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Requests for reprints should be addressed to Walid Saliba, MD, MPH, Department of Community Medicine and Epidemiology, Carmel Medical Center, 7 Michal St., Haifa 34362, Israel.
Department of Community Medicine and Epidemiology, Carmel Medical Center, Clalit Health Services, and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
Department of Community Medicine and Epidemiology, Carmel Medical Center, Clalit Health Services, and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
Department of Community Medicine and Epidemiology, Carmel Medical Center, Clalit Health Services, and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
Department of Community Medicine and Epidemiology, Carmel Medical Center, Clalit Health Services, and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, IsraelDepartment of Epidemiology and Disease Prevention, Office of the Chief Physician, Clalit Health Services Headquarters, Tel Aviv, Israel
CHADS2 and CHA2DS2-VASc are validated scores used to predict stroke in patients with atrial fibrillation. Many of the individual risk factors included in these scores are also risk factors for atrial fibrillation. We aimed to examine the performance of CHADS2 and CHA2DS2-VASc scores in predicting new-onset atrial fibrillation in subjects without preexisting diagnosis of atrial fibrillation.
Methods
Using the computerized database of the largest health maintenance organization in Israel, we identified all adults aged 50 years or older without atrial fibrillation prior to January 1, 2012. CHADS2 and CHA2DS2-VASc scores were calculated for each participant at study entry, and the cohort was followed for incident atrial fibrillation until December 31, 2014.
Results
Of 1,062,073 subjects without preexisting diagnosis of atrial fibrillation; 23,223 developed atrial fibrillation during a follow-up of 3,053,754 person-years (incidence rate, 0.76 per 100 person-years). Incidence rate of atrial fibrillation increased in a graded manner with increasing CHA2DS2-VASc score: 0.17, 0.21, 0.49, 0.94, 1.65, 2.31, 2.75, 3.39, 4.09, and 6.71 per 100 person-years for CHA2DS2-VASc score of 0 to 9 points, respectively (P < .001). The hazard ratio for atrial fibrillation for each 1-point increase in CHA2DS2-VASc score was 1.57 (95% confidence interval [CI], 1.56-1.58). Results were similar for CHADS2 score. The area under the receiver operating characteristic curve to predict new-onset atrial fibrillation was 0.728 (95% CI, 0.725-0.711) and 0.744 (95% CI, 0.741-0.747) for CHADS2 and CHA2DS2-VASc scores, respectively.
Conclusions
CHADS2 and CHA2DS2-VASc scores are directly associated with the incidence of new-onset atrial fibrillation, and have a relatively high performance for atrial fibrillation prediction.
Stroke occurring in patients with atrial fibrillation is associated with increased mortality and morbidity, severe disability, greater rate of stroke recurrence, and longer hospitalization.
and CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years [doubled], Diabetes, prior Stroke or TIA [doubled] – Vascular disease, Age 65-74 years, and Sex category [female])
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
are 2 well-validated risk-stratification scores for predicting stroke in patients with atrial fibrillation. CHA2DS2-VASc score was recommended for risk assessment of stroke by the 2010 European Society of Cardiology,
ESC Committee for Practice Guidelines (CPG) 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
and the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines for the management of patients with atrial fibrillation.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Because these risk factors are included in CHADS2 and CHA2DS2-VASc scores, we sought to assess the association between CHADS2 and CHA2DS2-VASc scores and new-onset atrial fibrillation in subjects without preexisting diagnosis of atrial fibrillation, and to examine the discrimination performance of these scores for the prediction of new-onset atrial fibrillation, using data from a population-based electronic medical records database of the largest health maintenance organization in Israel.
Materials and Methods
Data Source
Clalit Health Service (CHS) is a not-for-profit health care provider covering more than half of the Israeli population (∼4,200,000 members).
The electronic medical records database of CHS includes data from multiple sources: primary care physicians, specialty clinics in the community, hospitalizations, laboratories, and pharmacies. A chronic disease registry is compiled from these data sources. Diagnoses are captured in the registry by diagnosis-specific algorithms, employing code reading (eg, International Classification of Diseases-9th Revision and International Classification of Primary Care), text reading, laboratory test results, and disease-specific drug usage. A record is kept of the sources and dates used to establish the diagnosis, with the earliest recorded date considered the starting date of the diagnosis.
Study Population
The CHS computerized database was retrospectively searched for all adult subjects ages 50 years or older on January 1, 2012 (study entry). A total of 1,137,198 subjects were identified; this group was used to estimate the prevalence of atrial fibrillation according to CHADS2 and CHA2DS2-VASc scores categories. To evaluate the incidence of new-onset atrial fibrillation, we excluded 75,125 subjects who carried a diagnosis of atrial fibrillation prior to study entry. The remaining 1,062,073 subjects constituted the cohort for assessing the association of CHADS2 and CHA2DS2-VASc scores with the incidence of new-onset atrial fibrillation.
Follow-Up
The cohort was followed for incident new-onset atrial fibrillation from January 1, 2012 until December 31, 2014. Subjects without atrial fibrillation were censored at the date of their death, changing health care provider, or at the end of follow-up, whichever came first. Mortality was established by matching our data with the National Death Index.
Study Variables
Demographic and clinical variables were retrieved from the CHS computerized database for calculation of CHADS2 and CHA2DS2-VASc scores. CHADS2 and CHA2DS2-VASc are risk-stratification scores ranging from 0 to 6 and from 0 to 9, respectively, depending on the number and weight of the score's risk components.
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
Both CHADS2 and CHA2DS2-VASc score were calculated for each participant at study entry.
Statistical Analyses
Continuous variables are presented as means and standard deviations and were compared using the unpaired Student t test. Categorical variables are presented as counts and percentages, and were compared using the chi-squared test. The prevalence of atrial fibrillation was calculated as the proportion of those with a preexisting diagnosis of atrial fibrillation at baseline. The annualized incidence density rates of atrial fibrillation were estimated by dividing the number of incident cases of new-onset atrial fibrillation by the total follow-up period, and were expressed as a number per 100 person-years of observation. Kaplan Meier curves were used to estimate the cumulative incidence of atrial fibrillation according to CHADS2 and CHA2DS2-VASc scores categories. Cox proportional hazard regression models were used to assess the associations between CHADS2 and CHA2DS2-VASc scores and time to atrial fibrillation, and to assess the independent association of the individual components risk factors included in CHADS2 and CHA2DS2-VASc scores with new-onset atrial fibrillation. We evaluated the discriminatory performances of CHADS2 and CHA2DS2-VASc scores in predicting new-onset atrial fibrillation, using the area under the receiver operating characteristics (ROC) curves.
All statistical analyses were performed using IBM SPSS Statistics 22.0 (IBM, New York, NY). For all analyses, P < .05 for the 2-tailed tests was considered statistically significant.
Results
The Prevalence of Atrial Fibrillation
A total of 1,137,198 adults were identified. The mean age was 65.7 (SD 11.2) years, and 54.7% were females. The distribution of the individual components risk factors of CHADS2 and CHA2DS2-VASc scores are presented in Table 1.
Table 1Distribution of the Individual Components Risk Factors of CHADS2 and CHA2DS2-VASc Score; CHS Cohort, Israel 2012
All subjects (including subjects with preexisting diagnosis of atrial fibrillation at baseline). This group was used to assess the prevalence of atrial fibrillation.
The cohort study (including only subjects without preexisting diagnosis of atrial fibrillation at baseline). This group was used to assess the incidence of atrial fibrillation.
(n = 1,062,073)
Age (y)
Mean (SD)
65.0 (10.9)
65.7 (11.2)
Median (IQR)
63.0 (56.0-73.0)
64.0 (57.0-74.0)
Age categories
<65 y
590,354 (55.6%)
602,749 (53.0%)
65-74.9 y
247,362 (23.3%)
265,009 (23.3%)
≥75 y
224,357 (21.1%)
269,440 (23.7%)
Female sex
582,664 (54.9%)
621,501 (54.7%)
Diabetes mellitus
259,408 (24.4%)
287,228 (25.3%)
Hypertension
494,444 (46.6%)
556,075 (48.9%)
Congestive heart failure
28,522 (2.7%)
48,809 (4.3%)
History of stroke or TIA
78,181 (7.4%)
96,030 (8.4%)
Vascular disease
112,333 (10.6%)
139,876 (12.3%)
CHS = Clalit Health Service; IQR = interquartile range; TIA = transient ischemic attack.
∗ All subjects (including subjects with preexisting diagnosis of atrial fibrillation at baseline). This group was used to assess the prevalence of atrial fibrillation.
† The cohort study (including only subjects without preexisting diagnosis of atrial fibrillation at baseline). This group was used to assess the incidence of atrial fibrillation.
Overall, 75,125 subjects had a diagnosis of atrial fibrillation at baseline (atrial fibrillation prevalence rate 6.6%). Atrial fibrillation prevalence rate increased in a graded manner across CHA2DS2-VASc score (range: 1.0%-49.2%), and CHADS2 score categories (range: 1.3%-47.1%) (Figure 1).
Figure 1Prevalence of atrial fibrillation according to CHA2DS2-VASc and CHADS2 scores categories.
A total of 1,062,073 adults without preexisting atrial fibrillation were included in the cohort study. The mean age was 65 (SD 10.9) years, and 54.9% were female. The distribution of the individual components risk factors of CHADS2 and CHA2DS2-VASc scores are presented in Table 1.
Overall, 23,223 subjects had a new-onset atrial fibrillation during a follow-up of 3,053,754 person-years (atrial fibrillation incidence density rate, 0.76 per 100 person-years). Atrial fibrillation incidence density rate increased in a graded manner across CHA2DS2-VASc score categories: 0.17, 0.21, 0.49, 0.94, 1.65, 2.31, 2.75, 3.39, 4.09, and 6.71 per 100 person-years in subjects with CHA2DS2-VASc score of 0 to 9, respectively (P < .001) (Table 2). The cumulative incidence of atrial fibrillation according to CHA2DS2-VASc score categories is shown in Figure 2A. On Cox proportional hazard regression analysis, the hazard ratio (HR) for atrial fibrillation associated with each 1-point increase in CHA2DS2-VASc score was 1.57 (95% confidence interval [CI], 1.56-1.58) (Table 2). The HR for atrial fibrillation in subjects within each CHA2DS2-VASc score category in comparison with subjects with CHA2DS2-VASc score of 0 is shown in Table 2.
Table 2Hazard Ratios and Incidence Density Rate of Atrial Fibrillation by CHA2DS2-VASc Score Category; CHS Cohort, Israel 2012
Score
Number of Subjects (%)
Number of Incident AF
Follow-Up Time (Person-Years)
Incidence Density Rate of AF (Per 100 Person-Years)
HR (95% CI)
0
153,010 (14.4%)
788
451,879
0.17
Reference
1
301,196 (28.4%)
1842
890,365
0.21
1.19 (1.09-1.29)
2
210,491 (19.8%)
3023
615,809
0.49
2.81 (2.60-3.04)
3
164,463 (15.5%)
4449
470,815
0.94
5.42 (5.02-5.84)
4
121,589 (11.4%)
5563
336,952
1.65
9.46 (8.78-10.19)
5
63,182 (5.9%)
3894
168,349
2.31
13.24 (12.26-14.29)
6
30,097 (2.8%)
2105
76,679
2.75
15.70 (14.47-17.04)
7
13,615 (1.3%)
1120
32,992
3.39
19.40 (17.71-21.25)
8
3781 (0.4%)
353
8632
4.09
23.34 (20.59-26.46)
9
649 (0.1%)
86
1282
6.71
38.16 (30.54-47.67)
Total
1,062,073
23,223
3,053,754
0.76
1.57 (1.56-1.58)
For each 1-point increase
AF = atrial fibrillation; CHS = Clalit Health Service; CI = confidence interval; HR = hazard ratio.
A similar graded increasing trend in atrial fibrillation incidence density rate was observed across CHADS2 score categories: 0.20, 0.59, 1.34, 2.14, 2.33, 3.13, and 5.25 per 100 person-years in subjects with CHADS2 score of 0 to 6, respectively (P < .001). The cumulative incidence of atrial fibrillation according to CHADS2 score categories is shown in Figure 2B. The HR for atrial fibrillation associated with each 1-point increase in CHADS2 score was 1.73 (95% CI, 1.71-1.74) (Table 3). The HR for atrial fibrillation in subjects within each CHADS2 score category in comparison with subjects with CHADS2 score of 0 is shown in Table 3.
Table 3Hazard Ratios and Incidence Density Rate of Atrial Fibrillation by CHADS2 Score Category; CHS Cohort, Israel 2012
Score
Number of Subjects (%)
Number of Incident AF
Follow-Up Time (Person-Years)
Incidence Density Rate of AF (Per 100 Person-Years)
HR (95% CI)
0
437,297 (41.2%)
2549
1,292,154
0.20
Reference
1
289,721 (27.3%)
5000
843,433
0.59
3.00 (2.86-3.15)
2
206,751 (19.5%)
7781
582,150
1.34
6.77 (6.47-7.08)
3
73,351 (6.9%)
4209
196,787
2.14
10.82 (10.30-11.37)
4
37,240 (3.5)
2262
97,028
2.33
11.79 (11.14-12.48)
5
15,421 (1.5%)
1176
37,519
3.13
15.83 (14.77-16.96)
6
2292 (0.2%)
246
4683
5.25
24.42 (23.18-30.11)
Total
1,062,073
23,223
3,053,754
0.76
1.73 (1.71-1.74)
For each 1-point increase
AF = atrial fibrillation; CHS = Clalit Health Service; CI = confidence interval; HR = hazard ratio.
The Discriminatory Performance of CHADS2 and CHA2DS2-VASc Scores in Predicting New-Onset Atrial Fibrillation
The area under the ROC curve to predict new-onset atrial fibrillation was 0.728 (95% CI, 0.725-0.711) for CHADS2 score, and 0.744 (95% CI, 0.741-0.747) for CHA2DS2-VASc scores (Figure 3).
Figure 3Area under the receiver operating characteristic curve (AUC) for predicting new-onset atrial fibrillation based on CHA2DS2-VASc and CHADS2 scores. CI = confidence interval.
The Independent Association Between Risk Factors and the Risk of Atrial Fibrillation
In a multivariate Cox proportional hazard analysis, all risk factors included in CHADS2 and CHA2DS2-VASc scores were independently associated with the risk of new-onset atrial fibrillation (Table 4). Age, congestive heart failure, and hypertension had the strongest association with atrial fibrillation incidence in both CHADS2 and CHA2DS2-VASc models. Female sex was associated with 9% decrease in atrial fibrillation risk, HR 0.91 (95% CI, 0.88-0.93), compared with males (Table 4).
Table 4Multivariate Cox Proportional Regression Models for the Association Between the Individual Components Risk Factors of CHA2DS2-VASc and CHADS2 and Risk of Atrial Fibrillation; CHS Cohort, Israel 2012
Risk Factor
CHA2DS2-VASc Score HR (95% CI)
CHADS2 Score HR (95% CI)
Age
<65 y
Reference
Age <75 y
65-74.9 y
2.63 (2.53-2.74)
(Reference)
≥75 y
5.78 (5.57-6.00)
3.61 (3.51-3.71)
Sex
Males
Reference
-
Females
0.91 (0.88-0.93)
-
Diabetes mellitus
1.20 (1.17-1.24)
1.26 (1.23-1.30)
Hypertension
1.87 (1.81-1.93)
2.21 (2.14-2.29)
Congestive heart failure
2.08 (1.99-2.18)
2.46 (2.36-2.57)
History of stroke or TIA
1.24 (1.20-1.29)
1.33 (1.29-1.38)
Vascular diseases
1.41 (1.36-1.46)
-
CHS = Clalit Health Service; CI = confidence interval; HR = hazard ratio; TIA = transient ischemic attack.
This study shows that CHADS2 and CHA2DS2-VASc scores have a relatively high performance for the prediction of new-onset atrial fibrillation. The incidence rate of new-onset atrial fibrillation increased in a stepwise fashion with the increase of CHADS2 and CHA2DS2-VASc risk-stratification scores.
Clinically unrecognized and asymptomatic atrial fibrillation is a potentially important cause of stroke, supporting efforts for early detection of atrial fibrillation in at-risk individuals.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) showed that asymptomatic atrial fibrillation detected by implanted devices was associated with a 2.5-fold increased risk of ischemic stroke.
Screening for atrial fibrillation is recommended by the European Society of Cardiology guidelines in patients 65 years or older, by opportunistic screening by pulse palpation, followed by an electrocardiogram (ECG) in those with an irregular pulse.
ESC Committee for Practice Guidelines (CPG) 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
Our study suggests that use of CHADS2 and CHA2DS2-VASc scores may be useful in identifying high-risk subjects who might benefit from screening with ECG and prolonged ECG monitoring to detect subclinical paroxysmal atrial fibrillation.
Few studies have examined the prediction ability for atrial fibrillation of either CHADS2 score alone
CHADS2 score has been found to be useful in risk estimation and stratification of new-onset atrial fibrillation with area under the ROC curve of 0.713, in a cohort study from Taiwan. However, 89.5% of subjects in this cohort had CHADS2 score of 0, and only a small number of the subjects were in higher scores, a fact that might have led to nonrobust estimates of atrial fibrillation incidence rate in high scores categories.
CHADS2 and CHA2DS2-VASc scores were found to predict new-onset atrial fibrillation in a cohort of patients with acute coronary syndrome with area under the ROC curve of 0.71 for each score. In this study the incidence rate of atrial fibrillation in each score category had not been provided, as the authors grouped high scores categories into one group because of the small number of patients in the higher scores.
The high performance of CHADS2 and CHA2DS2-VASc scores in predicting new-onset atrial fibrillation might be explained by the fact that the main risk factors for atrial fibrillation are included in CHADS2 and CHA2DS2-VASc scores,
American College of Cardiology/American Heart Association Task Force on Practice Guidelines 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
as confirmed by this study (Table 4). These risk factors may directly contribute to left atrial remodeling, a process characterized by dilatation and mechanical dysfunction of the left atrium.
Furthermore, CHADS2 score was found to be an independent predictor of atrial fibrillation recurrence after catheter ablation in patients with paroxysmal atrial fibrillation.
This study shows that previous history of stroke or TIA is an independent predictor for new-onset atrial fibrillation (Table 4). Although, according to the medical records, atrial fibrillation was first detected after the diagnosis of stroke or TIA, this association most likely reflects reversal causality, meaning that it actually reflects unrecognized atrial fibrillation that had occurred prior to stroke. Previous studies have shown that paroxysmal atrial fibrillation was common among patients with cryptogenic stroke, with various approaches showing different detection rate of atrial fibrillation in patients with cryptogenic stroke.
The reasons for these sex differences remain unclear, but might be mediated by the effect of sex hormones. Based on experimental studies, it has been suggested that estrogen may attenuate atrial electrical remodeling, thereby decreasing the susceptibility to atrial fibrillation.
Italian Tamoxifen Study Group Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy.
Use of hormonal replacement therapy was found to be associated with decreased risk of new-onset atrial fibrillation in women in the first year after myocardial infarction.
On the other hand, the Women's Health Initiative randomized controlled trials showed a modest increased risk of atrial fibrillation among postmenopausal women assigned to hormonal replacement therapy.
Finally, it should be acknowledged that the lower risk of atrial fibrillation in females may merely reflect residual confounding.
The crude prevalence of and incidence density rate of atrial fibrillation were 6.6% and 0.76 per 100 person-years, respectively, in our study. These rates are slightly different from the prevalence of 5.5% and incidence density rate of 0.99 per 100 person-years found in the Rotterdam study.
Albeit having mean age similar to our study, these differences most likely stem from different distribution of risk factors for atrial fibrillation in the 2 populations, and from modalities used to detect new episodes of atrial fibrillation. The follow-up ECG that was performed in the Rotterdam study might have resulted in a higher incidence rate of atrial fibrillation.
The major strength of this study is the large population-based samples size, which has the power to generate stable and robust estimates of annualized incidence rates of atrial fibrillation within each score category. However, this study has some limitations: firstly, the fact that atrial fibrillation diagnosis was not based on prolonged ECG monitoring, some cases of atrial fibrillation could have been misclassified as nonatrial fibrillation. However, this misclassification is expected to underestimate the true incidence of atrial fibrillation. Our cohort study is observational in nature, and as such, it might have been affected by residual confounding. However, it should be acknowledged that we did not seek to prove a cause-and-effect relationship between CHADS2 and CHA2DS2-VASc scores and atrial fibrillation. Our aim was to assess the usefulness of the simple CHADS2 and CHA2DS2-VASc scores in predicting atrial fibrillation, considering the reductionism of these tools that are based on widely available clinical data. Yet, it is conceivable that the prediction accuracy can be improved by adding to the model other atrial fibrillation risk factors such as echocardiographic measurements that are not available in the CHS database. Future studies are needed to assess the additive role of other risk factors in improving the prediction accuracy of atrial fibrillation.
Conclusions
CHADS2 and CHA2DS2-VASc scores have a relatively high performance for atrial fibrillation prediction. CHADS2 and CHA2DS2-VASc scores are easy to remember and simple to calculate. Using these scores in subjects without atrial fibrillation can enhance rapid clinical assessment to identify those who are at risk who might benefit from screening for atrial fibrillation. More studies are needed to replicate these findings.
References
Wolf P.A.
Abbott R.D.
Kannel W.B.
Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study.
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
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