Incidence and Predictors of Rehospitalization of Acute Heart Failure Patients Hidehiro Kaneko,1 MD, Shinya Suzuki,1 MD, Masato Goto,1 MD, Takuto Arita,1 MD, Yasufumi Yuzawa,1 MD, Naoharu Yagi,1 MD, Nobuhiro Murata,1 MD, Yuko Kato,1 MD, Hiroto Kano,1 MD, Shunsuke Matsuno,1 MD, Takayuki Otsuka,1 MD, Tokuhisa Uejima,1 MD, Yuji Oikawa,1 MD, Koichi Sagara,1 MD, Kazuyuki Nagashima,1 MD, Hajime Kirigaya,1 MD, Hitoshi Sawada,1 MD, Tadanori Aizawa,1 MD, Junji Yajima,1 MD, and Takeshi Yamashita,1 MD Summary Repeated hospitalization due to acute decompensated heart failure (HF) is a pandemic health problem in Japan. However, it is difficult to predict rehospitalization after discharge for acute decompensated HF. We used a single hospital-based cohort from the Shinken Database 2004–2012, comprising all new patients (n = 19,994) who visited the Cardiovascular Institute Hospital. A total of 282 patients discharged after their first acute HF admission were included in the analysis. The median follow-up period was 908 ± 865 days. Of these patients, rehospitalization due to worsening HF occurred in 55 patients. The cumulative rate of rehospitalization was 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years. Patients with rehospitalization were older than those without rehospitalization. Prevalence of diabetes mellitus (DM) was more common in patients with rehospitalization. Average heart rate (HR) tended to be higher in patients with rehospitalization. Loop diuretics were more commonly used at hospital discharge in patients with rehospitalization. Multivariate Cox regression analysis revealed that age ≥ 75 years, DM, HR ≥ 75 bpm at discharge, and use of loop diuretics at discharge were independent predictors for rehospitalization. The number of these independent risk factors could be used to clearly discriminate between the HF rehospitalization low-, middle- and high-risk patients. HF rehospitalization commonly occurred in patients who were discharged after their first acute HF admission. Older age, DM, increased HR, and loop diuretics use at discharge were independently associated with HF rehospitalization. By simply counting these risk factors, we might be able to predict the risk of HF rehospitalization after discharge. (Int Heart J 2015; 56: 219-225) Key words: Heart rate, Elderly, Diabetes mellitus, Diuretics, Japanese
I
n developed countries, heart failure (HF) is the most common cause of hospitalization in aged populations.1) For example, over the age of 65 years, HF hospitalization resulted in 6.5 million hospital days annually in the United States.2) Understandably, hospitalization is closely associated with increased mortality in outpatients with chronic HF. HF admission is also an economical problem. Hospital admission due to worsening HF is the largest contributor of unexpected readmissions cost.3) In Japan, HF admission, especially repeated hospital admission due to worsening HF, is also common and a serious problem. Some large registries focused on the prognosis of Japanese HF patients and reported determinant factors for all-cause or cardiovascular mortality.4,5) However, there are limited data regarding the predictors of rehospitalization due to worsening HF.6) Interestingly, the prognostic determinants for HF rehospitalization seem to be not similar to those for mortality. For example, the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), which is one of the largest registries that enrolled Japanese hospitalized
HF patients, demonstrated that beta-blocker use at hospital discharge was associated with a significant reduced risk of allcause mortality and cardiac mortality after hospital discharge, but was not associated with the incidence of HF rehospitalization.7) Therefore, we need to clarify the prognostic factors of HF rehospitalization in the Japanese population. Accordingly, we have been conducting a hospital-based cohort study of the Shinken Database since 2004 to investigate the prevalence and prognosis of patients with cardiovascular diseases in Japan.8-11) Among them, we examined patients admitted to our institute due to acute decompensated HF and aimed to clarify the incidence and predictors of HF readmission after hospital discharge in acute decompensated HF patients.
Methods The Shinken Database includes all new patients who visited the Cardiovascular Institute
Study population and protocol:
From the 1 Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan. This work was supported by the Japanese Society for the Promotion of Science (Hidehiro Kaneko). Address for correspondence: Hidehiro Kaneko, MD, The Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19 Nishiazabu, Minato-ku, Tokyo 106-0031, Japan. E-mail: [email protected] Received for publication September 8, 2014. Revised and accepted September 30, 2014. Released in advance online on J-STAGE February 27, 2015. All rights reserved by the International Heart Journal Association. 219
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in Tokyo, Japan (“Shinken” is a Japanese abbreviation for the name of the hospital), and excludes patients who are foreign travellers and those with active cancer. This hospital-based database was established to investigate the prevalence and prognosis of cardiovascular diseases in the urban areas of Japan.12-15) The registry began in June 2004, and patients have been continually registered to the database annually. The present study analyzed data from this database collected between June 2004 and March 2013 (Shinken Database 2004– 2012) and included 19,994 new visiting patients. Among them, 537 patients were admitted to our institute due to acute decompensated HF. We excluded HF patients with primary valvular heart disease (n = 138), prior history of valve surgery (n = 15), acute coronary syndrome (n = 24), in-hospital death (n = 4), and prior history of HF admission (n = 74). In the end, 282 patients were examined in the present study (Figure 1). The median follow-up period was 908 ± 865 days. Ethics: The Ethics Committee of the Cardiovascular Institute approved this study, and all patients provided written informed consent. Data collection: For each patient, after undergoing electrocardiography and chest radiography, cardiovascular status was evaluated by echocardiography and blood laboratory data at the time of hospital admission. As initial clinical parameters, collected data included gender, age, body mass index, and coexisting conditions. In most patients, additional echocardiographic parameters included left ventricular end-diastolic dimension (LVDd), left ventricular end-systolic dimension (LVDs), interventricular septum thickness (IVST), posterior wall thickness (PWT), and LV ejection fraction (LVEF). An estimated glomerular filtration rate (eGFR) was calculated using the eGFR equation for the Japanese population: eGFR = 194 × (serum creatinine)-1.094 × (age)-0.287 × (0.739, if the patient is female).16) A baseline eGFR < 60 mL·minute-1·1.73m-2 was used to define chronic kidney disease (CKD).17) Anemia was defined as a hemoglobin level of < 11 g/dL. Idiopathic dilated cardiomyopathy was diagnosed by the presence of global LV dilatation with impaired systolic function (in general LVDd ≥ 55 mm and LVEF < 50%) occurring in the absence of known cardiac causes. Hypertrophic cardiomyopathy was diagnosed by echocardiography when hypertrophy (IVST or PWT > 12 mm) without hypertension was present. We defined HFpEF patients as HF patients with preserved LVEF (ie, LVEF > 50%), and HFrEF patients as HF patients with reduced LVEF (ie, LVEF ≤ 50%), as previously described.8,18) Patients were divided into three groups by clinical scenario (CS): CS1, systolic blood pressure (BP) at admission > 140 mmHg; CS2, ≥ 100 mmHg; CS3, < 100 mmHg.19) We confirmed HF events (HF requiring hospitalization or death due to HF) that were classified into the International Classification of Diseases, 10th revision, code I50, using the medical records of our hospital or by the information obtained from follow-up. Statistical analysis: Categorical and consecutive data regarding patient background are presented as numbers (%) and the mean ± standard deviation, respectively. The chi-square test was used for comparisons between groups, and the unpaired ttest was used for comparison of consecutive variables. Longterm, event-free survival was estimated using Kaplan-Meier curves and the log-rank test to assess the significance of differences between the groups. Multiple Cox regression analysis including variables with P values ≤ 0.10 on univariate analysis
was performed to determine the predictors of HF rehospitalization. A probability value of < 0.05 was considered to indicate a statistically significant difference. Statistical analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA), version 19.0 software.
Results Among the 282 patients, HF rehospitalization occurred in 55 patients. The cumulative rate of rehospitalization was 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years (Figure 2). Patients with rehospitalization were older than those without rehospitalization (73 ± 13 versus 68 ± 14 years, P = 0.024). A gender difference was not seen between the two groups. Patients with rehospitalization had a higher prevalence of diabetes mellitus (DM) (42% versus 24%, P = 0.007). The
Figure 1. Patient flow chart of the present study.
Figure 2. Incidence of heart failure rehospitalization in patients who were discharged after their first acute HF admission.
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prevalence of ischemic cardiomyopathy (ICM) tended to be higher in patients with rehospitalization (42% versus 29%, P = 0.058). The prevalence of CKD, dilated cardiomyopathy, and atrial fibrillation were comparable between the two groups. Btype natriuretic peptide levels at hospital admission were also comparable between patients with and without rehospitalization. The distribution of CS classification was not significantly different between the two groups (Table I). Echocardiography revealed that LVDd and LVDs were similar between patients with and without rehospitalization. LVEF and the distribution of HFpEF and HFrEF were also comparable between the two groups (Table II). Systolic BP at discharge was comparable between patients with and without rehospitalization. Diastolic BP at discharge was lower in patients with rehospitalization (67 ± 11 Table I. Characteristics of Patients Rehospitalization Rehospitalization Absent Present (n = 227) (n = 55) Age (years) Male sex BMI (kg/m2) Hypertension Diabetes Mellitus Smoking CKD Anemia ICM DCM HCM HHD AF BNP (pg/mL) CS I II III
68 ± 14 70% 24 ± 5 59% 24% 38% 14% 20% 29% 16% 2.6% 5.7% 39% 760 ± 729
73 ± 13 67% 24 ± 4 60% 42% 35% 11% 22% 42% 13% 5.5% 10.9% 35% 918 ± 714
37% 60% 2.7%
35% 58% 7.7%
P 0.024 0.737 0.960 0.849 0.007 0.646 0.588 0.741 0.058 0.546 0.287 0.169 0.563 0.150 0.216
BMI indicates body mass index; CKD, chronic kidney disease; ICM, ischemic cardiomyopathy; DCM, idiopathic dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HHD, hypertensive heart disease; AF, atrial fibrillation; BNP, brain natriuretic peptide; and CS, clinical scenario.Data are expressed as mean ± standard deviation, or percentage.
Table II. Echocardiography Findings Rehospitalization Rehospitalization Absent Present (n = 227) (n = 55) IVST (mm) PWT (mm) LVDd (mm) LVDs (mm) LVEF (%) HFpEF HFrEF LAD (mm)
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10.3 ± 4.8 9.3 ± 1.9 53.2 ± 9.5 41.4 ± 13.2 44.3 ± 20.2 40% 60% 43.0 ± 9.2
10.1 ± 2.6 9.1 ± 2.0 53.5 ± 11.6 43.0 ± 14.5 43.0 ± 19.6 36% 64% 43.9 ± 10.0
P 0.838 0.444 0.776 0.442 0.656 0.571 0.571 0.527
IVST indicates interventricular septum thickness; PWT, posterior wall thickness; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVEF, left ventricular ejection fraction; HFpEF, heart failure with preserved LVEF; HFrEF, heart failure with reduced LVEF; and LAD, left atrial dimension. Data are expressed as mean ± standard deviation, or percentage.
versus 71 ± 11 mmHg, P = 0.025). HR at discharge tended to be higher in patients with rehospitalization (77 ± 15 versus 73 ± 13 bpm, P = 0.065) (Table III). Beta-blockers, renin-angiotensin system inhibitors, and antiarrhythmic drugs were similarly used at hospital discharge between patients with and without rehospitalization. Loop diuretics were more commonly used in patients with rehospitalization (91% versus 72%, P = 0.003) (Table IV). Multivariate Cox regression analysis (forced entry method) including the covariates age ≥ 75 years, DM, ICM, diastolic BP at discharge ≥ 70 mmHg, heart rate at discharge ≥ 75 bpm and loop diuretics use at discharge demonstrated that age ≥ 75 years (HR 1.850, 95% CI 1.031-3.321, P = 0.039) DM (HR 1.892, 95% CI 1.044-3.427, P = 0.035), HR at discharge ≥ 75 bpm (HR 1.813, 95% CI 1.005-3.272, P = 0.048), and loop diuretics use at discharge (HR 2.622, 95% CI 1.0053.272, P = 0.043) were independent determinants of HF rehospitalization (Table V). According to the number of risk factors, we categorized study patients into a low risk group (number of risks = 0 or 1), middle risk group (number of risks = 2), and high risk group (number of risks = 3 or 4). As the data sets are not complete for all patients, we could not categorize 27 patients. Finally, we
Table III. Vital Signs at Hospital Discharge Rehospitalization Rehospitalization Absent Present (n = 227) (n = 55) SBP (mmHg) DBP (mmHg) HR (bpm)
123 ± 16 71 ± 11 73 ± 13
120 ± 18 67 ± 11 77 ± 15
P 0.303 0.025 0.065
SBP indicates systolic blood pressure; DBP, diastolic blood pressure; and HR, heart rate. Data are expressed as mean ± standard deviation.
Table IV. Medication at Hospital Discharge Rehospitalization Rehospitalization Absent Present (n = 227) (n = 55) Beta-blockers RAS-Is AAD Statins Loop Diuretics Aldosterone antagonists Digitalis
66% 74% 12% 26% 72% 38% 13%
69% 76% 15% 36% 91% 46% 16%
P 0.671 0.671 0.593 0.143 0.003 0.303 0.484
RAS-I indicates renin-angiotensin system inhibitor; and AAD, antiarrhythmic drug. Data are expressed as percentage.
Table V. Determinants of Heart Failure Rehospitalization
Age ≥ 75 years Diabetes Mellitus HR ≥75 bpm Loop Diuretics
HR
95% CI
P
1.850 1.892 1.813 2.622
1.031-3.321 1.044-3.427 1.005-3.272 1.005-3.272
0.039 0.035 0.048 0.043
Cox regression analysis for heart failure rehospitalization. HR indicates hazard ratio; CI, confidence interval; and HR, heart rate.
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categorized 96 patients into the low risk group, 98 patients into the middle risk group, and 61 patients into the high risk group. Heart failure rehospitalization occurred in 8 patients (8%) in the low risk group, 21 patients (21%) in the middle risk group, and 19 patients (31%) in the high risk group. Kaplan-Meier curves and the log-rank test demonstrated that the incidence of HF rehospitalization increased with the number of these independent risk factors in a dependent manner (Log-rank P < 0.001) (Figure 3). The number of risk factors could be used to discriminate between the HF rehospitalization low-, middle- and high-risk patients (the cumulative rate of rehospitalization was 6.7% at 1 year, 8.4% at 2 years, and 12.5% at 3 years in patients scoring 0 and 1, 8.7% at 1 year, 23.7% at 2 years, and 26.1% at 3 years in patients scoring 2, and 28.6% at 1 year, 36.8% at 2 years, and 45.8% at 3 years in patients scoring 3 and 4) (Figure 4).
Discussion The present study reports data from an observational cohort of HF patients that were analyzed to clarify the incidence and the predictors of HF rehospitalization. The major findings of the present study were as follows: 1) HF rehospitalization occurred in 55/282 of the patients who were discharged after their first acute HF admission. The cumulative rate of rehospi-
Figure 3. Kaplan-Meier curves for heart failure rehospitalization.
Figure 4. Cumulative rate of heart failure rehospitalization according to the number of risk factors.
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talization was 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years. 2) Patients with rehospitalization were older than those without rehospitalization. DM was more common in patients with rehospitalization. Average HR at discharge tended to be higher in those with rehospitalization. Loop diuretics were more commonly used at discharge in patients with rehospitalization. 3) Multivariate Cox regression analysis revealed that age ≥ 75 years, diabetes mellitus, HR ≥ 75 bpm at discharge, and use of loop diuretics at discharge were independent predictors for HF rehospitalization. 4) The number of these risk factors present could be used to clearly discriminate between the HF rehospitalization low-, middle- and high-risk subjects. Compared with previous studies performed in Western countries,3,20,21) the rehospitalization rate of Japanese HF patients seems to be lower.4) In the present study, rehospitalization due to worsening HF occurred with cumulative rates of rehospitalization of 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years, findings that are in agreement with a previous Japanese study.4) The epidemiology of HF in Japan is different from that in Western countries with respect to ethnic background and etiology and these differences might contribute to the lower incidence of HF rehospitalization in Japan. Although the HF rehospitalization rate is lower in Japan, it is commonly observed in our daily clinical practice. However, there are limited data focusing on the predictors for the rehospitalization of acute HF patients. In the present study, older age, DM, increased HR, and loop diuretic use at the time of hospital discharge were independently associated with HF rehospitalization. About 70% of heart failure rehospitalization occurred within one year after hospital discharge, suggesting the importance of the careful observation of HF patients in the early phase after hospital discharge. So far we have performed the routine checkup of HF patients at 9 months after hospital discharge. However, according to the results of the present study, we might need to perform routine checkups at earlier phases after hospital discharge to identify signs of worsening HF. Various previous studies have demonstrated that elderly HF patients had poor outcomes.22-24) Elderly HF patients are different from younger HF patients in terms of etiologies, comorbidities, left ventricular (LV) function (systolic and diastolic function), and treatment. Furthermore, treatment is often complicated by multiple comorbidities and it is difficult to administer evidence-based therapies in elderly patients.22-24) Concordant with the present study, Hamaguchi, et al reported that the rehospitalization rate was significantly higher in Japanese elderly HF patients.25) Our country has the highest proportion of elderly citizens in the world. Therefore, improving the management of HF in elderly patients is quite important in Japanese clinical practice. Diabetes mellitus (DM) is closely associated with a higher risk of HF independent of the presence of coronary heart disease and hypertension. DM itself may sometimes induce diabetic cardiomyopathy and cause LV dysfunction. The close link between DM and HF was previously confirmed by the Framingham Study 26) and the risk of HF development in patients with DM is associated with the severity of hyperglycemia.27,28) However, intensive glucose control unfortunately has not been shown to decrease HF development in patients with DM.29) Moreover, some types of antidiabetic agents are difficult to administer to HF patients. Thiazolidinediones some-
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times cause fluid retention and edema as a major side effect. These agents are not recommended in HF patients and contraindicated in HF patients ≥ NYHA III.30) Although the risk is quite low, metformin is contraindicated in HF requiring pharmacological management due to the risk of lactic acidosis. Further study is needed to establish the optimal treatment for DM in HF patients. Previous studies have reported that an increased HR was associated with higher all-cause and cardiovascular mortality, and that resting HF was increased in HF patients.31-34) On the other hand, a lot of clinical research focused on beta-blockers in chronic HF patients also suggested an association between the reduction in mortality and the magnitude of HR reduction.35-38) Beta-blockers were only promising agents for HR reduction in HF patients. However, beta-blockers also had various side effects and limitations and it is not easy to increase the dose of a beta-blocker for HR reduction. In addition, betablockade has other protective effects for HF such as attenuating apoptosis 39,40) and improving adrenergic signal transduction.41,42) Thus, decreased HR in beta-blocker use may be an epiphenomenon or the consequence of an improved status of HF. Against this background, a selective bradycardia agent acting on the If channel in the sinus node 43,44) has been investigated for the purpose of HR reduction. Ivabradine is currently the only agent available for clinical use. In the SHIFT trial, patients with symptomatic HF had a higher baseline HR, and ivabradine significantly reduced the combined primary endpoint of cardiovascular death and hospital admission for worsening HF, largely through reducing hospital admission.45) Furthermore, the beneficial effect of ivabradine in the SHIFT trial was related to the magnitude of HR reduction.33) Unfortunately, we could not yet use ivabradine in Japan. Ivabradine seems to have potential considering the importance of HR control in HF patients. Diuretics are the cornerstone and are indispensable drugs for the initial treatment of acute HF. The control of fluid retention in HF patients with volume overload can be mostly achieved by using loop diuretics.46,47) However, there are various possible adverse effects associated with loop diuretics, including worsening renal function, neurohormonal activation, electrolyte abnormalities, and cardiac fibrosis.48-51) Previous studies have demonstrated that the use of diuretics was associated with poor clinical outcomes in HF patients with LV dysfunction.49,52,53) Concordant with the present study, loop diuretic use at hospital discharge was reported to be associated with adverse outcomes including an increased rehospitalization rate in hospitalized Japanese HF patients.54) We need to taper the dose of loop diuretics and terminate their use if possible after stabilization of acute HF. We should avoid the routine longterm use of loop diuretics in HF patients who have no evidence of fluid retention. Study limitations: The present study has several limitations. Our hospital is a single-department cardiovascular facility, therefore, the results of this study cannot be generalized to all medical centers. Furthermore, the sample size of the present study was limited, and thus, the statistical power might not be strong enough for any negative data to be conclusive. We established a comprehensive database with demographic, physiological, and clinical variables that we adjusted for in the analyses. However, as with all observational studies, it is possible that unmeasured confounders may influence the results. BNP
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levels at hospital discharge and the clinical findings and signs of congestion such as jugular vein dilatation, pleural effusion, and increased central venous pressure were closely associated with the rehospitalization of acute heart failure patients. However, because of the nature of the retrospective study, we had too limited data for these parameters at discharge to analyze. Therefore, we could not examine the association of these parameters and HF rehospitalization. Conclusion: HF rehospitalization commonly occurred in patients who were discharged after their first acute HF admission. Older age, DM, increased HF, and loop diuretic use at discharge were independently associated with HF rehospitalization. By counting these risk factors, we might simply be able to predict the risk of HF rehospitalization after hospital discharge.
Acknowledgments We wish to thank Shiro Ueda and Nobuko Ueda of Medical Edge Co Ltd, for assembling the database using the Clinical Study Supporting System (CliSSS), and Ineko Hayakawa, Hiroaki Arai, and Hiroshi Aoki for their assistance with the data management and system administration.
Disclosure Conflict of interest: None of the authors has any conflict of in-
terest pertaining to this manuscript.
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KANEKO, ET AL spective cohort of Shinken Database 2004-2011. J Cardiol 2013; 62: 102-9. Kaneko H, Suzuki S, Uejima T, et al. Prevalence and the longterm prognosis of functional mitral regurgitation in Japanese patients with symptomatic heart failure. Heart Vessels 2014; 29: 8017. Kaneko H, Suzuki S, Goto M, et al. Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season. J Cardiol (in press) Kaneko H, Yajima J, Oikawa Y, et al. Recent characteristics and outcomes of Japanese stable angina pectoris after percutaneous coronary intervention. An observational cohort study using the Shinken Database. Int Heart J 2013; 54: 335-40. Suzuki S, Yamashita T, Ohtsuka T, et al. Prevalence and prognosis of patients with atrial fibrillation in Japan: a prospective cohort of Shinken Database 2004. Circ J 2008; 72: 914-20. Kaneko H, Koike A, Senoo K, et al. Role of cardiopulmonary dysfunction and left atrial remodeling in development of acute decompensated heart failure in chronic heart failure with preserved left ventricular ejection fraction. J Cardiol 2012; 59: 359-65. Kaneko H, Yajima J, Oikawa Y, et al. Obesity paradox in Japanese patients after percutaneous coronary intervention: an observation cohort study. J Cardiol 2013; 62: 18-24. Kaneko H, Yajima J, Oikawa Y, et al. Impact of aging on the clinical outcomes of Japanese patients with coronary artery disease after percutaneous coronary intervention. Heart Vessels 2014; 29: 156-64. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982-92. Kaneko H, Yajima J, Oikawa Y, et al. Effects of statin treatment in patients with coronary artery disease and chronic kidney disease. Heart Vessels 2014; 29: 21-8. Goda A, Yamashita T, Suzuki S, et al. Heart failure with preserved versus reduced left ventricular systolic function: a prospective cohort of Shinken Database 2004-2005. J Cardiol 2010; 55: 108-16. Mebazaa A, Gheorghiade M, Piña IL, et al. Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes. Crit Care Med 2008; 36: S129-39. (Review) Joynt KE, Orav EJ, Jha AK. The association between hospital volume and processes, outcomes, and costs of care for congestive heart failure. Ann Intern Med 2011; 154: 94-102. Ross JS, Chen J, Lin Z, et al. Recent national trends in readmission rates after heart failure hospitalization. Circ Heart Fail 2010; 3: 97-103. Komajda M, Hanon O, Hochadel M, et al. Management of octogenarians hospitalized for heart failure in Euro Heart Failure Survey I. Eur Heart J 2007; 28: 1310-8. Mahjoub H, Rusinaru D, Soulière V, Durier C, Peltier M, Tribouilloy C. Long-term survival in patients older than 80 years hospitalised for heart failure. A 5-year prospective study. Eur J Heart Fail 2008; 10: 78-84. Komajda M, Hanon O, Hochadel M, et al. Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II. Eur Heart J 2009; 30: 478-86. Hamaguchi S, Kinugawa S, Goto D, et al. 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)-. Circ J 2011; 75: 2403-10. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974; 34: 29-34. Iribarren C, Karter AJ, Go AS, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation 2001; 103: 2668-73. Held C, Gerstein HC, Yusuf S, et al. Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation 2007; 115: 1371-5.
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29. Control Group,Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009; 52: 2288-98. 30. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119: e391-479. (Review) 31. Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007; 50: 823-30. (Review) 32. Ahmadi-Kashani M, Kessler DJ, Day J, et al. Heart rate predicts outcomes in an implantable cardioverter-defibrillator population. Circulation 2009; 120: 2040-5. 33. Böhm M, Swedberg K, Komajda M, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 2010; 376: 886-94. 34. Heusch G. Heart rate and heart failure. Not a simple relationship. Circ J 2011; 75: 229-36. (Review) 35. Lechat P, Escolano S, Golmard JL, et al. Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the Cardiac Insufficiency BIsoprolol Study (CIBIS). Circulation 1997; 96: 2197-205. 36. Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation 2001; 103: 1428-33. 37. Metra M, Torp-Pedersen C, Swedberg K, et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial. Eur Heart J 2005; 26: 2259-68. 38. Konishi M, Haraguchi G, Kimura S, et al. Comparative effects of carvedilol vs bisoprolol for severe congestive heart failure. Circ J 2010; 74: 1127-34. 39. Sabbah HN, Sharov VG, Gupta RC, Todor A, Singh V, Goldstein S. Chronic therapy with metoprolol attenuates cardiomyocyte apoptosis in dogs with heart failure. J Am Coll Cardiol 2000; 36: 1698705. 40. Chen G, Zhou X, Florea S, et al. Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis. Basic Res Cardiol 2010; 105: 573-81. 41. Leineweber K, Rohe P, Beilfuss A, et al. G-protein-coupled receptor kinase activity in human heart failure: effects of beta-adrenoceptor blockade. Cardiovasc Res 2005; 66: 512-9. 42. Brodde OE. Beta-adrenoceptor blocker treatment and the cardiac beta-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure. Naunyn Schmiedebergs Arch Pharmacol 2007; 374: 361-72. (Review) 43. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs 2004; 64: 1757-65. (Review) 44. Chen PS, Joung B, Shinohara T, Das M, Chen Z, Lin SF. The initiation of the heart beat. Circ J 2010; 74: 221-5. (Review) 45. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebocontrolled study. Lancet 2010; 376: 875-85. 46. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005; 46: e1-82. (Review) 47. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Interna-
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REHOSPITALIZATION OF ACUTE HEART FAILURE PATIENTS tional Society for Heart and Lung Transplantation. Circulation 2009; 119: 1977-2016. Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med 1985; 103: 1-6. Cooper HA, Dries DL, Davis CE, Shen YL, Domanski MJ. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation 1999; 100: 1311-5. López B, Querejeta R, González A, Sánchez E, Larman M, Díez J. Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure. J Am Coll Cardiol 2004; 43: 2028-35. McCurley JM, Hanlon SU, Wei SK, Wedam EF, Michalski M, Haigney MC. Furosemide and the progression of left ventricular
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dysfunction in experimental heart failure. J Am Coll Cardiol 2004; 44: 1301-7. 52. Hasselblad V, Gattis Stough W, Shah MR, et al. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial. Eur J Heart Fail 2007; 9: 1064-9. 53. Ahmed A, Husain A, Love TE, et al. Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an observational study using propensity score methods. Eur Heart J 2006; 27: 14319. 54. Hamaguchi S, Kinugawa S, Tsuchihashi-Makaya M, et al. Loop diuretic use at discharge is associated with adverse outcomes in hospitalized patients with heart failure: a report from the Japanese cardiac registry of heart failure in cardiology (JCARE-CARD). Circ J 2012; 76: 1920-7.
I
n developed countries, heart failure (HF) is the most common cause of hospitalization in aged populations.1) For example, over the age of 65 years, HF hospitalization resulted in 6.5 million hospital days annually in the United States.2) Understandably, hospitalization is closely associated with increased mortality in outpatients with chronic HF. HF admission is also an economical problem. Hospital admission due to worsening HF is the largest contributor of unexpected readmissions cost.3) In Japan, HF admission, especially repeated hospital admission due to worsening HF, is also common and a serious problem. Some large registries focused on the prognosis of Japanese HF patients and reported determinant factors for all-cause or cardiovascular mortality.4,5) However, there are limited data regarding the predictors of rehospitalization due to worsening HF.6) Interestingly, the prognostic determinants for HF rehospitalization seem to be not similar to those for mortality. For example, the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), which is one of the largest registries that enrolled Japanese hospitalized
HF patients, demonstrated that beta-blocker use at hospital discharge was associated with a significant reduced risk of allcause mortality and cardiac mortality after hospital discharge, but was not associated with the incidence of HF rehospitalization.7) Therefore, we need to clarify the prognostic factors of HF rehospitalization in the Japanese population. Accordingly, we have been conducting a hospital-based cohort study of the Shinken Database since 2004 to investigate the prevalence and prognosis of patients with cardiovascular diseases in Japan.8-11) Among them, we examined patients admitted to our institute due to acute decompensated HF and aimed to clarify the incidence and predictors of HF readmission after hospital discharge in acute decompensated HF patients.
Methods The Shinken Database includes all new patients who visited the Cardiovascular Institute
Study population and protocol:
From the 1 Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan. This work was supported by the Japanese Society for the Promotion of Science (Hidehiro Kaneko). Address for correspondence: Hidehiro Kaneko, MD, The Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19 Nishiazabu, Minato-ku, Tokyo 106-0031, Japan. E-mail: [email protected] Received for publication September 8, 2014. Revised and accepted September 30, 2014. Released in advance online on J-STAGE February 27, 2015. All rights reserved by the International Heart Journal Association. 219
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in Tokyo, Japan (“Shinken” is a Japanese abbreviation for the name of the hospital), and excludes patients who are foreign travellers and those with active cancer. This hospital-based database was established to investigate the prevalence and prognosis of cardiovascular diseases in the urban areas of Japan.12-15) The registry began in June 2004, and patients have been continually registered to the database annually. The present study analyzed data from this database collected between June 2004 and March 2013 (Shinken Database 2004– 2012) and included 19,994 new visiting patients. Among them, 537 patients were admitted to our institute due to acute decompensated HF. We excluded HF patients with primary valvular heart disease (n = 138), prior history of valve surgery (n = 15), acute coronary syndrome (n = 24), in-hospital death (n = 4), and prior history of HF admission (n = 74). In the end, 282 patients were examined in the present study (Figure 1). The median follow-up period was 908 ± 865 days. Ethics: The Ethics Committee of the Cardiovascular Institute approved this study, and all patients provided written informed consent. Data collection: For each patient, after undergoing electrocardiography and chest radiography, cardiovascular status was evaluated by echocardiography and blood laboratory data at the time of hospital admission. As initial clinical parameters, collected data included gender, age, body mass index, and coexisting conditions. In most patients, additional echocardiographic parameters included left ventricular end-diastolic dimension (LVDd), left ventricular end-systolic dimension (LVDs), interventricular septum thickness (IVST), posterior wall thickness (PWT), and LV ejection fraction (LVEF). An estimated glomerular filtration rate (eGFR) was calculated using the eGFR equation for the Japanese population: eGFR = 194 × (serum creatinine)-1.094 × (age)-0.287 × (0.739, if the patient is female).16) A baseline eGFR < 60 mL·minute-1·1.73m-2 was used to define chronic kidney disease (CKD).17) Anemia was defined as a hemoglobin level of < 11 g/dL. Idiopathic dilated cardiomyopathy was diagnosed by the presence of global LV dilatation with impaired systolic function (in general LVDd ≥ 55 mm and LVEF < 50%) occurring in the absence of known cardiac causes. Hypertrophic cardiomyopathy was diagnosed by echocardiography when hypertrophy (IVST or PWT > 12 mm) without hypertension was present. We defined HFpEF patients as HF patients with preserved LVEF (ie, LVEF > 50%), and HFrEF patients as HF patients with reduced LVEF (ie, LVEF ≤ 50%), as previously described.8,18) Patients were divided into three groups by clinical scenario (CS): CS1, systolic blood pressure (BP) at admission > 140 mmHg; CS2, ≥ 100 mmHg; CS3, < 100 mmHg.19) We confirmed HF events (HF requiring hospitalization or death due to HF) that were classified into the International Classification of Diseases, 10th revision, code I50, using the medical records of our hospital or by the information obtained from follow-up. Statistical analysis: Categorical and consecutive data regarding patient background are presented as numbers (%) and the mean ± standard deviation, respectively. The chi-square test was used for comparisons between groups, and the unpaired ttest was used for comparison of consecutive variables. Longterm, event-free survival was estimated using Kaplan-Meier curves and the log-rank test to assess the significance of differences between the groups. Multiple Cox regression analysis including variables with P values ≤ 0.10 on univariate analysis
was performed to determine the predictors of HF rehospitalization. A probability value of < 0.05 was considered to indicate a statistically significant difference. Statistical analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA), version 19.0 software.
Results Among the 282 patients, HF rehospitalization occurred in 55 patients. The cumulative rate of rehospitalization was 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years (Figure 2). Patients with rehospitalization were older than those without rehospitalization (73 ± 13 versus 68 ± 14 years, P = 0.024). A gender difference was not seen between the two groups. Patients with rehospitalization had a higher prevalence of diabetes mellitus (DM) (42% versus 24%, P = 0.007). The
Figure 1. Patient flow chart of the present study.
Figure 2. Incidence of heart failure rehospitalization in patients who were discharged after their first acute HF admission.
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prevalence of ischemic cardiomyopathy (ICM) tended to be higher in patients with rehospitalization (42% versus 29%, P = 0.058). The prevalence of CKD, dilated cardiomyopathy, and atrial fibrillation were comparable between the two groups. Btype natriuretic peptide levels at hospital admission were also comparable between patients with and without rehospitalization. The distribution of CS classification was not significantly different between the two groups (Table I). Echocardiography revealed that LVDd and LVDs were similar between patients with and without rehospitalization. LVEF and the distribution of HFpEF and HFrEF were also comparable between the two groups (Table II). Systolic BP at discharge was comparable between patients with and without rehospitalization. Diastolic BP at discharge was lower in patients with rehospitalization (67 ± 11 Table I. Characteristics of Patients Rehospitalization Rehospitalization Absent Present (n = 227) (n = 55) Age (years) Male sex BMI (kg/m2) Hypertension Diabetes Mellitus Smoking CKD Anemia ICM DCM HCM HHD AF BNP (pg/mL) CS I II III
68 ± 14 70% 24 ± 5 59% 24% 38% 14% 20% 29% 16% 2.6% 5.7% 39% 760 ± 729
73 ± 13 67% 24 ± 4 60% 42% 35% 11% 22% 42% 13% 5.5% 10.9% 35% 918 ± 714
37% 60% 2.7%
35% 58% 7.7%
P 0.024 0.737 0.960 0.849 0.007 0.646 0.588 0.741 0.058 0.546 0.287 0.169 0.563 0.150 0.216
BMI indicates body mass index; CKD, chronic kidney disease; ICM, ischemic cardiomyopathy; DCM, idiopathic dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HHD, hypertensive heart disease; AF, atrial fibrillation; BNP, brain natriuretic peptide; and CS, clinical scenario.Data are expressed as mean ± standard deviation, or percentage.
Table II. Echocardiography Findings Rehospitalization Rehospitalization Absent Present (n = 227) (n = 55) IVST (mm) PWT (mm) LVDd (mm) LVDs (mm) LVEF (%) HFpEF HFrEF LAD (mm)
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10.3 ± 4.8 9.3 ± 1.9 53.2 ± 9.5 41.4 ± 13.2 44.3 ± 20.2 40% 60% 43.0 ± 9.2
10.1 ± 2.6 9.1 ± 2.0 53.5 ± 11.6 43.0 ± 14.5 43.0 ± 19.6 36% 64% 43.9 ± 10.0
P 0.838 0.444 0.776 0.442 0.656 0.571 0.571 0.527
IVST indicates interventricular septum thickness; PWT, posterior wall thickness; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVEF, left ventricular ejection fraction; HFpEF, heart failure with preserved LVEF; HFrEF, heart failure with reduced LVEF; and LAD, left atrial dimension. Data are expressed as mean ± standard deviation, or percentage.
versus 71 ± 11 mmHg, P = 0.025). HR at discharge tended to be higher in patients with rehospitalization (77 ± 15 versus 73 ± 13 bpm, P = 0.065) (Table III). Beta-blockers, renin-angiotensin system inhibitors, and antiarrhythmic drugs were similarly used at hospital discharge between patients with and without rehospitalization. Loop diuretics were more commonly used in patients with rehospitalization (91% versus 72%, P = 0.003) (Table IV). Multivariate Cox regression analysis (forced entry method) including the covariates age ≥ 75 years, DM, ICM, diastolic BP at discharge ≥ 70 mmHg, heart rate at discharge ≥ 75 bpm and loop diuretics use at discharge demonstrated that age ≥ 75 years (HR 1.850, 95% CI 1.031-3.321, P = 0.039) DM (HR 1.892, 95% CI 1.044-3.427, P = 0.035), HR at discharge ≥ 75 bpm (HR 1.813, 95% CI 1.005-3.272, P = 0.048), and loop diuretics use at discharge (HR 2.622, 95% CI 1.0053.272, P = 0.043) were independent determinants of HF rehospitalization (Table V). According to the number of risk factors, we categorized study patients into a low risk group (number of risks = 0 or 1), middle risk group (number of risks = 2), and high risk group (number of risks = 3 or 4). As the data sets are not complete for all patients, we could not categorize 27 patients. Finally, we
Table III. Vital Signs at Hospital Discharge Rehospitalization Rehospitalization Absent Present (n = 227) (n = 55) SBP (mmHg) DBP (mmHg) HR (bpm)
123 ± 16 71 ± 11 73 ± 13
120 ± 18 67 ± 11 77 ± 15
P 0.303 0.025 0.065
SBP indicates systolic blood pressure; DBP, diastolic blood pressure; and HR, heart rate. Data are expressed as mean ± standard deviation.
Table IV. Medication at Hospital Discharge Rehospitalization Rehospitalization Absent Present (n = 227) (n = 55) Beta-blockers RAS-Is AAD Statins Loop Diuretics Aldosterone antagonists Digitalis
66% 74% 12% 26% 72% 38% 13%
69% 76% 15% 36% 91% 46% 16%
P 0.671 0.671 0.593 0.143 0.003 0.303 0.484
RAS-I indicates renin-angiotensin system inhibitor; and AAD, antiarrhythmic drug. Data are expressed as percentage.
Table V. Determinants of Heart Failure Rehospitalization
Age ≥ 75 years Diabetes Mellitus HR ≥75 bpm Loop Diuretics
HR
95% CI
P
1.850 1.892 1.813 2.622
1.031-3.321 1.044-3.427 1.005-3.272 1.005-3.272
0.039 0.035 0.048 0.043
Cox regression analysis for heart failure rehospitalization. HR indicates hazard ratio; CI, confidence interval; and HR, heart rate.
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categorized 96 patients into the low risk group, 98 patients into the middle risk group, and 61 patients into the high risk group. Heart failure rehospitalization occurred in 8 patients (8%) in the low risk group, 21 patients (21%) in the middle risk group, and 19 patients (31%) in the high risk group. Kaplan-Meier curves and the log-rank test demonstrated that the incidence of HF rehospitalization increased with the number of these independent risk factors in a dependent manner (Log-rank P < 0.001) (Figure 3). The number of risk factors could be used to discriminate between the HF rehospitalization low-, middle- and high-risk patients (the cumulative rate of rehospitalization was 6.7% at 1 year, 8.4% at 2 years, and 12.5% at 3 years in patients scoring 0 and 1, 8.7% at 1 year, 23.7% at 2 years, and 26.1% at 3 years in patients scoring 2, and 28.6% at 1 year, 36.8% at 2 years, and 45.8% at 3 years in patients scoring 3 and 4) (Figure 4).
Discussion The present study reports data from an observational cohort of HF patients that were analyzed to clarify the incidence and the predictors of HF rehospitalization. The major findings of the present study were as follows: 1) HF rehospitalization occurred in 55/282 of the patients who were discharged after their first acute HF admission. The cumulative rate of rehospi-
Figure 3. Kaplan-Meier curves for heart failure rehospitalization.
Figure 4. Cumulative rate of heart failure rehospitalization according to the number of risk factors.
Int Heart J March 2015
talization was 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years. 2) Patients with rehospitalization were older than those without rehospitalization. DM was more common in patients with rehospitalization. Average HR at discharge tended to be higher in those with rehospitalization. Loop diuretics were more commonly used at discharge in patients with rehospitalization. 3) Multivariate Cox regression analysis revealed that age ≥ 75 years, diabetes mellitus, HR ≥ 75 bpm at discharge, and use of loop diuretics at discharge were independent predictors for HF rehospitalization. 4) The number of these risk factors present could be used to clearly discriminate between the HF rehospitalization low-, middle- and high-risk subjects. Compared with previous studies performed in Western countries,3,20,21) the rehospitalization rate of Japanese HF patients seems to be lower.4) In the present study, rehospitalization due to worsening HF occurred with cumulative rates of rehospitalization of 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years, findings that are in agreement with a previous Japanese study.4) The epidemiology of HF in Japan is different from that in Western countries with respect to ethnic background and etiology and these differences might contribute to the lower incidence of HF rehospitalization in Japan. Although the HF rehospitalization rate is lower in Japan, it is commonly observed in our daily clinical practice. However, there are limited data focusing on the predictors for the rehospitalization of acute HF patients. In the present study, older age, DM, increased HR, and loop diuretic use at the time of hospital discharge were independently associated with HF rehospitalization. About 70% of heart failure rehospitalization occurred within one year after hospital discharge, suggesting the importance of the careful observation of HF patients in the early phase after hospital discharge. So far we have performed the routine checkup of HF patients at 9 months after hospital discharge. However, according to the results of the present study, we might need to perform routine checkups at earlier phases after hospital discharge to identify signs of worsening HF. Various previous studies have demonstrated that elderly HF patients had poor outcomes.22-24) Elderly HF patients are different from younger HF patients in terms of etiologies, comorbidities, left ventricular (LV) function (systolic and diastolic function), and treatment. Furthermore, treatment is often complicated by multiple comorbidities and it is difficult to administer evidence-based therapies in elderly patients.22-24) Concordant with the present study, Hamaguchi, et al reported that the rehospitalization rate was significantly higher in Japanese elderly HF patients.25) Our country has the highest proportion of elderly citizens in the world. Therefore, improving the management of HF in elderly patients is quite important in Japanese clinical practice. Diabetes mellitus (DM) is closely associated with a higher risk of HF independent of the presence of coronary heart disease and hypertension. DM itself may sometimes induce diabetic cardiomyopathy and cause LV dysfunction. The close link between DM and HF was previously confirmed by the Framingham Study 26) and the risk of HF development in patients with DM is associated with the severity of hyperglycemia.27,28) However, intensive glucose control unfortunately has not been shown to decrease HF development in patients with DM.29) Moreover, some types of antidiabetic agents are difficult to administer to HF patients. Thiazolidinediones some-
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times cause fluid retention and edema as a major side effect. These agents are not recommended in HF patients and contraindicated in HF patients ≥ NYHA III.30) Although the risk is quite low, metformin is contraindicated in HF requiring pharmacological management due to the risk of lactic acidosis. Further study is needed to establish the optimal treatment for DM in HF patients. Previous studies have reported that an increased HR was associated with higher all-cause and cardiovascular mortality, and that resting HF was increased in HF patients.31-34) On the other hand, a lot of clinical research focused on beta-blockers in chronic HF patients also suggested an association between the reduction in mortality and the magnitude of HR reduction.35-38) Beta-blockers were only promising agents for HR reduction in HF patients. However, beta-blockers also had various side effects and limitations and it is not easy to increase the dose of a beta-blocker for HR reduction. In addition, betablockade has other protective effects for HF such as attenuating apoptosis 39,40) and improving adrenergic signal transduction.41,42) Thus, decreased HR in beta-blocker use may be an epiphenomenon or the consequence of an improved status of HF. Against this background, a selective bradycardia agent acting on the If channel in the sinus node 43,44) has been investigated for the purpose of HR reduction. Ivabradine is currently the only agent available for clinical use. In the SHIFT trial, patients with symptomatic HF had a higher baseline HR, and ivabradine significantly reduced the combined primary endpoint of cardiovascular death and hospital admission for worsening HF, largely through reducing hospital admission.45) Furthermore, the beneficial effect of ivabradine in the SHIFT trial was related to the magnitude of HR reduction.33) Unfortunately, we could not yet use ivabradine in Japan. Ivabradine seems to have potential considering the importance of HR control in HF patients. Diuretics are the cornerstone and are indispensable drugs for the initial treatment of acute HF. The control of fluid retention in HF patients with volume overload can be mostly achieved by using loop diuretics.46,47) However, there are various possible adverse effects associated with loop diuretics, including worsening renal function, neurohormonal activation, electrolyte abnormalities, and cardiac fibrosis.48-51) Previous studies have demonstrated that the use of diuretics was associated with poor clinical outcomes in HF patients with LV dysfunction.49,52,53) Concordant with the present study, loop diuretic use at hospital discharge was reported to be associated with adverse outcomes including an increased rehospitalization rate in hospitalized Japanese HF patients.54) We need to taper the dose of loop diuretics and terminate their use if possible after stabilization of acute HF. We should avoid the routine longterm use of loop diuretics in HF patients who have no evidence of fluid retention. Study limitations: The present study has several limitations. Our hospital is a single-department cardiovascular facility, therefore, the results of this study cannot be generalized to all medical centers. Furthermore, the sample size of the present study was limited, and thus, the statistical power might not be strong enough for any negative data to be conclusive. We established a comprehensive database with demographic, physiological, and clinical variables that we adjusted for in the analyses. However, as with all observational studies, it is possible that unmeasured confounders may influence the results. BNP
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levels at hospital discharge and the clinical findings and signs of congestion such as jugular vein dilatation, pleural effusion, and increased central venous pressure were closely associated with the rehospitalization of acute heart failure patients. However, because of the nature of the retrospective study, we had too limited data for these parameters at discharge to analyze. Therefore, we could not examine the association of these parameters and HF rehospitalization. Conclusion: HF rehospitalization commonly occurred in patients who were discharged after their first acute HF admission. Older age, DM, increased HF, and loop diuretic use at discharge were independently associated with HF rehospitalization. By counting these risk factors, we might simply be able to predict the risk of HF rehospitalization after hospital discharge.
Acknowledgments We wish to thank Shiro Ueda and Nobuko Ueda of Medical Edge Co Ltd, for assembling the database using the Clinical Study Supporting System (CliSSS), and Ineko Hayakawa, Hiroaki Arai, and Hiroshi Aoki for their assistance with the data management and system administration.
Disclosure Conflict of interest: None of the authors has any conflict of in-
terest pertaining to this manuscript.
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