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Eur J Cardiothorac Surg 2006;30:300-304
© 2006 Elsevier Science NL

Predictive factors of stroke in patients undergoing coronary bypass grafting: statins are protective

Victor Aboyans*, Louis Labrousse, Philippe Lacroix, Jérôme Guilloux, Seifeddine Sekkal, Alexandre Le Guyader, Elisabeth Cornu, Marc Laskar

Department of Thoracic & Cardiovascular Surgery and Vascular Medicine, Dupuytren University Hospital, 2, Ave. Martin Luther King, 87042 Limoges, France

Received 8 September 2005; received in revised form 13 March 2006; accepted 20 March 2006.

* Corresponding author. Address: Department of Thoracic & Cardiovascular Surgery and Angiology, Dupuytren University Hospital, 2, Ave. Martin Luther King, 87042 Limoges, France. Tel.: +33 555 05 63 71; fax: +33 555 05 63 84. (Email: victor.aboyans{at}unilim.fr).


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: Despite major improvement in surgical techniques and intensive care management, stroke remains one of the most devastating complications of coronary artery bypass grafting (CABG). We aimed to determine factors predicting the occurrence of stroke during CABG. A special interest was focused on preoperative therapies. Methods: We prospectively enrolled 810 consecutive candidates for CABG alone in a specific database, including all pre- and perioperative data (history, clinical, therapeutic, cardiac catheterization, surgical and intensive care data). Univariate tests and then multiple logistic regression analysis were used to determine independent predictive factors. Results: During the first postoperative month, stroke occurred in 11 cases and transient ischemic attack (TIA) in 4 additive cases (cumulative rate: 1.85%). After the multivariate analysis, the following factors remained significant (p < 0.05) in the predictive model, with corresponding odds ratios between brackets: redo cardiac surgery (7.45), unstable cardiac status (4.74), past history of cerebrovascular disease (4.14), past history of peripheral arterial disease (3.55), whereas the presence of preoperative statins was protective (0.24, 95% IC: 0.07–0.78). The addition of perioperative data (aortic calcification, postoperative arrhythmia, on/off-pump surgery) did not change the final predictive model. Conclusion: To our knowledge, this is the first real-world observational report highlighting the interest of statins for the prevention of stroke in the very special situation of CABG. Even though according to randomized trials coronary patients have a benefit from these drugs, a special level of interest should be directed towards those presenting the above-mentioned risk factors.

Key Words: Coronary artery bypass surgery • Stroke, Cardiovascular drugs


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Despite major improvements in surgical techniques and intensive care management, stroke remains one of the most devastating complications of coronary artery bypass grafting (CABG). In a general review of 33 studies, the overall prevalence of stroke in a pooled population of 106,211 patients undergoing CABG is estimated at 2% [1]. This rate rises dramatically with the increasing age of the patients, up to 9% in octogenarians [1], with a high mortality rate and considerable psychological and economic burden. Observational studies have already reported redo surgery, unstable cardiac conditions, history of cerebrovascular disease or peripheral arterial disease, arrhythmia, left main coronary stenosis and aortic calcification and manipulation as risk factors [1–4].

However, the potential effects of preoperative drugs and their interaction with stroke risk factors have poorly been studied in this field. We sought to determine risk factors predicting the occurrence of stroke during CABG, by a two-step analysis, studying first the preoperative data, and including next perioperative data. A special interest was focused on preoperative therapies, in order to assess their potentials to further or prevent postoperative stroke.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
In a specific database, we prospectively enrolled 810 consecutive candidates who were admitted for isolated CABG. Patients with combined valvular or vascular surgery were excluded. All pre- and perioperative data were collected in a standard form. Patients were considered smokers when they were actively smoking or had stopped within the 2 years prior to surgery. Diabetes was defined by a fasting blood glucose at entry ≥ 11.1 mmol/l or taking oral anti-diabetic drugs and/or insulin. Those with a blood pressure ≥ 160/90 mmHg measured twice before surgery or taking anti-hypertensive drugs for that purpose were considered as having hypertension. Hypercholesterolemia was defined by a fasting blood cholesterol level at entry > 2.40 g/l before surgery or taking any lipid lowering agent for a history of high blood cholesterol. Supra-ventricular arrhythmia was defined by the presence of sustained atrial fibrillation or flutter on the preoperative ECG. Patients were considered under each treatment if they started taking it at least 4 weeks prior to surgery. As all patients were under anti-platelet drugs for coronary disease (excepted those under anti-coagulants due to the high risk of embolic complications, e.g., arrhythmia), these medications were excluded from the analysis since a strong interaction was present in the statistical analysis. History of cerebrovascular disease combined any report of stroke or TIA and/or any carotid surgery prior to enrollment. History of peripheral arterial disease combined any history of lower limbs revascularization or presence of intermittent claudication. Patients operated on emergency (coronary angiography surgery delay < 48 h) were excluded from the analysis. Patients with acute coronary syndrome operated beyond 48 h and/or presenting hemodynamic instability were considered in an unstable cardiac status and were included in the study. Peroperative data concerned the number of bypasses performed, whether the revascularization was complete (all the arteries with significant stenoses scheduled to be bypassed were actually operated), and the requirement of a cardiopulmonary bypass or an off-pump surgery. During off-pump surgery, a lateral clamping (side-biting) of the aorta was systematically used during that period. Aortic calcification was noted according to surgical findings in the operation report. Surgeons reported aortic calcification as mild or severe. We binary coded aortic calcification of any extent, in order to avoid inter-operator variability. For conservative results, no comment on aorta quality was considered as normal. Finally, we reviewed all the postoperative electrocardiograms, including printed monitoring alerts and medical observations. Paroxysmal (≥5 complexes) and sustained arrhythmia were noted. In the absence of any preoperative supraventricular arrhythmia, the presence of postoperative SV arrhythmia was considered as new.

Cardiovascular outcome data were collected during the first postoperative month. The cerebrovascular accident (CVA) end-point, which was the purpose of this study, combined the occurrence of stroke or transient ischemic attack (TIA). The diagnosis was made by any cardiologist, anesthesiologist, or physician taking care of the patient after surgery. Neurologists were consulted in dubious cases, in order to have a specialized consultation and diagnosis confirmation when necessary. Cerebral scans were obtained for all cases in order to eliminate hemorrhagic cerebral accidents.

For statistical analysis, data are reported as mean ± SD. In the univariate analysis, risk factors for CVA were compared using Fisher's exact-test for discrete variables and Student's t-test for continuous variables. Two multiple logistic regression analyses were then run including variables with a p < 0.25 in the univariate analysis. The first model included only preoperative data, whereas the second included in addition perioperative data. A stepwise backward analysis excluded progressively all nonsignificant values. Age was forced in the model to obtain adjusted hazard ratios. A p-value ≤ 0.05 was considered statistically significant.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Seven hundred and three men and 107 women (mean age 66 ± 9.3 years) consecutively benefited from 3.1 ± 0.9 coronary grafts. Complete revascularization was noted in 84.5%. Cardiopulmonary bypass (CPB) was used in 84.2% of cases (mean duration of 89 ± 28 min). General data are reported in Table 1 . Regarding statin therapy, following drugs were used during that period: pravastatin, 209 patients (26%); simvastatin, 95 patients (12%); atorvastatin, 90 patients (11%); cerivastatin, 53 patients (7%); fluvastatin, 8 patients (1%).


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Table 1. Baseline characteristics
 
Stroke occurred in 11 cases (4 fatal) and a TIA was noted in 4 additive cases during the first month following surgery (cumulative CVA rate: 1.85%). In only one fatal case, the occurrence of an atrial fibrillation within hours preceding stroke was directly attributed to that event in the medical report. The univariate comparison of patients with and without postoperative CVA is presented in Table 2 .


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Table 2. Predictive factors of cerebrovascular accidents during the first postoperative period: univariate analysis
 
For the multivariate analysis, we first obtained a predictive model including only preoperative data (Table 3 ). Following factors remained significant: redo cardiac surgery, unstable cardiac status, history of cerebrovascular disease and peripheral arterial disease, whereas taking statins preoperatively was significantly associated with a fourfold lower risk. No interaction between any specific statin molecule and outcome was found (data not shown). Additionally, we found no interaction between hypercholesterolemia (in history or revealed in preoperative blood sample) and statins regarding the occurrence of TIA or stroke. In a second model, we added the perioperative data studied in the univariate analysis. None of the perioperative data remained independently predictive in the stepwise analysis. Hence, this second model led to similar results (Table 3).


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Table 3. Age-adjusted predictive model of occurrence of postoperative cerebrovascular accidents after stepwise logistic regression analysis
 
Fig. 1 displays the distribution of cerebrovascular accidents in four risk groups, as revealed in our study. Except one case (of redo surgery), none of the patients with any of these risk factors but taking statins had a postoperative cerebral event.


Figure 1
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Fig. 1. Distribution of cerebrovascular accidents according to the presence of major risk factors and statins therapy. Black bars correspond to those without preoperative statins, and gray bars correspond to those who were under preoperative statins. Aside each bar, the number of events reported to the total number of patients in that subgroup is presented. CBVD: history of cerebrovascular disease, PAD: peripheral arterial disease.

 

    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
In this prospective study, we assessed the risk factors of stroke during CABG, especially regarding the potential interactions between these factors and concomitant treatments. The main original finding in this study is that taking statins at least 4 weeks prior to surgery revealed to be significantly and independently associated with lower risk of perioperative cerebrovascular events. Additionally, we confirm the predictive values of unstable coronary or hemodynamic status, redo surgery, and a history of cerebrovascular or peripheral arterial disease. The size of our cohort probably did not enable to reveal other factors in our predictive model. The low rate of stroke (1.36%) and overall cerebrovascular accidents (1.85%) permit us only to detect stronger predictive factors in this study.

To our knowledge, this is the first report presenting the interest of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in the prevention of stroke in the very particular situation of CABG. Recent clinical trials evidenced a significant reduction in ischemic stroke in patients with coronary artery disease, both with and without elevated serum cholesterol levels [5–8]. These findings, supported by two meta-analyses [9,10], demonstrated significant risk reduction of stroke by statins. There is emerging evidence suggesting that beyond the lowering effect on LDL-cholesterol, statins would present pleiotropic and neuroprotective effects, which could explain these considerable clinical results. Simvastatin in the Asymptomatic Carotid Artery Progression Study (ACAPS) [11] and pravastatin in the Pravastatin, Lipids, and Atherosclerosis in the Carotid arteries (PLAC-II) [12] study demonstrated a slowing and even reduction of carotid intima-media thickness. In another study using transesophageal echocardiography [13], a significant reduction of aortic atherosclerotic lesions, well-known source of stroke, was observed under pravastatin. The plaque stabilization process is improved by statins in experimental studies, through a high number of biological pathways [14,15]. In a human study comparing carotid endarterectomy specimens of patients treated or not by pravastatin, Crisby et al. [16] observed many biological differences in favor of plaque stability in pravastatin-treated patients. Besides these anti-atherosclerotic effects, several studies show favorable effects of statins on inflammation, vasomotor function, local fibrinolysis, and reduction of platelets reactivity [15,17]. In a randomized study versus placebo, postoperative thrombocytosis is dramatically reduced by a preoperative simvastatin therapy [18]. Experimental data with statins in animal models point out potentials to limit the cerebral ischemic insult, not only by improving blood flow but also by providing neuroprotection through modifications in different NOS isoforms production [19].

In the field of cardiovascular surgery, the long-term effects of statins seem favorable [20]. Nevertheless, data on potentials of statins to decrease adverse cardiovascular effects in the immediate postoperative period are scarce. Dotani et al. [21] presented a retrospective study on 323 patients operated in their institution. The composite end-point of death, myocardial infarction and unstable angina were significantly reduced in patients under statins in the 60 days postoperative period (OR = 0.09, p = 0.02). The occurrence of stroke alone during that period was not significantly reduced. In a randomized trial comparing simvastatin versus placebo on 77 patients undergoing CABG [18], there was a trend to a lower rate of myocardial infarction beyond 7 days (18% vs 0%, p = 0.09). No difference on neurological adverse outcomes was noted. Conversely to these two latter studies, a larger number of patients studied here permitted to reveal specific benefits of statins in the prevention of post-CABG stroke, even after taking into account several associated risk factors. Recently, Pan et al. [22] reported the benefit of statins in patients undergoing CABG with cardiopulmonary bypass. In the multivariate analysis of a propensity-matched cohort of 1362 patients, statins were independently associated with a composite end-point of 30-day all-cause mortality and stroke. However, in that study, the association between statins and stroke alone was not significant. Compared to that cohort, our population study is older, with a larger proportion of diabetics.

Our study presents some limitations inherent to those in any observational analysis. Even in the multivariate analysis, we cannot exclude potential unknown confounders. Basically, the observation reported here would require a randomized double-blind trial. However, statins have already evidenced dramatic benefits in coronary patients, as soon as the immediate period after an acute coronary syndrome [8,23]. Yet, ethical considerations may disapprove such a trial. Thus, the major interest of our study is to provide original clinical observations in line with the above-mentioned experimental findings, and to foster research on pathways of occurrence of stroke, especially during CABG. Another limitation of this study is the lack of any neuropsychological testing which would have enabled the assessment of more subtle differences in mentation and behavior, which are a new field of research for statins today [19].

Regarding other risk factors of stroke described in the literature [1–4], we only found a trend to a higher risk in case of arrhythmia in the univariate analysis, with a nonsignificant (p = 0.20) hazard ratio at 2.2 in the multivariate model, prior to its exclusion. Kapetanakis et al. [4] found also only a similar trend when several factors were concomitantly studied. Regarding the lack of significant association between aortic calcification and CVA in our study, several points should be discussed. First, the presence of these lesions was based on aortic palpation during surgery. We did not perform systematic TEE or epicardic echography, known to be more accurate. Additionally, in line with the literature [24], severe aortic calcifications were more frequent in patients with PAD and history of cerebrovascular disease (2.7% in the absence of these two conditions vs 7.1% when present, p < 0.01). Since the two former variables were strongly associated with postoperative CABG, this might contribute to weaken the association of the latter with our endpoint. Finally, in more than 34% of cases with severe aortic calcification, the surgeon opted for an off-pump surgery, versus 15% in other cases (p < 0.02). Changing the surgical strategy might also affect the association of these lesions with stroke.


    5. Conclusion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
In this prospective observational study, we determined several risk factors of cerebrovascular accidents after CABG. Conversely, the use of statins prior to CABG was inversely associated with postoperative stroke, suggesting a protective role. This has been observed through the analysis of several subgroups at high risk of postoperative stroke. Even though, according to randomized studies, coronary patients have a benefit from these drugs, a special level of interest should be directed towards patients presenting those factors prior a coronary bypass surgery. Further studies are needed to clarify the pathways explaining this relationship.


    Footnotes
 
{star} Presented in part during the 77th Scientific Session of the American Heart Association, New Orleans, LA, USA, November 7–10, 2004.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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