Journal: JACC Heart Fail

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Abstract

Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial.

Burkhoff D, Borlaug BA, Shah SJ, Zolty R, ... Preston IR, Rich S
Objectives
The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF).
Background
There are no proven effective treatments for patients with PH-HFpEF.
Methods
Patients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages.
Results
Thirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (-1.4 mm Hg; 95% confidence interval [CI]: -7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (-3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo.
Conclusions
Six weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603).

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

JACC Heart Fail: 02 Apr 2021; epub ahead of print
Burkhoff D, Borlaug BA, Shah SJ, Zolty R, ... Preston IR, Rich S
JACC Heart Fail: 02 Apr 2021; epub ahead of print | PMID: 33839076
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Abstract

Global Differences in Burden and Treatment of Ischemic Heart Disease in Acute Heart Failure: REPORT-HF.

Tromp J, Ouwerkerk W, Cleland JGF, Angermann CE, ... Lam CSP, Dickstein K
Objectives
The primary aim of the current study was to investigate global differences in prevalence, association with outcome, and treatment of ischemic heart disease (IHD) in patients with acute heart failure (AHF) in the REPORT-HF (International Registry to Assess Medical Practice With Longitudinal Observation for Treatment of Heart Failure) registry.
Background
Data on IHD in patients with AHF are primarily from Western Europe and North America. Little is known about global differences in treatment and prognosis of patients with IHD and AHF.
Methods
A total of 18,539 patients with AHF were prospectively enrolled from 44 countries and 365 centers in the REPORT-HF registry. Patients with a history of coronary artery disease, an ischemic event causing admission for AHF, or coronary revascularization were classified as IHD. Clinical characteristics, treatment, and outcomes of patients with and without IHD were explored.
Results
Compared with 8,766 (47%) patients without IHD, 9,773 (53%) patients with IHD were older, more likely to have a left ventricular ejection fraction <40% (heart failure with reduced ejection fraction [HFrEF]), and reported more comorbidities. IHD was more common in lower income compared with high-income countries (61% vs. 48%). Patients with IHD from countries with low health care expenditure per capita or without health insurance less likely underwent coronary revascularization or used anticoagulants at discharge. IHD was independently associated with worse cardiovascular death (hazard ratio: 1.21; 95% confidence interval: 1.09 to 1.35). The association between IHD and cardiovascular death was stronger in HFrEF compared with heart failure with preserved ejection fraction (pinteraction <0.001).
Conclusions
In this large global contemporary cohort of patients with AHF, IHD was more common in low-income countries and conveyed worse 1-year mortality, especially in HFrEF. Patients in regions with the greatest burden of IHD were less likely to receive coronary revascularization and treatment for IHD.

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

JACC Heart Fail: 01 Apr 2021; epub ahead of print
Tromp J, Ouwerkerk W, Cleland JGF, Angermann CE, ... Lam CSP, Dickstein K
JACC Heart Fail: 01 Apr 2021; epub ahead of print | PMID: 33839078
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Abstract

Worsening Heart Failure Episodes Outside a Hospital Setting in Heart Failure with Preserved Ejection Fraction: The PARAGON-HF Trial.

Vaduganathan M, Cunningham JW, Claggett BL, Causland FM, ... Solomon S, Desai AS
Objectives
To evaluate the frequency and prognostic implications of urgent heart failure (HF) visits in a large global clinical trial of HF with preserved ejection fraction (HFpEF).
Background
Episodes of worsening HF managed without hospitalization are common and prognostically important in HF with reduced ejection fraction (EF). The significance of these ambulatory worsening HF events in HFpEF is uncertain.
Methods
PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) randomly assigned 4,796 patients with HFpEF (≥45%) to treatment with sacubitril/valsartan vs. valsartan with a primary composite endpoint of total HF hospitalizations and cardiovascular death. Urgent ambulatory HF visits requiring intravenous diuretic treatment were prospectively collected and adjudicated by a blinded committee. We examined the effect of study treatment on a prespecified expanded composite of cardiovascular death and worsening HF events (including HF hospitalizations and urgent HF visits) and the effect of each type of HF event on subsequent mortality.
Results
Of 884 first worsening HF events, 66 (7.5%) were urgent HF visits. Patients whose first episode of worsening HF event was an urgent visit had similar age, comorbidities, baseline N-terminal prohormone of B-type natriuretic peptide, and Meta-Analysis Global Group in Chronic Heart Failure risk scores to those in whom the first HF event was a hospitalization (all comparisons p > 0.05). Regardless of the treatment setting, patients with a first episode of worsening HF had higher rates of subsequent death (19.2 per 100 patient-years; 95% confidence interval [CI]: 16.9 to 21.8 for HF hospitalization and 10.1 per 100 patients-years; 95% CI: 5.4 to 18.7 for urgent HF visit) compared with those who did not experience worsening HF (death rate 4.0 per 100 patient-years; 95% CI: 3.6 to 4.4). Including total urgent HF visits in the composite study endpoint added 95 total events and would have shortened the trial duration needed for event accrual. The addition of urgent HF visits in a prespecified composite endpoint reinforced the treatment efficacy of sacubitril/valsartan compared with valsartan (rate ratio 0.86; 95% CI: 0.75 to 0.99; p = 0.040).
Conclusions
Like HF hospitalizations, worsening HF events treated in the ambulatory setting are prognostically important in HFpEF. Inclusion of these events in the composite primary endpoint underscores the benefit of sacubitril/valsartan compared with valsartan in PARAGON-HF. (Prospective Comparison of ARNI with ARB 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: 01 Apr 2021; epub ahead of print
Vaduganathan M, Cunningham JW, Claggett BL, Causland FM, ... Solomon S, Desai AS
JACC Heart Fail: 01 Apr 2021; epub ahead of print | PMID: 33839075
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Abstract

Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF.

Ferreira JP, Verdonschot J, Wang P, Pizard A, ... Zannad F, HOMAGE (Heart Omics in AGEing) Consortium
Objectives
This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.
Background
In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.
Methods
Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis.
Results
A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care (\"control\"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).
Conclusions
Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450).

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

JACC Heart Fail: 30 Mar 2021; 9:268-277
Ferreira JP, Verdonschot J, Wang P, Pizard A, ... Zannad F, HOMAGE (Heart Omics in AGEing) Consortium
JACC Heart Fail: 30 Mar 2021; 9:268-277 | PMID: 33549556
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Abstract

Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists: An Analysis of DAPA-HF.

Shen L, Kristensen SL, Bengtsson O, Böhm M, ... Jhund PS, McMurray JJV
Objectives
The purpose of this study was to assess the efficacy and safety of dapagliflozin in patients taking or not taking an mineralocorticoid receptor antagonist (MRA) at baseline in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.
Background
MRAs and sodium glucose co-transporter 2 inhibitors each have diuretic activity, lower blood pressure, and reduce glomerular filtration rate (GFR). Therefore, it is important to investigate the safety, as well as efficacy, of their combination.
Methods
A total of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) were randomized to placebo or dapagliflozin 10 mg daily. The efficacy of dapagliflozin on the primary composite outcome (cardiovascular death or episode of worsening heart failure) and its components was examined according to MRA use, as were predefined safety outcomes.
Results
A total of 3,370 patients (71%) were treated with an MRA and they were younger (65 vs. 69 years of age), less often from North America (9% vs. 26%), had worse New York Heart Association functional class (35% vs. 25% in class III/IV), lower left ventricular ejection fraction (30.7% vs. 31.9%) and systolic blood pressure (120.3 vs. 125.5 mm Hg), but higher estimated GFR (67.1 vs. 62.6 ml/min/1.73 m2), than patients not taking an MRA. The benefit of dapagliflozin compared with placebo was similar in patients taking or not taking an MRA: hazard ratio: 0.74 (95% confidence interval [CI]: 0.63 to 0.87) versus 0.74 (95% CI: 0.57 to 0.95), respectively, for the primary endpoint (p value for interaction = 0.97); similar findings were observed for secondary endpoints. In both MRA subgroups, safety outcomes were similar in patients randomized to dapagliflozin or placebo.
Conclusions
Dapagliflozin was similarly efficacious and safe in patients with HFrEF taking or not taking an MRA, supporting the use of both drugs together. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).

Copyright © 2021. Published by Elsevier Inc.

JACC Heart Fail: 30 Mar 2021; 9:254-264
Shen L, Kristensen SL, Bengtsson O, Böhm M, ... Jhund PS, McMurray JJV
JACC Heart Fail: 30 Mar 2021; 9:254-264 | PMID: 33549554
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Abstract

Splanchnic Nerve Block Mediated Changes in Stressed Blood Volume in Heart Failure.

Fudim M, Patel MR, Boortz-Marx R, Borlaug BA, ... Sunagawa K, Burkhoff D
Objectives
The authors estimated changes of stressed blood volume (SBV) induced by splanchnic nerve block (SNB) in patients with either decompensated or ambulatory heart failure with reduced ejection fraction (HFrEF).
Background
The splanchnic vascular capacity is a major determinant of the SBV, which in turn determines cardiac filling pressures and may be modifiable through SNB.
Methods
We analyzed data from 2 prospective, single-arm clinical studies in decompensated HFrEF (splanchnic HF-1; resting hemodynamics) and ambulatory heart failure (splanchnic HF-2; exercise hemodynamics). Patients underwent invasive hemodynamics and short-term SNB with local anesthetics. SBV was simulated using heart rate, cardiac output, central venous pressure, pulmonary capillary wedge pressure, systolic and diastolic systemic arterial and pulmonary artery pressures, and left ventricular ejection fraction. SBV is presented as ml/70 kg body weight.
Results
Mean left ventricular ejection fraction was 21 ± 11%. In patients with decompensated HFrEF (n = 11), the mean estimated SBV was 3,073 ± 251 ml/70 kg. At 30 min post-SNB, the estimated SBV decreased by 10% to 2,754 ± 386 ml/70 kg (p = 0.003). In ambulatory HFrEF (n = 14) patients, the mean estimated SBV was 2,664 ± 488 ml/70 kg and increased to 3,243 ± 444 ml/70 kg (p < 0.001) at peak exercise. The resting estimated SBV was lower in ambulatory patients with HFrEF than in decompensated HFrEF (p = 0.019). In ambulatory patients with HFrEF, post-SNB, the resting estimated SBV decreased by 532 ± 264 ml/70 kg (p < 0.001). Post-SNB, with exercise, there was no decrease of estimated SBV out of proportion to baseline effects (p = 0.661).
Conclusions
The estimated SBV is higher in decompensated than in ambulatory heart failure. SNB reduced the estimated SBV in decompensated and ambulatory heart failure. The reduction in estimated SBV was maintained throughout exercise. (Splanchnic Nerve Anesthesia in Heart Failure, NCT02669407; Abdominal Nerve Blockade in Chronic Heart Failure, NCT03453151).

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

JACC Heart Fail: 30 Mar 2021; 9:293-300
Fudim M, Patel MR, Boortz-Marx R, Borlaug BA, ... Sunagawa K, Burkhoff D
JACC Heart Fail: 30 Mar 2021; 9:293-300 | PMID: 33714749
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Abstract

Thromboembolism in Heart Failure Patients in Sinus Rhythm: Epidemiology, Pathophysiology, Clinical Trials, and Future Direction.

Lin AY, Dinatolo E, Metra M, Sbolli M, ... Butler J, Greenberg BH
Despite advances in medical and device therapy, patients with heart failure remain at high risk for morbidity and mortality. Experimental and clinical studies have shown an association between heart failure and a hypercoagulable state, and that patients with heart failure experience an increased incidence of stroke and other thromboembolic events, regardless of whether they are in atrial fibrillation. Although oral anticoagulation is recommended when atrial fibrillation is present, the benefits of this therapy in patients with heart failure in sinus rhythm are uncertain. Older randomized controlled trials comparing warfarin with antiplatelet therapy were, for the most part, underpowered and failed to show convincing benefits of warfarin therapy in this population. Several recent studies that assessed the effects of low-dose direct-acting oral anticoagulant therapy in patients with coronary artery disease in sinus rhythm either included or specifically targeted patients with heart failure. Post hoc analysis of their results showed that this treatment strategy was associated with improved outcomes in patients with acute coronary syndrome or stable coronary artery disease and also a significant reduction in thromboembolic events, including ischemic stroke. This review presents the rationale for anticoagulant therapy in patients with heart failure in sinus rhythm, discusses gaps in our knowledge base, offers suggestions for when anticoagulation might be considered, and identifies potential directions for future research.

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

JACC Heart Fail: 30 Mar 2021; 9:243-253
Lin AY, Dinatolo E, Metra M, Sbolli M, ... Butler J, Greenberg BH
JACC Heart Fail: 30 Mar 2021; 9:243-253 | PMID: 33714744
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Abstract

ECMO as a Bridge to Left Ventricular Assist Device or Heart Transplantation.

DeFilippis EM, Clerkin K, Truby LK, Francke M, ... Uriel N, Topkara VK
Objectives
The purpose of this study was to compare outcomes between patients on extracorporeal membrane oxygenation (ECMO) bridged to left ventricular assist device (LVAD) versus heart transplantation (HT) using registry data.
Background
Patients with heart failure supported with ECMO represent the highest priority in the new HT allocation system. For patients on ECMO, bridging to LVAD may be non-inferior compared with bridging to HT.
Methods
Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) from 2006 to 2017 and United Network for Organ Sharing (UNOS) database from 2006 to June 2019 requiring ECMO were included. Cause-specific hazard models were created and cumulative incidence functions were calculated with mortality, transplantation, and re-transplantation as competing events.
Results
A total of 906 patients received ECMO as bridge to VAD (n = 587, 64.8%) or as bridge to HT (n = 319, 35.2%). Patients bridged directly to HT were younger (age 46.3 ± 15.4 years vs. 52.1 ± 13.2 years; p < 0.001) and more likely to be female (93 [29.2%] vs. 139 [23.7%]; p = 0.022). Patients bridged directly to HT were more likely to have a nonischemic cardiomyopathy, restrictive physiologies, and allograft failure; (p < 0.05 for all). ECMO use increased over time in both UNOS and INTERMACS. There was no significant difference in mortality between groups (Gray\'s p = 0.581). This remained true even when the analysis was restricted to transplant-listed or eligible patients as well as patients with dilated phenotypes (excluding patients with congenital heart disease, restrictive phenotypes, and allograft failure).
Conclusions
There was no difference in mortality on pump support compared with posttransplant mortality among those bridged from ECMO to LVAD or HT.

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

JACC Heart Fail: 30 Mar 2021; 9:281-289
DeFilippis EM, Clerkin K, Truby LK, Francke M, ... Uriel N, Topkara VK
JACC Heart Fail: 30 Mar 2021; 9:281-289 | PMID: 33714743
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Abstract

Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study).

Anthony C, Imran M, Pouliopoulos J, Emmanuel S, ... Macdonald P, Jabbour A
Objectives
This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT).
Background
Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs.
Methods
In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection.
Results
Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 μg/l vs. 8.6 ± 2.8 μg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 μg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = -13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = -2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = -32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 μmol/l vs. 9 ± 21.8 μmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups.
Conclusions
The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 30 Mar 2021; 9:301-313
Anthony C, Imran M, Pouliopoulos J, Emmanuel S, ... Macdonald P, Jabbour A
JACC Heart Fail: 30 Mar 2021; 9:301-313 | PMID: 33795116
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Abstract

Sex Differences in Clinical Course and Patient-Reported Outcomes Among Patients Hospitalized for Heart Failure.

Blumer V, Greene SJ, Wu A, Butler J, ... O\'Connor CM, Mentz RJ
Objectives
The goal of this study was to evaluate differences in clinical and patient-reported outcomes between women and men hospitalized for acute HF.
Background
Among patients hospitalized for heart failure (HF), it is unclear if symptom burden, response to therapy, and patient-reported quality of life (QOL) are different in women as compared with men.
Methods
The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized 7,141 patients hospitalized for HF with reduced or preserved ejection fraction (EF) to receive nesiritide or placebo in addition to standard care. Clinical endpoints included 30-day mortality and rehospitalization and 180-day mortality. Patient-reported QOL was assessed at baseline, discharge, and 30 days using the EuroQOL 5 dimensions (EQ-5D) survey.
Results
Among 7,141 total patients, 4,697 (65.8%) were men and 2,444 (34.2%) were women. Among patients with EF ≤40%, women were less likely to receive angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker and beta-blocker therapy, and less likely to have an implantable cardioverter-defibrillator (all p < 0.03). Signs and symptoms of HF were similar between men and women (all p > 0.05), but women experienced less in-hospital weight loss and urine output (all p < 0.01). In unadjusted and adjusted analyses, men and women had similar risk of all mortality and rehospitalization endpoints (all p ≥ 0.41). Women reported lower EQ-5D utility and visual analogue scores at admission, discharge, and 30 days. Women continued to have significantly lower EQ-5D scores at all in-hospital and post-discharge time points after adjustment for clinical characteristics (all p < 0.01).
Conclusions
In this acute HF population, women had similar risk of mortality and rehospitalization as compared with men, but experienced worse patient-reported QOL during and after hospitalization that persisted after adjustment for demographic and clinical factors. Current acute HF management may work similarly in either sex for purposes of preventing clinical events, but may be less equipped to improve patient-reported outcomes in women as compared with men.

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

JACC Heart Fail: 09 Mar 2021; epub ahead of print
Blumer V, Greene SJ, Wu A, Butler J, ... O'Connor CM, Mentz RJ
JACC Heart Fail: 09 Mar 2021; epub ahead of print | PMID: 33714746
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Abstract

Pragmatic Design of Randomized Clinical Trials for Heart Failure: Rationale and Design of the TRANSFORM-HF Trial.

Greene SJ, Velazquez EJ, Anstrom KJ, Eisenstein EL, ... Mentz RJ, TRANSFORM-HF Investigators
Randomized clinical trials are the foundation of evidence-based medicine and central to practice guidelines and patient care decisions. Nonetheless, randomized trials in heart failure (HF) populations have become increasingly difficult to conduct and are frequently associated with slow patient enrollment, highly selected populations, extensive data collection, and high costs. The traditional model for HF trials has become particularly difficult to execute in the United States, where challenges to site-based research have frequently led to modest U.S. representation in global trials. In this context, the TRANSFORM-HF (Torsemide Comparison with Furosemide for Management of Heart Failure) trial aims to overcome traditional trial challenges and compare the effects of torsemide versus furosemide among patients with HF in the United States. Loop diuretic agents are regularly used by most patients with HF and practice guidelines recommend optimal use of diuretic agents as key to a successful treatment strategy. Long-time clinical experience has contributed to dominant use of furosemide for loop diuretic therapy, although preclinical and small clinical studies suggest potential advantages of torsemide. However, due to the lack of appropriately powered clinical outcome studies, there is insufficient evidence to conclude that torsemide should be routinely recommended over furosemide. Given this gap in knowledge and the fundamental role of loop diuretic agents in HF care, the TRANSFORM-HF trial was designed as a prospective, randomized, event-driven, pragmatic, comparative-effectiveness study to definitively compare the effect of a treatment strategy of torsemide versus furosemide on long-term mortality, hospitalization, and patient-reported outcomes among patients with HF. (TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure [TRANSFORM-HF]; NCT03296813).

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 09 Mar 2021; epub ahead of print
Greene SJ, Velazquez EJ, Anstrom KJ, Eisenstein EL, ... Mentz RJ, TRANSFORM-HF Investigators
JACC Heart Fail: 09 Mar 2021; epub ahead of print | PMID: 33714745
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Abstract

Changes in Use of Left Ventricular Assist Devices as Bridge to Transplantation With New Heart Allocation Policy.

Mullan CW, Chouairi F, Sen S, Mori M, ... Desai NR, Ahmad T
Objectives
The goal of this study was to describe outcomes of patients with bridge to heart transplantation (BTT) after changes were made to the donor heart allocation system.
Background
Left ventricular assist devices (LVADs) have been used as a BTT. On October 18, 2018, the donor heart allocation system in the United States was updated.
Methods
This study identified adults in the United Network for Organ Sharing database with durable, continuous-flow LVAD at listing or implanted while listed between April 2017 and April 2020. Baseline recipient and donor characteristics, waitlist survival, and post-transplantation outcomes were compared pre- and post-allocation system change.
Results
A total of 1,794 patients met inclusion criteria: 983 in the pre-change period and 814 afterward. The number of patients listed with LVAD decreased nationally over time from 102 in April 2017 to 12 in April 2020 (p < 0.001). The proportion of patients with LVAD at time of transplant decreased from 47% to 14%. Before the change, the majority were Status 1A (75.8%) at transplantation; afterward, most were Status 2/3 (67.8%). Transplantation rates were not different (85.4% vs. 83.6%; p = 0.225), but waitlist time decreased in the post period (82 vs. 65 days; p = 0.004). Donors were more likely to be high risk (39.0% vs. 32.2%; p = 0.005), and both ischemic times and distance traveled increased (3.4 h vs. 3.1 h; p < 0.001; 199 miles vs. 82 miles; p < 0.001). Waitlist survival did not change, but post-transplantation survival was worse in patients with BTT post-change (p < 0.001).
Conclusions
The number of patients with BTT on the transplant list decreased steadily and dramatically after the allocation system change. Although time to transplant decreased, there was an increase in post-transplant mortality. These data suggest that the risks and benefits of LVAD implantation as a BTT have changed under the new allocation system and that the appropriate indication for this treatment strategy warrants a re-evaluation.

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

JACC Heart Fail: 06 Mar 2021; epub ahead of print
Mullan CW, Chouairi F, Sen S, Mori M, ... Desai NR, Ahmad T
JACC Heart Fail: 06 Mar 2021; epub ahead of print | PMID: 33714748
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Impact:
Abstract

Burden of Heart Failure Signs and Symptoms, Prognosis, and Response to Therapy: The PARAGON-HF Trial.

Jering K, Claggett B, Redfield MM, Shah SJ, ... McMurray JJV, Solomon SD
Objectives
This study investigated the prognostic importance of heart failure (HF) signs and symptoms in patients with heart failure and preserved ejection fraction (HFpEF), and the effect of sacubitril/valsartan on HF signs and symptoms.
Background
In patients with HFpEF, worsening of HF symptoms, as a marker of cardiac decompensation, is frequently the reason for hospitalization. In this heterogenous disease entity, the prognostic value of HF signs and symptoms with regard to cardiovascular (CV) outcomes is poorly defined.
Methods
The authors examined the association between baseline HF signs and symptoms (rest dyspnea, exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, edema, jugular venous distension, rales, and third heart sound) as well as burden of these HF signs and symptoms (classified as ≤2 and ≥3 HF signs and symptoms) and the primary composite of total HF hospitalizations and CV death, its components, and all-cause death in 4,725 patients enrolled in PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HFpEF) with available signs and symptoms at randomization. Response to sacubitril/valsartan on the basis of the presence of signs and symptoms was evaluated. Effects of sacubitril/valsartan on signs and symptoms over time were assessed using binary repeated-measures logistic regression.
Results
Patients with high (≥3) burden of HF signs and symptoms (n = 1,772 [38%]) were more commonly women, had slightly lower left ventricular ejection fractions, higher body mass index, and more advanced New York Heart Association functional class compared with patients with low (≤2) burden (n = 2,953 [62%]) (p < 0.001 for all). Levels of N-terminal pro-B-type natriuretic peptide did not differ significantly between groups (p = 0.14). Greater burden of signs and symptoms was associated with higher risk for total HF hospitalizations and CV death (rate ratio [RR]: 1.50; 95% confidence interval [CI]: 1.30 to 1.74) and all-cause death (RR: 1.41; 95% CI: 1.21 to 1.65). Among individual signs and symptoms, orthopnea (RR: 1.29; 95% CI: 1.04 to 1.61) and rales (RR: 1.52; 95% CI: 1.10 to 2.10) were most predictive of the primary endpoint. Treatment response to sacubitril/valsartan was not significantly modified by burden of HF signs and symptoms (p for interaction = 0.08), though patients with orthopnea appeared to derive greater benefit from sacubitril/valsartan (RR: 0.67; 95% CI: 0.49 to 0.90) than those without orthopnea (RR: 0.97; 95% CI: 0.82 to 1.14; p for interaction = 0.04). Compared with valsartan, sacubitril/valsartan did not significantly decrease overall burden of HF signs and symptoms over time (odds ratio: 0.84; 95% CI: 0.67 to 1.07) but did reduce exertional dyspnea (odds ratio: 0.76; 95% CI: 0.63 to 0.93).
Conclusions
High burden of HF signs and symptoms, particularly the presence of orthopnea and rales, portends a higher risk for adverse CV events in patients with HF with preserved ejection fraction. Sacubitril/valsartan did not significantly decrease the burden of HF signs and symptoms over time but did reduce exertional dyspnea relative to valsartan. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 04 Mar 2021; epub ahead of print
Jering K, Claggett B, Redfield MM, Shah SJ, ... McMurray JJV, Solomon SD
JACC Heart Fail: 04 Mar 2021; epub ahead of print | PMID: 33714741
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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 © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 27 Feb 2021; 9:179-189
Arora S, Sivaraj K, Hendrickson M, Chang PP, ... Rosamond W, Vavalle JP
JACC Heart Fail: 27 Feb 2021; 9:179-189 | PMID: 33309575
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Impact:
Abstract

Unexpectedly Low Natriuretic Peptide Levels in Patients With Heart Failure.

Bachmann KN, Gupta DK, Xu M, Brittain E, ... Wells QS, Wang TJ
Objectives
The purpose of this study was 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: 27 Feb 2021; 9:192-200
Bachmann KN, Gupta DK, Xu M, Brittain E, ... Wells QS, Wang TJ
JACC Heart Fail: 27 Feb 2021; 9:192-200 | 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: 27 Feb 2021; 9:215-223
Pandey A, Vaduganathan M, Patel KV, Ayers C, ... de Lemos JA, Everett BM
JACC Heart Fail: 27 Feb 2021; 9:215-223 | PMID: 33422434
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Impact:
Abstract

The Impact of Patients With Cardiac Amyloidosis in HFpEF Trials.

Oghina S, Bougouin W, Bézard M, Kharoubi M, ... Damy T, Bodez D
Heart failure with preserved ejection fraction (HFpEF) is an increasingly diagnosed condition whose failure to respond to new drugs effective in heart failure with reduced ejection fraction is of great concern. HFpEF is an incompletely understood and markedly heterogeneous syndrome, but cardiac amyloidosis is increasingly recognized as one of its various causes. The specific hemodynamic and pathophysiological features of cardiac amyloidosis result in poor tolerance of heart failure medications and in worse outcomes compared with other causes. Until recently, patients considered for HFpEF trials were not routinely screened for cardiac amyloidosis. This review examines how real-world patients with cardiac amyloidosis met inclusion criteria for 8 major HFpEF clinical trials, including the recent PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial. This review discusses how the presence in the trial populations of a subset of patients with cardiac amyloidosis might contribute to explain the absence of efficacy of medications for HFpEF in trials so far. A multistep screening strategy is suggested in which patients with red flags for cardiac amyloidosis undergo both a light chain assay and technetium-labeled cardiac scintigraphy (technetium-labeled cardiac scintigraphy scan), which, when negative, rule out cardiac amyloidosis. Using this strategy would allow the testing of new medications for HFpEF in populations containing no patients with cardiac amyloidosis, thus potentially increasing the likelihood of showing therapeutic efficacy, and finally making some effective treatment available.

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

JACC Heart Fail: 27 Feb 2021; 9:169-178
Oghina S, Bougouin W, Bézard M, Kharoubi M, ... Damy T, Bodez D
JACC Heart Fail: 27 Feb 2021; 9:169-178 | PMID: 33549560
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Impact:
Abstract

Predictive Value of Cardiopulmonary Exercise Testing Parameters in Ambulatory Advanced Heart Failure.

Lala A, Shah KB, Lanfear DE, Thibodeau JT, ... Mancini DM, REVIVAL Investigators
Objectives
This study sought to determine cardiopulmonary exercise (CPX) predictors of the combined outcome of durable mechanical circulatory support (MCS), transplantation, or death at 1 year among patients with ambulatory advanced heart failure (HF).
Background
Optimal CPX predictors of outcomes in contemporary ambulatory advanced HF patients are unclear.
Methods
REVIVAL (Registry Evaluation of Vital Information for ventricular assist devices [VADs] in Ambulatory Life) enrolled 400 systolic HF patients, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles 4-7. CPX was performed by 273 subjects 2 ± 1 months after study enrollment. Discriminative power of maximal (peak oxygen consumption [peak VO2]; VO2 pulse, circulatory power [CP]; peak systolic blood pressure • peak VO2], peak end-tidal pressure CO2 [PEtCO2], and peak Borg scale score) and submaximal CPX parameters (ventilatory efficiency [VE/VCO2 slope]; VO2 at anaerobic threshold [VO2AT]; and oxygen uptake efficiency slope [OUES]) to predict the composite outcome were assessed by univariate and multivariate Cox regression and Harrell\'s concordance statistic.
Results
At 1 year, there were 39 events (6 transplants, 15 deaths, 18 MCS implantations). Peak VO2, VO2AT, OUES, peak PEtCO2, and CP were higher in the no-event group (all p < 0.001), whereas VE/VCO2 slope was lower (p < 0.0001); respiratory exchange ratio was not different. CP (hazard ratio [HR]: 0.89; p = 0.001), VE/VCO2 slope (HR: 1.05; p = 0.001), and peak Borg scale score (HR: 1.20; p = 0.005) were significant predictors on multivariate analysis (model C-statistic: 0.80).
Conclusions
Among patients with ambulatory advanced HF, the strongest maximal and submaximal CPX predictor of MCS implantation, transplantation, or death at 1 year were CP and VE/VCO2, respectively. The patient-reported measure of exercise effort (Borg scale score) contributed substantially to the prediction of outcomes, a surprising and novel finding that warrants further investigation. (Registry Evaluation of Vital Information for VADs in Ambulatory Life [REVIVAL]; NCT01369407).

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

JACC Heart Fail: 27 Feb 2021; 9:226-236
Lala A, Shah KB, Lanfear DE, Thibodeau JT, ... Mancini DM, REVIVAL Investigators
JACC Heart Fail: 27 Feb 2021; 9:226-236 | PMID: 33549559
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Impact:
Abstract

Impact of Geographic Region on the COMMANDER-HF Trial.

Ferreira JP, Cleland JGF, Lam CSP, van Veldhuisen DJ, ... Greenberg B, Zannad F
Objectives
This study sought to compare patient characteristics, outcomes, and treatment effects among regions in the COMMANDER-HF trial.
Background
Globalization of cardiovascular trials increases generalizability. However, regional differences may also introduce heterogeneity in results.
Methods
Incidence rates and interactions with treatment were recorded in pre-specified regions: Eastern Europe, Western Europe and South Africa, North America, Asia-Pacific, and Latin America.
Results
Most patients (n = 3,224; 64.2%) were from Eastern Europe; 458 (9.1%) were from Western Europe and South Africa; 149 (3.0%) were from North America; 733 (14.6%) were from Asia-Pacific; and 458 (9.1%) were from Latin America. Compared with patients from Eastern Europe, patients from Western Europe and South Africa, North America, and Asia-Pacific were older and more likely to have coronary interventions and cardiac devices. Patients from Eastern Europe had the lowest event rates. For the primary outcome of myocardial infarction (MI), stroke, or all-cause death, event rates (100/year) were 11.6 in Eastern Europe (10.8 to 12.5); 19.5 (16.5 to 23.0) in Western Europe and South Africa; 14.2 (10.5 to 19.2) in North America; 17.7 (15.4 to 20.3) in Asia-Pacific; and 18.6 (15.6 to 22.1) in Latin America. There was a lower incidence of bleeding in Eastern Europe. Blood concentrations of rivaroxaban (Xarelto, Titusville, New Jersey) at 4 weeks were undetectable in 21% patients from Eastern Europe (n = 128) compared to 5% in other regions (n = 42). There was no evidence of treatment-by-region heterogeneity for the primary outcome (interactionp = 0.14), but a favorable effect on the secondary outcome of MI, stroke, or cardiovascular death was observed in Western Europe and South Africa, North America, and Latin America but not in Eastern Europe and Asia-Pacific (interactionp = 0.017).
Conclusions
In the COMMANDER-HF study, patients from Eastern Europe had a lower risk profile and fewer cardiovascular and bleeding events, possibly related to lower treatment adherence. Those differences might have influenced the effect of rivaroxaban therapy. (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure [COMMANDER HF]; NCT01877915).

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

JACC Heart Fail: 27 Feb 2021; 9:201-211
Ferreira JP, Cleland JGF, Lam CSP, van Veldhuisen DJ, ... Greenberg B, Zannad F
JACC Heart Fail: 27 Feb 2021; 9:201-211 | PMID: 33549557
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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 © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2021; 9:127-136
Murphy SP, Prescott MF, Camacho A, Iyer SR, ... Solomon SD, Januzzi JL
JACC Heart Fail: 30 Jan 2021; 9:127-136 | PMID: 33189632
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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 © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2021; 9:85-95
Gommans DHF, Revuelta-Lopez E, Lupon J, Cserkóová A, ... Bayés-Genis A, van Kimmenade RRJ
JACC Heart Fail: 30 Jan 2021; 9:85-95 | 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 (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 © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2021; 9:100-111
Khayyat-Kholghi M, Oparil S, Davis BR, Tereshchenko LG
JACC Heart Fail: 30 Jan 2021; 9:100-111 | PMID: 33189627
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Impact:
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 © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2021; 9:146-157
Felker GM, McMurray JJV, Cleland JG, O'Connor CM, ... Seiffert D, Ye J
JACC Heart Fail: 30 Jan 2021; 9:146-157 | PMID: 33248986
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Impact:
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 (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure), 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 © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2021; 9:137-145
Khan MS, Felker GM, Piña IL, Camacho A, ... Januzzi JL, Butler J
JACC Heart Fail: 30 Jan 2021; 9:137-145 | PMID: 33309581
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Impact:
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
Objectives
Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), this study aimed to determine whether there is a differential effect between variant transthyretin amyloidosis (ATTRv) and wild-type transthyretin (ATTRwt).
Background
ATTR-CM is a progressive, fatal disorder resulting from mutations in the ATTRv or the deposition of denatured 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 © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 30 Jan 2021; 9:115-123
Rapezzi C, Elliott P, Damy T, Nativi-Nicolau J, ... Sultan MB, Maurer MS
JACC Heart Fail: 30 Jan 2021; 9:115-123 | PMID: 33309574
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Impact:

This program is still in alpha version.