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CARDIOVASCULAR ANESTHESIA

Full-Dose Aprotinin Use in Coronary Artery Bypass Graft Surgery: An Analysis of Perioperative Pharmacotherapy and Patient Outcomes

David Royston, FRCA^*, Jerrold H. Levy, MD, Jane Fitch, MD, Wulf Dietrich, MD, Simon C. Body, MBChB, MPH^||, John M. Murkin, MD^¶, Bruce D. Spiess, MD^#, and Andrea Nadel, PhD^**

From the *Department of Anesthesia, Harefield Hospital, London, UK; Department of Anesthesiology, Emory University, Atlanta, Goergia; Department of Anesthesiology, University of Oklahoma, Oklahoma City, Oklahoma; Department of Anesthesiology, German Heart Center Munich, Munich, Germany; ||Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ¶Department of Anesthesia, University of Western Ontario, London, Ontario, Canada; #Department of Anesthesiology, VCURES Shock Center, Virginia Commonwealth University/Medical College of Virginia Campus, Richmond, Virginia; and **Global Statistics, Bayer Pharmaceuticals Corporation, West Haven, Connecticut.

Address correspondence and reprint requests to David Royston, FRCA, Department of Anaesthesia and Critical Care, Royal Brompton and Harefield NHS Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex, UB9 6JH, UK. Address e-mail to dave{at}tharg.demon.co.uk.

	Abstract

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BACKGROUND: Inappropriate activation of hemostasis and inflammation may contribute to postoperative morbidity and mortality. The serine protease inhibitor, aprotinin, has been shown to prevent tissue and organ injury in laboratory and animal studies. In this retrospective analysis, we evaluated the relationship of aprotinin therapy with organ dysfunction in humans undergoing coronary artery bypass graft surgery (CABG).

METHODS: Data from prospective randomized, double-blind, placebo-controlled studies evaluating the safety and efficacy of full-dose aprotinin (2 million KIU load, 2 million KIU pump prime, and 0.5 million KIU/h continuous infusion) to reduce blood loss and transfusion requirements in patients undergoing CABG (placebo, n = 861; aprotinin, n = 862) were examined retrospectively. Primary end-points were death, adverse cerebrovascular outcome, myocardial infarction (MI), and pharmacological interventions (inotropic drugs, vasopressors, and antiarrhythmics).

RESULTS: Univariate analysis showed that relative to placebo, full-dose aprotinin therapy was associated with significant effects on the incidence of adverse cerebrovascular outcome (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.19–0.93; P = 0.03) and use of inotropic drugs (OR 0.79, 95% CI 0.65–0.97; P = 0.02), vasopressors (OR 0.74, 95% CI 0.61–0.90; P < 0.01), and antiarrhythmics (OR 0.79, 95% CI 0.65–0.96; P = 0.02), but not death (OR = 1.00, 95% CI 0.54–1.85; P = 1.0) or MI (OR 0.92, 95% CI 0.64–1.31; P = 0.6). Multivariate analysis confirmed results of univariate analysis.

CONCLUSIONS: This retrospective analysis of data collected from prospective, randomized, placebo-controlled studies in CABG shows that full-dose aprotinin use was associated with a lower risk of adverse cerebrovascular outcomes and a reduced need for use of vasoactive drugs; the risk of death and perioperative MI was not affected by aprotinin therapy.

	Introduction

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Multiple randomized, double-blind, placebo-controlled trials have convincingly demonstrated that aprotinin administration leads to important clinical reduction in postoperative bleeding and the need for allogeneic blood transfusion after primary cardiac (1–3), repeat cardiac (2,4–6), major orthopedic (7), and hepatic transplant (8) surgery. Although the mechanisms are not clearly known, the antifibrinolytic effects of the drug are believed to contribute to the blood transfusion-sparing effects of aprotinin (9–11). Unlike other widely used antifibrinolytic drugs, such as -aminocaproic acid and tranexamic acid, aprotinin also reduces the circulating concentrations of markers elevated in the inflammatory response to surgery (12,13). Multiple studies in animals and isolated organ systems have shown that aprotinin protects against organ dysfunction, in particular myocardial dysfunction induced by ischemia-reperfusion or inflammatory processes (14).

Aprotinin has been reported to inhibit the vasodilatation associated with hepatic failure (15), and to reduce inotrope and vasopressor use during hepatic transplantation (16–18) and surgery for pediatric congenital heart disease (19). Secondary and meta-analyses of cardiac surgery trials have found, and when compared with placebo, aprotinin use is associated with less overall morbidity, adverse cerebrovascular outcome (20–23), and a trend for lower rates of atrial fibrillation (22) without evidence of an effect on rates of renal impairment, myocardial ischemia, or thrombotic complications (20–24), and mortality (21). However, an evaluation focusing on the effect of aprotinin on vasoactive drug use has not been conducted.

We hypothesized that aprotinin, given during adult myocardial revascularization surgery, would be associated with decreased cardiovascular morbidity and mortality, including pharmacological interventions as a surrogate for impaired organ function. To address this hypothesis, we retrospectively analyzed data collected in prospective, randomized trials submitted to the Food and Drug Administration (FDA) for licensure of Trasylol® (aprotinin injection).

	METHODS

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The safety and efficacy of coronary artery bypass graft (CABG) surgery database of Trasylol® (aprotinin, Bayer Corporation, West Haven, CT) was retrospectively examined. Data were prospectively collected from the five randomized, double-blind, placebo-controlled trials of "full-dose" aprotinin (see later for description) used as pivotal or supportive documentation for submission to the FDA as part of drug approval (Fig. 1). The studies were conducted in male and female patients aged over 18 yr, from January 1990 through May 1995 at 37 medical institutions (Denmark, 1; Israel, 2; and United States, 34) with IRB approval and individual written informed patient consent. Data from these individual trials have been published (1,3–5,25), except for those of 37 patients from an unpublished pilot study. The analyses included data from patients undergoing primary or reoperative CABG with the use of cardiopulmonary bypass (CPB), without concomitant procedures. Exclusion criteria for enrolment included age <18 yr, concomitant surgical procedures (e.g., valvular surgery, aneurysmectomy, and carotid endarterectomy), a history of any bleeding diathesis, known hematologic abnormality, refusal of blood products, or known or suspected allergy to aprotinin. Two studies (1,25) excluded patients with serum creatinine >1.9 mg/dL, as well as those having diabetes mellitus with serum creatinine above the upper limit of normal. Patients receiving aspirin therapy were included and stratified per protocol. Perioperative care including CPB, cardioplegia, and postoperative intensive care procedures were those practiced routinely at each center, including intra- and postoperative blood conservation techniques (e.g., cell salvage, reinfusion of thoracic drainage, hemodilution). Predonation of autologous blood was not allowed. Across studies, heparin-initial loading doses ranged from 300 to 400 IU/kg. Subsequent heparin administration used one of the three methods, dependent on the routine practice of each center. A time and weight adjusted regimen (load, 300 IU/kg; additional doses 150 IU/kg after 90 min of CPB), heparin/protamine titration using the Hepcon System (Medtronic, Minneapolis, MN), or, in the case of one study (5), to maintain celite-activated clotting time >480 s was used. Protamine dosing was determined according to investigator or institutional preferences. During surgery, red blood cell transfusion was given when the hematocrit was <18%. Postoperatively, red blood cell transfusion was given when the hematocrit was between 21% and 25%. Allogeneic blood transfusion was allowed at any time if required by the clinical condition of the patient. Guidelines for transfusion of other blood products were not specified and were at the discretion of the institution and clinicians.

View larger version (27K): [in this window] [in a new window]   Figure 1. Flow Chart Depicting Subjects Valid for Safety in the United States Coronary Artery Bypass Graft (CABG) Database. Patients undergoing primary and repeat CABG were enrolled in prospective, randomized, placebo-controlled trials evaluating the safety and efficacy of Trasylol (aprotinin injection). The current analysis includes those evaluating full-dose aprotinin (n = 1723). Numerical headings (e.g., D92-) represent individual study designations for each clinical trial.

Patients received saline placebo or aprotinin using the following dosing regimen after induction of anesthesia, but before sternotomy (6): 1 mL test dose, then 2 x 10⁶ KIU IV over 15–20 min, followed by continuous IV infusion of 5 x 10⁵ KIU per hour for the duration of surgery; an additional 2 x 10⁶ KIU was added to the priming fluid of the CPB circuit. Patients in the placebo group received an identical volume of saline. The randomization for each study was computer generated in blocks for patient allocation within clinical centers. The institution and investigators were provided with identical case packs identified only by random number and containing bottles typically labeled load, infusion, and oxygenator.

Data Collection
Data were collected using standardized case report forms that included demography, cardiac-specific, and general medical history, details of surgery (including extracorporeal system used, heparin, and protamine doses, hematocrit and hemoglobin results, details of coronary artery grafting and blood conservation techniques), transfusion requirements, concomitant medication usage, laboratory results, and adverse event information. Adverse events were coded using the standardized Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) terminology. Concomitant medications were coded using the World Health Organization Drug Dictionary (WHO-DD). Data for the patient's length of stay in the intensive care unit and hospital were also captured. All data were maintained as SAS datasets and analyzed using SAS software (SAS Institute, Cary, NC.)

End-Points
Adverse Ischemic Events
Myocardial infarction (MI) was assessed on a blinded basis by the core electrocardiographic (ECG) laboratory at St Louis University Medical Center, St. Louis, MO on the basis of ECG criteria and cardiac enzyme evidence in three of the studies (1,3,4) (Table 1). All ECGs were classified according to the MN code (26). A definite MI was defined as either a new two-step worsening in Q wave criteria (26) or a new development of persistent left bundle branch block or acute myocardial necrosis at postmortem. Probable MI was defined as an increase in concentration of creatinine kinase MB isoform above 120 IU or a new one-step MN code Q wave worsening (26) with an abnormally prolonged temporal profile of creatinine kinase MB isoform concentrations as determined by the core ECG laboratory (1,3,4). New intra- or postoperative use of intraaortic balloon counterpulsation was an adverse myocardial outcome. Intraaortic balloon counterpulsation data from the unpublished pilot study were incomplete (see Table 1), and as such, the denominator for this parameter in addition to MI is less than that of the total patient population.

Cerebrovascular Outcomes
An adverse cerebral outcome was defined as any adverse event coding in the case report forms as "cerebrovascular accident," "cerebral embolism," "cerebral hemorrhage," "cerebral infarct," or "cerebral ischemia," and diagnosed by any member of the patient's clinical care team. Further description of adverse cerebral outcomes (e.g., global or focal) were not routinely captured for analysis. Regular or repeat formal neurologic evaluation was not mandated as part of the protocol of any of the studies. There was no central adjudication of neurologic events.

Mortality
Mortality was defined as in-hospital death or death within 30 days of the initial surgical hospitalization.

Renal Medications
Medications for renal impairment were evaluated to provide an additional perspective of possible effects on renal function, as serum creatinine data were prospectively collected in the trials and have been published. In data pooled from the United States studies of patients undergoing CABG, the incidence of serum creatinine >0.5 mg/dL above pretreatment is not significantly different from placebo (27). In the present analysis, renal impairment was suggested if patients received diuretics during the same postoperative period.

Cardiovascular Pharmacotherapy
Patients receiving a newly prescribed inotropic drug, vasopressor, or antiarrhythmic drug were analyzed. Vasoactive drug use, however, was not dictated by the protocol. Administration of these drugs, independent of duration (as actual timing of use was not recorded in the database), was noted during the time from the start of surgery until the end of the intensive care unit stay (inotropic drugs) or through hospital discharge (vasopressors and antiarrhythmics). Subjects reporting use of antiarrhythmic drugs before surgery were not counted in the respective groups in the analyses. The pharmacological intervention end-point categories were defined by review of all medications used by patients in the database and were selected by name and specific WHO-DD code. The search terms are shown in Appendix.

Data Analysis
Continuous demographic parameters were compared between treatment groups with a general linear model. Categorical demographic parameters, preoperative risk variables, and principal end-points (adverse cerebrovascular outcome, MI, or requirement for vasoactive medication) were compared between treatment groups with a logistic model. All models were adjusted for study period (older studies versus newer), pretreatment with aspirin (within 5 days) and stratification (primary/reoperation procedure) in addition to treatment (full-dose aprotinin versus placebo). In addition, principle end-points were examined with a stepwise logistic procedure. All covariates, excluding the aprotinin treatment indicator, that were significant in univariate analyses (P < 0.10) were made available for inclusion in the first stage of the forward stepwise logistic regression. Entry and retention in the model required P < 0.10. The aprotinin treatment indicator was then added to the chosen models; significance of aprotinin at this stage (P < 0.05) indicates that aprotinin is an independent predictor of outcome. In addition to incidence rates, odds ratios and 95% confidence limits of the odds ratios were used to summarize these analyses.

	RESULTS

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Data from 1723 patients (placebo, 861; aprotinin, 862) were available for analysis. There were no significant differences between groups regarding mean age, mean weight, or gender (Table 2). Similarly, a comparison between groups for patients with preoperative risk factors for cardiovascular, cerebrovascular, and hematological events showed no significant differences (Table 3). As the original studies were specifically designed for licensure purposes to evaluate blood loss and transfusion requirements in both primary and repeat CABG patients, these detailed efficacy variables for each surgical subpopulation are reported elsewhere (27).

The effects of aprotinin therapy on the hypothesized outcome variables in all CABG patients studied are shown in Table 4. Data for renal effects are not shown as nearly all patients received diuretics during the surgery and intensive care unit period, preventing discrimination between aprotinin therapy and placebo regarding intraoperative and early postoperative renal function. The incidence of investigator-reported renal failure was 2% each in the placebo and full-dose aprotinin groups. The incidence of adverse cerebrovascular outcome, as well as use of inotropic, vasopressor, or antiarrhythmic pharmacotherapy, was significantly reduced in those patients who were randomly allocated to treatment with aprotinin. For primary CABG patients only, patients treated with aprotinin showed significantly reduced use of inotropic drugs (33.2% vs 28.4%, P = 0.048) and vasopressors (55.9% vs 50.6%, P = 0.0052), whereas in the reoperative CABG subpopulation, adverse cerebrovascular outcome (5.26% vs 0.61%, P = 0.035) and antiarrhythmic use (60.8% vs 47.9%, P = 0.016) were significant between aprotinin and placebo groups. Significant predictors (P < 0.1) shown to impact the outcome variables evaluated in this analysis are shown in Table 5. Multivariate regression analysis incorporating the significant predictors does not substantially alter the significance of observed differences between placebo and aprotinin (Table 5). Aprotinin was an independent predictor of outcomes. The impact of aprotinin therapy, after multivariate regression analysis, on the odds ratio for each event or intervention is shown in Figure 2.

View larger version (8K): [in this window] [in a new window]   Figure 2. Effect of aprotinin therapy on outcome variables shown as odds ratios with 95% confidence intervals (CI). Data displayed are for those outcome variables significantly different between the treatment and nontreatment group after multivariate regression analysis indicating aprotinin is an independent predictor of outcome. Data are shown on a logarithmic scale. Use of an inotrope or vasopressor was for period of surgery and intensive care. Other factors were during the whole operative and postoperative period.

	DISCUSSION

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This retrospective analysis of data collected in five prospectively randomized, double-blind, placebo-controlled studies of aprotinin in adult cardiac surgery showed that use of full-dose aprotinin therapy was associated with a significant reduction in the incidence of postoperative adverse cerebrovascular outcomes and reduced need for cardiovascular pharmacological interventions, including inotropic drugs, vasopressors, and antiarrhythmic medications. Although these studies were originally conducted more than 10 yr ago, specifically for the evaluation of blood loss, transfusion, and safety end-points, these data provide insight into the growing understanding of the potential benefits of aprotinin during CABG surgery.

The analysis failed to confirm the finding from the meta-analysis of Levi et al. (21) of a reduction in mortality in aprotinin-treated patients. This may reflect the greater number of patients (n = 3212) and studies (n = 26) incorporated into that analysis. The current analysis did, however, confirm the lack of influence of the full-dose aprotinin regimen on postoperative myocardial infarction in the general CABG population (22–24). These findings are not in concordance with recently published propensity-adjusted analyses of nonrandomized databases (28,29).

Previous studies have associated aprotinin therapy with a reduced incidence of stroke. In these investigations, Levy et al. (4) and Frumento et al. (30) observed no strokes in the full-dose aprotinin group (0/73 and 0/26, respectively), variable results in the half-dose aprotinin groups (0/70 and 15/67, respectively), and high stroke rates in the controls (5/72 and 9/56, respectively). Such data suggest that full-dose aprotinin therapy might be associated with some factor that, in its absence, led to higher rates in the control high-risk population. However, these studies reported incidences of stroke in the control groups more than reported for the general CABG population in the Society of Thoracic Surgeons database (31) (1.6%) and in the placebo population of the current analysis (2.4%). Thus, the current findings may be more broadly generalizable to the wider CABG surgery population. These data showing a reduced risk of adverse cerebrovascular outcome in patients treated with aprotinin (57%) is concordant with that summarized from a larger series, including a Cochrane review (24) of data describing adults scheduled for nonurgent surgery, and those reported recently by Sedrakyan et al. (22) for CABG surgery (risk reduction, 47%).

The reduced administration of inotropic and vasopressor medications in the surgical and intensive care unit period associated with aprotinin therapy might have been anticipated based on previous reports (16–19). The direct action of aprotinin in ischemia-reperfusion injury is likely due to inhibition of local cytokine generation (14). In contrast, the reported reduction in the need for inotropic drug and vasopressor support during hepatic transplantation (18), and the improved arterial blood pressure and organ perfusion when aprotinin was administered to patients with cirrhosis (15), suggests an inhibition of circulating factor(s) that can depress myocyte function. In addition, the significant reduction in the transfusion of blood products to patients in the studies analyzed here may have contributed to a reduced burden of circulating inflammatory mediators (32). In the same way, the mechanism for a reduced use of drugs to suppress arrhythmias and adverse cerebrovascular outcome in the current analysis is conjectural.

Retrospective database analyses, as with all experimental approaches, have advantages as well as limitations (33). As all of the original studies were randomized, double-blind, placebo-controlled trials of aprotinin, patient selection bias for drug therapy, which is often a limitation of retrospective analyses, including those evaluating aprotinin therapy, was not an issue. These data were submitted to the FDA for licensure, and thus were coded, reported, collected, verified, and evaluated in a rigorous and uniform manner. The homogenous data set allowed for pooling of data across studies, increasing the sample size, patient exposure, frequency of outcomes and adverse events, and statistical power to detect important differences. Retrospective analyses, however, are subject to investigator bias via interpretation of findings in the context of preconceived viewpoints, and repeated retrospective evaluation of a data set also raises the probability of a type I error (i.e., finding a significant result due purely to chance occurrence). In this analysis, the authors determined outcomes of interest after careful evaluation of study case report forms and from lists of adverse events and pharmacotherapies without any notation of treatment group. Only MI and mortality were defined per protocol, and other adverse outcomes, such as adverse cerebrovascular outcome and pharmacotherapy surrogate markers, were not defined a priori as part of the original experimental designs.

The use of specific medications to treat hemodynamic and rhythm disturbances was chosen as a clinically relevant end-point to assess patient outcome for two reasons. Although there was no protocol for guiding institution of pharmacological interventions, these medications were started in response to an aberration in cardiovascular function deemed clinically important. Since clinicians remained blinded to study treatment, these decisions were not biased towards whether the patients received aprotinin or placebo. Inotropic, vasopressor, or antiarrhythmic drug administration thus should reflect the incidence of clinically important cardiovascular events beyond that provided by the hard outcomes of MI, adverse cerebrovascular outcome, or mortality. In the studies included in the analysis, all concomitantly administered medications were recorded as part of regulatory safety requirements. It is therefore unlikely that the medications sought in the current analysis would have been omitted from the patient case record form, and thus from the database.

This retrospective analysis of data collected from prospective, randomized, placebo-controlled studies in CABG shows that full-dose aprotinin use was associated with a lower risk of adverse cerebrovascular outcome and a reduced need for use of vasoactive drugs. The data suggest that future studies investigating the effects of aprotinin therapy in cardiac surgery should focus on cardiovascular events beyond its well established blood-sparing properties.

	APPENDIX: SEARCH TERMS FOR PHARMACOLOGICAL INTERVENTIONS

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Commonly accepted synonyms of the following drugs (including salt forms and proprietary names) recognized as interventional inotropic medications were: Amrinone, dobutamine, epinephrine, isoproterenol, milrinone, and norepinephrine; those recognized as interventional vasopressor medications were ephedrine, norepinephrine, phenylephrine, and pseudoephedrine. Interventional antiarrhythmic medications included adenosine, amiodarone, digitoxin, digoxin, disopyramide, encainide, moricizine, flecainide, lidocaine, mexiletine, procainamide, propafenone, quinidine and their synonyms.

	Footnotes

 
Accepted for publication July 10, 2006.

	REFERENCES

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999