Nonclinical Cardiovascular Assessment of the Soluble Guanylate Cyclase Stimulator Vericiguat.

Vericiguat and its metabolite M-1 were assessed for proarrhythmic risk in nonclinical in vitro and in vivo studies. In vitro manual voltage-clamp recordings at room temperature determined the effect of vericiguat on human Ether-a-go-go Related Gene (hERG) K+ channels. Effects of vericiguat and M-1 on hERG K+, Nav1.5, hCav1.2, hKvLQT1/1minK, and hKv4.3 channels were investigated via automated voltage-clamp recordings at ambient temperature. Effects of vericiguat and M-1 on hERG K+ and Nav1.5 channels at pathophysiological conditions were explored via manual voltage-clamp recordings at physiologic temperature. Single oral doses of vericiguat (0.6, 2.0, and 6.0 mg/kg) were assessed for in vivo proarrhythmic risk via administration to conscious telemetered dogs; electrocardiogram (ECG) and hemodynamic parameters were monitored. ECG recordings were included in 4- and 39-week dog toxicity studies. In manual voltage-clamp recordings, vericiguat inhibited hERG K+-mediated tail currents in a concentration-dependent manner (20% threshold inhibitory concentration ∼1.9 µM). In automated voltage-clamp recordings, neither vericiguat nor M-1 were associated with biologically relevant inhibition (>20%) of hNav1.5, hCav1.2, hKvLQT1, and hKv4.3. No clinically relevant observations were made for hNav1.5 and hKvLQT1 under simulated pathophysiological conditions. Vericiguat was associated with expected mode-of-action-related dose-dependent changes in systolic arterial blood pressure (up to -20%) and heart rate (up to +53%). At maximum vericiguat dose, corrected QT (QTc) interval changes from baseline varied slightly (-6 to +1%) depending on correction formula. Toxicity studies confirmed absence of significant QTc interval changes. There was no evidence of an increased proarrhythmic risk from nonclinical studies with vericiguat or M-1. SIGNIFICANCE STATEMENT: There was no evidence of an increased proarrhythmic risk from in vitro and in vivo nonclinical studies with vericiguat or M-1. The integrated risk assessment of these nonclinical data combined with existing clinical data demonstrate administration of vericiguat 10 mg once daily in patients with heart failure with reduced ejection fraction is not associated with a proarrhythmic risk.

Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction: The VICTORIA Biomarker Substudy.

BACKGROUND: Circulating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect. METHODS AND RESULTS: High-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14-1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed. CONCLUSIONS: hs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.

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

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

Impact of ADCY9 Genotype on Response to Anacetrapib.

BACKGROUND: Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to cholesteryl ester transfer protein (CETP) inhibitor therapy differs by ADCY9 genotype, prompting the ongoing dal-GenE trial in individuals with a particular genetic profile. The randomized placebo-controlled REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification) demonstrated the clinical efficacy of the CETP inhibitor anacetrapib among patients with preexisting atherosclerotic vascular disease. In the present study, we examined the impact of ADCY9 genotype on response to anacetrapib in the REVEAL trial. METHODS: Individuals with stable atherosclerotic vascular disease who were treated with intensive atorvastatin therapy received either anacetrapib 100 mg daily or matching placebo. Cox proportional hazards models, adjusted for the first 5 principal components of ancestry, were used to estimate the effects of allocation to anacetrapib on major vascular events (a composite of coronary death, myocardial infarction, coronary revascularization, or presumed ischemic stroke) and the interaction with ADCY9 rs1967309 genotype. RESULTS: Among 19 210 genotyped individuals of European ancestry, 2504 (13.0%) had a first major vascular event during 4 years median follow-up: 1216 (12.6%) among anacetrapib-allocated participants and 1288 (13.4%) among placebo-allocated participants. Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 genotype: hazard ratio (HR) = 0.92 (95% CI, 0.81-1.05) for GG; HR = 0.94 (95% CI, 0.84-1.06) for AG; and HR = 0.93 (95% CI, 0.76-1.13) for AA genotype carriers, respectively; genotypic P for interaction = 0.96. Furthermore, there were no associations between ADCY9 genotype and the proportional reductions in the separate components of major vascular events or meaningful differences in lipid response to anacetrapib. CONCLUSIONS: The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib. The ongoing dal-GenE study will provide direct evidence as to whether there is any specific pharmacogenetic interaction with dalcetrapib. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT01252953. URL: http://www.isrctn.com. Unique identifier: ISRCTN48678192. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2010-023467-18.

Effect of Vericiguat vs Placebo on Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The VITALITY-HFpEF Randomized Clinical Trial.

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.

Characterization of Anacetrapib Distribution into the Lipid Droplet of Adipose Tissue in Mice and Human Cultured Adipocytes.

Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP), associated with reduction in LDL cholesterol and increase in HDL cholesterol in hypercholesterolemic patients. Anacetrapib was not taken forward into filing/registration as a new drug for coronary artery diease, despite the observation of a ∼9% reduction in cardiovascular risk in a large phase III cardiovascular outcomes trial (REVEAL). Anacetrapib displayed no adverse effects throughout extensive preclinical safety evaluation, and no major safety signals were observed in clinical trials studying anacetrapib, including REVEAL. However, anacetrapib demonstrated a long terminal half-life in all species, thought to be due, in part, to distribution into adipose tissue. We sought to understand the dependence of anacetrapib's long half-life on adipose tissue and to explore potential mechanisms that might contribute to the phenomenon. In mice, anacetrapib localized primarily to the lipid droplet of adipocytes in white adipose tissue; in vitro, anacetrapib entry into cultured human adipocytes depended on the presence of a mature adipocyte and lipid droplet but did not require active transport. In vivo, the entry of anacetrapib into adipose tissue did not require lipase activity, as the distribution of anacetrapib into adipose was-not affected by systemic lipase inhibition using poloaxamer-407, a systemic lipase inhibitor. The data from these studies support the notion that the entry of anacetrapib into adipose tissue/lipid droplets does not require active transport, nor does it require mobilization or entry of fat into adipose via lipolysis.

Structural insights into neuronal K+ channel-calmodulin complexes.

Calmodulin (CaM) is a ubiquitous intracellular calcium sensor that directly binds to and modulates a wide variety of ion channels. Despite the large repository of high-resolution structures of CaM bound to peptide fragments derived from ion channels, there is no structural information about CaM bound to a fully folded ion channel at the plasma membrane. To determine the location of CaM docked to a functioning KCNQ K(+) channel, we developed an intracellular tethered blocker approach to measure distances between CaM residues and the ion-conducting pathway. Combining these distance restraints with structural bioinformatics, we generated an archetypal quaternary structural model of an ion channel-CaM complex in the open state. These models place CaM close to the cytoplasmic gate, where it is well positioned to modulate channel function.

Clinical Pharmacokinetic and Pharmacodynamic Profile of Vericiguat.

Vericiguat is an oral soluble guanylate cyclase stimulator and enhances the cyclic guanosine monophosphate pathway independently of nitric oxide as well as synergistically in normal- and low-nitric oxide conditions. This review describes the pharmacokinetic and pharmacodynamic profile of vericiguat and summarizes the effect of vericiguat on cardiac electrophysiology and population pharmacokinetic/pharmacodynamic relationships. Vericiguat demonstrates virtually complete absorption and increased exposure with food. Vericiguat has high oral bioavailability when taken with food (93.0%) with dose-proportional pharmacokinetics in healthy volunteers. Vericiguat has slightly less than dose-proportional pharmacokinetics with a slight decrease in bioavailability at higher doses in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Vericiguat is a low-clearance drug, with a half-life of approximately 20 h in healthy volunteers and 30 h in patients with HFrEF. Most drug metabolism is achieved by glucuronidation. Vericiguat has pharmacodynamic effects as expected from its pharmacological mechanism of action (i.e., relaxation of the smooth muscles in the vasculature leading to changes in hemodynamics). In the VICTORIA trial (NCT02861534), which enrolled patients with HFrEF, no meaningful exposure-response relationships for the incidence of symptomatic hypotension or syncope were evident. There were no significant imbalances in the incidence of undesirable hemodynamic-related effects (symptomatic hypotension and syncope) in subgroups with HFrEF defined by sex, age, race, and renal impairment. In addition, most patients achieved the 10-mg target dose per the blood pressure-guided titration regimen. No dose adjustments due to body weight, age, sex, race, or hepatic/renal impairment are necessary in adult patients with HFrEF. Observed and predicted changes in vericiguat exposure when co-administered with perpetrator drugs were small and not clinically meaningful. In addition, vericiguat has low potential as a perpetrator to affect exposure and/or pharmacodynamic effects of drugs commonly prescribed in patients with heart failure; therefore, no dose adjustment of these drugs is required in patients taking vericiguat. There is limited experience on the combined use of vericiguat with long-acting nitrates in patients with HFrEF. The ongoing VICTOR trial (NCT05093933), which is investigating vericiguat in patients with HFrEF, permits the co-administration of long-acting nitrates. Combined use of vericiguat and phosphodiesterase type-5 inhibitors has not been studied in patients with HFrEF and is therefore not recommended because of the potential increased risk for symptomatic hypotension. Vericiguat was not associated with electrophysiological abnormalities in preclinical and clinical studies up to the approved dose of 10 mg at steady state. Vericiguat is approved for the treatment of recently decompensated patients with worsening HFrEF. Vericiguat's safety and efficacy profile in patients with HFrEF will be further characterized by the VICTOR trial (NCT05093933) in adults without recent decompensation and in a pediatric population with HF due to left ventricular systolic dysfunction (VALOR trial, NCT05714085).

Accelerometer vs. other activity measures in heart failure with preserved ejection fraction: the VITALITY-HFpEF trial.

AIMS: The relationship between accelerometry data and changes in Kansas City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) or 6 min walk test (6MWT) is not well understood. METHODS AND RESULTS: VITALITY-HFpEF accelerometry substudy (n = 69) data were assessed at baseline and 24 weeks. Ordinal logistic regression models were used to assess the association between accelerometry activity and deterioration, improved, or unchanged KCCQ-PLS (≥8.33 and ≤ -4.17 points) and 6MWT (≥32 vs. ≤ -32 m). KCCQ-PLS score deteriorated in 16 patients, improved in 34, and was unchanged in 19. 6MWT deteriorated in 8 patients, improved in 21, and was unchanged in 19. Mean accelerometer wear was 21.4 (±2.1) h/day. Changes in hours active from baseline to 24 weeks were not significantly different among patients who exhibited deterioration, improvement, or no change in KCCQ-PLS [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.71-1.18; P = 0.48] or 6MWT (OR 1.21, 95% CI 0.91-1.60; P = 0.18). Similar lack of association was observed for other accelerometry metrics and change in KCCQ and 6MWT. These findings were unaffected when KCCQ and 6MWT were examined as continuous variables. CONCLUSIONS: Accelerometer-based activity measures did not correlate with subjective or objective standard measures of health status and functional capacity in heart failure with preserved ejection fraction. Further investigation of their relationships to clinical outcomes is required.

Contemporary outpatient management of patients with worsening heart failure with reduced ejection fraction: Clinical outcome results from the CHART-HF study.

Background: Based on available data from randomized clinical trials, patients with heart failure with reduced ejection fraction (HFrEF) and worsening HF events (WHFE) have substantial disease burden and poor outcomes. WHFE clinical outcome data in non-clinical trial patients, more representative of the US clinical practice, has not been demonstrated. Methods and results: CHART-HF collected data from two complementary, non-clinical trial cohort with HFrEF (LVEF <45 %): 1) 1,000 patients from an integrated delivery network and 2) 458 patients from a nationwide physician panel. CHART-HF included patients with WHFE between 2017 and 2019 followed by an index outpatient cardiology visit ≤6 months, and patients without WHFE in a given year between 2017 and 2019, with the last outpatient cardiology visit in the same year as the index visit. Compared to patients without WHFE (after covariate adjustment, all p < 0.05), patients with WHFE had a greater risk of HF-related hospitalization (hazard ratio [HR]: 1.53-2.40) and next WHFE event (HR: 1.67-2.41) following index visits in both cohorts. Conclusion: HFrEF patients with recent WHFE consistently had worse clinical outcomes in these non-clinical trial cohorts. Despite advances in therapies, unmet need to improve clinical outcomes in HFrEF patients with WHFE remains.

Vericiguat and Cardiovascular Outcomes in Heart Failure by Baseline Diabetes Status: Insights From the VICTORIA Trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) significantly worsens heart failure (HF) prognosis. OBJECTIVES: This study sought to investigate the impact of T2DM on outcomes in patients enrolled in VICTORIA and assess the efficacy of vericiguat in patients with and without T2DM. METHODS: Patients with HF with reduced ejection fraction were randomized to receive vericiguat or placebo in addition to standard therapy. The primary outcome was a composite of cardiovascular death or first heart failure hospitalization (HFH). A Cox proportional hazards model was used to calculate HRs and 95% CIs to assess if the effect of vericiguat differed by history of T2DM. RESULTS: Of 5,050 patients enrolled, 3,683 (72.9%) had glycosylated hemoglobin (HbA1c) measured at baseline. Of these, 2,270 (61.6%) had T2DM, 741 (20.1%) had pre-T2DM, 449 (12.2%) did not have T2DM, and 178 (4.8%) had undiagnosed T2DM. The risks of the primary outcome, HFH, and all-cause and cardiovascular mortality were high across all categories. The efficacy of vericiguat on the primary outcome did not differ in patients stratified by T2DM by history (HR: 0.92; 95% CI: 0.81-1.04), T2DM measured by HbA1c (HR: 0.77; 95% CI: 0.49-1.20), and pre-T2DM measured by HbA1c (HR: 0.88; 95% CI: 0.68-1.13) and in those with normoglycemia (HR: 1.02: 95% CI: 0.75-1.39; P for interaction = 0.752). No significant differences were observed in subgroups with respect to the efficacy of vericiguat on HFH and all-cause or cardiovascular death. CONCLUSIONS: In this post hoc analysis of VICTORIA, vericiguat compared with placebo significantly reduced the risk of cardiovascular death or HFH in patients with worsening HF with reduced ejection fraction regardless of T2DM status. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [Mk-1242-001] [VICTORIA]; NCT02861534).

Treatment patterns of patients with worsening heart failure with reduced ejection fraction.

AIMS: Patients with HFrEF and worsening HF events (WHFE) are at particularly high risk and urgently need disease-modifying therapy. CHART-HF assessed treatment patterns and reasons for medication decisions among HFrEF patients with and without WHFE. METHODS AND RESULTS: CHART-HF collected retrospective electronic medical records of outpatients with HF and EF < 45% between 2017-2019 from a nationwide panel of 238 cardiologists (458 patients) and the Geisinger Health System (GHS) medical record (1000 patients). The index visit in the WHFE cohort was the first outpatient cardiologist visit ≤6 months following the WHFE, and in the reference cohort was the last visit in a calendar year without WHFE. Demographic characteristics were similar between patients with and without WHFE in both the nationwide panel and GHS. In the nationwide panel, the proportion of patients with versus without WHFE receiving ≥50% of guideline-recommended dose on index visit was 35% versus 40% for beta blocker, 74% versus 83% for ACEI/ARB/ARNI, and 48% versus 49% for MRA. The proportion of patients receiving ≥50% of guideline-recommended dose was lower in the GHS: 29% versus 34% for beta-blocker, 16% versus 31% for ACEI/ARB/ARNI, and 18% versus 22% for MRA. For patients with and without WHFE, triple therapy on index date was 42% and 44% of patients from the nationwide panel, and 14% and 17% in the GHS. Comparing end of index clinic visit with 12-month follow-up in the GHS, the proportion of patients on no GDMT increased from 14% to 28% in the WHFE cohort and from 14 to 21% in the non-WHFE group. CONCLUSIONS: Major gaps in use of GDMT, particularly combination therapy, remain among US HFrEF patients. These gaps persist during longitudinal follow-up and are particularly large among patients with recent WHFE.

Vericiguat, a novel sGC stimulator: Mechanism of action, clinical, and translational science.

Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is approved for the treatment of heart failure (HF) with reduced ejection fraction (HFrEF). Decreased nitric oxide (NO) availability, sGC desensitization to NO, sGC deficiency, and reduced cyclic guanosine monophosphate (cGMP) signaling are potential contributing factors for HF disease progression. Vericiguat works via stimulation of sGC in the critical NO-sGC-cGMP pathway. Vericiguat is primarily metabolized by glucuronidation via uridine diphosphate-glucuronosyltransferase (UGT) isoforms UGT1A1 and UGT1A9. Urinary excretion and renal clearance of vericiguat are low. No intrinsic factor had a clinically relevant effect on vericiguat exposure. Vericiguat has low drug-drug interaction potential with no clinically relevant pharmacokinetic or pharmacodynamic interactions observed with warfarin, digoxin, aspirin, or sacubitril/valsartan. The global phase III study VICTORIA included patients with HFrEF who had a recent HF hospitalization or intravenous diuretic treatment for HF. Treatment with vericiguat on top of standard of care resulted in a 10% relative reduction in the primary composite outcome of death from cardiovascular causes or first hospitalization for HF. Vericiguat was well-tolerated with low incidence of symptomatic hypotension and syncope compared to placebo. Given its positive benefit-risk profile, vericiguat is an important option for high-risk patients with HFrEF who are already on guideline-directed medical therapy and had recent worsening of HF. Future efforts to develop additional effective therapies are needed to further reduce morbidity and mortality in patients with HF.

Patient-Reported Frailty and Functional Status in Heart Failure With Preserved Ejection Fraction: Insights From VITALITY-HFpEF.

BACKGROUND: The association between frailty and health status in patients with heart failure with preserved ejection fraction (HFpEF) is not well known. OBJECTIVES: The authors examined the association between: 1) patient-reported frailty, measured by the Fried frailty phenotype, Kansas City Cardiomyopathy Questionnaire Physical Limitation Score (KCCQ-PLS), 6-minute walking distance (6MWD), and other baseline characteristics; 2) baseline frailty compared with KCCQ-PLS and 24-week 6MWD; 3) frailty and changes in KCCQ-PLS and 6MWD; and 4) vericiguat and frailty at 24 weeks. METHODS: In a post hoc analysis, patients in the VITALITY-HFpEF (Patient-reported Outcomes in Vericiguat-treated Patients With HFpEF) trial were categorized as not frail (0 symptoms), prefrail (1-2 symptoms), and frail (≥3 symptoms) according to patient-reported number of frailty symptoms. Correlations and linear regression models were used to examine the association between frailty and other measures, and between frailty and KCCQ-PLS at baseline with 24-week 6MWD. RESULTS: Among 739 patients, 27.3% were not frail, 37.6% were prefrail, and 35.0% were frail at baseline. Frail patients were older, more likely to be women, and less likely to be from Asia. Baseline KCCQ-PLS and 6MWD (mean ± SD) among not frail, prefrail, and frail patients was 68.2 ± 23.2, 61.7 ± 22.6, and 48.4 ± 23.8 and 328.5 ± 117.1 m, 310.8 ± 98.9 m, and 250.7 ± 104.3 m (P < 0.01 for both). After accounting for baseline 6MWD, frailty status at baseline, but not KCCQ-PLS, was significantly associated with 6MWD at 24 weeks. By 24 weeks, 47.5% of patients had no change in frailty, 45.5% had become less frail, and 7.0% had become more frail. Treatment with vericiguat did not alter frailty status at 24 weeks. CONCLUSIONS: Patient-reported frailty is modestly correlated with both the KCCQ-PLS and 6MWD but offers prognostic insight into 6MWD at 24 weeks. (Patient-reported Outcomes in Vericiguat-treated Patients With HFpEF [VITALITY-HFpEF]; NCT03547583).

Relationship between baseline electrocardiographic measurements and outcomes in patients with high-risk heart failure: Insights from the VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial.

AIMS: Whether electrocardiographic (ECG) measurements predict mortality in chronic heart failure with reduced ejection fraction (HFrEF) is unknown. METHODS AND RESULTS: We studied 4880 patients from the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial with a baseline 12-lead ECG. Associations between ECG measurements and mortality were estimated as hazard ratios (HR) and adjusted for the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, N-terminal pro-B-type natriuretic peptide, and index event. Select interactions between ECG measurements, patient characteristics and mortality were examined. Over a median of 10.8 months, there were 824 cardiovascular (CV) deaths (214 sudden) and 1005 all-cause deaths. Median age was 68 years (interquartile range [IQR] 60-76), 24% were women, median ejection fraction was 30% (IQR 23-35), 41% had New York Heart Association class III/IV, and median MAGGIC score was 24 (IQR 19-28). After multivariable adjustment, significant associations existed between heart rate (per 5 bpm: HR 1.02), QRS duration (per 10 ms: HR 1.02), absence of left ventricular hypertrophy (HR 0.64) and CV death, and similarly so with all-cause death (HR 1.02; HR 1.02; HR 0.61, respectively). Contiguous pathologic Q waves were significantly associated with sudden death (HR 1.46), and right ventricular hypertrophy with all-cause death (HR 1.44). The only sex-based interaction observed was for pathologic Q waves on CV (men: HR 1.05; women: HR 1.64, pinteraction = 0.024) and all-cause death (men: HR 0.99; women: HR 1.57; pinteraction = 0.010). Whereas sudden death doubled in females, it did not differ among males (male: HR 1.25, 95% confidence interval [CI] 0.87-1.79; female: HR 2.50, 95% CI 1.23-5.06; pinteraction = 0.141). CONCLUSION: Routine ECG measurements provide additional prognostication of mortality in high-risk HFrEF patients, particularly in women with contiguous pathologic Q waves.

Age, Sex, and Outcomes in Heart Failure With Reduced EF: Insights From the VICTORIA Trial.

BACKGROUND: Age and sex influence treatment and outcomes in patients with heart failure (HF). OBJECTIVES: The authors examined the associations of age and sex with clinical characteristics, background therapies, outcomes, and response to vericiguat in this post hoc analysis of 5,050 VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) patients with HF and reduced ejection fraction; 1,568 (31%) were ≥75 years of age, of whom 445 (24%) were women. METHODS: Clinical characteristics were compared across age (<65, 65 to <75, and ≥75 years) and sex. The treatment effect of vericiguat was estimated by age and sex on the primary composite outcome (time to first HF hospitalization or cardiovascular death) using Cox proportional hazards regression. RESULTS: Compared with younger patients, those ≥75 years of age had more class III and IV symptoms, higher N-terminal pro-B-type natriuretic peptide levels, and worse kidney function but had the lowest use of triple therapy. No sex differences in triple therapy existed by age, but achieving target doses of triple therapy was less likely in older patients. Men ≥75 years of age were more than twice as likely to receive defibrillators and 65% more likely to undergo cardiac resynchronization than women. The primary composite outcome was nominally lower in women than men across all age groups. Vericiguat dosing did not differ between sexes in each age group, and its beneficial effect on the primary endpoint was not modified by age (continuous age, Pinteraction = 0.169; categorical age, Pinteraction = 0.189); and sex (3-way interaction; P = 0.847). CONCLUSIONS: Although elderly women received less intense background HF therapy than men, their prognosis was nominally better. The benefit of vericiguat was independent of age and sex. (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).

Evolution of NT-proBNP During Prerandomization Screening in VICTORIA: Implications for Clinical Outcomes and Efficacy of Vericiguat.

BACKGROUND: Selecting high-risk patients with heart failure with potentially modifiable cardiovascular events is a priority. Our objective was to evaluate NT-proBNP (N-terminal pro-B-type natriuretic peptide) changes during a 30-day screening to establish (1) the frequency and direction of changes; (2) whether a relationship exists between changes in NT-proBNP and the primary composite outcome of cardiovascular death and heart failure hospitalization; and (3) whether changes in NT-proBNP relate to vericiguat's clinical benefit. METHODS: VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) randomized 5050 patients with heart failure with reduced ejection fraction and a recent worsening heart failure event. We studied 3821 patients who had NT-proBNP measured during screening and at randomization. RESULTS: Sixteen hundred exhibited a >20% reduction, 1412 had ≤20% change, and 809 showed a >20% rise in NT-proBNP levels. As compared with the primary composite outcome of 28.4/100 patient-years (497 events; 31.1%) in patients with a >20% decline in NT-proBNP, those with >20% during screening had worse outcomes; 48.8/100 patient-years (359 events; 44.4%); adjusted hazard ratio, 1.61 (95% CI, 1.39-1.85). Those patients with a ≤20% change in NT-proBNP had intermediate outcomes; 39.2/100 patient-years (564 events; 39.9%); adjusted hazard ratio, 1.33 (95% CI, 1.17-1.51). No relationship existed between NT-proBNP changes during screening and vericiguat's effect on cardiovascular death and heart failure hospitalization. CONCLUSIONS: Substantial differences occurred in the rates of cardiovascular death and heart failure hospitalization, especially in patients with a >20% change in NT-proBNP levels during screening interval. Sequential NT-proBNP levels add important prognostic information meriting consideration in future heart failure trials. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.

Ejection Fraction, Biomarkers, and Outcomes and Impact of Vericiguat on Outcomes Across EF in VICTORIA.

BACKGROUND: Vericiguat reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HF) in patients with worsening HF and reduced left ventricular ejection fraction (LVEF). OBJECTIVES: The authors assessed the association of LVEF with biomarker levels, risk of outcome, and whether the effect of vericiguat was homogeneous across LVEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction) trial. METHODS: Patients were grouped by LVEF tertiles (≤24%, 25%-33%, and >33%). Patient characteristics, clinical outcomes, and efficacy and safety of vericiguat were examined by tertile. Prespecified biomarkers including N-terminal pro-B-type natriuretic peptide, cardiac troponin T, growth differentiation factor 15, interleukin 6, high-sensitivity C-reactive protein, and cystatin C were examined. RESULTS: The mean LVEF was 29% ± 8% (range: 5%-45%). A pattern of higher N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and interleukin 6 was evident in patients in the lowest LVEF tertile vs the other tertiles. Patients with lower LVEF experienced higher rates of the composite outcome (41.7%, 36.3%, and 33.4% for LVEF ≤24, 25-33, and >33; P < 0.001). There was no significant treatment effect heterogeneity of vericiguat across LVEF groups (adjusted HR from lowest to highest tertiles: 0.79 [95% CI: 0.68-0.94]; 0.95 [95% CI: 0.82-1.11]; 0.94 [95% CI: 0.79-1.11]; P for interaction = 0.222), although the HR was numerically lower in the lowest tertile. There was also no heterogeneity of effect for CVD and HF hospitalization individually (P interaction for CVD = 0.964; HF hospitalization = 0.438). Discontinuation of treatment because of adverse events, symptomatic hypotension, or syncope was consistent across the range of LVEF. CONCLUSIONS: Patients with lower LVEF had a distinctive biomarker profile and a higher risk for adverse clinical outcomes vs those with a higher LVEF. There was no significant interaction for the benefit of vericiguat across LVEF tertiles, although the largest signal for benefit in both the primary outcome and HF hospitalizations was noted in tertile 1 (LVEF ≤24%). (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

Population Pharmacokinetics of Vericiguat in Patients With Heart Failure With Reduced Ejection Fraction: An Integrated Analysis.

Vericiguat, a novel stimulator of soluble guanylate cyclase (sGC), is indicated for the treatment of patients following a hospitalization for heart failure or need for outpatient intravenous diuretics, with symptomatic chronic heart failure and ejection fraction less than 45%. Pharmacokinetic (PK) data from the phase II trial SOCRATES-REDUCED (Soluble Guanylate Cyclase Stimulator in Heart Failure Study) and the phase III trial VICTORIA (Vericiguat Global Study in Patients With Heart Failure With Reduced Ejection Fraction) were used to characterize vericiguat PK. A total of 8,092 concentration records from 2,321 participants (362 from SOCRATES-REDUCED and 1,959 from VICTORIA) were utilized for the development of the population PK model. The final PK model was a one-compartment model with first-order absorption and linear elimination. Baseline body weight and time-varying body weight were identified as statistically significant covariates affecting apparent clearance (CL/F) and volume of distribution, respectively. Age, sex, race, bilirubin, estimated glomerular filtration rate, and albumin did not affect vericiguat PK. Baseline disease-related factors, such as left ventricular ejection fraction, New York Heart Association (NYHA) class, and N-terminal pro B-type natriuretic peptide, also did not influence vericiguat PK. Since vericiguat is a titrated drug, the impact of vericiguat PK on the titration to and maintenance of the target dose in VICTORIA was assessed. The distribution of steady-state doses in VICTORIA was similar across CL/F quartiles, suggesting that the ability to reach and maintain dosing at the target 10-mg dose was not related to vericiguat exposure.

Defining changes in physical limitation from the patient perspective: insights from the VITALITY-HFpEF randomized trial.

AIMS: Clinically important thresholds in patient-reported outcomes measures like the Kansas City Cardiomyopathy Questionnaire (KCCQ) have not been defined for patients with heart failure and preserved ejection fraction (HFpEF). The aim of this study was to estimate meaningful thresholds for improvement or worsening in the KCCQ physical limitation score (PLS) in patients with HFpEF. METHODS AND RESULTS: In this pre-specified analysis from VITALITY-HFpEF, anchor- and distribution-based approaches were used to estimate thresholds for improvement or worsening in the KCCQ-PLS using Patient Global Impression of Change (PGIC) as an anchor. The KCCQ-PLS contains six elements, with each increment in response resulting in a change of 4.17 points when converted to a 0-100 scale. The mean change in KCCQ-PLS from baseline to week 12 was calculated for each PGIC group to estimate a meaningful within-patient change. Of 789 patients enrolled, 698 had complete KCCQ-PLS and PGIC data at week 12. The mean (± standard deviation) changes in KCCQ-PLS corresponding to PGIC changes of 'a little better', 'better', and 'much better' were 5.7 ± 18.6, 11.6 ± 19.3, and 18.4 ± 25.3 points, respectively. The scores of patients who responded 'a little better' (n = 177) overlapped substantially with those who reported 'no change' (n = 193; mean change 2.8 ± 18.9). The mean change in KCCQ-PLS for patients responding 'a little worse' (n = 32) was -2.6 ± 18.0 points. The threshold for meaningful within-patient change in KCCQ-PLS based on distribution-based analyses was 12.3 points. Using area under the curve (AUC) analyses of KCCQ-PLS, the sensitivity and specificity of a 4.17-point change were 0.61 and 0.57, for an 8.33-point change they were 0.49 and 0.64, and for a 12.5-point change they were 0.44 and 0.72 for being at least a little better on the PGIC (AUC = 0.54). CONCLUSION: In the VITALITY-HFpEF trial, a change in KCCQ-PLS of ≥8.33 points (corresponding to an improvement in ≥2 response categories of KCCQ-PLS) may represent the minimal clinically important difference for improvement and a change of ≤ -4.17 points (corresponding to a worsening in ≥1 response category of KCCQ-PLS) may suggest deterioration in patients with HFpEF.