Predictors of Long-Term Adverse Outcomes in Elderly Patients Over 80 Years Hospitalized With Heart Failure

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1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Heart Failure Predictors of Long-Term Adverse Outcomes in Elderly Patients Over 80 Years Hospitalized With Heart Failure A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) Sanae Hamaguchi, MD, PhD; Shintaro Kinugawa, MD, PhD; Daisuke Goto, MD, PhD; Miyuki Tsuchihashi-Makaya, PhD; Takashi Yokota, MD, PhD; Satoshi Yamada, MD, PhD; Hisashi Yokoshiki, MD, PhD; Akira Takeshita, MD, PhD; Hiroyuki Tsutsui, MD, PhD for the JCARE-CARD Investigators Background: Aging is associated with adverse outcomes in patients with cardiac diseases. Whether elderly patients hospitalized with heart failure (HF) had increased risks for mortality and rehospitalization compared with younger patients during the long-term follow-up was examined. The predictors of these adverse outcomes were also identified. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of 2,675 patients hospitalized with worsening HF and the outcomes were followed up. The majority of elderly patients were female, had lower body mass index (BMI), a higher rate of ischemic, valvular, and hypertensive heart disease as etiologies of HF, a lower estimated glomerular filtration rate (egfr), lower hemoglobin, and higher left ventricular ejection fraction values. Even after adjustment for covariates, the elderly patients were associated with higher risks of adverse outcomes. The predictors for all-cause death were: lower egfr, lower BMI, male sex, sustained ventricular tachycardia or fibrillation (VT/VF), and the use of diuretics at discharge. Conclusions: Among patients hospitalized with HF, elderly patients had a worse prognosis than younger patients. Lower egfr, lower BMI, male sex, sustained VT/VF, and diuretic use were independent predictors for all-cause death in these patients with higher risk. (Circ J 2011; 75: ) Key Words: Elderly; Heart failure; Mortality; Outcomes; Prognosis The prevalence of heart failure (HF) increases with age and reaches as high as 10% in patients older than 80 years of age. 1 HF is one of the leading causes of death and hospitalization for elderly patients. 2 Recent studies reported that outcomes are particularly poor in elderly patients, especially those older than 80 years (octogenarians). 3 5 Moreover, elderly HF patients differ from younger patients in terms of etiologies, comorbidities, left ventricular (LV) function, and treatment. Treatment is often complicated by the presence of multiple comorbidities and in fact, evidence-based therapies are less frequently used in these patients. 3 5 However, these previous studies were performed mainly in the USA and Europe. Therefore, the clinical characteristics and the long-term outcomes of HF patients older than 80 years were not analyzed in a broad cohort of patients encountered in clinical practice in Japan. The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of patients hospitalized with HF from January 2004 to June 2005, and the outcomes including death and rehospitalization were followed until The JCARE-CARD study enrolled 2,675 patients admitted with HF in a web-based registry at 164 participating hospitals with an average follow up of 2.1 years. The aim of the present study was to determine the clinical characteristics and long-term outcomes including mortality and rehospitalization of HF patients older than 80 years of age Received March 8, 2011; revised manuscript received April 27, 2011; accepted May 23, 2011; released online July 21, 2011 Time for primary review: 30 days Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan Dr Akira Takeshita deceased on March 15, Mailing address: Hiroyuki Tsutsui, MD, PhD, Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo , Japan. htsutsui@med.hokudai.ac.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 2404 HAMAGUCHI S et al. Figure 1. Distribution of age among the total cohort of study patients (n=2,675). and compare the outcomes of these patients with those of younger patients registered in the JCARE-CARD database. Methods Patients The details of the JCARE-CARD have been described previously Briefly, eligible patients were those hospitalized due to worsening HF as the primary cause of admission. The study hospitals were encouraged to register the patients as consecutively as possible. For each patient, baseline data included: (1) age, sex, and body mass index (BMI); (2) causes of HF; (3) medical history; (4) prior procedures; (5) vital signs; (6) laboratory data; (7) echocardiographic data; and (8) medication use at discharge. The data were entered into a web-based electronic data capture (EDC) system licensed by the JCARE- CARD group ( A total cohort of 2,675 patients, registered in JCARE- CARD, were divided into 2 groups according to age: 80 (n=765; 29%) or <80 years old (n=1,910; 71%) at the time of discharge from the index hospitalization. Outcomes The status of all patients was surveyed by June 2008 and the following information of the outcomes was obtained from the participating cardiologists by using a web-based EDC system: (1) all-cause death; (2) cardiac death, defined as death due to HF, myocardial infarction and other causes such as pulmonary embolism; (3) rehospitalization due to an exacerbation of HF that required more than a continuation of their usual therapy on prior admission; and (4) the composite endpoint of all-cause death and rehospitalization due to worsening HF. The endpoints were adjudicated by the cardiologists in each participating hospital. Out of 2,675 patients, 126 (4.7%) patients died during the index hospitalization and 244 patients (9.1%) were missed during follow up. Only patients who survived the index hospitalization and could be followed were included in the follow-up analysis. Follow-up data could thus be obtained in 2,305 out of 2,675 patients (86.2%); 620 patients were 80 years old and 1,685 patients were <80 years old. The mean post discharge follow-up period was 781±315 days (2.1±0.9 years). Statistical Analysis Patient characteristics and treatments were compared using the Pearson chi-square test for categorical variables, Student s t-test for normally distributed continuous variables, and the Mann-Whitney U-test for continuous variables not normally distributed. Cumulative event-free rates during follow up were derived using the method of Kaplan and Meier. The relationship between age and outcomes was evaluated among patients with multivariable adjustment. The covariates, sex, BMI, cause of HF (ischemic, valvular heart disease, hypertensive, and dilated cardiomyopathy), medical history [diabetes, dyslipidemia, stroke, chronic obstructive pulmonary disease (COPD), prior myocardial infarction, smoking, prior ventricular tachycardia or fibrillation (VT/VF)], New York Heart association (NYHA) functional class, heart rate, systolic blood pressure (SBP), egfr, hemoglobin, LV ejection fraction (LVEF), and medication use [angiotensin converting enzyme (ACE) inhibitor, β-blocker, diuretics, nitrate, antiarrhythmic, aspirin, warfarin, statin] were used in developing the post-discharge Cox proportional hazard models. The results were reported as hazard ratios (HR), 95% confidence intervals (CI), and P values. The HR for outcomes of

3 Elderly Patients and Heart Failure 2405 Table 1. Patient Characteristics Characteristics Total (n=2,675) Age (years) <80 (n=1,910) > 80 (n=765) P value Age, years (mean ± SD) 71.0± ± ±4.2 <0.001 Male, % <0.001 BMI, kg/m ± ± ±3.4 <0.001 Causes of HF, % Ischemic Valvular <0.001 Hypertensive <0.001 Dilated cardiomyopathy <0.001 Medical history, % Hypertension <0.001 Diabetes mellitus <0.001 Dyslipidemia <0.001 Hyperuricemia Prior stroke COPD Smoking <0.001 Prior myocardial infarction Atrial fibrillation Sustained VT/VF Procedures, % PCI CABG Valvular surgery <0.001 PPM <0.001 CRT ICD NYHA functional class at discharge, % Vital signs at discharge Heart rate, beats/min 70.5± ± ± SBP, mmhg 117±19 116±19 119±18 <0.001 DBP, mmhg 66.1± ± ±10.3 <0.001 Laboratory data at discharge egfr, ml min m ± ± ±20.5 <0.001 Hemoglobin, g/dl 12.0± ± ±4.2 <0.001 Plasma BNP, pg/ml 390± ± ± Echocardiographic parameters LV EDD, mm 56.1± ± ±10.2 <0.001 LV ESD, mm 44.1± ± ±11.6 <0.001 LVEF, % 42.2± ± ±17.4 <0.001 Data are shown as percent or mean ± SD. BMI, body mass index; HF, heart failure; COPD, chronic obstructive pulmonary disease; VT/VF, ventricular tachycardia/ fibrillation; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; PPM, permanent pacemaker; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; NYHA, New York Heart Association; SBP, systolic blood pressure; DBP, diastolic blood pressure; egfr, estimated glomerular filtration rate; BNP, B-type natriuretic peptide; LV, left ventricular; EDD, end-diastolic diameter; ESD, end-systolic diameter; EF, ejection fraction. the patients 80 years old was compared with those <80 years old. A P value of <0.05 was used as criteria for variables to stay in the model. SPSS version 16.0 J for Windows was used for all statistical analyses. Results Patient Characteristics Figure 1 shows the distribution of the baseline age among the total cohort of study patients (n=2,675). The mean and median ages were 71.0±13.4 (mean ± SD) and 73.0 years old, respec-

4 2406 HAMAGUCHI S et al. Table 2. Medication Use at Hospital Discharge Total (n=2,675) Age (years) <80 (n=1,910) > 80 (n=765) P value ACE inhibitor, % ARB, % ACE inhibitor or ARB, % <0.001 β-blocker, % <0.001 Diuretics, % Loop diuretics, % Spironolactone, % Digitalis, % Ca channel blocker, % Nitrates, % <0.001 Antiarrhythmics, % <0.001 Aspirin, % <0.001 Other antiplatelet drugs, % Warfarin, % <0.001 Statin, % ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. Table 3. Medication Use at Hospital Discharge in Patients With a LVEF <40% Total (n=1,165) Age (years) <80 (n=940) > 80 (n=225) P value ACE inhibitor, % ARB, % ACE inhibitor or ARB, % <0.001 β-blocker, % <0.001 ACE inhibitor or ARB and β-blocker, % <0.001 Spironolactone, % All abbreviations are as per Tables 1,2. Table 4. Unadjusted and Adjusted HRs for Outcomes According to Age Outcomes Age (years) <80 (n=1,685) > 80 (n=620) All-cause death (%) 247 (14.7%) 227 (36.6%) P value Unadjusted HR (95%CI) ( ) <0.001 Adjusted HR (95%CI) ( ) <0.001 Cardiac death (%) 148 (8.8%) 144 (23.2%) Unadjusted HR (95%CI) ( ) <0.001 Adjusted HR (95%CI) ( ) <0.001 Rehospitalization due to worsening HF (%) 557 (33.1%) 279 (45.0%) Unadjusted HR (95%CI) ( ) <0.001 Adjusted HR (95%CI) ( ) All-cause death or rehospitalization (%) 649 (38.5%) 367 (59.2%) Unadjusted HR (95%CI) ( ) <0.001 Adjusted HR (95%CI) ( ) <0.001 The Cox regression model was used in the analysis and was adjusted for the following covariates: sex, BMI, cause of HF (ischemic, valvular heart disease, hypertensive, dilated cardiomyopathy), medical history (diabetes, dyslipidemia, stroke, COPD, prior myocardial infarction, smoking, VT/VF), NYHA functional class at discharge, heart rate, SBP, egfr, hemoglobin, LVEF, and medication use (ACE inhibitor, β-blocker, diuretics, nitrate, antiarrhythmic, aspirin, warfarin, statin). Patients <80 years old were a reference group. HR, hazard ratio; CI, confidence interval. All other abbreviations are as per Table 1. tively. Clinical characteristics for the total cohort of patients and those classified into 2 groups according to age ( 80 and <80 years old) are provided in Table 1. Elderly patients were more frequently women and had significantly lower BMI. They had more ischemic, valvular, and hypertensive etiology and less dilated cardiomyopathy than younger patients. They had more comorbidities including hypertension, prior stroke, COPD, and prior myocardial infarction than younger patients, whereas diabetes mellitus and dyslipidemia were more common in younger

5 Elderly Patients and Heart Failure 2407 Figure 2. Kaplan-Meier survival curves free from all-cause death (A), cardiac death (B), rehospitalization due to worsening HF (C), and all-cause death or rehospitalization (D) in patients with HF <80 years old (black lines, n=1,685) vs. 80 years old (red lines, n=620) at discharge. CI, confidence intervals; HF, heart failure; HR, hazard ratios. Table 5. Predictors of Adverse Outcomes Including All-Cause Death, Cardiac Death, and Rehospitalization due to Worsening HF in Elderly Patients With HF Adjusted HR 95%CI P value All-cause death egfr (per 1 ml min m 2 decrease) <0.001 BMI (per 1 kg/m 2 decrease) Male sex Sustained VT/VF Use of diuretics Cardiac death egfr (per 1 ml min m 2 decrease) BMI (per 1 kg/m 2 decrease) No β-blocker use Ischemic etiology Rehospitalization due to worsening HF egfr (per 1 ml min m 2 decrease) <0.001 Nitrate use No hypertensive heart disease The Cox regression model was used in the analysis and adjusted for the following covariates: age, sex, BMI, cause of HF (ischemic, valvular heart disease, hypertensive, dilated cardiomyopathy), medical history (diabetes, dyslipidemia, stroke, COPD, prior myocardial infarction, smoking, VT/VF, NYHA functional class at discharge, heart rate, SBP, egfr, hemoglobin, LVEF), and medication use (ACE inhibitor, β-blocker, diuretics, nitrate, antiarrhythmic, aspirin, warfarin, statin). All abbreviations are as per Tables 1,4.

6 2408 HAMAGUCHI S et al. patients. They had less VT/VF history and a lower incidence of implantable cardioverter defibrillator implantation. The SBP at discharge was significantly higher, but diastolic blood pressure (DBP) was lower in elderly patients. The egfr and hemoglobin concentration were significantly lower. LV end-diastolic and end-systolic diameters were significantly smaller in elderly patients and LVEF was significantly higher. However, the NYHA functional class was significantly higher in elderly patients. Medication use at hospital discharge was also compared between groups (Table 2). The use of an ACE inhibitor or angiotensin receptor blocker (ARB), spironolactone, and a β-blocker was significantly lower in elderly patients. Conversely, diuretics, aspirin, nitrate, and warfarin were more commonly prescribed to them. Antiarrhythmic agents and statin were used less frequently in elderly patients. Even in the subgroup of patients with a LVEF <40%, the use of an ACE inhibitor or ARB, spironolactone, β-blocker, and ACE inhibitor or ARB and a β-blocker was significantly lower in elderly patients (Table 3). Postdischarge Clinical Outcomes During the follow-up period of 2.1 years after hospital discharge, the rates of adverse outcomes were as follows: allcause death 20.6%, cardiac death 12.7%, rehospitalization due to worsening HF 36.3%, and all-cause death or rehospitalization 44.1%. The unadjusted rates of all-cause death, cardiac death, rehospitalization due to worsening HF, and all-cause death or rehospitalization due to worsening HF were significantly higher in elderly patients (Table 4). Even after adjustment for covariates in multivariable Cox proportional hazard models, elderly patients were associated with a significantly higher adverse risk of all-cause death (HR 2.152, 95%CI , P<0.001), cardiac death (HR 2.383, 95%CI , P<0.001), rehospitalization due to worsening HF (HR 1.446, 95%CI , P=0.001), and all-cause death or rehospitalization (HR 1.635, 95%CI , P<0.001) (Table 4 and Figure 2). Predictors of Adverse Outcomes in Elderly Patients In elderly patients, all-cause death was independently associated with lower egfr, lower BMI, male sex, sustained VT/ VF, and diuretic use in patients older than 80 years (Table 5). Cardiac death was independently associated with a lower egfr, lower BMI, no β-blocker use, and ischemic etiology (Table 5). Rehospitalization due to worsening HF was independently associated with a lower egfr, nitrate use, and no hypertensive heart disease (Table 5). Discussion The present study demonstrated, by using the JCARE-CARD database, that patients older than 80 years hospitalized with HF had worse prognosis than younger patients during the long-term follow-up period up to 2.1 years. Moreover, a lower egfr, lower BMI, male sex, sustained VT/VF, and diuretic use were independent predictors for all-cause death, and a lower egfr, lower BMI, no β-blocker use at discharge, and ischemic etiology were independent predictors for cardiac death in elderly patients. Our findings have confirmed the previous findings, 3 5,16 that elderly HF patients differ from younger patients in terms of etiologies, comorbidities, and LV function, and treatment and outcomes are particularly poor in unselected Japanese patients older than 80 years. Consistent with previous studies, 3 5,16 19 the clinical characteristics of HF patients older than 80 years were different from younger patients (Table 1). Elderly patients were more frequently women, had lower BMI, higher SBP and lower DBP, more hypertensive etiology with preserved LVEF, and more comorbidities such as hypertension, renal dysfunction, anemia, prior stroke, COPD, and prior myocardial infarction. The frequency of diabetes mellitus and dyslipidemia was lower in older patients, which might be related to the high mortality rates in patients with these comorbidities, reducing therefore the likelihood of survival until the age of 80 years old. In contrast, younger patients had more dilated cardiomyopathy with reduced LVEF and sustained VT/VF history. The use of guideline-based standard medications, such as an ACE inhibitor or ARB, β-blocker, and spironolactone was significantly lower in elderly patients in this study (Tables 2,3). These findings were also consistent with previous studies. 3 5,16,17 Several explanations were postulated for the underprescription of these medications in elderly patients. First, elderly patients with HF often had co-morbidities, such as renal dysfunction and COPD, which might limit the use of these medications due to poor tolerability. Second, in the routine clinical practice, evidence-based use of HF medications might not be widely recognized and might not be performed due to the fear of side effects. The attention might be focused on the improvement of symptoms rather than long-term outcomes. Elderly patients had worse prognosis than younger patients during the long-term follow-up period up to 2.1 years (Table 4 and Figure 2). These findings were also consistent with previous studies. 5,16,19 Furthermore, in the present study, lower egfr, lower BMI, male sex, sustained VT/VF, and diuretic use were independent predictors for all-cause death in elderly patients (Table 5). Lower egfr and BMI were also associated with cardiac death (Table 5). In the Euro Heart Failure Survey (EHFS) II, serum creatinine remained a strong independent predictor of mortality in HF patients older than 80 years. 4 In our previous study using the same patient JCARE- CARD database, there was a 1.4% increase in the risk for all-cause death or rehospitalization due to worsening HF for each 1-ml min m 2 decrease in egfr after multivariable adjustment, and lower egfr was associated with poor outcomes even in the subgroup of patients older than 65 years. 7 Therefore, EHFS II as well as JCARE-CARD confirmed prognostic implications of renal dysfunction in elderly patients with HF. These findings indicate the need to manage and care for renal dysfunction to prevent adverse outcomes, especially in elderly patients with HF. Lower BMI was also independently associated with increased all-cause as well as cardiac mortality in not only elderly patients shown in the present study but also in all patients with HF. 15 The use of diuretics at discharge was independently associated with higher mortality in the elderly patients. This finding is consistent with multiple clinical observations that suggested an association between diuretic use and worsening outcomes in patients with HF In the Studies Of Left Ventricular Dysfunction (SOLVED) trial, the use of a diuretic was associated with a 37% increase in the risk of arrhythmic death after controlling for multiple other variables of disease severity. 20 Analysis of the data from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial demonstrated a nearly linear relationship between loop diuretic dose and mortality over 6 months of follow up in patients hospitalized with HF. 22 Administration of diuretics in patients with HF might activate the renin-angiotensin-aldosterone system as well as the sympathetic nervous system, both of which play a determinate role in HF progression. It might also decrease

7 Elderly Patients and Heart Failure 2409 intravascular volume, worsening renal function, and cause electrolyte imbalances such as hypokalemia, hyponatremia, and hypomagnesaemia. In the present study, we confirmed the risk of overuse of diuretics particularly in the elderly HF patients. Moreover, in elderly patients, no β-blocker use was associated with the increased risk for cardiac death. In our previous study, even after adjustment for the covariate and propensity score, the discharge use of a β-blocker was associated with a 51% decrease in the risk of cardiac death after hospital discharge in the patients with a LVEF of <40%. 13 In the EHFS, underuse and an under dose of HF medications were observed in the elderly. However, there was a significant improvement for prescription rates of ACE inhibitors or ARBs, β-blockers, and aldosterone antagonists at discharge in patients over 80 years when compared between EHFS I during and II during (56% vs. 76%, 25% vs. 53%, 15% vs. 38%, respectively; all P<0.001). 3,4 The rate of β-blocker use in this study was lower than that performed by EHFS II at approximately the same time (34.4%), and there might still be room for improvement in β-blocker use in Japan. We confirmed that β-blocker use was associated with a long-term survival benefit in the elderly HF patients as well as in HF patients with a reduced LVEF, suggesting that a greater use of a β-blocker might reduce the risk of cardiac death also in elderly patients. In acute HF, a lower LVEF and a lower SBP are strong predictors for poor prognosis. 23,24 In this study, these parameters were not demonstrated to predict long-term prognosis. Patients with a higher SBP were more likely to have HF with a preserved EF and had a better prognosis in the short-term follow up. 10,23 However, HF patients with a preserved EF had a similar mortality risk and equally high rates of rehospitalization as those with reduced EF during the long-term follow up. 10 Study Limitations Several limitations inherent in the design of the registry should be considered. First, the present study was not a prospective randomized trial and, despite covariate adjustment, other measured and unmeasured factors might have influenced the outcomes. As is widely known, prognosis of chronic HF is strongly determined by an exercise tolerance. Unfortunately, in the JCARE-CARD database, the data for cardiopulmonary exercise testing were not collected. Therefore, we could not assess the association between exercise tolerance and prognosis. Instead, we included resting heart rate as the parameter of autonomic nerve activity in the covariate of the Cox regression model. However, the resting heart rate was not the predictor for the outcomes. Furthermore, a wide QRS wave and serum hyponatremia are associated with adverse outcomes in acute HF. 25,26 However, QRS wave width and serum sodium concentration were not obtained in this study. We thus could not demonstrate the association between these parameters and prognosis and the effects of diuretic use on serum sodium concentration. Second, we did not collect the data for noncardiac diseases including malignancy and other fatal diseases. Third, disproportionate use of medications, such as an ACE inhibitor, ARB, and β-blocker, might affect the outcomes in elderly patients, even though these confounders were corrected in this study. Finally, the data were dependent on the accuracy of documentation and abstraction by individual medical centers that participated in this study. Conclusions Among patients hospitalized for HF, those patients older than 80 years had different characteristics from younger patients. Elderly patients had significantly adverse outcomes including all-cause death, cardiac death, and rehospitalization due to worsening HF. Lower egfr and BMI were significant predictors for death in these patients. Acknowledgments The JCARE-CARD investigators and participating cardiologists are listed in the Appendix of our previous publication. 6 This study could not have been carried out without the help, cooperation and support of the cardiologists from the survey institutions. We thank them for allowing us to obtain the data. The JCARE-CARD was supported by the Japanese Circulation Society and the Japanese Society of Heart Failure and by Health Sciences Research Grants from the Japanese Ministry of Health, Labor and Welfare (Comprehensive Research on Cardiovascular Diseases), and grants from the Japan Heart Foundation and the Japan Arteriosclerosis Prevention Fund. References 1. McMurray JJ, Pfeffer MA. Heart failure. Lancet 2005; 365: Redfield MM. Heart failure: An epidemic of uncertain proportions. N Engl J Med 2002; 347: Komajda M, Hanon O, Hochadel M, Follath F, Swedberg K, Gitt A, et al. Management of octogenarians hospitalized for heart failure in Euro Heart Failure Survey I. Eur Heart J 2007; 28: Komajda M, Hanon O, Hochadel M, Lopez-Sendon JL, Follath F, Ponikowski P, et al. Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II. Eur Heart J 2009; 30: Mahjoub H, Rusinaru D, Souliere V, Durier C, Peltier M, Tribouilloy C. 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