Journal: JACC Heart Fail

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Abstract

Cardiovascular and Renal Outcomes of Mineralocorticoid Receptor Antagonist Use in PARAGON-HF.

Jering KS, Zannad F, Claggett B, Mc Causland FR, ... Pfeffer MA, Solomon SD
Objectives
This study sought to evaluate the efficacy and safety of sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF) according to background mineralocorticoid receptor antagonist (MRA) therapy.
Background
Current guidelines recommend consideration of MRAs in selected patients with HFpEF. This study assessed cardiovascular outcomes, renal outcomes, and safety of sacubitril/valsartan compared with valsartan in patients with HFpEF according to background MRA treatment.
Methods
PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction) randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. In a pre-specified subgroup analysis, the effect of sacubitril/valsartan versus valsartan was evaluated according to baseline MRA use on the primary study composite of total heart failure hospitalizations and cardiovascular death using semiparametric proportional rates methods, as well as the renal composite of ≥50% decrease in estimated glomerular filtration rate, development of end-stage renal disease, or death from renal causes using Cox proportional hazards regression models. Annual decline in estimated glomerular filtration rate was analyzed with repeated-measures mixed-effect models. Key safety outcomes included incidence of hypotension, hyperkalemia, and elevations in serum creatinine above predefined thresholds.
Results
Patients treated with MRAs at baseline (n = 1,239, 26%), compared with MRA nonusers (n = 3,557, 74%), were younger (72 vs. 73 years), more often male (52% vs. 47%), had lower left ventricular ejection fraction (57% vs. 58%), and a higher proportion of prior HF hospitalization (59% vs. 44%) (all p < 0.001). Efficacy of sacubitril/valsartan compared with valsartan with regard to the primary cardiovascular (for MRA users: rate ratio: 0.73; 95% confidence interval [CI]: 0.56 to 0.95; vs. for MRA nonusers: rate ratio: 0.94; 95% CI: 0.79 to 1.11; p = 0.11) and renal endpoints (for MRA users: hazard ratio: 0.31; 95% CI: 0.13 to 0.76; vs. for MRA non-users: HR: 0.59; 95% CI: 0.36 to 0.95; p = 0.21) did not significantly vary by baseline MRA use. The incidence of key safety outcomes including hypotension and severe hyperkalemia (K > 6.0 mmol/l) did not vary by baseline MRA use. However, annual decline in estimated glomerular filtration rate was less with the combination of MRA and sacubitril/valsartan (for MRA users: absolute difference favoring sacubitril/valsartan: +1.2 ml/min/1.73 m per year; 95% CI: 0.6 to 1.7; vs. for MRA nonusers: +0.4; 95% CI: 0.1 to 0.7; p = 0.01).
Conclusions
Clinical efficacy of sacubitril/valsartan compared with valsartan with regard to predefined cardiorenal composite outcomes in PARAGON-HF was consistent in patients treated and not treated with MRA at baseline. Addition of sacubitril/valsartan rather than valsartan alone to MRA appears to be associated with a lesser decline in renal function and no increase in severe hyperkalemia. These data support possible added value of combination treatment with sacubitril/valsartan and MRA in patients with HFpEF. (Prospective Comparison of ARNI [angiotensin receptor -neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2020; 9:13-24
Jering KS, Zannad F, Claggett B, Mc Causland FR, ... Pfeffer MA, Solomon SD
JACC Heart Fail: 30 Dec 2020; 9:13-24 | PMID: 33189633
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Abstract

Improvement of Health Status Following Initiation of Sacubitril/Valsartan in Heart Failure and Reduced Ejection Fraction.

Piña IL, Camacho A, Ibrahim NE, Felker GM, ... Januzzi JL,
Background
Treatment of heart failure with reduced ejection fraction (EF) may improve patient-reported health outcomes.
Objectives
The purpose of this study was to determine timing and magnitude of change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores following initiation of sacubitril/valsartan and interaction with change in amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations.
Methods
From a single-arm, open-label study of patients initiated on sacubitril/valsartan, KCCQ-23 scores and NT-proBNP were obtained at baseline and follow-up through 12 months. Cross-sectional and longitudinal analyses evaluated magnitude and rate of change in KCCQ-23 scores and associations with NT-proBNP. Patient-level data from the randomized EVALUATE-HF study were used as historic controls.
Results
The analysis cohort (n = 678, age 64.7 years, 71.5% men, EF 28.9%) had a baseline KCCQ-23 overall score (OS) of 65.6. Following sacubitril/valsartan initiation, the majority (n = 412; 60.8%) of participants experienced a rise in KCCQ-23 OS ≥10 points; 26.0% increased by ≥20 points. Comparable improvement in KCCQ-23 scores was seen in various subgroups. Change in KCCQ-23 OS was inversely associated with change in circulating NT-proBNP concentrations. Among a control group of patients in EVALUATE-HF, linear rate of change in KCCQ-12 OS/14-day interval in the enalapril arm was 0.37 points (p = 0.06), whereas in the sacubitril/valsartan arm, scores increased at a rate of 1.19 points (p < 0.001), nearly identical to this dataset (1.08 points; p < 0.001).
Conclusions
Treatment of heart failure with reduced EF with sacubitril/valsartan is associated with rapid and significant improvement in KCCQ-23 scores which was significantly related to change in NT-proBNP. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2020; 9:42-51
Piña IL, Camacho A, Ibrahim NE, Felker GM, ... Januzzi JL,
JACC Heart Fail: 30 Dec 2020; 9:42-51 | PMID: 33189630
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Abstract

Heart Failure Hospitalization and Guideline-Directed Prescribing Patterns Among Heart Failure With Reduced Ejection Fraction Patients.

Srivastava PK, DeVore AD, Hellkamp AS, Thomas L, ... Hernandez AF, Fonarow GC
Objectives
The authors sought to evaluate the association of heart failure hospitalization (HFH) with guideline-directed medical therapy (GDMT) prescribing patterns among patients with heart failure with reduced ejection fraction (HFrEF).
Background
HFH represents an important opportunity to titrate GDMT among patients with HFrEF.
Methods
The CHAMP-HF (Change the Management of Patients With Heart Failure) registry is a prospective registry of adults with HFrEF (ejection fraction ≤40%). Using data from the CHAMP-HF registry (N = 4,365), adjusted time-to-event models were created to study the association of HFH with GDMT prescribing patterns.
Results
HFH (compared with no HFH) was positively associated with initiation of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), angiotensin receptor-neprilysin inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA). HFH positively associated with dose escalation of ACE inhibitor/ARB (probability ratio: 1.71, 95% confidence interval [CI]: 1.36 to 2.16) and MRA (probability ratio: 8.71, 95% CI: 4.19 to 18.10). In those on prior therapy, HFH was associated with discontinuation and de-escalation of all classes of GDMT. ACE inhibitor/ARB, angiotensin receptor-neprilysin inhibitor, beta-blocker, and MRA de-escalation/discontinuation after HFH was associated with increased risk of all-cause mortality with hazard ratios of 3.82 (95% CI: 2.42 to 6.03), 4.76 (95% CI: 2.06 to 11.03), 2.94 (95% CI: 2.04 to 4.25), and 4.81 (95% CI: 2.61 to 8.87), respectively.
Conclusions
HFH positively associated with changes in GDMT, including initiation, dose escalation, discontinuation, and dose de-escalation. De-escalation/discontinuation of GDMT after HFH associated with increased risk of all-cause mortality. Educational endeavors are needed to ensure GDMT is not inappropriately held in the setting of HFH. For those in whom GDMT must be held/decreased, improvement tools at discharge and post-discharge titration clinics may help ensure lifesaving GDMT regimens remain optimized.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2020; 9:28-38
Srivastava PK, DeVore AD, Hellkamp AS, Thomas L, ... Hernandez AF, Fonarow GC
JACC Heart Fail: 30 Dec 2020; 9:28-38 | PMID: 33309579
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Abstract

COVID-19 in Heart Transplant Recipients: A Multicenter Analysis of the Northern Italian Outbreak.

Bottio T, Bagozzi L, Fiocco A, Nadali M, ... Carrozzini M, Gerosa G
Objectives
The aim of this study was to assess the clinical course and outcomes of all heart transplant recipients affected by coronavirus disease-2019 (COVID-19) who were followed at the leading heart transplant centers of Northern Italy.
Background
The worldwide severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has created unprecedented challenges for public health, demanding exceptional efforts for the successful management and treatment of affected patients. Heart transplant patients represent a unique cohort of chronically immunosuppressed subjects in which SARS-CoV-2 may stimulate an unpredictable clinical course of infection.
Methods
Since February 2020, we enrolled all 47 cases (79% male) in a first cohort of patients, with a mean age of 61.8 ± 14.5 years, who tested positive for SARS-CoV-2, out of 2,676 heart transplant recipients alive before the onset of the COVID-19 pandemic at 7 heart transplant centers in Northern Italy.
Results
To date, 38 patients required hospitalization while 9 remained self-home quarantined and 14 died. Compared to the general population, prevalence (18 vs. 7 cases per 1,000) and related case fatality rate (29.7% vs. 15.4%) in heart transplant recipients were doubled. Univariable analysis showed older age (p = 0.002), diabetes mellitus (p = 0.040), extracardiac arteriopathy (p = 0.040), previous PCI (p = 0.040), CAV score (p = 0.039), lower GFR (p = 0.004), and higher NYHA functional classes (p = 0.023) were all significantly associated with in-hospital mortality. During the follow-up two patients died and a third patient has prolonged viral-shedding alternating positive and negative swabs. Since July 1st, 2020, we had 6 new patients who tested positive for SARS-CoV-2, 5 patients asymptomatic were self-quarantined, while 1 is still hospitalized for pneumonia. A standard therapy was maintained for all, except for the hospitalized patient.
Conclusions
The prevalence and mortality of SARS-CoV-2 should spur clinicians to immediately refer heart transplant recipients suspected as having SARS-CoV2 infection to centers specializing in the care of this vulnerable population.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2020; 9:52-61
Bottio T, Bagozzi L, Fiocco A, Nadali M, ... Carrozzini M, Gerosa G
JACC Heart Fail: 30 Dec 2020; 9:52-61 | PMID: 33309578
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Abstract

Clinical Outcomes in Patients With Heart Failure Hospitalized With COVID-19.

Bhatt AS, Jering KS, Vaduganathan M, Claggett BL, ... Vardeny O, Solomon SD
Objectives
The purpose of this study was to evaluate in-hospital outcomes among patients with a history of heart failure (HF) hospitalized with coronavirus disease-2019 (COVID-19).
Background
Cardiometabolic comorbidities are common in patients with severe COVID-19. Patients with HF may be particularly susceptible to COVID-19 complications.
Methods
The Premier Healthcare Database was used to identify patients with at least 1 HF hospitalization or 2 HF outpatient visits between January 1, 2019, and March 31, 2020, who were subsequently hospitalized between April and September 2020. Baseline characteristics, health care resource utilization, and mortality rates were compared between those hospitalized with COVID-19 and those hospitalized with other causes. Predictors of in-hospital mortality were identified in HF patients hospitalized with COVID-19 by using multivariate logistic regression.
Results
Among 1,212,153 patients with history of HF, 132,312 patients were hospitalized from April 1, 2020, to September 30, 2020. A total of 23,843 patients (18.0%) were hospitalized with acute HF, 8,383 patients (6.4%) were hospitalized with COVID-19, and 100,068 patients (75.6%) were hospitalized with alternative reasons. Hospitalization with COVID-19 was associated with greater odds of in-hospital mortality as compared with hospitalization with acute HF; 24.2% of patients hospitalized with COVID-19 died in-hospital compared to 2.6% of those hospitalized with acute HF. This association was strongest in April (adjusted odds ratio [OR]: 14.48; 95% confidence interval [CI]:12.25 to 17.12) than in subsequent months (adjusted OR: 10.11; 95% CI: 8.95 to 11.42; p <0.001). Among patients with HF hospitalized with COVID-19, male sex (adjusted OR: 1.26; 95% CI: 1.13 to 1.40) and morbid obesity (adjusted OR: 1.25; 95% CI: 1.07 to 1.46) were associated with greater odds of in-hospital mortality, along with age (adjusted OR: 1.35; 95% CI: 1.29 to 1.42 per 10 years) and admission earlier in the pandemic.
Conclusions
Patients with HF hospitalized with COVID-19 are at high risk for complications, with nearly 1 in 4 dying during hospitalization.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Dec 2020; 9:65-73
Bhatt AS, Jering KS, Vaduganathan M, Claggett BL, ... Vardeny O, Solomon SD
JACC Heart Fail: 30 Dec 2020; 9:65-73 | PMID: 33384064
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Abstract

Unexpectedly Low Natriuretic Peptide Levels in Patients With Heart Failure.

Bachmann KN, Gupta DK, Xu M, Brittain E, ... Wells QS, Wang TJ
Objectives
To determine the frequency of unexpectedly low natriuretic peptide (NP) levels in a clinical population.
Background
Higher NP concentrations are typically observed as a compensatory response to elevated cardiac wall stress. Under these conditions, low NP levels may be indicative of a \"NP deficiency.\"
Methods
We identified 3 clinical scenarios in which high B-type natriuretic peptide (BNP) levels would be expected: 1) hospitalization for heart failure (HF); 2) abnormal cardiac structure or function; or 3) abnormal hemodynamics. In Vanderbilt\'s electronic health record, 47,970 adult patients had BNP measurements. A total of 13,613 patients had at least 1 of the 3 conditions (hospitalized HF, n = 9,153; abnormal cardiac structure/function, n = 7,041; abnormal hemodynamics, n = 363). We quantified the frequency of low BNP levels. We performed whole exome sequencing of the NPPB gene in a subset of 9 patients.
Results
Very low BNP levels (<50 pg/ml) were observed in 4.9%, 14.0%, and 16.3% of patients with hospitalized HF, abnormal cardiac structure/function, or abnormal hemodynamics, respectively. A small proportion (0.1% to 1.1%) in each group had BNP levels below detection limits. Higher body mass index was the strongest predictor of unexpectedly low BNP. Exome sequencing did not reveal coding variation predicted to alter detection of BNP by clinical assays.
Conclusions
A subset of patients with confirmed HF or cardiac dysfunction have unexpectedly low BNP levels. Obesity is the strongest correlate of unexpectedly low BNP levels. Our findings support the possible existence of NP deficiency, which may render some individuals more susceptible to volume or pressure overload.

Published by Elsevier Inc.

JACC Heart Fail: 23 Dec 2020; epub ahead of print
Bachmann KN, Gupta DK, Xu M, Brittain E, ... Wells QS, Wang TJ
JACC Heart Fail: 23 Dec 2020; epub ahead of print | PMID: 33422435
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Abstract

Biomarker-Based Risk Prediction of Incident Heart Failure in Pre-Diabetes and Diabetes.

Pandey A, Vaduganathan M, Patel KV, Ayers C, ... de Lemos JA, Everett BM
Objectives
This study evaluated the application of a biomarker-based risk score to identify individuals with dysglycemia who are at high risk for incident heart failure (HF) and to inform allocation of effective preventive interventions.
Background
Risk stratification tools to identify patients with diabetes and pre-diabetes at highest risk for HF are needed to inform cost-effective allocation of preventive therapies. Whether a biomarker score can meaningfully stratify HF risk is unknown.
Methods
Participants free of cardiovascular disease from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], DHS [Dallas Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) were included. An integer-based biomarker score included high-sensitivity cardiac troponin T ≥6 ng/l, N-terminal pro-B-type natriuretic peptide ≥125 pg/ml, high-sensitivity C-reactive protein ≥3 mg/l, and left ventricular hypertrophy by electrocardiography, with 1 point for each abnormal parameter. The 5-year risk of HF was estimated among participants with diabetes and pre-diabetes across biomarker score groups (0 to 4).
Results
The primary analysis included 6,799 participants with dysglycemia (diabetes: 33.2%; pre-diabetes: 66.8%). The biomarker score demonstrated good discrimination and calibration for predicting 5- and 10-year HF risk among pre-diabetes and diabetes cohorts. The 5-year risk of HF among subjects with a biomarker score of ≤1 was low and comparable to participants with euglycemia (0.78%). The 5-year risk for HF increased in a graded fashion with an increasing biomarker score, with the highest risk noted among those with scores of ≥3 (diabetes: 12.0%; pre-diabetes: 7.8%). The estimated number of HF events that could be prevented using a sodium-glucose cotransporter-2 inhibitor per 1,000 treated subjects over 5 years was 11 for all subjects with diabetes and ranged from 4 in the biomarker score zero group to 44 in the biomarker score ≥3 group.
Conclusions
Among adults with diabetes and pre-diabetes, a biomarker score can stratify HF risk and inform allocation of HF prevention therapies.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 23 Dec 2020; epub ahead of print
Pandey A, Vaduganathan M, Patel KV, Ayers C, ... de Lemos JA, Everett BM
JACC Heart Fail: 23 Dec 2020; epub ahead of print | PMID: 33422434
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Abstract

Treatment of HF in an Era of Multiple Therapies: Statement From the HF Collaboratory.

Bhatt AS, Abraham WT, Lindenfeld J, Bristow M, ... O\'Connor CM, Butler J

The treatment of heart failure with reduced ejection fraction (HFrEF) has changed considerably over time, particularly with the sequential development of therapies aimed at antagonism of maladaptive biologic pathways, including inhibition of the sympathetic nervous system and the renin-angiotensin aldosterone system. The sequential nature of earlier HFrEF trials allowed the integration of new therapies tested against the background therapy of the time. More recently, multiple heart failure therapies are being evaluated simultaneously, and the number of therapeutic choices for treating HFrEF has grown considerably. In addition, implementation science has lagged behind discovery science in heart failure. Furthermore, given there are currently >200 ongoing clinical trials in heart failure, further complexities are anticipated. In an effort to provide a decision-making framework in the current era of expanding therapeutic options in HFrEF, the Heart Failure Collaboratory convened a multi-stakeholder group, including patients, clinicians, clinical investigators, the U.S. Food and Drug Administration, industry, and payers who met at the U.S. Food and Drug Administration campus on March 6, 2020. This paper summarizes the discussions and expert consensus recommendations.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 08 Dec 2020; epub ahead of print
Bhatt AS, Abraham WT, Lindenfeld J, Bristow M, ... O'Connor CM, Butler J
JACC Heart Fail: 08 Dec 2020; epub ahead of print | PMID: 33309582
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Abstract

Reverse Cardiac Remodeling Following Initiation of Sacubitril/Valsartan in Patients With Heart Failure With and Without Diabetes.

Khan MS, Felker GM, Piña IL, Camacho A, ... Januzzi JL, Butler J
Objective
This study sought to determine whether patients with heart failure and reduced ejection fraction (HFrEF) with type 2 diabetes mellitus (T2DM) have similar reverse cardiac remodeling with sacubitril/valsartan as patients without T2DM.
Background
Sacubitril/valsartan promotes reverse cardiac remodeling and improves outcomes in patients with HFrEF. Patients with HFrEF with T2DM have worse prognosis than those without T2DM.
Methods
In this post hoc analysis of PROVE-HF, we examined changes in N-terminal pro-b-type natriuretic peptide (NT-proBNP), measures of cardiac remodeling, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores from baseline to 12 months following initiation of sacubitril/valsartan between patients with HFrEF with and without T2DM. Using latent growth curve modeling, we evaluated the longitudinal association between changes in NT-proBNP, left ventricular ejection fraction, and KCCQ-OS.
Results
Among 794 patients enrolled, 361 (45.5%) had T2DM. NT-proBNP concentrations were modestly higher at baseline among patients with T2DM but were reduced after initiation of sacubitril/valsartan. Cross-sectional improvement was observed in left ventricular ejection fraction (T2DM: 28.3% at baseline and 37% at 12 months vs. non-T2DM: 28.1% at baseline and 38.3% at 12 months) and KCCQ-OS (T2DM: 71 at baseline and 83 at 12 months vs. non-T2DM: 76 at baseline and 88 at 12 months). Similar changes were also observed for other echocardiographic measures. In longitudinal analyses, the average NT-proBNP change was similar in patients with T2DM (-5.6% vs. -7.1% per 90-day interval; p = 0.64), whereas improvements in KCCQ-OS scores were slightly smaller (2.1 vs. 3.46 per 90-day interval; p = 0.07).
Conclusions
Sacubitril/valsartan favorably affects natriuretic peptide levels, reverse cardiac remodeling, and health status in patients with HFrEF with and without T2DM. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 08 Dec 2020; epub ahead of print
Khan MS, Felker GM, Piña IL, Camacho A, ... Januzzi JL, Butler J
JACC Heart Fail: 08 Dec 2020; epub ahead of print | PMID: 33309581
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Abstract

Prevalence and Prognostic Significance of Mitral Regurgitation in Acute Decompensated Heart Failure: The ARIC Study.

Arora S, Sivaraj K, Hendrickson M, Chang PP, ... Rosamond W, Vavalle JP
Objectives
This study investigates the prevalence and prognostic significance of mitral regurgitation (MR) in acute decompensated heart failure (ADHF) patients.
Background
Few studies characterize the burden of MR in heart failure.
Methods
The ARIC (Atherosclerosis Risk in Communities) study surveilled ADHF hospitalizations for residents ≥55 years of age in 4 U.S. communities. ADHF cases were stratified by left ventricular ejection fraction (LVEF): <50% and ≥50%. Odds of moderate or severe MR in patients with varying sex and race, and odds of 1-year mortality in those with higher MR severity were estimated using multivariable logistic regression.
Results
From 2005 to 2014, there were 17,931 weighted ADHF hospitalizations of which 49.2% had an LVEF <50% and 50.8% an LVEF ≥50%. Moderate or severe MR prevalence was 44.5% in those with an LVEF <50% and 27.5% in those with an LVEF ≥50%. Moderate or severe MR was more likely in females than males regardless of LVEF; LVEF <50% (odds ratio [OR]: 1.21 [95% confidence interval (CI): 1.11 to 1.33]), LVEF ≥50% (OR: 1.52 [95% CI: 1.36 to 1.69]). Among hospitalizations with an LVEF ≥50%, moderate or severe MR was less likely in blacks than whites (OR: 0.72 [95% CI: 0.64 to 0.82]). Higher MR severity was independently associated with increased 1-year mortality in those with an LVEF <50% (OR: 1.30 [95% CI: 1.16 to 1.45]).
Conclusions
Patients with ADHF have a significant MR burden that varies with sex and race. In ADHF patients with an LVEF <50%, higher MR severity is associated with excess 1-year mortality.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 01 Dec 2020; epub ahead of print
Arora S, Sivaraj K, Hendrickson M, Chang PP, ... Rosamond W, Vavalle JP
JACC Heart Fail: 01 Dec 2020; epub ahead of print | PMID: 33309575
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Abstract

Efficacy of Tafamidis in Patients With Hereditary and Wild-Type Transthyretin Amyloid Cardiomyopathy: Further Analyses From ATTR-ACT.

Rapezzi C, Elliott P, Damy T, Nativi-Nicolau J, ... Sultan MB, Maurer MS
Background
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal disorder resulting from mutations in the transthyretin gene (ATTRv) or the deposition of denatured wild-type transthyretin (ATTRwt).
Objectives
Tafamidis is an effective treatment for ATTR-CM, this study aimed to determine whether there is a differential effect between ATTRv and ATTRwt.
Methods
In pre-specified analyses from ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), baseline characteristics, all-cause mortality, and change from baseline to month 30 in 6-min walk test distance and Kansas City Cardiomyopathy Questionnaire Overall Summary score were compared in patients with ATTRwt and ATTRv.
Results
There were 335 patients with ATTRwt (201 tafamidis, 134 placebo) and 106 with ATTRv (63 tafamidis, 43 placebo) enrolled in ATTR-ACT. Patients with ATTRwt (vs. ATTRv) had less advanced disease at baseline and a lower rate of disease progression over the study. The reduction in all-cause mortality with tafamidis compared with placebo was not different between ATTRwt (hazard ratio: 0.706 [95% confidence interval (CI): 0.474 to 1.052]; p = 0.0875) and ATTRv (hazard ratio: 0.690 [95% CI: 0.408 to 1.167]; p = 0.1667). Tafamidis was associated with a similar reduction (vs. placebo) in the decline in 6-min walk test distance in ATTRwt (mean ± SE difference from placebo, 77.14 ± 10.78; p < 0.0001) and ATTRv (79.61 ± 29.83 m; p = 0.008); and Kansas City Cardiomyopathy Questionnaire Overall Summary score in ATTRwt (12.72 ± 2.10; p < 0.0001) and ATTRv (18.18 ± 7.75; p = 0.019).
Conclusions
Pre-specified analyses from ATTR-ACT confirm the poor prognosis of untreated ATTRv-related cardiomyopathy compared with ATTRwt, but show the reduction in mortality and functional decline with tafamidis treatment is similar in both disease subtypes. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy [ATTR-ACT]; NCT01994889).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 01 Dec 2020; epub ahead of print
Rapezzi C, Elliott P, Damy T, Nativi-Nicolau J, ... Sultan MB, Maurer MS
JACC Heart Fail: 01 Dec 2020; epub ahead of print | PMID: 33309574
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Abstract

Home Health Care Use and Post-Discharge Outcomes After Heart Failure Hospitalizations.

Sterling MR, Kern LM, Safford MM, Jones CD, ... Yancy CW, Albert NM
Objectives
This study compared the characteristics of Medicare beneficiaries who were hospitalized for heart failure (HF) and then discharged home who received home health care (HHC) to the characteristics of those who did not, and examined associations among HHC and readmission and mortality rates.
Background
After hospitalization for HF, some patients receive HHC. However, the use of HHC over time, the factors associated with its use, and the post-discharge outcomes after receiving it are not well studied.
Methods
This study used Get With The Guidelines-HF data, merged with Medicare fee-for-service claims. Propensity score matching and Cox proportional hazards models were used to evaluate the associations between HHC and post-discharge outcomes.
Results
From 2005 to 2015, 95,531 patients were admitted for HF, and 32,697 (34.2%) received HHC after discharge. The rate of HHC increased over time from 31.4% to 36.1% (p < 0.001). HHC recipients were older, more likely to be female, and had more comorbidities. HHC was associated with a higher risk of all-cause 30-day readmission (hazard ratio [HR]: 1.25; 95% confidence interval [CI]: 1.20 to 1.30), HF-specific 30-day readmission (HR: 1.20; 95% CI: 1.13 to 1.28), all-cause 90-day readmission (HR: 1.23; 95% CI: 1.19 to 1.26), HF-specific 90-day readmission (HR: 1.16; 95% CI: 1.11 to 1.22), and all-cause 30-and 90-day mortality, respectively (HR: 1.70; 95% CI: 1.56 to 1.86) and HR: 1.49; 95% CI: 1.41 to 1.57) compared to those who did not receive HHC.
Conclusions
Use of HHC after HF hospitalization increased among Medicare beneficiaries. HHC recipients were older and sicker than non-HHC recipients. Although HHC was associated with a higher risk of readmissions and mortality, this finding should be interpreted cautiously, given the presence of unmeasured variables that could affect receipt of HHC. Research is needed to determine whether the results reflect appropriate health care use.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Nov 2020; 8:1038-1049
Sterling MR, Kern LM, Safford MM, Jones CD, ... Yancy CW, Albert NM
JACC Heart Fail: 29 Nov 2020; 8:1038-1049 | PMID: 32800510
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Abstract

Associations Between Depressive Symptoms and HFpEF-Related Outcomes.

Chandra A, Alcala MAD, Claggett B, Desai AS, ... Pfeffer MA, Lewis EF
Objectives
This study analyzed changes in depressive symptoms in patients with heart failure and preserved ejection fraction (HFpEF) who were enrolled in the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial.
Background
There are limited longitudinal data for depressive symptoms in patients with HFpEF.
Methods
In patients enrolled in the United States and Canada (n = 1,431), depressive symptoms were measured using Patient Health Questionnaire-9 (PHQ-9). Clinically meaningful changes in PHQ-9 scores were defined as worse (≥3-point increase) or better (≥3-point decrease). Multivariate models were used to identify predictors of change in depressive symptoms. Cox proportional hazard models were used to determine the impact of symptom changes from baseline on subsequent incident cardiovascular events.
Results
At 12 months, 19% of patients experienced clinically worsening depressive symptoms, 31% better, and 49% unchanged. Independent predictors of clinically meaningful improvement in depressive symptoms included higher baseline PHQ-9 scores, male sex, lack of chronic obstructive pulmonary disease, and randomization to spironolactone. After data were adjusted for cardiovascular comorbidities, higher baseline PHQ-9 was associated with all-cause mortality (hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 1.02 to 1.16; p = 0.011), whereas worsening depressive symptoms at 12 months were associated with cardiovascular death (HR: 2.47; 95% CI: 1.32 to 4.63; p = 0.005) and all-cause mortality (HR: 1.82; 95% CI: 1.13 to 2.93; p = 0.014). Randomization to spironolactone was associated with modest but statistically significant reduction in depressive symptoms over the course of the trial (p = 0.014).
Conclusions
Higher baseline depressive symptoms and worsening depressive symptoms were associated with all-cause mortality. Randomization to spironolactone was associated with modest reduction in depressive symptoms. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).

Copyright © 2020. Published by Elsevier Inc.

JACC Heart Fail: 29 Nov 2020; 8:1009-1020
Chandra A, Alcala MAD, Claggett B, Desai AS, ... Pfeffer MA, Lewis EF
JACC Heart Fail: 29 Nov 2020; 8:1009-1020 | PMID: 32919912
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Impact:
Abstract

Estimating the Lifetime Benefits of Treatments for Heart Failure.

Ferreira JP, Docherty KF, Stienen S, Jhund PS, ... Zannad F, McMurray JJV
Objectives
This study compared ways of describing treatment effects. The objective was to better explain to clinicians and patients what they might expect from a given treatment, not only in terms of relative and absolute risk reduction, but also in projections of long-term survival.
Background
The restricted mean survival time (RMST) can be used to estimate of long-term survival, providing a complementary approach to more conventional metrics (e.g., absolute and relative risk), which may suggest greater benefits of therapy in high-risk patients compared with low-risk patients.
Methods
Relative and absolute risk, as well as the RMST, were calculated in heart failure with reduced ejection fraction (HFrEF) trials.
Results
As examples, in the RALES trial (more severe HFrEF), the treatment effect metrics for spironolactone versus placebo on heart failure hospitalization and/or cardiovascular death were a hazard ratio (HR) of 0.67 (95% confidence interval [CI]: 0.5 to 0.77), number needed to treat = 9 (7 to 14), and age extension of event-free survival +1.1 years (-0.1 to + 2.3 years). The corresponding metrics for EMPHASIS-HF (eplerenone vs. placebo in less severe HFrEF) were 0.64 (0.54 to 0.75), 14 (1 to 22), and +2.9 (1.2 to 4.5). In patients in PARADIGM-HF aged younger than 65 years, the metrics for sacubitril/valsartan versus enalapril were 0.77 (95% CI: 0.68 to 0.88), 23 (15 to 44), and +1.7 (0.6 to 2.8) years; for those aged 65 years or older, the metrics were 0.83 (95% CI: 0.73 to 0.94), 29 (17 to 83), and +0.9 (0.2 to 1.6) years, which provided evidence of a greater potential life extension in younger patients. Similar observations were found for lower risk patients.
Conclusions
RMST event-free (and overall) survival estimates provided a complementary means of evaluating the effect of therapy in relation to age and risk. They also provided a clinically useful metric that should be routinely reported and used to explain the potential long-term benefits of a given treatment, especially to younger and less symptomatic patients.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Nov 2020; 8:984-995
Ferreira JP, Docherty KF, Stienen S, Jhund PS, ... Zannad F, McMurray JJV
JACC Heart Fail: 29 Nov 2020; 8:984-995 | PMID: 33039448
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Impact:
Abstract

Utility of Restricted Mean Survival Time Analysis for Heart Failure Clinical Trial Evaluation and Interpretation.

Perego C, Sbolli M, Specchia C, Fiuzat M, ... O\'Connor CM, Psotka MA
Objectives
This study sought to demonstrate the statistical and utilitarian properties of restricted mean survival time (RMST) and restricted mean time lost (RMTL) for assessing treatments for heart failure (HF) with reduced ejection fraction.
Background
Although the hazard ratio (HR) is the most commonly used measure to quantify treatment effects in HF clinical trials, HRs may be difficult to interpret and require the proportional hazards assumption to be valid. RMST and RMTL are intuitive summaries of groupwise survival that measure treatment effects without model assumptions.
Methods
Patient time-to-event data were reconstructed from published landmark HF clinical trial Kaplan-Meier curves. We estimated RMST differences (ΔRMSTs) and RMTL ratios between treatment groups for primary and secondary outcomes, and compared test statistics and effect sizes with proportional hazards models. We fit Weibull estimations to extrapolate trial data to 5 years of treatment.
Results
Using RMSTs and RMTLs yielded similar statistical conclusions as HR analysis for a compendium of 16 HF clinical trials including 48,581 patients. RMTL ratios approximated HRs for each trial, but ΔRMSTs provided absolute effect sizes unavailable with HRs. For instance, spironolactone added 2.2 months of life over 34 months of treatment, and dapagliflozin added 0.3 months of life over 24 months of treatment. When normalized to 5-years follow-up with Weibull estimation, spironolactone and dapagliflozin added 6.0 months and 1.8 months of life for patients, respectively.
Conclusions
Statistically, RMST and RMTL perform similarly to proportional hazards modeling but may help patients by providing clinically relevant intuitive estimates of treatment effects without prohibitive assumptions.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Nov 2020; 8:973-983
Perego C, Sbolli M, Specchia C, Fiuzat M, ... O'Connor CM, Psotka MA
JACC Heart Fail: 29 Nov 2020; 8:973-983 | PMID: 33039446
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Impact:
Abstract

Cause of Death in Patients With Acute Heart Failure: Insights From RELAX-AHF-2.

Loungani RS, Teerlink JR, Metra M, Allen LA, ... Voors AA, Felker GM
Objectives
This study sought to better understand the discrepant results of 2 trials of serelaxin on acute heart failure (AHF) and short-term mortality after AHF by analyzing causes of death of patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF-2) trial.
Background
Patients with AHF continue to suffer significant short-term mortality, but limited systematic analyses of causes of death in this patient population are available.
Methods
Adjudicated cause of death of patients in RELAX-AHF-2, a randomized, double-blind, placebo-controlled trial of serelaxin in patients with AHF across the spectrum of ejection fraction (EF), was analyzed.
Results
By 180 days of follow-up, 11.5% of patients in RELAX-AHF-2 died, primarily due to heart failure (HF) (38% of all deaths). Unlike RELAX-AHF, there was no apparent effect of treatment with serelaxin on any category of cause of death. Older patients (≥75 years) had higher rates of mortality (14.2% vs. 8.8%) and noncardiovascular (CV) death (27% vs. 19%) compared to younger patients. Patients with preserved EF (≥50%) had lower rates of HF-related mortality (30% vs. 40%) but higher non-CV mortality (36% vs. 20%) compared to patients with reduced EF.
Conclusions
Despite previous data suggesting benefit of serelaxin in AHF, treatment with serelaxin was not found to improve overall mortality or have an effect on any category of cause of death in RELAX-AHF-2. Careful adjudication of events in the serelaxin trials showed that older patients and those with preserved EF had fewer deaths from HF or sudden death and more deaths from other CV causes and from noncardiac causes. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Nov 2020; 8:999-1008
Loungani RS, Teerlink JR, Metra M, Allen LA, ... Voors AA, Felker GM
JACC Heart Fail: 29 Nov 2020; 8:999-1008 | PMID: 33189635
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Impact:
Abstract

Health Care Use Before First Heart Failure Hospitalization: Identifying Opportunities to Pre-Emptively Diagnose Impending Decompensation.

Anderson K, Ross HJ, Austin PC, Fang J, Lee DS
Objectives
This study sought to describe the pattern of health care contacts in patients ultimately presenting with incident hospitalization for acute heart failure (HF) compared with chronic obstructive pulmonary disease (COPD) exacerbation or stable HF.
Background
Little is known about how effectively HF is detected before the first acute hospitalization.
Methods
We compared 79,389 patients divided into 3 matched population cohorts in Ontario, Canada (2006-2013) with incident acute HF hospitalization, incident COPD hospitalization, or stable HF. The outcome of interest was the aggregate number of health care contacts occurring in each of the thirteen 28-day periods in the year preceding the index hospitalization. Health care contacts were defined as the total number of outpatient physician visits, hospitalizations for unrelated conditions, or emergency department visits.
Results
Acutely hospitalized patients with HF had a significant increase in health care contacts as time approached the index hospitalization. Patients with acute HF had a 28% increase in health care contacts in the last time period before the index hospitalization (adjusted rate ratio [RR]: 1.28; 95% confidence interval [CI]: 1.25 to 1.31; p < 0.001) compared with matched COPD controls. Compared with stable HF, acutely hospitalized patients had a 75% increase in health care contacts during the same time period (RR: 1.75; 95% CI: 1.71 to 1.79; p < 0.001). HF patients 20 to 40 years of age had an accelerated increase in the rate of health care contacts compared with those ≥65 years of age before index HF hospitalization (RR: 1.18; 95% CI: 1.08 to 1.28; p < 0.001).
Conclusions
Patients consulted physicians multiple times before their incident acute HF hospitalization. These health care contacts could represent missed opportunities to prevent hospitalizations for HF.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 29 Nov 2020; 8:1024-1034
Anderson K, Ross HJ, Austin PC, Fang J, Lee DS
JACC Heart Fail: 29 Nov 2020; 8:1024-1034 | PMID: 33189631
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Abstract

Standardized Definitions for Evaluation of Heart Failure Therapies: Scientific Expert Panel From the Heart Failure Collaboratory and Academic Research Consortium.

Abraham WT, Psotka MA, Fiuzat M, Filippatos G, ... Anker SD, O\'Connor CM

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation.

Copyright © 2020. Published by Elsevier Inc.

JACC Heart Fail: 29 Nov 2020; 8:961-972
Abraham WT, Psotka MA, Fiuzat M, Filippatos G, ... Anker SD, O'Connor CM
JACC Heart Fail: 29 Nov 2020; 8:961-972 | PMID: 33199251
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Abstract

Effects of a Novel Nitroxyl Donor in Acute Heart Failure: The STAND-UP AHF Study.

Felker GM, McMurray JJV, Cleland JG, O\'Connor CM, ... Seiffert D, Ye J
Objectives
The primary objective was to identify well-tolerated doses of cimlanod in patients with acute heart failure (AHF). Secondary objectives were to identify signals of efficacy, including biomarkers, symptoms, and clinical events.
Background
Nitroxyl (HNO) donors have vasodilator, inotropic and lusitropic effects. Bristol-Myers Squibb-986231 (cimlanod) is an HNO donor being developed for acute heart failure (AHF).
Methods
This was a phase IIb, double-blind, randomized, placebo-controlled trial of 48-h treatment with cimlanod compared with placebo in patients with left ventricular ejection fraction ≤40% hospitalized for AHF. In part I, patients were randomized in a 1:1 ratio to escalating doses of cimlanod or matching placebo. In part II, patients were randomized in a 1:1:1 ratio to either of the 2 highest tolerated doses of cimlanod from part I or placebo. The primary endpoint was the rate of clinically relevant hypotension (systolic blood pressure <90 mm Hg or patients became symptomatic).
Results
In part I (n = 100), clinically relevant hypotension was more common with cimlanod than placebo (20% vs. 8%; relative risk [RR]: 2.45; 95% confidence interval [CI]: 0.83 to 14.53). In part II (n = 222), the incidence of clinically relevant hypotension was 18% for placebo, 21% for cimlanod 6 μg/kg/min (RR: 1.15; 95% CI: 0.58 to 2.43), and 35% for cimlanod 12 μg/kg/min (RR: 1.9; 95% CI: 1.04 to 3.59). N-terminal pro-B-type natriuretic peptide and bilirubin decreased during infusion of cimlanod treatment compared with placebo, but these differences did not persist after treatment discontinuation.
Conclusions
Cimlanod at a dose of 6 μg/kg/min was reasonably well-tolerated compared with placebo. Cimlanod reduced markers of congestion, but this did not persist beyond the treatment period. (Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure [STANDUP AHF]; NCT03016325).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 23 Nov 2020; epub ahead of print
Felker GM, McMurray JJV, Cleland JG, O'Connor CM, ... Seiffert D, Ye J
JACC Heart Fail: 23 Nov 2020; epub ahead of print | PMID: 33248986
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Abstract

Atrial Natriuretic Peptide and Treatment With Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction.

Murphy SP, Prescott MF, Camacho A, Iyer SR, ... Solomon SD, Januzzi JL
Objectives
This study sought to assess associations between longitudinal change in atrial natriuretic peptide (ANP) and reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).
Background
Neprilysin inhibition results in an increase of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan, including ANP.
Methods
In a prospective study of initiation and titration of sacubitril/valsartan in patients with HFrEF, blood was collected at scheduled time points into tubes containing protease inhibitors. This pre-specified exploratory analysis included patients in whom ANP was measured at baseline and serially through 12 months of treatment.
Results
Among 144 participants (mean age: 64.5 years; left ventricular ejection fraction: 30.8%), following initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with the majority of rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p < 0.001). There was a further trend toward a second increase from day 30 to day 45 (p = 0.07). At maximal rise, ANP had doubled. In longitudinal analyses, early rise in ANP was followed by a subsequent increase in urinary cycle guanosine monophosphate. Larger early increase in ANP was associated with larger later improvements in left ventricular ejection fraction and left atrial volume index (p < 0.001 for both).
Conclusions
Concentrations of ANP doubled after initiation of sacubitril/valsartan in patients with HFrEF. Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodeling. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 03 Nov 2020; epub ahead of print
Murphy SP, Prescott MF, Camacho A, Iyer SR, ... Solomon SD, Januzzi JL
JACC Heart Fail: 03 Nov 2020; epub ahead of print | PMID: 33189632
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Impact:
Abstract

Soluble Neprilysin and Corin Concentrations in Relation to Clinical Outcome in Chronic Heart Failure.

Gommans DHF, Revuelta-Lopez E, Lupon J, Cserkóová A, ... Bayés-Genis A, van Kimmenade RRJ
Objectives
This study investigated whether patients with chronic heart failure (HF) can be stratified according to the combination of soluble neprilysin and corin concentrations and whether this is related to clinical outcome.
Background
Natriuretic peptide processing by the enzymes corin and neprilysin plays a pivotal role in conversion of pro-natriuretic peptides to active natriuretic peptides, as well as their degradation, respectively.
Methods
A prospective cohort of patients with chronic HF (n = 1,009) was stratified into 4 equal groups based on high or low neprilysin/corin concentration relative to the median: 1) low neprilysin/low corin; 2) low neprilysin/high corin; 3) high neprilysin/low corin; and 4) high neprilysin/high corin. Cox regression survival analysis was performed for the composite primary endpoint of cardiovascular death and HF hospitalization.
Results
Median neprilysin and corin concentrations were not correlated (rho: -0.04; p = 0.21). Although in univariate analysis there was no association with outcome, after correction for baseline differences in age and sex, a significant association with survival was demonstrated: with highest survival in group 1 (low neprilysin/low corin) and lowest in group 4 (high neprilysin/high corin) (adjusted hazard ratio: 1.56; p = 0.003), which remained statistically significant after comprehensive multivariable analysis (adjusted hazard ratio: 1.41; p = 0.03).
Conclusions
Stratification of patients with chronic HF based on circulating neprilysin and corin concentrations is associated with clinical outcomes. These results suggest that regulation of these enzymes is of importance in chronic HF and may offer an interesting approach for classification of patients with HF in a step toward individualized HF patient management.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 03 Nov 2020; epub ahead of print
Gommans DHF, Revuelta-Lopez E, Lupon J, Cserkóová A, ... Bayés-Genis A, van Kimmenade RRJ
JACC Heart Fail: 03 Nov 2020; epub ahead of print | PMID: 33189629
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Abstract

Worsening Kidney Function Is the Major Mechanism of Heart Failure in Hypertension: The ALLHAT Study.

Khayyat-Kholghi M, Oparil S, Davis BR, Tereshchenko LG
Objectives
The authors aimed to quantify the extent to which the effect of antihypertensive drugs on incident heart failure (HF) is mediated by their effect on kidney function.
Background
The authors hypothesized that the dynamic change in kidney function is the mechanism behind differences in the rate of incident HF in ALLHAT trial (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) participants randomized to lisinopril and chlorthalidone, in comparison with those randomized to amlodipine and doxazosin.
Methods
Causal mediation analysis of ALLHAT data (1994 to 2002) included participants with available baseline and 24- to 48-month estimated glomerular filtration rate (eGFR) (N = 27,918; mean age 66 ± 7.4 years; 32.4% black, 56.3% men). Change in eGFR was the mediator. Incident symptomatic HF was the primary outcome. Hospitalized/fatal HF was the secondary outcome. Linear regression (for mediator) and logistic regression (for outcome) analyses were adjusted for demographics, cardiovascular disease, and risk factors.
Results
There were 1,769 incident HF events, including 1,359 hospitalized/fatal HF events. In fully adjusted causal mediation analysis, the relative change in eGFR mediated 18% of the effect of chlorthalidone, and 33% of lisinopril on incident symptomatic HF, and 25% of the effect of chlorthalidone, and 41% of lisinopril on hospitalized/fatal HF. In participants with diabetes, the relative change in eGFR mediated nearly 50% of the effect of lisinopril on incident symptomatic HF, whereas in diabetes-free participants, only 17%.
Conclusions
On the risk difference scale, change in eGFR accounts for up to 50% of the mechanism by which antihypertensive medications affect HF. (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]; NCT00000542).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 03 Nov 2020; epub ahead of print
Khayyat-Kholghi M, Oparil S, Davis BR, Tereshchenko LG
JACC Heart Fail: 03 Nov 2020; epub ahead of print | PMID: 33189627
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Impact:
Abstract

In-Hospital Therapy for Heart Failure With Reduced Ejection Fraction in the United States.

Greene SJ, Triana TS, Ionescu-Ittu R, Burne RM, ... Felker GM, Chen L
Objectives
This study sought to characterize in-hospital treatment patterns and associated patient outcomes among patients hospitalized for heart failure (HF) in U.S. clinical practice.
Background
Hospitalizations for HF are common and associated with poor patient outcomes. Real-world patterns of in-hospital treatment, including diuretic therapy, in contemporary U.S. practice are unknown.
Methods
Using Optum de-identified Electronic Health Record data from 2007 through 2018, patients hospitalized for a primary diagnosis of HF (ejection fraction ≤40%) and who were hemodynamically stable at admission, without concurrent acute coronary syndrome or end-stage renal disease, and treated with intravenous (IV) diuretic agents within 48 h of admission were identified. Patients were categorized into 1 of 4 mutually exclusive hierarchical treatment groups defined by complexity of treatment during hospitalization (intensified treatment with mechanical support or IV vasoactive therapy, IV diuretic therapy reinitiated after discontinuation for ≥1 day without intensified treatment, IV diuretic dose increase/combination diuretic treatment without intensified treatment or IV diuretic reinitiation, or uncomplicated).
Results
Of 22,677 patients hospitalized for HF with reduced ejection fraction (HFrEF), 66% had uncomplicated hospitalizations without escalation of treatment beyond initial IV diuretic therapy. Among 7,809 remaining patients, the highest level of therapy received was IV diuretic dose increase/combination diuretic treatment in 25%, IV diuretic reinitiation in 36%, and intensified therapy in 39%. Overall, 19% of all patients had reinitiation of IV diuretic agents (26% of such patients had multiple instances), 12% were simultaneously treated with multiple diuretics, and 61% were transitioned to oral diuretic agents before discharge. Compared with uncomplicated treatment, IV diuretic reinitiation and intensified treatment were associated with significantly longer median length of stay (uncomplicated: 4 days; IV diuretic reinitiation: 8 days; intensified: 10 days) and higher rates of in-hospital (uncomplicated: 1.6%; IV diuretic reinitiation: 4.2%; intensified: 13.2%) and 30-day post-discharge mortality (uncomplicated: 5.2%; IV diuretic reinitiation: 9.7%; intensified: 12.7%).
Conclusions
In this contemporary real-world population of U.S. patients hospitalized for HFrEF, one-third of patients had in-hospital treatment escalated beyond initial IV diuretic therapy. These more complex treatment patterns were associated with highly variable patterns of diuretic use, longer hospital lengths of stay, and higher mortality. Standardized and evidence-based approaches are needed to improve the efficiency and effectiveness of in-hospital HFrEF care.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2020; 8:943-953
Greene SJ, Triana TS, Ionescu-Ittu R, Burne RM, ... Felker GM, Chen L
JACC Heart Fail: 30 Oct 2020; 8:943-953 | PMID: 32800512
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Impact:
Abstract

N-Terminal Pro-B-Type Natriuretic Peptide and Clinical Outcomes: Vericiguat Heart Failure With Reduced Ejection Fraction Study.

Ezekowitz JA, O\'Connor CM, Troughton RW, Alemayehu WG, ... Hernandez AF, Armstrong PW
Objectives
The purpose of this study was to examine the treatment effect of vericiguat in relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at randomization.
Background
Vericiguat compared with placebo reduced the primary outcome of cardiovascular death (CVD) or heart failure hospitalization (HFH) in patients with HF with reduced ejection fraction (HFrEF) in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. Because an interaction existed between treatment and the primary outcome according to pre-specified quartiles of NT-proBNP at randomization, we examined this further.
Methods
This study evaluated the NT-proBNP relationship with the primary outcome in 4,805 of 5,050 patients as a risk-adjusted, log-transformed continuous variable. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented.
Results
Median NT-proBNP was 2,816 pg/ml (25th to 75th percentile: 1,556 to 5,314 pg/ml). The study treatment effect varied across the spectrum of NT-proBNP at randomization (with log transformation, p for interaction = 0.002). A significant association between treatment effects existed in patients with levels <4,000 pg/ml and remained evident up to 8,000 pg/ml. A 23% relative risk reduction occurred in the primary endpoint with NT-proBNP ≤4,000 pg/ml (HR: 0.77; 95% CI: 0.68 to 0.88). For NT-proBNP values ≤4,000 pg/ml (n = 3,100), the HR was 0.78 (95% CI: 0.67 to 0.90) for HFH and 0.75 (95% CI: 0.60 to 0.94) for CVD. For NT-proBNP ≤8,000 pg/ml (n = 4,133), the HR was 0.85 (95% CI: 0.76 to 0.95) for the primary outcome, 0.84 (95% CI: 0.75 to 0.95) for HFH, and 0.84 (95% CI: 0.71 to 0.99) for CVD. For NT-proBNP >8,000 pg/ml (n = 672), the HR was 1.16 (95% CI: 0.94 to 1.41) for the primary outcome.
Conclusions
A reduction in the primary composite endpoint and its CVD and HFH components was observed in patients on vericiguat compared with subjects on placebo with NT-proBNP levels up to 8,000 pg/ml. This provided new insight into the benefit observed in high-risk patients with worsening HFrEF. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2020; 8:931-939
Ezekowitz JA, O'Connor CM, Troughton RW, Alemayehu WG, ... Hernandez AF, Armstrong PW
JACC Heart Fail: 30 Oct 2020; 8:931-939 | PMID: 33039447
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Impact:
Abstract

Socioeconomic Gradients in Mortality Following HF Hospitalization in a Country With Universal Health Care Coverage.

Sulo G, Igland J, Øverland S, Sulo E, ... Roth GA, Tell GS
Objectives
This study explored the association between socioeconomic position (SEP) and long-term mortality following first heart failure (HF) hospitalization.
Background
It is not clear to what extent education and income-individually or combined-influence mortality among patients with HF.
Methods
This study included 49,895 patients, age 35+ years, with a first HF hospitalization in Norway during 2000 to 2014 and followed them until death or December 31, 2014. The association between education, income, and mortality was explored using Cox regression models, stratified by sex and age group (35 to 69 years and 70+ years).
Results
Compared with patients with primary education, those with tertiary education had lower mortality (adjusted hazard ratio [HR]: 0.89; 95% confidence interval [CI]: 0.78 to 0.99 in younger men; HR: 0.57; 95% CI: 0.43 to 0.75 in younger women; HR: 0.90; 95% CI: 0.84 to 0.97 in older men, and HR: 0.87; 95% CI: 0.81 to 0.93 in older women). After adjusting for educational differences, younger and older men and younger women in the highest income quintile had lower mortality compared with those in the lowest income quintile (HR: 0.63; 95% CI: 0.55 to 0.72; HR: 0.78; 95% CI: 0.63 to 0.96, and HR: 0.91; 95% CI: 0.86 to 0.97, respectively). The association between income and mortality was almost linear. No association between income and mortality was observed in older women.
Conclusions
Despite the well-organized universal health care system in Norway, education and income were independently associated with mortality in patients with HF in a clear sex- and age group-specific pattern.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 30 Oct 2020; 8:917-927
Sulo G, Igland J, Øverland S, Sulo E, ... Roth GA, Tell GS
JACC Heart Fail: 30 Oct 2020; 8:917-927 | PMID: 33039444
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Impact:
Abstract

Complete Hemodynamic Profiling With Pulmonary Artery Catheters in Cardiogenic Shock Is Associated With Lower In-Hospital Mortality.

Garan AR, Kanwar M, Thayer KL, Whitehead E, ... Burkhoff D, Kapur NK
Objectives
The purpose of this study was to investigate the association between obtaining hemodynamic data from early pulmonary artery catheter (PAC) placement and outcomes in cardiogenic shock (CS).
Background
Although PACs are used to guide CS management decisions, evidence supporting their optimal use in CS is lacking.
Methods
The Cardiogenic Shock Working Group (CSWG) collected retrospective data in CS patients from 8 tertiary care institutions from 2016 to 2019. Patients were divided by Society for Cardiovascular Angiography and Interventions (SCAI) stages and outcomes analyzed by the PAC-use group (no PAC data, incomplete PAC data, complete PAC data) prior to initiating mechanical circulatory support (MCS).
Results
Of 1,414 patients with CS analyzed, 1,025 (72.5%) were male, and 494 (34.9%) presented with myocardial infarction; 758 (53.6%) were in SCAI Stage D shock, and 263 (18.6%) were in Stage C shock. Temporary MCS devices were used in 1,190 (84%) of those in advanced CS stages. PAC data were not obtained in 216 patients (18%) prior to MCS, whereas 598 patients (42%) had complete hemodynamic data. Mortality differed significantly between PAC-use groups within the overall cohort (p < 0.001), and each SCAI Stage subcohort (Stage C: p = 0.03; Stage D: p = 0.05; Stage E: p = 0.02). The complete PAC assessment group had the lowest in-hospital mortality than the other groups across all SCAI stages. Having no PAC assessment was associated with higher in-hospital mortality than complete PAC assessment in the overall cohort (adjusted odds ratio: 1.57; 95% confidence interval: 1.06 to 2.33).
Conclusions
The CSWG is a large multicenter registry representing real-world patients with CS in the contemporary MCS era. Use of complete PAC-derived hemodynamic data prior to MCS initiation is associated with improved survival from CS.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2020; 8:903-913
Garan AR, Kanwar M, Thayer KL, Whitehead E, ... Burkhoff D, Kapur NK
JACC Heart Fail: 30 Oct 2020; 8:903-913 | PMID: 33121702
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Abstract

Hemocompatibility-Related Adverse Events and Survival on Venoarterial Extracorporeal Life Support: An ELSO Registry Analysis.

Chung M, Cabezas FR, Nunez JI, Kennedy KF, ... Kociol RD, Grandin EW
Objectives
This study sought to determine the frequency, incidence rates over time, association with mortality, and potential risk factors for hemocompatibility-related adverse events (HRAEs) occurring during venoarterial-extracorporeal life support (VA-ECLS).
Background
HRAEs are common complications of VA-ECLS. Studies examining relevant clinical predictors and the association of HRAEs with survival are limited by small sample size and single-center setting.
Methods
We queried adult patients supported with VA-ECLS from 2010 to 2017 in the Extracorporeal Life Support Organization database to assess the impact of HRAEs on in-hospital mortality.
Results
Among 11,984 adults meeting study inclusion, 8,457 HRAEs occurred; 62.1% were bleeding events. The HRAE rate decreased significantly over the study period (p trend <0.001), but rates of medical bleeding and ischemic stroke remained stable. HRAEs had a cumulative association with mortality in adjusted analysis: 1 event, odds ratio (OR) of 1.43; 2 events, OR of 1.86; ≥3 events, OR of 3.27 (p < 0.001 for all). HRAEs most strongly associated with mortality were medical bleeding, including intracranial (OR: 7.71), pulmonary (OR: 3.08), and gastrointestinal (OR: 1.95) hemorrhage and ischemic stroke (OR: 2.31); p < 0.001 for all. Risk factors included the following: for bleeding: older age, lower pH, and female sex; for thrombosis: younger age, male sex, Asian race, and non-polymethylpentene oxygenator; and for both: time on ECLS, central cannulation, and renal failure.
Conclusions
Although decreasing, HRAEs remain common during VA-ECLS and have a cumulative association with survival. Bleeding events are twice as common as thrombotic events, with a hierarchy of HRAEs influencing survival. Differential risk factors for bleeding and thrombotic complications exist and raise the possibility of a tailored approach to ECLS management.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2020; 8:892-902
Chung M, Cabezas FR, Nunez JI, Kennedy KF, ... Kociol RD, Grandin EW
JACC Heart Fail: 30 Oct 2020; 8:892-902 | PMID: 33121701
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Abstract

A Standardized and Comprehensive Approach to the Management of Cardiogenic Shock.

Tehrani BN, Truesdell AG, Psotka MA, Rosner C, ... Damluji AA, Batchelor WB

Cardiogenic shock is a hemodynamically complex syndrome characterized by a low cardiac output that often culminates in multiorgan system failure and death. Despite recent advances, clinical outcomes remain poor, with mortality rates exceeding 40%. In the absence of adequately powered randomized controlled trials to guide therapy, best practices for shock management remain nonuniform. Emerging data from North American registries, however, support the use of standardized protocols focused on rapid diagnosis, early intervention, ongoing hemodynamic assessment, and multidisciplinary longitudinal care. In this review, the authors examine the pathophysiology and phenotypes of cardiogenic shock, benefits and limitations of current therapies, and they propose a standardized and team-based treatment algorithm. Lastly, they discuss future research opportunities to address current gaps in clinical knowledge.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Oct 2020; 8:879-891
Tehrani BN, Truesdell AG, Psotka MA, Rosner C, ... Damluji AA, Batchelor WB
JACC Heart Fail: 30 Oct 2020; 8:879-891 | PMID: 33121700
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This program is still in alpha version.