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Ann Thorac Surg 2008;86:1195-1202. doi:10.1016/j.athoracsur.2008.06.048
© 2008 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Aprotinin in Primary Cardiac Surgery: Operative Outcome of Propensity Score-Matched Study

Dumbor L. Ngaage, FRCS (C-Th), MD*, Alexander R. Cale, FRCS (C-Th), MD, Michael E. Cowen, FRCS, Steven Griffin, FRCS (C-Th), Levant Guvendik, FRCS

Castle Hill Hospital, Kingston-Upon-Hull, East Yorkshire, United Kingdom

Accepted for publication June 9, 2008.

* Address correspondence to Mr Ngaage, Department of Cardiothoracic Surgery, Castle Hill Hospital, Kingston-Upon-Hull, East Yorkshire, HU16 5JQ, United Kingdom (Email: dngaage{at}yahoo.com).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Some recent multicenter series have questioned the safety of aprotinin in primary cardiac operations. We report a large, single-center experience with aprotinin therapy in primary cardiac operations and discuss the limitations and potential confounders of current treatment strategies.

Methods: We compared myocardial infarction, neurologic events, renal insufficiency, and operative death after first-time coronary or valve procedures, or both, in 3334 patients treated with full-dose aprotinin with 3417 patients not treated with aprotinin who underwent operation between March 1998 and January 2007. Further analysis was performed for 341 propensity score-matched pairs.

Results: There were substantial differences between the groups. Aprotinin patients were higher risk on account of older age, unstable symptoms, poor ejection fraction, preoperative hemodynamic support, emergency/urgent operations, and combined coronary/valve operations. Postoperative bleeding and blood product transfusion were considerably reduced in aprotinin patients, as was median duration of mechanical ventilation. Aprotinin was neither a predictor of postoperative myocardial infarction, renal insufficiency, neurologic dysfunction, or operative death. Achieving parity between the groups by propensity score matching eliminated the elevated rates of postoperative renal insufficiency, neurologic dysfunction, and operative death observed in aprotinin patients in the unmatched comparison. These adverse outcomes were evenly distributed between matched groups. Conversely, blood transfusion had univariate associations with all adverse outcome measures.

Conclusions: Full-dose aprotinin use was not associated with myocardial infarction, neurologic dysfunction, renal insufficiency, or death after coronary or valve operations. We observed less postoperative bleeding and blood product transfusion, and early extubation with the use of aprotinin.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Introduced into cardiac surgery fortuitously [1] and warmly embraced by cardiac surgeons as an effective antiinflammatory and hemostatic ally [2–4], yet beleaguered by dosage permutations [2, 5, 6], the serine protease inhibitor aprotinin sits at the center of controversy about its influence on surgical outcomes [7–12]. Is aprotinin a friend, a foe or a phoney? The proven hemostatic potential of aprotinin [3, 4] gave it an initial role in limiting postoperative bleeding and blood product transfusion in subsets of cardiac surgical patients with high risk of bleeding [13–15]. Cost considerations and recently, safety concerns, continue to drive the investigation of alternative pharmaceutic agents.

Cardiopulmonary bypass (CPB) engenders widespread systemic inflammatory response and potent derangement of the fibrinolytic and coagulation pathways. In addition, deliberate alteration of the coagulation system inherent in the conduct of extracorporeal circulation complicates postoperative hemostasis. Aprotinin curtails the adverse effects of CPB [16–18], but the procoagulant properties of aprotinin have prompted concerns about thromboembolic complications.

Some studies have suggested that it has a collaborative role in adversely influencing operative results [19], but recent observational studies have linked aprotinin with thromboembolic complications and death after cardiac operations [11, 20–22]. A large, prospective, observational multicenter trial [11] compared adverse outcomes after cardiac surgery in patients who received aprotinin in three different doses, tranexamic acid, aminocaproic acid, and no agent, and reported a direct link between aprotinin and postoperative myocardial infarction (MI), cardiac failure, cerebrovascular events, renal failure, and operative death. However, independent reports from some participating centers [14, 23, 24] contradict the finding of that study.

The lack of a strict study protocol, which allows for institutional practice variation in a multinational multicenter observational study and nonuniformity of aprotinin dosage, makes comparison difficult. Selection of patients with identical baseline and intraoperative characteristics, including consistent aprotinin dosage, common preoperative, intraoperative and postoperative management protocol, and uniform strategy for cerebral and renal protection implicit in the conduct of CPB, as has been used in this study, establishes parity between the groups and facilitates a robust comparison and determination of the effect of aprotinin on operative outcome.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Data are prospectively collected for all patients undergoing cardiac operations at Castle Hill Hospital and stored in an electronic database. The database was interrogated and clinical information retrieved for all patients who underwent coronary artery bypass grafting (CABG), aortic valve replacement, and mitral valve replacement/repair, either as isolated procedures or in combination, from March 1998 through January 2007. Clinical data relating to patient demography, disease symptoms and presentation, reports of angiography and echocardiography, and intraoperative and postoperative outcomes were collated for analysis. The Medical and Ethics Committee of Castle Hill Hospital approved the use of patients' data for this study.

Surgical access was by median sternotomy for all patients, and the operation was performed with mild hypothermic CPB (core temperatures 32° to 34°C). Intraoperative myocardial protection was by cardioplegic or cross-clamp fibrillatory arrest. All aprotinin patients received the full Hammersmith dose; a test dose, 2 million kallikrein-inhibitory units (KIU) in the pump prime, and 2 million KIU administered intravenously before skin incision, followed by 500,000 KIU/h during cardiopulmonary bypass. Heparin (300 units/kg) was adjusted to achieve and maintain a kaolin-activated clotting time greater than 480 seconds during CPB. The effect of heparin was reversed using protamine at a dose of 100 mg per 300 units of heparin, with additional doses where necessary, to achieve a kaolin-activated clotting time within 10 seconds of the preoperative level. Aprotinin was continued postoperatively if there was significant bleeding at 50,000 KIU/h until chest drainage was less than 50 mL/h for up to 4 hours.

Statistical Analysis
The study primary end points were major adverse postoperative events; namely, MI (new and persistent S-T changes, new Q waves on electrocardiography), neurologic dysfunction (confusion, transient and permanent neurologic deficit), renal insufficiency (serum creatinine > 200 µm/L), and operative death (death in the hospital and within 30 days postoperatively). Secondary end points included total blood loss, transfusion of blood products (packed red blood cells, platelets, fresh frozen plasma, and cryoprecipitate), and reoperation for bleeding or tamponade.

Initially an unmatched comparison between treatment groups was done with {chi}2 test for categoric variables, and t tests were used for continuous variables if the distribution was symmetric and Mann Whitney U test if nonsymmetric. Predictors of the primary end points were identified using multivariate stepwise logistic regression model constructed with the covariates listed in Table 1.


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  		Table 1 Baseline and Operative Characteristics of Patients Who Did or Did Not Receive Aprotinin During Coronary or Valve Operations, or Both
 
Propensity score modelling was used to perform a one-to-one matching using all baseline covariates, most of which were identified by univariate analysis to differ significantly between the groups (see Appendix). The Matching 4.5.3 package [25] in version. 2.6.0 for Windows (Microsoft, Redmond, WA) [26] were used for this analysis. Initial balance tests indicated that the groups were poorly balanced on several covariates; therefore, the distance between covariates was restricted using the calliper option within the Matching package. A restriction that covariate distance within a matched pair should be no more than 10–4 standard deviations of the covariate for all covariates was found to give improved results. This led to 341 matched aprotinin and no-aprotinin treatment pairs. In the matched comparison between treatment groups, paired t tests were used for postoperative blood loss, a test of marginal homogeneity was used for operative death, and the McNemar test was used for the remaining outcomes.


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SPSS 15 software (SPSS Inc, Chicago, IL) was used for all analysis except the propensity score modelling. A two-sided value of p < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Unmatched Comparison
Table 1 reports the contrasting characteristics of the two groups. Aprotinin patients were at a higher surgical risk owing to older age, severe symptoms, greater prevalence of impaired ventricular function, and continuous infusion of heparin or nitrates, or both, until the time of operation, and preoperative support with inotropic drugs and intraaortic balloon pump counterpulsation. In addition, they often had urgent or emergency procedures and frequently underwent valve repair/replacement with or without CABG, with longer ischemic times and duration of extracorporeal circulation. The operative details also differed vastly between aprotinin and no aprotinin patients. More aprotinin patients underwent complex and combined cardiac procedures.

Postoperative renal insufficiency, neurologic events, and operative death were more frequent among aprotinin patients, as summarized in Table 2. Postoperative MI was evenly distributed between the aprotinin (1.4%, n = 46) and no aprotinin groups (1.0%, n = 34; p = 0.14). Aprotinin was not an independent predictor for MI, neurologic dysfunction, renal insufficiency, or operative death. Total blood loss and transfusion of blood products (packed red blood cells, fresh frozen plasma, platelets and cryoprecipitate) were remarkably less for aprotinin patients, and duration of mechanical ventilation was also shorter in this group. In general, patients who received blood transfusion were older, more symptomatic preoperatively, at a higher operative risk, and had longer duration of mechanical ventilation, with higher rates of postoperative MI, renal insufficiency, neurologic dysfunction, and operative death (Table 3).


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  		Table 2 Operative Outcome of Patients Undergoing Coronary Artery Bypass Grafting or Valve Operations, or Both, With and Without Aprotinin
 

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  		Table 3 Differences in Baseline Variables and Outcome Measures for Patients Who Did or Did Not Receive Blood Transfusion
 
Propensity Score-Matched Comparison
We obtained 341 matched pairs by propensity score matching from a study population of 6751 (10%). The comparability of the matched groups in baseline and operative characteristics is summarized in Table 4. The respective numbers of occluded coronary arteries (2.2 ± 1.1 for the aprotinin group vs 2.2 ± 1.0 for the no aprotinin group, p = 0.09) and number of bypass grafts (2.3 ± 1.1 vs 2.3 ± 1.2, p > 0.99) were similar for the groups. Postoperative MI was equally less frequent in aprotinin and no aprotinin patients.


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  		Table 4 Comparison of Baseline Characteristics, Operative Factors and Postoperative Complications in Propensity Score-Matched Groups
 
The differences observed in the incidence rates of the primary end points between the unmatched groups were not maintained in the propensity score-matched comparison. Postoperative neurologic dysfunction, renal insufficiency, and operative death were evenly distributed between the groups. All neurologic events (confusion, transient and permanent neurologic deficit) were observed in 4% of aprotinin vs 2% of no aprotinin group (p = 0.36), with a stroke rate of 2% vs 1% (p = 0.76). Equivalent numbers of patients in both groups had postoperative renal insufficiency: of 12 aprotinin and 13 no aprotinin patients, only 1 from the no aprotinin group required hemodialysis. The overall operative mortality rates were comparable at 2% for aprotinin group vs 1% for no aprotinin group (p = 0.36). Procedure-specific mortality rates for the aprotinin patients were equivalent to the no aprotinin group, at 2.1% vs 1.5% (p = 0.58) for CABG, and 0% vs 0% for aortic valve replacement and mitral valve replacement/repair.

The secondary end points were consistent for both comparisons. Aprotinin patients had a substantial reduction in blood loss at 300 mL (interquartile range [IQR] 230 to 485 mL) vs 600 mL (IQR, 413 to 878 mL; p < 0.001), blood product transfusion rate (29% vs 47%; p < 0.001), and the median duration of mechanical ventilation at 3 hours (IQR, 2 to 5 hours) vs 4 hours (IQR, 2 to 6 hours; p = 0.004). The rates of reopening for bleeding or tamponade, or both, were equivalent for both groups.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
In routine clinical practice, there is strong selection bias for aprotinin use in high-surgical-risk patients, as illustrated by the prominent disparities between the unmatched groups and the small number of matched pairs (about 10%); expectedly, therefore, the operative outcome was worse in aprotinin patients. The use of aprotinin, however, did not contribute to these adverse outcomes; rather, major differences in patient profiles and operative characteristics between the groups were responsible for the higher rates of postoperative renal failure, neurologic dysfunction, and operative death observed in the aprotinin group. Propensity score-matched analysis, like the multivariate analysis (Table 5), supported an innocuous role of aprotinin in these outcome measures in patients undergoing primary CABG or valve replacement/repair, or both.


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  		Table 5 Independent Predictors of the Primary End Points Identified by Multivariate Logistic Regression Analysis
 
Although our findings are consistent with other recent reports [27–30], they contradict the reports of Mangano [11] and Fergusson [31] and their associates. The observational study of Mangano and colleagues [11] reported a correlation between cardiovascular, renal, and cerebrovascular adverse outcomes with aprotinin use. In that study, more patients who received aprotinin underwent complex operations compared with those who had aminocaproic acid, tranexamic acid, or the control group. Unlike that series, which used propensity adjustment for selection bias not controlled by multivariable methods, we included all variables in propensity modelling to obtain scores that were comparable between the groups for the patients selected. Although this method resulted in significant reduction of study sample size, the findings were similar to the analysis of the whole study population.

The randomized multicenter clinical trial of Fergusson and colleagues [31] recruited 5401 high-risk patients but randomized only 2331 into a three-arm study comparing aprotinin with tranexamic acid and aminocaproic acid. No difference was observed in the incidence of postoperative MI, neurologic dysfunction, and renal failure in that study; however, operative mortality was higher in the aprotinin group. The study included patients undergoing repeat CABG, isolated mitral procedures, CABG combined with valves, and multiple valve repairs or replacements and aortic operations, but did not indicate the distribution of the very high-risk operations between the groups; neither did it report the procedure-specific mortality rates to enable a fair comparison.

An advantage of our study is the equivalence in type of operation between the groups. Most randomized trials [14, 32–34], nonrandomized studies [9, 12], and meta-analysis [7, 10] have not found any direct relationship between aprotinin and postoperative MI, cerebrovascular events, or death. In fact, a neuroprotective effect of full-dose aprotinin has been reported [35] and attributed to its antifibrinolytic properties. Similarly, animal research predominantly reports the therapeutic benefit with aprotinin to include neurologic [36], myocardial [37], and renal protection [38]. Interestingly, no connection between cardiac, renal, or neurologic damage has been reported with aprotinin use outside of cardiac operations [39, 40]. These conflicting reports reflect a gap in our understanding of the systemic effects of aprotinin in patients undergoing cardiac procedures.

Aprotinin use is regularly associated with a considerable reduction in postoperative bleeding and transfusion of blood products, and our study reproduces these findings. It is noteworthy that aprotinin patients were extubated earlier, probably as a result of reduced postoperative bleeding and a curtailed systemic inflammatory response, but the length of hospitalization was not affected, probably because of the higher operative risk. Patients who were not treated with aprotinin had substantial blood loss and were also more likely to receive blood transfusions. Although a causal relationship could not be established in this study, a powerful association was observed between blood transfusion and postoperative MI, renal insufficiency, neurologic dysfunction, and operative death.

Given the hemostatic efficacy of aprotinin, there is genuine concern about its thrombotic potential. Multiple dosage regimes, variable plasma levels [5], possible interaction with other hemostatic agents frequently used in cardiac procedures, and absence of direct monitoring of its in vivo activity (as is routine for other pharmaceutic agents used to alter coagulation during extracorporeal circulation) are key limitations of aprotinin. Even though aprotinin has laudable hemostatic and antiinflammatory properties, these and other concerns remain unresolved and deserve further investigation. For example, the clinical end point used in the determination of the adequacy of therapy and hence when to discontinue aprotinin treatment is not clearly defined. It is also not known if the dosage of protamine used for heparin reversal should be modified in patients receiving aprotinin. The influence of aprotinin on the outcome of cardiac operations in patients who continue antiplatelet and warfarin therapy until the time of operation is also not known and was not investigated in this study.

In our experience, the use of full-dose aprotinin was not associated with a higher incidence of postoperative MI, neurologic dysfunction, renal insufficiency, or operative death after CABG or valve operations (or both). Aprotinin use substantially reduced blood loss and transfusion and facilitated early extubation after cardiac operations. The lack of a clear understanding of the pharmacokinetics and interactions with other coagulation-altering drugs used in cardiac interventions leaves some unanswered questions and may contribute to the discordant experiences reported in the literature.


   Appendix
 


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

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