Vericiguat in patients with chronic heart failure and reduced ejection fraction (VICTOR): a double-blind, placebo-controlled, randomised, phase 3 trial.

Background: Vericiguat is indicated to reduce the risk of cardiovascular death and hospitalisation for heart failure in patients with heart failure and reduced ejection fraction (HFrEF) following a recent worsening event. The aim of the VICTOR trial was to assess the effect of vericiguat in patients with HFrEF without recent heart failure worsening.

Methods: In this double-blind, placebo-controlled, phase 3 trial, conducted at 482 sites across 36 countries, patients aged 18 years or older with HFrEF (left ventricular ejection fraction of ≤40%) without heart failure hospitalisation within 6 months or outpatient intravenous diuretic use within 3 months before randomisation were randomly assigned (1:1) using an intervention randomisation system with interactive response technology to oral vericiguat (target 10 mg dose) or matching placebo.

Vericiguat for patients with heart failure and reduced ejection fraction across the risk spectrum: an individual participant data analysis of the VICTORIA and VICTOR trials.

Background: Following completion of the VICTORIA trial, vericiguat was approved for the treatment of worsening heart failure with reduced ejection fraction (HFrEF) and received a class IIb recommendation in European and North American guidelines. The subsequent VICTOR trial evaluated the use of vericiguat in patients with HFrEF and no recent worsening. We aimed to assess the effect of vericiguat on clinical endpoints through pooled analyses of patient-level data from the VICTORIA and VICTOR trials.

Effect of Vericiguat on Worsening Heart Failure in Compensated Outpatients with HFrEF: Insights from VICTOR.

Background: In the VICTOR trial, in a contemporary ambulatory cohort with heart failure and reduced ejection fraction (HFrEF) and no recent hospitalization, the primary outcome of hospitalization for heart failure (HHF) and cardiovascular death was not statistically significantly reduced with vericiguat. Vericiguat reduced risk of mortality but not HHF. In this ambulatory compensated cohort, time to first HHF may underestimate the overall worsening HF burden by failing to consider the high proportion of outpatient worsening HF events.

Assessing Benefit in Heart Failure Patients with Reduced Ejection Fraction: Analysis of the VICTORIA Trial Using Novel Prognostic Risk Stratification.

Background: Randomized trials remain the standard for evaluating novel therapies. Primary endpoint(s) risk heterogeneity may dilute treatment efficacy. The 5-step stratified testing and amalgamation routine (5-STAR) methodology helps address these limitations.

Vericiguat and mortality in heart failure and reduced ejection fraction: the VICTOR trial.

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.

Safety and tolerability of a 5 mg starting dose of vericiguat among patients with heart failure: The VELOCITY study.

Aims: In clinical practice, simplifying the number of medication titration steps while maintaining safety may improve the likelihood of patients with heart failure (HF) achieving target doses of guideline-directed medical therapy (GDMT). The VELOCITY study examined whether removing the 2.5 mg initiation step for vericiguat, and instead initiating therapy at 5 mg daily, would be safe and well-tolerated.

Baseline characteristics of contemporary trial participants with heart failure and reduced ejection fraction: The VICTOR trial.

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.

Vericiguat Global Study in Participants with Chronic Heart Failure: Design of the VICTOR trial.

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.

Projecting the benefit of vericiguat in PARADIGM-HF and DAPA-HF populations: Insights from the VICTORIA trial.

Aims: The VICTORIA trial demonstrated a significant reduction in the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death with vericiguat relative to placebo in high-risk HF. This study aimed to contextualize treatment effects of vericiguat in populations with varying risk profiles simulated from the PARADIGM-HF and DAPA-HF trials.

Methods: Subgroups of VICTORIA participants (n = 5050) were generated to simulate PARADIGM-HF and DAPA-HF trial populations.

How to make cardiology clinical trials more inclusive.

Cardiovascular clinical trials continue to under-represent children, older adults, females and people from ethnic minority groups relative to population disease distribution. Here we describe strategies to foster trial representativeness, with proposed actions at the levels of trial funding, design, conduct and dissemination. In particular, trial representativeness may be increased through broad recruitment strategies and site selection criteria that reflect the diversity of patients in the catchment area, as well as limiting unjustified exclusion criteria and using pragmatic designs that minimize research burden on patients (including embedded and decentralized trials).

Diuretic use and outcomes in patients with heart failure with reduced ejection fraction: Insights from the VICTORIA trial.

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).

Recurrent heart failure hospitalizations increase the risk of mortality in heart failure patients with atrial fibrillation and type 2 diabetes mellitus in the United Kingdom: a retrospective analysis of Clinical Practice Research Datalink database.

Background: Heart failure (HF) is a global illness and is a leading cause of hospitalizations. Recurrent HF hospitalization (HFH) is associated with increased risk of cardiovascular (CV) and all-cause mortality, thereby burdening the health system. Type 2 diabetes mellitus (T2DM) and atrial fibrillation (AF) are two important comorbidities in patients living with HF.

Hospitalization Rates in Patients with Heart Failure and Reduced Ejection Fraction Initiating Sacubitril/Valsartan or Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers: A Retrospective Cohort Study.

Introduction: The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (SAC/VAL) has shown benefit in patients with symptomatic heart failure (HF), including those naïve to renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and is considered the preferred RAASi for chronic HF. Real-world data on ARNI, specifically in RAASi-naïve patients, are limited. This study compared real-world outcomes of ARNI (SAC/VAL) vs.

Burden and Quality of Life Among Female and Male Patients with Heart Failure in Europe: A Real-World Cross-Sectional Study.

Purpose: To characterize symptoms, clinical burden, and health-related quality of life (HRQoL) among women and men with heart failure (HF) with a left ventricular ejection fraction (LVEF) of ≤60% in Europe.

Patients And Methods: A real-world cross-sectional study was conducted in France, Germany, Italy, Spain, and United Kingdom from June to November 2019. Patient record forms were completed by 257 cardiologists and 158 general practitioners for consecutive patients with HF.

Caregivers of Patients with Heart Failure: Burden and the Determinants of Health-Related Quality of Life.

Purpose: To assess the burden among caregivers of patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤60%. The burden by New York Heart Association (NYHA) functional class was also characterized.

Patients And Methods: A cross-sectional study was conducted in France, Germany, Italy, Spain, and UK from June to November 2019.

Recurrent heart failure hospitalizations increase the risk of cardiovascular and all-cause mortality in patients with heart failure in Sweden: a real-world study.

Aims: Heart failure (HF) is a leading cause of hospitalization and is associated with high morbidity and mortality. We examined the impact of recurrent HF hospitalizations (HFHs) on cardiovascular (CV) mortality among patients with HF in Sweden.

Methods And Results: Adults with incident HF were identified from linked national health registers and electronic medical records from 01 January 2005 to 31 December 2013 for Uppsala and until 31 December 2014 for Västerbotten.

Real-world effectiveness and safety of sacubitril/valsartan in heart failure: A systematic review.

Background: PARADIGM-HF demonstrated superiority of sacubitril/valsartan (sac/val) over enalapril in patients with heart failure with reduced ejection fraction (HFrEF). However, patients in clinical practice may differ in their characteristics and overall risk compared with patients in clinical trials, and additional outcomes can be observed in real world (RW). Hence, a systematic review was conducted to identify and describe RW data on sac/val.

Recurrent hospitalizations are associated with increased mortality across the ejection fraction range in heart failure.

Aims: The proportion of patients hospitalized for heart failure (HF) with preserved left ventricular ejection fraction (LVEF) is rising, but no approved treatment exists, in part owing to incomplete characterization of this particular HF phenotype. In order to better define the characteristics of HF phenotypes in Finland, a large cohort with 12 years' follow-up time was analysed.

Methods And Results: Patients diagnosed between 2005 and 2017 at the Hospital District of Southwest Finland were stratified according to LVEF measure and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels.

Recurrent heart failure hospitalizations are associated with increased cardiovascular mortality in patients with heart failure in Clinical Practice Research Datalink.

Aims: Heart failure (HF) is a leading cause of hospitalization and is associated with high morbidity and mortality post-diagnosis. Here, we examined the impact of recurrent HF hospitalization (HFH) on cardiovascular (CV) and all-cause mortality among HF patients.

Methods And Results: Adult HF patients identified in the Clinical Practice Research Datalink with a first (index) hospitalization due to HF recorded in the Hospital Episode Statistics data set from January 2010 to December 2014 were included.

A Database Cohort Study to Assess the Risk of Angioedema Among Patients with Heart Failure Initiating Angiotensin-Converting Enzyme Inhibitors in the USA.

Introduction: Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce.

Objective: This non-interventional study aimed to estimate the incidence of and risk factors for angioedema in patients with HF initiating an ACEI in real-world practice.

Methods: This was a retrospective cohort study using claims data from the PharMetrics Plus database, supplemented with consumer health data, from 1 January 2007 to 31 March 2015.

Negative effects of rofecoxib treatment on cardiac function after ischemia-reperfusion injury in APOE3Leiden mice are prevented by combined treatment with thromboxane prostanoid-receptor antagonist S18886 (terutroban).

Objective: Selective cyclooxygenase-2 inhibition by rofecoxib was associated with increased risk of cardiovascular events. We hypothesized that concomitant treatment with thromboxane prostanoid receptor antagonist S18886 might ameliorate possible negative effects. We evaluated the effects of S18886, rofecoxib, and the interaction of both compounds in a combined treatment on myocardial infarct (MI) size and cardiac function after experimental ischemia/reperfusion injury in hyperlipidemic APOE*3Leiden transgenic mice.

Thromboxane A2/prostaglandin H2 receptor activation mediates angiotensin II-induced postischemic neovascularization.

Objective: We analyzed the involvement of thromboxane (TX) A2/prostaglandin (PG) H2 (TP) receptor in ischemia-induced neovascularization in mice.

Methods And Results: Unilateral hindlimb ischemia was induced by right femoral artery ligature in male C57BL/6J mice (n=7 per group). Animals were then treated with or without TP receptor antagonist (S18886, 5 or 10 mg/kg per day; ramatroban, 10 mg/kg per day) or aspirin (30 mg/kg per day) in drinking water for 21 days.

The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice.

Arachidonic acid metabolites, some of which may activate thromboxane A(2) receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with S18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. Diabetic mice were treated with S18886 (5 mg .

The thromboxane A2 receptor antagonist S18886 prevents enhanced atherogenesis caused by diabetes mellitus.

Background: S18886 is an orally active thromboxane A2 (TXA2) receptor (TP) antagonist in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. We previously showed that S18886 inhibits atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice by a mechanism independent of platelet-derived TXA2. Atherosclerosis is accelerated by diabetes and is associated with increased TXA(2) and other eicosanoids that stimulate TP.