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J Thorac Cardiovasc Surg 2006;132:909-917
© 2006 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Aprotinin use in thoracic aortic surgery: Safety and outcomes

Artyom Sedrakyan, MD, PhDa,b,*, Albert Wu, MD, MPHb,c, George Sedrakyan, MDd, Marie Diener-West, PhDe, Maryann Tranquilli, RNa, John Elefteriades, MDa

a Department of Surgery, Yale University School of Medicine, New Haven, Conn
b Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md
c Health Services Research and Development Center, Johns Hopkins University, Baltimore, Md
d Nork-Marash Cardiac Surgery Hospital, Yerevan, Armenia
e Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md.

Received for publication November 1, 2005; accepted for publication June 6, 2006.

* Address for reprints: Artyom Sedrakyan, MD, PhD, Department of Health Policy and Management, Johns Hopkins School of Public Health, 624 N. Broadway, PO Box 485, Baltimore, MD 21295. (Email: asedraky{at}jhsph.edu).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objectives: Previous studies of aprotinin use in thoracic aortic surgery, limited in size and design, reported minimal information regarding outcomes other than blood loss and transfusion. The evaluation of impact of aprotinin on surgical outcomes in a large sample is needed.

Methods: Patients at Yale New Haven Hospital undergoing thoracic aortic surgery (aneurysm repair, dissections, penetrating ulcers, intramural hematomas) between 1995 and 2003 were considered for inclusion. Each patient receiving aprotinin was matched to a control per preoperative profile (age, gender, urgency of surgery, dissection/location of aortic disease). Data (surgical specifics, demographic variables, comorbidities, disease location-related variables, preoperative medications, intraoperative medications, surgical/operative data) were abstracted from the records of successfully matched aprotinin-treated patients and controls (n = 168). Comparison and determination of success of matching were performed using bivariate analyses. Outcome variables were compared using statistical tests for paired data. Supplementary unpaired and regression analyses were also performed.

Results: Baseline demographics of groups were similar, although controls had reduced history of aortic disease, but greater intraoperative use of lysine analogs (P < .05). Aprotinin significantly reduced platelet transfusion (P < .05). Paired bivariate analyses showed a tendency toward reduced ventilation time, pulmonary complications, and permanent arrhythmias (P < .05) associated with aprotinin. Supplementary analyses were supportive only for pulmonary complications and permanent arrhythmias.

Conclusions: The current evaluation substantiates previous reports that aprotinin may be safe to use and likely to improve some outcomes of thoracic aortic surgery. However, further studies for rare safety and efficacy end points are warranted.

Abbreviations and Acronyms ACT = activated clotting time; CABG = coronary artery bypass graft; ECM = extracellular matrix; DHCA = deep hypothermic cardiac arrest; KIU = kallikrein inactivation unit


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Thoracic aortic surgery with or without deep hypothermic arrest is associated with altered hemostasis that results in increased postoperative bleeding.1,2Go The surgery is also associated with high rates of stroke and mortality.3,4Go Multiple factors may be associated with these events: extensive surgical stress, need for complete inhibition of coagulation process, hemodilution, ischemia, and reperfusion.

Aprotinin (Trasylol, Bayer Pharmaceuticals Corp, West Haven, Conn) is a broad-spectrum, nonspecific serine protease inhibitor that has been shown to be associated with reduced inflammatory response and organ-protective effects.5-7Go Mechanisms for these beneficial effects include decrease in fibrinolysis, inhibition of neutrophil activation, preservation of platelet membranes, and inhibition of kallikrein.8-10Go Aprotinin is also known for its ability to reduce blood loss and blood transfusion requirements in cardiac surgery.11-13Go However, the safety and efficacy in thoracic aortic surgery are still considered controversial. Two small studies in thoracic aortic surgery have reported that aprotinin is not associated with a reduction in blood loss14,15Go and that it is associated with renal dysfunction.14,15Go Another large study did not support renal failure concerns related to aprotinin but also did not report reduction in blood transfusion in patients undergoing operation with the deep hypothermia technique.16Go Conversely, recent studies reported a beneficial effect of aprotinin on blood transfusion requirements and also dismissed safety concerns related to aprotinin in thoracic aortic surgery with or without deep hypothermia.17-19Go Most previous studies were limited in size, design, and follow-up evaluations. In addition, they reported little information about outcomes of the surgery other than blood transfusion. Accordingly, the primary goal of the current study is to determine whether the use of aprotinin is associated with improved outcomes of surgery including, but not limited to, reduction in blood transfusion requirements.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
More than 380 patients underwent thoracic aortic surgery at Yale New Haven Hospital by the end of 2003. All patients undergoing surgery for aneurysm repair, dissections, penetrating ulcers, and intramural hematomas were considered for inclusion in the study. Given the use of aprotinin in high-risk patients and sample-size limitations, each patient receiving aprotinin was matched to a control. Matching was performed on the basis of an electronic data source that captured preoperative profiles of the patients (M. T., A. S.). The sample included patients who underwent surgery between 1995 and 2003. However, more than 90% (n = 152) of the patients underwent surgery after 1999. Matching variables included age (±2 years), gender, urgency of surgery (urgent, emergency, elective), deep hypothermic cardiac arrest (DHCA) use, time/year of the surgery (±1 year), dissection, and location of aortic disease (ascending, arch, descending). Successful matching was achieved for 84 patients receiving aprotinin. Overall, 168 patients were included in the study, and detailed clinical and nonclinical information were abstracted from medical records for all patients by an experienced cardiothoracic nurse (M. T.). The study was approved by the Yale University School of Medicine Human Investigations Committee.

Surgical Specifics
In most cases cerebral protection was performed by DHCA. Retrograde brain perfusion was not used in these patients. Carbon dioxide flooding of the field was used for all recent operations to prevent air embolism. In addition, cerebrospinal fluid drainage was used for descending thoracic aortic operations. Only full-dose aprotinin (full Hammersmith dose: 2 million kallikrein inactivation units [KIU] intravenously, 2 million KIU pump prime, and 0.5 million KIU/h continuous infusion) was used unless there was a major renal impairment. Activated clotting time (ACT) monitoring was based on kaolin, and an ACT of 500 seconds was considered adequate. There was no strict protocol on infusion of aprotinin during circulatory arrest because the drug was discontinued by some anesthesiologists and continued by others.

Study Variables
Demographic variables included age, gender, race, body mass index, and body surface area. Comorbidities included family history of aortic disease, smoking status, diabetes, history of renal disease, hypertension, cerebrovascular disease, peripheral vascular disease, chronic obstructive pulmonary disease, coronary heart disease, obesity, New York Heart Association functional class, and preoperative arrhythmia (mostly atrial fibrillation). Disease location-related variables were lesion location (ascending, arch descending), aortic stenosis, aortic insufficiency, previous vascular/cardiac surgery, and ejection fraction.

Preoperative medication data included beta-blocker, calcium channel blocker, angiotensin-converting enzyme inhibitor, and aspirin or clopidogrel use. Intraoperative medications included aminocaproic acid/tranexamic acid, Hetastarch (Sigma-Aldrich, St Louis, Mo), albumin, and fibrin glue. Surgery-related data included aortic dissection, preoperative shock, urgent or emergency surgery, cardiac catheterization, preoperative hemoglobin, and preoperative hematocrit. Operative data included cardiopulmonary bypass time, crossclamp time, circulatory arrest time when DHCA was used, use of blood cardioplegia, coronary artery bypass graft (CABG) surgery, and valve surgery. Continuous outcomes included 24-hour drainage, packed red blood cells, fresh frozen plasma, platelet use, hemoglobin (on day 1), hematocrit (on day 1), total ventilation time, total intensive care unit time, and total length of stay. Dichotomous outcomes included embolism, myocardial infarction, stroke, transient cerebrovascular accident, renal failure, pulmonary complications, infection, arrhythmia, permanent arrhythmia, mortality, combined end point of stroke myocardial infarction or mortality, any complication (embolism, myocardial infarction, stroke, renal failure, pulmonary complication, permanent arrhythmia, or death), and length of stay more than 7 days.

Statistical Analysis
In the first step of the analyses, descriptive statistics for study variables were calculated. Then, bivariate analyses were performed to compare characteristics of patients receiving aprotinin with those of controls and to determine the success of matching. The t test was used to compare the groups with regard to continuous variables. The chi-square test was used to compare the groups with regard to dichotomous outcomes. If sample size requirements for chi-square were not met, the Fisher exact test was used to compare the groups. In the third stage of the analyses, aprotinin recipients and controls were compared regarding outcome variables. Because of matching performed in pairs, we used the paired t test for continuous outcomes such as red blood cells, fresh frozen plasma, platelet transfusion, and other variables.

The McNemar test was used for dichotomous outcomes such as occurrence of death, stroke, atrial fibrillation, and other variables. In these analyses 84 pairs were available that were separated into concordant and discordant pairs (Table 4). AQ Test statistics were based on discordant pairs, and odds ratios were calculated. Confidence interval (95%) calculations for odds ratios are based on exact binomial distribution.


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  		TABLE 4. Paired analysis of aprotinin and dichotomous clinical outcomes
 
These analyses were supplemented (Appendixes 1–3) with unmatched analyses and regression analyses to provide supplementary information. We used the Statistical Analysis System (SAS Institute, release 8.02, Cary, NC) and STATA statistical software (release 8.0, College Station, Tex) for data management and analysis.


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  		APPENDIX 1. Unpaired analysis for continuous clinical outcomes
 

   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The mean age of patients was 61.7 years, and 38.1% were female. Those with ascending aortic disease constituted the majority of the patients (Table 1), and aortic dissection was observed in 36% of patients (Table 2). Matching patients receiving aprotinin with control patients was successful with only a few differences between the groups. Patients receiving aprotinin were more likely to have a family history of aortic disease compared with controls (Table 1), and controls were more likely to receive antifibrinolytics (epsilon aminocaproic acid [Amicar, Amgen Inc, Thousand Oaks, Calif]AQ or tranexamic acid) (Table 2). Thus, aprotinin in this study was essentially compared with an alternative blood loss reduction strategy that included antifibrinolytic therapy more than 50% of the time.


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  		TABLE 1. Baseline demographics, comorbidities, and disease-specific variables in treatment groups
 

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  		TABLE 2. Preoperative medications and operative variables in the treatment groups
 
In paired data analyses, aprotinin recipients received fewer platelets (on average 0.6 packs per person; 4 units within each pack) and had a shorter ventilation period in the intensive care unit (mean difference 13 hours) (Table 3). Supplementary unpaired analysis did not provide strong statistically significant evidence for reduced ventilation time, although a tendency toward reduced time on the ventilator was still apparent. Reduction in platelet requirements was robust in both analyses. There was evidence for a substantial reduction in 24-hour drainage in patients receiving aprotinin (Appendix 1).


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  		TABLE 3. Paired analysis of aprotinin and continuous clinical outcomes
 
Paired data analyses for dichotomous outcomes have shown fewer pulmonary complications and permanent arrhythmias with aprotinin use (Table 4). A strong tendency toward reduction in the outcome defined as any complication (see "Study Variables") was also observed. Supplementary unpaired analyses also provided evidence for reduced pulmonary complications and a strong tendency toward reduction in permanent arrhythmias (Appendix 2). No other statistically significant associations were found.


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  		APPENDIX 2. Unpaired analysis for dichotomous clinical outcomes
 
Supplementary multivariable regression models provided evidence for reduced occurrence of permanent arrhythmias and reduced requirements for platelets (Appendix 3). Similarly, there was a strong tendency toward reduction of pulmonary complications and total ventilation. The tendency toward reduction in any complication was less robust in these analyses.


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  		APPENDIX 3. Unconditional multivariable analyses for selected outcomes
 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Even in the hands of experienced surgeons, thoracic aortic surgery is associated with significant morbidity and mortality.20Go The current evaluation shows that aprotinin use in thoracic aortic surgery is likely to be associated with some improved outcomes in this setting. The most robust observations were substantial reductions in platelet requirements. However, it is still possible that platelets were used as part of the prophylactic intervention rather than a measure to reduce bleeding (outcome). There was also reduction in permanent arrhythmia and possibly pulmonary complications. There is some evidence for reduced 24-hour drainage in the subset of 113 patients in the supplementary analyses. Limitations related to missing data did not permit more complete analysis of this outcome. Overall, aprotinin recipients tended to have fewer complications, although statistically significant improvements for rare outcomes such as stroke and mortality were not observed.

Aprotinin is known to reduce blood loss and blood transfusion requirements in CABG and cardiac surgery in general.11,12,21Go However, efficacy and safety data published for use in thoracic aortic surgery and deep hypothermic circulatory arrest (Table 5) have been both positive17-19Go and negative.14-16Go The current analysis, in patients undergoing thoracic aortic surgery with and without deep hypothermic arrest, provides level II evidence that aprotinin is likely safe to use and possibly reduces blood loss and transfusion requirements in this population.


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  		TABLE 5. Summary of literature on aprotinin use in deep hypothermic circulatory arrest
 
Prospective, randomized, controlled data evaluating aprotinin use in CABG surgery show no significant adverse impact on renal function,11Go although reports in thoracic aortic surgery indicate adverse,14,15Go transient,18,19Go or no16,17Go effects on this parameter. In the current analysis, aprotinin recipients at baseline trended toward an increase in history of renal failure. Despite this baseline, aprotinin recipients showed no increase in this outcome compared with controls (odds ratio, 0.33; P = .3). However, large confidence intervals (0.01-4.15) around the risk estimate do not exclude this possibility. Because aprotinin has been shown to artificially prolong ACT values, maintaining adequate heparinization is important,17Go particularly in procedures with deep hypothermic arrest. Critical evaluation of this issue suggests that excessive mortality and complication rates, including renal dysfunction, have been reported when the adequacy of anticoagulation is questionable.22Go Minimal target ACT values of 600 to 1000 seconds have been used to monitor heparinization,18,22,23Go as well as maintaining heparin levels greater than 2.7 to 3.5 U/kg.16,22Go In our study, kaolin-based monitoring and an ACT of 500 or greater were used.

The current evaluation in thoracic aortic surgery shows that aprotinin therapy is associated with a reduction in arrhythmias. These data are aligned with those of a recent meta-analysis of CABG studies showing a trend in reduced atrial fibrillation rates for those patients treated with aprotinin.11Go Alternatively, sample-size limitations do not exclude the possibility of this benefit occurring by chance alone. A mechanism for this possible effect is unclear, although animal models show that aprotinin reduces myocardial ischemia-reperfusion injury,24-26Go and ischemia-reperfusion injury is associated with mitochondrial dysfunction and subsequent atrial fibrillation in patients undergoing cardiac surgery.27Go Concurrently, reduction in platelet transfusion may have a beneficial impact on this parameter in patients undergoing cardiac surgery.28Go Further evaluation of this possible effect is warranted, because perioperative arrhythmias increase resource use and costs in the cardiac setting.

Our analysis indicates that aprotinin therapy may be associated with improved pulmonary outcomes. Previous studies have reported improvement on various pulmonary parameters in patients treated with aprotinin relative to controls, including mean airway pressures and Pa[scap]co[r]2 levels,29Go alveolar-arterial oxygen gradients,30,31Go and time on ventilation.32,33Go An impact on pulmonary function may mechanistically be associated with reduced systemic inflammatory effects,5-7Go although the effect of aprotinin to significantly reduce platelet transfusion may also have a role in improvements in this parameter.28Go

In patients undergoing thoracic aortic surgery, rates of stroke (descending aorta, 5%; ascending aorta, 8%) and death (descending and thoracoabdominal aortas, 8%; ascending and arch, 2.5%) are relatively high compared with other cardiac procedures.20Go Meta-analyses have shown that in CABG surgery, aprotinin therapy is associated with a reduction in stroke with no apparent effect on mortality,11Go whereas across different cardiac surgeries (CABG and valve combined) aprotinin seems to be associated with reduced mortality.12Go Conversely, several anecdotal reports of fatal thrombosis in hypothermic circulatory arrest with the use of aprotinin,34-37Go as well as the use of antifibrinolytic aminocaproic acid,38Go exist in the literature. These case series merit consideration and further data collection effort in the future. In the current evaluation in thoracic aortic surgery, although the sample size was reasonably large, power limitations were observed in determination of possible differences in stroke, transient cerebrovascular accident, fatal thrombosis, and mortality.

We believe that the current evaluation of a large cohort of carefully matched patients who underwent thoracic aortic surgery at a major teaching hospital has added more evidence to the safety and efficacy of aprotinin in this setting. These data substantiate previous reports that aprotinin can be safe and possibly improve some outcomes in thoracic aortic surgery. Further studies for rare safety and efficacy end points are warranted.


   Footnotes
 
The chart review, data collection, and data analysis conducted in this study were supported by an investigator-initiated proposal and subsequent phase IV funding by Bayer Pharmaceuticals Corporation, West Haven, Conn, the manufacturer of aprotinin. Artyom Sedrakyan and John Elefteriades report lecture fees and grant support from Bayer Pharmaceuticals Corporation.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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