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Ann Thorac Surg 1999;67:1283-1287
© 1999 The Society of Thoracic Surgeons

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Original Articles

-aminocaproic acid administration and stroke following coronary artery bypass graft surgery

^a Department of Anesthesiology, The Mount Sinai Medical Center, New York, New York, USA
^b Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina USA
^c Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina USA
^d Department of Neurology, Duke University Medical Center, Durham, North Carolina USA
^e Department of Surgery, Duke University Medical Center, Durham, North Carolina USA

Accepted for publication October 27, 1998.

Address reprint requests to Dr Bennett-Guerrero, Department of Anesthesiology, Mount Sinai Medical Center, Box 1010, One Gustave L. Levy Place, New York, NY, 10029-6574;
e-mail: elliott_guerrero{at}smtplink.mssm.edu

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. -aminocaproic acid is routinely used to reduce bleeding during cardiac surgery. Anecdotal reports of thrombotic complications have led to speculation regarding this drug’s safety. We investigated the association between -aminocaproic acid administration and postoperative stroke.

Methods. Six thousand two hundred ninety-eight patients undergoing isolated coronary artery bypass graft surgery between 1989 and 1995 were studied. Data was obtained from the Duke Cardiovascular Database as well as from an automated intraoperative anesthesia record keeper. Patients identified as having postoperative stroke were reviewed and confirmed by a board certified neurologist blinded to -aminocaproic acid administration.

Results. Postoperative stroke occurred in 97 patients (1.5%). Three thousand one hundred thirty-five (49.8%) patients received -aminocaproic acid. Increased age was associated with a higher incidence of postoperative stroke (p = 0.0001). In contrast, there was no significant difference (p = 0.7370) in the incidence of stroke between use of -aminocaproic acid (1.3%) and nonuse (1.7%). Multivariable logistic regression found no significant effect of -aminocaproic acid use on stroke after accounting for age, date of surgery, and history of diabetes.

Conclusions. This series suggests that -aminocaproic acid administration does not increase the risk of postoperative stroke.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
More than 500,000 cardiac operations are performed in the United States annually. Bleeding is a common complication of these procedures and results in increased operative time and blood transfusion requirements with its attendant risk and cost. Although the etiology of bleeding is multifactorial, fibrinolysis is thought to play an important role. -aminocaproic acid, a synthetic lysine analogue, is a competitive inhibitor of plasminogen and plasmin [1] and has been shown to reduce bleeding associated with cardiac surgery [2].

Despite this drug’s proved efficacy, some clinicians have refrained from administering -aminocaproic acid based on concerns that the drug may cause a prothrombotic state and lead to thrombus induced complications such as stroke [3–5]. A reluctance to use this agent may also stem from anecdotal reports of thrombotic complications following -aminocaproic acid administration [6–13], reports of accelerated thrombus formation on pulmonary artery catheters [14], and a recent study demonstrating that reduced fibrinolysis and bleeding were not associated with reduced thrombin formation indicating the potential for a prothrombotic state postoperatively [15].

Previous controlled trials with synthetic antifibrinolytic agents in cardiac surgical patients observed no increase in the incidence of postoperative stroke [2]. These studies, however, lacked adequate power to detect a small difference in the incidence of major neurologic complications. We therefore tested the association between -aminocaproic acid administration and postoperative neurologic complications in a large series of patients undergoing coronary artery bypass graft surgery.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
The Duke Cardiovascular Database has supported the prospective entry of clinical coronary angiography and outcomes data since 1971. Outcome data were obtained for determination of clinical efficacy and quality assurance in all patients undergoing coronary artery bypass grafting.

In addition to the well-defined Duke Cardiovascular Database, since 1988 an automated anesthesia record keeper (Synergy, San Diego, CA) has been used at the Duke Heart Center during all cardiac surgical procedures. Data from this automated intraoperative anesthesia record keeper was downloaded to an anesthesia information network.

Database patient selection
With Institutional Review Board approval, patients undergoing isolated coronary artery bypass graft surgery at the Duke Heart Center between 1989 and 1995 were identified in the cardiovascular databases. To maximize the homogeneity of the population, patients undergoing concomitant procedures (such as valvular heart surgery, carotid endarterectomy, aortic surgery, etc) were excluded from analysis. Patients undergoing isolated valve surgery were excluded from the study. Patients who received aprotinin were also excluded from the study.

-aminocaproic acid administration
A query of the Duke Anesthesia Information Network database identified patients that had received -aminocaproic acid intraoperatively. Administration of -aminocaproic acid was considered to be a categorical variable with patients receiving doses from 5 to 20 grams by bolus or infusion.

Determination of outcome
Patients identified as having major postoperative neurologic complications (stroke, transient ischemic attack (TIA), or coma) were identified from the Duke Cardiovascular Database. The initial determination of these outcomes was by the surgical team at the time of the patient’s discharge and entered into the database at that time. Verification of this outcome was performed retrospectively using confirmatory ICD-9 discharge codes followed by individual review of chart information and CT scan by a board certified neurologist for all patients identified with a perioperative neurologic event.

Operative management
The intraoperative management of patients undergoing cardiac surgery did not change significantly during the study interval. Typical management included oral methadone and benzodiazepine premedication, with intravenous catheter, radial arterial, and pulmonary arterial catheters inserted. Induction of anesthesia was accomplished in a majority of cases with combinations of midazolam hydrochloride and fentanyl citrate supplemented with isoflurane. Pancuronium or vecuronium was used for muscle relaxation. All patients underwent standard nonpulsatile hypothermic (28°–34°C) cardiopulmonary bypass with a membrane oxygenator and hemodilution. Porcine heparin was administered as a bolus of 300 units/kg and supplemented as necessary to maintain a celite activated coagulation time of > 450 seconds during cardiopulmonary bypass. Alpha-stat blood gas management was used at all times. A bladder or rectal temperature of >35° C was required prior to separation from cardiopulmonary bypass. Heparin was neutralized with 1 mg protamine/100 units heparin. Following cardiopulmonary bypass, crystalloid and colloid solutions were administered to optimize intravascular volume, temperature was maintained >35° C by convective warming, and systolic and mean systemic arterial blood pressures were maintained as per institutional and individual patients’ requirements using vasoactive agents as necessary.

Selection of predictor variables
To control for previously identified predictors of perioperative stroke, we selected age and diabetes as important predictors of perioperative stroke to be used as covariates in a multivariate analysis. In previous studies age accounted for >45% of the determined risk variation in the model [16]. Because of the substantial variations in -aminocaproic acid usage over the study period (Fig 1 ), date of surgery was also added as a covariate in the multivariate analysis to help control for historical variation in -aminocaproic acid use. Possible variation in surgical or anesthesia practice, including administration of -aminocaproic acid, was also tested.

View larger version (30K): [in this window] [in a new window]   Fig 1. Percentage of patients undergoing coronary artery bypass graft surgery with new postoperative stroke or coma and percentage of patients receiving -aminocaproic acid (EACA) over a 6.5 year period. Each data point represents a 6 month period. Total number of patients was 6298.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
A total of 6,298 patients satisfied study enrollment criteria. These cases were evenly distributed over the time course of the study. The number of cases per calendar year quarter ranged from 170 (2.7%) to 298 (4.8%) with no significant deviation. Age ranged from 22 to 93, with 25th percentile, median, and 75th percentile of 56, 65, and 71 respectively, and mean (standard deviation) of 63.5 (10.3). Age was very uniformly distributed over the study period and there was no significant change in age over time (p = 0.1528). Demographic information is provided in Table 1.

Overall, a major neurologic complication occurred in 97 patients (1.5%). Increased age was associated with a higher incidence of postoperative stroke or coma (p = 0.0001, odds ratio 2.015, 95% confidence limits 1.594 to 2.576 per 10 year increase). No significant difference in occurrence of stroke or coma was found between cases in which -aminocaproic acid was used (1.3%, n = 42 of 3135) versus cases in which it was not used (1.7%, n = 55 of 3163). This result was seen in the raw, unadjusted analysis (p = 0.1996, OR = 0.767 favoring -aminocaproic acid group), as well as in a multivariate logistic regression adjusting for age and diabetes but not date of surgery (-aminocaproic acid p = 0.1280, OR = 0.729). After accounting for date of surgery, the final analysis again found no association of -aminocaproic acid and stroke or coma (drug effect p = 0.7370, OR = 1.11; overall model ² = 44.5, degrees of freedom = 4, p = 0.0001, c-index = 0.69). Assessment of surgeon and anesthesiologist as predictor variables demonstrated no association of either factor with stroke or coma, and neither changed the results of the overall model.

Date of surgery warranted special concern because of its close association with -aminocaproic acid use. In the unadjusted univariate analysis, a significant but weak association of surgery date with stroke was seen (p = 0.0422, OR = 0.895 per year, c-index = 0.56). In the final multivariate model described above, date of surgery was nonsignificant (p = 0.0722, OR = 0.859 per year) but was kept in the model because of the importance of accounting for it. The date by -aminocaproic acid interaction was also nonsignificant. As noted above, the -aminocaproic acid effect was tested with and without adjusting for surgery date, with the same conclusion reached with either analysis.

Power
This study observed a 0.4% difference in neurologic complications between the two study groups, with a lower incidence of stroke or coma in the patients who received -aminocaproic acid. The sample size of 6,258 gave us 80% power to detect a two-tailed difference between groups as small as 1%, that is, between a complication rate of 2.5% versus 1.5%. A sample size of nearly 30,000 would have been required to give 80% power to determine significance in a difference as small as the 0.4% observed, and even then the difference would have been in favor of the patients who received -aminocaproic acid.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Our study observed no association between -aminocaproic acid administration and risk of major neurologic complications following coronary artery bypass graft surgery. Our results are consistent with numerous clinical trials in which the use of synthetic antifibrinolytic agents was not associated with an increase in the incidence of postoperative stroke [2]. These studies, however, were designed to evaluate the efficacy of these agents and did not have adequate power to detect a small difference in rare neurologic complications.

-aminocaproic acid has been shown to reduce bleeding associated with cardiac surgery [2]. Despite this efficacy, some clinicians have refrained from administering -aminocaproic acid based on concerns that the drug may increase the incidence of serious thrombotic complications, including stroke [3–13]. Cerebral thrombosis occurred in patients who received -aminocaproic acid for several days as therapy for subarachnoid hemorrhage [9, 12, 13]. Thrombotic complications have also developed in patients who received -aminocaproic acid for the treatment of disseminated intravascular coagulation and upper urinary tract bleeding [6–8, 11]. These cases are unrelated to the setting of cardiac surgery in which -aminocaproic acid is administered for a short period of time to prevent fibrinolysis during cardiopulmonary bypass. However, recent studies have demonstrated that, despite efficacy in reducing postoperative bleeding, thrombin formation was not altered, producing the potential for a postoperative prothrombotic effect with -aminocaproic acid [15]. This has led to continued concern over its safety, but we were not able to demonstrate any association between -aminocaproic acid use and perioperative neurologic complications.

There are several limitations to this study. Although the incidence of stroke in our study is consistent with incidences reported in several large series of patients undergoing cardiac surgery (1.2%–3.1%) [17–19], neurologic outcomes were determined at the time of discharge by the patient’s care team and confirmed retrospectively by a board certified neurologist. Prospective assessment with preoperative and postoperative testing would have increased the incidence of neurologic events detected. In this study, it is extremely unlikely that any nonstrokes were classified as strokes (no false positives). However, as discussed, it is possible that some strokes occurred undiagnosed, resulting in misclassification (false negatives). A sensitivity analysis reveals how much error there could be in the data before a different conclusion would be warranted. First of all, there is no reason to think there would be any association between -aminocaproic acid use and failure to diagnose stroke; the missed strokes would, in all likelihood, be proportionally distributed randomly between the -aminocaproic acid and non--aminocaproic acid groups, especially in as large a group as this. In that case, there would clearly still be no difference between groups in incidence of stroke. Even in the worst possible case, if every undiagnosed stroke occurred in the -aminocaproic acid treatment group, there would have to have been 36 missed strokes, all in the -aminocaproic acid group, to conclude that the proportion of strokes in the -aminocaproic acid patients is larger than in non--aminocaproic acid patients.

In another scenario, if the true overall stroke rate was 3%, and the undiagnosed strokes were distributed unevenly between 2 groups, the difference in stroke rate between groups would remain not significant unless more than 2.4 times as many strokes were undiagnosed in the -aminocaproic acid group than in the other group. Finally, if the overall stroke rate was 5%, more than 1.5 times as many strokes would have to be undiagnosed in the -aminocaproic acid group than in the non--aminocaproic acid group before the proportion of strokes in the 2 groups would become significantly different.

Another limitation relates to the fact that the percentage of patients receiving -aminocaproic acid increased during the study period. The control group in our study therefore represents, in large part, a historical control group as demonstrated in Figure 1. To control for the influence of the date of surgery on neurologic outcome, we included date of surgery as a variable in our multivariable analysis. Age represents the major stratifying factor in any analysis, because >45% of the variability in stroke rate is associated with increasing age [16]. In the patients whose preoperative stroke risk index data was available from 1989 to 1995, we identified a significant increase in the stroke risk over time. Therefore, based on risk, if any bias in this study is present, it is toward an increase in stroke rate over time.

Another limitation of this study is that all known perioperative risk factors for stroke were not included in the analysis. We placed priority on obtaining as large a sample size as possible to optimize the power of the study for a relatively rare event such as stroke. This resulted in a limitation of risk factors assessed given the lack of reliable data for some of these factors early on in the data set. We believe in the validity of our results because we included age as a covariate, and as mentioned above, age accounts for the majority of variability in a previously published stroke risk index [16].

This analysis was designed to address the issue of major neurologic complications after cardiac surgery as related to use of -aminocaproic acid. -aminocaproic acid has come under scrutiny due to the fact that it produces antifibrinolytic activity, and yet at the same time does not alter thrombin formation [15]. This could, theoretically, lead to a prothrombotic state. Our large series is of importance due to the lack of large FDA safety trials examining an association between -aminocaproic acid and adverse neurologic complications. However, this study was not designed to test the association between -aminocaproic acid administration and the incidences of other thrombotic complications such as myocardial infarction, renal failure, deep venous thrombosis or pulmonary embolus. To date, no clinical trial has proved that any of these postoperative complications are or are not related to the administration of the synthetic antifibrinolytic agents -aminocaproic acid or tranexamic acid.

Postoperative stroke and coma are devastating complications that have a high mortality rate and result in increased suffering and use of health care resources [17]. It has been estimated that major neurologic complications following cardiac surgery result in health care expenditures of 2 billion to 4 billion dollars annually [17]. A significant number of these complications occur several days after surgery that has led to speculation over mechanism of injury [20]. Our results indicate no association between the use of -aminocaproic acid and postoperative stroke. Further studies are warranted to determine if -aminocaproic acid administration increases the incidence of other types of thrombotic complications.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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