CLINICAL RESEARCH STUDY
CHA2DS2-VASc Score Is Directly Associated with the Risk of Pulmonary Embolism in Patients with Atrial Fibrillation Walid Saliba, MD, MPH,a,b Gad Rennert, MD, PhDa,c a Department of Community Medicine and Epidemiology, Carmel Medical Center, Clalit Health Services, and Bruce Rappaport Faculty of Medicine, TechnioneIsrael Institute of Technology, Haifa, Israel; bInternal Medicine C, Ha’emek Medical Center, Afula, Israel; c Department of Epidemiology and Disease Prevention, Office of the Chief Physician, Clalit Health Services Headquarters, Tel Aviv, Israel.
ABSTRACT BACKGROUND: The risk stratification score, which includes Congestive heart failure, Hypertension, Age 75 [doubled], Diabetes, Stroke [doubled]- Vascular disease, Age 65-74, and Sex category [female] (CHA2DS2-VASc), is used to predict stroke in atrial fibrillation. However, whether high CHA2DS2-VASc score carries a higher risk of pulmonary embolism remains unknown. We aimed to investigate the association between the severity of CHA2DS2-VASc score and the incidence of pulmonary embolism. METHODS: A total of 73,541 adults with atrial fibrillation diagnosed before January 1, 2012, and no history of pulmonary embolism, were retrospectively identified from the computerized database of the Clalit Health Services, which is the largest not-for-profit health maintenance organization in Israel. The CHA2DS2-VASc score was calculated for each subject at study entry. The cohort was followed for the first occurrence of pulmonary embolism until December 31, 2012 (70,210 person-years). RESULTS: Pulmonary embolism developed in 158 subjects, representing an incidence of 225.0 per 100,000 person-years. The incidence of pulmonary embolism increased with increasing CHA2DS2-VASc score (P < .001). On Cox proportional analysis, CHA2DS2-VASc score was significantly associated with pulmonary embolism (hazard ratio, 1.22; 95% confidence interval [CI], 1.13-1.32) for a 1-point increase in CHA2DS2VASc score. The results were similar after adjusting for anticoagulants and antiplatelet use (hazard ratio, 1.24; 95% CI, 1.14-1.34), and remained unchanged after further adjustment for active malignancy. The predictive values for pulmonary embolism were similar for CHA2DS2-VASc score and the classic risk stratification score which includes Congestive heart failure, Hypertension, Age >75 years, Diabetes, and Stroke [doubled] (CHADS2); the areas under the receiver operating characteristic curves were 0.619 (95% CI, 0.579-0.660) and 0.616 (95% CI, 0.575-0.656), respectively. CONCLUSIONS: CHA2DS2-VASc score is directly associated with the incidence of pulmonary embolism in atrial fibrillation. Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, 45-52 KEYWORDS: Atrial fibrillation; CHA2DS2-VASc; Mortality; Pulmonary embolism
Subjects with atrial fibrillation have a higher tendency to form thrombus in the left atrium, particularly in the appendages, predisposing them to increased risk of stroke.1 The risk stratification score, which includes Congestive Funding: None. Conflict of Interest: None. Authorship: Both authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Walid Saliba, MD, MPH, Department of Internal Medicine C, Ha’emek Medical Center, 18101 Afula, Israel. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2013.10.004
heart failure, Hypertension, Age 75 [doubled], Diabetes, Stroke [doubled] e Vascular disease, Age 65-74, and Sex category [female] (CHA2DS2-VASc), is a well-validated risk stratification score for stroke prediction in patients with atrial fibrillation and serves to determine the need for anticoagulants.2,3 Although a causeeeffect relationship has not been firmly established, available data suggest that most components of the CHA2DS2-VASc score also are potential risk factors for venous thromboembolism.4-14 Congestive heart failure, hypertension, and age are well-established risk factors for venous thromboembolism.4-8 The risk of venous
46
The American Journal of Medicine, Vol 127, No 1, January 2014
thromboembolism also was found to be higher in diabetic diagnosed before January 1, 2012, and who were alive at patients.8-10 An association between venous thromboemthat date. We included only subjects aged 18 years. For bolism and atherosclerosis also was reported.11-14 Although the purpose of this study, we considered only first-time the 2 entities may share common risk factors, it has been pulmonary embolism; therefore, subjects who had a hissuggested that atherosclerosis has the potential to promote tory of pulmonary embolism before January 1, 2012, were the development of venous thromboembolism by activation excluded (a total of 73,541 subjects with atrial fibrillation of both platelets and blood coagwere included in the study). ulation and increase in fibrin CLINICAL SIGNIFICANCE turnover.14 Follow-up Moreover, several studies sug CHA2DS2-VASc score is directly associThe cohort of subjects with atrial gest that atrial fibrillation could be ated with the incidence of pulmonary fibrillation was followed retrospecassociated with an increased risk of embolism in patients with atrial 4,15 tively for the first event of pulmopulmonary embolism. Although fibrillation. nary embolism from January 1, still under major debate, clot for2012, to December 31, 2012. Sub CHA2DS2-VASc and CHADS2 score have mation in the right atrium, which jects without the event of interest seems to occur more frequently in similar and modest predictive value for 16-19 and those who died during the study patients with atrial fibrillation, pulmonary embolism in patients with period were censored at the date of was proposed as a potential mechatrial fibrillation. their death. Mortality was estabanism for the increased risk of pul lished by matching our data with the Anticoagulant use is associated with monary embolism in patients with 17,20 National Death Index using a decreased risk of pulmonary embolism in atrial fibrillation. distinct identification number that patients with atrial fibrillation. Thus, the hypothesis that each resident of Israel holds. CHA2DS2-VASc score may be associated with an increased risk of pulmonary embolism in patients with atrial fibrillation seems Study Variables and Definition of Terms plausible. Although the CHA2DS2-VASc score is recomVariables that were retrieved from the CHS computerized mended by the European Society of Cardiology as a risk database were demographic and clinical variables that are stratification for stroke prevention, it has been derived using components of the CHA2DS2-VASc score. The CHA2DS2any thromboembolism event, including pulmonary emboVASc score is a risk stratification score that ranges from lism.3 However, the association between the severity of 0 to 9 depending on the number and weight of the score risk CHA2DS2-VASc score and the risk of pulmonary embolism components and is calculated as follows: congestive heart in patients with atrial fibrillation was not previously studied failure (1 point), hypertension (1 point), age 65 to 74.9 years separately from stroke. We presumed that the Clalit Health (1 point), age 75 years (2 points), diabetes mellitus Services (CHS) database, which is a population-based data(1 points), stroke (2 point), vascular disease (1 point), and base, may provide a suitable platform that may help clarify female gender (1 point).2,3 The CHA2DS2-VASc score this issue. was calculated at the study entry for each participant.
MATERIALS AND METHODS Study Population and Data Source We used data from the CHS database,21,22 which is a notfor-profit health maintenance organization covering more than half of the Israeli population. The centralized electronic databases of the CHS includes data from multiple sources: primary care physician, specialty clinic 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, using both code reading (eg, International Classification of Diseases, Ninth Revision and International Classification of Primary Care) and text reading. A record is kept of the sources and dates used to establish the diagnosis, with the earliest recorded date being considered the starting date. The CHS computerized database was searched retrospectively for all members in whom atrial fibrillation was
Antithrombotic therapy with oral anticoagulation and antiplatelets was established by searching the pharmacy database for any prescription filled during the 4 months before enrollment into the study. Anticoagulants that were considered included those that were in use in Israel for stroke prevention at the time of the study: vitamin K antagonists, direct thrombin inhibitors, direct factor Xa inhibitors, and antiplatelet agents, which included aspirin and clopidogrel. Antithrombotic therapy was classified into 3 groups: (1) antiplatelets (if antiplatelets were the only antithrombotic therapy used), (2) anticoagulants (if anticoagulants were the only antithrombotic therapy used), and (3) combination therapy (when both anticoagulants and antiplatelets were used).
Statistical Methods Continuous variables that are normally distributed are summarized with mean standard deviation, and skewed variables are summarized with median and interquartile range. Categoric variables are presented as proportions. We
Saliba and Rennert
CHA2DS2-VASc Score and Pulmonary Embolism
estimated the incidence rates of pulmonary embolism by dividing the number of incident cases by the total follow-up period in each CHA2DS2-VASc score. The P for trend of the incidence rate was calculated using Poisson regression. For descriptive purposes only (description of baseline characteristics and distribution of time to event with Kaplan-Meier curves), the CHA2DS2-VASc score was classified into 5 equal interval categories: category 1 (0-1 points), category 2 (2-3 points), category 3 (4-5 points), category 4 (6-7 points), and category 5 (8-9 points). For analytic purposes, to assess the association with pulmonary embolism, the CHA2DS2-VASc score was tested as an ordinal variable. Cox proportional hazard regression analysis was used to assess the association between time to pulmonary embolism and CHA2DS2-VASc score. The association was estimated with hazard ratio (HR) with 95% confidence interval (CI) (for 1-point increase in CHA2DS2VASc score). Three models are presented: Model 1 includes only CHA2DS2-VASc (the crude model), model 2 also includes antithrombotic therapy (anticoagulants and antiplatelet use), and model 3 also includes active malignancy. An interaction factor was examined between CHA2DS2VASc score and anticoagulant use. The predictive value for pulmonary embolism of CHA2DS2-VASc score and the classic risk stratification score which includes Congestive
47
heart failure, Hypertension, Age >75 years, Diabetes, and Stroke [doubled] (CHADS2) was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic curve. For all analyses, a P value less than .05 for the 2-tailed tests was considered statistically significant. All statistical analyses were performed using SPSS 18.0 (SPSS Inc, Chicago, Ill).
RESULTS A total of 73,541 subjects with atrial fibrillation, but without a history of pulmonary embolism, were included in the study. The mean age was 74.3 years (standard deviation, 12.9), the median age was 77.0 years (interquartile range, 67.0-84.0), and 37,280 (50.7%) were female. A history of a stroke was detected in 16,577 subjects (22.5%), and 27,742 subjects (37.7%) were taking anticoagulants at the time of enrollment in the study (Table 1). The proportions of subjects in each CHA2DS2-VASc score category was as follows: 10.2% in category 1, 23.4% in category 2, 38.7% in category 3, 22.8% in category 4, and 4.9% in category 5 (Table 1). The demographic and clinical baseline characteristics of the study cohort presented by the CHA2DS2-VASc score’s 5 categories are shown in Table 1. Even among those with the highest CHA2DS2-VASc score, less than half of subjects were receiving anticoagulant treatment.
Table 1 Distribution of Demographic, Clinical Characteristics, and CHA2DS2-VASc Score Components According to CHA2DS2-VASc Score Category; CHS Cohort, Israel 2012 CHA2DS2-VASc Score Category
Variables Age (y)
CHA2DS2-VASc Score Is Directly Associated with the Risk of Pulmonary Embolism in Patients with Atrial Fibrillation Walid Saliba, MD, MPH,a,b Gad Rennert, MD, PhDa,c a Department of Community Medicine and Epidemiology, Carmel Medical Center, Clalit Health Services, and Bruce Rappaport Faculty of Medicine, TechnioneIsrael Institute of Technology, Haifa, Israel; bInternal Medicine C, Ha’emek Medical Center, Afula, Israel; c Department of Epidemiology and Disease Prevention, Office of the Chief Physician, Clalit Health Services Headquarters, Tel Aviv, Israel.
ABSTRACT BACKGROUND: The risk stratification score, which includes Congestive heart failure, Hypertension, Age 75 [doubled], Diabetes, Stroke [doubled]- Vascular disease, Age 65-74, and Sex category [female] (CHA2DS2-VASc), is used to predict stroke in atrial fibrillation. However, whether high CHA2DS2-VASc score carries a higher risk of pulmonary embolism remains unknown. We aimed to investigate the association between the severity of CHA2DS2-VASc score and the incidence of pulmonary embolism. METHODS: A total of 73,541 adults with atrial fibrillation diagnosed before January 1, 2012, and no history of pulmonary embolism, were retrospectively identified from the computerized database of the Clalit Health Services, which is the largest not-for-profit health maintenance organization in Israel. The CHA2DS2-VASc score was calculated for each subject at study entry. The cohort was followed for the first occurrence of pulmonary embolism until December 31, 2012 (70,210 person-years). RESULTS: Pulmonary embolism developed in 158 subjects, representing an incidence of 225.0 per 100,000 person-years. The incidence of pulmonary embolism increased with increasing CHA2DS2-VASc score (P < .001). On Cox proportional analysis, CHA2DS2-VASc score was significantly associated with pulmonary embolism (hazard ratio, 1.22; 95% confidence interval [CI], 1.13-1.32) for a 1-point increase in CHA2DS2VASc score. The results were similar after adjusting for anticoagulants and antiplatelet use (hazard ratio, 1.24; 95% CI, 1.14-1.34), and remained unchanged after further adjustment for active malignancy. The predictive values for pulmonary embolism were similar for CHA2DS2-VASc score and the classic risk stratification score which includes Congestive heart failure, Hypertension, Age >75 years, Diabetes, and Stroke [doubled] (CHADS2); the areas under the receiver operating characteristic curves were 0.619 (95% CI, 0.579-0.660) and 0.616 (95% CI, 0.575-0.656), respectively. CONCLUSIONS: CHA2DS2-VASc score is directly associated with the incidence of pulmonary embolism in atrial fibrillation. Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, 45-52 KEYWORDS: Atrial fibrillation; CHA2DS2-VASc; Mortality; Pulmonary embolism
Subjects with atrial fibrillation have a higher tendency to form thrombus in the left atrium, particularly in the appendages, predisposing them to increased risk of stroke.1 The risk stratification score, which includes Congestive Funding: None. Conflict of Interest: None. Authorship: Both authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Walid Saliba, MD, MPH, Department of Internal Medicine C, Ha’emek Medical Center, 18101 Afula, Israel. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2013.10.004
heart failure, Hypertension, Age 75 [doubled], Diabetes, Stroke [doubled] e Vascular disease, Age 65-74, and Sex category [female] (CHA2DS2-VASc), is a well-validated risk stratification score for stroke prediction in patients with atrial fibrillation and serves to determine the need for anticoagulants.2,3 Although a causeeeffect relationship has not been firmly established, available data suggest that most components of the CHA2DS2-VASc score also are potential risk factors for venous thromboembolism.4-14 Congestive heart failure, hypertension, and age are well-established risk factors for venous thromboembolism.4-8 The risk of venous
46
The American Journal of Medicine, Vol 127, No 1, January 2014
thromboembolism also was found to be higher in diabetic diagnosed before January 1, 2012, and who were alive at patients.8-10 An association between venous thromboemthat date. We included only subjects aged 18 years. For bolism and atherosclerosis also was reported.11-14 Although the purpose of this study, we considered only first-time the 2 entities may share common risk factors, it has been pulmonary embolism; therefore, subjects who had a hissuggested that atherosclerosis has the potential to promote tory of pulmonary embolism before January 1, 2012, were the development of venous thromboembolism by activation excluded (a total of 73,541 subjects with atrial fibrillation of both platelets and blood coagwere included in the study). ulation and increase in fibrin CLINICAL SIGNIFICANCE turnover.14 Follow-up Moreover, several studies sug CHA2DS2-VASc score is directly associThe cohort of subjects with atrial gest that atrial fibrillation could be ated with the incidence of pulmonary fibrillation was followed retrospecassociated with an increased risk of embolism in patients with atrial 4,15 tively for the first event of pulmopulmonary embolism. Although fibrillation. nary embolism from January 1, still under major debate, clot for2012, to December 31, 2012. Sub CHA2DS2-VASc and CHADS2 score have mation in the right atrium, which jects without the event of interest seems to occur more frequently in similar and modest predictive value for 16-19 and those who died during the study patients with atrial fibrillation, pulmonary embolism in patients with period were censored at the date of was proposed as a potential mechatrial fibrillation. their death. Mortality was estabanism for the increased risk of pul lished by matching our data with the Anticoagulant use is associated with monary embolism in patients with 17,20 National Death Index using a decreased risk of pulmonary embolism in atrial fibrillation. distinct identification number that patients with atrial fibrillation. Thus, the hypothesis that each resident of Israel holds. CHA2DS2-VASc score may be associated with an increased risk of pulmonary embolism in patients with atrial fibrillation seems Study Variables and Definition of Terms plausible. Although the CHA2DS2-VASc score is recomVariables that were retrieved from the CHS computerized mended by the European Society of Cardiology as a risk database were demographic and clinical variables that are stratification for stroke prevention, it has been derived using components of the CHA2DS2-VASc score. The CHA2DS2any thromboembolism event, including pulmonary emboVASc score is a risk stratification score that ranges from lism.3 However, the association between the severity of 0 to 9 depending on the number and weight of the score risk CHA2DS2-VASc score and the risk of pulmonary embolism components and is calculated as follows: congestive heart in patients with atrial fibrillation was not previously studied failure (1 point), hypertension (1 point), age 65 to 74.9 years separately from stroke. We presumed that the Clalit Health (1 point), age 75 years (2 points), diabetes mellitus Services (CHS) database, which is a population-based data(1 points), stroke (2 point), vascular disease (1 point), and base, may provide a suitable platform that may help clarify female gender (1 point).2,3 The CHA2DS2-VASc score this issue. was calculated at the study entry for each participant.
MATERIALS AND METHODS Study Population and Data Source We used data from the CHS database,21,22 which is a notfor-profit health maintenance organization covering more than half of the Israeli population. The centralized electronic databases of the CHS includes data from multiple sources: primary care physician, specialty clinic 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, using both code reading (eg, International Classification of Diseases, Ninth Revision and International Classification of Primary Care) and text reading. A record is kept of the sources and dates used to establish the diagnosis, with the earliest recorded date being considered the starting date. The CHS computerized database was searched retrospectively for all members in whom atrial fibrillation was
Antithrombotic therapy with oral anticoagulation and antiplatelets was established by searching the pharmacy database for any prescription filled during the 4 months before enrollment into the study. Anticoagulants that were considered included those that were in use in Israel for stroke prevention at the time of the study: vitamin K antagonists, direct thrombin inhibitors, direct factor Xa inhibitors, and antiplatelet agents, which included aspirin and clopidogrel. Antithrombotic therapy was classified into 3 groups: (1) antiplatelets (if antiplatelets were the only antithrombotic therapy used), (2) anticoagulants (if anticoagulants were the only antithrombotic therapy used), and (3) combination therapy (when both anticoagulants and antiplatelets were used).
Statistical Methods Continuous variables that are normally distributed are summarized with mean standard deviation, and skewed variables are summarized with median and interquartile range. Categoric variables are presented as proportions. We
Saliba and Rennert
CHA2DS2-VASc Score and Pulmonary Embolism
estimated the incidence rates of pulmonary embolism by dividing the number of incident cases by the total follow-up period in each CHA2DS2-VASc score. The P for trend of the incidence rate was calculated using Poisson regression. For descriptive purposes only (description of baseline characteristics and distribution of time to event with Kaplan-Meier curves), the CHA2DS2-VASc score was classified into 5 equal interval categories: category 1 (0-1 points), category 2 (2-3 points), category 3 (4-5 points), category 4 (6-7 points), and category 5 (8-9 points). For analytic purposes, to assess the association with pulmonary embolism, the CHA2DS2-VASc score was tested as an ordinal variable. Cox proportional hazard regression analysis was used to assess the association between time to pulmonary embolism and CHA2DS2-VASc score. The association was estimated with hazard ratio (HR) with 95% confidence interval (CI) (for 1-point increase in CHA2DS2VASc score). Three models are presented: Model 1 includes only CHA2DS2-VASc (the crude model), model 2 also includes antithrombotic therapy (anticoagulants and antiplatelet use), and model 3 also includes active malignancy. An interaction factor was examined between CHA2DS2VASc score and anticoagulant use. The predictive value for pulmonary embolism of CHA2DS2-VASc score and the classic risk stratification score which includes Congestive
47
heart failure, Hypertension, Age >75 years, Diabetes, and Stroke [doubled] (CHADS2) was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic curve. For all analyses, a P value less than .05 for the 2-tailed tests was considered statistically significant. All statistical analyses were performed using SPSS 18.0 (SPSS Inc, Chicago, Ill).
RESULTS A total of 73,541 subjects with atrial fibrillation, but without a history of pulmonary embolism, were included in the study. The mean age was 74.3 years (standard deviation, 12.9), the median age was 77.0 years (interquartile range, 67.0-84.0), and 37,280 (50.7%) were female. A history of a stroke was detected in 16,577 subjects (22.5%), and 27,742 subjects (37.7%) were taking anticoagulants at the time of enrollment in the study (Table 1). The proportions of subjects in each CHA2DS2-VASc score category was as follows: 10.2% in category 1, 23.4% in category 2, 38.7% in category 3, 22.8% in category 4, and 4.9% in category 5 (Table 1). The demographic and clinical baseline characteristics of the study cohort presented by the CHA2DS2-VASc score’s 5 categories are shown in Table 1. Even among those with the highest CHA2DS2-VASc score, less than half of subjects were receiving anticoagulant treatment.
Table 1 Distribution of Demographic, Clinical Characteristics, and CHA2DS2-VASc Score Components According to CHA2DS2-VASc Score Category; CHS Cohort, Israel 2012 CHA2DS2-VASc Score Category
Variables Age (y)
