O’Connor, Christopher M.

Abstract Aims The efficacy and safety of vericiguat in patients with chronic heart failure with reduced ejection fraction (HFrEF) on contemporary heart failure (HF) therapies and without recent worsening was investigated in the VICTOR trial, yet some subgroups may be more susceptible to symptomatic hypotension. Methods and results Among VICTOR trial participants that received at least one dose of study drug or placebo, we describe the systolic blood pressure (SBP) trajectories over time (mean change from baseline), symptomatic hypotension events and efficacy of vericiguat in potentially vulnerable patient subgroups: lower baseline blood pressure (SBP ≤110 mmHg), older patients (>75 years) and those taking angiotensin receptor–neprilysin inhibitors (ARNI) or sodium–glucose co-transporter 2 inhibitors (SGLT2i) at baseline. The efficacy outcomes of cardiovascular death and HF hospitalization and cardiovascular death alone across baseline SBP were examined using Cox proportional hazards models. Overall SBP trajectories showed a small initial decline from baseline in vericiguat-treated patients compared with placebo (placebo-corrected differences of −1.17 [−1.84, −0.50], p = 0.0007) that was relatively stable throughout follow-up. This trajectory was similar in those >75 years (vs. younger) as well as those receiving ARNI or SGLT2i (as compared with those not receiving these) or those with SBP ≤110 mmHg at baseline (compared with >110 mmHg). Symptomatic hypotension occurred in 11.3% of vericiguat-treated patients compared with 9.2% of placebo-treated patients with an adjusted hazard ratio of 1.24 (95% confidence interval 1.06–1.46), which was similar across age, SBP, SGLT2i and ARNI groups (all interaction p >0.05). The treatment effect of vericiguat compared with placebo on the efficacy outcomes was similar across the spectrum of baseline SBP (both interaction p >0.15). Conclusions Vericiguat showed a slight adjusted decrease in SBP and resulted in more symptomatic hypotension compared with placebo but was overall well-tolerated in a broad population with HFrEF on contemporary therapy even among those predisposed to hypotension. Treatment effects on efficacy outcomes were consistent regardless of baseline SBP.

Abstract Background and Aims In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF). VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality. Methods VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the pre-specified secondary endpoint of cardiovascular death. All-cause death, sudden cardiac death, and death related to HF were also assessed. Results Over a median of 19.7 months (inter-quartile range 14.6–25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71–0.97; P = .020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74–0.97; P = .015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56–0.99; P = .042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54–0.94; P = .016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels. Conclusions In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.

Abstract Aims To describe the baseline characteristics of the participants in the VICTOR (Vericiguat Global Study in Patients with Chronic Heart Failure; NCT05093933) trial and compare them to recent trials in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results Baseline characteristics were evaluated in 6105 patients randomized to vericiguat or placebo. The mean age of the participants was 67 ± 11 years, 23.6% were women, 64.4% were White, and 10.7% were self-identified Black. Overall, 29.1% of participants were enrolled in Latin and South America, 27.8% and 18.5% in Eastern and Western Europe, 14.0% in Asia-Pacific and 10.6% in North America. The mean left ventricular ejection fraction was 30 ± 7% and 79% had New York Heart Association class II symptoms. Mean estimated glomerular filtration rate was 70.9 ± 24.0 ml/min/1.73 m2. Median N-terminal pro-B-type natriuretic peptide level was 1476 (970–2495) pg/ml and 47.5% of participants had no prior hospitalization for heart failure. Baseline therapy included 94.4% beta-blockers, 94.3% renin–angiotensin system modulation (including 56.0% on an angiotensin receptor–neprilysin inhibitor), 77.7% mineralocorticoid receptor antagonists, 59.1% sodium–glucose cotransporter 2 inhibitors, and 32.9% implantable cardioverter-defibrillators. Overall characteristics were relatively similar to other recent HFrEF trials but the VICTOR trial enrolled a higher proportion of participants receiving contemporary drug and device therapy. Conclusion The VICTOR trial enrolled the most optimally treated population in a phase III heart failure trial. These features will facilitate assessment of the benefit of vericiguat and elucidate the outcomes of patients on up-to-date medical therapy.

Introduction: Despite the use of different definitions for worsening heart failure (WHF) in prior clinical trials and registries, an in-hospital WHF event has consistently been associated with worse patient outcomes. WHF is being considered as a potential endpoint to support drug approval. We combined patients from two acute HF trials conducted by the HF Network (ROSE-AHF and DOSE-AHF) to understand how different WHF definitions are associated with event rates. Methods: WHF was defined as persistent or worsening HF requiring rescue therapy including IV vasoactive agents, ultrafiltration, or mechanical support over 72 hours after randomization in ROSE and also included additional open label loop or thiazide diuretic in DOSE. We assessed the relationship between WHF and the composite endpoint (CE) of re-hospitalization, emergency room visits for HF and mortality through 60 days. We also assessed for a differential relationship of WHF from 0-24 hours, 24-48 hours and 48-72 hours post-randomization. Results: The overall incidence of WHF was 14.6% (24.1% in DOSE and 6.3% in ROSE). Patients who developed WHF had lower baseline systolic blood pressure, less peripheral edema and higher BUN. In the combined dataset, WHF was associated with an increase in the CE (hazard ratio [HR] 1.64; 95% confidence interval [CI] 1.11-2.42; p-value 0.01). However, the association between WHF and 60-day outcomes was significant in ROSE but not in DOSE (Table). The development of WHF between 48-72 hours compared with 0-24 hours or 24-48 hours was associated with improved outcomes ([HR] 0.48, 95% CI 0.27 - 0.88, p-value 0.02 and [HR] 0.45, 95% CI 0.26 - 0.78, p-value 0.004, respectively). Conclusions: A WHF definition that incorporated intensification of diuretics increased the event rate but was not associated with worse 60-day outcomes. The timing of a WHF event also had a differential association with outcomes. These data support the use of a standardized WHF definition in clinical trials.

Abstract 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.

Background: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N -acetyl-β- d -glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation–Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis. Methods: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C. Results: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300–815 mg), which induced a urine output of 8425 mL (interquartile range, 6341–10 528 mL) over the 72-hour intervention period. Levels of N -acetyl-β- d -glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P >0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (−8.7 ng/mg; interquartile range, −169 to 35 ng/mg; P <0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin ( P =0.21), N -acetyl-β- d -glucosaminidase ( P =0.46), or kidney injury molecule 1 ( P =0.22). Increases in neutrophil gelatinase-associated lipocalin, N -acetyl-β- d -glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69–0.91; P =0.001). Conclusions: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.

Abstract 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 &lt; 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.

Background— In-hospital worsening heart failure (WHF) is an important event that has inconsistent definitions used across trials. We used data from 2 acute heart failure (HF) trials from the National Institutes of Health HF Network, DOSE (Diuretic Optimization Strategies Evaluation) and ROSE (Renal Optimization Strategies), to understand event rates associated with different WHF definitions. Methods and Results— We pooled data from 668 patients in DOSE and ROSE and assessed the relationship between WHF and the composite end point of rehospitalization, emergency room visits for HF, and mortality through 60 days. We also assessed for a differential relationship between the timing of WHF development and outcomes. The overall incidence of WHF was 14.6% (24.1% in DOSE, 6.3% in ROSE, and 5.0% in DOSE using the ROSE definition). WHF was associated with an increase in the composite end point (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.11–2.42; P =0.01). However, the association between WHF and outcomes was significantly stronger in ROSE than in DOSE (HR, 2.67; 95% CI, 1.45–4.91; P <0.01 and HR, 1.28; 95% CI, 0.79–2.08; P =0.31, respectively). Development of WHF between baseline to 24 hours compared with 24 to 48 hours or 48 to 72 hours demonstrated a trend toward improved outcomes (HR, 0.49; 95% CI, 0.21–1.17; P =0.11 and HR, 0.45; 95% CI, 0.20–1.04; P =0.06, respectively). Conclusions— A WHF definition that excluded the intensification of diuretics resulted in a lower event rate but a stronger association with outcomes. These data support the need for continued efforts to standardize WHF definitions in clinical trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00577135 (DOSE) and NCT01132846 (ROSE).

Background— Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results— We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, –4.2 [–4.9, –3.5] mg/dL and –3.5 [–4.2, –2.7] mg/dL at 12 and 24 weeks, respectively, both P <0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P =0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P =0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P =0.36). Conclusions— In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00987415.