Usefulness of the CHADS2 Score for Prognostic Stratification in Patients With Coronary Artery Disease Having Coronary Artery Bypass Grafting

Accepted Manuscript Usefulness of the CHADS2 Score for Prognostic Stratification in Patients with Coronary Artery Disease Having Coronary Artery Bypass Grafting Dai-Yin Lu, MD, Chin-Chou Huang, MD, Po-Hsun Huang, MD, PhD, Jaw-Wen Chen, MD, Tzeng-Ji Chen, MD, PhD, Shing-Jong Lin, MD, PhD, Wan-Leong Chan, MD, Chiu-Yang Lee, Hsin-Bang Leu, MD, PhD PII:

S0002-9149(16)31935-X

DOI:

10.1016/j.amjcard.2016.11.035

Reference:

AJC 22291

To appear in:

The American Journal of Cardiology

Received Date: 25 August 2016 Revised Date:

16 November 2016

Accepted Date: 17 November 2016

Please cite this article as: Lu D-Y, Huang C-C, Huang P-H, Chen J-W, Chen T-J, Lin S-J, Chan WL, Lee C-Y, Leu H-B, Usefulness of the CHADS2 Score for Prognostic Stratification in Patients with Coronary Artery Disease Having Coronary Artery Bypass Grafting, The American Journal of Cardiology (2017), doi: 10.1016/j.amjcard.2016.11.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Usefulness of the CHADS2 Score for Prognostic Stratification in Patients with Coronary Artery Disease Having Coronary Artery Bypass Grafting

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Dai-Yin Lu, MDa,e,f, Chin-Chou Huang, MDa,e,g, Po-Hsun Huang, MD, PhDa,e,f, Jaw-Wen Chen, MDa,f, Tzeng-Ji Chen, MD, PhDb,h, Shing-Jong Lin, MD, PhDa,e,f, Wan-Leong Chan,

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Division of Cardiology, Department of Medicine,

c

Healthcare and Management Center, dDivision of Cardiovascular Surgery, Department of

Department of Family Medicine,

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MDa,c, *Chiu-Yang Leed, and Hsin-Bang Leu, MD, PhDa,c,e

Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; eDepartment of Medicine, f

Institute of Clinical Medicine, gInstitute of Pharmacology, hInstitute of Hospital and Health

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Care Administration, National Yang-Ming University, Taipei, Taiwan

*Chiu-Yang Lee is a co-corresponding author

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Running title: CHADS2 score and prognosis after coronary artery bypass grafting

* Correspondence to: Hsin-Bang Leu, M.D., Ph.D. Healthcare and Management Center, Taipei Veterans General Hospital 201 Sec. 2, Shih-Pai Road, Taipei, Taiwan. E-mail: [email protected] TEL: +886-28712121 ext.342 1

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Abstract

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Current risk model for long-term survival prediction in isolated coronary artery

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bypass graft surgery (CABG) is complicated while a simple useful model is still

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lacking. We aim to investigate if CHADS2 score could predict long term outcome for

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patients after CABG. From 2000 to 2007, we identified a study cohort consisting of

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patients who underwent coronary bypass surgery in the Taiwan National Health

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Insurance Research Database. After operation, all cases were followed to track the

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incidence of major cardiovascular events (MACE) and overall mortality. During a

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mean 5.1 year follow-up, 638 patients experienced major cardiovascular events. 625

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passed away at the end of follow-up, while 204 died of cardiovascular cause. Subjects

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with higher CHADS2 scores had significantly higher 10-year overall mortality and

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cardiovascular death, as well as the incidence of MACE. After adjustment with

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co-morbid condition and prescribed medications, CHADS2 was independently

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associated with increased risks of all-cause mortality (hazard ratio (HR): 1.36; 95%

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confidence interval (CI): 1.29-1.44) and cardiovascular mortality (HR: 1.37, 95% CI: 1.24-1.52). In conclusion, CHADS2 score provides a quick and useful tool in

predicting long-term outcome for patients after coronary artery bypass surgery.

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Keywords: coronary artery bypass surgery, CHADS2 score, survival 1

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Introduction

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The CHADS2 score is used for embolic risk stratification and guidance in the

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management of patients with atrial fibrillation (AF).1 In addition to the risk of embolic

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stroke, it has been shown to provide valuable insight for other outcome variables to

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patients with different cardiovascular risk profiles.2 Our previous study demonstrated

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the CHADS2 score as a valuable prognostic index on clinical outcome in patients with

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acute myocardial infarction3. However, it is unclear if CHADS2 score can be applied

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for prognostic stratification for coronary artery disease (CAD) patients after coronary

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artery bypass graft surgery (CABG). The aim of the present study evaluates whether

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CHADS2 score predict long-term clinical outcomes and identify high risk patients for

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those who underwent CABG.

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Methods

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We conducted a nationwide cohort study using Taiwan’s National Health

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Insurance Research Database (NHIRD), which was released by the Taiwan National

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Health Research Institutes (NHRI). The National Health Insurance (NHI) system is a

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mandatory universal health insurance program that offers comprehensive medical care

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coverage to all residents of Taiwan. The current study was conducted using NHIRD

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dataset which contained patients' medical claim records, including coverage for

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outpatient and emergency department visit, hospitalization, and prescription drugs.

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The present study was exempt from full review by the Institutional Review Board of

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Taipei Veterans General Hospital, because the NHIRD consisted of de-identified

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secondary data released to the public for research purposes.

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A cohort dataset comprising 1,000,000 randomly sampled people who were alive

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since 2000 were used. This dataset has been confirmed by NHRI to be representative

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of the Taiwanese population.4 The study population was identified as patients who,

from January 1, 2000 to December 31, 2009, had coronary artery disease and

underwent

isolated

CABG

subsequently

by

the

NHI

Treatment

Coding

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(68023A-68025B, 97901K-97918B). Patients were excluded if they underwent

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combined cardiac surgery along with CABG, such as valve surgery, aortic root 3

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reconstruction or replacement. Information about important comorbidities, such as

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hypertension, diabetes mellitus, heart failure, previous stroke or transient ischemic

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attack (TIA), AF, hyperlipidemia, and chronic obstructive pulmonary disease, was

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retrieved from the medical diagnosis based on the codes from the International

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Classification of Diseases (ICD)-9-CM codes.

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The CHADS2 score was calculated for each patient by assigning 1 point for each

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history of heart failure, hypertension, diabetes mellitus, age ≧75 years, and 2 points

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for an episode of stroke or TIA prior to surgery. The study patients were divided into

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3 groups according to their CHADS2 scores: 0 to 1, 2, and 3 to 6 scores.1

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The primary end point was defined as overall mortality, defined as death record

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in NHIRD with any cause. Cardiovascular (CV) death was defined as documentation

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of diagnoses involving ischemic heart disease, acute coronary syndrome, heart failure,

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cerebrovascular disease, arrhythmia, great vessel or peripheral vascular disease,

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valvular heart disease and sudden cardiac death, in last clinic or emergency

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department visit 1 month before death or last hospitalization 3 months before death.

Secondary endpoints were major adverse cardiovascular events (MACE), defined as acute coronary syndrome (ICD-9-CM codes 410.0 to 413), and ischemic cerebral

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infarction (ICD-9-CM codes 433.0 to 437.1). All patients were followed until they

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either reached the study end point or reached the end of study follow-up. The 4

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accuracy of diagnosis of the aforementioned cardiovascular events was validated by

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our previous study.5 Myocardial revascularization was recorded by the NHI

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Treatment Coding (33076A-33078B, 97511K-97532B)

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Data are presented as mean and standard deviation for normally distributed

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continuous variables, and as proportions for categorical variables. Differences

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between continuous values were assessed using an unpaired 2-tailed t test for

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normally distributed variables. Differences between nominal variables were compared

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using the χ 2 test. The prognostic differences between patients with a CHADS2 score

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of 0 to 1, 2, and 3 to 6 were analyzed by Kaplan-Meier survival analysis. To compare

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survival curves among different patient groups, a log-rank test was used. Cox

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proportional hazards models were used to identify the predictors of MACE, CV death

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and all-cause mortality with adjustment for age, history of AF, use of anti-platelet

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agents, beta-blocker, renin-angiotensin system (RAS) blockades and statin. A p value

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of < 0.05 was considered statistically significant. The analyses were performed using

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the statistical package SPSS, version 18.0 (SPSS Inc., Chicago, IL, USA)

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Results

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A total of 3036 patients (mean 65 years old, 76% men) were enrolled in this

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study. The average hospitalization was 19.4 days, and 112 (4%) died within 30 days

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after surgery. After a mean 5.1 year follow-up, 625 (21%) patients passed away.

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Among them, 204 (33% of deceased patients) deaths were associated with

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cardiovascular causes, and chronic ischemic heart disease is the leading cause of

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cardiovascular mortality (Figure 1). The baseline characteristics of the survival and

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deceased patients were described in Table 1.

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The histogram of CHADS2 score in the study population was demonstrated in

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Figure 2, and most patients (95%) had at least 1 score. When the patients were

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classified into 3 groups according to the CHADS2 score (0 to 1, 2, and 3 to 6) as

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previous study reported,1 subjects with higher scores (3 to 6) had more co-morbidities,

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including heart failure, hypertension, diabetes, chronic kidney disease, chronic

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obstructive pulmonary disease and hyperlipidemia. They were more frequently prescribed with renin angiotensin system blockade, but less statin use (Table 2).

During index hospitalization for bypass surgery, patients with higher CHADS2 scores

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had longer hospital stay. They also had the highest overall mortality among the three

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groups, and the curves separated 12 months after operation (Figure 3). 6

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In Cox survival analysis, the CHADS2 score was a significant predictor of

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all-cause mortality (hazard ratio (HR) and 95% confidence interval (CI): 1.44,

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1.37-1.52) as well as MACE and CV mortality (Table 3, model 1). After accounting

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for age, history of atrial fibrillation, use of anti-platelet agents, beta-blocker, RAS

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blockade and statin, CHADS2 remained independently associated with total mortality

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(HR:1.36, 95% CI:1.29-1.44) and CV mortality (HR: 1.37, 95% CI:1.24-1.52) (Table

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3, model 2). A score≧3 was correlated with more than 3-fold of the risk of total

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mortality as well as CV mortality compared to a score no≦1.

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In the subgroup analyses, a higher CHADS2 score was consistently associated

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with a higher risk for all-cause mortality in various subpopulations, either for age ≧

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or < 75 years, men or women, with or without history of chronic heart failure,

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hypertension, diabetes, previous stroke/TIA or AF (Figure 4).

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Discussion

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Using a large-scale nationwide database, this study provides realistic detail about

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long-term outcome for patients who underwent CABG. In addition, the CHADS2

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score is a useful tool in risk stratification and long-term survival for patients who

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underwent bypass surgery.

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The average hospital stay in Taiwanese population was 19.4 days, which was

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much longer compared with an average of 6 to 7 days from a Canadian report.6 The

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long duration of hospitalization may be a reflection of comorbidities resulted from

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aging. The mean age of our patients who performed bypass surgery was 65, much

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older than other study populations.7,8 Although the 30-day mortality was slightly

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higher than in other Asian-Pacific reports,9,10 there was no difference in 10-year

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mortality.7 Our patients were under higher risks during peri-operative period, but they

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did not have a more aggressive course after discharge.

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The original purpose of CHADS2 score is for risk stratification in stroke

prevention of atrial fibrillation, and later it has also been demonstrated as a useful tool in predicting cardiovascular death in patients with established or at high risk of

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atherothrombosis.11 Our previous study has demonstrated the CHADS2 score as a

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valid prognostic index on clinical outcome in patients with acute myocardial 8

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infarction.3 In fact, each component of CHADS2 score are also either risk factors of

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documented cardiovascular diseases, and stroke per se also causes disability and

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immobility, further contributing to mortality.

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In this study, the CHADS2 score was given a different perspective as a risk

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stratification model for patient undergone bypass surgery. Patients with a CHADS2

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score≧2 was associated with a higher risk of long term cardiovascular events.

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Current American College of Cardiology/American Heart Association and the

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European Society of Cardiology guidelines suggested CABG should be considered

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over percutaneous coronary intervention (PCI) if there is unprotected left main,

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multi-vessel with proximal left anterior descending coronary artery disease, or with

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complicated coronary lesions.12,13 In the present study, the CHADS2 score was

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proportional to long-term cardiovascular risks in patients with coronary artery disease

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undergone bypass surgery: for patients with score 0 or 1, the outcome was pretty good

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with a 10-year survival rate around 90%. On the contrary, patients with≧3 scores

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were associated with significantly lower overall survival (70%). Since the information

of each component in CHADS2 score is easy to obtain, with a quick calculation, clinicians can identify high risk population for long term outcome despite after

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successful bypass surgery. Furthermore, these advantages improve communications

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between cardiovascular experts and patients by helping patients understand their own 9

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long-term risks and become more compliant in order to get better control on

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co-morbidities. A higher pre-operative CHADS2 score consistently correlated with worse

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long-term outcomes both in the elder and the young regardless of other co-existing

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morbidities. Although age is one of the component in CHADS2 score and it seems

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intuitive that patients greater than 75 years old have worse 10-year survival than those

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who are younger. Even in the same age group, however, patients who have higher

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CHADS2 scores were still associated with higher risk of mortality. After FREEDOM

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Trial, co-morbidity with diabetes mellitus has been an important determinant

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concerning the appropriate strategy of myocardial revascularization for patients with

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coronary artery disease.14 The present study demonstrated that CHADS2 score could

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be applied to patients either with or without diabetes mellitus to estimate long-term

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outcome.

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There are some limitations of our study. First, some habitual risk factors, such as

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smoking, obesity or sedentary lifestyle, were not recorded in the National Registry

Database. Besides, information about biochemical profile and parameters of cardiac

performance, such as serum creatinine or LVEF was unavailable. Therefore

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comparison between CHADS2 score and risk calculator from ASCERT trial was not

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performed, and further investigation is needed. Although it does not contain as many 10

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variables as the ASCERT calculator, the easy use of CHADS2 score could still help

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clinicians make a quick assumption. Finally, detailed information about the

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complexity of coronary artery lesions, like the SYNTAX score,15 and about the

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operative procedure, including use of cardiopulmonary bypass pump,16,17 total or

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non-total arterial revascularization,18,19 were not retrieved. These factors are

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associated with the durability of bypass graft vessels, and consequently long-term

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cardiovascular outcomes.

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In conclusion, CHADS2 score is useful in predicting long-term prognosis in

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patients with coronary artery disease undergoing bypass surgery. A higher CHADS2 score is independently associated with a higher risk of ten-year overall mortality.

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Disclosures

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The authors have no conflicts of interest to disclose.

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Figure legends

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Figure 1. Cause of death in patients undergone coronary artery bypass grafting during

3

10-year follow-up.

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Figure 2. Histogram of CHADS2 score in study population.

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Figure 3. 10-year survival curve in patients undergone coronary artery bypass grafting

6

with CHADS2 score 0-1, 2, and 3-6.

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Figure 4. Hazard ratio (HR) and 95% confidence interval (CI) of CHADS2 score on

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all-cause mortality in subgroup analyses.

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ACCEPTED MANUSCRIPT Table 1. Baseline characteristics of the study population undergone coronary artery bypass grafting

Variable

Survival

Mortality

(n=3036)

(n = 2411)

(n = 625)

65 ± 11

64 ± 11

69 ± 9

2295 (76%)

1835 (76%)

460 (74%)

0.212

CHADS2

2.4 ± 1.4

2.2 ± 1.3

2.9 ± 1.4

<0.001

Hospital stay (days)

19 ± 11

19 ± 10

24 ± 17

<0.001

Hypertension

2632 (87%)

2066 (86%)

566 (91%)

0.002

Heart failure

1096 (36%)

752 (31%)

344 (55%)

<0.001

Diabetes mellitus

1604 (53%)

1230 (51%)

374 (60%)

<0.001

Age (years)

Previous stroke/transient ischemic attack

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Overall

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stratified by call-cause mortality p value

<0.001

686 (23%)

498 (21%)

188 (30%)

<0.001

761 (25%)

497 (21%)

264 (42%)

<0.001

1409 (46%)

1085 (45%)

324 (52%)

0.003

2037 (67%)

1673 (69%)

364 (58%)

<0.001

268 (9%)

190 (8%)

78 (13%)

<0.001

2965 (98%)

2374 (99%)

591 (95%)

<0.001

2709 (89%)

2217 (92%)

492 (79%)

<0.001

Renin-angiotensin-aldosterone system blockade

2630 (87%)

2112 (88%)

518 (83%)

0.003

Statin

2199 (72%)

1896 (79%)

303 (46%)

<0.001

Chronic kidney disease Chronic obstructive pulmonary disease

Medications Anti-platelet

AC C

Beta-blockade

EP

Atrial fibrillation/flutter

TE D

Hyperlipidemia

Data are presented as mean ± standard deviation or n (%)

ACCEPTED MANUSCRIPT Table 2. Baseline characteristics of the population undergone coronary artery bypass grafting with CHADS2 score 0 to 1, 2, and 3 to 6 0-1 score

2 scores

3-6 scores

(n =876)

(n = 908)

(n=1252)

60 ± 11

65 ± 10

69 ± 10

708 (81%)

673 (74%)

914 (73%)

<0.001

0.8 ± 0.4

2

3.8 ± 0.9

<0.001

17 ± 9

19 ± 11

22 ± 13

<0.001

Hypertension

556 (64%)

846 (93%)

1230 (98%)

<0.001

Heart failure

55 (6%)

Diabetes mellitus

83 (10%)

Men CHADS2 score

Previous stroke/ transient ischemic attack

<0.001

224 (25%)

817 (65%)

<0.001

607 (67%)

914 (73%)

<0.001

M AN U

Hospital stay (days)

p value

RI PT

Age (years)

SC

Variable

0 (0)

14 (2%)

672 (54%)

<0.001

94 (11%)

216 (24%)

451 (36%)

<0.001

284 (32%)

400 (44%)

726 (58%)

<0.001

505 (58%)

627 (69%)

905 (72%)

<0.001

45 (5%)

77 (9%)

146 (12%)

<0.001

845 (97%)

893 (98%)

1227 (98%)

0.018

779 (89%)

819 (90%)

1111 (89%)

0.463

Renin-angiotensin-aldosterone system blockade

689 (79%)

806 (89%)

1135 (91%)

<0.001

Statin

669 (76%)

687 (76%)

843 (67%)

<0.001

Chronic kidney disease Chronic obstructive pulmonary disease

Medications Anti-platelet

AC C

Beta-blockade

EP

Atrial fibrillation/flutter

TE D

Hyperlipidemia

Data are presented as mean ± standard deviation or n (%)

ACCEPTED MANUSCRIPT Table 3. Hazard ratios of CHADS2 scores for major adverse cardiovascular events, cardiovascular mortality and all-cause mortality Uni-variate CHADS2/group

events/cases

Multi-variate

Hazard ratio

Hazard ratio p value

1.51 (1.36-1.67)

<0.001

-

Major adverse cardiovascular events Per 1 score change

p value (95% confidence interval)

RI PT

(95% confidence interval)

Group change

1.43 (1.28-1.60)

<0.001

1

-

125/876

1

2

169/908

1.41 (1.12-1.78)

0.004

1.26 (1.00-1.59)

0.056

3

318/1252

2.24 (1.82-2.75)

<0.001

1.98 (1.59-2.47)

<0.001

1.44 (1.31-1.58)

<0.001

1.37 (1.24-1.52)

<0.001

M AN U

SC

1

Cardiovascular mortality Per 1 score change Group change 28/876

1

-

2

45/907

1.68 (1.05-2.69)

0.032

1.66 (1.03-2.69)

0.040

3

131/1252

4.04 (2.68-6.09)

<0.001

3.57 (2.29-5.57)

<0.001

1.44 (1.37-1.52)

<0.001

1.36 (1.29-1.44)

<0.001

89/876

1

-

1

-

160/908

1.93 (1.49-2.50)

<0.001

1.87 (1.44-2.44)

<0.001

376/1252

3.95 (3.13-4.99)

<0.001

3.40 (2.65-4.37)

<0.001

Per 1 score change

1 2 3

AC C

Group change

EP

All-cause mortality

TE D

1

Multi-variate analysis: adjusted for age, history of atrial fibrillation, use of anti-platelet agent, beta-blocker, renin- angiotensin-aldosterone system blockade and statin Group 1: CHADS2 score = 0-1; Group 2: CHADS2 score = 2; Group 3: CHADS2 score =3-6

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

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