heart failure ( hf ) is a major cause of death among the elderly in many countries and has become a significant public health problem.1 , 2 the chads2 and cha2ds2vasc scores are risk assessment tools to predict stroke in patients with atrial fibrillation ( af)3 and can be used to guide anticoagulation therapy,4 , 5 in complement with or as a substitute of other risk scores for af.6 the cha2ds2vasc score has been proved to be more sensitive than the chads2 score to predict cardioembolic events in af patients.7 in recent years , the use of the cha2ds2vasc score in predicting ischemic stroke , thromboembolism , and death has extended beyond the originally proposed af field.8 , 9 it has been reported that high cha2ds2vasc score are associated with mortality in patients with acute coronary syndrome,10 irrespective of the presence or absence of af . therefore , the aims of the present study were to verify the value of the cha2ds2vasc score as a risk assessment tool for mortality in patients with hf , irrespective of the presence or absence of af . this was a prospective observational study that enrolled consecutive symptomatic hf patients hospitalized for treatment of decompensated hf at fukushima medical university between 2009 and 2013 . patients were defined based on the framingham criteria11 and new york heart association ( nyha ) class    ii at enrollment , and those with acute coronary syndrome were excluded ( figure  1 ) . the patients were divided into three groups based on their cha2ds2vasc score during hospitalization ( patients were given : 1 point for an age 65 to 74  years , female sex , hf , hypertension , diabetes mellitus , and vascular disease ; and 2 points for an age 75  years or older , previous stroke / transient ischemic attack : and these were summed up as of 19 points ) : score 13 group ( n  =  316 ) , score 46 group ( n  =  549 ) and score 79 group ( n  =  145).4 we compared the clinical features and results from laboratory tests and echocardiography among the three groups . hypertension was defined as recent use of antihypertensive drugs , or systolic blood pressure    140  mmhg , and/or diastolic blood pressure  >  90  mmhg . diabetes was defined as recent use of insulin or antidiabetic drugs , a fasting blood glucose value of  >  126  mg / dl , and/or a hemoglobin a1c value of  >  6.5% . dyslipidemia was defined as recent use of cholesterollowering drugs , a triglyceride value of  >  150  mg / dl , a lowdensity lipoprotein cholesterol value of  >  140  mg / dl , and/or a highdensity lipoprotein cholesterol value of < 40  mg / dl . the estimated glomerular filtration rate ( gfr ) was measured by the modification of diet in renal disease formula.12 chronic kidney disease was defined as an estimated gfr  <  60  ml / min/1.73  m.12 anemia was defined as hemoglobin of <  12.0  g / dl in females and <  13.0  g / dl in males.2 af was identified by an electrocardiogram performed during hospitalization and/or medical records including past history . the patients were followed up until march 2015 for allcause mortality , which was the primary outcome of our study . cardiac death was adjudicated by independent experienced cardiologists and included death due to worsened hf in accordance with the framingham criteria,11 ventricular fibrillation documented by electrocardiogram or other implantable devices and acute coronary syndrome . noncardiac death included death due to cancer , respiratory failure , renal failure , infection , sepsis , stroke , or digestive hemorrhage etc . status and dates of death were obtained from the patients ' medical records or their referring cardiologists . survival time was calculated from the date of hospitalization until the date of death or last followup . reporting of the study conforms to strobe along with references to strobe and the broader equator guidelines.13 
  echocardiography was performed blindly by an experienced echocardiographer using the standard techniques . echocardiographic parameters included left ventricular ejection fraction ( lvef ) , left atrial volume , the ratio of early transmitral flow velocity to mitral annular velocity ( mitral valve e / e ) , inferior vena cava diameter , peak systolic pulmonary artery pressure ( spap ) and right ventricular fractional area change.14 the lvef was calculated using simpson 's method . mitral valve e / e was calculated by transmitral doppler flow and tissue doppler imaging . spap was calculated by adding the right atrial pressure ( estimated by the diameter and collapsibility of the inferior vena cava ) to the systolic trans tricuspid pressure gradient.14 the right ventricular fractional area change , defined as ( end diastolic area end systolic area)/end diastolic area    100 , is a measure of right ventricular systolic function.14 all measurements were performed using ultrasound systems ( acuson sequoia , siemens medical solutions usa , inc . , mountain view , ca , usa ) . normally distributed data are presented as mean    sd and nonnormally distributed data are presented as median ( interquartile range ) . we used the analysis of variance ( anova ) followed by tukey 's posthoc test . the kaplan  meier method was used for presenting the eventfree rate , and the logrank test was used for initial comparisons . univariable and multivariable cox proportional hazard analyses were used to analyze predictors of allcause mortality to adjust confounding factors . hazard ratio ( hr ) and 95% confidence interval ( ci ) the cha2ds2vasc score to predict allcause mortality in the cox proportional hazards regression model was analysed by cstatistics . to prepare for potential confounding , we considered the following clinical factors , which are not included in the elements of the cha2ds2vasc score and are generally known to affect the risk of mortality in hf patients : the levels of systolic blood pressure , heart rate , nyha class above iii , presence of ischemic etiology , reduced lvef ( <  50% ) , af , chronic kidney disease , anemia , hyponatremia ( <  135  meq / l ) , and usage of rasinhibitors , blockers , diuretics , inotropic agents , antidiabetic agents , and statins . furthermore , to assess the potential heterogeneity of associations between cha2ds2vasc score and allcause mortality , we conducted subgroup analyses . interactions between cha2ds2vasc scores and clinically relevant variables , including systolic blood pressure ( mean , 128  mmhg ) , heart rate ( mean , 83  bpm ) , presence of nyha class above iii , reduced lvef ( lvef <  50% ) , ischemic etiology , af , chronic kidney disease , anemia , and hyponatremia , were estimated by a cox proportional hazards regression model , and are shown in a forest plot . a value of p  <  0.05 was considered statistically significant for all comparisons . this was a prospective observational study that enrolled consecutive symptomatic hf patients hospitalized for treatment of decompensated hf at fukushima medical university between 2009 and 2013 . patients were defined based on the framingham criteria11 and new york heart association ( nyha ) class    ii at enrollment , and those with acute coronary syndrome were excluded ( figure  1 ) . the patients were divided into three groups based on their cha2ds2vasc score during hospitalization ( patients were given : 1 point for an age 65 to 74  years , female sex , hf , hypertension , diabetes mellitus , and vascular disease ; and 2 points for an age 75  years or older , previous stroke / transient ischemic attack : and these were summed up as of 19 points ) : score 13 group ( n  =  316 ) , score 46 group ( n  =  549 ) and score 79 group ( n  =  145).4 we compared the clinical features and results from laboratory tests and echocardiography among the three groups . hypertension was defined as recent use of antihypertensive drugs , or systolic blood pressure    140  mmhg , and/or diastolic blood pressure  >  90  mmhg . diabetes was defined as recent use of insulin or antidiabetic drugs , a fasting blood glucose value of  >  126  mg / dl , and/or a hemoglobin a1c value of  >  6.5% . dyslipidemia was defined as recent use of cholesterollowering drugs , a triglyceride value of  >  150  mg / dl , a lowdensity lipoprotein cholesterol value of  >  140  mg / dl , and/or a highdensity lipoprotein cholesterol value of < 40  mg / dl . the estimated glomerular filtration rate ( gfr ) was measured by the modification of diet in renal disease formula.12 chronic kidney disease was defined as an estimated gfr  <  60  ml / min/1.73  m.12 anemia was defined as hemoglobin of <  12.0  g / dl in females and <  13.0  g / dl in males.2 af was identified by an electrocardiogram performed during hospitalization and/or medical records including past history . the patients were followed up until march 2015 for allcause mortality , which was the primary outcome of our study . cardiac death was adjudicated by independent experienced cardiologists and included death due to worsened hf in accordance with the framingham criteria,11 ventricular fibrillation documented by electrocardiogram or other implantable devices and acute coronary syndrome . noncardiac death included death due to cancer , respiratory failure , renal failure , infection , sepsis , stroke , or digestive hemorrhage etc . status and dates of death were obtained from the patients ' medical records or their referring cardiologists . survival time was calculated from the date of hospitalization until the date of death or last followup . reporting of the study conforms to strobe along with references to strobe and the broader equator guidelines.13 echocardiographic parameters included left ventricular ejection fraction ( lvef ) , left atrial volume , the ratio of early transmitral flow velocity to mitral annular velocity ( mitral valve e / e ) , inferior vena cava diameter , peak systolic pulmonary artery pressure ( spap ) and right ventricular fractional area change.14 the lvef was calculated using simpson 's method . mitral valve e / e was calculated by transmitral doppler flow and tissue doppler imaging . spap was calculated by adding the right atrial pressure ( estimated by the diameter and collapsibility of the inferior vena cava ) to the systolic trans tricuspid pressure gradient.14 the right ventricular fractional area change , defined as ( end diastolic area end systolic area)/end diastolic area    100 , is a measure of right ventricular systolic function.14 all measurements were performed using ultrasound systems ( acuson sequoia , siemens medical solutions usa , inc . normally distributed data are presented as mean    sd and nonnormally distributed data are presented as median ( interquartile range ) . we used the analysis of variance ( anova ) followed by tukey 's posthoc test . the kaplan  meier method was used for presenting the eventfree rate , and the logrank test was used for initial comparisons . univariable and multivariable cox proportional hazard analyses were used to analyze predictors of allcause mortality to adjust confounding factors . hazard ratio ( hr ) and 95% confidence interval ( ci ) the cha2ds2vasc score to predict allcause mortality in the cox proportional hazards regression model was analysed by cstatistics . to prepare for potential confounding , we considered the following clinical factors , which are not included in the elements of the cha2ds2vasc score and are generally known to affect the risk of mortality in hf patients : the levels of systolic blood pressure , heart rate , nyha class above iii , presence of ischemic etiology , reduced lvef ( <  50% ) , af , chronic kidney disease , anemia , hyponatremia ( <  135  meq / l ) , and usage of rasinhibitors , blockers , diuretics , inotropic agents , antidiabetic agents , and statins . furthermore , to assess the potential heterogeneity of associations between cha2ds2vasc score and allcause mortality , we conducted subgroup analyses . interactions between cha2ds2vasc scores and clinically relevant variables , including systolic blood pressure ( mean , 128  mmhg ) , heart rate ( mean , 83  bpm ) , presence of nyha class above iii , reduced lvef ( lvef <  50% ) , ischemic etiology , af , chronic kidney disease , anemia , and hyponatremia , were estimated by a cox proportional hazards regression model , and are shown in a forest plot . a value of p  <  0.05 was considered statistically significant for all comparisons . the clinical features of the present study 's subjects are summarized in table  1 . the score 79 group had a higher prevalence of female gender , more comorbidities , including hypertension , diabetes , chronic kidney disease , anemia , stroke and vascular disease , a higher age , and a higher systolic blood pressure than the score 13 and score 46 groups . comparisons of laboratory data and parameters of echocardiography among the three groups are shown in table  2 . the score 79 group had lower levels of hemoglobin , estimated gfr , total protein , albumin , and higher levels of btype natriuretic peptide , creactive protein , and glucose than the score 13 group . with regard to parameters of echocardiography , left and right ventricular systolic function did not differ among the three groups , and mitral valve e / e was higher in the score 79 group than in the score 13 group . comparisons of clinical features among cha2ds2vasc score class ( n  =  1011 ) ckd , chronic kidney disease ; lvef , left ventricular ejection fraction ; nyha , new york heart association ; ras , reninangiotensinaldosterone system ; tia , transient ischemic attack . p  <  0.01 vs. low score group , 
 p  <  0.01 vs. moderate score group . laboratory data and echocardiographic data bnp , btype natriuretic peptide ; egfr , estimated glomerular filtration ; hdl , high density lipoprotein cholesterol ; ldl , low density lipoprotein cholesterol , lvef , left ventricular ejection fraction ; mitral valve e / e , ratio of the peak transmitral velocity during early diastole to the peak mitral valve annular velocity during early diastole ; rvfac , right ventricular fractional area change ; spap , systolic pulmonary artery pressure . p  <  0.01 vs. low score group , 
 p  <  0.01 vs. moderate score group . 
 data are presented as median ( interquartile range ) . during the followup period ( median 801  days ) , there were 151 cardiac deaths , including 119 due to worsening hf and 32 with ventricular fibrillation , and 113 noncardiac deaths ( cancer , n  =  29 ; respiratory failure and/or pneumonia , n  =  27 ; infection / sepsis , n  =  18 ; stroke , n  =  11 ; renal failure / multiple organ failure , n  =  9 ; digestive hemorrhage , n  =  6 ; aneurysm , n  =  4 ; and other problems n  =  9 ) . we estimated the cstatistic for cha2ds2vasc score ( 0.664 , 95% ci : 0.6250.702 ) . the number of patients and mortality according to each cha2ds2vasc score is shown in the 
 table s1 
 . as shown in figure  2 , allcause mortality was significantly higher in the score 46 group and score 79 group than in the score 13 group ( p  <  0.001 ) . furthermore , as shown in figures  3  and  4 , allcause mortalities were significantly higher in the score 46 group and score 79 group than in the score 13 groups ( p  < 0.001 ) in the hf patients , irrespective of the presence or absence of af ( figure  3a and b ) , ischemic or nonischemic etiology ( figure  4a and b ) , and reduced or preserved ejection fraction ( ef ) ( figure  4c and d ) . the cox proportional hazard model was used to examine the prognostic value of the cha2ds2vasc score in hf patients ( table  3 ) . kaplan meier analysis for allcause mortality in the score 13 group , the score 46 group , and the score 79 group in hf patients . meier analysis for allcause mortality in the score 13 group , the score 46 group , and the score 79 group in heart failure ( hf ) patients with atrial fibrillation ( af ) ( a ) and without af ( b ) . * p  <  0.05 . kaplan  meier analysis for allcause mortality in the score 13 group , the score 46 group , and the score 79 group in heart failure ( hf ) patients with ischemic etiology ( a ) , nonischemic etiology ( b ) , reduced left ventricular ejection fraction ( lvef ) ( c ) , and preserved lvef ( d ) . cox proportional hazard model of allcause mortality in heart failure : impact of cha2ds2vasc score 
 adjusted model : adjusted for systolic blood pressure , heart rate , nyha class over iii , presence of ischemic etiology , reduced left ventricular ejection fraction , atrial fibrillation , chronic kidney disease , anemia , hyponatremia , and usage of rasinhibitors , blockers , calcium channel blockers , diuretics , inotropic agents , antidiabetic agents , statins , antiplatelets , and anticoagulations . 
 adjusted model : adjusted for nyha class over iii , presence of ischemic etiology , reduced left ventricular ejection fraction , chronic kidney disease , anemia , hyponatremia , and usage of rasinhibitors , blockers , diuretics , inotropic agents , antidiabetic agents , and statins . in the multivariable analysis , the higher cha2ds2vasc score was an independent predictor of allcause mortality in hf patients irrespective of the presence or absence of af , after adjusting for other confounding factors . interaction analyses rendered similar results to subgroup analyses , with the additional benefit of being able to statistically test for differences in associations between cha2ds2vasc score and allcause mortality between subgroups . in figure  5 , a forest plot illustrates the association between the cha2ds2vasc score and allcause mortality in subgroups after adjustment for interactions between the cha2ds2vasc score and prespecified clinically important variables . there was no interaction the subgroup analysis describes associations between cha2ds2vasc scores and allcause mortality in subgroups after adjustment for interactions between the cha2ds2vasc scores and prespecified clinically important variables . ckd , chronic kidney disease ; lvef , left ventricular ejection fraction ; nyha , new york heart association . we emphasized that cha2ds2vasc score was useful in predicting mortality in hf patients , irrespective of the presence or absence of af , ischemic or nonischemic etiology , and reduced or preserved ef . in hf patients , af is a frequent comorbidity and its prevalence is related to the severity of the clinical status of patients.15 hf and af share common riskfactors , and the occurrence of either of them may induce the onset of a vicious circle which , in turn , facilitates the manifestation of the other.16 although the chads2 and cha2ds2vasc score series are predictors of stroke in af patients,3 their predictivity has recently extended beyond their original field as follows : ( 1 ) ischemic stroke in patients with coronary artery disease without af,17 ( 2 ) mortality , recurrences of stroke , and major cardiovascular events in stroke patients without af,18 ( 3 ) mortality in stroke survivors with or without af,19 ( 4 ) hospitalization for cardiovascular causes in af patients,20 and ( 5 ) hf hospitalization and cardiac death in hf patients who underwent cardiac resynchronization therapy.21 in addition , it has been recently reported that cha2ds2vasc score was associated with not only thromboembolic complications but also mortality in patients with hf.22 the absolute risk of thromboembolic complications in hf patients at high cha2ds2vasc scores is higher in those without af than in those with af,22 concordant with our data . unlike the previous data,22 we focused on the impact of cha2ds2vasc scores on mortality under some clinically important backgrounds including nyha class , lvef , etiology of hf , and presence of chronic kidney disease , anemia , hyponatremia , and several medications . in our data , the predictivity of the cha2ds2vasc score for mortality was consistent under consideration of other important confounders and several situations , such as those the presence or absence of af , ischemic or nonischemic etiology , reduced or preserved ef . although the cha2ds2vasc components indeed may increase the risk of mortality , not all the individual components have been identified as mortality risk factors in the hf population . it is suggested that 841% of hf patients have diabetes mellitus,23 which is associated with increased mortality and morbidity.24 , 25 it is also reported that hf patients have higher mortality after stroke.26 one possible explanation for this phenomenon might be a strokeinduced amplification of cardiac failure due to autonomic dysregulation and aspiration resulting in pneumonia.26 , 27 hf patients with ischemic etiology have higher mortality.1 , 2 a few studies have revealed that hf patients with peripheral artery disease had poor prognosis.28 , 29 on the other hand , female is associated with a decreased mortality.1 , 2 
  in addition , the chads2 risk factors may directly contribute to left atrial remodeling , a process characterized by dilatation and mechanical dysfunction of the left atrium.30 the chads2 and cha2ds2vasc scores are associated with left atrial dysfunction , even in patients without baseline af.31 in af patients , the chads2 score is related to systemic inflammation and left atrial thrombus formation.32 
  our study has several strengths , and differs from previous studies.10 , 22 for instance , the present study is the first to show the association of high cha2ds2vasc score with high allcause mortality in hf patients , under consideration of several confounders and background , using multivariable analyses and subgroup analyses . in addition , hf diagnosis was made and detailed causes of death were determined by our experienced cardiologists . there are several limitations to the present study . conducted as a prospective observational study in a single institution with relatively small number of subjects , it is possible that the present study is somewhat underpowered to accurately estimate the association between cha2ds2vasc score and mortality in hf . although we assessed using the multivariable cox proportional hazard regression analyses and subgroup analyses , the effects of differences in comorbidities among the three groups might not have been completely adjusted , and the present results should be viewed as preliminary . therefore , further studies with a larger population are needed . our study has several strengths , and differs from previous studies.10 , 22 for instance , the present study is the first to show the association of high cha2ds2vasc score with high allcause mortality in hf patients , under consideration of several confounders and background , using multivariable analyses and subgroup analyses . in addition , hf diagnosis was made and detailed causes of death were determined by our experienced cardiologists . conducted as a prospective observational study in a single institution with relatively small number of subjects , it is possible that the present study is somewhat underpowered to accurately estimate the association between cha2ds2vasc score and mortality in hf . although we assessed using the multivariable cox proportional hazard regression analyses and subgroup analyses , the effects of differences in comorbidities among the three groups might not have been completely adjusted , and the present results should be viewed as preliminary . therefore , further studies with a larger population are needed . cha2ds2vasc score , which is a simple and comprehensive risk assessment score , provides important information concerning prognosis in hf patients . in hf patients , irrespective of af , the cha2ds2vasc score would identify those at a higher risk of mortality . table  s1 . comparisons of allcause mortality among each cha2ds2vasc score ( n  =  1011 ) . kaplan  meier analysis for ( a ) rehospitalization and ( b ) cardiac mortality in the score 13 group , the score 46 group , and the score 79 group in heart failure patients .