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Ann Thorac Surg 2003;75:479-483
© 2003 The Society of Thoracic Surgeons

Original article: cardiovascular

Stroke after cardiac surgery: a retrospective analysis of the effect of aprotinin dosing regimens

Robert J. Frumento, MS, MPHa*, Catherine M.N. O’Malley, FFARCSIa, Elliott Bennett-Guerrero, MDa

a Department of Anesthesiology, Columbia University College of Physicians and Surgeons, New York, New York, USA

Accepted for publication September 15, 2002.

* Address reprint requests to Dr Frumento, Columbia University College of Physicians and Surgeons, Department of Anesthesiology (PH5-505), 630 West 168th St, New York, NY 10032-3784, USA
e-mail: rf356{at}columbia.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
BACKGROUND: Half-dose aprotinin (HDA) appears to be equivalent to full-dose aprotinin (FDA) in its ability to prevent bleeding. However, data regarding the potential effect of aprotinin use and dosage on other outcomes such as the occurrence of perioperative stroke are limited. It has been postulated that the higher level of kallikrein inhibition obtained with FDA dosing may be required for end-organ protection. Therefore, we performed a retrospective study in cardiac surgery patients at high risk for developing stroke to determine the relative effects of FDA and HDA regimens on the incidence of postoperative stroke.

METHODS: Records of 1,524 patients undergoing cardiac surgery over a 15-month period were reviewed. Patients at high risk for stroke were selected if they met all of the following predefined criteria: age greater than 70 years, history of hypertension, history of diabetes mellitus, history of stroke or transient ischemic attack, and presence of aortic atheroma. A validated preoperative stroke risk index was calculated for each patient. Postoperative stroke required confirmation by computed tomography or magnetic resonance imaging. Patients were divided into three groups according to whether they were administered no aprotinin, HAD, or FDA.

RESULTS: A total of 149 patients fulfilled the criteria for being at high risk for stroke. Stroke risk index was very similar (p = 0.56) in the three groups: those who received no aprotinin and served as a control group (124 ± 15, n = 56), those who were given HDA (123 ± 12, n = 67), and those who received FDA (122 ± 11 n = 26). Preoperative and intraoperative characteristics were also similar between the three study groups. Overall, the incidence of stroke was 16% (24/149). The incidence of stroke differed (p < 0.05) among the three groups: no aprotinin 16% (9/56), HDA 22% (15/67), and FDA 0% (0/26).

CONCLUSIONS: In this retrospective study of cardiac surgery patients at high risk for postoperative stroke, the administration of FDA but not HDA was associated with a lower incidence of stroke.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Stroke is a devastating complication of cardiac surgery, and no effective preventive strategies have been established [1]. Recent attention has focused on the identification of a subgroup of cardiac surgery patients who are most likely to develop postoperative stroke. An observational study of 273 cardiac surgery patients at high risk for cerebral injury revealed a postoperative stroke rate of 8.4% [2]. In this series, patients with stroke were four times more likely to die during hospitalization and 15 times more likely to be discharged to a chronic care facility than were patients without postoperative stroke.

Aprotinin, a serine protease inhibitor, has both antifibrinolytic and platelet preserving activity [3, 4] and reduces blood loss and transfusion requirements in cardiac surgery patients. It has been shown that half-dose aprotinin (HDA) is equivalent to full-dose aprotinin (FDA) with regard to bleeding outcomes [5]. A retrospec-tive analysis of the aprotinin clinical study database showed that patients who received aprotinin had fewer postoperative strokes than did patients who received placebo [6]. Although not specifically designed to assess aprotinin and stroke risk, a prospective study in patients undergoing repeat coronary artery bypass graft surgery reported that administration of FDA was associated with a decreased incidence of stroke [7]. This putative neuroprotective effect of aprotinin, however, has not been evaluated in cardiac surgery patients who are at increased risk for stroke. It has been postulated that the level of protease inhibition needed to affect stroke incidence may not be achieved by the half-dose regimen in these patients [8].

Therefore, we carried out a retrospective study in cardiac surgery patients at high risk for developing stroke to determine whether the intraoperative administration of aprotinin altered the incidence of postoperative stroke and, in particular, to determine whether there was any difference in stroke incidence between patients who received HDA and FDA.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Study population
Approval was obtained from the hospital institutional review board. A systematic review of the medical records of 1,524 patients who underwent cardiac surgery between December 1999 and March 2001 at a major United States tertiary care medical center was performed. We selected patients at high risk for stroke, defined as the patient meeting all of the following five criteria: presence of aortic atheroma on transesophageal echocardiography; history of hypertension; history of diabetes mellitus; age greater than 70 years; and history of stroke or transient ischemic attack. As indicated in Figure 1, only patients who were undergoing surgery with cardiopulmonary bypass (CPB) were included.



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  		Fig 1. Schematic summary of study patient inclusion process.

 
Patients were divided into three groups according to whether they received no aprotinin (control group), FDA, or HDA. The FDA group received a loading dose of 280 mg before initiation of CPB and 280 mg in the CPB prime, followed by an intravenous infusion at 70 mg/h. The HDA group received a loading dose of 140 mg before initiation of CPB and 140 mg in the CPB prime, followed by an intravenous infusion at 35 mg/h. In all patients, the intravenous infusions of aprotinin were commenced at the start of CPB and were discontinued at the end of surgery immediately before transfer from the operating room to the intensive care unit. At our center, the administration of HDA or FDA is not governed by protocol and the choice of aprotinin dose is determined by physician preference.

Definition of postoperative stroke
Postoperative stroke was defined as a new cerebral infarct confirmed by computed tomography or magnetic resonance imaging. Our study was not designed to investigate the impact of aprotinin dosing on cognitive decline or strokes that could not be confirmed by imaging.

Preoperative stroke risk index
The preoperative risk of stroke was calculated for each patient using the validated Multi-Center Study of Perioperative Ischemia (McSPI) preoperative stroke risk index [9]. The stroke risk index is determined by first assigning points for the presence of a number of clinical predictors. The number of points received is then plotted against a risk score on a nomogram for computing the risk of stroke.

Statistical analysis
The primary outcome variable was postoperative stroke, defined as a new cerebral infarct confirmed by computed tomography or magnetic resonance imaging. The proportion of patients with postoperative stroke in each of the three groups was compared using contingency tables. Differences in the preoperative and demographic factors, intraoperative characteristics, surgical procedure performed, and stroke risk index among the three groups were tested using contingency tables for categorical endpoints and analysis of variance, followed by unpaired t tests when appropriate for continuous endpoints. Differences were considered significant at a probability level of p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Of 1,524 patients screened, 149 met all of the predefined criteria for increased risk of stroke (Fig 1). Of these patients, 93 received aprotinin and 56 did not. Full-dose aprotinin was administered to 26 of 93 patients (28%), whereas 67 of 93 (72%) received the half-dose (HDA) regimen. There were no differences among the three groups with regard to patient demographics, perioperative risk factors, or procedures performed (Tables 1 and 2).


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  		Table 2. Perioperative Patient Characteristics

 

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  		Table 1. Patient Preoperative Demographics

 
Preoperative stroke risk index values (mean ± SD) were very similar in the control (124 ± 15), HDA (123 ± 12), and FDA (122 ± 11) groups (Fig 2). The overall incidence of stroke was 16% (24/149). The incidence of stroke was 16% (15/93) in patients who received aprotinin and 16% (9/56) in the control group (p = 0.6). The incidence of postoperative stroke in patients administered FDA was 0% (0/26) compared with 22% (15/67) in patients administered HDA. The incidence of stroke in the FDA group was significantly less than the incidence of stroke in the control or HDA groups (p = 0.03, 95% CI 0% to 11.5%).



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  		Fig 2. Stroke risk index in patients receiving no aprotinin (Control group), full-dose aprotinin, and half-dose aprotinin.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
In this retrospective study, we demonstrated that the intraoperative administration of FDA to cardiac surgery patients at high risk for perioperative stroke was associated with a reduced incidence of stroke. We chose to study patients who were at high risk for postoperative stroke, as they may be more likely to benefit from any potential neuroprotective effect that aprotinin might offer. Certain characteristics have been shown in various studies to be independent risk factors for the occurrence of stroke after cardiac surgery. These include presence of proximal aortic arteriosclerosis [1, 10], history of hypertension [1, 11, 12], history of diabetes mellitus [1, 9, 11, 12], age greater than 70 years [1, 2, 9, 11, 12], and history of stroke or transient ischemic attack [1, 9, 11, 12]. We identified patients at high risk for stroke by the presence of these characteristics and compared the stroke risk index between study groups. The stroke risk indices (mean ± SD) in the FDA group (122 ± 11), HDA (123 ± 12), and control groups (124 ± 15) were extremely similar. The overall incidence of stroke in this population was 16% (24/149), confirming that the application of our criteria selected patients who were at higher risk for this complication.

Previous studies in cardiac surgery patients have shown that FDA and HDA have similar beneficial effects on bleeding outcomes [5]. However, there is evidence to suggest that FDA may be superior to HDA in terms of outcomes other than bleeding. For example, Levy and colleagues [7] demonstrated a trend toward lower mortality and myocardial infarction rates in patients who received FDA compared with patients treated with HDA. It has been suggested, therefore, that the full-dose regimen is superior to the half-dose regimen in terms of both safety and efficacy [8]. In our study, patients at high risk for stroke who received FDA during cardiac surgery had a lower incidence of postoperative stroke than did patients who received no aprotinin or patients who were treated with the half-dose regimen. These results are consistent with the findings of an analysis of pooled data from studies of aprotinin administration to cardiac surgery patients [8]. These data demonstrated a significant reduction in the incidence of stroke in FDA-treated patients compared with placebo-treated patients.

The mechanism by which aprotinin may exert its neuroprotective effect is not known. It has been suggested that aprotinin may be neuroprotective by means of antiinflammatory effects. Inflammatory cells and mediators are important contributing and confounding factors in ischemic brain injury [13]. Consistent with our results, recent reports have shown no difference in inflammatory cytokine production in CPB patients administered HDA or placebo [14, 15], whereas other studies have shown a significant reduction of these markers in patients administered high-dose aprotinin [16]. In addition, thrombin mediated activation of central nervous system protease-activated receptors (PAR) may contribute to brain injury associated with stroke [17]. Aprotinin inhibits thrombin-mediated PAR activation [18, 19], and experimental evidence suggests that inhibition of thrombin attenuates neurodegeneration after an ischemic insult [20]. Finally, inhibition of platelet PAR receptors by aprotinin inhibits thrombin-induced platelet activation, which implies that aprotinin may have significant antithrombotic effects [18, 19]. Therefore, aprotinin may prevent or decrease the severity of stroke by its effects as an antiinflammatory agent and by its inhibition of PAR

Our study is limited by its retrospective nature. An unavoidable limitation of any retrospective study is the lack of patient randomization. Operations were carried out by four attending cardiac surgeons. Therefore, it is theoretically possible that clinician bias may have favored one dose regimen over the other, and that differences in surgical technique may have influenced the incidence of postoperative stroke. It is extremely reassuring, however, that patient demographics (Table 1) and perioperative characteristics (Table 2) were remarkably similar in the three study groups. Importantly, the validated stroke risk index values were extremely similar in the three study groups. Indeed, it seems more likely that if any bias were to have occurred, it would have led to higher-risk patients receiving FDA and to more strokes in that group, which did not happen.

For the purposes of this study, we included patients who exhibited gross neurologic deficits that were confirmed as thrombotic strokes by an imaging study. The intensive care unit team examined all patients in this study, and some minor strokes may have been missed. Using this definition, we observed an incidence of stroke of 16%. Aprotinin may have different effects on stroke versus cognitive decline. It is possible that FDA may not have eliminated or prevented strokes but fairly significantly minimized the magnitude of injury, making them less likely to be diagnosed using our criteria. This potential criticism of our study, although theoretically possible, would not invalidate the clinical relevance of our findings, because even a reduction in the severity of the injury would have a major effect on patient outcomes. Our study was not designed to investigate the impact of aprotinin dosing on more subtle forms of neurologic dysfunction such as cognitive decline.

In summary, in this retrospective study of cardiac surgery patients at high risk for postoperative stroke, administration of full-dose but not HDA was associated with a lower incidence of stroke. As there does not appear to be any increased risk from using FDA, apart from its higher cost, our study suggests that it may be worthwhile to administer FDA to patients who are at a high risk for stroke. Given the devastating consequences of stroke in these patients, we hope that our findings can be reproduced in a prospective, blinded, randomized trial.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Roach G.W., Kanchuger M., Mangano C.M., et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996;335:1857-1863.[Abstract/Free Full Text]
  2. Wolman R.L., Nussmeier N.A., Aggarwal A., et al. Cerebral injury after cardiac surgery: identification of a group at extraordinary risk. Multicenter Study of Perioperative Ischemia Research Group (McSPI) and the Ischemia Research Education Foundation (IREF) Investigators. Stroke 1999;30:514-522.[Abstract/Free Full Text]
  3. Royston D. High-dose aprotinin therapy: a review of the first five years’ experience. J Cardiothorac Vasc Anesth 1992;6:76-100.[Medline]
  4. Blauhut B., Gross C., Necek S., et al. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;101:958-967.[Abstract]
  5. Speekenbrink R.G., Wildevuur C.R., Sturk A., Eijsman L. Low-dose and high-dose aprotinin improve hemostasis in coronary operations. J Thorac Cardiovasc Surg 1996;112:523-530.[Abstract/Free Full Text]
  6. Levy J.H. Hemostatic agents and their safety. J Cardiothorac Vasc Anesth 1999;13(Suppl 1):6-11.[Medline]
  7. Levy J.H., Pifarre R., Schaff H.V., et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995;92:2236-2244.[Abstract/Free Full Text]
  8. Smith P.K., Muhlbaier L.H. Aprotinin: safe and effective only with the full-dose regimen. Ann Thorac Surg 1996;62:1575-1577.[Free Full Text]
  9. Newman M.F., Wolman R., Kanchuger M., et al. Multicenter preoperative stroke risk index for patients undergoing coronary artery bypass graft surgery. Multicenter Study of Perioperative Ischemia (McSPI) Research Group. Circulation 1996;94(Suppl):II74-80.
  10. van der Linden J., Hadjinikolaou L., Bergman P., Lindblom D. Postoperative stroke in cardiac surgery is related to the location and extent of atherosclerotic disease in the ascending aorta. J Am Coll Cardiol 2001;38:131-135.[Abstract/Free Full Text]
  11. Engelman D.T., Cohn L.H., Rizzo R.J. Incidence and predictors of tias and strokes following coronary artery bypass grafting: report and collective review. Heart Surg Forum 1999;2:242-245.[Medline]
  12. Borger M.A., Ivanov J., Weisel R.D., et al. Stroke during coronary bypass surgery: principal role of cerebral macroemboli. Eur J Cardio-thorac Surg 2001;19:627-632.[Abstract/Free Full Text]
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  14. Seghaye M.C., Duchateau J., Grabitz R.G., et al. Influence of low-dose aprotinin on the inflammatory reaction due to cardiopulmonary bypass in children. Ann Thorac Surg 1996;61:1205-1211.[Abstract/Free Full Text]
  15. Ashraf S., Tian Y., Cowan D., et al. "Low-dose" aprotinin modifies hemostasis but not proinflammatory cytokine release. Ann Thorac Surg 1997;63:68-73.[Abstract/Free Full Text]
  16. Tassani P., Augustin N., Barankay A., et al. High-dose aprotinin modulates the balance between proinflammatory, and anti-inflammatory responses during coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2000;14:682-686.[Medline]
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