Özet

Background: This study aims to investigate the value of the CHA2DS2-VASc score in predicting long-term major cardiovascular events following coronary artery bypass grafting.

Methods: Between January 2008 and January 2010, a total of 559 patients (445 males, 114 females; mean age: 62.7±9.1 years; range, 35 to 84 years) who underwent elective coronary artery bypass grafting were retrospectively analyzed. At a mean of 10.7±3.1-year follow-up, major cardiovascular events were considered as the primary endpoint.

Results: The multivariate Cox hazard analysis identified the CHA2DS2-VASc score as an independent predictor of major cardiovascular events (hazard ratio: 1.615; 95% confidence interval: 1.038-2.511; p=0.034). The receiver operating characteristic curve analyses revealed that 3.5 was the most optimal cut-off value of the score predicting major cardiovascular events and the patients were divided into two groups accordingly. The Kaplan-Meier analysis demonstrated a significantly higher incidence of major cardiovascular events in proportion to a higher CHA2DS2-VASc score (p<0.001).

Conclusion: CHA2DS2-VASc score ?4, which includes many risk factors for cardiovascular events, can be used as an independent predictor of long-term major cardiovascular events after coronary artery bypass grafting.

Coronary artery bypass grafting (CABG) as a cornerstone therapy of multivessel or left main coronary artery disease (CAD) due to its long-lasting survival benefits is the most common open-heart procedure performed worldwide today.[1,2]

As evidenced by guidelines, long-term outcome following CABG is dependent on the prevention of major cardiovascular events (MACEs) which may be reduced by choosing the risky patients and following them closely to apply more aggressive treatment strategies.[3] However, current r isk scores of CABG, such as the Society of Thoracic Surgeons (STS) score and European System for Cardiac Operative Risk Evaluation (EuroSCORE), have mainly focused on short-term morbidity and mortality.[4-6] Moreover, Synergy between percutaneous coronary intervention (PCI) with Taxus and Cardiac Surgery (SYNTAX) score was found to be an independent predictor of long-term MACEs following PCI, but not after CABG.[7,8] Thus, the lack of knowledge about which patients should be closely monitored for MACEs following CABG needs to be overcome.

The CHA2DS2-VASc score was developed to evaluate the risk for long-term ischemic stroke in patients with atrial fibrillation (A-fib),[9] using risk factors of ischemic stroke in patients with CAD, based on large cohort studies.[10,11] Moreover, the difference of the CHA2DS2-VASc (congestive heart failure [HF], hypertension, age ≥75 [doubled], diabetes, stroke [doubled], vascular disease, age 65-74, and sex category [female]) over the older CHADS2 (cardiac failure, hypertension, age, diabetes mellitus [DM], stroke [doubled]) score is additional CAD risk factors like female sex and vascular disease. Not surprisingly, as its all components are traditional risk factors of atherosclerosis, the predictive value of this score has been recently shown on mid-term myocardial infarction (MI) following PCI and on short-term ischemic stroke after PCI and CABG, even in non- A-Fib population.[12] However, it is not clear that these findings are also true for long-term MACEs in CABG patients. The usefulness of the CHADS2 score for predicting long-term cardiovascular mortality in CABG patients has been reported; however, the literature is lacking in the predictive value of the newer CHA2DS2-VASc score.[13] The meta-analysis of Zhu et al.[14] showed the better discriminative capacity of the CHA2DS2-VASc vs. C HADS2 score. In the present study, we aimed to investigate the value of the CHA2DS2-VASc score in predicting long-term MACEs following CABG.

Yöntem

This single-center, retrospective study was conducted at Istinye University and Bursa VM Medical Park Hospital, Department of Cardiovascular Surgery between January 2008 and January 2010. Patients who underwent elective isolated on-pump CABG were enrolled according to the inclusion and exclusion criteria. The inclusion criteria were as follows: triple-vessel disease, severe left main stem artery stenosis or left main equivalent disease, and two-vessel disease with proximal left anterior descending artery (LAD) stenosis. Exclusion criteria were as follows: critical preoperative state (need for inotropic drug support or intra-aortic balloon pumping [IABP], acute renal failure, need for respiratory support, history of preoperative cardiopulmonary resuscitation), previous heart surgery, MI within three weeks (cTnI>0.01 ng/mL) and missing data (n=51). Finally, 559 patients (445 males, 114 females; mean age: 62.7±9.1 years; range, 35 to 84 years) were included.

Patients characteristics
Preoperative characteristics of the patients included age, sex, smoking status, hypertension, hyperlipidemia, DM, family history of CAD, obesity (body mass index >30 kg/m²), chronic obstructive pulmonary disease (COPD), peripheral vascular disease (PVD), asymptomatic carotid stenosis, history of cerebrovascular accident (CVA), history of MI, unstable angina pectoris (USAP), history of PCI, left ventricular (LV) dysfunction, mild mitral insufficiency, the number of vessel disease, and presence of left main coronary artery (LMCA) stenosis, EuroSCORE, and CHA2D2-VASc score.

The CHA2DS2-VASc score was calculated by assigning 1 point each for congestive HF, hypertension, age 65 to 74 years, DM, vascular disease (history of MI or PCI, peripheral or CAD), and female sex and 2 points each for previous CVA, or age ≥75 years.[9]

The diagnosis of DM was based on the previous history of diabetes or fasting plasma glucose ≥126 mg/dL or hemoglobin A1c ≥6.5%. The diagnosis of COPD was based on the previous history of bronchodilator treatment or the forced expiratory volume in 1 sec (FEV1)/forced vital capacity (FVC) ratio <0.70. Carotid stenosis was defined as a ≥50% narrowing of the internal carotid artery. Peripheral vascular disease was defined as an arterial disease affecting the vasculature of extremities with a ≥50% diameter narrowing or history of intervention. A LV dysfunction was defined as an ejection fraction of <0.50).

Pre- and postoperative data were retrospectively collected from hospital records. Incomplete revascularization was defined as untreated diameter stenosis of more than 50% in a major epicardial coronary artery. Drainage was defined as the amount of drainage collected in the first 24 h. Blood transfusion was defined as the sum of the blood units used during the hospital stay. Perioperative MI was defined as cardiac troponin I (cTnI) >5 µg/L during hospitalization. Renal complication was defined as an increase of at least ≥100% in basal serum creatinine. A pulmonary complication was defined for pleural effusion, atelectasis, phrenic nerve palsy, diaphragmatic dysfunction, pneumonia, acute respiratory distress syndrome, pneumothorax, or chylothorax. Prolonged mechanical ventilation time was defined as total intubation time greater than 10 h. A neurological complication included new transient ischemic attack, stroke or encephalopathy occurring in the perioperative period. Early reoperation was defined as any hospitalization due to CABG-related complications (such as sternal dehiscence, mediastinitis) or cardiovascular problems (such as MI, congestive HF, rhythm disturbance, neurological complications, pulmonary embolism).

Surgical procedure
Following median sternotomy, the left internal thoracic artery and other conduits were prepared simultaneously. Heparin was administered to keep the activated clotting time (ACT) greater than 450 sec. All procedures were performed without using an aortic cross-clamping and cardioplegia. Cardiopulmonary bypass (CPB) was established with an ascending aortic arterial cannula and a right atrial two-stage venous cannula, using a membrane oxygenator and a roller pump. All patients were cooled to 34°C. The mean arterial blood pressure was maintained in the range of 60 to 90 mmHg. Distal anastomoses were performed by end-to-side or side-to-side techniques with a running 7/0 Prolene® s uture, u sing a myocardial stabilizer device (Octopus IV, Medtronic Inc., Minneapolis, MN, US). Proximal anastomoses of dyslipidemia was based on the previous history of total cholesterol ≥200 mg/dL or low-density lipoprotein (LDL) ≥130 mg/dL. Vessel disease was defined as stenosis of >50% of major epicardial coronary arteries. Estimated creatinine clearance (CrCl) was calculated using the Cockcroft-Gault formula: CrCl (mL/min) = ([140-age] × weight [kg])/(serum creatinine [mg/dL] × 72) (× 0.85 for women) from baseline blood samples. The diagnosis were performed using a 6/0 Prolene® suture during the heating period using an aortic side-clamp. After completion of CPB and cannula removal, heparin was neutralized with protamine providing an ACT of fewer than 160 sec. Acetylsalicylic acid at a dose of 100 mg and subcutaneous enoxaparin were initiated on the postoperative 24 h.

Follow-up
Long-term follow-up was obtained through outpatient clinic visits, hospitals records and phone calls. All-cause mortality (patient death reported by relatives or hospital records) and MACE (MI, repeated CABG or PCI, need for dual-chamber pacemaker or rehospitalization due to decompensated HF, stroke, cardiac-related or sudden death) were evaluated.

The primary endpoint of this study is to identify the predictive value of the CHA2DS2-VASc score on long-term MACE following CABG.

Statistical analysis
Statistical analysis was performed using the IBM SPSS version 26.0 software (IBM Corp., Armonk, NY, USA). Continuous variables were expressed in mean ± standard deviation (SD), while categorical variables were expressed in number and frequency. The Mann-Whitney U test was used to compare nonparametric continuous variables, the Student t-test was used to compare parametric continuous variables, and the chi-square test was used to compare categorical variables. The cumulative survival curves for long-term MACEs were constructed with the use of the Kaplan-Meier method, while differences between the CHA2DS2-VASc groups were evaluated with log-rank tests. The receiver operating characteristics (ROC) curve was used to detect the optimal cut-off value for predicting MACEs. Cox regression analysis was performed to determine independent predictors of MACE, with those variables with a p value of <0.05 in the univariate analysis included in the stepwise multivariate model. The hazard ratio (HR) and 95% confidence intervals (CIs) were calculated. The association between variables was tested using Spearman or Pearson correlation coefficient. A two-tailed p value of <0.05 was considered statistically significant.

Bulgular

In the univariate analyses, age, female sex, hypertension, insulin-dependent diabetes mellitus (IDDM), PVD, asymptomatic carotid artery stenosis, history of CVA, previous MI, CrCL, hemoglobin (Hb) level, LV dysfunction, EuroSCORE II, CHA2D2-VASc, the mean number of red blood cell transfusion units, renal complications were associated with an increased incidence of MACEs. While assessing the independent effect of all potential risk factors on MACE occurrence in multivariate analysis, CHA2DS2-VASc (HR: 1.615, <95% CI: 1.038-2.512; p=0.034), Hb level (HR: 0.917, <95% CI: 0.857-0.981; p=0.012) and previous MI (HR: 1.419, <95% CI: 1.007-2.000; p=0.045) were identified as independent predictors of MACEs (Table 1).

Table 1: Cox Regression Analysis for Independent Predictors of Long-Term MACEs

The ROC curve of CHA2DS2-VASc revealed an area under the curve (AUC) value of 0.63 (95% CI: 0.583-0.675, p<0.001) and the most optimal cut-off value to predict the MACE was ≥3.5 with 44.6% sensitivity and 75.3% specificity (Figure 1). The patients were divided into two groups according to this cut-off value. Group 1 consisted of 369 patients with CHA2DS2-VASc score <4, while Group 2 consisted of 190 patients with CHA2DS2-VASc score ≥4.

Figure 1: ROC curve analysis.
The diagonal represents the no-effect line (AUC=0.50), with curves above this line representing increasing diagnostic accuracy. CHA2DS2-VASc score accurately predicted MACE (AUC, 0.63; 95% CI: 0.583-0.675; p<0.001). The optimal cut-off to predict MACE is 3.5 with a sensitivity of 44.6% and specificity of 75.3%. AUC: Area under the curve.

Baseline characteristics are shown in Table 2. According to the components of the CHA2DS2-VASc score, Group 2 patients were significantly older (p<0.001), more diabetic (p<0.001), predominantly female (p<0.001) and more hypertensive (p<0.001) or had more LV dysfunction (p<0.001), asymptomatic carotid stenosis (p<0.001), and history of CVA (p<0.001). Moreover, Group 2 consisted of significantly more patients with IDDM (p<0.001), obesity (p<0.001), and hyperlipidemia (p<0.001). Furthermore, Group 2 patients had a significantly lower CrCL (p<0.001) and lower Hb level (p=0.035). Additionally, Group 2 had significantly more mild mitral insufficiency (p=0.006) and three-vessel disease (p<0.001) or higher mean number of vessel disease (p<0.001). Contrarily, the lower CHA2D2-VASc group included significantly more active smokers (p<0.001).

Table 2: Baseline characteristics according to CHA2DS2-VASc groups

Peri- and early postoperative characteristics of the patients are shown in Table 3. The operative characteristics of the two groups were similar regarding CPB time, incomplete revascularization, mean number of distal anastomosis and endarterectomy. Moreover, no significant difference was found between groups in term of amount of drainage, low cardiac output (LCO), perioperative MI, prolonged respiratory support, pulmonary complications, A-fib duration, and early reoperation. However, patients with higher CHA2DS2-VASc score required more blood transfusion (p<0.001) or inotropic support (p=0.018) and showed significantly more renal complication (p<0.001), neurological complication (p<0.001), perioperative A-fib (p<0.001), and mediastinitis (p=0.029). Furthermore, higher CHA2DS2-VASc score were associated with prolonged intensive care unit (ICU) stay (p<0.001), and hospital stay (p<0.001), or increased incidence of early rehospitalization (p<0.001) and in-hospital mortality (p=0.004).

Table 3: Peri- and postoperative characteristics of the patients stratified by CHA2DS2-VASc groups

Long-term follow-up characteristics are shown in Table 4. Patients in Group 2 showed a significantly lower MACE-free survival (Group 1, 126.45±37.08 months; Group 2, 98.63±48.29 months; p<0.001). Accordingly, the higher CHA2D2-VASc score was related to significantly more cumulative MACE at one year (p<0.001), at five years (p<0.001), at 10 years (p<0.001). Moreover, patients with higher CHA2DS2-VASc score showed higher all-cause mortality (p<0.001), cardiovascular mortality (p<0.001), MI (p<0.001), late reintervention (p=0.003), and stroke (p=0.003). However, non-cardiovascular mortality did not differ between the groups (p=0.68). Kaplan-Meier analysis of freedom from MACE revealed significantly lower MACE free survival in Group 2 (Group 1, 60.2%; Group 2, 38.9%; p<0.001 by the log-rank test) (Figure 2).

Table 4: Long-term outcomes according to CHA2DS2-VASc groups

Figure 2: Kaplan-Meier estimates of MACE-free survival (p<0.001 by the log-rank test).
MACE: Major cardiovascular event.

Tartışma

In the present study, we investigated the value of the CHA2DS2-VASc score in predicting long-term MACEs following CABG. First and foremost, long-term MACE after CABG was significantly predicted by a high CHA2DS2-VASc score. Second, long-term cardiovascular mortality following CABG was correlated with a high CHA2DS2-VASc score, whereas non-cardiovascular mortality was not.

Care after coronary revascularization is primarily focused on preventing recurrent MACE with an incidence as high as 51% at 10 years.[4,15] However, a standard evaluation tool for predicting the longterm MACE for this population is lacking. Thus, a practical tool is needed that effectively stratifies the risk of long-term cardiovascular events after CABG, to personalize treatment strategies.

The CHA2DS2-VASc score, CHADS2 score and CHA2DS2-VASc-HS score comprise clusters of common cardiovascular risk factors associated with thromboembolism. Unsurprisingly, strong correlations are reported among CHA2DS2-VASc-HS score, which incorporated hyperlipidemia and smoking, and severity of CAD,[16] CHADS2 scores and long-term all-cause mortality following CABG,[13] CHA2DS2-VASc score and post-procedural ischemic stroke after PCI and CABG,[12] CHADS2 score and long-term mortality after acute coronary syndrome,[17] CHA2DS2-VASc score and in-hospital MACE.[18] However, evidence regarding usage of CHA2DS2-VASc score for risk stratification after CABG in the long-term is lacking.

In the current study, the CHA2D2-VASc score was an independent predictor of long-term MACE, unlike EuroSCORE II. This finding can be explained by our study protocol which exclude half of the EuroSCORE II parameters which focused on in-hospital follow-up such as urgency, recent MI, critical preoperative stat, redo or combined surgery. Accordingly, Barili et al.[19] reported that EuroSCORE II performance fades for mortality at follow-up longer than 30 days. On the contrary, the CHA2D2-VASc score was created and approved for long-term stroke risk prediction and all of its components like HF, age, diabetes, history of stroke, vascular disease, and female sex were mainly predictors of CAD severity and course of MACE.[9]

Besides its components, we revealed that the high CHA2DS2-VASc score was related to factors pointing to severity and complexity of atherosclerosis, such as dyslipidemia, decreased CrCl levels, similar to the previous CHAD2 score studies.[13,20] As the SHINANO registry revealed CHA2DS2-VASc score ≥3 was associated with the increased Syntax score, we also found that mean vascular disease was greater in CHA2DS2-VASc score ≥4.[21] Moreover, we revealed that a high CHA2DS2-VASc score was associated with higher body mass index (BMI). According to the SHINANO registry, our study showed Hb level and CHA2D2-VASc score were inversely related, which has been recently shown as an independent predictor of MACE.[22] In the light of all these facts, it can be speculated that the CHA2DS2-VASc score is strongly correlated with the severity of CAD which increases the vulnerability to MACE.

Despite similar operative data such as CPB time, the number of distal anastomoses, endarterectomy or incomplete revascularization rate, patient with high CHA2D2-VASc score needed more perioperative inotropic support which might be related to the HF component of the score. Unsurprisingly, by its primary purpose and previous studies, high CHA2DS2-VASc score was found to be correlated with increased postoperative neurological complication and A-fib rate.[9,14] Moreover, the higher CHA2DS2-VASc score group showed more postoperative renal complication according to the lower preoperative CrCL level, consistent with the literature.[18] Although no significant difference was found in terms of postoperative drainage, a higher CHA2DS2-VASc score was related to significantly more blood transfusion. Even if this finding may also be affected by decreased basic Hb levels in the same group of patients, the association of blood transfusion with mortality has been clearly proven.[23] Our study revealed that patients with higher CHA2DS2-VASc score were more likely to have mediastinitis. Although it is considered that this finding may be affected by basic BMI, recent literature showed the same tendency independent from BMI.[18] As a sum of all these morbidities, unsurprisingly, a high CHA2DS2-VASc score was found to be associated with a prolonged hospital stay, ICU stay, and increased rehospitalization. Furthermore, similar to the recent studies, we also revealed the relationship between increased in-hospital mortality and high CHA2DS2-VASc score.[18]

As shown in previous publications with PCI, patients with high CHA2DS2-VASc scores showed significantly lower MACE-free survival, and also higher MACE at one year, at five years, and 10 years following CABG.[21,24] Myocardial infarction, stroke and reintervention were detected significantly more in patients with high CHA2DS2-VASc scores. Correlated to the report of Lu et al.[13] evaluating CHADS2 score, our study showed a similar correlation between cardiovascular mortality and high CHA2DS2-VASc score. In addition, as the non-cardiovascular mortality was not found to be correlated with the score, the relation between all-cause mortality and CHA2DS2-VASc score seems to be mainly affected by cardiovascular mortality.

The SHINANO registry, as a multi-center, prospective study, revealed a CHA2DS2-VASc score ≥5 was predictive for long-term MACEs after PCI.[21] Moreover, the CHA2DS2-VASc score ≥4 in patients with HF without AF was found to be an absolute risk for thromboembolic complications compared to patients with AF.[25] In this study, we identified, for the first time, that a CHA2DS2-VASc score ≥4 was the optimal value to predict long-term MACEs following elective isolated CABG.

The limitations to this study are the reflection of a single-center experience and retrospective design. However, our population consisted of homogeneous, consecutive unselected CABG patients, relevant to most patients undergoing CABG in the general population. Moreover, all patients were submitted to the same technique, under the same experienced surgeon supervision; therefore, the technical differences which may interact with the incidence of MACE were excluded.

In conclusion, a CHA2DS2-VASc score ?4 is independently associated with the risk of major cardiovascular events following coronary artery bypass grafting in the long term. This practical predictor may help to identify individuals at high risk for adverse outcomes and candidates who may require more aggressive management strategies in daily practice. Further multi-center, large-scale, prospective, randomized-controlled trials are needed to confirm these results.

Ethics Committee Approval: The study protocol was approved by the Istinye University Human Research Ethics Committee (date: 22.12.2021, no: 21-113). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patient Consent for Publication: A written informed consent was obtained from each patient. Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Idea/concept: A.E., O.G.; Design: A.E., O.G., S.E.; Data Collection: H.O., Z.A.C.; Control/ supervision: S.E.; Analysis: O.G.; Writing article: A.E., O.G.; Critical review: S.E.; References: A.Y.; Materials: H.O., Z.A.C.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

Kaynaklar

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