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Consider the choice of outcome for overall treatment benefit in a clinical trial which measures the first time to each of several clinical events. We describe several new variants of the win ratio that incorporate the time spent in each clinical state over the common follow‐up, where clinical state means the worst clinical event that has occurred by that time. One version allows restriction so that death during follow‐up is most important, while time spent in other clinical states is still accounted for. Three other variants are described; one is based on the average pairwise win time, one creates a continuous outcome for each participant based on expected win times against a reference distribution and another that uses the estimated distributions of clinical state to compare the treatment arms. Finally, a combination testing approach is described to give robust power for detecting treatment benefit across a broad range of alternatives. These new methods are designed to be closer to the overall treatment benefit/harm from a patient's perspective, compared to the ordinary win ratio. The new methods are compared to the composite event approach and the ordinary win ratio. Simulations show that when overall treatment benefit on death is substantial, the variants based on either the participants' expected win times (EWTs) against a reference distribution or estimated clinical state distributions have substantially higher power than either the pairwise comparison or composite event methods. The methods are illustrated by re‐analysis of the trial heart failure: a controlled trial investigating outcomes of exercise training. [ABSTRACT FROM AUTHOR]

Aims: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. Methods and results: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1–39, 41–80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post‐randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1–39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41–80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post‐randomization diuretic dose changes for vericiguat and placebo showed similar rates of up‐titration (19.6 and 20.2/100 person‐years), down‐titration (16.8 and 18.1/100 person‐years), and stopping diuretics (22.9 and 24.2/100 person‐years). Conclusions: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high‐risk population. The efficacy of vericiguat was consistent across the range of diuretic doses. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide. Methods and results: In this randomized, double‐blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT‐proBNP at baseline was 1487 (interquartile range: 847–2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post‐furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion. Conclusions: For patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload. [ABSTRACT FROM AUTHOR]

Aim: Vericiguat significantly reduced the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death in the VICTORIA trial. It is unknown if these outcome benefits are related to reverse left ventricular (LV) remodelling with vericiguat in patients with HF with reduced ejection fraction (HFrEF). The aim of this study was to compare the effects of vericiguat versus placebo on LV structure and function after 8 months of therapy in patients with HFrEF. Methods and results: Standardized transthoracic echocardiography (TTE) was performed at baseline and after 8 months of therapy in a subset of HFrEF patients in VICTORIA. The co‐primary endpoints were changes in LV end‐systolic volume index (LVESVI) and LV ejection fraction (LVEF). Quality assurance and central reading were performed by an echocardiographic core laboratory blinded to treatment assignment. A total of 419 patients (208 vericiguat, 211 placebo) with high‐quality paired TTE at baseline and 8 months were included. Baseline clinical characteristics were well balanced between treatment groups and echocardiographic characteristics were representative of patients with HFrEF. LVESVI significantly declined (60.7 ± 26.8 to 56.8 ± 30.4 ml/m2; p < 0.01) and LVEF significantly increased (33.0 ± 9.4% to 36.1 ± 10.2%; p < 0.01) in the vericiguat group, but similarly in the placebo group (absolute changes for vericiguat vs. placebo: LVESVI −3.8 ± 15.4 vs. −7.1 ± 20.5 ml/m2; p = 0.07 and LVEF +3.2 ± 8.0% vs. +2.4 ± 7.6%; p = 0.31). The absolute rate per 100 patient‐years of the primary composite endpoint at 8 months tended to be lower in the vericiguat group (19.8) than the placebo group (29.6) (p = 0.07). Conclusions: In this pre‐specified echocardiographic study, significant improvements in LV structure and function occurred over 8 months in both vericiguat and placebo in a high‐risk HFrEF population with recent worsening HF. Further studies are warranted to define the mechanisms of vericiguat's benefit in HFrEF. [ABSTRACT FROM AUTHOR]

Aim: We assessed a subset of the 5040 patients in VICTORIA receiving sacubitril/valsartan, either at randomization (n = 731) or post-randomization drop-in use (n = 425), to evaluate the relationship between the efficacy and safety of combination therapy with vericiguat.Methods and Results: The efficacy of vericiguat on the primary composite endpoint, heart failure (HF) hospitalization, and all-cause mortality was assessed. Safety outcomes included symptomatic hypotension, syncope, worsening renal function, and hyperkalaemia. At randomization, 731 patients received sacubitril/valsartan; they were more frequently from Western Europe or North America, had lower ejection fraction and systolic blood pressure, and more use of triple background HF therapy (65.9% vs. 58.6%), biventricular pacemakers (17.9% vs. 14.1%), or implantable cardioverter defibrillators (42.3% vs. 25.3%). For patients on versus not on sacubitril/valsartan at randomization, adjusted hazard ratios (95% confidence intervals) for vericiguat's treatment effect on the primary composite outcome, cardiovascular death, and HF hospitalization were 0.92 (0.71-1.19) versus 0.89 (0.80-0.98), 0.71 (0.45-1.12) versus 0.95 (0.82-1.11), and 0.98 (0.74-1.29) versus 0.87 (0.78-0.98), respectively. No significant interaction existed between sacubitril/valsartan and vericiguat's treatment effect (p-values for interaction: 0.81, 0.23 and 0.47, respectively). Post-randomization, more drop-in sacubitril/valsartan use occurred in those assigned to placebo (n = 238) versus vericiguat (n = 187) (p = 0.007). Symptomatic hypotension (21.0% vs. 23.1%; p = 0.41), renal dysfunction (29.9% vs. 31.9%; p = 0.50), and hyperkalaemia (10.3% vs. 7.9%; p = 0.20) in patients receiving sacubitril/valsartan (n = 992) for ≥3 months were not different by treatment arm.Conclusions: Concomitant use of sacubitril/valsartan for at least 3 months did not alter the efficacy of vericiguat and was similarly safe and tolerated in both study arms. Sacubitril/valsartan was initiated more frequently after randomization in patients assigned to placebo versus vericiguat.Clinical Trial Registration: ClinicalTrials.gov NCT02861534. [ABSTRACT FROM AUTHOR]

Aims: Coronary artery disease (CAD) portends worse outcomes in heart failure (HF). We aimed to characterize patients with CAD and worsening HF with reduced ejection fraction (HFrEF) and evaluate post hoc whether vericiguat treatment effect varied according to CAD. Methods and results: Cox proportional hazards were generated for the primary endpoint of cardiovascular death or HF hospitalization (CVD/HFH). CAD was defined as previous myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting. Of 5048 patients in VICTORIA with available data on CAD status, 2704 had CAD and were older, were more frequently male, diabetic, and had a lower glomerular filtration rate than those without CAD (all p <0.0001). Use of implantable cardioverter defibrillators and cardiac resynchronization therapy (CRT) was higher in patients with versus without CAD (33.5% vs. 21.1%; p <0.0001 and 16.3% vs. 12.8%; p = 0.0006). The primary endpoint of CVD/HFH was higher in those with versus without CAD (40.6 vs. 30.1/100 patient‐years; adjusted hazard ratio [HR] 1.23; p <0.001) as was all‐cause mortality (17.9% vs. 12.7%; adjusted HR 1.32; p <0.001). The primary outcome of CVD/HFH associated with vericiguat in patients with or without CAD was 38.8 versus 27.6 per 100 patient‐years and for placebo was 42.6 versus 32.7 per 100 patient‐years (interaction p = 0.78). Conclusion: In this post hoc study, CAD was associated with more CVD and HFH in patients with HFrEF and worsening HF. Vericiguat was beneficial and safe regardless of concomitant CAD. [ABSTRACT FROM AUTHOR]

Introduction: Black patients have a higher incidence of heart failure (HF) and worse outcomes than white patients. Guidelines recommend palliative care for patients with advanced HF, but no studies have examined outcomes in a black patient cohort. Methods: This is a post hoc analysis of the Palliative Care in Heart Failure trial, which randomized patients to usual care plus a palliative care intervention (UC+PAL) or usual care (UC). Quality of life (QoL) was measured using Kansas City Cardiomyopathy Questionnaire (KCCQ) and Functional Assessment of Chronic Illness Therapy-Palliative Care scale (FACIT-Pal). Results: Black patients represented 41% of the 148 patients. At six months, QoL improved more in UC+PAL than UC for both racial subgroups. The difference was greater for black than white patients (difference: KCCQ 10.8 vs. 2.5; FACIT-Pal: 14.8 vs. 3.9). However, the findings were not statistically significant. Conclusions: Larger studies are needed to assess the benefits of palliative care for black patients with HF. ClinicalTrials.gov Identifier: NCT01589601. [ABSTRACT FROM AUTHOR]

Aims: N‐terminal pro‐b‐type natriuretic peptide (NT‐proBNP) values may be influenced by patient factors beyond the severity of illness, including atrial fibrillation (AF), renal dysfunction, or increased body mass index (BMI). We hypothesized that these factors may influence the achievement of NT‐proBNP targets and clinical outcomes. Methods: A total of 894 patients with heart failure with reduced ejection fraction were enrolled in The Guiding Evidence‐Based Therapy Using Biomarker Intensified Treatment trial. NT‐proBNP was analysed every 3 months. Results: Forty per cent of patients had AF, the median estimated glomerular filtration rate (eGFR) was 59 mL/min/1.73 m2 [interquartile range (IQR) 43–76], and median BMI was 29 kg/m2 (IQR 25–34). Patients with AF, eGFR < 60 mL/min/1.73 m2, or a BMI < 29 kg/m2 had a higher level of NT‐proBNP at randomization and over all study visits (all P values < 0.001). Over 18 months, the rate of change of NT‐proBNP was less for patients with AF (compared with those without AF, P = 0.037) and patients with an eGFR < 60 mL/min/1.73 m2 (compared with eGFR > 60 mL/min/1.73 m2, P < 0.001). The rate of change of NT‐proBNP was similar for patients with a BMI above or below the median value. Using the 90 day NT‐proBNP, patients with AF, lower eGFR, or lower BMI were less likely to achieve the target NT‐proBNP < 1000 pg/mL than patients without AF, higher eGFR, or higher BMI, respectively. None of these differed between the Usual Care or Guided Care arm for AF, eGFR, or BMI (Pinteractions all NS). Conclusions: Patients with AF, a lower BMI, or worse renal function are less likely to achieve a lower or target NT‐proBNP. Clinicians should be aware of these factors both when interpreting NT‐proBNP levels and making therapeutic decisions about heart failure therapies. [ABSTRACT FROM AUTHOR]

We examined the relationship between pain severity and outcomes in patients with heart failure with reduced ejection fraction (HFrEF) in the HF-ACTION randomized controlled trial. Trends of health-related quality of life (HRQoL) measures grouped by patients' self-reported baseline bodily pain severity were compared using correlation tests, and the association between pain severity and clinical outcomes (including a primary composite endpoint of all-cause mortality and all-cause hospitalization) was assessed using multivariable adjusted analyses. Of the 2310 patients, 22.9% reported no pain, 45.8% very mild/mild, 24.9% moderate, and 6.4% severe/very severe. Greater pain severity was associated with worse HRQoL measures (EuroQoL-5D-3L and Kansas City Cardiomyopathy Questionnaire; both p < 0.0001). Compared to those reporting no pain, patients reporting severe/very severe pain had greater risk for the primary endpoint (adjusted hazard ratio 1.42, 95% confidence interval 1.11–1.83, p = 0.01). In patients with HFrEF, greater pain severity was associated with worse HRQoL and clinical outcomes. Trial Registration: NCT00047437 [ABSTRACT FROM AUTHOR]

Background: Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM. Methods: Targeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed. Results: A total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p = 2 × 10−7, and were differentially associated in participants with and without DM (beta 1.58, p = 8 × 10−8 vs. 0.67, p = 9 × 10−4, respectively; p value for interaction = 0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p = 0.24) than in those without DM (mean ∆ 0.16, p = 0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p = 2.74 × 10−8), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p = 3.21 × 10−9 v. HR 0.90, p = 0.104, p value for interaction = 0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study. Conclusions: LCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM. Trial Registration clinicaltrials.gov Identifier: NCT00047437. [ABSTRACT FROM AUTHOR]

Aims: We evaluated the relation between baseline and new‐onset atrial fibrillation (AF) and outcomes, and assessed whether vericiguat modified the likelihood of new‐onset AF in patients with worsening heart failure (HF) with reduced ejection fraction in VICTORIA. Methods and results: Of 5050 patients randomized, 5010 with recorded AF status at baseline were analysed. Patients were classified into three groups: no known AF (n = 2661, 53%), history of AF alone (n = 992, 20%), and AF on randomization electrocardiogram (n = 1357, 27%). Compared with those with no AF, those with history of AF alone had a higher risk of cardiovascular death [adjusted hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.01–1.47] without excess myocardial infarction or stroke; neither type of AF was associated with a higher risk of the primary composite outcome (time to cardiovascular death or first HF hospitalization), HF hospitalizations, or all cause‐death. The beneficial effect of vericiguat on the primary composite outcome and its components was evident irrespective of AF status at baseline. Over a median follow‐up of 10.8 months, new‐onset AF occurred in 6.1% of those with no AF and 18.3% with history of AF alone (P < 0.0001). These events were not influenced by vericiguat treatment (adjusted HR 0.93, 95% CI 0.75–1.16; P = 0.51), but were associated with an increase in the hazard of both primary and secondary outcomes. Conclusions: Atrial fibrillation was present in nearly half of this high‐risk population with worsening HF. A history of AF alone at baseline portends an increased risk of cardiovascular death. Neither type of AF affected the beneficial effect of vericiguat. Development of AF post‐randomization was associated with an increase in both cardiovascular death and HF hospitalization which was not influenced by vericiguat. [ABSTRACT FROM AUTHOR]

Aims: Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2. We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function. Methods and results: In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2. During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11–1.47; P < 0.001), but the beneficial effects of vericiguat on the primary outcome were similar in patients with or without WRF (interaction P = 0.76). Conclusion: Renal function trajectories were similar between vericiguat‐ and placebo‐treated patients and the beneficial effects of vericiguat on the primary outcome were consistent across the full range of eGFR and irrespective of WRF. [ABSTRACT FROM AUTHOR]

Aims: Nitroxyl provokes vasodilatation and inotropic and lusitropic effects in animals via post-translational modification of thiols. We aimed to compare effects of the nitroxyl donor cimlanod (BMS-986231) with those of nitroglycerin (NTG) or placebo on cardiac function in patients with chronic heart failure with reduced ejection fraction (HFrEF).Methods and Results: In a randomized, multicentre, double-blind, crossover trial, 45 patients with stable HFrEF were given a 5 h intravenous infusion of cimlanod, NTG, or placebo on separate days. Echocardiograms were done at the start and end of each infusion period and read in a core laboratory. The primary endpoint was stroke volume index derived from the left ventricular outflow tract at the end of each infusion period. Stroke volume index with placebo was 30 ± 7 mL/m2 and was lower with cimlanod (29 ± 9 mL/m2 ; P = 0.03) and NTG (28 ± 8 mL/m2 ; P = 0.02). Transmitral E-wave Doppler velocity on cimlanod or NTG was lower than on placebo and, consequently, E/e' (P = 0.006) and E/A ratio (P = 0.003) were also lower. NTG had similar effects to cimlanod on these measurements. Blood pressure reduction was similar with cimlanod and NTG and greater than with placebo.Conclusion: In patients with chronic HFrEF, the haemodynamic effects of cimlanod and NTG are similar. The effects of cimlanod may be explained by venodilatation and preload reduction without additional inotropic or lusitropic effects. Ongoing trials of cimlanod will further define its potential role in the treatment of heart failure. [ABSTRACT FROM AUTHOR]

Depression is a frequent and debilitating comorbidity that affects heart failure (HF) patients. Up to 30% of HF patients suffer from depression and even more have depressive symptoms. Moreover, depression carries a risk for HF, especially in high-risk groups, and is significantly associated with worse quality of life and clinical outcomes. The pathophysiology of depression and HF is poorly understood, but both diseases share several mechanisms and risk factors, including dysregulation of platelet reactivity, inflammation, neuroendocrine function, arrhythmias, high-risk behaviours, and social factors. Current HF guidelines advise to screen HF patients for depression and several screening questionnaires are available. Ultimately, the diagnosis of depression is based on DSM-5 criteria. Depression treatment consists of non-pharmacological and pharmacological therapies. Non-pharmacological therapies, such as exercise training and cognitive-behavioural therapy, have been shown to have beneficial effects on depressive symptoms. Selective serotonin reuptake inhibitors, the mainstay of antidepressant therapy, appear to be safe in HF but have not shown superiority over placebo in HF in short- and long-term randomized clinical trials. New therapies to treat depression are under investigation and may offer the opportunity to improve depression management in HF, including N-methyl-D-aspartate receptor antagonists, repetitive transcranial magnetic stimulation and omega-3 supplementation. New technologies may offer several advantages for the screening and diagnosis of depression but they remain to be tested in future research. In this review, we examine the intersection of depression and HF, summarize the epidemiology and pathophysiology, and discuss new opportunities to diagnose and treat HF patients with depression. [ABSTRACT FROM AUTHOR]

Importance: Patients with heart failure and preserved ejection fraction (HFpEF) are at high risk of mortality, hospitalizations, and reduced functional capacity and quality of life.Objective: To assess the efficacy of the oral soluble guanylate cyclase stimulator vericiguat on the physical limitation score (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ).Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled, multicenter trial of 789 patients with chronic HFpEF and left ventricular ejection fraction 45% or higher with New York Heart Association class II-III symptoms, within 6 months of a recent decompensation (HF hospitalization or intravenous diuretics for HF without hospitalization), and with elevated natriuretic peptides, enrolled at 167 sites in 21 countries from June 15, 2018, through March 27, 2019; follow-up was completed on November 4, 2019.Interventions: Patients were randomized to receive vericiguat, up-titrated to 15-mg (n = 264) or 10-mg (n = 263) daily oral dosages, compared with placebo (n = 262) and randomized 1:1:1.Main Outcomes and Measures: The primary outcome was change in the KCCQ PLS (range, 0-100; higher values indicate better functioning) after 24 weeks of treatment. The secondary outcome was 6-minute walking distance from baseline to 24 weeks.Results: Among 789 randomized patients, the mean age was 72.7 (SD, 9.4) years; 385 (49%) were female; mean EF was 56%; and median N-terminal pro-brain natriuretic peptide level was 1403 pg/mL; 761 (96.5%) completed the trial. The baseline and 24-week KCCQ PLS means for the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 60.0 and 68.3, 57.3 and 69.0, and 59.0 and 67.1, respectively, and the least-squares mean changes were 5.5, 6.4, and 6.9, respectively. The least-squares mean difference in scores between the 15-mg/d vericiguat and placebo groups was -1.5 (95% CI, -5.5 to 2.5; P = .47) and between the 10-mg/d vericiguat and placebo groups was -0.5 (95% CI, -4.6 to 3.5; P = .80). The baseline and 24-week 6-minute walking distance mean scores in the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 295.0 m and 311.8m , 292.1 m and 318.3 m, and 295.8 m and 311.4 m, and the least-squares mean changes were 5.0 m, 8.7 m, and 10.5 m, respectively. The least-squares mean difference between the 15-mg/d vericiguat and placebo groups was -5.5 m (95% CI, -19.7 m to 8.8 m; P = .45) and between the 10-mg/d vericiguat and placebo groups was -1.8 m (95% CI, -16.2 m to 12.6 m; P = .81), respectively. The proportions of patients who experienced symptomatic hypotension were 6.4% in the 15-mg/d vericiguat group, 4.2% in the 10-mg/d vericiguat group, and 3.4% in the placebo group; those with syncope were 1.5%, 0.8%, and 0.4%, respectively.Conclusions and Relevance: Among patients with HFpEF and recent decompensation, 24-week treatment with vericiguat at either 15-mg/d or 10-mg/d dosages compared with placebo did not improve the physical limitation score of the KCCQ.Trial Registration: ClinicalTrials.gov Identifier: NCT03547583. [ABSTRACT FROM AUTHOR]

Aim: Istaroxime is a first‐in‐class agent which acts through inhibition of the sarcolemmal Na+/K+ pump and activation of the SERCA2a pump. This study assessed the effects of a 24 h infusion of istaroxime in patients hospitalised for acute heart failure (AHF). Methods and results: We included patients hospitalised for AHF with left ventricular ejection fraction ≤40% and E/e' > 10. Patients were randomised to a 24 h intravenous infusion of placebo or istaroxime at doses of 0.5 μg/kg/min (cohort 1: placebo n = 19; istaroxime n = 41) or 1.0 μg/kg/min (cohort 2: placebo n = 20, istaroxime n = 40). The primary endpoint of change in E/e' ratio from baseline to 24 h decreased with istaroxime vs. placebo (cohort 1: −4.55 ± 4.75 istaroxime 0.5 μg/kg/min vs. −1.55 ± 4.11 placebo, P = 0.029; cohort 2: −3.16 ± 2.59 istaroxime 1.0 μg/kg/min vs. −1.08 ± 2.72 placebo, P = 0.009). Both istaroxime doses significantly increased stroke volume index and decreased heart rate. Systolic blood pressure increased with istaroxime, achieving significance with the high dose. Self‐reported dyspnoea and N‐terminal pro‐brain natriuretic peptide improved in all groups without significant differences between istaroxime and placebo. No significant differences in cardiac troponin absolute values or clinically relevant arrhythmias were observed during or after istaroxime infusion. Serious cardiac adverse events (including arrhythmias and hypotension) did not differ between placebo and istaroxime groups. The most common adverse events were injection site reactions and gastrointestinal events, the latter primarily with istaroxime 1.0 μg/kg/min. Conclusions: In patients hospitalised for AHF with reduced ejection fraction, a 24 h infusion of istaroxime improved parameters of diastolic and systolic cardiac function without major cardiac adverse effects. [ABSTRACT FROM AUTHOR]

Patients hospitalized for heart failure (HF) remain at high risk for early readmission. A post hoc analysis was performed of the biomarker substudy of the ASCEND-HF trial. An in-hospital congestion score was derived using orthopnea, pedal edema, and NT-proBNP levels. Its added prognostic value beyond traditional risk factors was assessed by determining the net reclassification index (NRI). Study participants (n = 884) had a median age (years) of 67 (55–77), 68% were male, and the median (25th–75th) ejection fraction (%) was 26 (20–40). After adjustment, increasing congestion score was associated with 30-day all-cause mortality or HF hospitalization (odds ratio = 1.51, 95% confidence interval [CI] 1.28–1.77, p < 0.001) and 180-day all-cause mortality (hazard ratio = 1.48, 95% CI 1.28–1.72, p < 0.001). However, adding the congestion score to the multivariable model did not significantly impact the NRI. A higher in-hospital congestion score portended a poor short-term prognosis but did not significantly reclassify risk. [ABSTRACT FROM AUTHOR]

Aims: Non-cardiac comorbidities are highly prevalent in patients with heart failure (HF). Our objective was to define the association between non-cardiac comorbidity burden and clinical outcomes, costs of care, and length of stay within a large randomized trial of acute HF patients.Methods and Results: Patients with complete medical history for the following comorbidities were included: diabetes mellitus, chronic obstructive pulmonary disease, chronic liver disease, history of cancer within the last 5 years, chronic renal disease (baseline serum creatinine >3.0 mg/mL), current smoking, alcohol abuse, depression, anaemia, peripheral arterial disease, and cerebrovascular disease. Patients were classified by overall burden of non-cardiac comorbidities (0, 1, 2, 3, and 4+). Hierarchical generalized linear models were used to assess associations between comorbidity burden and 30-day all-cause death or HF hospitalization and 180-day all-cause death in addition to costs of care and length of stay. A total of 6945 patients were included in the final analysis. Mean comorbidity number was 2.2 (± 1.34). Patients with 4+ comorbidities had higher rates of 30-day all-cause death/HF hospitalization as compared with patients with no comorbidities [odds ratio (OR) 3.32, 95% confidence interval (CI) 1.61-6.84; P < 0.01]. Similar results were seen with respect to 180-day death (OR 2.13, 95% CI 1.33-3.43; P < 0.01). Higher comorbidity burden was associated with higher 180-day costs of care and length of stay.Conclusions: Higher comorbidity burden is associated with poor clinical outcomes, higher costs of care, and extended length of stay. Further studies are needed to define the impact of comorbidity management programmes on outcomes for HF patients. [ABSTRACT FROM AUTHOR]

Despite improvements in outcomes in the last few decades for heart failure (HF) with reduced ejection fraction (HFrEF), there still remains a need for novel therapies as many patients incompletely recover with existing therapies and progress to advanced HF. In this review, we will discuss recent advances in the management of HFrEF with a focus on upcoming therapies that hold the greatest promise for clinical use. We will discuss novel pharmacological therapies and areas of uncertainty with existing therapies. We will also discuss the potential utility and controversy surrounding novel interventions for HF such as percutaneous mitral valve repair, atrial fibrillation ablation, and other emerging interventions with positive signals for benefit in HFrEF. Finally, we will summarize the current state of stem cell and gene therapy for HFrEF and future directions. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Aims: Recently, bio-adrenomedullin (bio-ADM) was proposed as a congestion marker in heart failure (HF). In the present study, we aimed to study whether bio-ADM levels at discharge from a hospital admission for worsening HF could provide additional information on (residual) congestion status, diuretic dose titration and clinical outcomes.Methods and Results: Plasma bio-ADM was measured in 1236 acute HF patients in the PROTECT trial at day 7 or discharge. Median discharge bio-ADM was 33.7 [21.5-61.5] pg/mL. Patients with higher discharge bio-ADM levels were hospitalised longer, had higher brain natriuretic peptide levels, and poorer diuretic response (all P < 0.001). Bio-ADM was the strongest predictor of discharge residual congestion (clinical congestion score > 3) (odds ratio 4.35, 95% confidence interval 3.37-5.62; P < 0.001). Oedema at discharge was one of the strongest predictors of discharge bio-ADM (β = 0.218; P < 0.001). Higher discharge loop diuretic doses were associated with a poorer diuretic response during hospitalisation (β = 0.187; P < 0.001) and higher bio-ADM levels (β = 0.084; P = 0.020). High discharge bio-ADM levels combined with higher use of loop diuretics were independently associated with a greater risk of 60-day HF rehospitalisation (hazard ratio 4.02, 95% confidence interval 2.23-7.26; P < 0.001).Conclusion: In hospitalised HF patients, elevated pre-discharge bio-ADM levels were associated with higher discharge loop diuretic doses and reflected residual congestion. Patients with combined higher bio-ADM levels and higher loop diuretic use at discharge had an increased risk of rehospitalisation. Assessment of discharge bio-ADM levels may be a readily applicable marker to identify patients with residual congestion at higher risk of early hospital readmission. [ABSTRACT FROM AUTHOR]

Aim: Describe the distinguishing features of heart failure (HF) patients with reduced ejection fraction (HFrEF) in the VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) trial.Methods and Results: Key background characteristics were evaluated in 5050 patients randomized in VICTORIA and categorized into three cohorts reflecting their index worsening HF event. Differences within the VICTORIA population were assessed and compared with PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure). VICTORIA patients had increased risk of mortality and rehospitalization: New York Heart Association class (40% class III), atrial fibrillation (45%), diabetes (47%), hypertension (79%) and mean estimated glomerular filtration rate of 61.5 mL/min/1.73 m2 . Baseline standard of HF care was very good: 60% received triple therapy. Their N-terminal pro-B-type natriuretic peptide was 3377 pg/mL [interquartile range (IQR) 1992-6380]. Natriuretic peptides were 30% higher level in the 67% patients with HF hospitalization <3 months, compared to those within 3-6 months of HF hospitalization and those randomized after recent outpatient intravenous diuretic therapy. Overall the median MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score in VICTORIA was 23 (IQR 18-27) as compared to the MAGGIC risk score in PARADIGM-HF of 20 (IQR 16-24).Conclusions: VICTORIA comprises a broadly generalizable high-risk population of three unique clinical strata of worsening chronic HFrEF despite very good HF therapy. VICTORIA will establish the role of vericiguat, a soluble guanylate cyclase stimulator, in HFrEF. [ABSTRACT FROM AUTHOR]

Aims: We sought to better understand the role of percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) and moderate or severe left ventricular systolic dysfunction. Methods and results: Using data from the Duke Databank for Cardiovascular Disease, we analysed patients who underwent coronary angiography at Duke University Medical Center (1995–2012) that had stable CAD amenable to PCI and left ventricular ejection fraction ≤35%. Patients with acute coronary syndrome or Canadian Cardiovascular Society class III or IV angina were excluded. We used propensity‐matched Cox proportional hazards to evaluate the association of PCI with mortality and hospitalizations. Of 901 patients, 259 were treated with PCI and 642 with medical therapy. PCI propensity scores created from 24 variables were used to assemble a matched cohort of 444 patients (222 pairs) receiving PCI or medical therapy alone. Over a median follow‐up of 7 years, 128 (58%) PCI and 125 (56%) medical therapy alone patients died [hazard ratio 0.87 (95% confidence interval 0.68, 1.10)]; there was also no difference in the rate of a composite endpoint of all‐cause mortality or cardiovascular hospitalization [hazard ratio 1.18 (95% confidence interval 0.96, 1.44)] between the two groups. Conclusions: In this well‐profiled, propensity‐matched cohort of patients with stable CAD amenable to PCI and moderate or severe left ventricular systolic dysfunction, the addition of PCI to medical therapy did not improve long‐term mortality, or the composite of mortality or cardiovascular hospitalization. The impact of PCI on other outcomes in these high‐risk patients requires further study. [ABSTRACT FROM AUTHOR]

Aim: To describe differences in patient characteristics and outcomes by ethnicity in patients with diabetes mellitus (DM) and heart failure (HF) with reduced ejection fraction (HFrEF, ejection fraction ≤35%) in a multi-ethnic cohort.Methods and Results: Patient level data from two cohorts (HF-ACTION and ASIAN-HF) were combined, and patients grouped by self-reported ethnicity. DM was defined as the presence of a clinical diagnosis and/or receiving anti-diabetic therapy. A total of 6214 (1324 whites, 674 blacks, 1297 Chinese, 1510 Indians, 717 Malays, 692 Japanese/Koreans) patients were included. The overall prevalence of DM was 39.5% (n = 2454). The prevalence of DM was lowest in whites (29.3%), followed by Japanese/Koreans (34.1%), blacks (35.9%), Chinese (42.3%), Indians (44.2%), and highest in Malays (51.9%). The correlation between age, sex, body mass index, coronary artery disease, hypertension, atrial fibrillation, peripheral vascular disease and chronic kidney disease with DM differed significantly by ethnicity (P for interaction <0.05). The strongest correlations were seen in Malay women, whites with obesity, Indians with coronary artery disease and hypertension, and blacks with chronic kidney disease. On multivariable analyses, DM was significantly associated with the composite of 1-year overall mortality/HF hospitalization (hazard ratio 1.37, 95% confidence interval 1.19-1.57; P < 0.001), with no interaction by ethnicity (P for interaction =0.31).Conclusions: There is marked heterogeneity in the prevalence and correlates of DM among different ethnic groups with HF worldwide. Subgroups particularly predisposed to DM warrant special attention, since DM increases the combined risk of morbidity and mortality in all ethnicities with HF. [ABSTRACT FROM AUTHOR]

Although traditional renin-angiotensin system antagonists including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have revolutionized the treatment of cardiovascular disease (CVD), the pivotal PARADIGM-HF trial demonstrated that sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was superior to an angiotensin-converting enzyme inhibitor in reducing cardiovascular morbidity and mortality in patients with heart failure and reduced ejection fraction. However, despite international regulatory approval and strong recommendations in the guidelines, uptake of sacubitril/valsartan has been disappointing. Sacubitril/valsartan is now the focus of a large programme of clinical trials testing the hypothesis that ARNIs may supplant conventional renin-angiotensin system inhibitors across the spectrum of CVD, including hypertension, secondary prevention after myocardial infarction, and heart failure with preserved ejection fraction. This review summarizes the existing evidence, knowledge gaps, and future directions of ARNIs in CVD based on discussions between clinical trialists, industry representatives, and regulatory authorities at the 2016 Global CardioVascular Clinical Trialists Forum in Washington, D.C. [ABSTRACT FROM AUTHOR]

Aims: The incidence of and factors associated with sudden cardiac death (SCD) early after an acute heart failure (HF) hospital admission have not been well defined.Methods and Results: We assessed SCD and ventricular arrhythmias in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, which included patients with acute HF with reduced or preserved ejection fraction. SCD, resuscitated SCD (RSCD), and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) were adjudicated from randomization through 30 days and were combined into a composite endpoint. Baseline characteristics associated with this composite were determined by logistic regression. RSCD and VT/VF were included as time-dependent variables in a Cox model evaluating the association of these variables with 180-day all-cause mortality. Among 7011 patients, the 30-day all-cause mortality rate was 3.8%; SCD accounted for 17% of these deaths. The 30-day composite event rate was 1.8% (n = 121). Ten patients had more than one event with 30-day Kaplan-Meier event rates of 0.6% for SCD [95% confidence interval (CI) 0.5%-0.9%, n = 43], 0.4% for RSCD (95% CI 0.2%-0.5%, n = 24), and 0.9% for VT/VF (95% CI 0.7%-1.2%, n = 64). In the multivariable model, chronic obstructive pulmonary disease, history of VT, male sex, and longer QRS duration were associated with SCD, RSCD, or VT/VF. A RSCD or VT/VF event was associated with higher 180-day mortality (adjusted hazard ratio 6.6, 95% CI 4.8-9.1, P < 0.0001).Conclusions: Approximately 2% of patients admitted for acute HF experienced SCD, RSCD, or VT/VF within 30 days of admission, and SCD accounted for 17% of all deaths within 30 days. [ABSTRACT FROM AUTHOR]

Aims: Patients hospitalized for heart failure (HF) are at high risk for 30-day readmission. This study sought to examine the timings and causes of readmission within 30 days of an HF hospitalization.Methods and Results: Timing and cause of readmission in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial were assessed. Early and late readmissions were defined as admissions occurring within 0-7 days and 8-30 days post-discharge, respectively. Patients who died in hospital or remained hospitalized at day 30 post-randomization were excluded. Patients were compared by timing and cause of readmission. Logistic and Cox proportional hazards regression analyses were used to identify independent risk factors for early vs. late readmission and associations with 180-day outcomes. Of the 6584 patients (92%) in the ASCEND-HF population included in this analysis, 751 patients (11%) were readmitted within 30 days for any cause. Overall, 54% of readmissions were for non-HF causes. The median time to rehospitalization was 11 days (interquartile range: 6-18 days) and 33% of rehospitalizations occurred by day 7. Rehospitalization within 30 days was independently associated with increased risk for 180-day all-cause death [hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.93-2.94; P < 0.001]. Risk for 180-day all-cause death did not differ according to early vs. late readmission (HR 0.99, 95% CI 0.67-1.45; P = 0.94).Conclusions: In this hospitalized HF trial population, a significant majority of 30-day readmissions were for non-HF causes and one-third of readmissions occurred in the first 7 days. Early and late readmissions within the 30-day timeframe were associated with similarly increased risk for death. Continued efforts to optimize multidisciplinary transitional care are warranted to improve rates of early readmission. [ABSTRACT FROM AUTHOR]

Aims: Changes in systolic blood pressure (SBP) during an admission for acute heart failure (AHF), especially those leading to hypotension, have been suggested to increase the risk for adverse outcomes.Methods and Results: We analysed associations of SBP decrease during the first 24 h from randomization with serum creatinine changes at the last time-point available (72 h), using linear regression, and with 30- and 180-day outcomes, using Cox regression, in 1257 patients in the VERITAS study. After multivariable adjustment for baseline SBP, greater SBP decrease at 24 h from randomization was associated with greater creatinine increase at 72 h and greater risk for 30-day all-cause death, worsening heart failure (HF) or HF readmission. The hazard ratio (HR) for each 1 mmHg decrease in SBP at 24 h for 30-day death, worsening HF or HF rehospitalization was 1.01 [95% confidence interval (CI) 1.00-1.02; P = 0.021]. Similarly, the HR for each 1 mmHg decrease in SBP at 24 h for 180-day all-cause mortality was 1.01 (95% CI 1.00-1.03; P = 0.038). The associations between SBP decrease and outcomes did not differ by tezosentan treatment group, although tezosentan treatment was associated with a greater SBP decrease at 24 h.Conclusions: In the current post hoc analysis, SBP decrease during the first 24 h was associated with increased renal impairment and adverse outcomes at 30 and 180 days. Caution, with special attention to blood pressure monitoring, should be exercised when vasodilating agents are given to AHF patients. [ABSTRACT FROM AUTHOR]

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ("guided therapy") with inconsistent results.Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF).Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care.Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group.Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events.Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups.Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes.Trial Registration: clinicaltrials.gov Identifier: NCT01685840. [ABSTRACT FROM AUTHOR]

Hospitalisation for acute heart failure remains a major public health problem with high prevalence, morbidity, mortality, and cost. Prior attempts to develop new therapies for this condition have not been successful. Nitroxyl (HNO) plays a unique role in cardiovascular physiology by direct post-translational modification of thiol residues on target proteins, specifically SERCA2a, phospholamban, the ryanodine receptor and myofilament proteins in cardiomyocytes. In animal models, these biological effects lead to vasodilatation, increased inotropy and lusitropy, but without tachyphylaxis, pro-arrhythmia or evidence of increased myocardial oxygen demand. BMS-986231 is an HNO donor being developed as a therapy for heart failure, and initial studies in patients with heart failure support the potential clinical value of these physiological effects. In this manuscript, we describe the ongoing phase II development programme for BMS-986231, which consists of three related randomised placebo-controlled clinical trials, StandUP-AHF, StandUP-Imaging and StandUP-Kidney, which are designed to provide evidence of tolerability and efficacy as well as confirm the anticipated physiological effects in patients with heart failure with reduced ejection fraction. These studies will set the stage for the further study of BMS-986231 in future phase III clinical trials. [ABSTRACT FROM AUTHOR]

Aims: A 5-point change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) is commonly considered to be a clinically significant difference in health status in patients with heart failure. We evaluated how the magnitude of change relates to subsequent clinical outcomes.Methods and Results: Using data from the HF-ACTION trial of exercise training in chronic heart failure (n = 2331), we used multivariable Cox regression with piecewise linear splines to examine the relationship between change in KCCQ overall summary score from baseline to 3 months (range 0-100; higher scores reflect better health status) and subsequent all-cause mortality/hospitalization. Among 2038 patients with KCCQ data at the 3-month visit, KCCQ scores increased from baseline by ≥5 points for 45%, scores decreased by ≥5 points for 23%, and scores changed by <5 points for the remaining 32% of patients. There was a non-linear relationship between change in KCCQ and outcomes. Worsening health status was associated with increased all-cause mortality/hospitalization (adjusted hazard ratio 1.07 per 5-point KCCQ decline; 95% confidence interval 1.03-1.12; P < 0.001). In contrast, improving health status, up to an 8-point increase in KCCQ, was associated with decreased all-cause mortality/hospitalization (adjusted hazard ratio 0.93 per 5-point increase; 95% confidence interval 0.90-0.97; P < 0.001). Additional improvements in health status beyond an 8-point increase in KCCQ was not associated with all-cause death or hospitalization (P = 0.42).Conclusion: In patients with heart failure, small changes in KCCQ are associated with changing future risk, but more research will be necessary to understand how different magnitudes of improving health status affect outcomes. [ABSTRACT FROM AUTHOR]