Voors, Adriaan A.

Abstract Background Cardiovascular inflammation is thought to play a central role in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF), but no therapies specifically targeting inflammation in this setting are currently available. Purpose Here we describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the IL-6 ligand, in patients with HFpEF/HFmrEF and cardiovascular inflammation. Methods ATHENA and HERMES are international, multicenter, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation to ziltivekimab 15 mg or placebo, both administered subcutaneously once-monthly on top of standard of care. Eligible participants have a left ventricular ejection fraction >40%, elevated NTproBNP and serum high sensitivity C reactive protein ≥2 mg/L. The primary endpoint in ATHENA (n=680) is the change in Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score at 12 months. The primary endpoint in HERMES (n=4900) is the composite of CV death, hospitalization for HF or urgent HF visit. The study is event-driven and will target 845 primary events (Figure 1). Conclusions ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.Fig 1.ATHENA and HERMES trial designsFor image description, please refer to the figure legend and surrounding text.

Abstract Aims We hypothesized that targeting interleukin-6—a cytokine central to NOD-like receptor protein 3 (NLRP3) inflammasome activation that is associated with both the onset and progression of heart failure (HF)—may be beneficial in patients with HF and circulating evidence of cardiovascular inflammation but without overtly reduced ejection fraction (EF). We describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the interleukin-6 ligand, in patients with HF and mildly reduced or preserved EF (HFmrEF/HFpEF) and cardiovascular inflammation. Methods ATHENA (n = 673) and HERMES (n = 4900) are international, multi-centre, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation (high-sensitivity C-reactive protein ≥2 mg/l) to ziltivekimab 15 mg or placebo, administered subcutaneously once monthly on top of standard of care. Eligible participants have a left ventricular EF >40%, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and serum high-sensitivity C-reactive protein ≥2 mg/l. The primary endpoint in ATHENA is the change in Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score at 12 months. The primary endpoint in HERMES is time to first composite of cardiovascular death, hospitalization for HF, or urgent HF visit. ATHENA has a fixed duration of 12 months, whereas the HERMES trial is event driven (∼845 adjudicated primary events) with a minimum exposure of 6 months from randomization to the last treatment visit. Conclusion ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.

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.

BACKGROUND: Despite favorable hemodynamic and neurohormonal effects, endothelin receptor antagonists have not improved outcomes in patients with heart failure (HF), possibly because they cause fluid retention. METHODS: In this randomized, double-blind, multicenter trial (SERENADE [Macitentan in Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease]), we evaluated the effects of an endothelin receptor antagonist, macitentan, in patients with HF, left ventricular ejection fraction ≥40%, and pulmonary vascular disease. After a 4-week placebo run-in (to ensure clinical stability), followed by a 5-week single-blind macitentan run-in, patients who did not exhibit fluid retention were randomized to macitentan or placebo. The primary end point was change in NT-proBNP (N-terminal pro-B-type natriuretic peptide; baseline to 24 weeks); secondary end points included change in KCCQ (Kansas City Cardiomyopathy Questionnaire) clinical summary score (baseline to 24 weeks) and time to worsening HF by 52 weeks. RESULTS: Of 230 patients enrolled, 28 were excluded during the placebo run-in, 60 excluded during the macitentan run-in, and 142 were randomized. Macitentan had no effect on change in NT-proBNP (geometric mean ratio [macitentan/placebo], 1.02 [90% CI, 0.88–1.19]; P =0.79) or on secondary end points (placebo-corrected change in KCCQ clinical summary score, −3.5 [90% CI, −8.2 to +1.2]; P =0.22). Worsening HF occurred in 20 (28%) patients assigned to macitentan and 13 (18%) assigned to placebo (hazard ratio, 1.48 [90% CI, 0.83–2.67]; P =0.24). More macitentan-treated patients developed fluid retention (16 [23%] versus 10 [14%]) and cardiac adverse events (33 [46%] versus 22 [31%]) versus placebo. CONCLUSIONS: Despite a novel enrichment trial design to target pulmonary vascular disease and exclude treatment-related fluid retention in patients with HF and preserved/mildly reduced left ventricular ejection fraction, macitentan neither lowered NT-proBNP nor improved HF outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT03153111 and NCT03714815.

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.

Abstract Aims In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy. Methods The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo. Conclusion VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF.

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.

BackgroundHeart rate and systolic blood pressure (SBP) are prognostic markers in heart failure (HF) with reduced ejection fraction (HFrEF). Their combination in rate pressure product (RPP) as well as their role in heart failure with preserved ejection fraction (HFpEF) remains unclear.HypothesisRPP and its components are associated with HFpEF outcomes.MethodsWe performed an analysis of Acute Study of Clinical Effectiveness of Nesiritide in Subjects With Decompensated Heart Failure (ASCEND‐HF; http://www.clinicaltrials.gov NCT00475852), which studied 7141 patients with acute HF. HFpEF was defined as left ventricular ejection fraction ≥40%. Outcomes were assessed by baseline heart rate, SBP, and RPP, as well as the change of these variables using adjusted Cox models.ResultsAfter multivariable adjustment, in‐hospital change but not baseline heart rate, SBP, and RPP were associated with 30‐day mortality/HF hospitalization (hazard ratio [HR]: 1.17 per 5‐bpm heart rate, HR: 1.20 per 10‐mm Hg SBP, and HR: 1.02 per 100 bpm × mm Hg RPP; all P < 0.05). Baseline SBP was associated with 180‐day mortality (HR: 0.88 per 10‐mm Hg, P = 0.028). Though change in RPP was associated with 30‐day mortality/HF hospitalization, the RPP baseline variable did not provide additional associative information with regard to outcomes when compared with assessment of baseline heart rate and SBP variables alone.ConclusionsAn increase in heart rate and SBP from baseline to discharge was associated with increased 30‐day mortality/HF hospitalization in HFpEF patients with acute exacerbation. These findings suggest value in monitoring the trend of vital signs during HFpEF hospitalization.

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.