[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Figure 1.  Comparisons of Modes of Death Among Patients in the 3 Study Groups
Comparisons of Modes of Death Among Patients in the 3 Study Groups

ACS indicates acute coronary syndrome; CVD, cardiovascular death; HFmrEF, heart failure with midrange ejection fraction; and HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICH, intracranial hemorrhage; SCD, sudden cardiac death.

Figure 2.  Kaplan-Meier Survival Curves for All-Cause Death, Cardiovascular Death, and Sudden Cardiac Death Among Patients in the 3 Study Groups
Kaplan-Meier Survival Curves for All-Cause Death, Cardiovascular Death, and Sudden Cardiac Death Among Patients in the 3 Study Groups

HFmrEF indicates heart failure with midrange ejection fraction; HFpEF, heart failure with preserved ejection fraction; and HFrEF, heart failure with reduced ejection fraction.

Figure 3.  Bayesian Modeling for Cardiovascular Death and Sudden Cardiac Death Among Patients in the 3 Study Groups
Bayesian Modeling for Cardiovascular Death and Sudden Cardiac Death Among Patients in the 3 Study Groups

Solid lines indicate that the association between factors and mortality in each study group are statistically significant, and dashed lines indicate that those associations are not statistically significant. Factors are shown in black if they have at least one significant association with mortality, and factors are shown in gray if they do not have any significant associations with mortality in each study group. Numbers in parentheses indicate path coefficients of each factor to the mortality in each study group. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BUN, blood urea nitrogen; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HFmrEF, heart failure with midrange ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IHD, ischemic heart disease; MRA, mineralocorticoid receptor antagonist.

Table 1.  Baseline Characteristics and Medications at Dischargea
Baseline Characteristics and Medications at Dischargea
Table 2.  Comparisons of Mode of Death Among the 3 Study Groups
Comparisons of Mode of Death Among the 3 Study Groups
1.
Hunt  SA, Abraham  WT, Chin  MH,  et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society.  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): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society.   Circulation. 2005;112(12):e154-e235.PubMedGoogle Scholar
2.
Gheorghiade  M, Vaduganathan  M, Fonarow  GC, Bonow  RO.  Rehospitalization for heart failure: problems and perspectives.   J Am Coll Cardiol. 2013;61(4):391-403. doi:10.1016/j.jacc.2012.09.038 PubMedGoogle ScholarCrossref
3.
Teerlink  JR, Cotter  G, Davison  BA,  et al; RELAXin in Acute Heart Failure (RELAX-AHF) Investigators.  Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.   Lancet. 2013;381(9860):29-39. doi:10.1016/S0140-6736(12)61855-8 PubMedGoogle ScholarCrossref
4.
O’Connor  CM, Starling  RC, Hernandez  AF,  et al.  Effect of nesiritide in patients with acute decompensated heart failure.  Published correction appears in N Engl J Med. 2011;365(8):773.  N Engl J Med. 2011;365(1):32-43. doi:10.1056/NEJMoa1100171 PubMedGoogle ScholarCrossref
5.
Konstam  MA, Gheorghiade  M, Burnett  JC  Jr,  et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators.  Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.   JAMA. 2007;297(12):1319-1331. doi:10.1001/jama.297.12.1319 PubMedGoogle ScholarCrossref
6.
Maggioni  AP, Dahlström  U, Filippatos  G,  et al; Heart Failure Association of the European Society of Cardiology (HFA).  EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot).   Eur J Heart Fail. 2013;15(7):808-817. doi:10.1093/eurjhf/hft050 PubMedGoogle ScholarCrossref
7.
Tavazzi  L, Senni  M, Metra  M,  et al; IN-HF (Italian Network on Heart Failure) Outcome Investigators.  Multicenter prospective observational study on acute and chronic heart failure: one-year follow-up results of IN-HF (Italian Network on Heart Failure) outcome registry.   Circ Heart Fail. 2013;6(3):473-481. doi:10.1161/CIRCHEARTFAILURE.112.000161 PubMedGoogle ScholarCrossref
8.
Yamamoto  E, Kato  T, Ozasa  N,  et al; KCHF Study Investigators.  Kyoto Congestive Heart Failure (KCHF) study: rationale and design.   ESC Heart Fail. 2017;4(3):216-223. doi:10.1002/ehf2.12138 PubMedGoogle ScholarCrossref
9.
Yaku  H, Ozasa  N, Morimoto  T,  et al; KCHF Study Investigators.  Demographics, management, and in-hospital outcome of hospitalized acute heart failure syndrome patients in contemporary real clinical practice in Japan: observations from the prospective, multicenter Kyoto Congestive Heart Failure (KCHF) Registry.   Circ J. 2018;82(11):2811-2819. doi:10.1253/circj.CJ-17-1386 PubMedGoogle ScholarCrossref
10.
Kitai  T, Tang  WHW, Xanthopoulos  A,  et al.  Impact of early treatment with intravenous vasodilators and blood pressure reduction in acute heart failure.   Open Heart. 2018;5(2):e000845. doi:10.1136/openhrt-2018-000845 PubMedGoogle Scholar
11.
Mentz  RJ, O’Connor  CM.  Pathophysiology and clinical evaluation of acute heart failure.   Nat Rev Cardiol. 2016;13(1):28-35. doi:10.1038/nrcardio.2015.134 PubMedGoogle ScholarCrossref
12.
Sabbah  HN.  Pathophysiology of acute heart failure syndrome: a knowledge gap.   Heart Fail Rev. 2017;22(6):621-639. doi:10.1007/s10741-017-9651-2 PubMedGoogle ScholarCrossref
13.
O’Connor  CM, Miller  AB, Blair  JE,  et al; Efficacy of Vasopressin Antagonism in heart Failure Outcome Study with Tolvaptan (EVEREST) investigators.  Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program.   Am Heart J. 2010;159(5):841-849.e1. doi:10.1016/j.ahj.2010.02.023PubMedGoogle ScholarCrossref
14.
Felker  GM, Teerlink  JR, Butler  J,  et al.  Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study.   J Am Coll Cardiol. 2014;64(15):1591-1598. doi:10.1016/j.jacc.2014.05.071 PubMedGoogle ScholarCrossref
15.
Steinberg  BA, Zhao  X, Heidenreich  PA,  et al; Get With the Guidelines Scientific Advisory Committee and Investigators.  Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes.   Circulation. 2012;126(1):65-75. doi:10.1161/CIRCULATIONAHA.111.080770 PubMedGoogle ScholarCrossref
16.
Meta-analysis Global Group in Chronic Heart Failure (MAGGIC).  The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis.   Eur Heart J. 2012;33(14):1750-1757. doi:10.1093/eurheartj/ehr254 PubMedGoogle ScholarCrossref
17.
Chan  MM, Lam  CS.  How do patients with heart failure with preserved ejection fraction die?   Eur J Heart Fail. 2013;15(6):604-613. doi:10.1093/eurjhf/hft062 PubMedGoogle ScholarCrossref
18.
Senni  M, Paulus  WJ, Gavazzi  A,  et al.  New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes.   Eur Heart J. 2014;35(40):2797-2815. doi:10.1093/eurheartj/ehu204 PubMedGoogle ScholarCrossref
19.
Lund  LH, Donal  E, Oger  E,  et al; KaRen Investigators.  Association between cardiovascular vs. non-cardiovascular co-morbidities and outcomes in heart failure with preserved ejection fraction.   Eur J Heart Fail. 2014;16(9):992-1001. doi:10.1002/ejhf.137 PubMedGoogle ScholarCrossref
20.
Cubbon  RM, Gale  CP, Kearney  LC,  et al.  Changing characteristics and mode of death associated with chronic heart failure caused by left ventricular systolic dysfunction: a study across therapeutic eras.   Circ Heart Fail. 2011;4(4):396-403. doi:10.1161/CIRCHEARTFAILURE.110.959882 PubMedGoogle ScholarCrossref
21.
Ueda  T, Kawakami  R, Horii  M,  et al.  Noncardiovascular death, especially infection, is a significant cause of death in elderly patients with acutely decompensated heart failure.   J Card Fail. 2014;20(3):174-180. doi:10.1016/j.cardfail.2013.12.007 PubMedGoogle ScholarCrossref
22.
Vaduganathan  M, Patel  RB, Michel  A,  et al.  Mode of death in heart failure with preserved ejection fraction.   J Am Coll Cardiol. 2017;69(5):556-569. doi:10.1016/j.jacc.2016.10.078 PubMedGoogle ScholarCrossref
23.
Junttila  MJ, Barthel  P, Myerburg  RJ,  et al.  Sudden cardiac death after myocardial infarction in patients with type 2 diabetes.   Heart Rhythm. 2010;7(10):1396-1403. doi:10.1016/j.hrthm.2010.07.031 PubMedGoogle ScholarCrossref
24.
Yancy  CW, Jessup  M, Bozkurt  B,  et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines.  2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.   J Am Coll Cardiol. 2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05.019 PubMedGoogle ScholarCrossref
25.
Moss  AJ, Zareba  W, Hall  WJ,  et al; Multicenter Automatic Defibrillator Implantation Trial II Investigators.  Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.   N Engl J Med. 2002;346(12):877-883. doi:10.1056/NEJMoa013474 PubMedGoogle ScholarCrossref
26.
Bardy  GH, Lee  KL, Mark  DB,  et al; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators.  Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.   N Engl J Med. 2005;352(3):225-237. doi:10.1056/NEJMoa043399 PubMedGoogle ScholarCrossref
27.
Chatterjee  NA, Moorthy  MV, Pester  J,  et al; PRE-DETERMINE Study Group.  Sudden death in patients with coronary heart disease without severe systolic dysfunction.   JAMA Cardiol. 2018;3(7):591-600. doi:10.1001/jamacardio.2018.1049 PubMedGoogle ScholarCrossref
28.
Stecker  EC, Vickers  C, Waltz  J,  et al.  Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study.   J Am Coll Cardiol. 2006;47(6):1161-1166. doi:10.1016/j.jacc.2005.11.045 PubMedGoogle ScholarCrossref
29.
de Vreede-Swagemakers  JJ, Gorgels  AP, Dubois-Arbouw  WI,  et al.  Out-of-hospital cardiac arrest in the 1990's: a population-based study in the Maastricht area on incidence, characteristics and survival.   J Am Coll Cardiol. 1997;30(6):1500-1505. doi:10.1016/S0735-1097(97)00355-0 PubMedGoogle ScholarCrossref
30.
Baigent  C, Landray  MJ, Reith  C,  et al; SHARP Investigators.  The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.   Lancet. 2011;377(9784):2181-2192. doi:10.1016/S0140-6736(11)60739-3 PubMedGoogle ScholarCrossref
31.
Solomon  SD, Zelenkofske  S, McMurray  JJ,  et al; Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators.  Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both.   N Engl J Med. 2005;352(25):2581-2588. doi:10.1056/NEJMoa043938 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    EXPAND ALL
    Risk stratification for sudden cardiac death in heart failure population. Do we have to reconsider our approach?
    Konstantinos A. Gatzoulis M.D., Ph.D., Christos-Konstantinos Antoniou M.D., Ph.D. Petros Arsenos M.D., Ph.D., Polychronis Dilaveris M.D., Ph.D., Skevos Sideris M.D., Ph.D., Dimitrios Tsiachris M.D., Ph.D., Dimitrios Tousoulis M.D., Ph.D. | First Department of Cardiology, National and Kapodistrian University of Athens, School of Medicine
    In this interesting paper (1), using a large cohort of heart failure (HF) patients, prospectively observed following a HF-related hospitalization, Kitai et al offer significant information regarding mortality, as well as its main causes, quite subversive to the established rationale of using the left ventricular ejection fraction (LVEF) as the sole risk stratifier for sudden cardiac death (SCD).

    Unexpectedly, cardiovascular and SCD rates did not differ between LVEF-based HF categories. This is in contrast with previous studies (Seattle Heart Failure Model - Mozaffarian et al Circulation 2007), where the relative incidence of SCD to non-SCD decreased from 7 to
    0.2 in early versus advanced HF stages. Indeed, authors report that there is a non-negligible SCD risk in HF patients currently not offered the protection of an implantable cardioverter-defibrillator (ICD). It could be argued that modern heart failure classification per LVEF (preserved, moderately reduced and reduced) is not compatible anymore with the concept of using a dichotomous value of LVEF <35% for ICD allocation in the primary prevention setting.
    Kitai et al are right in stressing the need for studies in order to "identify patients who would optimally benefit from ICD implantation irrespective of the LVEF level", however they do not mention currently undertaken efforts to reshape our approach to SCD risk stratification in nonischemic dilated and ischemic cardiomyopathy patients, irrespectively of their LVEF (PROTECT-ICD - Zaman et al Heart Lung and Circulation 2016, CMR-GUIDE - Selvanayagam et al ANEC 2017, ReCONSIDER - Gatzoulis et al HJC 2020) and, more importantly, fail to take into account already published solid evidence for the value of alternative approaches (Halliday et al Circulation 2017, Gatzoulis et al EHJ 2019). More specifically, our group recently published the findings of the PRESERVE EF (Gatzoulis et al EHJ 2019), a prospective study of post-MI patients with LVEFs in the ≥40% range, using a tiered, programmed ventricular stimulation-inclusive approach with presence of noninvasive risk factors (NIRFs) leading to further invasive electrophysiological assessment to risk-stratify them in terms of primary SCD prevention, and offer ICDs to those deemed high risk (NIRFs present and inducible). Following a mean follow up of 32 months, 9 out of 41 high risk patients (22%) experienced a major arrhythmic event that was interrupted by the device, yielding an annual incidence of 8.2% for the SCD-equivalent endpoint.

    In any case, we agree with the essence of the message authors are trying to impart (Gatzoulis et al ANEC 2017), however, we believe that the additional information included in the present comment is complementary to their findings and useful in correctly putting into perspective their ramifications for primary SCD prevention.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    Cardiology
    May 7, 2020

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

    Author Affiliations
    • 1Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Japan
    • 2Center for Clinical Research and Innovation, Kobe City Medical Center General Hospital, Kobe, Japan
    • 3Department of Clinical Epidemiology, Hyogo College of Medicine, Nishinomiya, Japan
    • 4Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
    • 5Department of Cardiology, Kurashiki Central Hospital, Kurashiki, Japan
    • 6Department of Cardiology, Shiga General Hospital, Moriyama, Japan
    • 7Division of Cardiology, Osaka Red Cross Hospital, Osaka, Japan
    • 8Division of Cardiology, Tenri Hospital, Tenri, Japan
    • 9Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio
    JAMA Netw Open. 2020;3(5):e204296. doi:10.1001/jamanetworkopen.2020.4296
    Key Points español 中文 (chinese)

    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.

    Abstract

    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.

    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 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 the association. Proportional hazards assumption violations were estimated by generalized linear regression of scaled Schoenfeld residuals on time. Continuous variables were dichotomized by median values or clinically meaningful reference values.

    We introduced a bayesian network to estimate associations between risk factors and mortality. A bayesian network is a probabilistic graphical model in which conditional dependencies among multiple factors are represented by edges. We constructed a bayesian network and assumed multinomial distribution for the outcome variable and binomial distribution for the other variables. With the use of the data without any missing values, the posterior distributions of variables were obtained using the Markov chain Monte Carlo method. We set 4 separate sampling sequences, each consisting of 1000 random samples, half of which were discarded for convergence. Sampling convergence was evaluated using Gelman-Rubin statistics and by visually inspecting trace plots. All prior variables were set as noninformative.

    Statistical analyses were performed using JMP, version 14.0.0 (SAS Institute Inc) and R, version 3.5.1 (R Foundation for Statistical Computing), with probabilistic programming language Stan (Stan Development Team) for all bayesian analyses.

    Results
    Patient Characteristics

    A total of 3717 patients (mean [SD] age, 77.7 [12.0] years; 2049 [55.1%] male) were included in the study. A total of 1000 patients (26.9%) had ischemic heart failure. The mean (SD) heart rate was 71/min (13/min), the mean (SD) systolic blood pressure was 116 (18) mm Hg, and the mean (SD) diastolic blood pressure was 64 (12) mm Hg. The mean (SD) LVEF at baseline was 46.4% (16.2%). Among the 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%) having as having HFpEF (LVEF, ≥50%).

    Comparisons of baseline patient characteristics among the 3 groups and missing values in each variable are given in Table 1. Older age was associated with increased likelihood of LVEF (mean [SD] age in HFrEF group: 73.8 [13.6] years; mean [SD] age in HFmrEF group: 78.1 [11.0] years; and mean [SD] age in HFpEF group: 80.7 [9.9] years; P < .001), and an increased prevalence of LVEF among women was observed (HFrEF group: 458 [33.1%]; HFmrEF: 283 [40.3%]; and HFpEF: 927 [56.8%]; P < .001). An ischemic origin was most frequent in patients with HFrEF, whereas hypertension and atrial fibrillation were most frequent in patients with HFpEF.

    Incidence of Death

    The median follow-up period was 470 days (interquartile range, 357-649 days) after discharge, and the 1-year follow-up rate was 96%. During the follow-up period, 848 deaths were observed, and the overall mortality rate was 22.8%. Causes of death were adjudicated as cardiovascular deaths in 523 patients (14.1%; 61.7% of total mortality) and noncardiovascular deaths in 322 patients (8.7%; 38.0% of total mortality). The causes of cardiovascular death included heart failure exacerbation in 324 patients (8.7%), SCDs in 98 patients (2.6%), stroke or intracranial hemorrhage in 38 patients (1.0%), acute coronary syndrome in 9 patients (0.2%), and vascular-related deaths in 13 patients (0.3%). The causes of noncardiovascular death included infection in 122 patients (3.3%), malignant tumor in 71 patients (1.9%), and respiratory failure in 30 patients (0.8%) (Table 2).

    The observed modes of deaths among the 3 groups are compared in Figure 1. No significant differences were found among the 3 groups with respect to all-cause death (HFrEF group: 298 patients [21.6%; 95% CI, 19.5%-23.8%]; HFmrEF group: 158 patients [22.5%; 95% CI, 19.5%-25.7%]; and HFpEF group: 392 patients [24.0%; 95% CI, 22.0%-26.2%]; P = .26), cardiovascular death (HFrEF group: 203 patients [14.7%; 95% CI, 12.9%-16.6%]; HFmrEF group: 97 patients [13.8%; 95% CI, 11.4%-16.5%]; and HFpEF group: 223 patients [13.7%; 95% CI, 12.1%-15.4%]; P = .71), and SCD (HFrEF group: 44 patients [3.2%; 95% CI, 2.4%-4.2%]; HFmrEF group: 14 patients [2.0%; 95% CI, 1.2%-3.3%]; and HFpEF group: 40 patients [2.5%; 95% CI, 1.8%-3.3%]; P = .23). Figure 2 shows the Kaplan-Meier survival curves for all-cause death, cardiovascular death, and noncardiovascular death among the 3 groups.

    Factors Associated With Each Mode of Death

    In the multivariable Cox proportional hazards regression analyses, the factors confirmed as the independent variables associated with all-cause death in all the study patients were older age, female sex, no prescription of ACEIs or ARBs, anemia, low albumin levels, high BUN levels, and low estimated glomerular filtration rate (eGFR) (eTable 1 in the Supplement). Among these variables, older age, no prescription of ACEIs or ARBs, low albumin levels, and high BUN levels were consistently associated with all-cause death in all subgroups. Some of these same factors, including older age, no prescription of ACEIs or ARBs, and high BUN levels, were consistently associated with cardiovascular death in the entire population and the subgroups (eTables 2-4 in the Supplement). In addition, factors such as no prescription of β-blockers or MRAs, anemia, and low eGFR were independently associated with cardiovascular death in the HFrEF group. Some of these same factors, including low eGFR and no prescription of MRAs, were independently associated with cardiovascular death in the HFpEF group. Older age, female sex, anemia, low albumin levels, high BUN levels, and no prescription of ACEIs or ARBs were also associated with noncardiovascular death.

    The results of bayesian modeling for estimating cardiovascular death and SCD are shown in Figure 3. Guideline-directed heart failure medications, such as β-blockers, ACEIs or ARBs, and MRAs, were associated with a lower incidence of SCD in patients with HFrEF and in patients with HFpEF. Other factors associated with an increased risk of SCD were hyponatremia, HFrEF in female patients, hypoalbuminemia and wide QRS in patients with HFmrEF, increased heart rate, and hyponatremia and female sex in patients with HFpEF. Similarly, β-blockers, ACEIs or ARBs, and MRAs were also associated with a lower incidence of cardiovascular death in the HFrEF group and in the HFpEF group.

    Discussion

    The current analysis investigated the postdischarge mode of death in 3717 hospitalized patients with ADHF and among LVEF subgroups (HFrEF, HFmrEF, and HFpEF). The major findings of this study were as follows: (1) overall mortality in hospitalized patients with ADHF after discharge was 22.8% during a median follow-up of 470 days with a 96% follow-up rate; (2) cardiovascular deaths accounted for 61.7% of total mortality and noncardiovascular deaths accounted for 38.0% of total mortality; (3) heart failure exacerbation was the leading cause of cardiovascular death, and SCD was the second most frequent cause of cardiovascular death; and (4) this finding was consistent among the LVEF subgroups (HFrEF vs HFmrEF vs HFpEF), with the risk of SCD being comparable in the HFpEF and HFrEF groups.

    ADHF is a complex clinical syndrome, and multiple factors and underlying mechanisms may contribute to postdischarge mortality in individual patients.10-12 Despite improvement in intensive treatment of acute phases and multidisciplinary approaches to improve postdischarge outcomes, patients hospitalized for ADHF have a substantial mortality risk of 10% to 20% during the 6 months after discharge.2-5 Thus, a better understanding of the mode of death and a better characterization of risks associated with mode-specific causes of death may provide insights into the underlying mechanism to improve patient outcomes. In particular, comparisons of the mode of death among strictly defined populations with HFrEF, HFmrEF, and HFpEF are important for clinical practice.

    In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, which included 4133 patients with HFrEF hospitalized for ADHF, 1080 deaths occurred during a median follow-up of 9.9 months. Heart failure exacerbation was the leading cause of death (47.2%), and SCD was the second-leading cause of death (30.0%).13 In the Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in Acute Heart Failure (RELAX-AHF) trial, which included 1161 patients with acute heart failure, heart failure exacerbation was a leading cause of cardiovascular death (35%), and SCD was the second-leading cause of cardiovascular death (23%).14 Similarly, the current analysis demonstrated that heart failure exacerbation was the leading cause of cardiovascular death, and SCD was the second-leading cause of death. Of interest, SCD was reported to be the second-leading cause of death even in the HFpEF group, and the rate was comparable to that in the HFrEF group. However, the nonnegligible prevalence of SCD is debatable. A similar incidence of SCD was reported in patients with and without left ventricular systolic dysfunction, with a similar potential benefit from implantable cardioverter defibrillator (ICD) prophylaxis.15

    HFpEF has been reported to be associated with similar or slightly lower mortality than HFrEF.16,17 Although heart failure death and SCD account for most cardiovascular deaths among patients with HFpEF, similar to patients with HFrEF,18 the major difference in the cause of death between patients with HFrEF and those with HFpEF has been the larger prevalence of noncardiovascular deaths in the HFpEF group.16,17,19,20 In the Framingham Heart Study, 1025 deaths in the mixed HFrEF and HFpEF population between 1971 and 2004 were analyzed, and 38% of deaths reportedly had a noncardiovascular mode.21 Similarly, another study reported that 40% of deaths were attributable to noncardiovascular modes during 20 months after discharge in 459 patients admitted with ADHF, mixed HFrEF, and HFpEF.22 A previous study23 reported that 42% of deaths in patients with HFpEF had noncardiovascular causes. Consistent with previous reports,16,19 the rate of noncardiovascular death was higher in the HFpEF group in the current analysis. In a previous study,23 infection was the leading cause of noncardiovascular death, causing 38% of total noncardiovascular deaths, and malignant tumor was the second-leading cause of noncardiovascular death (22%), findings that were consistent with the those in the LVEF subgroups in the current study.

    Reduced LVEF remains the major selection criterion for ICD placement according to the current guidelines,24 and increasing evidence supports that ICD is an effective treatment of primary and secondary SCD in patients with left ventricular systolic dysfunction.25,26 However, given the substantial amount of SCD observed in patients with LVEFs higher than 35% who do not qualify for ICD placement based on the current criteria,26-29 our results pose the question of whether the ICD criteria should be determined only by LVEF. Although no data are currently available to examine the role of ICD treatment in patients with HFpEF, observational data suggest that SCD contributes substantially to the overall mortality in these patients.30,31 However, considering the high incidence of nonarrhythmic heart failure deaths and that ICD placement in patients with HFrEF yielded conflicting results for overall mortality despite increased frequency of adequate ICD shocks, additional studies are needed to identify patients who would optimally benefit from ICD implantation irrespective of the LVEF level.

    Strengths and Limitations

    This study has strengths. It provides insight regarding the prevalence, nature, and variables associated with death in patients with postdischarge ADHF, with a high follow-up rate, strictly adjudicated mode of death, and potentially important implications for improvement in survival. The study included central adjudication of end points and a large contemporary patient population across the spectrum of LVEF.

    This study has limitations. First, this was a post hoc analysis from a prospective, observational cohort study with inherent associated limitations. Despite covariate adjustment, we could not exclude the influence of other measured and unmeasured confounding. In particular, we did not consider any interim cardiovascular events associated with heart failure death or SCD that may have modified the disease trajectories. Second, it is possible that our data are not generalizable to all patients with ADHF. Particularly, the current cohort included a large number of patients with de novo heart failure rather than acute worsening of chronic heart failure, leading to a small number of patients with ICD implantation at the time of discharge. In addition, the patient population was elderly, and the prevalence of an ischemic origin of heart failure was lower than that reported in other clinical series outside Japan. The diagnosis of nonischemic cardiomyopathy was made by physicians in each participating center, and not all patients with a nonischemic origin underwent coronary angiography during the hospitalization. We did not have data on the number of patients who had ICD implantation during the follow-up after discharge. Third, diagnosis of heart failure origin was not based on biopsy results or imaging findings. In addition, we did not have information regarding whether any of the patients with HFpEF or HFmrEF recovered from HFrEF. In addition, information regarding circumstances of SCD was not available. Thus, there is a possibility that specific patients with cardiomyopathy, such as hypertrophic cardiomyopathy, restrictive cardiomyopathy, and cardiac amyloidosis, were included in the registry. In particular, underdiagnosed cardiac amyloidosis may be associated with a high incidence of SCD in the HFpEF cohort. Additional studies are needed to test this hypothesis.

    Conclusions

    In this study, the incidences of cardiovascular death and sudden cardiac death were comparable among the heart failure subtypes. Use of β-blockers and ACEIs or ARBs was associated with lower mortality in patients with HFpEF and HFmrEF. Given the nonnegligible incidence of SCD in patients with HFpEF, an additional study appears to be warranted to identify the high-risk subset in this population.

    Back to top
    Article Information

    Accepted for Publication: March 5, 2020.

    Published: May 7, 2020. doi:10.1001/jamanetworkopen.2020.4296

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Kitai T et al. JAMA Network Open.

    Corresponding Author: Takao Kato, MD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan (tkato75@kuhp.kyoto-u.ac.jp).

    Author Contributions: Drs Kitai and Kato had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Kitai, Morimoto, Yaku, Nagao, Tamaki, Ozasa, Kato, Kimura.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Kitai, Miyakoshi, Yaku, Murai.

    Critical revision of the manuscript for important intellectual content: Kitai, Morimoto, Yaku, Kaji, Furukawa, Inuzuka, Nagao, Tamaki, Yamamoto, Ozasa, Tang, Kato, Kimura.

    Statistical analysis: Kitai, Miyakoshi, Morimoto, Ozasa, Kato.

    Administrative, technical, or material support: Yaku, Inuzuka, Yamamoto, Ozasa, Kato.

    Supervision: Kitai, Yaku, Furukawa, Nagao, Kimura.

    Conflict of Interest Disclosures: Dr Miyakoshi reported receiving personal fees from Teijin Pharma Ltd during the conduct of the study and from Chuai Pharmaceutical Co Ltd. outside the submitted work. Dr Furukawa reported receiving personal fees from Daiichi Sankyo and from Bayer outside the submitted work. Dr Tang reported serving as a consultant to Sequana Medical Inc and receiving personnel fees from Springer Nature as editor of journal articles (not relevant to the topic of this article). No other disclosures were reported.

    References
    1.
    Hunt  SA, Abraham  WT, Chin  MH,  et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society.  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): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society.   Circulation. 2005;112(12):e154-e235.PubMedGoogle Scholar
    2.
    Gheorghiade  M, Vaduganathan  M, Fonarow  GC, Bonow  RO.  Rehospitalization for heart failure: problems and perspectives.   J Am Coll Cardiol. 2013;61(4):391-403. doi:10.1016/j.jacc.2012.09.038 PubMedGoogle ScholarCrossref
    3.
    Teerlink  JR, Cotter  G, Davison  BA,  et al; RELAXin in Acute Heart Failure (RELAX-AHF) Investigators.  Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.   Lancet. 2013;381(9860):29-39. doi:10.1016/S0140-6736(12)61855-8 PubMedGoogle ScholarCrossref
    4.
    O’Connor  CM, Starling  RC, Hernandez  AF,  et al.  Effect of nesiritide in patients with acute decompensated heart failure.  Published correction appears in N Engl J Med. 2011;365(8):773.  N Engl J Med. 2011;365(1):32-43. doi:10.1056/NEJMoa1100171 PubMedGoogle ScholarCrossref
    5.
    Konstam  MA, Gheorghiade  M, Burnett  JC  Jr,  et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators.  Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.   JAMA. 2007;297(12):1319-1331. doi:10.1001/jama.297.12.1319 PubMedGoogle ScholarCrossref
    6.
    Maggioni  AP, Dahlström  U, Filippatos  G,  et al; Heart Failure Association of the European Society of Cardiology (HFA).  EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot).   Eur J Heart Fail. 2013;15(7):808-817. doi:10.1093/eurjhf/hft050 PubMedGoogle ScholarCrossref
    7.
    Tavazzi  L, Senni  M, Metra  M,  et al; IN-HF (Italian Network on Heart Failure) Outcome Investigators.  Multicenter prospective observational study on acute and chronic heart failure: one-year follow-up results of IN-HF (Italian Network on Heart Failure) outcome registry.   Circ Heart Fail. 2013;6(3):473-481. doi:10.1161/CIRCHEARTFAILURE.112.000161 PubMedGoogle ScholarCrossref
    8.
    Yamamoto  E, Kato  T, Ozasa  N,  et al; KCHF Study Investigators.  Kyoto Congestive Heart Failure (KCHF) study: rationale and design.   ESC Heart Fail. 2017;4(3):216-223. doi:10.1002/ehf2.12138 PubMedGoogle ScholarCrossref
    9.
    Yaku  H, Ozasa  N, Morimoto  T,  et al; KCHF Study Investigators.  Demographics, management, and in-hospital outcome of hospitalized acute heart failure syndrome patients in contemporary real clinical practice in Japan: observations from the prospective, multicenter Kyoto Congestive Heart Failure (KCHF) Registry.   Circ J. 2018;82(11):2811-2819. doi:10.1253/circj.CJ-17-1386 PubMedGoogle ScholarCrossref
    10.
    Kitai  T, Tang  WHW, Xanthopoulos  A,  et al.  Impact of early treatment with intravenous vasodilators and blood pressure reduction in acute heart failure.   Open Heart. 2018;5(2):e000845. doi:10.1136/openhrt-2018-000845 PubMedGoogle Scholar
    11.
    Mentz  RJ, O’Connor  CM.  Pathophysiology and clinical evaluation of acute heart failure.   Nat Rev Cardiol. 2016;13(1):28-35. doi:10.1038/nrcardio.2015.134 PubMedGoogle ScholarCrossref
    12.
    Sabbah  HN.  Pathophysiology of acute heart failure syndrome: a knowledge gap.   Heart Fail Rev. 2017;22(6):621-639. doi:10.1007/s10741-017-9651-2 PubMedGoogle ScholarCrossref
    13.
    O’Connor  CM, Miller  AB, Blair  JE,  et al; Efficacy of Vasopressin Antagonism in heart Failure Outcome Study with Tolvaptan (EVEREST) investigators.  Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program.   Am Heart J. 2010;159(5):841-849.e1. doi:10.1016/j.ahj.2010.02.023PubMedGoogle ScholarCrossref
    14.
    Felker  GM, Teerlink  JR, Butler  J,  et al.  Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study.   J Am Coll Cardiol. 2014;64(15):1591-1598. doi:10.1016/j.jacc.2014.05.071 PubMedGoogle ScholarCrossref
    15.
    Steinberg  BA, Zhao  X, Heidenreich  PA,  et al; Get With the Guidelines Scientific Advisory Committee and Investigators.  Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes.   Circulation. 2012;126(1):65-75. doi:10.1161/CIRCULATIONAHA.111.080770 PubMedGoogle ScholarCrossref
    16.
    Meta-analysis Global Group in Chronic Heart Failure (MAGGIC).  The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis.   Eur Heart J. 2012;33(14):1750-1757. doi:10.1093/eurheartj/ehr254 PubMedGoogle ScholarCrossref
    17.
    Chan  MM, Lam  CS.  How do patients with heart failure with preserved ejection fraction die?   Eur J Heart Fail. 2013;15(6):604-613. doi:10.1093/eurjhf/hft062 PubMedGoogle ScholarCrossref
    18.
    Senni  M, Paulus  WJ, Gavazzi  A,  et al.  New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes.   Eur Heart J. 2014;35(40):2797-2815. doi:10.1093/eurheartj/ehu204 PubMedGoogle ScholarCrossref
    19.
    Lund  LH, Donal  E, Oger  E,  et al; KaRen Investigators.  Association between cardiovascular vs. non-cardiovascular co-morbidities and outcomes in heart failure with preserved ejection fraction.   Eur J Heart Fail. 2014;16(9):992-1001. doi:10.1002/ejhf.137 PubMedGoogle ScholarCrossref
    20.
    Cubbon  RM, Gale  CP, Kearney  LC,  et al.  Changing characteristics and mode of death associated with chronic heart failure caused by left ventricular systolic dysfunction: a study across therapeutic eras.   Circ Heart Fail. 2011;4(4):396-403. doi:10.1161/CIRCHEARTFAILURE.110.959882 PubMedGoogle ScholarCrossref
    21.
    Ueda  T, Kawakami  R, Horii  M,  et al.  Noncardiovascular death, especially infection, is a significant cause of death in elderly patients with acutely decompensated heart failure.   J Card Fail. 2014;20(3):174-180. doi:10.1016/j.cardfail.2013.12.007 PubMedGoogle ScholarCrossref
    22.
    Vaduganathan  M, Patel  RB, Michel  A,  et al.  Mode of death in heart failure with preserved ejection fraction.   J Am Coll Cardiol. 2017;69(5):556-569. doi:10.1016/j.jacc.2016.10.078 PubMedGoogle ScholarCrossref
    23.
    Junttila  MJ, Barthel  P, Myerburg  RJ,  et al.  Sudden cardiac death after myocardial infarction in patients with type 2 diabetes.   Heart Rhythm. 2010;7(10):1396-1403. doi:10.1016/j.hrthm.2010.07.031 PubMedGoogle ScholarCrossref
    24.
    Yancy  CW, Jessup  M, Bozkurt  B,  et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines.  2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.   J Am Coll Cardiol. 2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05.019 PubMedGoogle ScholarCrossref
    25.
    Moss  AJ, Zareba  W, Hall  WJ,  et al; Multicenter Automatic Defibrillator Implantation Trial II Investigators.  Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.   N Engl J Med. 2002;346(12):877-883. doi:10.1056/NEJMoa013474 PubMedGoogle ScholarCrossref
    26.
    Bardy  GH, Lee  KL, Mark  DB,  et al; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators.  Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.   N Engl J Med. 2005;352(3):225-237. doi:10.1056/NEJMoa043399 PubMedGoogle ScholarCrossref
    27.
    Chatterjee  NA, Moorthy  MV, Pester  J,  et al; PRE-DETERMINE Study Group.  Sudden death in patients with coronary heart disease without severe systolic dysfunction.   JAMA Cardiol. 2018;3(7):591-600. doi:10.1001/jamacardio.2018.1049 PubMedGoogle ScholarCrossref
    28.
    Stecker  EC, Vickers  C, Waltz  J,  et al.  Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study.   J Am Coll Cardiol. 2006;47(6):1161-1166. doi:10.1016/j.jacc.2005.11.045 PubMedGoogle ScholarCrossref
    29.
    de Vreede-Swagemakers  JJ, Gorgels  AP, Dubois-Arbouw  WI,  et al.  Out-of-hospital cardiac arrest in the 1990's: a population-based study in the Maastricht area on incidence, characteristics and survival.   J Am Coll Cardiol. 1997;30(6):1500-1505. doi:10.1016/S0735-1097(97)00355-0 PubMedGoogle ScholarCrossref
    30.
    Baigent  C, Landray  MJ, Reith  C,  et al; SHARP Investigators.  The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.   Lancet. 2011;377(9784):2181-2192. doi:10.1016/S0140-6736(11)60739-3 PubMedGoogle ScholarCrossref
    31.
    Solomon  SD, Zelenkofske  S, McMurray  JJ,  et al; Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators.  Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both.   N Engl J Med. 2005;352(25):2581-2588. doi:10.1056/NEJMoa043938 PubMedGoogle ScholarCrossref
    ×