Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Cardiac Troponin and Treatment Effects of Omecamtiv Mecarbil: Results From the GALACTIC-HF Study.

BACKGROUND: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329). METHODS: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil. RESULTS: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2). CONCLUSIONS: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI.

The HFSA Advanced Heart Failure and Transplant Cardiology Fellowship Consensus Conference.

There is waning interest among cardiology trainees in pursuing an Advanced Heart Failure/Transplant Cardiology (AHFTC) fellowship as evidenced by fewer applicants in the National Resident Matching Program match to this specialty. This trend has generated considerable attention across the heart failure community. In response, the Heart Failure Society of America convened the AHFTC Fellowship Task Force with a charge to develop strategies to increase the value proposition of an AHFTC fellowship. Subsequently, the HFSA sponsored the AHFTC Fellowship Consensus Conference April 26-27, 2023. Before the conference, interviews of 44 expert stakeholders diverse across geography, site of practice (traditional academic medical center or other centers), specialty/area of expertise, sex, and stage of career were conducted virtually. Based on these interviews, potential solutions to address the declining interest in AHFTC fellowship were categorized into five themes: (1) alternative training pathways, (2) regulatory and compensation, (3) educational improvements, (4) exposure and marketing for pipeline development, and (5) quality of life and mental health. These themes provided structure to the deliberations of the AHFTC Fellowship Consensus Conference. The recommendations from the Consensus Conference were subsequently presented to the HFSA Board of Directors to inform strategic plans and interventions. The HFSA Board of Directors later reviewed and approved submission of this document. The purpose of this communication is to provide the HF community with an update summarizing the processes used and concepts that emerged from the work of the HFSA AHFTC Fellowship Task Force and Consensus Conference.

The Effect of Omecamtiv Mecarbil in Hospitalized Patients as Compared With Outpatients With HFrEF: An Analysis of GALACTIC-HF.

BACKGROUND: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients. METHODS AND RESULTS: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51). CONCLUSIONS: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients.

Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial.

AIMS: Effective and safe decongestion remains a major goal for optimal management of patients with acute heart failure (AHF). The effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on decongestion-related endpoints in the EMPULSE trial (NCT0415775) were evaluated. METHODS AND RESULTS: A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL), WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal pro-B-type natriuretic peptide levels, hemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points, adjusted mean differences (95% confidence interval) at Days 15, 30, and 90 were: for WL -1.97 (-2.86, -1.08), -1.74 (-2.73, -0.74); -1.53 (-2.75, -0.31) kg; for WL-adjusted: -2.31 (-3.77, -0.85), -2.79 (-5.03, -0.54), -3.18 (-6.08, -0.28) kg/40 mg furosemide i.v. or equivalent; respectively (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90 (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days) with the win ratio of 1.75 (95% confidence interval 1.37, 2.23; P < 0.0001). CONCLUSION: Initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective and sustained decongestion which was associated with clinical benefit at Day 90.

Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial.

BACKGROUND: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized). METHODS: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model. RESULTS: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01-2.20], 1.37 [0.94-1.99], and 1.48 [1.00-2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32-8.59], P=0.03; 4.80 [95% CI, 0.00-9.61], P=0.05; 4.66 [95% CI, 0.32-9.01], P=0.04; 4.85 [95% CI, 0.77-8.92], P=0.02; and 4.40 points [95% CI, 0.33-8.48], P=0.03, respectively). CONCLUSIONS: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT0415775.

Pathophysiology and Therapeutic Approaches to Acute Decompensated Heart Failure.

Acute decompensated heart failure (ADHF) is one of the leading admission diagnoses worldwide, yet it is an entity with incompletely understood pathophysiology and limited therapeutic options. Patients admitted for ADHF have high in-hospital morbidity and mortality, as well as frequent rehospitalizations and subsequent cardiovascular death. This devastating clinical course is partly due to suboptimal medical management of ADHF with persistent congestion upon hospital discharge and inadequate predischarge initiation of life-saving guideline-directed therapies. While new drugs for the treatment of chronic HF continue to be approved, there has been no new therapy approved for ADHF in decades. This review will focus on the current limited understanding of ADHF pathophysiology, possible therapeutic targets, and current limitations in expanding available therapies in light of the unmet need among these high-risk patients.

Effects of omecamtiv mecarbil in heart failure with reduced ejection fraction according to blood pressure: the GALACTIC-HF trial.

AIM: Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). METHODS AND RESULTS: The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. CONCLUSION: In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

Influence of atrial fibrillation on efficacy and safety of omecamtiv mecarbil in heart failure: the GALACTIC-HF trial.

AIMS: In GALACTIC-HF, the cardiac myosin activator omecamtiv mecarbil compared with placebo reduced the risk of heart failure events or cardiovascular death in patients with heart failure with reduced ejection fraction. We explored the influence of atrial fibrillation or flutter (AFF) on the effectiveness of omecamtiv mecarbil. METHODS AND RESULTS: GALACTIC-HF enrolled patients with New York Heart Association (NYHA) Class II-IV heart failure, left ventricular ejection fraction ≤35%, and elevated natriuretic peptides. We assessed whether the presence or absence of AFF, a pre-specified subgroup, modified the treatment effect for the primary and secondary outcomes, and additionally explored effect modification in patients who were or were not receiving digoxin. Patients with AFF (n = 2245, 27%) were older, more likely to be randomized as an inpatient, less likely to have a history of ischaemic aetiology or myocardial infarction, had a worse NYHA class, worse quality of life, lower estimated glomerular filtration rate, and higher N-terminal pro-B-type natriuretic peptide. The treatment effect of omecamtiv mecarbil was modified by baseline AFF (interaction P = 0.012), with patients without AFF at baseline deriving greater benefit. The worsening of the treatment effect by baseline AFF was significantly more pronounced in digoxin users than in non-users (interaction P = 0.007); there was minimal evidence of effect modification in those patients not using digoxin (P = 0.47) or in digoxin users not in AFF. CONCLUSION: Patients in AFF at baseline were less likely to benefit from omecamtiv mecarbil than patients without AFF, although the attenuation of the treatment effect was disproportionally concentrated in patients with AFF who were also receiving digoxin.Clinical Trial Registration: NCT02929329.

Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events. METHODS: We randomly assigned 5988 patients with class II through IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. RESULTS: Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit requiring intravenous treatment (432 versus 546 patients [empagliflozin versus placebo, respectively]; hazard ratio, 0.77 [95% CI, 0.67-0.87]; P<0.0001). This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio, 0.71 [95% CI, 0.52-0.96]; P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio, 0.73 [95% CI, 0.55-0.97]; P=0.033). Compared with patients in the placebo group, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 versus 610; hazard ratio, 0.76 [95% CI, 0.67-0.86]; P<0.0001), and patients assigned to empagliflozin were 20% to 50% more likely to have a better New York Heart Association functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions. CONCLUSIONS: In patients with heart failure with preserved ejection fraction, empagliflozin produced a meaningful, early, and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. METHODS: We randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. RESULTS: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio [HR], 0.76; 95% CI, 0.67-0.87; P<0.0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50-0.90; P=0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47-0.87; P=0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 [HR, 0.67; 95% CI, 0.56-0.78; P<0.0001]). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63-0.78; P<0.0001). CONCLUSIONS: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Effects of Serelaxin in Patients with Acute Heart Failure.

BACKGROUND: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 µg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).

Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial.

Importance: Exercise limitation is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF) but is not consistently improved by any of the current guideline-directed medical therapies. Objective: To determine whether omecamtiv mecarbil, a novel direct myosin activator that improves cardiac performance and reduces the risk for cardiovascular death or first HF event in HFrEF, can improve peak exercise capacity in patients with chronic HFrEF. Design, Setting, and Participants: Phase 3, double-blind, placebo-controlled randomized trial of patients with HFrEF (left ventricular ejection fraction ≤35%), New York Heart Association class II-III symptoms, N-terminal pro-B-type natriuretic peptide level of 200 pg/mL or greater, and baseline peak oxygen uptake (V̇o2) of 75% or less of predicted. Patients were randomized in a 2:1 ratio (omecamtiv mecarbil to placebo) between March 2019 and May 2021 at 63 sites in North America and Europe, with the last patient visit occurring on November 29, 2021. Interventions: Omecamtiv mecarbil (n = 185) or matching placebo (n = 91), given orally twice daily at a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels, for 20 weeks. Main Outcomes and Measures: The primary end point was a change in exercise capacity (peak V̇o2) from baseline to week 20. Secondary end points included total workload, ventilatory efficiency, and daily physical activity as determined by accelerometry. Results: Among 276 patients who were randomized (median age, 64 years; IQR, 55-70 years; 42 women [15%]), 249 (90%) completed the trial. The median left ventricular ejection fraction was 28% (IQR, 21-33) and the median baseline peak V̇o2 was 14.2 mL/kg/min (IQR, 11.6-17.4) in the omecamtiv mecarbil group and 15.0 mL/kg/min (IQR, 12.0-17.2) in the placebo group. Mean change in peak V̇o2 did not differ significantly between the omecamtiv mecarbil and placebo groups (mean, -0.24 mL/kg/min vs 0.21 mL/kg/min; least square mean difference, -0.45 mL/kg/min [95% CI, -1.02 to 0.13]; P = .13). Adverse events included dizziness (omecamtiv mecarbil: 4.9%, placebo: 5.5%), fatigue (omecamtiv mecarbil: 4.9%, placebo: 4.4%), heart failure events (omecamtiv mecarbil: 4.9%, placebo: 4.4%), death (omecamtiv mecarbil: 1.6%, placebo: 1.1%), stroke (omecamtiv mecarbil: 0.5%, placebo: 1.1%), and myocardial infarction (omecamtiv mecarbil: 0%, placebo: 1.1%). Conclusions and Relevance: In patients with chronic HFrEF, omecamtiv mecarbil did not significantly improve exercise capacity over 20 weeks compared with placebo. These findings do not support the use of omecamtiv mecarbil for treatment of HFrEF for improvement of exercise capacity. Trial Registration: ClinicalTrials.gov Identifier: NCT03759392.

Challenges and Potential Improvements to Patient Access to Pharmaceuticals: Examples From Cardiology.

Patient access to a drug after US regulatory approval is controlled by complex interactions between governmental and third-party payers, pharmacy benefit managers, distributers, manufacturers, health systems, and pharmacies that together mediate the receipt of goods by patients after prescription by clinicians. Recent medication approvals highlight why and how the distribution of clinically beneficial novel therapies is controlled. Although imposed limitations on availability may be rational considering the fiduciary responsibilities of payers and escalating spending on health care and pharmaceuticals, transparency and communication are lacking, and some utilization management may disproportionately affect vulnerable populations. Analysis of the current health insurance landscape suggests mechanisms by which patient access to appropriate medications can be improved and patient and clinician frustration reduced while acknowledging the financial realities of the pharmaceutical marketplace. We propose creation of a shared, standardized, and transparent process for coverage decisions that minimizes administrative barriers and is defensible on the basis of clinical and cost-effectiveness evidence. These reforms would benefit patients and improve the efficiency of the pharmaceutical system.

Regional variation of effects of new antidiabetic medications in cardiovascular outcome trials.

BACKGROUND: In international trials, glucagon-like protein-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2Is) were effective in improving cardiovascular (CV) outcomes. METHODS: We assessed the effect of GLP-1RAs and SGLT2Is treatment effect on CV endpoints by geographical region in multiple international trials using random effects weighted least squares meta-regressions. RESULTS: The estimated effects of both SGLT2Is and GLP-1RAs on major adverse CV events (MACE) in North America (SGLT2Is n = 12,399, HR 0.90, 95% CI 0.81-1.01; GLP-1RAs n = 12,515, HR 0.95, 95% CI 0.83- 1.09) and in Europe (SGLT2Is n = 19,435, HR 0.93, 95% CI 0.85-1.02; GLP-1RAs n = 22,812, HR 0.88, 95% CI 0.79-0.99) were numerically lower but not statistically different to the rest of the world (ROW) (SGLT2Is n = 15,127, HR 0.83, 95% CI 0.75-0.92, p-value for interaction 0.26; GLP-1RAs n = 17,494, HR 0.82, 95% CI 0.73-0.92, p-value for interaction 0.28). Effects of SGLT2Is on heart failure readmission or CV death varied significantly by region (P = 0.0094). The effect of SGLT2Is was significantly smaller in Europe (n = 18,653, HR 0.86, 95% CI 0.78-0.95) than in the ROW (n = 12,463, HR 0.68, 95% CI 0.61-0.76, P = 0.0024). The smaller effect in North America (n = 9776, HR 0.76, 95% CI 0.66-0.87) did not differ significantly from that in the ROW (P = 0.2370). CONCLUSION: The effects of SGLT2Is on HF events are larger in the ROW. Further analyses and studies are needed to better elucidate the differential effects of SGLTIs and GLP-1RAs by geographical regions.

The Additive Prognostic Value of Serial Plasma Interleukin-6 Levels over Changes in Brain Natriuretic Peptide in Patients with Acute Heart Failure.

BACKGROUND: Elevated plasma interleukin-6 (IL-6) concentrations are frequently observed in patients with acute heart failure (AHF). However, the predictive value of serial IL-6 measurements beyond brain natriuretic peptide (BNP) remains poorly characterized. METHODS AND RESULTS: This was a retrospective analysis of the PROTECT cohort (2033 patients with AHF). Plasma IL-6 and BNP levels were determined on days 1, 2, 7 and 14 after admission for AHF in 1591 (78.3%), 1462 (71.9%), 1445 (71.1%) and 1451 (71.4%) patients, respectively. The primary endpoint was 180-day all-cause mortality. The median day-1 IL-6 concentration was 11.1 pg/mL (IQR: 6.6, 20.9) and decreased to 10.1 pg/mL (IQR: 5.6-18.5) at day-7. Higher cross-sectional IL-6 concentrations at all time-points predicted the primary endpoint, independent of a risk model for this cohort and changes in BNP. Each doubling of IL-6 between day-1 and day-7 predicted the primary endpoint independent of baseline IL-6 concentrations, the risk model, baseline BNP and changes in BNP [HR (95% CI): 1.18 (1.07-1.30), p=0.0013]. Collectively, 214 (17%) patients experienced at least a doubling of their IL-6 concentrations between day-1 and day-7. CONCLUSIONS: We demonstrate that the temporal evolution patterns of IL-6 in patients with AHF have additive prognostic value independent of changes in BNP.

Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure.

In this document, we propose a universal definition of heart failure (HF) as the following: HF is a clinical syndrome with symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and or objective evidence of pulmonary or systemic congestion. We propose revised stages of HF as follows. At-risk for HF (Stage A), for patients at risk for HF but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease. Pre-HF (stage B), for patients without current or prior symptoms or signs of HF, but evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels. HF (Stage C), for patients with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality. Advanced HF (Stage D), for patients with severe symptoms and/or signs of HF at rest, recurrent hospitalizations despite guideline-directed management and therapy (GDMT), refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care. Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). The classification includes HF with reduced EF (HFrEF): HF with an LVEF of ≤40%; HF with mildly reduced EF (HFmrEF): HF with an LVEF of 41% to 49%; HF with preserved EF (HFpEF): HF with an LVEF of ≥50%; and HF with improved EF (HFimpEF): HF with a baseline LVEF of ≤40%, a ≥10-point increase from baseline LVEF, and a second measurement of LVEF of >40%.

Drug development in oncology and devices-lessons for heart failure drug development and approval? a review.

Heart failure (HF) and cancer are of the most common diseases globally, both associated with significant adverse outcomes and greatly impaired quality of life. Despite those similarities, over the last 15 years, the United States (USA) and European authorities have approved only 5 and 3 new drugs for HF respectively, none using an accelerated process and none for patients with either acute HF (AHF) or with HF and preserved ejection fraction (HFpEF). During the same period, more than 100 new drugs were approved for treatment of various cancers, several receiving accelerated approval. HF drugs in the last 15 years were mostly approved for reduction in mortality, whereas most approved cancer drugs addressed disease progression and surrogate markers. Consequently, the size of the trials in HF were far greater than those in oncology which was associated with lower probability of success. Given the larger study size and smaller probability of approval, pharma progressively reduces the necessary investments in new HF drugs. We suggest for HF drugs be developed, especially those used to treat patients with HFpEF and AHF, consideration of approval based beyond morbidity and mortality on improvements in symptoms and functional capacity and, like oncology, based on measures of disease progression and end organ damage. At the same time, HF drug development should adopt some approaches used in other diseases (such as oncology) focusing on better defining specific phenotypes and defining specific disease-related targets for new drugs.

Conducting clinical trials in heart failure during (and after) the COVID-19 pandemic: an Expert Consensus Position Paper from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues.

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.