Effects of RBT-1 on preconditioning response biomarkers in patients undergoing coronary artery bypass graft or heart valve surgery: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Background: RBT-1 is a combination drug of stannic protoporfin (SnPP) and iron sucrose (FeS) that elicits a preconditioning response through activation of antioxidant, anti-inflammatory, and iron-scavenging pathways, as measured by heme oxygenase-1 (HO-1), interleukin-10 (IL-10), and ferritin, respectively. Our primary aim was to determine whether RBT-1 administered before surgery would safely and effectively elicit a preconditioning response in patients undergoing cardiac surgery. Methods: This phase 2, double-blind, randomised, placebo-controlled, parallel-group, adaptive trial, conducted in 19 centres across the USA, Canada, and Australia, enrolled patients scheduled to undergo non-emergent coronary artery bypass graft (CABG) and/or heart valve surgery with cardiopulmonary bypass. Patients were randomised (1:1:1) to receive either a single intravenous infusion of high-dose RBT-1 (90 mg SnPP/240 mg FeS), low-dose RBT-1 (45 mg SnPP/240 mg FeS), or placebo within 24-48 h before surgery. The primary outcome was a preoperative preconditioning response, measured by a composite of plasma HO-1, IL-10, and ferritin. Safety was assessed by adverse events and laboratory parameters. Prespecified adaptive criteria permitted early stopping and enrichment. This trial is registered with ClinicalTrials.gov, NCT04564833. Findings: Between Aug 4, 2021, and Nov 9, 2022, of 135 patients who were enrolled and randomly allocated to a study group (46 high-dose, 45 low-dose, 44 placebo), 132 (98%) were included in the primary analysis (46 high-dose, 42 low-dose, 44 placebo). At interim, the trial proceeded to full enrollment without enrichment. RBT-1 led to a greater preconditioning response than did placebo at high-dose (geometric least squares mean [GLSM] ratio, 3.58; 95% CI, 2.91-4.41; p < 0.0001) and low-dose (GLSM ratio, 2.62; 95% CI, 2.11-3.24; p < 0.0001). RBT-1 was generally well tolerated by patients. The primary drug-related adverse event was dose-dependent photosensitivity, observed in 12 (26%) of 46 patients treated with high-dose RBT-1 and in six (13%) of 45 patients treated with low-dose RBT-1 (safety population). Interpretation: RBT-1 demonstrated a statistically significant cytoprotective preconditioning response and a manageable safety profile. Further research is needed. A phase 3 trial is planned. Funding: Renibus Therapeutics, Inc.

Hierarchical End Points in Prior Heart Failure Trials and the HEART-FID Trial.

BACKGROUND: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome. METHODS: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome. RESULTS: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes. CONCLUSIONS: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Vitamin D Levels in Black Americans and the Association With Left Ventricular Remodeling and Incident Heart Failure With Preserved Ejectin Fraction: The Jackson Heart Study.

BACKGROUND: In observational studies, a lower serum vitamin D3 concentration has been associated with an increased risk of cardiovascular disease. However, the associations between serum vitamin D3 levels and left ventricular (LV) structure and heart failure with preserved ejection fraction (HFpEF) have not been well-characterized among Black Americans. The prevalence of vitamin D3 deficiency is higher among Black Americans than in other race/ethnicity groups. We hypothesized that serum vitamin D3 levels are associated with LV concentric remodeling and incident HFpEF in Black Americans. METHODS AND RESULTS: Among 5306 Black Americans in the Jackson Heart Study cohort, we investigated the relationships between serum vitamin D3 levels and LV structure and function, evaluated with echocardiography, and incident HF hospitalization, categorized as either HF with reduced EF (HFrEF; an EF of <50%) or HFpEF (an EF of ≥50%). After adjustment for possible confounding factors, lower vitamin D3 levels were associated with greater relative wall thickness (ß for 1 standard deviation [SD] increase -0.003, 95% confidence interval -0.005 to -0.000). Over a median follow-up period of 11 years (range 10.2-11.0 years), 340 participants developed incident HF (7.88 cases per 1000 person-years), including 146 (43%) HFrEF and 194 (57%) HFpEF cases. After adjustment, higher serum vitamin D3 levels were associated with decreased hazard for HF overall (hazard ratio for 1 SD increase 0.88, 95% confidence interval 0.78-0.99) driven by a significant association with HFpEF (hazard ratio for 1 SD increase 0.84, 95% confidence interval 0.71-0.99). CONCLUSIONS: In this community-based Black American cohort, lower serum vitamin D3 levels were associated with LV concentric remodeling and an increased hazard for HF, mainly HFpEF. Further investigation is required to examine whether supplementation with vitamin D3 can prevent LV concentric remodeling and incident HFpEF in Black Americans.

Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial.

AIMS: To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13-43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: -0.10 mmol/l (95% confidence interval, CI -0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. CONCLUSION: Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

Contemporary outpatient management of patients with worsening heart failure with reduced ejection fraction: Rationale and design of the CHART-HF study.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and worsening HF events (WHFE) represent a distinct subset of patients with a substantial comorbidity burden, greater potential for intolerance to medical therapy, and high risk of subsequent death, hospitalization and excessive healthcare costs. Although multiple therapies have been shown to be efficacious and safe in this high-risk population, there are limited real-world data regarding factors that impact clinical decision-making when initiating or modifying therapy. Likewise, prior analyses of US clinical practice support major gaps in medical therapy for HFrEF and few medication changes during longitudinal follow-up, yet granular data on reasons why clinicians do not initiate or up-titrate guideline-directed medication are lacking. METHODS: We designed the CHART-HF study, an observational study of approximately 1,500 patients comparing patients with and without WHFE (WHFE defined as receipt of intravenous diuretics in the inpatient, outpatient, or emergency department setting) who had an index outpatient visit in the US between 2017 and 2019. Patient-level data on clinical characteristics, clinical outcomes, and therapy will be collected from 2 data sources: a single integrated health system, and a national panel of cardiologists. Furthermore, clinician-reported rationale for treatment decisions and the factors prioritized with selection and optimization of therapies in real-world practice will be obtained. To characterize elements of clinician decision-making not documented in the medical record, the panel of cardiologists will review records of patients seen under their care to explicitly note their primary reason for initiating, discontinuing, and titrating medications specific medications, as well as the reason for not making changes to each medication during the outpatient visit. CONCLUSIONS: Results from CHART-HF have the potential to detail real-world US practice patterns regarding care of patients with HFrEF with versus without a recent WHFE, to examine clinician-reported reasons for use and non-use of guideline-directed medical therapy, and to characterize the magnitude and nature of clinical inertia toward evidence-based medication changes for HFrEF.

Dietary interventions and nutritional supplements for heart failure: a systematic appraisal and evidence map.

AIMS: To appraise meta-analytically determined effect of dietary interventions and nutritional supplements on heart failure (HF)-related outcomes, and create an evidence map to visualize the findings and certainty of evidence. METHODS AND RESULTS: Online databases were systematically searched for meta-analyses of randomized controlled trials (RCTs) evaluating the effect of dietary interventions and nutritional supplements on HF outcomes and incidence. These were then updated if new RCTs were available. Estimates were pooled using a random-effects model and reported as risk ratios (RRs) or mean differences with 95% confidence intervals. We identified 14 relevant meta-analyses, to which 21 new RCTs were added. The total evidence base reviewed included 122 RCTs (n = 176 097 participants) assessing 14 interventions. We found that coenzyme Q10 was associated with lower all-cause mortality [RR 0.69 (0.50-0.96); I2  = 0%; low certainty of evidence] in HF patients. Incident HF risk was reduced with Mediterranean diet [RR 0.45 (0.26-0.79); I2  = 0%; low certainty of evidence]. Vitamin E supplementation was associated with a small but significant increase in the risk of HF hospitalization [RR 1.21 (1.04-1.40); I2 = 0%; moderate certainty of evidence]. There was moderate certainty of evidence that thiamine, vitamin D, iron, and L-carnitine supplementation had a beneficial effect on left ventricular ejection fraction. CONCLUSION: Coenzyme Q10 may reduce all-cause mortality in HF patients, while a Mediterranean diet may reduce the risk of incident HF; however, the low certainty of evidence warrants the need for further RCTs to confirm a definite clinical role. RCT data were lacking for several common interventions including intermittent fasting, caffeine, DASH diet, and ketogenic diet. More research is needed to fill the knowledge gap.

Dosing of losartan in men versus women with heart failure with reduced ejection fraction: the HEAAL trial.

AIMS: In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit. METHODS AND RESULTS: The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and machine learning algorithms. The mean age was 66 years and 30% of patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses [hazard ratio (95% confidence interval) comparing high- vs. low-dose losartan for the composite outcome of all-cause death or all-cause hospitalization: 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women; interaction P = 0.018]. Female sex clustered along with older age, ischaemic heart failure, New York Heart Association class III/IV, and estimated glomerular filtration rate <60 mL/min. Patients with these features had a poorer response to high-dose losartan. Subgroup analyses supported no benefit from high-dose losartan in patients with poorer kidney function and severe heart failure symptoms. CONCLUSIONS: Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g. kidney function, age, and symptoms) may influence the response to high-dose losartan, suggesting that sex-based subgroup findings may be biased by other confounders.

Management of heart failure and type 2 diabetes mellitus: Maximizing complementary drug therapy.

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and occurs in ~25% of patients with heart failure (HF). Patients with co-morbid HF and T2DM are at elevated risk of adverse outcomes, making optimization of complementary drug therapies essential. While research is ongoing, recent advances in drug therapy, including the introduction of sacubitril/valsartan for HF with reduced ejection fraction and the finding of positive cardiovascular effects of glucose-lowering agents (particularly sodium-glucose co-transporter-2 [SGLT2] inhibitors) have the potential to transform pharmacologic management of co-morbid HF and T2DM. In this review, we provide a comprehensive overview of cardiovascular clinical trials of therapies for HF and diabetes mellitus to date and identify areas requiring further investigation. We also discuss the pathophysiologic overlap of the two diseases and explore the complementary therapeutic effects of HF and T2DM drugs, with a particular focus on sacubitril/valsartan and SGLT2 inhibitors.

Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA-HF trial.

AIMS: In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF), high-dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low-dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long-acting active metabolites of spironolactone [canrenone and 7α-thiomethylspironolactone (7α-TMS)] in the high-dose group could have contributed to these neutral results. METHODS AND RESULTS: In patients randomized to high-dose spironolactone not previously treated with spironolactone (high-dose-naïve, n = 112), concentrations of canrenone and 7α-TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P < 0.005), indicating that steady-state concentrations had not been reached by 48 h. In patients previously on low-dose, high-dose spironolactone (high-dose-previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P < 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high-dose groups had higher concentrations of both metabolites than the low-dose spironolactone group (P < 0.0001). Moreover, concentrations of both metabolites were higher in high-dose-previous vs. high-dose-naïve patients (P < 0.01), indicating that previous spironolactone use was significant, and that steady-state has not been reached in high-dose-naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints. CONCLUSIONS: Lower-than-anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high-dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA-HF trial.

Spironolactone in Acute Heart Failure Patients With Renal Dysfunction and Risk Factors for Diuretic Resistance: From the ATHENA-HF Trial.

BACKGROUND: Acute heart failure (HF) patients with renal insufficiency and risk factors for diuretic resistance may be most likely to derive incremental improvement in congestion with the addition of spironolactone. METHODS: The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) trial randomized 360 acute HF patients with reduced or preserved ejection fraction to spironolactone 100 mg daily or usual care for 96 hours. The current analysis assessed the effects of study therapy within tertiles of baseline estimated glomerular filtration rate (eGFR) and subgroups at heightened risk for diuretic resistance. RESULTS: Across eGFR tertiles, there was no incremental benefit of high-dose spironolactone on any efficacy endpoint, including changes in log N-terminal pro-B-type natriuretic peptide and signs and symptoms of congestion (all P for interaction ≥ 0.06). High-dose spironolactone had no significant effect on N-terminal pro-B-type natriuretic peptide reduction regardless of blood pressure, diabetes mellitus status, and loop diuretic dose (all P for interaction ≥ 0.38). In-hospital changes in serum potassium and creatinine were similar between treatment groups for all GFR tertiles (all P for interaction ≥ 0.18). Rates of inpatient worsening HF, 30-day worsening HF, and 60-day all-cause mortality were numerically higher among patients with lower baseline eGFR, but relative effects of study treatment did not differ with renal function (all P for interaction ≥ 0.27). CONCLUSIONS: High-dose spironolactone did not improve congestion over usual care among patients with acute HF, irrespective of renal function and risk factors for diuretic resistance. In-hospital initiation or continuation of spironolactone was safe during the inpatient stay, even when administered at high doses to patients with moderate renal dysfunction.

Identifying responders to oral iron supplementation in heart failure with a reduced ejection fraction: a post-hoc analysis of the IRONOUT-HF trial.

BACKGROUND: The IRONOUT-HF trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with heart failure with a reduced ejection fraction (HFrEF) and iron deficiency. METHODS: The IRONOUT-HF trial was a double-blind, placebo-controlled, randomized clinical trial designed to test the efficacy and safety of oral iron polysaccharide compared to matching placebo among patients with HFrEF and iron deficiency. Study participants received oral iron polysaccharide 150 mg twice daily or matching placebo for 16 weeks. Response to oral iron was defined as a ferritin level >300 ng/mL or a ferritin level 100-300 ng/mL with a transferrin saturation >20% at the end of the study. RESULTS: The final analytical cohort included 98 patients with HFrEF and iron deficiency at baseline. Study participants had a median (25, 75) age of 63 years (54 years, 71 years), included 40% women (N = 39). After 16 weeks of therapy, 24 patients (24%) responded to oral iron supplementation while 74 patients (76%) remained iron deficient despite treatment. There was no association between response to oral iron supplementation and improvement in functional status (i.e. peak VO2 or anaerobic threshold), myocardial stress (i.e. NT-proBNP levels), or HRQOL (i.e. Kansas City Cardiomyopathy Questionnaire) at week 16. CONCLUSION: This study failed to identify a subset of responders more likely to derive a clinical benefit from oral iron therapy and does not support its routine use in patients with symptomatic HFrEF and iron deficiency.

Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials.

BACKGROUND: Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. METHODS AND RESULTS: Patient data from the National Heart, Lung, and Blood Institute Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72-hour fluid output per total equivalent loop diuretic dose. Data from DOSE-AHF was then used to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72 hours, the high-DE group had median fluid output of 9071 ml (interquartile range: 7240-11775) with median furosemide dose of 320 mg (220-480) compared with 8030 ml (6300-9915) and 840 mg (600-1215) respectively for the low DE group. Cystatin C was independently associated with DE (odds ratio 0.36 per 1mg/L increase; 95% confidence interval: 0.24-0.56; P < 0.001). Independently from baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with estimated glomerular filtration rate below the median, those randomized to a high-dose strategy had improved symptoms compared with those randomized to a low-dose strategy. CONCLUSIONS: Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response identifies a high-risk population.

Temporal Relation Between Myocardial Fibrosis and Heart Failure With Preserved Ejection Fraction: Association With Baseline Disease Severity and Subsequent Outcome.

Importance: Among myriad changes occurring during the evolution of heart failure with preserved ejection fraction (HFpEF), cardiomyocyte-extracellular matrix interactions from excess collagen may affect microvascular, mechanical, and electrical function. Objective: To investigate whether myocardial fibrosis (MF) is similarly prevalent both in those with HFpEF and those at risk for HFpEF, similarly associating with disease severity and outcomes. Design, Setting, and Participants: Observational cohort study from June 1, 2010, to September 17, 2015, with follow-up until December 14, 2015, at a cardiovascular magnetic resonance (CMR) center serving an integrated health system. Consecutive patients with preserved systolic function referred for CMR were eligible. Cardiovascular magnetic resonance was used to exclude patients with cardiac amyloidosis (n = 19). Exposures: Myocardial fibrosis quantified by extracellular volume (ECV) CMR measures. Main Outcome and Measures: Baseline BNP; subsequent hospitalization for heart failure or death. Results: Of 1174 patients identified (537 [46%] female; median [interquartile range {IQR}] age, 56 [44-66] years), 250 were "at risk" for HFpEF given elevated brain-type natriuretic peptide (BNP) level; 160 had HFpEF by documented clinical diagnosis, and 745 did not have HFpEF. Patients either at risk for HFpEF or with HFpEF demonstrated similarly higher prevalence/extent of MF and worse prognosis compared with patients with no HFpEF. Among those at risk for HFpEF or with HFpEF, the actual diagnosis of HFpEF was not associated with significant differences in MF (median ECV, 28.2%; IQR, 26.2%-30.7% vs 28.3%; IQR, 25.5%-31.4%; P = .60) or prognosis (log-rank 0.8; P = .38). Over a median of 1.9 years, 61 patients at risk for HFpEF or with HFpEF experienced adverse events (19 hospitalization for heart failure, 48 deaths, 6 with both). In those with HFpEF, ECV was associated with baseline log BNP (disease severity surrogate) in multivariable linear regression models, and was associated with outcomes in multivariable Cox regression models (eg, hazard ratio 1.75 per 5% increase in ECV, 95% CI, 1.25-2.45; P = .001 in stepwise model) whether grouped with patients at risk for HFpEF or not. Conclusions and Relevance: Among myriad changes occurring during the apparent evolution of HFpEF where elevated BNP is prevalent, MF was similarly prevalent in those with or at risk for HFpEF. Conceivably, MF might precede clinical HFpEF diagnosis. Regardless, MF was associated with disease severity (ie, BNP) and outcomes. Whether cells and secretomes mediating MF represent therapeutic targets in HFpEF warrants further evaluation.

Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial.

Importance: Persistent congestion is associated with worse outcomes in acute heart failure (AHF). Mineralocorticoid receptor antagonists administered at high doses may relieve congestion, overcome diuretic resistance, and mitigate the effects of adverse neurohormonal activation in AHF. Objective: To assess the effect of high-dose spironolactone and usual care on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels compared with usual care alone. Design, Setting, and Participants: This double-blind and placebo (or low-dose)-controlled randomized clinical trial was conducted in 22 US acute care hospitals among patients with AHF who were previously receiving no or low-dose (12.5 mg or 25 mg daily) spironolactone and had NT-proBNP levels of 1000 pg/mL or more or B-type natriuretic peptide levels of 250 pg/mL or more, regardless of ejection fraction. Interventions: High-dose spironolactone (100 mg) vs placebo or 25 mg spironolactone (usual care) daily for 96 hours. Main Outcomes and Measures: The primary end point was the change in NT-proBNP levels from baseline to 96 hours. Secondary end points included the clinical congestion score, dyspnea assessment, net urine output, and net weight change. Safety end points included hyperkalemia and changes in renal function. Results: A total of 360 patients were randomized, of whom the median age was 65 years, 129 (36%) were women, 200 (55.5%) were white, 151 (42%) were black, 8 (2%) were Hispanic or Latino, 9 (2.5%) were of other race/ethnicity, and the median left ventricular ejection fraction was 34%. Baseline median (interquartile range) NT-proBNP levels were 4601 (2697-9596) pg/mL among the group treated with high-dose spironolactone and 3753 (1968-7633) pg/mL among the group who received usual care. There was no significant difference in the log NT-proBNP reduction between the 2 groups (-0.55 [95% CI, -0.92 to -0.18] with high-dose spironolactone and -0.49 [95% CI, -0.98 to -0.14] with usual care, P = .57). None of the secondary end point or day-30 all-cause mortality or heart failure hospitalization rate differed between the 2 groups. The changes in serum potassium and estimated glomerular filtration rate at 24, 48, 72, and 96 hours. were similar between the 2 groups. Conclusions and Relevance: Adding treatment with high-dose spironolactone to usual care for patients with AHF for 96 hours was well tolerated but did not improve the primary or secondary efficacy end points. Trial Registration: clinicaltrials.gov Identifier: NCT02235077.

Novel Endpoints for Heart Failure Clinical Trials.

PURPOSE OF REVIEW: With the growing prevalence of heart failure, there is a particular need to develop new pharmacologic treatments that can improve outcomes. While there are several approved therapies for heart failure with reduced ejection fraction, there is currently no approved agent for those with preserved ejection fraction. The current review aimed to explore the utility of alternate endpoints to mortality and hospitalization. RECENT FINDINGS: There is increased interest in the use of alternative endpoints such as functional status and quality of life for heart failure drug development to focus on patients feeling better in addition to improving outcomes. This should ideally be measured using objective as well as subjective parameters. While mortality and hospitalization remain important endpoints for clinical trials in heart failure, other more patient-centered outcomes are attractive alternatives yet how to best incorporate these in a trial setting remains to be elucidated.

Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial.

IMPORTANCE: Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. OBJECTIVE: To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. DESIGN, SETTING, AND PARTICIPANTS: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites. INTERVENTIONS: Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). RESULTS: Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P > .05. CONCLUSIONS AND RELEVANCE: Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02188784.

Rationale and Design of the ATHENA-HF Trial: Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure.

Although therapy with mineralocorticoid receptor antagonists (MRAs) is recommended for patients with chronic heart failure (HF) with reduced ejection fraction and in post-infarction HF, it has not been studied well in acute HF (AHF) despite being commonly used in this setting. At high doses, MRA therapy in AHF may relieve congestion through its natriuretic properties and mitigate the effects of adverse neurohormonal activation associated with intravenous loop diuretics. The ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) trial is a randomized, double-blind, placebo-controlled study of the safety and efficacy of 100 mg/day spironolactone versus placebo (or continued low-dose spironolactone use in participants who are already receiving spironolactone at baseline) in 360 patients hospitalized for AHF. Patients are randomized within 24 h of receiving the first dose of intravenous diuretics. The primary objective is to determine if high-dose spironolactone, compared with standard care, will lead to greater reductions in N-terminal pro-B-type natriuretic peptide levels from randomization to 96 h. The secondary endpoints include changes in the clinical congestion score, dyspnea relief, urine output, weight change, loop diuretic dose, and in-hospital worsening HF. Index hospital length of stay and 30-day clinical outcomes will be assessed. Safety endpoints include risk of hyperkalemia and renal function. Differences among patients with reduced versus preserved ejection fraction will be determined. (Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure [ATHENA-HF]; NCT02235077).

Utility of positron emission tomography for drug development for heart failure.

Only about 1 in 5,000 investigational agents in a preclinical stage acquires Food and Drug Administration approval. Among many reasons for this includes an inefficient transition from preclinical to clinical phases, which exponentially increase the cost and the delays the process of drug development. Positron emission tomography (PET) is a nuclear imaging technique that has been used for the diagnosis, risk stratification, and guidance of therapy. However, lately with the advance of radiochemistry and of molecular imaging technology, it became evident that PET could help novel drug development process. By using a PET radioligand to report on receptor occupancy during novel agent therapy, it may help assess the effectiveness, efficacy, and safety of such a new medication in an early preclinical stage and help design successful clinical trials even at a later phase. In this article, we explore the potential implications of PET in the development of new heart failure therapies and review PET's application in the respective pathophysiologic pathways such as myocardial perfusion, metabolism, innervation, inflammation, apoptosis, and cardiac remodeling.

In-Hospital Diuretic Agent Use and Post-Discharge Clinical Outcomes in Patients Hospitalized for Worsening Heart Failure: Insights From the EVEREST Trial.

OBJECTIVES: The aim of this study was to characterize the association between decongestion therapy and 30-day outcomes in patients hospitalized for heart failure (HF). BACKGROUND: Loop diuretic agents are commonly prescribed for the treatment of symptomatic congestion in patients hospitalized for HF, but the association between loop diuretic agent dose response and post-discharge outcomes has not been well characterized. METHODS: Cox proportional hazards models were used to estimate the association among average loop diuretic agent dose, congestion status at discharge, and 30-day post-discharge all-cause mortality and HF rehospitalization in 3,037 subjects hospitalized with worsening HF enrolled in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) study. RESULTS: In univariate analysis, subjects exposed to high-dose diuretic agents (≥160 mg/day) had greater risk for the combined outcome than subjects exposed to low-dose diuretic agents (18.9% vs. 10.0%; hazard ratio: 2.00; 95% confidence interval: 1.64 to 2.46; p < 0.0001). After adjustment for pre-specified covariates of disease severity, the association between diuretic agent dose and outcomes was not significant (hazard ratio: 1.11; 95% confidence interval: 0.89 to 1.38; p = 0.35). Of the 3,011 subjects with clinical assessments of volume status, 2,063 (69%) had little or no congestion at hospital discharge. Congestion status at hospital discharge did not modify the association between diuretic agent exposure and the combined endpoint (p for interaction = 0.84). CONCLUSIONS: Short-term diuretic agent exposure during hospital treatment for worsening HF was not an independent predictor of 30-day all-cause mortality and HF rehospitalization in multivariate analysis. Congestion status at discharge did not modify the association between diuretic agent dose and clinical outcomes.