loss and the need for transfusion associated with heart surgery 15 ; currently, Health Canada and the European Medicines Agency believe the accumulated evidence on the benefits of aprotinin outweighs its risks in isolated CABG surgery. 7,8 In a prospective cohort study in 2006, Mangano and colleagues 2 reported that aprotinin was associated with an increased risk of renal failure, MI, heart failure, stroke, encephalopathy, and mortality (2.8% versus 1.3%; P=0.02). Consequently, in 2006, the Food and Drug Administration listed renal dysfunction, along with anaphylaxis, graft occlusion, and stroke, among the drug's safety concerns. 16 However, the association between aprotinin and renal failure was disputed by Furnary and colleagues in 2007, who suggested that this was a confounding variable because renal impairment was also related to an increased packed red cell transfusion in the setting of cardiac surgery. 17 In 2007, Mangano and colleagues reanalyzed the 2006 data and reported that aprotinin was independently predictive of 5-year mortality. 6 A possible limitation of this analysis was that the authors failed to report whether the surgery was on or off pump, and this variable may have influenced not only the choice of antifibrinolytic agent but also clinical outcomes. The Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration reviewed the evidence from these studies; the committee could not endorse the findings after questions about the methods used, and because the data had not been independently reviewed by the Food and Drug Administration. 18 Another source of concern about aprotinin's safety was a preliminary report in 2006, from the manufacturer's own database, that showed a higher risk of death and acute renal failure in patients undergoing CABG who received aprotinin compared with patients who had received other antifibrinolytics. 19 This study was limited by its inability to account for the proportion of patients undergoing long-term dialysis when assessing the need for postoperative dialysis. The BART (Blood Conservation Using Antifibrinolytics in a Randomized Trial), published in 2008, 5 was a blinded randomized controlled trial comparing aprotinin, tranexamic acid, and aminocaproic acid in patients undergoing high-risk cardiac surgery. The trial was terminated early on the advice of the  safety committee because of a nonsignificant increase in mortality associated with aprotinin. Although the BART had the benefit of being a blinded randomized controlled trial, several limitations were identified in its conduct, in particular the unexplained exclusion of 137 patients from the analysis after randomization. 20 In view of conflicting findings reported, further analyses based on high-quality data are warranted to provide further evidence on the safety of perioperative aprotinin administration. The present post hoc ART analysis found that aprotinin administration was significantly associated with an increased risk of hospital death, AKI, and need for intra-aortic balloon pump insertion postoperatively, thus supporting previous reports. We could not demonstrate a definitive association between aprotinin administration and need for renal replacement therapy, but this might be partially attributed to the relatively low baseline renal risk of the present population. We also found that aprotinin administration was associated with a significantly increased risk of late mortality. Although aprotinin administration was associated with reduced incidence of red blood cell transfusion in the original sample (Table S2), this association was no longer present after matching, which also accounted for participating centers. This observation suggests that in the ART, different transfusion policies, rather than aprotinin itself, might have influenced red blood cell transfusion exposure.
The main limitations of the present analyses are obviously the nonrandomized comparison (despite the close matching in the propensity-scored patients) and the few outcome events, with consequently wide CIs. Despite PS modeling, we cannot exclude a residual selection bias based on unmeasured or unmeasurable characteristics. Another limitation is that the exact dose of aprotinin administered was not collected and, therefore, a dose-response association cannot be excluded. However, a previous metaanalysis did not find any association between dose and adverse events. 21 In conclusion, we found that the use of aprotinin was associated with an excess of early death and this also translated into an increased cardiac-related mortality at 5 years. Aprotinin is currently offered to many patients undergoing CABG, and the present analysis supports the hypothesis that aprotinin use might be associated with an increase in avoidable deaths. Therefore, a word of caution should be exercised by local authorities on the liberal use of aprotinin during isolated CABG before stronger evidence of its safety profile will be available.