Higher CHA 2 DS 2 -VASc Score Is Associated With Increased Mortality in Acute Pulmonary Embolism

Abstract

Background:

CHA₂DS₂-VASc score has been validated in risk prediction for stroke and thromboembolism in patients with atrial fibrillation (AF). Association of CHA₂DS₂-VASc score with higher risk of venous thromboembolism and pulmonary embolism (PE) has also been shown. In this study, we investigated the long-term prognostic value of CHA₂DS₂-VASc score in patients with acute pulmonary embolism (APE).

Methods:

Consecutive patients with APE presenting to our emergency department were retrospectively recruited. Patients with AF and who died secondary to causes other than PE were excluded from the study. The CHA₂DS₂-VASc score and pulmonary embolism severity index (PESI) were calculated.

Results:

Two hundred seventy seven participants were included in the study. The mortality rate was 18.7%. Twenty-two cases died within 30 days, and 30 cases died during the follow-up period (median: 13 months). The mean CHA₂DS₂-VASc score was significantly higher in dead patients compared to survivors (3.61 ± 1.35 vs 1.95 ± 1.52, P < .01). In multivariate regression analysis, systolic pulmonary artery pressure (hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 1.01-1.06, P = .02), PESI score (HR: 1.010, 95% CI: 1.004-1.017, P < .01), and CHA₂DS₂-VASc score (HR: 1.67, 95% CI: 1.19-2.16, P < .01) were found to be independently correlated with mortality. The patients whose CHA₂DS₂-VASc score was between 1 and 3 had 5.67 times and patients whose CHA₂DS₂-VASc score was ≥4 had 16.8 times higher risk of mortality compared to patients with CHA₂DS₂-VASc score = 0.

Conclusion:

Patients with higher CHA₂DS₂-VASc scores had higher rates of mortality after APE.

Keywords

acute pulmonary embolism mortality

Introduction

Acute pulmonary embolism (APE) is a common clinical presentation of venous thromboembolism (VTE) and is associated with high mortality rates, especially in patients presenting with hemodynamic instability.¹ Cardiovascular risk factors such as hypertension (HT), diabetes mellitus (DM), hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, and obesity have been shown to be associated with an increased risk of VTE.² Besides, pulmonary embolism (PE) risk is higher in patients with cardiovascular diseases such as myocardial infarction (MI) and heart failure (HF),^3,4 and patients with VTE have an increased risk of MI and stroke.⁵

Several prognostic indicators of mortality such as admission clinical properties and laboratory parameters have been defined in APE.^6

–10 Pulmonary embolism severity index (PESI) is a powerful predictor of worse prognosis, and clinical use of PESI is recommended by the European Society of Cardiology.^7,11,12

CHADS₂ and CHA₂DS₂-VASc scores have been widely used in patients with atrial fibrillation (AF) for the prediction of risk of thromboembolic events and also for the management of anticoagulant therapies.^13,14 Higher CHA₂DS₂-VASc scores have been shown to be correlated with a higher risk of APE in patients with AF.¹⁵ In addition, potential clinical use of CHA₂DS₂-VASc score in patients with HF and coronary artery disease (CAD) has been shown.^16,17

Several reports suggest that there is a close association between components of the CHA₂DS₂-VASc score and risk of VTE.^{18

–25} From this point of view, we speculated the hypothesis that higher CHA₂DS₂-VASc scores might be associated with risk of mortality in patients with APE.

Materials and Methods

Study Population

Medical records of our institution were screened for patients who were treated with the diagnosis of APE between January 2011 and January 2015. Initially, a total number of 343 participants were recruited. The exclusion criteria were acute coronary syndrome within the previous 30 days, renal or hepatic failure, acute infectious disease, severe chronic obstructive pulmonary disease, active cancer, heart rhythm other than sinus on 12-lead electrocardiogram, use of anticoagulant drugs before the admission, anemia (a hemoglobin level <13 g/dL in men and <12 g/dL in women), history of blood transfusion within the last 3 months, hematological disorders, and use of immunosuppressant medication. In addition, we excluded cases with a history of PE. According to these criteria, 45 cases were excluded from further analysis.

For the evaluation of long-term events, hospital records, telephone interviews, and state-wide death registry database were used. Patients who were defined to die secondary to causes other than PE were excluded from the study. This group included 7 cases of acute coronary syndrome, 2 cases of cerebrovascular accident, 4 cases of HF, and 8 cases of noncardiac death. Finally, a total number of 277 patients were included in the study. In all of the analysis, we have compared dead patients with survived patients. The study was approved by the local ethics committee.

Definitions

Acute PE was diagnosed by the presence of typical clinical symptoms and abnormal findings in the laboratory parameters, transthoracic echocardiography, and contrast-enhanced computed tomography (CT). In the study population, all of the cases had CT imaging.

Demographic and clinical variables that are components of the CHA₂DS₂-VASc score were obtained from the hospital database. The CHA₂DS₂-VASc score is a risk stratification score that ranges from 0 to 9 and is calculated as follows: congestive HF (1 point), HT (1 point), age 65 to 74.9 years (1 point), age ≥75 years (2 points), DM (1 point), stroke (2 points), vascular disease (1 point), and female gender (1 point).²⁶ The CHA₂DS₂-VASc score was calculated for each patient. We separated patients into 3 groups such as CHA₂DS₂-VASc score = 0, between 1 and 3, and ≥4.

Pulmonary embolism severity index is a validated scoring tool estimating 30-day mortality related to APE.⁹ For risk stratification, patients’ PESI scores that included 11 parameters (age, male sex, cancer, chronic HF, chronic pulmonary disease, pulse rate, systolic blood pressure [BP], respiratory rate, temperature, altered mental status, and arterial oxyhemoglobin saturation) were calculated.⁷ Hypertension was defined as the use of antihypertensive drugs or initial BP over 140/90 mm Hg, DM was defined as the use of antidiabetic drugs or fasting plasma glucose levels of >126 mg/dL, and hyperlipidemia was defined as total serum cholesterol levels >240 mg/dL. Smoking status was defined as current tobacco use. Hypotension was defined as a systolic BP <90 mm Hg or a pressure drop of more than 40 mm Hg for longer than 15 minutes if not caused by a new-onset arrhythmia, hypovolemia, or sepsis.⁷ Congestive HF was defined as moderate to severe systolic dysfunction or patients with recent decompensated HF requiring hospitalization, irrespective of ejection fraction.²⁶ Vascular disease was defined as history of MI, peripheral arterial disease, or aortic atherosclerosis.¹³

Laboratory Analysis

According to the hospital protocol, venous blood samples were taken from antecubital vein and collected in calcium EDTA tubes during the emergency admission. Blood counts were studied by an autoanalyzer (Cell-Dyn 3700, Abbott Laboratories, Illinois, USA) within 30 minutes after blood sampling. The results of other routine biochemical laboratory parameters, such as maximal troponin I, brain natriuretic peptide (BNP), d-dimer levels, were collected using electronic database of the hospital.

Echocardiography and CT Imaging

A complete echocardiographic study was performed with Vivid 3 system (General Electric, Norway) during the initial evaluation of the patients. Systolic pulmonary arterial pressure (sPAP) was calculated by adding transtricuspid pressure gradient to mean right atrial pressure estimated from inferior vena cava diameter and motion during respiration as follows: mean right atrial pressure was estimated to be 5 mm Hg if there was a complete collapse of a normal diameter inferior vena cava during inspiration; 10 mm Hg if a normal diameter inferior vena cava collapse was >50%; 15 mm Hg if a dilated inferior vena cava collapsed by >50% with inspiration; and 20 mm Hg if there was no visible evidence of dilated inferior vena cava collapse.²⁷

Multislice spiral 64-slice CT was performed in the radiology clinic using PE protocol (field of view: 35 cm, section thickness: 3 mm, contrast material volume: 135 mL, and contrast material injection rate: 4 mL/s). Diagnosis of APE was established in case of a complete or partial luminal filling defect in the main pulmonary artery or its branches.

Medications

Enoxaparin was commenced in all patients with a dose of 1 mg/kg twice a day immediately after the diagnosis of APE was ascertained. Thrombolytic treatment (tissue plasminogen activator [tPA]) was given as an intravenous infusion of 100 mg in 2 hours in patients with hemodynamic instability. Oral warfarin therapy was started in all patients on the day of admission, except for the cases treated with tPA who had warfarin treatment 24 hours after the therapy. Patients continued oral anticoagulation therapy for at least 3 months after discharge. The duration of oral warfarin therapy was left to the discretion of the primary physician.

Statistical Analysis

All data were presented as a mean ± standard deviation (SD) or a median [interquartile range] for parametric variables and as percentages for categorical variables. Continuous variables were checked for the normal distribution assumption using Kolmogorov-Smirnov statistics. Differences between survivors and nonsurvivors were evaluated using independent samples t test or Mann-Whitney U test. Categorical variables were tested by Pearson χ² test and Fisher exact test. Cox regression analyses were used to investigate the univariable and multivariable predictors of mortality during the study period. Forward stepwise multivariable regression models using parameters with P < .10 were created in Cox regression analyses. Kaplan-Meier estimates and curves were generated (Figure 1), and CHA₂DS₂-VASc subgroups were compared using log-rank tests. P values were 2 sided, and values <.05 were considered statistically significant. All statistical studies were carried out using Statistical Package for Social Sciences software (SPSS 16.0 for Windows; SPSS Inc, Chicago, Illinois).

Figure 1.

Kaplan-Meier curve showing the significant mortality difference between CHA₂DS₂-VASc subgroups.

Results

During a follow-period of 13 [15] months, 52 (18.7%) patients died. Twenty-two of the dead participants died within 30 days. Clinical, demographic, and laboratory characteristics of the survived and dead patients are summarized in Tables 1 and 2. Between the 2 groups, significant differences were observed in terms of age, gender, systolic BP, history of HT, congestive HF, CAD, and cerebrovascular disease. The mean PESI scores and systolic pulmonary artery pressure were significantly higher in the dead patients compared to the survived patients (151 ± 60 vs 77 ± 24 mm Hg and 71 ± 18 vs 49 ± 10 mm Hg; P < .01 and P < .01, respectively). Hemoglobin, white blood cell count, fasting glucose, maximal troponin I, and BNP levels were significantly higher, and total cholesterol, HDL cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were significantly lower in dead patients compared to survived patients. However, platelets, urea, creatinine, and maximal d-dimer levels were similar between the 2 groups. The frequency of patients who received thrombolytic therapy was not different between the survived and nonsurvived group (24% vs 23%; P = .84).

Table 1.

Comparison of Demographic and Clinic Parameters and Clinical Outcome of the Study Population.

	Study Population (n = 277)	Survivors (n = 225)	Nonsurvivors (n = 52)	P ^a
Age, years	63.9 ± 17.6	61.7 ± 17.7	73.3 ± 13.6	<.01
Gender: male, n (%)	113 (40)	99 (44)	14 (26)	.02
HT, n (%)	112 (40)	82 (36)	40 (76)	<.01
DM, n (%)	27 (10)	19 (8.4)	8 (15)	.13
HF, n (%)	12 (4)	5 (2)	7 (13)	<.01
Vascular disease, n (%)	40 (14)	25 (11)	15 (29)	<.01
Stroke, n (%)	9 (3)	3 (1)	6 (11)	<.01
CHA₂DS₂-VASc score	2.26 ± 1.65	1.95 ± 1.52	3.61 ± 1.35	<.01
SBP	107 ± 23	110 ± 23	99 ± 21	.02
Thrombolytic therapy, n (%)	68 (24)	56 (24)	12 (23)	.84
PESI score	91.1 ± 44.8	77 ± 24	151 ± 60	<.01
sPAP, mm Hg	53.1 ± 15.0	49 ± 10	71 ± 18	<.01
Clinical outcome
Follow-up, months	13 [15]	13 [19]	12.5 [22]	.32
Mortality at 30 days, n (%)	-	-	22 (42)	NA
Long-term mortality, n (%)	-	-	30 (57)	NA
CHA₂DS₂-VASc = 0, n (%)	52 (18)	51 (22)	1 (2)
CHA₂DS₂-VASc = 1-3, n (%)	155 (55)	135 (60)	20 (38)	<.01
CHA₂DS₂-VASc ≥4, n (%)	70 (25)	39 (17)	31 (59)

Abbreviations: DM, diabetes mellitus; HF, heart failure; HT, hypertension; NA, not available; PESI, pulmonary embolism severity index; SBP, systolic blood pressure; sPAP, systolic pulmonary arterial pressure.

^aP value is calculated by comparison of survivors to nonsurvivors.

Table 2.

Comparison of Laboratory Parameters in the Study Population.

	Study Population (n = 277)	Survivors (n = 225)	Nonsurvivors (n = 52)	P ^a
Hemoglobin (g/dL)	12.1 ± 1.95	12.3 ± 1.9	11.6 ± 2.0	.04
WBC count (10³/L)	6.6 [10.2]	5.9 [9.7]	7.6 [5.6]	<.01
Platelets (10³/L)	236 ± 85	232 ± 87	240 ± 82	.62
Fasting glucose (mg/dL)	125 [49]	123 [43]	139 [74]	.02
Urea (mg/dL)	24.3 ± 14.2	23.5 ± 13.5	28.1 ±16.8	.06
Creatinine (mg/dL)	1.09 ± 0.6	1.1 ± 0.5	1.2 ± 0.4	.24
Total cholesterol (mg/dL)	178 ± 48	180 ± 45	160 ± 44	<.01
LDL cholesterol (mg/dL)	112 ± 37	118 ± 35	92 ± 42	<.01
HDL cholesterol (mg/dL)	44 ± 11	46 ± 11	41 ± 11	<.01
Triglycerides (mg/dL)	151 ± 69	134 ± 42	155 ± 63	<.01
d-Dimer (ng/mL)	1570 [2030]	1540 [1950]	1860 [4530]	.31
Troponin I (ng/mL)	0.07 [0.30]	0.08 [0.31]	0.26 [0.86]	.02
BNP (pg/mL)	345 [520]	335 [450]	550 [580]	<.01

Abbreviations: BNP, brain natriuretic peptide; HDL, high-density lipoprotein; LDL, low-density lipoprotein; WBC, white blood cell.

^aP value is calculated by comparison of survivors to nonsurvivors.

The mean CHA₂DS₂-VASc score was significantly higher in dead patients compared to survivors (3.61 ± 1.35 vs 1.95 ± 1.52, P < .01). The frequency of patients whose CHA₂DS₂-VASc score = 0 (2% vs 22%) and CHA₂DS₂-VASc score = 1 to 3 (38% vs 60%) was lower, and the frequency of patients with CHA₂DS₂-VASc score ≥4 was higher in nonsurvivors (59% vs 17%, P < .01) compared to survivors.

In univariate Cox regression analysis, age, gender, systolic BP, PESI score, sPAP, troponin I, BNP, and CHA₂DS₂-VASc score were found to be correlated with mortality in the study population (Table 3). In multivariate regression analysis, using model adjusted for the aforementioned parameters, CHA₂DS₂-VASc score (hazard ratio [HR]: 1.67, 95% confidence interval [CI]: 1.19-2.16, P < .01), PESI scores (HR: 1.010, 95% CI: 1.004-1.017, P < .01), and sPAP (HR: 1.03, 95% CI: 1.01-1.06, P = .02) were found to be independently correlated with mortality. The patients whose CHA₂DS₂-VASc score = 1 to 3 had 5.67 times higher risk for mortality, and patients whose CHA₂DS₂-VASc score ≥4 had 16.8 times higher risk for mortality compared to patients with CHA₂DS₂-VASc score = 0 (P < .01 and P < .01). In Kaplan-Meier curve, patients with CHA₂DS₂-VASc score = 1 to 3 and patients with CHA₂DS₂-VASc score ≥4 had significantly higher risk for mortality (log-rank P < .01).

Table 3.

Univariate and Multivariate Cox Regression Analysis of Possible Predictors of Total Mortality in the Study Population.

Variables	Unadjusted HR (95% CI)	P	Adjusted HR (95% CI)	P
Age^a	1.04 (1.02-1.07)	<.01	-	-
Male gender^a	0.39 (0.21-0.72)	<.01	-	-
Smoking	1.13 (0.52-2.46)	.76	-	-
Systolic BP	0.98 (0.97-0.99)	<.01	1.01 (0.97-1.02)	.66
sPAP	1.05 (1.04-1.07)	<.01	1.03 (1.01-1.06)	.02
Thrombolytic treatment	1.23 (0.64-2.36)	.54	-	-
Total cholesterol	0.98 (0.97-0.99)	.03	0.99 (0.98-1.01)	.81
Troponin I	1.41 (1.04-1.91)	<.01	1.19 (0.79-2.11)	.55
d-dimer	1.001 (0.99-1.002)	.32	-	-
BNP	1.002 (1.001-1.003)	<.01	1.001 (0.99-1.002)	.10
PESI score	1.020 (1.016-1.024)	<.01	1.010 (1.004-1.017)	<.01
CHA₂DS₂-VASc score	1.79 (1.49-2.14)	<.01	1.67 (1.19-2.16)	<.01
CHA₂DS₂-VASc subgroups
CHA₂DS₂-VASc = 0	Reference		Reference
CHA₂DS₂-VASc = 1-3	11.1 (1.46-24.35)	<.01	5.67 (1.14-19.21)	<.01
CHA₂DS₂-VASc ≥ 4	36.3 (4.9-81.5)	<.01	16.8 (2.2-52.5)	<.01

Abbreviations: BNP, brain natriuretic peptide; BP, blood pressure; CI, confidence interval; HR, hazard ratio; PESI, pulmonary embolism severity index; sPAP, systolic pulmonary arterial pressure.

^aThese parameters were not included in the multivariable model as they are components of the CHA₂DS₂-VASc score.

Discussion

In this study, we have shown that mortality rate of APE increased with increasing CHA₂DS₂-VASc scores. Patients whose CHA₂DS₂-VASc score ≥4 had 16.8 times higher risk for mortality compared to patients with CHA₂DS₂-VASc score = 0. The CHA₂DS₂-VASc scoring system is easy to apply and is familiar to clinicians in daily practice. Thus, we suppose that it may have clinical use in patients with APE besides PESI.

Several studies suggest that VTE of unknown origin and cardiovascular disorders may share common risk factors.^25,28 The atherosclerotic risk factors such as obesity, diabetes, arterial HT, and dyslipidemia have also been demonstrated to be risk factors for VTE.^{21,24,29

–32} Activation of platelets and coagulation cascade triggered by atherosclerosis that causes fibrin turnover is the basis of pathogenesis consequently.^33

–36 Diabetes mellitus is associated with increased levels of procoagulant factors.³⁷ Dyslipidemia is associated with hypercoagulability, endothelial dysfunction, and increased platelet aggregation.³⁸

Many of the risk factors of VTE and atherosclerosis are also the components of CHA₂DS₂-VASc score. The higher CHADS₂ and CHA₂DS₂-VASc scores are associated with poor prognosis in cardiovascular diseases. Yaghi et al reported an association between presence of CHADS₂ components and stroke-related in-hospital mortality in patients with AF.³⁹ Poçi et al noticed the correlation between CHADS₂ score and poor prognosis in patients with acute coronary syndrome who do not have AF.⁴⁰ Paoletti Perini et al mentioned that CHA₂DS₂-VASc score is an independent predictor of major clinical events at 30-month follow-up in patients with HF.¹⁶ Thus, we speculated the hypothesis that higher CHA₂DS₂-VASc scores may be associated with worse prognosis in patients with APE.

Saliba and Rennert have shown the association between CHA₂DS₂-VASc score and incidence of PE in a large number of participants with AF.¹⁵ They have emphasized that patients with AF having higher CHA₂DS₂-VASc score also had a higher risk for PE. In addition, they have shown that all-cause mortality rate increased with increasing CHA₂DS₂-VASc score. However, the association of CHA₂DS₂-VASc score with mortality rate after APE was not reported. In our study, we have excluded cases with AF, and for the first time in the literature, our findings implicate the prognostic value of CHA₂DS₂-VASc in APE even if the participants are in sinus rhythm.

Pulmonary embolism severity index is accepted as a reliable clinical prognostic score for 30-day mortality.⁹ In our study, the mean PESI scores were significantly higher in dead patients compared to survivors. In multivariate regression analysis, sPAP, PESI scores, and CHA₂DS₂-VASc score were found to be independently correlated with mortality. Some differences have been observed in our study population compared to large-scale studies of PE. In our study, female patients had higher mortality rates compared to males. This is a contradictory finding when PESI score is concerned, as male gender is a negative prognostic parameter in PESI. This study was performed in a tertiary center, which may affect the proportion of patients with high-risk features in the study population. As most of the study participants were referred from other hospitals, our findings may not directly reflect the general population. This result implies that the use of CHA₂DS₂-VASc score besides PESI score may give additional prognostic information in patients with APE.

Limitations

This is a retrospective, observational, and single-center study with limited number of patients and has inherent limitations of a retrospective design. The duration and effectiveness of the anticoagulant therapy during follow-up period could not be standardized. Nevertheless, all of the patients had international normalized ratio controls monthly after hospital discharge (according to the hospital protocol) for at least 3 months.

Conclusion

CHA₂DS₂-VASc score that is usually used in patients with AF can also be used for risk prediction in patients with sinus rhythm and APE. CHA₂DS₂-VASc score may further give prognostic clues besides PESI score, which is a well-validated score for risk stratification in APE. Further prospective studies are warranted to investigate the clinical use of CHA₂DS₂-VASc score in APE.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Stein

Matta

Keyes

Willyerd

. Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism. Am J Med. 2012;125(5):478–484.

Ageno

Becattini

Brighton

Selby

Kamphuisen

. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation. 2008;117(1):93–102.

Sørensen

Horvath-Puho

Lash

. Heart disease may be a risk factor for pulmonary embolism without peripheral deep venous thrombosis. Circulation. 2011;124(13):1435–1441.

Prandoni

Pesavento

Sorensen

. Prevalence of heart diseases in patients with pulmonary embolism with and without peripheral venous thrombosis: findings from a cross-sectional survey. Eur J Intern Med. 2009;20(5):470–473.

Sørensen

Horvath-Puho

Pedersen

Baron

Prandoni

. Venous thromboembolism and subsequent hospitalization due to acute arterial cardiovascular events: a 20-year cohort study. Lancet. 2007;370(9601):1773–1779.

Goldhaber

Visani

De Rosa

. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):1386–1389.

Konstantinides

Torbicki

Agnelli

. ESC Committee for Practice Guidelines (CPG). Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2014;35(43):3033–3069.

Kucher

Goldhaber

. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation. 2003;108(18):2191-2194.

Aujesky

Obrosky

Stone

. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med. 2005;172(8):1041-1046.

10.

Agnelli

Becattini

. Acute pulmonary embolism. N Engl J Med. 2010;363(3):266–274.

11.

Chan

Woods

Shorr

. The validation and reproducibility of the pulmonary embolism severity index. J Thromb Haemost. 2010;8(7):1509–1514.

12.

Donzé

Le Gal

Fine

. Prospective validation of the Pulmonary Embolism Severity Index. A clinical prognostic model for pulmonary embolism. Thromb Haemost. 2008;100(5):943–948.

13.

European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace. 2010;12(10):1360–1420.

14.

Olesen

Lip

Hansen

. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ. 2011;342:d124.

15.

Saliba

Rennert

. CHA2DS2-VASc score is directly associated with the risk of pulmonary embolism in patients with atrial fibrillation. Am J Med. 2014;127(1):45–52.

16.

Paoletti Perini

Bartolini

Pieragnoli

. CHADS2 and CHA2DS2-VASc scores to predict morbidity and mortality in heart failure patients candidates to cardiac resynchronization therapy. Europace. 2014;16(1):71–80.

17.

Cetin

Cakici

Zencir

. Prediction of coronary artery disease severity using CHADS2 and CHA2DS2-VASc scores and a newly defined CHA2DS2-VASc-HS score. Am J Cardiol. 2014;113(6):950–956.

18.

Huerta

Johansson

Wallander

García Rodríguez

. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med. 2007;167(9):935–943.

19.

British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax. 2003;58(6):470–483.

20.

Dean

Abraham

. Venous thromboembolic disease in congestive heart failure. Congest Heart Fail. 2010;16(4):164–169.

21.

Goldhaber

Grodstein

Stampfer

. A prospective study of risk factors for pulmonary embolism in women. JAMA. 1997;277(8):642–645.

22.

Hong

Zhu

Pilgram

Sicard

Bae

. Coronary artery calcification and risk factors for atherosclerosis in patients with venous thromboembolism. Atherosclerosis. 2005;183(1):169–174.

23.

Tsai

Cushman

Rosamond

Heckbert

Polak

Folsom

. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002;162(10):1182–1189.

24.

Petrauskiene

Falk

Waernbaum

Norberg

Eriksson

. The risk of venous thromboembolism is markedly elevated in patients with diabetes. Diabetologia. 2005;48(5):1017–1021.

25.

Prandoni

Bilora

Marchiori

. An association between atherosclerosis and venous thrombosis. N Engl J Med. 2003;348(15):1435–1441.

26.

Camm

Lip

De Caterina

. 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. Europace. 2012;14(10):1385–1413.

27.

Seward

Tajik

AJ.

The Echo Manual. 3rd ed. Philadelphia, PA: LWW; 2009:401–415.

28.

Prandoni

Ghirarduzzi

Prins

. Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis. J Thromb Haemost. 2006;4(9):1891–1896.

29.

Hansson

Eriksson

Welin

Svardsudd

Wilhelmsen

. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: “the Study of Men Born in 1913”. Arch Intern Med. 1999;159(16):1886–1890.

30.

Samama

. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med. 2000;160(22):3415–3420.

31.

Vaya

Mira

Ferrando

. Hyperlipidemia and venous thromboembolism in patients lacking thrombophilic risk factors. Br J Haematol. 2002;118(1):255–259.

32.

Deguchi

Pecheniuk

Elias

Averell

Griffin

. High density lipoprotein deficiency and dyslipoproteinemia associated with venous thrombosis in men. Circulation. 2005;112(6):893–899.

33.

Libby

. Multiple mechanisms of thrombosis complicating atherosclerotic plaques. Clin Cardiol. 2000;23(suppl 6):3–7.

34.

Libby

Simon

. Thrombosis and atherosclerosis. In: Colman

Hirsh

Marder

, eds. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:743–752.

35.

Sueishi

Ichikawa

Kato

Nakagawa

Chen

. Atherosclerosis: coagulation and fibrinolysis. Semin Thromb Hemost. 1998;24(3):255–260.

36.

Holvoet

Collen

. Thrombosis and atherosclerosis. Curr Opin Lipidol. 1997;8(5):320–328.

37.

Colwell

Nesto

. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care. 2003;26(7):2181–2188.

38.

Doggen

Smith

Lemaitre

Heckbert

Roosendaal

Psaty

. Serum lipid levels and the risk of venous thrombosis. Arterioscler Thromb Vasc Biol. 2004;24(10):1970–1975.

39.

Yaghi

Sherzai

Pilot

Sherzai

Elkind

. The CHADS2 components are associated with stroke-related in-hospital mortality in patients with atrial fibrillation. J Neurol Sci. 2015;24(10):2404–2407.

40.

Poçi

Hartford

Karlsson

Herlitz

Edvardsson

Caidahl

. Role of the CHADS2 score in acute coronary syndromes: risk of subsequent death or stroke in patients with and without atrial fibrillation. Chest. 2012;141(6):1431–1440.