Clinical Characteristics, Management, and Outcomes of Japanese Patients Hospitalized for Heart Failure With Preserved Ejection Fraction　― A Report From the Japanese Heart Failure Syndrome With Preserved Ejection Fraction (JASPER) Registry ―

Abstract

Background: Despite the specific characteristics of heart failure with preserved ejection fraction (HFpEF) having been demonstrated predominantly from registries in Western countries, important international differences exist in terms of patient characteristics, management and medical infrastructure between Western and Asian countries.

Methods and Results: We performed nationwide registration of consecutive Japanese hospitalized HFpEF patients with left ventricular EF ≥50% from 15 sites between November 2012 and March 2015. Follow-up data were obtained up to 2 years post-discharge. A total of 535 patients were registered. The median age was 80 years and 50% were female. The most common comorbid conditions were hypertension (77%) and atrial fibrillation (AF: 62%), but body mass index was relatively low. In-hospital mortality rate was 1.3% and the median length of hospitalization was 16 days. By 2 years post-discharge, 40.8% of patients had all-cause death or HF hospitalization. Approximately one-half of deaths had a cardiac cause. Lower serum albumin on admission was one of the strongest independent determinants of worse clinical outcome.

Conclusions: Japanese HFpEF patients were less obese, but had a substantially higher prevalence of AF and lower incidence of subsequent events compared with previous reports. Our findings indicated that specific preventative and therapeutic strategies focusing on AF and nutritional status might need to be considered for Japanese hospitalized patients with HFpEF.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a well-known condition that has been increasing in prevalence and incidence, accounting for around half of all HF presentations.^1,2 Currently, annual HFpEF admissions are estimated at approximately 500,000 in the United States (USA) and over 100,000 in Japan.^3,4 Recent data predominantly from Western countries have clarified the clinical characteristics of HFpEF, including its specific comorbidities and outcomes.^1,2,5–12 For instance, patients with HFpEF have an increased burden of obesity, anemia, diabetes mellitus and chronic obstructive pulmonary disease (COPD) when compared with those with HF with reduced ejection fraction (HFrEF).⁵ The short-term mortality rate up to 90 days from admission for HF in HFpEF patients is similar to that in HFrEF patients, but the difference in longer-term mortality rates between patients with HFpEF and HFrEF varies among registries, population-based studies and meta-analyses.^1,2,6–9

Although international guidelines for the management of HF are quite similar,^13,14 important geographic variations exist in patients’ characteristics, clinical practice patterns and healthcare resources and expenditure, particularly between Western and Asian countries.^15,16 Notably, Japanese patients hospitalized for HF have a substantially lower prevalence of ischemic heart disease (IHD), obesity and COPD, and longer length of hospital stay than US patients.^17,18 These racial and geographical differences may influence clinical outcomes.¹⁹ Furthermore, the recommended management for HFpEF patients focuses on the appropriate treatment of comorbid conditions because of a lack of specific medication that can improve the outcomes for HFpEF patients in contrast to those for HFrEF patients.^13,14,20 From this point of view, physicians need to know the region-specific clinical characteristics, management, and outcomes of HFpEF patients in each country; however, these have not been fully elucidated in Asia, especially in Japan. Several previous reports have presented epidemiological information of hospitalized HFpEF patients with comparison to HFrEF,^7,21–24 but patients in those studies were registered before relatively recent Japanese and Western HF guidelines published in 2011–2012.^14,25,26 Furthermore, the previous studies other than the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) in Japanese hospitalized HFpEF patients were retrospective and/or single center studies and had relatively small sample sizes (n=73–169, JCARE-CARD [n=429]). Strong prognostic determinants of subsequent HF-specific adverse events (death and HF admission) also have not been fully identified in Japanese hospitalized HFpEF patients in a larger study population, even in JCARE-CARD.

Accordingly, we investigated the clinical demographics, treatment, and long-term outcomes, including important prognostic determinants, in Japanese hospitalized HFpEF patients using data from a recently registered HFpEF-specific nationwide cohort study in Japan, the Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry.

Methods

Study Design

The JASPER registry is a multicenter, observational, prospective cohort that includes consecutive patients aged ≥20 years requiring hospitalization with a diagnosis of acute HF according to the Framingham criteria²⁷ by at least 2 experienced cardiologists, with preserved left ventricular (LV) systolic function defined as LVEF ≥50% by the modified Simpson method or LV fractional shortening ≥25% by echocardiography. Patients with acute coronary syndrome, receiving hemodialysis or with a history of heart transplantation were excluded.

The patients’ demographic data including comorbid conditions, clinical signs, laboratory and echocardiographic data, in-hospital treatment including oral and intravenous medications, and length of hospital stay were obtained. Regarding the precipitating factors for HF admission, we used the Electronic Data Capture (EDC) system for collecting the clinical data from each site. Each site could select individual precipitating factors from a dropdown list on the EDC system. Thus, expert cardiologists at each site chose the most appropriate precipitating factor from these categories based on their clinical judgment. Mortality was defined as death from any cause, death from cardiovascular (CV) causes including sudden cardiac death (SCD) and death from worsening HF, myocardial infarction, cerebrovascular accident or other CV disease, and death from non-CV cause. Death was considered as SCD unless a specific CV other than SCD or non-CV cause was identified by the primary physician.

Follow-up was performed at discharge and at 12 and 24 months after discharge by direct contact with patients or their physicians at the hospital or outpatient clinic, telephone interview of patients or, if deceased, of family members, and by mail, by dedicated coordinators and investigators. In this study, because patient information was anonymized and de-identified prior to analyses, written informed consent was not obtained from each patient. However, we publicized the study by posting a summary of the protocol (with an easily understood description) on the website of the National Cerebral and Cardiovascular Center; the notice clearly informed patients of their right to refuse enrolment. These procedures for informed consent and enrolment were in accordance with the detailed regulations regarding informed consent described in the guidelines, and this study, including the procedure for enrolment, was approved by the Institutional Review Board of each site, and registered under the Japanese UMIN Clinical Trials Registration (UMIN000010601).

Statistical Analysis

Continuous variables are presented as mean±SD when normally distributed, and as median and interquartile range (IQR) when non-normally distributed. Comparisons of parameters across atrial fibrillation (AF) status groups were made by Kruskal-Wallis test for continuous variables, and by chi-squared test or Fisher’s exact test for dichotomous variables, when appropriate.

The cumulative incidence of the composite of all-cause death and HF rehospitalization, CV death, non-CV death and HF rehospitalization was estimated using Kaplan-Meier curves.

The association between parameters and the composite of all-cause death and HF readmission was assessed by Cox proportional hazards regression. Univariate factors that had a value of P<0.05 were identified according to the number of events. Finally, these factors were entered into the multivariate model to assess the independent prognostic determinants on admission of the composite of all-cause death and HF rehospitalization. Moreover, stepwise selection with a P-value of 0.10 for backward elimination was used to select the best predictive model in the total population.

All tests were 2-tailed, and a value of P<0.05 was considered statistically significant. All analyses were performed with Stata MP64 version 15 (StataCorp, College Station, TX, USA).

Results

Baseline Characteristics, Treatment and In-Hospital Death in JASPER and Comparison With HFpEF Registries in the USA

A total of 535 consecutive hospitalized HFpEF patients from 15 university or teaching hospitals were registered in the JASPER registry. Table 1 shows their baseline characteristics. Median age was 80 years and 50% were female. The prevalence of hypertension, IHD and AF were 77%, 28% and 62%, respectively. Median B-type natriuretic peptide (BNP) level was 414 pg/mL on admission. Intravenous diuretics were frequently used in 81% of HFpEF patients, and 60% were treated with vasodilators (Table 1). A total of 7 patients (1.3%; 5 with cardiac cause and 2 with non-cardiac cause) died during hospitalization for a median of 16 days (Table 1).

Table 1. Baseline Patient Characteristics on Admission, and In-Hospital Treatment and Death of Patients in the JASPER Registry

Variables	Overall (n=535)	Missing
Age, years	80 (73–84)	0 (0)
Female	267 (50.0)	0 (0)
BMI, kg/m2	23.9±4.7	19 (3.5)
NYHA functional class on admission		22 (4.1)
I	4 (0.1)
II	110 (20.6)
III	212 (39.6)
IV	187 (35.0)
NYHA functional class at discharge		53 (9.9)
I	183 (34.2)
II	269 (50.3)
III	29 (5.4)
IV	1 (0.4)
Vital signs on admission
Heart rate, beats/min	80 (66–100)	0 (0)
SBP, mmHg	147 (124–171)	0 (0)
DBP, mmHg	76 (64–92)	4 (0.7)
Vital signs at discharge
Heart rate, beats/min	66 (60–74)	10 (1.9)
SBP, mmHg	113 (102–124)	9 (1.7)
DBP, mmHg	60 (53–68)	10 (1.9)
Past history
Smoking	237 (44.3)	18 (3.4)
Prior HF admission	194 (36.3)	18 (3.4)
Prior MI	66 (12.3)	7 (1.3)
CAD	148 (27.7)	11 (2.1)
AF	329 (61.5)	6 (1.1)
Diabetes mellitus	204 (38.1)	3 (0.6)
Hypertension	413 (77.2)	2 (0.4)
Dyslipidemia	226 (42.2)	4 (0.8)
CVA	124 (23.2)	10 (1.9)
PAD	55 (10.3)	23 (4.3)
CKD	272 (50.8)	2 (0.4)
COPD/asthma	58 (10.8)	11 (2.1)
Sleep apnea syndrome	44 (8.2)	59 (11.0)
Depression	8 (1.5)	10 (1.9)
Liver disease	35 (6.5)	4 (0.8)
Clinical signs
Breathlessness	486 (90.8)	9 (1.7)
Elevated JVP	242 (45.2)	64 (12.0)
Lower extremity edema	381 (71.2)	5 (0.9)
Laboratory data on admission
Sodium, mEq/L	141 (138–142)	0 (0)
BUN, mg/dL	22 (16–31)	0 (0)
Creatinine, mg/dL	1.04 (0.76–1.47)	0 (0)
Hemoglobin, g/dL	11.2±2.2	0 (0)
BNP, pg/mL	414 (225–681)	9 (1.7)
Troponin T, ng/dL	0.032 (0.020–0.055)	308 (57.6)
Potassium, mEq/L	4.2±0.7	0 (0)
White blood cell count, /μL	6,400 (5,000–8,600)	0 (0)
C-reactive protein, mg/dL	0.41 (0.13–1.40)	8 (1.5)
Albumin, g/dL	3.7 (3.3–4.0)	31 (5.8)
Total cholesterol, mg/dL	157±38	79 (14.8)
Total bilirubin, mg/dL	0.7 (0.5–1.0)	6 (1.1)
Laboratory data at discharge
Sodium, mEq/L	140 (137–141)	12 (2.2)
BUN, mg/dL	25 (18–37)	12 (2.2)
Creatinine, mg/dL	1.10 (0.84–1.59)	12 (2.2)
Hemoglobin, g/dL	11.5±2.0	13 (2.4)
BNP, pg/mL	154 (75–303)	103 (19.3)
Potassium, mEq/L	4.3±0.5	12 (2.2)
C-reactive protein, mg/dL	0.24 (0.09–0.80)	52 (9.7)
Albumin, g/dL	3.6 (3.3–4.0)	114 (21.3)
Total bilirubin, mg/dL	0.6 (0.4–0.8)	41 (7.7)
Echocardiography
LVEF, %	60 (54–65)	37 (6.9)
LVFS, %	35 (30–40)	56 (10.5)
LAD, mm	45 (39–50)	93 (17.3)
LVDD, mm	47±7	42 (7.9)
LVPWD, mm	10 (9–12)	77 (14.4)
LVIVSD, mm	11 (9–12)	75 (14.0)
E wave, cm/s	98 (77–117)	111 (20.8)
A wave, cm/s	79±32	322 (60.2)
DcT, ms	180 (150–230)	123 (23.0)
e′ (septum), cm/s	5.5 (4.2–7.2)	213 (39.8)
e′ (lateral), cm/s	7.8 (5.9–10.1)	337 (63.0)
TRPG, mmHg	36±13	66 (12.3)
IVCD, mm	19±6	53 (9.9)
Initial treatments
Intravenous diuretics	431 (80.6)	0 (0)
Vasodilators	323 (60.4)	0 (0)
Nitrates	156 (29.2)	0 (0)
Carperitide	245 (45.8)	0 (0)
Inotropes	22 (4.1)	0 (0)
Dobutamine	18 (3.4)	0 (0)
PDE-III inhibitors	6 (1.1)	0 (0)
Digitalis	27 (5.1)	0 (0)
NIPPV	99 (18.5)	0 (0)
IPPV	9 (1.7)	0 (0)
In-hospital death	7 (1.3)	0 (0)
Cardiac	5 (0.9)	0 (0)
Non-cardiac	2 (0.4)	0 (0)
Length of hospital stay, median (IQR) days	16 (11–23)	0 (0)

Values are mean±standard deviation, median (IQR) or percentage. AF, atrial fibrillation; BMI, body mass index; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DBP, diastolic blood pressure; DcT, deceleration time; HF, heart failure; IPPV, invasive positive pressure ventilation; IQR, interquartile range; IVCD, inferior vena cava diameter; JASPER, Japanese Heart Failure Syndrome with Preserved Ejection Fraction; JVP, jugular vein pressure; LAD, left atrial dimension; LVDD, left ventricular (LV) diastolic diameter; LVEF, LV ejection fraction; LVFS, LV fractional shortening; LVIVSD, LV interventricular septum diameter; LVPWD, LV posterior wall diameter; MI, myocardial infarction; NIPPV, non-invasive positive pressure ventilation; NYHA, New York Heart Association; PAD, peripheral artery disease; PDE-III, phosphodiesterase enzyme-III; SBP, systolic blood pressure; TRPG, tricuspid regurgitation pressure gradient.

A comparison of patients’ characteristics and in-hospital death between the JASPER and US HFpEF registries^2,11,28 is shown in Table 2. Japanese hospitalized HFpEF patients were older, less obese, and had a lower rate of female sex compared with the published US HFpEF registries. The prevalence of IHD, diabetes mellitus and COPD were lower, and that of AF and cerebrovascular accident were higher in Japanese patients than in US patients. Japanese patients had higher sodium levels and lower serum creatinine and BNP levels compared with US patients. More than 60% of Japanese patients, but only 18% of US patients, were treated with intravenous vasodilators regardless of similar systolic blood pressure (SBP) on admission. Hospital stay was substantially longer and the in-hospital death rate was lower in Japan than in the USA. Japanese patients were more frequently prescribed angiotensin-receptor blockers and mineral corticoid antagonists at discharge than US patients registered to OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) (Figure 1). Regarding precipitating factors for HF admission, dietary non-compliance was more frequently observed, and medication non-compliance and renal failure were less frequently observed in Japanese patients than in US patients registered to GWTG-HF (Get With The Guidelines-Heart Failure) (Figure 2A).

Table 2. Comparison of HF Registries for Hospitalized HFpEF Patients

Variables	JASPER	ADHERE	OPTIMIZE-HF	GWTG-HF
Reference no.	–	[10]	[2]	[11]
No. of patients	535	26,322	10,072	40,354
EF criteria, %	≥50	≥40	>50	≥50
Age, years	80 (73–84)	73.9±13.2	75.6±13.1	78 (67–85)
Female, %	50.0	62	68	63
BMI, kg/m2	23.9±4.7	–	–	29 (24–35)
NYHA functional class, %
III	39.6	–	62	–
IV	35.0	34	44	–
Heart rate, beats/min	80 (66–100)	86.8±22.0	84±21	80 (68–94)
SBP, mmHg	147 (124–171)	152.5±32.7	150±33	145 (125–167)
DBP, mmHg	76 (64–92)	78.7±20.6	75±19	–
Past history, %
Prior MI	12.3	24	–	–
CAD	27.7	50	32	44
AF	61.5	21	32	34
Diabetes mellitus	38.1	45	41	46
Hypertension	77.2	77	77	80
Dyslipidemia	42.2	–	–	43
CVA	23.2	–	–	15
PAD	10.3	17	–	11.9
CKD	50.8	26	–	52
COPD/asthma	10.8	31	–	33
Laboratory data
Sodium, mEq/L	141 (138–142)	–	137.8±4.8	138 (136–141)
BUN, mg/dL	22 (16–31)	29.3±19.3	–	–
Creatinine, mg/dL	1.04 (0.76–1.47)	1.7±1.5	1.2 (1.0–1.8)	1.3 (1.0–1.9)
Hemoglobin, g/dL	11.2±2.2	–	11.8±2.0	11.5 (10.2–12.9)
BNP, pg/mL	414 (225–681)	–	537 (287–997)	551 (271–1,081)
Troponin T, ng/dL	0.032 (0.020–0.055)	–	–	0.05 (0.02–0.10)
Initial treatment, %
Intravenous diuretics	80.6	91	–	–
Vasodilators	60.4	18	–	–
Nitrates	29.2	12	–	–
Carperitide	45.8	–	–	–
Inotropes	4.1	8	–	–
Dobutamine	3.4	3	–	–
PDE-III inhibitors	1.1	1	–	–
In-hospital death, n (%)	1.3	2.8	2.9	2.5
Length of hospital stay, median (IQR) days	16 (11–23)	4.9 (3.1–7.6)	–	–

ADHERE, Acute Decompensated Heart Failure National Registry; EF, ejection fraction; GWTG-HF, Get With the Guidelines-Heart Failure; HFpEF, HF with preserved ejection fraction; OPTIMIZE-HF, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure. Other abbreviations as in Table 1.

Figure 1.

Medications on admission and at discharge of patients with heart failure with preserved ejection fraction in Japan (JASPER) or the USA (OPTIMIZE-HF). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; JASPER, Japanese Heart Failure Syndrome with Preserved Ejection Fraction; MRA, mineral corticoid-receptor antagonist; OPTIMIZE-HF, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure.

Figure 2.

Precipitating factors for heart failure admission in Japan and the USA. (A) JASPER and GWTG-HF; (B) across AF status. AF, atrial fibrillation; GWTG-HF, Get With the Guidelines-Heart Failure; JASPER, Japanese Heart Failure Syndrome with Preserved Ejection Fraction; SR, sinus rhythm.

Baseline Characteristics Across AF Status

Because of the higher prevalence of AF in Japanese patients than in US patients, we compared the patients’ characteristics among AF status stratified by AF history and rhythm (AF or sinus rhythm) on admission. Patients with an AF history had a higher prevalence of prior HF admission with higher prescription rates of loop diuretics, mineral corticoid receptor antagonists, digitalis and anticoagulation agents, and tended to have a higher frequency of dietary non-compliance among the precipitating factors for HF admission than those without (Table 3, Figure 2B). Patients with no AF history and in sinus rhythm on admission had higher SBP on admission with smaller left atrial size and higher frequency of uncontrolled hypertension as a major cause of HF admission, compared with the other groups (Table 3, Figure 2B). Around 5% of patients (n=20) who had AF rhythm on admission without an AF history had a higher heart rate and frequency of arrhythmia as a major precipitating factor for HF admission compared with the other groups (Table 3, Figure 2B).

Table 3. Baseline Patient Characteristics and Findings on Admission Stratified by History of AF and Rhythm on Admission

Variables	No history of AF		History of AF		P value
	SR on admission (n=180)	AF on admission (n=20)	SR on admission (n=44)	AF on admission (n=199)
Age, years	79 (69–84)	83 (76–87)	81 (73–85)	81 (76–85)	0.033
Female	91 (50.6)	11 (55.0)	20 (45.5)	91 (45.7)	0.71
BMI, kg/m2	23.7 (21.0–26.9)	23.5 (21.7–25.0)	22.7 (20.6–26.8)	23.3 (21.1–26.2)	0.86
NYHA functional class					0.23
I	0 (0)	0 (0)	1 (2.4)	2 (1.0)
II	28 (16.4)	7 (35.0)	6 (14.3)	44 (22.9)
III	72 (42.1)	6 (30.0)	21 (50.0)	71 (37.0)
IV	71 (41.5)	7 (35.0)	14 (33.3)	75 (39.1)
Heart rate, beats/min	75 (64–93)	115 (78–135)	67 (60–78)	82 (69–105)	<0.001
SBP, mmHg	160 (129–190)	134 (114–160)	152 (125–163)	140 (122–166)	<0.001
DBP, mmHg	75 (61–92)	79 (69–102)	71 (64–88)	75 (64–93)	0.66
Past history
Smoking	77 (44.3)	7 (36.8)	19 (44.2)	101 (52.9)	0.26
Prior HF admission	46 (26.9)	4 (20.0)	23 (53.5)	92 (47.9)	<0.001
Prior MI	32 (18.1)	2 (10.0)	5 (11.6)	19 (9.6)	0.11
CAD	61 (35.1)	6 (30.0)	11 (26.8)	50 (25.1)	0.21
Diabetes mellitus	72 (40.5)	7 (35.0)	21 (47.7)	78 (39.4)	0.73
Hypertension	145 (80.6)	18 (90.0)	33 (75.0)	143 (72.6)	0.14
Dyslipidemia	92 (51.7)	14 (70.0)	15 (34.1)	68 (34.5)	<0.001
CVA	31 (17.6)	4 (20.0)	12 (29.3)	57 (28.8)	0.065
PAD	17 (9.7)	4 (20.0)	6 (14.3)	19 (10.1)	0.46
CKD	97 (53.9)	4 (20.0)	25 (56.8)	106 (53.3)	0.030
COPD/Asthma	22 (12.3)	0 (0)	6 (14.3)	25 (13.0)	0.38
Sleep apnea syndrome	16 (9.9)	1 (5.0)	4 (10.3)	20 (11.3)	0.84
Clinical signs
Breathlessness	162 (91.5)	17 (85.0)	41 (95.4)	184 (92.9)	0.51
Elevated JVP	66 (42.3)	11 (55.0)	23 (57.5)	103 (60.0)	0.013
Lower extremity edema	123 (68.7)	13 (65.0)	34 (79.1)	150 (75.8)	0.28
Laboratory data on admission
Sodium, mEq/L	141 (138–142)	141 (138–143)	140 (138–142)	141 (138–142)	0.94
BUN, mg/dL	22 (16–35)	24 (20–32)	23 (17–34)	21 (16–30)	0.38
Creatinine, mg/dL	1.2 (0.7–1.9)	1.0 (0.8–1.3)	1.2 (0.8–1.6)	1.0 (0.8–1.4)	0.12
BNP, pg/mL	455 (274–847)	552 (248–972)	424 (203–641)	340 (188–538)	0.005
Hemoglobin, g/dL	10.8 (9.4–12.7)	11.9 (10.0–12.8)	10.8 (9.9–11.8)	10.9 (9.8–12.5)	0.63
Echocardiography
LVEF, %	60 (54–65)	55 (50–60)	59 (52–65)	60 (55–65)	0.023
LAD, mm	42 (37–46)	46 (38–52)	47 (42–50)	48 (43–54)	<0.001
LVDD, mm	48 (43–52)	48 (44–53)	47 (44–51)	46 (42–51)	0.41
LVPWD, mm	11 (9–12)	10 (9–11)	11 (9–12)	10 (9–11)	0.27
LVIVSD, mm	11 (10–13)	11 (8–12)	11 (10–12)	11 (9–12)	0.24
LVMI, g/m2	119 (100–149)	120 (83–132)	118 (102–135)	112 (91–134)	0.070
E wave, cm/s	90 (68–105)	104 (89–137)	101 (84–117)	105 (83–123)	<0.001
DcT, ms	200 (159–247)	168 (145–178)	207 (171–265)	166 (139–208)	<0.001
e′ (septum), cm/s	4.8 (3.8–6.8)	4.4 (3.6–5.1)	5.0 (3.7–5.6)	6.8 (4.8–7.9)	<0.001
TRPG, mmHg	36 (27–43)	32 (23–47)	35 (27–45)	36 (30–46)	0.45
IVCD, mm	19 (14–22)	21 (16–25)	22 (17–24)	20 (17–24)	0.005
Medications before admission
ACEIs/ARBs	96 (53)	11 (55)	26 (59)	118 (59)	0.68
β-blockers	71 (39)	6 (30)	26 (59)	83 (42)	0.074
Loop diuretics	76 (42)	7 (35)	26 (59)	128 (64)	<0.001
MRAs	21 (12)	3 (15)	12 (27)	59 (30)	<0.001
Digitalis	6 (3)	1 (5)	4 (9)	39 (20)	<0.001
Anticoagulation	15 (8)	4 (20)	33 (75)	146 (73)	<0.001

Values are mean±standard deviation, median (IQR) or percentages. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; LVMI, left ventricular mass index; MRA, mineral corticoid-receptor antagonist; SR, sinus rhythm. Other abbreviations as in Tables 1,2.

Long-Term Clinical Outcomes and Mode of Death

During a median follow-up period of 731 (IQR 552–813) days, 476 (94.4%) and 363 (72.0%) patients were successfully followed up at 1 year and 2 years after discharge, respectively (Figure 3). Among them, 17.9%, 7.6%, 2.9%, 4.6% and 10.3% of patients experienced all-cause death or HF hospitalization, all-cause death, CV death, non-CV death and HF hospitalization at 1-year post-discharge, respectively (Figure 3). At 2 years post-discharge, 40.8%, 20.9%, 10.5%, 10.5% and 23.1% of patients had all-cause death or HF hospitalization, all-cause death, CV death, non-CV death and HF hospitalization at 1-year post-discharge, respectively (Figure 3). Figure 4 shows the mode of death: almost half of deaths had a cardiac cause, and 24% and 21% of CV deaths were SCD and HF deaths, respectively.

Figure 3.

Long-term post-discharge outcomes for patients with heart failure with preserved ejection fraction in Japan. CV, cardiovascular; HF, heart failure.

Figure 4.

Mode of death for patients with heart failure with preserved ejection fraction in Japan. CV, cardiovascular; HF, heart failure; SCD, sudden cardiac death.

Determinants of Long-Term Death or HF Hospitalization

Multivariate Cox regression analyses demonstrated that lower SBP and lower serum albumin level on admission, and NYHA class III/IV and plasma BNP level at discharge were independently associated with the post-discharge composite outcome of all-cause death and HF admission in either covariate selection (Table 4).

Table 4. Cox Proportional Hazards Model for Post-Discharge Composite of All-Cause Death and Worsening HF

Variables	Univariable analysis		Multivariable analysis (significant covariates in univariate analyses)		Multivariable analysis (stepwise selection)
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Age	1.03 (1.01–1.05)	0.002	1.00 (0.98–1.02)	0.64	NS	–
Female	1.00 (0.73–1.36)	0.99	NS	–	NS	–
BMI	0.95 (0.92–0.99)	0.015	1.00 (0.96–1.05)	0.85	NS	–
NYHA class IV on admission	0.84 (0.60–1.16)	0.29	NS	–	NS	–
NYHA class III or IV at discharge	3.19 (1.92–5.30)	<0.001	2.77 (1.51–5.07)	0.001	1.01 (1.00–1.02)	0.003
Heart rate on admission	1.00 (0.996–1.007)	0.63	NS	–	NS	–
Heart rate at discharge	1.01 (1.00–1.02)	0.18	NS	–	NS	–
SBP on admission	0.99 (0.988–0.997)	0.001	0.99 (0.99–1.00)	0.026	0.99 (0.99–1.000)	0.012
SBP at discharge	0.99 (0.98–1.00)	0.14	NS	–	NS	–
Prior HF admission	1.88 (1.38–2.56)	<0.001	1.33 (0.87–2.02)	0.19	NS	–
Prior MI	1.39 (0.92–2.12)	0.121	NS	–	NS	–
CAD	1.23 (0.88–1.71)	0.22	NS	–	NS	–
AF	1.40 (1.00–1.95)	0.051	0.96 (0.62–1.49)	0.85	NS	–
Diabetes	0.97 (0.70–1.33)	0.84	NS	–	NS	–
Hypertension	0.94 (0.65–1.34)	0.72	NS	–	NS	–
Dyslipidemia	0.68 (0.49–0.93)	0.017	1.23 (0.78–1.95)	0.37	NS	–
CVA	1.50 (1.07–2.09)	0.018	1.30 (0.84–2.01)	0.24	NS	–
PAD	1.49 (0.95–2.31)	0.080	NS	–	NS	–
CKD	1.08 (0.80–1.47)	0.61	NS	–	NS	–
COPD/asthma	1.54 (0.99–2.39)	0.056	NS	–	NS	–
Depression	0.76 (0.19–3.06)	0.70	NS	–	NS	–
Liver disease	1.08 (0.58–1.99)	0.81	NS	–	NS	–
Sodium on admission	0.95 (0.92–0.98)	<0.001	0.96 (0.91–1.00)	0.068	0.96 (0.92–1.00)	0.041
Sodium at discharge	0.94 (0.91–0.98)	0.002	NS	–	NS	–
BUN on admission	1.009 (1.002–1.016)	0.014	NS	–	NS	–
BUN at discharge	1.02 (1.01–1.02)	<0.001	1.01 (1.00–1.02)	0.050	NS	–
Creatinine on admission	1.15 (0.99–1.34)	0.061	NS	–	NS	–
Creatinine at discharge	1.20 (1.04–1.38)	0.012	NS	–	NS	–
Hemoglobin on admission	0.90 (0.84–0.97)	0.004	NS	–	NS	–
Hemoglobin at discharge	0.84 (0.77–0.92)	<0.001	0.94 (0.83–1.06)	0.30	NS	–
Log BNP on admission	1.21 (1.01–1.44)	0.035	NS	–	NS	–
Log BNP at discharge	1.61 (1.35–1.92)	<0.001	1.35 (1.09–1.68)	0.006	1.34 (1.08–1.65)	0.007
Potassium on admission	1.29 (1.03–1.62)	0.027	0.92 (0.64–1.31)	0.64	NS	–
Potassium at discharge	1.01 (0.75–1.37)	0.94	NS	–	NS	–
CRP on admission	1.05 (1.00–1.09)	0.049	NS	–	NS	–
CRP at discharge	1.13 (1.03–1.24)	0.009	0.96 (0.85–1.09)	0.54	NS	–
Albumin on admission	0.44 (0.31–0.63)	<0.001	0.56 (0.35–0.90)	0.016	0.51 (0.33–0.79)	0.002
Albumin at discharge	0.47 (0.34–0.68)	<0.001	NS	–	NS	–
Total cholesterol on admission	1.00 (0.99–1.00)	0.75	NS	–	NS	–
Total bilirubin on admission	1.10 (0.85–1.42)	0.45	NS	–	NS	–
LVEF	1.00 (0.98–1.02)	0.94	NS	–	NS	–
Use of ACEIs or ARBs at discharge	0.71 (0.52–0.99)	0.042	0.96 (0.61–1.51)	0.85	NS	–
Use of β-blockers at discharge	1.29 (0.93–1.80)	0.132	NS	–	NS	–
Use of MRAs at discharge	1.22 (0.89–1.69)	0.22	NS	–	NS	–
Use of loop diuretics at discharge	1.30 (0.90–1.90)	0.163	NS	–	NS	–
Use of statins at discharge	0.57 (0.39–0.82)	0.002	0.60 (0.36–1.01)	0.055	NS	–

CI, confidence interval; CRP, C-reactive protein; HR, hazard ratio; NS, not selected. Other abbreviations as in Tables 1–3.

Discussion

The JASPER registry provides the clinical characteristics, in-hospital treatment, and outcomes of Japanese hospitalized HFpEF patients. The major findings of our study were as follows: (1) in contrast to US hospitalized HFpEF patients, Japanese patients had a substantially higher prevalence of AF but lower prevalences of obesity, IHD, diabetes mellitus, COPD and renal insufficiency; (2) the clinical presentation of Japanese hospitalized HFpEF patients might be mostly characterized by uncontrolled hypertension and flush pulmonary edema without AF, or AF with repeated HF admissions; (3) Japanese HFpEF patients had longer hospital stay and lower in-hospital death rate than US patients; (4) approximately 40% of HFpEF patients experienced adverse events, including death or HF hospitalization, within 2 years post-discharge, and half of them died of CV causes; and (5) lower SBP and lower serum albumin level on admission, and NYHA class III/IV and the plasma BNP level at discharge were powerful and robust determinants of long-term death and HF hospitalization.

Large-scale clinical trials and real-world registries predominantly from Western countries have demonstrated that the main features of HFpEF patients are advanced age and female sex, and these patients have multiple comorbid conditions, including obesity or overweight,²⁹ systemic hypertension, type 2 diabetes mellitus³⁰ and renal insufficiency. Of them, obesity/overweight has reached epidemic proportions in patients with HFpEF, and its prevalence is surprisingly high at around 85%.²⁹ Shah et al recently proposed the emerging mechanisms for the development of HFpEF.³¹ Systemic inflammation, mainly caused by these predominant comorbidities, may affect myocardial remodeling and dysfunction in HFpEF through an enhanced endothelium-cardiomyocyte signaling cascade with coronary microvascular endothelial dysfunction.³¹ Furthermore, obese HFpEF patients show interesting pathophysiological features such as greater biventricular remodeling, volume overload, worse exercise capacity, more profound hemodynamic instability, and impaired pulmonary vasodilation.³² In contrast to these findings, our Japanese HFpEF patients had markedly lower BMI (mean 23.9 kg/m² in JASPER vs. median 29 kg/m² in GWTG-HF), but the prevalence of AF was 3-hold higher in JASPER (61.5%) when compared with US hospitalized HFpEF cohorts (21–34%).

Although the actual reason for the marked difference in the prevalence of AF between JASPER and the US HFpEF registries is unclear, we can speculate it is based in the lower prevalence of obesity, IHD, diabetes mellitus, COPD and renal insufficiency, all of which have been recently considered as major/emerging risk factors for developing HFpEF.^29–31 As a consequence, AF could become a relatively key comorbidity for HFpEF development in Japanese patients compared with US patients. Because AF precedes, is present concurrently with, or occurs subsequent to the onset of HFpEF,³³ it may play important roles in the development and maintenance of HFpEF, especially in Japanese patients. The hospitalized HFpEF patients in this study could be characterized by the following 3 phenotypes after comparison of clinical characteristics across AF status and precipitating factors for HF admission: (1) uncontrolled hypertension with flush pulmonary edema without AF, (2) sudden onset of AF, and (3) AF with repeated HF admissions. Thus, AF and hypertension might be the main therapeutic targets for the prevention of HFpEF development and worsening HF in Japanese patients. In addition, dietary non-compliance was the most frequent precipitating factor for HF admission in this cohort (24.5% of all precipitating factors). Optimizing patient education and disease management strategies based on these population-specific precipitating factors for HF admission could lead to prevention of worsening HF.^34–36 Future studies should focus on testing interventions targeting these contributing factors.

The overall absolute rate of in-hospital death for patients with HFpEF in the present study (1.3%) differed from that reported in the OPTIMIZE-HF (2.9%), ADHERE (2.8%) and GWTG-HF (2.5%) cohorts, despite the longer hospital stay for Japanese patients. These differences were largely related to differences in the cohorts’ characteristics, treatment, and the setting of the study, including the enrolment period as well as the definition of HFpEF. Nevertheless, a recent report from Singapore showed similar findings regarding in-hospital death (1.2%).³⁷ In terms of long-term clinical outcomes, our study revealed that HFpEF in Japanese is not always a benign entity, having a 2-year mortality rate of 20.9%. The JCARE-CARD registry reported a similar mortality of approximately 19% after a mean follow-up of 2.4 years.⁷ The 2-year all-cause mortality rate of Singapore hospitalized patients with HFpEF was higher at 26.6%.³⁷ Despite the differences in the studies, mortality rates remain high in Asian HFpEF patients. On the other hand, around half of hospitalized US HFpEF patients registered to GWTG-HF died during the 2 years after admission.³⁸ In addition, the composite event of all-cause death or HF hospitalization at 2 years occurred more frequently in these US HFpEF patients (≈85%) when compared with Japanese patients (40.8%). However, these event rates were estimated in a limited US population that was registered to GWTG-HF linked to the Medicare database (≥65 years old). As a consequence, the relatively older age of the US patients (median, 82 years) than of the Japanese patients (median, 80 years) could have contributed to the subsequent event rates. Other differences in the patient populations, such as ethnicity and medical culture, may also have contributed to these modest differences in in-hospital and long-term mortality rates between Asian and Western countries. The rate of CV death has been reported to be approximately 50–60% in HFpEF patients,^37,39 and our study showed similar findings for the rate of CV death (51.8%) and mode of CV death in JASPER to those in the I-PRESERVE and CHARM-Preserved trials.³⁹

It should be noted that a lower serum albumin level was one of the most powerful predictors of outcome in this HFpEF patients. Hypoalbuminemia in HF is probably from multiple causes, including malnutrition, inflammation, reduced synthesis because of hepatic congestion, hemodilution, and impaired anabolic–catabolic balance.⁴⁰ Pathophysiologically, severe hypoalbuminemia accelerates fluid retention and systemic edema through a decline in plasma oncotic pressure, which may result in further progression of cardiac and renal impairment accompanied by diuretic resistance in HF patients.⁴¹ Importantly, the determinants of clinical outcome differ between HFpEF and HFrEF,³⁷ and hypoalbuminemia would be an important strong prognostic determinant in HFpEF patients especially.^42,43 These reports support our findings, and serum albumin could be an important nutritional marker. Accordingly, prospective investigations of the potential preventative or therapeutic role of nutritional intervention for hypoalbuminemia in HFpEF patients are warranted.

Study Limitations

Although consecutive hospitalized HFpEF patients were registered from 16 nationwide sites in JASPER, the sample size was relatively smaller than those in previous reports predominantly from Western countries despite being the largest sample size in Japan. Because JASPER is a registry specifically focusing on HFpEF, and therefore HFrEF patients were not simultaneously registered, we could not compare the characteristics and outcomes between these HF phenotypes. In Table 3, patients who were categorized as having no history of AF and AF on admission had an enlarged left atrial dimension similar to those with the history of AF. We tried to obtain each patient’s history as appropriate; however, it would be difficult to determine AF history without ECG evidence. Thus, these patients might have a history of AF. Finally, only 72.0% of patients were successfully followed up at 2 years after discharge, leading to a substantial selection bias, despite there being no statistically difference regarding baseline characteristics related to long-term adverse events across the follow-up status (Table S1).

In conclusion, our analyses revealed that Japanese hospitalized HFpEF patients had a substantially higher prevalence of AF but a lower prevalence of obesity, IHD, diabetes mellitus, COPD and renal insufficiency, a longer hospital stay and lower subsequent event rates compared with US patients. Lower serum albumin level was one of the most powerful independent and robust determinants of long-term death and HF hospitalization. These findings indicated that specific preventative and therapeutic strategies focusing on AF and nutritional status might need to be considered for Japanese patients hospitalized with HFpEF.

Acknowledgments

The authors are grateful for the contributions of all the investigators, clinical research coordinators, data managers, and laboratory technicians involved in the JASPER registry. This work was supported by a grant from the Japan Cardiovascular Research Foundation (T.A., 24-4-2).

Disclosures

The authors report no relationships that could be construed as a conflict of interest.

Supplementary Information

For supplemental material including the Table S1, and a list of investigators, clinical research coordinators and data managers, please see the online version of this article. Supplementary data associated with this article can be found in the online version.

Supplementary Files

Supplementary File 1

Appendix S1

Table S1. Comparison of baseline characteristics related to long-term adverse events across the follow-up status

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0073

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