Journal: JACC Heart Fail

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Abstract

Angiotensin-Neprilysin Inhibition in Black Americans: Data From the PIONEER-HF Trial.

Berardi C, Braunwald E, Morrow DA, Mulder HS, ... DeVore AD,
Objectives
This study compared the efficacy and safety of sacubitril/valsartan to enalapril in Black and non-Black Americans with acute decompensated heart failure (ADHF).
Background
Black patients have a different response to treatment with angiotensin-converting enzyme inhibitors compared with other racial and ethnic groups. How Black patients with ADHF respond to sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, is unclear. PIONEER-HF was a double-blind randomized clinical trial of sacubitril/valsartan versus enalapril in hospitalized patients with ADHF following hemodynamic stabilization.
Methods
In a pre-specified subgroup analysis, we examined changes in N-terminal pro-B-type natriuretic peptide, clinical outcomes, and safety according to race.
Results
The study population, all enrolled in the United States, included 316 (36%) Black participants, 515 (58%) White participants, and 50 (5.7%) participants of other racial groups. The reduction in N-terminal pro-B-type natriuretic peptide concentration at weeks 4 and 8 was significantly greater with sacubitril/valsartan than enalapril in both Black (ratio of change with sacubitril/valsartan vs. enalapril: 0.71; 95% confidence interval [CI]: 0.58 to 0.88) and non-Black patients (ratio of change: 0.71; 95% CI: 0.61 to 0.83; interaction p = 1.00). Compared with enalapril, sacubitril/valsartan also reduced the pre-specified exploratory composite of cardiovascular death or HF rehospitalization in both Black (hazard ratio: 0.47; 95% CI: 0.24 to 0.93) and non-Black patients (hazard ratio: 0.65; 95% CI: 0.40 to 1.06; interaction p = 0.44).
Conclusions
Among Black patients admitted with ADHF in the United States, the in-hospital initiation of sacubitril/valsartan was more effective than enalapril in reducing natriuretic peptide levels and the composite of cardiovascular death or HF rehospitalization. The effect of sacubitril/valsartan did not differ by race. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).

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

JACC Heart Fail: 03 Sep 2020; epub ahead of print
Berardi C, Braunwald E, Morrow DA, Mulder HS, ... DeVore AD,
JACC Heart Fail: 03 Sep 2020; epub ahead of print | PMID: 32919915
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Abstract

Sacubitril/Valsartan and Sudden Cardiac Death According to Implantable Cardioverter-Defibrillator Use and Heart Failure Cause: A PARADIGM-HF Analysis.

Rohde LE, Chatterjee NA, Vaduganathan M, Claggett B, ... McMurray JJV, Solomon SD
Objectives
The purpose of this study was to investigate the effect of sacubitril/valsartan therapy on sudden cardiac death (SCD) according to the use of and eligibility for an implantable cardioverter-defibrillator (ICD), stratified by heart failure cause.
Background
SCD still accounts for a significant proportion of overall mortality in heart failure with reduced ejection fraction (HFrEF).
Methods
Patients enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial (n = 8,399) were evaluated to assess patterns of ICD implantation and eligibility according to clinical guidelines. The impact of ICD (adjusted for propensity of ICD implantation) and sacubitril/valsartan therapy on SCD was evaluated by using cause-specific Cox models and competing risk analysis.
Results
At baseline, of the 7,145 patients (85%) eligible for ICD implantation, only 1,243 (15%) had an ICD. Use of ICD varied by region with the highest rates in North America (56%) and lowest in Asia-Pacific (1.7%). In a propensity score-adjusted analysis, use of an ICD was associated with a 56% lower risk of SCD in ICD-eligible patients, in both patients with ischemic (p < 0.001) and nonischemic cardiomyopathy (p = 0.02). Sacubitril/valsartan reduced SCD risk in patients with an ICD (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.25 to 0.99) and in those who were eligible for but did not receive an ICD (HR: 0.81; 95% CI: 0.67 to 0.98). This effect was particularly evident in nonischemic cardiomyopathy (p < 0.05), although interaction with the cause of HF was not significant (p = 0.11 in subjects using an ICD and p = 0.25 in eligible nonusers).
Conclusions
Use of an ICD was associated with lower rates of SCD, regardless of HF cause but was underused in most regions of the world in the PARADIGM-HF study. Sacubitril/valsartan reduced SCD risk regardless of use of an ICD or eligibility, particularly in ICD users and nonischemic cardiomyopathy.

Copyright © 2020. Published by Elsevier Inc.

JACC Heart Fail: 03 Sep 2020; epub ahead of print
Rohde LE, Chatterjee NA, Vaduganathan M, Claggett B, ... McMurray JJV, Solomon SD
JACC Heart Fail: 03 Sep 2020; epub ahead of print | PMID: 32919916
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Abstract

Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.

Mann DL, Greene SJ, Givertz MM, Vader JM, ... Braunwald E,

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).

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

JACC Heart Fail: 29 Sep 2020; 8:789-799
Mann DL, Greene SJ, Givertz MM, Vader JM, ... Braunwald E,
JACC Heart Fail: 29 Sep 2020; 8:789-799 | PMID: 32641226
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Abstract

Sacubitril/Valsartan: Neprilysin Inhibition 5 Years After PARADIGM-HF.

Docherty KF, Vaduganathan M, Solomon SD, McMurray JJV

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms among patients with chronic heart failure with reduced ejection fraction compared to enalapril, the gold standard angiotensin-converting enzyme inhibitor. In the 5 years since the publication of the results of PARADIGM-HF, further insight has been gained into integrating a neprilysin inhibitor into a comprehensive multidrug regimen, including a renin-angiotensin aldosterone system (RAS) blocker. This paper reviews the current understanding of the effects of sacubitril/valsartan and highlights expected developments over the next 5 years, including potential new indications for use. Additionally, a practical, evidence-based approach is provided to the clinical integration of sacubitril/valsartan among patients with heart failure with reduced ejection fraction.

Copyright © 2020. Published by Elsevier Inc.

JACC Heart Fail: 29 Sep 2020; 8:800-810
Docherty KF, Vaduganathan M, Solomon SD, McMurray JJV
JACC Heart Fail: 29 Sep 2020; 8:800-810 | PMID: 33004114
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Abstract

NT-proBNP Response to Sacubitril/Valsartan in Hospitalized Heart Failure Patients With Reduced Ejection Fraction: TRANSITION Study.

Pascual-Figal D, Wachter R, Senni M, Bao W, ... Prescott MF,
Objectives
This study examined the effects of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and determined patient characteristics associated with favorable NT-proBNP reduction response.
Background
NT-proBNP levels reflect cardiac wall stress and predict event risk in patients with acute decompensated heart failure (ADHF).
Methods
Post-hoc analysis of the TRANSITION (Comparison of Pre- and Post-discharge Initiation of Sacubitril/Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event) study, including stabilized ADHF patients with reduced ejection fraction, randomized to open-label sacubitril/valsartan initiation in-hospital (pre-discharge) versus post-discharge. NT-proBNP was measured at randomization (baseline), discharge, and 4 and 10 weeks post-randomization. A favorable NT-proBNP response was defined as reduction to ≤1,000 pg/ml or >30% from baseline.
Results
In patients receiving sacubitril/valsartan in-hospital, NT-proBNP was reduced by 28% at discharge, with 46% of patients obtaining favorable NT-proBNP reduction response compared with a 4% reduction and 18% favorable response rate in patients initiated post-discharge (p < 0.001). NT-proBNP was reduced similarly in patients initiating sacubitril/valsartan pre- and post-discharge (reduction at 4 weeks: 25%/22%; 10 weeks: 38%/34%) with comparable favorable response rates (46%/42% and 51%/48% at 4 and 10 weeks, respectively). NT-proBNP favorable response at 4 weeks was associated with lower risk of first heart failure (HF) rehospitalization or cardiovascular death through 26 weeks (hazard ratio: 0.57; 95% confidence interval [CI]: 0.38 to 0.86; p = 0.007). Predictors of a favorable response at 4 weeks were starting dose ≥49/51 mg twice daily, higher baseline NT-proBNP, lower baseline serum creatinine, de novo HF, no atrial fibrillation, angiotensin-converting enzyme inhibitor-naive or angiotensin receptor blocker-naive, and no prior myocardial infarction.
Conclusions
In-hospital initiation of sacubitril/valsartan produced rapid reductions in NT-proBNP, statistically significant at discharge. A favorable NT-proBNP response over time was associated with a better prognosis and predicted by higher starting dose and predisposing clinical profile. (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event [TRANSITION]; NCT02661217).

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

JACC Heart Fail: 29 Sep 2020; 8:822-833
Pascual-Figal D, Wachter R, Senni M, Bao W, ... Prescott MF,
JACC Heart Fail: 29 Sep 2020; 8:822-833 | PMID: 32800508
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Abstract

Myocardial Infarction in Heart Failure With Preserved Ejection Fraction: Pooled Analysis of 3 Clinical Trials.

Cunningham JW, Vaduganathan M, Claggett BL, John JE, ... Pfeffer MA, Solomon SD
Objectives
The authors investigated the relationship between past or incident myocardial infarction (MI) and cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF).
Background
MI and HFpEF share some common risk factors. The prognostic significance of MI in patients with HFpEF is uncertain.
Methods
The authors pooled data from 3 trials-CHARM Preserved (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity), I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function), and the Americas region of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) (N = 8,916)-and examined whether MI before or following enrollment independently predicted CV death and heart failure (HF) hospitalization.
Results
At baseline, 2,668 patients (30%) had history of MI. Prior MI was independently associated with greater risk of CV death (4.7 vs. 3.5 events/100 patient-years [py], adjusted hazard ratio [HR]: 1.42 [95% confidence interval (CI): 1.23 to 1.64]; p < 0.001). Excess sudden death drove this difference (1.9 vs. 1.2 events/100 py, adjusted HR: 1.55 [95% CI: 1.23 to 1.97]; p < 0.001). There was no difference in HF hospitalization (5.9 vs. 5.5 events/100 py, adjusted HR: 1.05, 95% CI: 0.92 to 1.19) or HF death by prior MI. During follow-up, MI occurred in 336 patients (3.8%). Risk of CV death increased 31-fold in the first 30 days after first post-enrollment MI, and remained 58% higher beyond 1 year after MI. Risk of first or recurrent HF hospitalization increased 2.4-fold after MI.
Conclusions
Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes. Patients with HFpEF who experience MI are at high risk of subsequent CV death and HF hospitalization. These data highlight the importance of primary and secondary prevention of MI in patients with HFpEF. (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve]; NCT00095238; and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302).

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

JACC Heart Fail: 30 Jul 2020; 8:618-626
Cunningham JW, Vaduganathan M, Claggett BL, John JE, ... Pfeffer MA, Solomon SD
JACC Heart Fail: 30 Jul 2020; 8:618-626 | PMID: 32387067
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Abstract

Application of Diagnostic Algorithms for Heart Failure With Preserved Ejection Fraction to the Community.

Selvaraj S, Myhre PL, Vaduganathan M, Claggett BL, ... Shah AM, Solomon SD
Objectives
This study sought to describe characteristics and risk of adverse outcomes associated with the HFPEF and HFA-PEFF scores among participants in the community with unexplained dyspnea.
Background
Diagnosing heart failure with preserved ejection fraction (HFpEF) can be challenging. The HFPEF and HFA-PEFF scores have recently been developed to estimate the likelihood that HFpEF is present among patients with unexplained dyspnea.
Methods
The study included 4,892 ARIC (Atherosclerosis Risk In Communities) study participants 67 to 90 years of age at visit 5 (2011 to 2013) without other common cardiopulmonary causes of dyspnea. Participants were categorized as asymptomatic (76.6%), having known HFpEF (10.3%), and having tertiles of each score among those with ≥moderate, self-reported dyspnea (13.1%). The primary outcome was heart failure (HF) hospitalization or death.
Results
Mean age was 75 ± 5 years, 58% were women, and 22% were black. After a mean follow-up of 5.3 ± 1.2 years, rates of HF hospitalization or death per 1,000 person-years for asymptomatic and known HFpEF were 20.7 (95% confidence interval [CI]: 18.9 to 22.7) and 71.6 (95% CI: 61.6 to 83.3), respectively. Among 641 participants with unexplained dyspnea, rates were 27.7 (95% CI: 18.2 to 42.1), 44.9 (95% CI: 34.9 to 57.7), and 47.3 (95% CI: 36.5 to 61.3) (tertiles of HFPEF score) and 31.8 (95% CI: 20.3 to 49.9), 32.4 (95% CI: 23.4 to 44.9), and 54.3 (95% CI: 43.8 to 67.3) (tertiles of HFA-PEFF score). Participants with unexplained dyspnea and scores above the diagnostic threshold suggested for each algorithm, HFPEF score ≥6 and HFA-PEFF score ≥5, had equivalent risk of HF hospitalization or death compared with known HFpEF. Among those with unexplained dyspnea, 28% had \"discordant\" findings (only high risk by 1 algorithm), while 4% were high risk by both.
Conclusions
Participants with unexplained dyspnea and higher HFPEF or HFA-PEFF scores face substantial risks of HF hospitalization or death. A significant fraction of patients are classified discordantly by using both algorithms.

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

JACC Heart Fail: 30 Jul 2020; 8:640-653
Selvaraj S, Myhre PL, Vaduganathan M, Claggett BL, ... Shah AM, Solomon SD
JACC Heart Fail: 30 Jul 2020; 8:640-653 | PMID: 32535127
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Abstract

Splanchnic Nerve Block for Chronic Heart Failure.

Fudim M, Boortz-Marx RL, Ganesh A, DeVore AD, ... Hernandez AF, Patel MR
Objectives
We hypothesized that splanchnic nerve blockade (SNB) would attenuate increased exercise-induced cardiac filling pressures in patients with chronic HF.
Background
Chronic heart failure (HF) is characterized by limited exercise capacity driven in part by an excessive elevation of cardiac filling pressures.
Methods
This is a prospective, open-label, single-arm interventional study in chronic HF patients. Eligible patients had a wedge pressure ≥15 mm Hg at rest or ≥25 mm Hg with exercise on baseline right heart catheterization. Patients underwent cardiopulmonary exercise testing with invasive hemodynamic assessment, followed by percutaneous SNB with ropivacaine.
Results
Nineteen patients were enrolled, 15 of whom underwent SNB. The average age was 58 ± 13 years, 7 (47%) patients were women and 6 (40%) were black. Left ventricular ejection fraction was ≤35% in 14 (93%) patients. No procedural complications were encountered. SNB reduced mean pulmonary arterial pressure at peak exercise from 54.1 ± 14.4 (pre-SNB) to 45.8 ± 17.7 mm Hg (p < 0.001) (post-SNB). Similarly, SNB reduced exercise-induced wedge pressure from 34.8 ± 10.0 (pre-SNB) to 25.1 ± 10.7 mm Hg (p < 0.001) (post-SNB). The cardiac index changed with peak exercise from 3.4 ± 1.2 (pre-SNB) to 3.8 ± 1.1 l/min/m (p = 0.011) (post-SNB). After SNB, patients exercised for approximately the same duration at a greater workload (33 ± 24 W vs. 50 ± 30 W; p = 0.019) and peak oxygen consumption VO (9.1 ± 2.5 vs. 9.8 ± 2.7 ml/kg/min; p = 0.053).
Conclusions
SNB reduced resting and exercise-induced pulmonary arterial and wedge pressure with favorable effects on cardiac output and exercise capacity. Continued efforts to investigate short- and long-term effects of SNB in chronic HF are warranted. Clinical Trials Registration (Abdominal Nerve Blockade in Chronic Heart Failure; NCT03453151).

Copyright © 2020. Published by Elsevier Inc.

JACC Heart Fail: 30 Aug 2020; 8:742-752
Fudim M, Boortz-Marx RL, Ganesh A, DeVore AD, ... Hernandez AF, Patel MR
JACC Heart Fail: 30 Aug 2020; 8:742-752 | PMID: 32535123
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Abstract

Impaired Exercise Tolerance in Heart Failure With Preserved Ejection Fraction: Quantification of Multiorgan System Reserve Capacity.

Nayor M, Houstis NE, Namasivayam M, Rouvina J, ... Malhotra R, Lewis GD

Exercise intolerance is a principal feature of heart failure with preserved ejection fraction (HFpEF), whether or not there is evidence of congestion at rest. The degree of functional limitation observed in HFpEF is comparable to patients with advanced heart failure and reduced ejection fraction. Exercise intolerance in HFpEF is characterized by impairments in the physiological reserve capacity of multiple organ systems, but the relative cardiac and extracardiac deficits vary among individuals. Detailed measurements made during exercise are necessary to identify and rank-order the multiorgan system limitations in reserve capacity that culminate in exertional intolerance in a given person. We use a case-based approach to comprehensively review mechanisms of exercise intolerance and optimal approaches to evaluate exercise capacity in HFpEF. We also summarize recent and ongoing trials of novel devices, drugs, and behavioral interventions that aim to improve specific exercise measures such as peak oxygen uptake, 6-min walk distance, heart rate, and hemodynamic profiles in HFpEF. Evaluation during the clinically relevant physiological perturbation of exercise holds promise to improve the precision with which HFpEF is defined and therapeutically targeted.

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

JACC Heart Fail: 30 Jul 2020; 8:605-617
Nayor M, Houstis NE, Namasivayam M, Rouvina J, ... Malhotra R, Lewis GD
JACC Heart Fail: 30 Jul 2020; 8:605-617 | PMID: 32535122
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Abstract

Prognostic Implications of Staging Right Heart Failure in Patients With Significant Secondary Tricuspid Regurgitation.

Dietz MF, Prihadi EA, van der Bijl P, Ajmone Marsan N, Delgado V, Bax JJ
Objectives
The purpose of this study was to evaluate the prognostic value of staging right heart failure (RHF) in patients with significant secondary tricuspid regurgitation (TR).
Background
Right ventricular dysfunction (RVD), defined as tricuspid annular plane systolic excursion <17 mm and clinical signs of RHF, defined as New York Heart Association functional class ≥II, peripheral edema, or use of diuretics, do not always coincide in patients with significant secondary TR and may have different prognostic implications.
Methods
A total of 1,311 patients with significant secondary TR (median age: 71 [interquartile range: 62 to 78] years; 50% male) were divided into 4 RHF Stages according to the presence or absence of RVD and clinical signs of RHF: Stage 1 was defined as no RVD and no signs of RHF; Stage 2 indicated RVD but no signs of RHF; Stage 3 included RVD and signs of RHF; Stage 4 was defined as RVD and refractory signs of RHF at rest. Five-year mortality rates were compared across the 4 Stages of RHF, and the independent associates of mortality were identified by using multivariate Cox proportional hazards models.
Results
A total of 101 patients (8%) were classified as Stage 1, 124 (10%) as Stage 2, 683 (52%) as Stage 3, and 403 (31%) as Stage 4. Patients in higher Stages of RHF had more comorbidities and worse renal and left ventricular systolic function. Cumulative 5-year survival was 54%. RHF Stages 3 and 4 were independently associated with increased mortality compared to Stage 1 (hazard ratio: 2.110 [95% confidence interval (CI): 1.163 to 3.828] and 3.318 [95% CI: 1.795 to 6.133], respectively).
Conclusions
In patients with significant secondary TR, higher Stages of RHF are independently associated with all-cause mortality at long-term follow-up.

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

JACC Heart Fail: 30 Jul 2020; 8:627-636
Dietz MF, Prihadi EA, van der Bijl P, Ajmone Marsan N, Delgado V, Bax JJ
JACC Heart Fail: 30 Jul 2020; 8:627-636 | PMID: 32535118
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Abstract

Hemodynamic and Functional Impact of Epicardial Adipose Tissue in Heart Failure With Preserved Ejection Fraction.

Koepp KE, Obokata M, Reddy YNV, Olson TP, Borlaug BA
Objectives
This study determined the impact of excess epicardial adipose tissue (EAT) in patients with the obese phenotype of heart failure with preserved ejection fraction (HFpEF).
Background
Patients with HFpEF and an elevated body mass index differ from nonobese patients, but beyond generalized obesity, fat distribution may be more important. Increases in EAT are associated with excess visceral adiposity, inflammation, and cardiac fibrosis, and EAT has been speculated to play an important role in the pathophysiology of HFpEF, but no study has directly evaluated this question.
Methods
Patients with HFpEF and obesity (n = 169) underwent invasive hemodynamic exercise testing with expired gas analysis and echocardiography. Increased EAT was defined by echocardiography (EAT thickness ≥9 mm).
Results
Compared with obese patients without increased EAT (HFpEF, n = 92), obese patients with HFpEF with increased EAT (HFpEF; n = 77) displayed a higher left ventricular eccentricity index, indicating increased pericardial restraint, but similar resting biventricular structure and function. In contrast, hemodynamics were more abnormal in patients with HFpEF, with higher right atrial, pulmonary artery, and pulmonary capillary wedge pressures at rest and during exercise compared with those of patients with HFpEF. Peak oxygen consumption (VO) was reduced in both groups but was 20% lower in patients with HFpEF (p < 0.01).
Conclusions
Among patients with the obese phenotype of HFpEF, the presence of increased EAT is associated with more profound hemodynamic derangements at rest and exercise, including greater elevation in cardiac filling pressures, more severe pulmonary hypertension, and greater pericardial restraint, culminating in poorer exercise capacity. Further study is needed to understand the biology and treatment of excessive EAT in patients with HFpEF.

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

JACC Heart Fail: 30 Jul 2020; 8:657-666
Koepp KE, Obokata M, Reddy YNV, Olson TP, Borlaug BA
JACC Heart Fail: 30 Jul 2020; 8:657-666 | PMID: 32653449
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Abstract

Endomyocardial Biopsy Characterization of Heart Failure With Preserved Ejection Fraction and Prevalence of Cardiac Amyloidosis.

Hahn VS, Yanek LR, Vaishnav J, Ying W, ... Kass DA, Sharma K
Objectives
This study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathologic phenotypes and their association with clinical characteristics.
Background
Myocardial tissue analysis from a prospectively defined HFpEF cohort reflecting contemporary comorbidities is lacking.
Methods
Patients with HFpEF (EF ≥50%) referred to the Johns Hopkins HFpEF Clinic between August 2014 and September 2018 were enrolled for right heart catheterization and endomyocardial biopsy. Clinical features, echocardiography, hemodynamics, and tissue histology were determined and compared with controls (unused donor hearts) and HF with reduced EF (HFrEF).
Results
Of the 108 patients enrolled, median age was 66 years (25th to 75th percentile: 57 to 74 years), 61% were women, 57% were African American, 62% had a previous HF hospitalization, median systolic blood pressure was 141 mm Hg (25th to 75th percentile: 125 to 162 mm Hg), body mass index (BMI) was 37 kg/m (25th to 75th percentile: 32 to 45 kg/m), and 97% were on a loop diuretic. Myocardial fibrosis and myocyte hypertrophy were often present (93% and 88%, respectively); however, mild in 71% with fibrosis and in 52% with hypertrophy. Monocyte infiltration (CD68+ cells/mm) was greater in patients with HFpEF versus controls (60.4 cells/mm [25th to 75th percentile: 36.8 to 97.8] vs. 32.1 cells/mm [25th to 75th percentile: 22.3 to 59.2]; p = 0.02) and correlated with age and renal disease. Cardiac amyloidosis (CA) was diagnosed in 15 (14%) patients (HFpEF-CA: 7 patients with wild-type transthyretin amyloidosis [ATTR], 4 patients with hereditary ATTR, 3 patients with light-chain amyloidosis, and 1 patient with AA (secondary) amyloidosis), of which 7 cases were unsuspected. Patients with HFpEF-CA were older, with lower BMI, higher left ventricular mass index, and higher N-terminal pro-B-type natriuretic peptide and troponin I levels.
Conclusions
In this large, prospective myocardial tissue analysis of HFpEF, myocardial fibrosis and hypertrophy were common, CD68+ inflammation was increased, and CA prevalence was 14%. Tissue analysis in HFpEF might improve precision therapies by identifying relevant myocardial mechanisms.

Copyright © 2020. Published by Elsevier Inc.

JACC Heart Fail: 30 Aug 2020; 8:712-724
Hahn VS, Yanek LR, Vaishnav J, Ying W, ... Kass DA, Sharma K
JACC Heart Fail: 30 Aug 2020; 8:712-724 | PMID: 32653448
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Abstract

Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial.

Solomon SD, Jhund PS, Claggett BL, Dewan P, ... Langkilde AM, McMurray JJV
Objectives
This study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial.
Background
Both the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown.
Methods
DAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by sacubitril/valsartan group.
Results
A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan.
Conclusions
Dapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]; NCT03036124).

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

JACC Heart Fail: 29 Sep 2020; 8:811-818
Solomon SD, Jhund PS, Claggett BL, Dewan P, ... Langkilde AM, McMurray JJV
JACC Heart Fail: 29 Sep 2020; 8:811-818 | PMID: 32653447
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Impact:
Abstract

Sex Differences in Patients Receiving Left Ventricular Assist Devices for End-Stage Heart Failure.

Gruen J, Caraballo C, Miller PE, McCullough M, ... Ahmad T, Desai NR
Objectives
This study sought to use INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) results to evaluate sex differences in the use and clinical outcomes of left ventricular assist devices (LVAD).
Background
Despite a similar incidence of heart failure in men and women, prior studies have highlighted potential underuse of LVADs in women, and studies of clinical outcomes have yielded conflicting results.
Methods
Patients were enrolled from the INTERMACS study who underwent implantation of their first continuous-flow LVAD between 2008 and 2017, and survival analyses stratified by sex were conducted.
Results
Among the 18,868 patients, 3,984 (21.1%) were women. At 1 year, women were less likely to undergo heart transplantation than men (17.9% vs. 20.0%, respectively; p = 0.003). After multivariable adjustments, women had a higher risk of death (hazard ratio [HR]: 1.15; 95% confidence interval [CI]: 1.07 to 1.23; p < 0.001) and were more likely to incur post-implantation adverse events, including rehospitalization, bleeding, stroke, and pump thrombosis or device malfunction. Although women younger than 50 years of age had an increased risk of death compared to men of the same age (HR: 1.34; 95% CI: 1.12 to 1.6), men and women 65 years of age and older had a similar risk of death (HR: 1.09; 95% CI: 0.95 to 1.24).
Conclusions
This study found that women had a higher risk of mortality and adverse events after LVAD. Only 1 in 5 LVADs were implanted in women, and women were less likely to receive a heart transplant than men. Further investigation is needed to understand the causes of adverse events and potential underuse of advanced treatment options in women.

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

JACC Heart Fail: 30 Aug 2020; 8:770-779
Gruen J, Caraballo C, Miller PE, McCullough M, ... Ahmad T, Desai NR
JACC Heart Fail: 30 Aug 2020; 8:770-779 | PMID: 32653446
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Impact:
Abstract

Insufficient Calorie Intake Worsens Post-Discharge Quality of Life and Increases Readmission Burden in Heart Failure.

Bilgen F, Chen P, Poggi A, Wells J, ... Maurer MS, Hummel SL
Objectives
The purpose of this study was to evaluate the relationship between calorie intake and post-discharge outcomes in hospitalized patients with heart failure (HF).
Background
Malnutrition increases adverse outcomes in HF, and dietary sodium restriction may inadvertently worsen nutritional intake.
Methods
In a dietary intervention trial, baseline nutritional intake in HF inpatients was estimated using the Block Food Frequency Questionnaire (FFQ), and the Nutritional Risk Index (NRI) was calculated. Insufficient calorie intake was defined as <90% of metabolic needs, and a 15-point micronutrient deficiency score was created. Adjusted linear, logistic, and negative binomial regression were used to evaluate associations between insufficient calorie intake and quality of life (using the Kansas City Cardiomyopathy Questionnaire Clinical Summary [KCCQ-CS]), readmission risk, and days rehospitalized over 12 weeks.
Results
Among 57 participants (70 ± 8 years of age; 31% female; mean body mass index 32 ± 8 kg/m); median sodium and calorie intake amounts were 2,987 mg/day (interquartile range [IQR]: 2,160 to 3,540 mg/day) and 1,602 kcal/day (IQR: 1,201 to 2,142 kcal/day), respectively; 11% of these patients were screened as malnourished by the NRI. All patients consuming <2,000 mg/day sodium had insufficient calorie intake; this group also more frequently had dietary micronutrient and protein deficiencies. At 12 weeks, patients with insufficient calorie intake had less improvement in the KCCQ-CS score (β = -14.6; 95% confidence interval [CI]: -27.3 to -1.9), higher odds of readmission (odds ratio: 14.5; 95% CI: 2.2 to 94.4), and more days rehospitalized (incident rate ratio: 31.3; 95% CI: 4.3 to 229.3).
Conclusions
Despite a high prevalence for obesity and rare overt malnutrition, insufficient calorie intake was associated with poorer post-discharge quality of life and increased burden of readmission in patients with HF. Inpatient dietary assessment could improve readmission risk stratification and identify patients for nutritional intervention. (Geriatric Out of Hospital Randomized Meal Trial in Heart Failure [GOURMET-HF] NCT02148679).

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

JACC Heart Fail: 30 Aug 2020; 8:756-764
Bilgen F, Chen P, Poggi A, Wells J, ... Maurer MS, Hummel SL
JACC Heart Fail: 30 Aug 2020; 8:756-764 | PMID: 32653445
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Impact:
Abstract

Epicardial Adipose Tissue and Invasive Hemodynamics in Heart Failure With Preserved Ejection Fraction.

Gorter TM, van Woerden G, Rienstra M, Dickinson MG, ... Hoendermis ES, van Veldhuisen DJ
Objectives
This study examined associations between epicardial adipose tissue (EAT), invasive hemodynamics, and exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF).
Background
EAT is increased in patients with HFpEF and may play a role in the pathophysiology of this disorder.
Methods
Patients with heart failure and a left ventricular ejection fraction >45% who underwent right and left heart catheterization with simultaneous echocardiography were included. Pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP), right ventricular end-diastolic pressure (RVEDP), and pulmonary vascular resistance (PVR) were invasively measured. Obesity was defined as body mass index (BMI) ≥30 kg/m. EAT thickness alongside the right ventricle was measured on echocardiographic long- and short-axis views. Cardiopulmonary exercise testing was performed to obtain maximal oxygen uptake (VO-max).
Results
This study examined 75 patients, mean age 74 ± 9 years; 68% were women, mean BMI was 29 ± 6 kg/m, and 36% were obese. Higher BMI was strongly associated with increased EAT (r = 0.74; p < 0.001). Increased EAT was associated with higher RVEDP, independent of PVR (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.02 to 1.34; p = 0.03), but not independent of obesity (p = 0.10). Increased EAT and higher RVEDP were both associated with lower VO-max (r = -0.43; p < 0.001 and r = -0.43; p = 0.001, respectively). Increased EAT remained associated with lower VO-max after adjustment for PVR (OR: 0.64; 95% CI: 0.49 to 0.84; p = 0.002) and obesity (OR: 0.69; 95% CI: 0.53 to 0.92; p = 0.01). EAT thickness was not associated with left-sided filling pressures (i.e., PCWP and LVEDP).
Conclusions
In HFpEF, obesity and increased EAT were associated with higher right-sided filling pressures and with reduced exercise capacity.

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

JACC Heart Fail: 30 Jul 2020; 8:667-676
Gorter TM, van Woerden G, Rienstra M, Dickinson MG, ... Hoendermis ES, van Veldhuisen DJ
JACC Heart Fail: 30 Jul 2020; 8:667-676 | PMID: 32653444
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Impact:
Abstract

Utility of Biomarkers in Cardiac Amyloidosis.

Pregenzer-Wenzler A, Abraham J, Barrell K, Kovacsovics T, Nativi-Nicolau J

Cardiac amyloidosis is a growing field, with advancements in diagnosis and management. Cardiac biomarkers are used to predict survival and to develop severity staging systems. Cardiac biomarkers are also used in clinical practice to stratify patients for treatment and to evaluate response to therapies. The current review summarizes the major clinical utility of current biomarkers in patients with cardiac amyloidosis and provides insights about future areas of investigation.

Published by Elsevier Inc.

JACC Heart Fail: 30 Aug 2020; 8:701-711
Pregenzer-Wenzler A, Abraham J, Barrell K, Kovacsovics T, Nativi-Nicolau J
JACC Heart Fail: 30 Aug 2020; 8:701-711 | PMID: 32653441
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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: 11 Aug 2020; epub ahead of print
Greene SJ, Triana TS, Ionescu-Ittu R, Burne RM, ... Felker GM, Chen L
JACC Heart Fail: 11 Aug 2020; epub ahead of print | PMID: 32800512
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Impact:
Abstract

Efficacy and Safety of Sacubitril/Valsartan by Dose Level Achieved in the PIONEER-HF Trial.

Berg DD, Braunwald E, DeVore AD, Lala A, ... Velazquez EJ, Morrow DA
Objectives
This study sought to evaluate the efficacy and safety of sacubitril/valsartan according to dose level achieved in the PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode) trial.
Background
In patients hospitalized for acute decompensated heart failure (ADHF), in-hospital initiation and continuation of sacubitril/valsartan as compared with enalapril is well tolerated, achieves a greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP), and reduces the risk of cardiovascular death or rehospitalization for HF through 8 weeks. However, not all patients achieve the target dose of sacubitril/valsartan, and its efficacy and safety in such patients are of interest.
Methods
PIONEER-HF was a randomized, double-blind, active-controlled trial of sacubitril/valsartan versus enalapril in 881 patients stabilized during hospitalization for ADHF. Blinded study medication was administered for 8 weeks, with initial dosing selected based on the systolic blood pressure at randomization and titrated toward a target of sacubitril/valsartan 97/103 mg twice daily, or enalapril 10 mg twice daily, with an algorithm based on systolic blood pressure and the investigator\'s assessment of tolerability.
Results
At 4 weeks, 199 (55%) patients allocated to sacubitril/valsartan and 211 (60%) patients allocated to enalapril were dispensed the target dose. Baseline characteristics were similar in the 2 treatment groups within each dose level. There was no heterogeneity across dose levels in the effect of sacubitril/valsartan on the reduction in NT-proBNP (p = 0.69), the reduction in cardiovascular death or rehospitalization for heart failure (p = 0.42), or the pre-specified adverse events of special interest through 8 weeks.
Conclusions
In hemodynamically stabilized patients with ADHF, the efficacy and safety of sacubitril/valsartan are generally consistent across dose levels. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).

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

JACC Heart Fail: 29 Sep 2020; 8:834-843
Berg DD, Braunwald E, DeVore AD, Lala A, ... Velazquez EJ, Morrow DA
JACC Heart Fail: 29 Sep 2020; 8:834-843 | PMID: 32800511
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Impact:
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: 11 Aug 2020; epub ahead of print
Sterling MR, Kern LM, Safford MM, Jones CD, ... Yancy CW, Albert NM
JACC Heart Fail: 11 Aug 2020; epub ahead of print | PMID: 32800510
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Impact:
Abstract

Care Gaps in Adherence to Heart Failure Guidelines: Clinical Inertia or Physiological Limitations?

Jarjour M, Henri C, de Denus S, Fortier A, ... Rouleau JL, Ducharme A
Objectives
This study evaluated the impact of clinical and physiological factors limiting treatment optimization toward recommended medical therapy in heart failure (HF).
Background
Although guidelines aim to assist physicians in prescribing evidence-based therapies and to improve outcomes of patients with HF and reduced ejection fraction (HFrEF), gaps in clinical care persist.
Methods
Medical records of all patients with HFrEF followed for at least 6 months at the authors\' HF clinic (n = 511) allowed for drug optimization and were reviewed regarding the prescription rates of recommended pharmacological agents and devices (implantable cardioverter-defibrillator [ICD] or cardiac resynchronization therapy [CRT]). Then, an algorithm integrating clinical (New York Heart Association [NYHA] functional class, heart rate, blood pressure and biologic parameters (creatinine, serum potassium) based on the inclusion/exclusion criteria of landmark trials guiding these recommendations) was applied for each agent and device to identify potential explanations for treatment gaps.
Results
Gross prescription rates were high for beta-blockers (98.6%), mineralocorticoid receptor antagonist (MRA) (93.4%), vasodilators (90.3%), ICDs (75.1%), and CRT (82.1%) among those eligible, except for ivabradine (46.3%, n = 41). However, achievement of target physiological doses was lower (beta-blockers, 67.5%; MRA, 58.9%; and vasodilators, 63.4%), and one-fifth of patient dosages were still being up-titrated. Suboptimal doses were associated with older age (odds ratio [OR]: 1.221; p < 0.0001) and history of stroke or transient ischemic attack (TIA) (no vs. yes, OR: 0.264; p = 0.0336).
Conclusions
Gaps in adherence to guidelines exist in specialized HF setting and are mostly explained by limiting physiological factors rather than inertia. Older age and history of stroke/TIA, potential markers of frailty, are associated with suboptimal doses of guideline-directed medical therapy, suggesting that an individualized rather than a \"one-size-fits-all\" approach may be required.

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

JACC Heart Fail: 30 Aug 2020; 8:725-738
Jarjour M, Henri C, de Denus S, Fortier A, ... Rouleau JL, Ducharme A
JACC Heart Fail: 30 Aug 2020; 8:725-738 | PMID: 32800509
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Impact:
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: 03 Sep 2020; epub ahead of print
Chandra A, Alcala MAD, Claggett B, Desai AS, ... Pfeffer MA, Lewis EF
JACC Heart Fail: 03 Sep 2020; epub ahead of print | 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: 01 Oct 2020; epub ahead of print
Ferreira JP, Docherty KF, Stienen S, Jhund PS, ... Zannad F, McMurray JJV
JACC Heart Fail: 01 Oct 2020; epub ahead of print | PMID: 33039448
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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: 06 Oct 2020; epub ahead of print
Ezekowitz JA, O'Connor CM, Troughton RW, Alemayehu WG, ... Hernandez AF, Armstrong PW
JACC Heart Fail: 06 Oct 2020; epub ahead of print | PMID: 33039447
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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
The 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: 01 Oct 2020; epub ahead of print
Perego C, Sbolli M, Specchia C, Fiuzat M, ... O'Connor CM, Psotka MA
JACC Heart Fail: 01 Oct 2020; epub ahead of print | PMID: 33039446
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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: 01 Oct 2020; epub ahead of print
Sulo G, Igland J, Øverland S, Sulo E, ... Roth GA, Tell GS
JACC Heart Fail: 01 Oct 2020; epub ahead of print | PMID: 33039444
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.