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Circulation. 1999;99:81-89

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(Circulation. 1999;99:81-89.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Is {epsilon}-Aminocaproic Acid as Effective as Aprotinin in Reducing Bleeding With Cardiac Surgery?

A Meta-Analysis

John J. Munoz, MD; Nancy J. O. Birkmeyer, PhD; John D. Birkmeyer, MD; Gerald T. O'Connor, PhD, DSc; Lawrence J. Dacey, MD, MS

From the Departments of Surgery (J.J.M., N.J.O.B., J.D.B., L.J.D.) and Medicine (G.T.O.), Center for the Evaluative Clinical Sciences (G.T.O., J.D.B.), Dartmouth Medical School, Hanover, NH, and the VA Outcomes Group (J.J.M., J.D.B.), Veterans Affairs Medical Center, White River Junction, Vt.


*    Abstract
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 *Abstract
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Background—Although aprotinin is known to be effective in reducing postoperative hemorrhage after cardiac surgery, {epsilon}-aminocaproic acid, an alternative antifibrinolytic, is considerably less expensive. Because the results of 3 small randomized clinical trials comparing these 2 agents directly were inconclusive, we performed a meta-analysis to compare the relative effectiveness and adverse-effect profile of these 2 agents against placebo.

Methods and Results—Data from 52 randomized clinical trials published between 1985 and 1998 involving the use of {epsilon}-aminocaproic acid (n=9) or aprotinin (n=46) in patients undergoing cardiac surgery were abstracted. Our primary outcomes were total blood loss, red blood cell transfusion rates and amounts, reexploration, stroke, myocardial infarction, and mortality. The meta-analysis revealed substantial reductions in total blood loss with {epsilon}-aminocaproic acid and low-dose aprotinin (each with a 35% reduction versus placebo, P<0.001) and high-dose aprotinin (53% reduction, P<0.001). There were identical reductions in total postoperative transfusions with {epsilon}-aminocaproic acid (61% reduction versus placebo, P<0.010) and high-dose aprotinin (62% reduction, P<0.001). The proportion of patients transfused was similarly reduced with {epsilon}-aminocaproic acid (OR, 0.32; 95% CI, 0.15 to 0.69) and high-dose aprotinin (OR, 0.28; 0.22 to 0.37). Although both drugs reduced rates of reexploration to similar degrees, this effect was statistically significant only with high-dose aprotinin (OR, 0.39; 0.24 to 0.61). {epsilon}-Aminocaproic acid and aprotinin had no effect on risks of postoperative myocardial infarction or overall mortality.

Conclusions—Because the 2 antifibrinolytic agents appear to have similar efficacies, the considerably less-expensive {epsilon}-aminocaproic acid may be preferred over aprotinin for reducing hemorrhage with cardiac surgery.


Key Words: {epsilon}-aminocaproic acid • aprotinin • hemorrhage • meta-analysis • surgery


*    Introduction
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Postoperative hemorrhage is one of the most common complications of cardiac surgery. Although transfusion rates vary significantly among institutions,1 overall {approx}60% to 75% of patients undergoing open heart surgery receive transfusions.2 3 Re-exploration for hemorrhage is required in 2% to 6% of patients, with case-fatality rates ranging from 10% to 22%.4 5 In addition to its impact on patients' morbidity and mortality, bleeding and reexploration consume considerable resources as a result of increased operative time, blood product use, and prolonged intensive care unit and total hospital stays.

Prophylactic antifibrinolytic therapy is one approach to reducing postoperative hemorrhage. The most thoroughly evaluated antifibrinolytic agent is aprotinin. Its effectiveness in reducing postoperative hemorrhage has been established in >40 randomized clinical trials and 2 meta-analyses.2 6 However, aprotinin is expensive: {approx}$1000 for the conventional high-dose regimen (6 million KIU [kallikrein inhibiting units]) and {approx}$500 for the low-dose regimen (3 million KIU). In addition, there are concerns about potential thrombosis-related side effects and allergic reactions with antifibrinolytic agents. For these reasons, prophylactic use of aprotinin is often limited to patients at high risk for bleeding (eg, reoperations) or those for whom transfusions are not acceptable because of religious beliefs (eg, Jehovah's Witnesses).

An alternative to aprotinin is {epsilon}-aminocaproic acid, a synthetic antifibrinolytic. Although it shares some of the potential side effects of aprotinin, {epsilon}-aminocaproic acid is considerably cheaper ({approx}$40/average dose). Three randomized clinical trials have directly compared {epsilon}-aminocaproic acid and aprotinin in cardiac surgery. However, these studies were inconclusive owing to limited sample size.7 8 9 For this reason, we performed a meta-analysis to assess the relative effectiveness and side-effect profiles of the 2 antifibrinolytic agents compared with placebo.


*    Methods
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Literature Review and Study Selection
A comprehensive literature search was performed with the computerized Web-based OVID interface to MEDLINE. Keywords used in the search included "{epsilon}-aminocaproic acid," "aprotinin," "cardiac surgery," and "randomized." In addition to inspecting bibliographies of published review articles, we performed a bibliographic citation search using the SCI-EXPANDED database of the Web-based Institute for Scientific Information Citation Database. The search spanned the time interval between 1985 and 1998. Only English-language published articles were evaluated.

Trials included in this meta-analysis were selected for the following characteristics: (1) random allocation to drug treatment (high-dose aprotinin, low-dose aprotinin, and/or {epsilon}-aminocaproic acid) or placebo/control groups; (2) based exclusively on patients undergoing routine cardiac procedures (ie, primary or repeat CABG, valve replacement or repair, or both); and (3) explicit evaluation of >=1 of the following outcomes: total blood loss, amounts and/or rates of transfusion, reexploration, postoperative stroke, myocardial infarction, renal impairment, allergic hypersensitivity reactions, and mortality.

Outcomes Extraction
Outcomes data were extracted from each trial and entered into a computer file for analysis. Only published data were included. Data presented ambiguously in 4 studies were clarified by direct discussion with the primary authors.3 9 10 11

We evaluated blood loss by assessing total (intraoperative and postoperative) amounts in milliliters. To examine transfusion requirements, we considered only homologous packed red blood cell (pRBC) transfusions. Few trials provided sufficient information to allow us to examine use of autologous blood, platelets, cryoprecipitate, and plasma. For each trial, we abstracted the total number of pRBC units transfused in treatment and control groups and the proportion of patients transfused in each group. Transfusion requirements recorded in milliliters were transformed to pRBC units by a conversion factor of 350 mL/U. All instances of reexploration in the trials were included, regardless of the specified indication for surgery (eg, cardiac tamponade versus chest tube bleeding versus other) or the operative findings (eg, surgical versus nonsurgical bleeding). Stroke, myocardial infarction, renal impairment, and allergic reaction were categorized as defined by the individual trials.

Statistical and Stratified Analyses
To calculate intervention effects on bleeding and transfusion requirements, the mean and SDs of blood loss and pRBC units transfused were recorded for treatment and placebo/control groups in each trial. Using the methods described by Cochrane, we then calculated summary measures of absolute (mL and U) and relative (%) reductions in mean total blood loss and pRBC transfusions in patients receiving the active drug.12 For dichotomous outcomes (transfusion, reexploration, postoperative myocardial infarction, stroke, renal impairment, allergic reactions, and mortality), the total number of patient outcomes in the drug and placebo groups was recorded in 2x2 tables. We added 0.5 to every cell in any table containing 0 to improve bias and precision properties.13 The summary measure of effect used for the dichotomous outcomes was the Peto OR described by Yusuf et al.14 To account for variance between studies, random-effects models were used for continuous and dichotomous summary estimates of effect.15

Stratified analysis was performed to assess whether treatment effects varied according to whether or not trials were restricted to primary CABG or included patients undergoing "mixed" procedures (including CABG, valve, reoperation, and other cardiac procedures). We also performed stratified analysis according to specific study-design criteria, such as whether trials were placebo controlled or double-blinded.


*    Results
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Study Selection
Of the 52 trials that met our inclusion criteria (AppendixDownDownDownDown), most involved either high-dose (37 trials) or low-dose (17 trials) aprotinin, whereas only 9 considered {epsilon}-aminocaproic acid. Overall, 71% were double-blind, 71% were placebo-controlled, and 8% were multicenter studies.


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  		Table 2. Appendix Randomized Clinical Trials Included in Meta-Analysis


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  		Table 2A. Continued


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  		Table 2B. Continued


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  		Table 2C. Continued

Hemorrhage-Related Outcomes
Compared with their placebo/control counterparts, patients receiving antifibrinolytic therapy had substantially lower total blood loss (Figure 1ADown). {epsilon}-Aminocaproic acid and low-dose aprotinin each reduced total blood loss by 35% (P<0.001), whereas high-dose aprotinin reduced blood loss by 53% (P<0.001).



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  		Figure 1. Meta-analysis comparison of the amount of total blood loss (A) and pRBCs transfused (B) between treatment groups (error bars represent positive SDs).

{epsilon}-Aminocaproic acid was as effective in reducing transfusion requirements after cardiac surgery as aprotinin. Compared with their placebo counterparts, patients given {epsilon}-aminocaproic acid received 61% fewer pRBC transfusions (mean reduction, 0.74 U; Figure 1BUp). Patients receiving {epsilon}-aminocaproic acid were only 32% as likely to receive any pRBC transfusions (OR, 0.32; 95% CI, 0.15 to 0.69; P=0.004). These reductions in transfusion requirements were nearly identical to those observed with the high-dose aprotinin groups (the TableDown and Figure 2Down).


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  		Table 1. Postoperative Outcome Comparisons of Crude Event Rates



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  		Figure 2. Meta-analysis results evaluating ORs and 95% CIs for high-dose aprotinin, low-dose aprotinin, and {epsilon}-aminocaproic acid with respect to the given outcome variables.

Patients receiving prophylactic antifibrinolytic therapy also were less likely to undergo reexploration for bleeding after cardiac surgery. This reduction was only statistically significant for high-dose aprotinin (OR, 0.39; 95% CI, 0.24 to 0.61; P<0.001). Because of smaller sample sizes with {epsilon}-aminocaproic acid and low-dose aprotinin, effects of approximately similar magnitude did not reach statistical significance (OR, 0.54; 95% CI, 0.22 to 1.33; P=0.179; and OR, 0.56; 95% CI, 0.29 to 1.08, P=0.085, respectively; Figure 2Up).

Other Outcomes
Although there were consistent trends toward reduced stroke rates in patients receiving antifibrinolytics, these trends did not reach statistical significance ({epsilon}-aminocaproic acid: OR, 0.47; 95% CI, 0.15 to 1.56; P=0.22, high-dose aprotinin: OR, 0.56; 95% CI, 0.26 to 1.21; P=0.14; and low-dose aprotinin: OR, 0.54; 95% CI, 0.20 to 1.45; P=0.22; Figure 2Up). Prophylactic use of {epsilon}-aminocaproic acid or high- or low-dose aprotinin was not associated with significant differences in the incidence of postoperative myocardial infarction or overall mortality (the TableUp and Figure 2Up). There were insufficient data to evaluate the effect of {epsilon}-aminocaproic acid on risks of renal impairment and allergic reactions. Although information pertaining to these outcomes was also limited in the aprotinin trials, there was a statistically insignificant trend toward increased rates of renal dysfunction with high-dose aprotinin (OR, 1.46; 95% CI, 0.92 to 2.33; P=0.11) but not low-dose aprotinin (OR, 1.01; 95% CI, 0.65 to 1.57; P=0.96). High-dose aprotinin was associated with a similar, insignificant trend toward increased risk of allergic reactions (OR, 1.58; 95% CI, 0.59 to 4.23; P=0.36).

Stratified Analysis
Stratified analysis did not reveal important interactions between drug effectiveness and characteristics of the trials. Estimates of the effectiveness of high- and low-dose aprotinin and {epsilon}-aminocaproic acid in reducing transfusion requirements were similar when analysis was stratified according to whether studies were placebo-controlled or double-blind (data not shown). Furthermore, drug effectiveness in reducing transfusions was similar between trials restricted to primary CABG and those enrolling patients undergoing "mixed" procedures. Stratified analysis of less frequent outcomes, including reexploration, could not be performed (meaningfully) because of sample-size limitations.


*    Discussion
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 *Discussion
down arrowReferences
 
There remains little doubt that prophylactic use of antifibrinolytic therapy reduces postoperative hemorrhage in patients undergoing cardiac surgery. The proprietary drug aprotinin, the subject of 43 randomized clinical trials to date, has been most extensively studied. As in 2 previous meta-analyses, our study demonstrates that aprotinin substantially reduces the need for transfusions and reexploration after cardiac surgery.2 6 However, sufficient data to evaluate the considerably less-expensive antifibrinolytic {epsilon}-aminocaproic acid have only recently become available. When we incorporated several new trials involving this drug, our meta-analysis suggested that {epsilon}-aminocaproic acid had similar effectiveness in reducing hemorrhage after cardiac surgery.

Although our meta-analysis examined the relative effects of {epsilon}-aminocaproic acid and aprotinin against placebo, 3 randomized clinical trials have compared the 2 drugs directly. Trials conducted by Penta de Peppo et al7 and Menichetti et al8 compared {epsilon}-aminocaproic acid to high-dose aprotinin and determined the latter to be more effective in reducing postoperative blood loss. However, differences in postoperative transfusion requirements were not identified. In a larger, more recent trial,9 patients receiving {epsilon}-aminocaproic acid or low-dose aprotinin had lower transfusion rates than patients in the control group. However, no statistically or clinically significant differences were noted between the 2 drug groups.

{epsilon}-Aminocaproic acid and aprotinin were associated with trends toward large reductions in risk of postoperative stroke. However, unlike the findings of several aprotinin studies,3 16 associations between antifibrinolytic use and reduced stroke incidence were statistically insignificant in our analysis. Although the relationship remains unproven, some authors hypothesize that the kallikrein-inhibiting properties of aprotinin may reduce cerebral vasospasm.17 The biological explanation for the potential cerebrovascular protective effects of {epsilon}-aminocaproic acid is still unclear.

There remains little evidence that antifibrinolytic therapy increases the risk of thrombosis-related complications with cardiac surgery. In our analysis, neither {epsilon}-aminocaproic acid nor aprotinin was associated with appreciable differences in risk of myocardial infarction. Two randomized controlled trials showed slightly higher rates of coronary bypass graft closure with aprotinin; however, these findings were not statistically significant.18 19 Another randomized controlled trial conducted by Havel et al20 revealed no differences in bypass graft patency rates among patients receiving high-dose aprotinin, low-dose aprotinin, or placebo. To the best of our knowledge, the association between {epsilon}-aminocaproic acid and bypass graft patency has not been studied.

Limitations
Several potential limitations should be considered in assessing the validity of our findings. First, it is impossible to rule out publication bias. Studies showing large benefits with drug intervention may be more likely to be published than studies showing little or no benefit. Second, despite the large number of trials, the meta-analysis lacked sufficient statistical power to detect clinically important effects of treatment on relatively infrequent outcomes. For example, large apparent reductions in reexploration risk with {epsilon}-aminocaproic acid (OR, 0.54) and in stroke rates with both antifibrinolytic agents (OR, 0.47 to 0.56) were not statistically significant. For similar reasons, we cannot exclude clinically meaningful effects of {epsilon}-aminocaproic acid or aprotinin on risks of myocardial infarction and mortality.

Third, drug dosing and administration protocols varied across trials. Although all but 1 of the high-dose aprotinin trials were consistent in using the standard dose (6 million KIU),21 the low-dose aprotinin studies used dosing protocols ranging from 1 to 3 million KIU. Similarly, trials involving {epsilon}-aminocaproic acid used doses ranging from 7 to 30 g. Whether the effectiveness of these agents is dose related remains unanswered.

Finally, variable outcome definitions across trials may have limited our analysis in several ways. Renal toxicity remains among the major concerns with antifibrinolytic therapy, despite the inconclusive evidence supporting this relationship.22 23 Because trials used variable creatinine levels to define renal impairment, our ability to examine this potential adverse effect of aprotinin and {epsilon}-aminocaproic acid was severely limited. Other outcomes are also subject to misclassification. Stroke and myocardial infarction are both discretionary clinical diagnoses, and transfusion and reexploration frequently reflect discretionary treatment decisions. In double-blind trials (when surgeon is unaware of treatment allocation), random outcomes misclassification in drug and control groups would be expected to bias studies toward the null hypothesis (no drug effect). In nonblinded trials, however, outcomes misclassification could bias results toward larger drug effects. Despite these potential problems, the main effects of aprotinin and {epsilon}-aminocaproic acid were essentially unchanged in stratified analysis of blinded and nonblinded trials.

Conclusions
Aprotinin and {epsilon}-aminocaproic acid substantially reduce hemorrhage in patients undergoing cardiac surgery, without appreciable adverse effects. For these reasons, prophylactic antifibrinolytic therapy should be considered for routine use. Because the 2 drugs appear to have similar efficacies, the considerably less-expensive {epsilon}-aminocaproic acid may be preferred over aprotinin.


*    Footnotes
 
The views expressed herein do not necessarily represent those of the Department of Veterans Affairs or the United States government.

Address correspondence to Dr John J. Munoz, VA Outcomes Group (111B), Department of Veterans Affairs Hospital, White River Junction, VT 05009.

Received May 28, 1998; revision received September 2, 1998; accepted September 17, 1998.


*    References
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 *References
 

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