Journal: JACC Heart Fail

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Abstract

Intercountry Differences in Guideline-Directed Medical Therapy and Outcomes Among Patients With Heart Failure.

Fuery MA, Chouairi F, Januzzi JL, Moe GW, ... Ezekowitz J, Desai NR
Objectives
The aim of this study was to examine patterns of care and clinical outcomes among patients with heart failure with reduced ejection fraction (HFrEF) in the United States and Canada.
Background
In the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial, the use of N-terminal pro-B-type natriuretic peptide-guided titration of guideline-directed medical therapy (GDMT) was compared with usual care alone for patients with HFrEF in the United States and Canada. It remains unknown whether the country of enrollment had an impact on outcomes or GDMT use.
Methods
A total of 894 patients at 45 sites across the United States and Canada with HFrEF (ejection fraction ≤40%) were enrolled in the trial. Kaplan-Meier survival estimates stratified by country of enrollment were developed for the trial outcomes, and log-rank testing was compared between the groups. GDMT use and titration were also compared.
Results
U.S. patients were more likely to be younger, to be Black, to have higher body mass index, and to have histories of defibrillator placement or sleep apnea. Use of β-blockers was significantly higher in Canada at baseline (99.3% vs. 94.0%; p = 0.01) and 6 months (99.0% vs. 94.1%; p = 0.04), and use of mineralocorticoid receptor antagonists was higher in Canada at 6 months (68.3% vs. 55.1%; p = 0.01). Canadian patients were less likely to experience the primary study endpoint (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.45 to 0.93; p = 0.01) due to decreased rates of HF hospitalization (HR: 0.57; 95% CI: 0.38 to 0.86; p = 0.003). The differences in outcomes were driven by increased heart failure hospitalization among U.S. Black patients.
Conclusions
In GUIDE-IT, patients with HFrEF in Canada were significantly less likely to be hospitalized for heart failure. Differences in GDMT use, along with differences in sociodemographics and care delivery structures, may contribute to these differences, highlighting the importance of increasing diversity in clinical trials. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

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

JACC Heart Fail: 29 Jun 2021; 9:497-505
Fuery MA, Chouairi F, Januzzi JL, Moe GW, ... Ezekowitz J, Desai NR
JACC Heart Fail: 29 Jun 2021; 9:497-505 | PMID: 33992564
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Abstract

Temporal Trends and Factors Associated With Cardiac Rehabilitation Participation Among Medicare Beneficiaries With Heart Failure.

Pandey A, Keshvani N, Zhong L, Mentz RJ, ... Kitzman DW, Fonarow GC
Objectives
The purpose of this study was to assess temporal trends and factors associated with cardiac rehabilitation (CR) enrollment and participation among Medicare beneficiaries after the 2014 Medicare coverage expansion.
Background
CR improves exercise capacity, quality of life, and clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). In 2014, Medicare coverage for CR was expanded to include chronic HFrEF.
Methods
Among Medicare beneficiaries from quarter (Q) 1 2014 to Q2 2016, 11,696 patients from 14,258 hospitalizations with primary discharge diagnosis of HF were identified. Patients with HF with preserved ejection fraction were excluded. Quarterly CR participation rates among hospitalized HF patients within 6 months of discharge were identified through outpatient administrative claims. The predictors of CR participation were assessed with the use of a multivariable logistic regression model that included patient- and hospital-level characteristics. A secondary analysis to assess participation rates of CR after outpatient encounters for HF was performed.
Results
Overall, only 611 (4.3%) and 349 (2.2%) eligible patients participated CR after primary hospitalization or outpatient visit for HF, respectively. There was a modest, statistically significant increase in CR participation after HF admissions (2.8% in Q1 2014; 5.0% in Q2 2016; p < 0.001) without significant increase after outpatient visits for HF (2.6% to 3.8%; p = 0.21). Younger age, male sex, nonblack race, previous cardiovascular procedures, and hospitalization at hospitals with available CR facilities were all independently associated with CR participation.
Conclusions
CR participation among eligible Medicare beneficiaries with HFrEF was low with minimal increase since 2014 Medicare coverage decision. Sex, race, and institution-dependent variables were independent predictors of CR participation.

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

JACC Heart Fail: 29 Jun 2021; 9:471-481
Pandey A, Keshvani N, Zhong L, Mentz RJ, ... Kitzman DW, Fonarow GC
JACC Heart Fail: 29 Jun 2021; 9:471-481 | PMID: 33992563
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Abstract

Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy.

Jhund PS, Petrie MC, Robertson M, Mark PB, ... Macdougall IC, PIVOTAL Investigators and Committees
Objectives
This study sought to examine the effect of intravenous iron on heart failure events in hemodialysis patients.
Background
Heart failure is a common and deadly complication in patients receiving hemodialysis and is difficult to diagnose and treat.
Methods
The study analyzed heart failure events in the PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) trial, which compared intravenous iron administered proactively in a high-dose regimen with a low-dose regimen administered reactively. Heart failure hospitalization was an adjudicated outcome, a component of the primary composite outcome, and a prespecified secondary endpoint in the trial.
Results
Overall, 2,141 participants were followed for a median of 2.1 years. A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group (HR: 0.66; 95% CI: 0.46-0.94; P = 0.023). There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group, giving a rate ratio of 0.59 (95% CI: 0.40-0.87; P = 0.0084). Most patients presented with pulmonary edema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event.
Conclusions
Compared with a lower-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in patients undergoing hemodialysis, with large relative and absolute risk reductions. (UK Multicentre Open-label Randomised Controlled Trial Of IV Iron Therapy In Incident Haemodialysis Patients; 2013-002267-25).

Copyright © 2021. Published by Elsevier Inc.

JACC Heart Fail: 29 Jun 2021; 9:518-527
Jhund PS, Petrie MC, Robertson M, Mark PB, ... Macdougall IC, PIVOTAL Investigators and Committees
JACC Heart Fail: 29 Jun 2021; 9:518-527 | PMID: 34119470
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Abstract

Heart Rate as a Marker of Relapse During Withdrawal of Therapy in Recovered Dilated Cardiomyopathy.

Halliday BP, Vazir A, Owen R, Gregson J, ... Cleland JGF, Prasad SK
Objectives
The objective of this study was to determine the relationship between heart rate and relapse among patients in the TRED-HF (Therapy withdrawal in REcovered Dilated cardiomyopathy trial).
Background
Understanding markers and mechanisms of relapse among patients with recovered dilated cardiomyopathy (DCM) may enable personalized management.
Methods
The relationship between serial heart rate measurements and relapse was examined among patients in the TRED-HF trial, a randomized trial which examined the safety and feasibility of withdrawing heart failure therapy from 51 patients with recovered DCM over 6 months. In total, 25 patients were randomized to therapy withdrawal and 26 to continue therapy, of whom 25 subsequently began therapy withdrawal in a single arm crossover phase.
Results
The mean ± SD heart rate for those who had therapy withdrawn and did not relapse was 64.6 ± 10.7 beats/min at baseline and 74.7 ± 10.4 beats/min at follow-up, compared to 68.3 ± 11.3 beats/min at baseline and 86.1 ± 11.8 beats/min at follow-up for those who relapsed. After adjusting for differences in heart rate at baseline, patients who had therapy withdrawn and relapsed had a 10.4 beats/min (95% CI: 4.0-16.8) greater rise in heart rate than patients who had therapy withdrawn and did not relapse (P = 0.002). After data were adjusted for age, log N-terminal pro-B-type natriuretic peptide, and left ventricular ejection fraction (LVEF), heart rate (per 10 beats/min; hazard ratio [HR]: 1.65; 95% CI: 1.10-2.57; P = 0.01) and change in heart rate from baseline (per 10 beats/min; HR: 1.70; 95% CI: 1.12-2.57; p = 0.01) were associated with relapse. The results remained qualitatively the same after adjusting for beta-blocker dose.
Conclusions
For patients with DCM and improved LVEF, the rise in heart rate after treatment is withdrawn treatment identifies patients who are more likely to relapse. Whether the increase in heart rate is a marker or a mediator of relapse requires investigation. (Therapy withdrawal in REcovered Dilated cardiomyopathy trial [TRED]; NCT02859311).

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

JACC Heart Fail: 29 Jun 2021; 9:509-517
Halliday BP, Vazir A, Owen R, Gregson J, ... Cleland JGF, Prasad SK
JACC Heart Fail: 29 Jun 2021; 9:509-517 | PMID: 34119469
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Abstract

Physical Activity, Subclinical Myocardial Injury, and Risk of Heart Failure Subtypes in Black Adults.

Patel KV, Simek S, Ayers C, Neeland IJ, ... Berry JD, Pandey A
Objectives
This study sought to evaluate the independent associations and interactions between high-sensitivity cardiac troponin I (hs-cTnI) and physical activity (PA) with risk of heart failure (HF) subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF).
Background
Black adults are at high risk for developing HF. Physical inactivity and subclinical myocardial injury, as assessed by hs-cTnI concentration, are independent risk factors for HF.
Methods
Black adults from the Jackson Heart Study without prevalent HF who had hs-cTnI concentration and self-reported PA assessed at baseline were included. Adjusted Cox models were used to evaluate the independent and joint associations and interaction between hs-cTnI concentrations and PA with risk of HFpEF and HFrEF.
Results
Among 3,959 participants, 25.1% had subclinical myocardial injury (hs-cTnI ≥4 and ≥6 ng/l in women and men, respectively), and 48.2% were inactive (moderate-to-vigorous PA = 0 min/week). Over 12.0 years of follow-up, 163 and 150 participants had an incident HFpEF and HFrEF event, respectively. In adjusted analysis, higher hs-cTnI concentration (per 1-U log increase) was associated with higher risk of HFpEF (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.25 to 1.72]) and HFrEF (HR: 1.57; 95% CI: 1.35 to 1.83]). In contrast, higher PA (per 1-U log increase) was associated with a lower risk of HFpEF (HR: 0.93; 95% CI: 0.88 to 0.99]) but not HFrEF. There was a significant interaction between hs-cTnI and PA for risk of HFpEF (p interaction = 0.04) such that inactive participants with subclinical myocardial injury were at higher risk of HFpEF but active participants were not.
Conclusions
Among Black adults with subclinical myocardial injury, higher levels of PA were associated with attenuated risk of HFpEF.

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

JACC Heart Fail: 29 Jun 2021; 9:484-493
Patel KV, Simek S, Ayers C, Neeland IJ, ... Berry JD, Pandey A
JACC Heart Fail: 29 Jun 2021; 9:484-493 | PMID: 34119468
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Abstract

Lung Ultrasound-Guided Emergency Department Management of Acute Heart Failure (BLUSHED-AHF): A Randomized Controlled Pilot Trial.

Pang PS, Russell FM, Ehrman R, Ferre R, ... Li X, Collins SP
Objectives
The goal of this study was to determine whether a 6-h lung ultrasound (LUS)-guided strategy-of-care improves pulmonary congestion over usual management in the emergency department (ED) setting. A secondary goal was to explore whether early targeted intervention leads to improved outcomes.
Background
Targeting pulmonary congestion in acute heart failure remains a key goal of care. LUS B-lines are a semi-quantitative assessment of pulmonary congestion. Whether B-lines decrease in patients with acute heart failure by targeting therapy is not well known.
Methods
A multicenter, single-blind, ED-based, pilot trial randomized 130 patients to receive a 6-h LUS-guided treatment strategy versus structured usual care. Patients were followed up throughout hospitalization and 90 days\' postdischarge. B-lines ≤15 at 6 h was the primary outcome, and days alive and out of hospital (DAOOH) at 30 days was the main exploratory outcome.
Results
No significant difference in the proportion of patients with B-lines ≤15 at 6 h (25.0% LUS vs 27.5% usual care; P = 0.83) or the number of B-lines at 6 h (35.4 ± 26.8 LUS vs 34.3 ± 26.2 usual care; P = 0.82) was observed between groups. There were also no differences in DAOOH (21.3 ± 6.6 LUS vs 21.3 ± 7.1 usual care; P = 0.99). However, a significantly greater reduction in the number of B-lines was observed in LUS-guided patients compared with those receiving usual structured care during the first 48 h (P = 0.04).
Conclusions
In this pilot trial, ED use of LUS to target pulmonary congestion conferred no benefit compared with usual care in reducing the number of B-lines at 6 h or in 30 d\' DAOOH. However, LUS-guided patients had faster resolution of congestion during the initial 48 h. (B-lines Lung Ultrasound-Guided ED Management of Acute Heart Failure Pilot Trial; NCT03136198).

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

JACC Heart Fail: 28 Jun 2021; epub ahead of print
Pang PS, Russell FM, Ehrman R, Ferre R, ... Li X, Collins SP
JACC Heart Fail: 28 Jun 2021; epub ahead of print | PMID: 34246609
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Abstract

NT-proBNP for Risk Prediction in Heart Failure: Identification of Optimal Cutoffs Across Body Mass Index Categories.

Vergaro G, Gentile F, Meems LMG, Aimo A, ... de Boer RA, Emdin M
Objectives
The goal of this study was to assess the predictive power of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories.
Background
Concentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain.
Methods
Individual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), and mildly (BMI 30-34.9 kg/m2), moderately (BMI 35-39.9 kg/m2), or severely (BMI ≥40 kg/m2) obese. The prognostic role of NT-proBNP was tested for the endpoints of all-cause and cardiac death.
Results
The study population included 12,763 patients (mean age 66 ± 12 y; 25% women; mean left ventricular ejection fraction 33% ± 13%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (β = -0.174 for 1 kg/m2; P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-y all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men.
Conclusions
NT-proBNP maintains its independent prognostic value up to 40 kg/m2 BMI, and lower optimal risk-prediction cutoffs are observed in overweight and obese patients.

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

JACC Heart Fail: 28 Jun 2021; epub ahead of print
Vergaro G, Gentile F, Meems LMG, Aimo A, ... de Boer RA, Emdin M
JACC Heart Fail: 28 Jun 2021; epub ahead of print | PMID: 34246607
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Abstract

Prognostic Value of Urinary and Plasma C-Type Natriuretic Peptide in Acute Decompensated Heart Failure.

Ma X, Chen Y, Reginauld SH, Scott CG, ... Burnett JC, Sangaralingham SJ
Objectives
This study sought to characterize urinary and plasma C-type natriuretic peptide (CNP) in acute decompensated heart failure (ADHF) to define their relationship with clinical variables and to determine whether urinary and plasma CNP together add prognostic value.
Background
CNP is a protective hormone that is synthesized in the kidney and endothelium and possesses antiremodeling properties. Urinary and plasma CNP levels are elevated in pathophysiological conditions; however, their regulation and prognostic value in heart failure (HF) is unclear.
Methods
Urinary and plasma CNP were measured in 109 healthy subjects and 208 patients with ADHF; the 95th percentile of CNP values from healthy subjects established the normal contemporary cutoffs. Patients with ADHF were stratified based on urinary and plasma CNP levels for clinical characterization and the assessment of risk for adverse outcomes.
Results
There was no significant correlation between urinary and plasma CNP in both cohorts. Urinary and plasma CNP were significantly elevated in patients with ADHF, and both increased with disease severity and were positively correlated with plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP). Of the patients with ADHF, 23% had elevations in both urinary and plasma CNP, whereas 24% had normal CNP levels. During a median follow-up of 3 years, patients with elevated urinary and plasma CNP had a significantly higher risk of rehospitalization and/or death (HR: 1.79; P = 0.03) and rehospitalization (HR: 2.16; P = 0.01) after adjusting for age, sex, left ventricular ejection fraction, renal function, and plasma NT-proBNP. The C-statistic and integrated discrimination analyses further supported that the addition of urinary and plasma CNP to established risk models improved the prediction of adverse outcomes in patients with ADHF.
Conclusions
Urinary and plasma CNP are differentially regulated in ADHF, and elevations in both provided independent prognostic value for predicting adverse outcomes.

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

JACC Heart Fail: 28 Jun 2021; epub ahead of print
Ma X, Chen Y, Reginauld SH, Scott CG, ... Burnett JC, Sangaralingham SJ
JACC Heart Fail: 28 Jun 2021; epub ahead of print | PMID: 34246604
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Abstract

Integrating High-Sensitivity Troponin T and Sacubitril/Valsartan Treatment in HFpEF: The PARAGON-HF Trial.

Gori M, Senni M, Claggett B, Liu J, ... McMurray JJV, Solomon SD
Objectives
The authors examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF).
Background
hs-TnT is a marker of myocardial injury in HF.
Methods
The PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT.
Results
hs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT >14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro b-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P < 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P < 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (>17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07).
Conclusions
Higher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan.

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

JACC Heart Fail: 28 Jun 2021; epub ahead of print
Gori M, Senni M, Claggett B, Liu J, ... McMurray JJV, Solomon SD
JACC Heart Fail: 28 Jun 2021; epub ahead of print | PMID: 34246603
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Abstract

Rehabilitation Intervention in Older Patients With Acute Heart Failure With Preserved Versus Reduced Ejection Fraction.

Mentz RJ, Whellan DJ, Reeves GR, Pastva AM, ... O\'Connor CM, Kitzman DW
Objectives
This study assessed for treatment interactions by ejection fraction (EF) subgroup (≥45% [preserved EF (HFpEF); vs <45% [reduced EF; (HFrEF)]).
Background
The REHAB-HF trial showed that an early multidomain rehabilitation intervention improved physical function, frailty, quality-of-life, and depression in older patients hospitalized with acute decompensated heart failure (ADHF).
Methods
Three-month outcomes were: Short Physical Performance Battery (SPPB), 6-min walk distance (6MWD), and Kansas City Cardiomyopathy Questionnaire (KCCQ). Six-month end points included all-cause rehospitalization and death and a global rank of death, all-cause rehospitalization, and SPPB. Prespecified significance level for interaction was P ≤ 0.1.
Results
Among 349 total participants, 185 (53%) had HFpEF and 164 (47%) had HFrEF. Compared with HFrEF, HFpEF participants were more often women (61% vs 43%) and had significantly worse baseline physical function, frailty, quality of life, and depression. Although interaction P values for 3-month outcomes were not significant, effect sizes were larger for HFpEF vs HFrEF: SPPB +1.9 (95% CI: 1.1-2.6) vs +1.1 (95% CI: 0.3-1.9); 6MWD +40 meters (95% CI: 9 meters-72 meters) vs +27 (95% CI: -6 meters to 59 meters); KCCQ +9 (2-16) vs +6 (-2 to 14). All-cause rehospitalization rate was nominally lower with intervention in HFpEF but not HFrEF [effect size 0.83 (95% CI: 0.64-1.09) vs 0.99 (95% CI: 0.74-1.33); interaction P = 0.40]. There were significantly greater treatment benefits in HFpEF vs HFrEF for all-cause death [interaction P = 0.08; intervention rate ratio 0.63 (95% CI: 0.25-1.61) vs 2.21 (95% CI: 0.78-6.25)], and the global rank end point (interaction P = 0.098) with benefit seen in HFpEF [probability index 0.59 (95% CI: 0.50-0.68)] but not HFrEF.
Conclusions
Among older patients hospitalized with ADHF, compared with HFrEF those with HFpEF had significantly worse impairments at baseline and may derive greater benefit from the intervention. (A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).

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

JACC Heart Fail: 28 Jun 2021; epub ahead of print
Mentz RJ, Whellan DJ, Reeves GR, Pastva AM, ... O'Connor CM, Kitzman DW
JACC Heart Fail: 28 Jun 2021; epub ahead of print | PMID: 34246602
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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: 30 May 2021; 9:420-429
Mullan CW, Chouairi F, Sen S, Mori M, ... Desai NR, Ahmad T
JACC Heart Fail: 30 May 2021; 9:420-429 | PMID: 33714748
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Abstract

The Addition of a Defibrillator to Resynchronization Therapy Decreases Mortality in Patients With Nonischemic Cardiomyopathy.

Doran B, Mei C, Varosy PD, Kao DP, ... DeMets D, Bristow MR
Objectives
The aim of this study was to determine whether patients with heart failure with reduced ejection fraction (HFrEF) due to nonischemic etiology eligible for cardiac resynchronization therapy (CRT) benefit from an implantable cardioverter-defibrillator (ICD).
Background
It is uncertain whether CRT with an ICD (CRT-D) compared to without an ICD (CRT-P) is associated with a survival benefit in patients with nonischemic etiologies of HFrEF.
Methods
Analyses of the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial were performed, using Cox proportional hazards modeling stratified by HFrEF etiology of nonischemic cardiomyopathy (NICM) or ischemic cardiomyopathy (ICM). The primary outcome was all-cause mortality (ACM), and secondary outcomes were the combination of cardiovascular mortality or heart failure hospitalization and sudden cardiac death.
Results
Among patients randomized to CRT (n = 1,212), 236 (19.5%) died, 131 and 105 in the CRT-P and CRT-D arms, respectively. The unadjusted and adjusted hazard ratios (HRs) for CRT-D versus CRT-P were both 0.84 (95% confidence interval [CI]: 0.65 to 1.09) for ACM, with a significant device-etiology interaction (pinteraction = 0.015 adjusted; pinteraction = 0.040 unadjusted). In patients with NICM (n = 555), CRT-D versus CRT-P was associated with reduced ACM (adjusted HR: 0.54; 95% CI: 0.34 to 0.86), while patients with ICM (n = 657) did not exhibit a between-device reduction in ACM (adjusted HR: 1.05; 95% CI: 0.77 to 1.44). The effects of CRT-D versus CRT-P on sudden cardiac death (advantage CRT-D) and cardiovascular mortality or heart failure hospitalization (no difference between CRT-P and CRT-D) were similar between the 2 HFrEF etiologies.
Conclusions
COMPANION patients with NICM exhibited a decrease in ACM associated with CRT-D but not CRT-P treatment, whereas patients with ICM did not.

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

JACC Heart Fail: 30 May 2021; 9:439-449
Doran B, Mei C, Varosy PD, Kao DP, ... DeMets D, Bristow MR
JACC Heart Fail: 30 May 2021; 9:439-449 | PMID: 33992570
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Impact:
Abstract

REVeAL-HF: Design and Rationale of a Pragmatic Randomized Controlled Trial Embedded Within Routine Clinical Practice.

Ahmad T, Yamamoto Y, Biswas A, Ghazi L, ... Desai NR, Wilson FP
Heart failure (HF) is one of the most common causes of hospitalization in the United States and carries a significant risk of morbidity and mortality. Use of evidence-based interventions may improve outcomes, but their use is encumbered in part by limitations in accurate prognostication. The REVeAL-HF (Risk EValuation And its Impact on ClinicAL Decision Making and Outcomes in Heart Failure) trial is the first to definitively evaluate the impact of knowledge about prognosis on clinical decision making and patient outcomes. The REVeAL-HF trial is a pragmatic, completely electronic, randomized controlled trial that has completed enrollment of 3,124 adults hospitalized for HF, defined as having an N-terminal pro-B-type natriuretic peptide level of >500 pg/ml and receiving intravenous diuretic agents within 24 h of admission. Patients randomized to the intervention had their risk of 1-year mortality generated with information in the electronic health record and presented to their providers, who had the option to give feedback on their impression of this risk assessment. The authors are examining the impact of this information on clinical decision-making (use of HF pharmacotherapies, referral to electrophysiology, palliative care referral, and referral for advanced therapies like heart transplantation or mechanical circulatory support) and patient outcomes (length of stay, post-discharge 30-day rehospitalizations, and 1-year mortality). The REVeAL-HF trial will definitively examine whether knowledge about prognosis in HF has an impact on clinical decision making and patient outcomes. It will also examine the relationship between calculated, perceived, and real risk of mortality in this patient population. (Risk EValuation And Its Impact on ClinicAL Decision Making and Outcomes in Heart Failure [REVeAL-HF]; NCT03845660).

Copyright © 2021. Published by Elsevier Inc.

JACC Heart Fail: 30 May 2021; 9:409-419
Ahmad T, Yamamoto Y, Biswas A, Ghazi L, ... Desai NR, Wilson FP
JACC Heart Fail: 30 May 2021; 9:409-419 | PMID: 33992566
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Abstract

Response by Sex in Patient-Centered Outcomes With Baroreflex Activation Therapy in Systolic Heart Failure.

Lindenfeld J, Gupta R, Grazette L, Ruddy JM, ... Sears S, Zannad F
Objectives
The aim of this study was to assess sex differences in the efficacy and safety of baroreflex activation therapy (BAT) in the BeAT-HF (Baroreflex Activation Therapy for Heart Failure) trial.
Background
Patients were randomized 1:1 to receive guideline-directed medical therapy (GDMT) alone (control group) or BAT plus GDMT.
Methods
Pre-specified subgroup analyses including change from baseline to 6 months in 6-min walk distance (6MWD), quality of life (QoL) assessed using the Minnesota Living With Heart Failure Questionnaire (MLWHQ), New York Heart Association (NYHA) functional class, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were conducted in men versus women.
Results
Fifty-three women and 211 men were evaluated. Women had similar baseline NT-proBNP levels, 6MWDs, and percentage of subjects with NYHA functional class III symptoms but poorer MLWHQ scores (mean 62 ± 22 vs. 50 ± 24; p = 0.01) compared with men. Women experienced significant improvement from baseline to 6 months with BAT plus GDMT relative to GDMT alone in MLWHQ score (-34 ± 27 vs. -9 ± 23, respectively; p < 0.01), 6MWD (44 ± 45 m vs. -32 ± 118 m; p < 0.01), and improvement in NYHA functional class (70% vs. 27%; p < 0.01), similar to the responses seen in men, with no significant difference in safety. Women receiving BAT plus GDMT had a significant decrease in NT-proBNP (-43% vs. 7% with GDMT alone; difference -48%; p < 0.01), while in men this decrease was -15% versus 2%, respectively (difference -17%; p = 0.08), with an interaction p value of 0.05.
Conclusions
Women in BeAT-HF had poorer baseline QoL than men but demonstrated similar improvements with BAT in 6MWD, QoL, and NYHA functional class. Women had a significant improvement in NT-proBNP, whereas men did not. (Baroreflex Activation Therapy for Heart Failure [BeAT-HF]; NCT02627196).

Copyright © 2021. Published by Elsevier Inc.

JACC Heart Fail: 30 May 2021; 9:430-438
Lindenfeld J, Gupta R, Grazette L, Ruddy JM, ... Sears S, Zannad F
JACC Heart Fail: 30 May 2021; 9:430-438 | PMID: 33992562
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Abstract

Percutaneous Mitral Valve Annuloplasty in Patients With Secondary Mitral Regurgitation and Severe Left Ventricular Enlargement.

Anker SD, Starling RC, Khan MS, Friede T, ... Coats AJS, Butler J
Objectives
This study sought to determine the effect of percutaneous mitral valve annuloplasty with the Carillon device versus guideline-directed medical therapy (GDMT) alone in patients with secondary mitral regurgitation (MR) and severe left ventricular (LV) enlargement.
Background
The clinical impact of the Carillon device in patients with severe LV dilation is not well established.
Methods
This is a pooled analysis involving 3 prospective trials (TITAN [Transcatheter Implantation of Carillon Mitral Annuloplasty Device], TITAN II, and REDUCE FMR [CARILLON Mitral Contour System for Reducing Functional Mitral Regurgitation] trials) in which patients with functional MR and severe LV enlargement (LV end-diastolic diameter >65 mm) were treated with GDMT and the Carillon device versus GDMT alone. Key outcomes of this analysis were changes over 1 year of follow-up in mitral valve and LV echocardiographic parameters, functional outcome, quality of life, mortality, and heart failure hospitalization (HFH).
Results
A total of 95 patients (67 in the Carillon group, 28 in the GDMT group) with severe LV enlargement were included. In the Carillon group, all mitral valve and LV morphology parameters were significantly improved at 1 year. Regurgitant volume decreased by 12 ml (p < 0.001), MR grade decreased by 0.6 U (p < 0.001), LV end-diastolic volume decreased by 25 cm3 (p = 0.005), and LV end-systolic volume decreased by 21 cm3 (p = 0.01). Significant functional improvement differences were also noted between the Carillon group and the GDMT group including an improvement of Kansas City Cardiomyopathy Questionnaire score (15 ± 4 vs. 6 ± 6; p = 0.03). The incidence of HFH was 29.9% versus 50.0% and the cumulative rate of HFH was 0.43 versus 0.75 (p < 0.001).
Conclusions
In patients with functional MR and severe LV enlargement, the Carillon device improved mitral valve function, LV morphology, and functional outcome compared with patients receiving GDMT only. Preoperative LV dimension should not be a limiting factor when evaluating patient eligibility or anticipated response to therapy with the Carillon device.

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

JACC Heart Fail: 30 May 2021; 9:453-462
Anker SD, Starling RC, Khan MS, Friede T, ... Coats AJS, Butler J
JACC Heart Fail: 30 May 2021; 9:453-462 | PMID: 33992567
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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: 29 Apr 2021; 9:349-359
Tromp J, Ouwerkerk W, Cleland JGF, Angermann CE, ... Lam CSP, Dickstein K
JACC Heart Fail: 29 Apr 2021; 9:349-359 | PMID: 33839078
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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: 29 Apr 2021; 9:336-345
Blumer V, Greene SJ, Wu A, Butler J, ... O'Connor CM, Mentz RJ
JACC Heart Fail: 29 Apr 2021; 9:336-345 | 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: 29 Apr 2021; 9:325-335
Greene SJ, Velazquez EJ, Anstrom KJ, Eisenstein EL, ... Mentz RJ, TRANSFORM-HF Investigators
JACC Heart Fail: 29 Apr 2021; 9:325-335 | PMID: 33714745
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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: 29 Apr 2021; 9:386-397
Jering K, Claggett B, Redfield MM, Shah SJ, ... McMurray JJV, Solomon SD
JACC Heart Fail: 29 Apr 2021; 9:386-397 | PMID: 33714741
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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 0.1 ug/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: 29 Apr 2021; 9:360-370
Burkhoff D, Borlaug BA, Shah SJ, Zolty R, ... Preston IR, Rich S
JACC Heart Fail: 29 Apr 2021; 9:360-370 | PMID: 33839076
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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
This study sought 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: 29 Apr 2021; 9:374-382
Vaduganathan M, Cunningham JW, Claggett BL, Causland FM, ... Solomon S, Desai AS
JACC Heart Fail: 29 Apr 2021; 9:374-382 | PMID: 33839075
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This program is still in alpha version.