Title Mode of Death Among Japanese Adults With Heart Failure With Preserved, Midrange, and Reduced Ejection Fractio

IMPORTANCE Despite intensive treatment, hospitalized patients with acute decompensated heart failure (ADHF) have a substantial risk of postdischarge mortality. Limited data are available on the possible differences in the incidence and mechanisms of death among patients with heart failure with reduced ejection fraction (HFrEF), heart failure with midrange ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). OBJECTIVES To examine the incidences and mode of postdischarge mortality among patients with ADHF and to compare the risk profile among patients with HFrEF, HFmrEF, and HFpEF. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study of 4056 patients hospitalized for ADHF analyzed data from 3717 patients who were discharged from October 1, 2014, to March 31, 2016. Data analysis was performed from April 1 to August 31, 2019. EXPOSURES Death among patients with ADHF after hospital discharge. MAIN OUTCOMES AND MEASURES All-cause death and cause of postdischarge mortality after the index hospitalization by left ventricular ejection fraction (LVEF) subgroup. RESULTS A total of 3717 patients (mean [SD] age, 77.7 [12.0] years; 2049 [55.1%] male) were included in the study. The mean (SD) LVEF at baseline was 46.4% (16.2%). Among 3717 enrolled patients, 1383 (37.2%) were categorized as having HFrEF (LVEF, <40%), 703 (18.9%) as having HFmrEF (LVEF, 40%-49%), and 1631 (43.9%) as having HFpEF (LVEF, 50%). The incidence and causes of death were evaluated after discharge from the index hospitalization. The median follow-up period was 470 days (interquartile range, 357-649 days), and the 1-year follow-up rate was 96%. During follow-up, all-cause death occurred in 848 patients (22.8%; HFrEF group: 298 [21.5%; 95% CI, 19.5%-23.8%]; HFmrEF group: 158 [22.5%; 95% CI, 19.5%-25.7%]; and HRpEF group: 392 [24.0%; 95% CI, 22.0%-26.2%]; P = .26), cardiovascular deaths occurred in 523 patients (14.1%; HFrEF group: 203 [14.7%; 95% CI, 12.9%-16.6%]; HFmrEF group: 97 [13.8%; 95% CI, 11.4%-16.5%]; and HFpEF group: 223 [13.7%; 95% CI, 12.1%-15.4%]; P = .71), and sudden cardiac death occurred in 98 patients (2.6%; HFrEF group: 44 [3.2%; 95% CI, 2.4%-4.2%]; HFmrEF group: 14 [2.0%; 95% CI, 1.2%-3.3%]; and HFpEF group: 40 [2.5%; 95% CI, 1.8%-3.3%]; P = .23). The risks of causes of death were similar among the subtypes. CONCLUSIONS AND RELEVANCE The mode of death was similar among the heart failure subtypes. Given the nonnegligible incidence of sudden cardiac death in patients with HFpEF found in this study, further studies appear to be warranted to identify a high-risk subset in this population. JAMA Network Open. 2020;3(5):e204296. doi:10.1001/jamanetworkopen.2020.4296 Key Points Question Are there differences in the mode of death after hospital discharge in patients with reduced, midrange, and preserved left ventricular ejection fraction? Findings In this cohort study of 3717 hospitalized patients with acute decompensated heart failure with a median follow-up of 470 days, 848 patients died (523 cardiovascular deaths and 98 sudden cardiac deaths). The risks of each cause of death were comparable among the patients with heart failure with reduced, midrange, and preserved ejection fraction. Meaning This study found nonnegligible incidence of sudden cardiac death in patients with heart failure with preserved ejection fraction; further study appears to be warranted to identify a high-risk subset in this population. + Supplemental content Author affiliations and article information are listed at the end of this article. Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(5):e204296. doi:10.1001/jamanetworkopen.2020.4296 (Reprinted) May 7, 2020 1/12 Downloaded From: https://jamanetwork.com/ by a Kyoto University User on 05/13/2020 Introduction Heart failure has been an increasing public health concern, and hospitalization rates and costs of care for heart failure remain high.1 Substantial progress has been made in the management of chronic ambulatory heart failure with the availability of drugs such as β-blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs). However, morbidity and mortality among patients with heart failure are still high.2-5 Hospitalized patients with acute decompensated heart failure (ADHF) had an annual mortality rate of approximately 20%, which is higher than the rates among patients with chronic ambulatory heart failure.6,7 However, the incidence and mechanisms of death among patients with ADHF who are discharged from the hospital have not been well characterized. A better understanding of the cause and mode of death in these patients may lead to better insights into the underlying pathophysiologic mechanisms and new treatments for improving patient outcomes. In addition, limited data are available for the possible differences in the mode of mortality among patients with heart failure with reduced ejection fraction (HFrEF), heart failure with midrange ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). Therefore, we aimed to assess the prevalence and mode of mortality among patients with ADHF hospital after discharge and then compare the risk profile among patients with HFrEF, HFmrEF, and HFpEF. Methods Study Design The study design and primary results of the Kyoto Congestive Heart Failure (KCHF) registry have been reported previously.8,9 In brief, the KCHF registry was a multicenter, prospective cohort study that enrolled 4056 consecutive hospitalized patients with ADHF. The study was conducted from October 1, 2014, to March 31, 2016, at 19 centers in Japan after approval of each participating center’s ethics committee or institutional review board. A waiver of informed consent was granted by the institutional review boards because the study met the conditions of the Japanese ethical guidelines for epidemiologic study and the US policy for protecting human research participants. This prespecified post hoc analysis was approved by institutional review boards of each participating institution. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Among the 4056 enrolled patients in the KCHF registry, 3785 patients (93.3%) were discharged after the index hospitalization for ADHF. Clinical follow-up data were collected in October 2017, and the median follow-up period was 470 days. The attending physicians or research assistants at each participating facility collected clinical events data after the index hospitalization from hospital medical records or from patients, their relatives, or their referring physicians (with patient consent). After excluding 57 patients who were unavailable for follow-up after discharge and 11 patients who had a missing left ventricular ejection fraction (LVEF) measurement at baseline, a total of 3717 patients were included in the current analysis. Patients were divided based on their LVEF at baseline: less than 40% (HFrEF), 40% to 49% (HFmrEF), and 50% or higher (HFpEF). The eFigure in the Supplement shows the selection of these patients from the overall KCHF population. Data analysis was performed from April 1 to August 31, 2019. Patients’ baseline characteristics, including age, height, body weight, blood pressure, heart rate, laboratory data, and echocardiographic data, were recorded or measured at the time of hospital discharge. A baseline medication was defined as a medication at the time of discharge. Incident death and the cause of death were adjudicated up to 1 year. The causes of death were adjudicated by a central clinical events committee on the basis of prespecified criteria and were classified into cardiovascular death or noncardiovascular death. Cardiovascular death comprised death due to heart failure exacerbation, acute coronary syndrome, stroke and intracranial hemorrhage, or fatal ventricular arrhythmia; vascular-related death; sudden cardiac death (SCD); and other cardiac death JAMA Network Open | Cardiology Mode of Death Among Japanese Adults With Heart Failure JAMA Network Open. 2020;3(5):e204296. doi:10.1001/jamanetworkopen.2020.4296 (Reprinted) May 7, 2020 2/12 Downloaded From: https://jamanetwork.com/ by a Kyoto University User on 05/13/2020 causes. SCD was defined as unexplained death of a previously stable patient, including fatal ventricular arrhythmia and cardiac arrest. Noncardiovascular deaths included malignant tumors, infection (including pneumonia), renal failure, liver failure, respiratory failure, bleeding, and other causes. Statistical Analysis Categorical variables are expressed as numbers (percentages) and were compared using the χ2 test or the Fisher exact test, as appropriate. Continuous variables are expressed as means (SDs) or medians and interquartile ranges. On the basis of their distribution (qualitatively judged by histogram and Q-Q plot), continuous variables were compared with an unpaired, 2-tailed t test when normally distributed or with the Wilcoxon rank sum test when not normally distributed. Two-sided P < .05 was considered statistically significant. The Kaplan-Meier method was used to estimate cumulative incidence of events, and differences were compared using the log-rank test. A Cox proportional hazards regression model was used to evaluate the association between each variable and the incidence of all-cause death, cardiovascular death, and noncardiovascular death. Candidate variables for the multivariable model included age, sex, hypertension, diabetes, atrial fibrillation, anemia, chronic kidney disease, serum albumin level, blood urea nitrogen (BUN) level, and prescription of β-blockers, ACEIs or ARBs, and MRAs at discharge. All variables were selected a priori because they are risk factors for death or because of their ability to confound