BACKGROUND:Combined post- and precapillary pulmonary hypertension in heart failure with preserved ejection fraction involves remodeling in both the heart and pulmonary vasculature. Despite significant mortality, there are no proven therapies. METHODS:In this multicenter, randomized, placebo-controlled, phase 2 trial, adults received sotatercept (0.3 or 0.7 mg/kg) or placebo every 3 weeks. The primary end point was change in pulmonary vascular resistance at week 24. Hodges-Lehmann shift estimates described placebo-adjusted changes. RESULTS:A total of 164 patients were randomized 54:55:55 to sotatercept 0.3 mg/kg, 0.7 mg/kg, and placebo, and baseline median pulmonary vascular resistance was 5.2 (interquartile range, 4.0-6.9) Wood units. The median change from baseline in pulmonary vascular resistance at week 24 was -0.67 Wood units in the sotatercept 0.3 mg/kg group, -0.33 Wood units in the sotatercept 0.7 mg/kg group, and 0.26 Wood units in the placebo group. The Hodges-Lehmann shift estimates in pulmonary vascular resistance were -1.02 Wood units (95% CI, -1.81 to -0.23; P=0.004) for 0.3 mg/kg and -0.75 Wood units (95% CI, -1.52 to 0.03; P=0.024) for 0.7 mg/kg sotatercept. Reductions were observed in mean pulmonary arterial pressure (0.3 and 0.7 mg/kg: -9.19 mm Hg [95% CI, -13.00 to -5.38] and -9.22 [95% CI, -12.97 to -5.46]) and pulmonary arterial wedge pressure (0.3 and 0.7 mg/kg: -3.04 mm Hg [95% CI, -5.77 to -0.32] and -2.53 [95% CI, -5.33 to 0.28]). Changes in 6-minute walk distance were 20.3 m (95% CI, 1.5-39.1) for 0.3 mg/kg and 5.8 m (95% CI, -17.3 to 28.9) for 0.7 mg/kg sotatercept. The most common adverse events with sotatercept (both groups) were increased hemoglobin and diarrhea. CONCLUSIONS:These findings provide proof of concept for improved pulmonary vascular and cardiac hemodynamics after activin signaling inhibition with sotatercept in patients with combined post- and precapillary pulmonary hypertension in heart failure with preserved ejection fraction. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04945460.

BACKGROUND AND AIMS:It is uncertain whether the effect of vericiguat varies across levels of background guideline-directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). METHODS:We conducted an exploratory analysis of VICTOR, which enrolled 6105 ambulatory patients with HFrEF without recent worsening. GDMT exposure was classified as basic adherence (on vs. off), indication-corrected adherence (accounting for eligibility and contraindications), and dose-corrected adherence (≥50% target dose). A GDMT intensity score was computed from class-specific dose levels. The primary endpoint was the composite of cardiovascular death or first HF hospitalization. Stratified Cox proportional hazards regression models estimated adjusted hazard ratios for vericiguat versus placebo within GDMT strata, with treatment-by-GDMT interaction test. RESULTS:Baseline contemporary GDMT use was high (any ARNI/ACE/ARB 93.9%, ARNI 56%, SGLT2i 59%, MRA 78%, beta-blocker 94%). Basic adherence: adjusted HRs for the primary endpoint were similar whether or not patients were on ACEi/ARB, ARNI, any RAS inhibitor, beta-blocker, or SGLT2i. Dose-corrected adherence: adjusted HRs favored vericiguat in ARNI target-dose users (0.73; 0.57-0.93) and in any RAS target-dose users (0.77; 0.64-0.93), with lower risk on vericiguat in patients not meeting MRA target dose (0.67; 0.48-0.95); interaction P-values were nominally significant. The GDMT intensity score showed no significant interaction with treatment. Patterns for cardiovascular death and all-cause death paralleled the primary endpoint. CONCLUSIONS:In ambulatory patients with HFrEF receiving contemporary GDMT, we did not find convincing evidence that the neutral effect of vericiguat on cardiovascular death or first HF hospitalization was modified by GDMT class, dose attainment, or overall intensity, in a cohort with very high background GDMT use and limited power for interaction testing. These exploratory, hypothesis-generating findings do not establish independent efficacy or pathway additivity for vericiguat and should not be used to guide clinical recommendations regarding GDMT sequencing.

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.

Aim Describe the baseline characteristics of the VICTOR (Vericiguat Global Study in Patients with Chronic Heart Failure) trial with comparison to the most recent randomized controlled trials in patients with heart failure with reduced ejection fraction (HFrEF). Methods and Results VICTOR is a double-blind, placebo-controlled, parallel-group, 1:1 randomized, event-driven trial testing the effects of oral vericiguat (target dose 10 mg) vs. placebo in ambulatory patients with HFrEF and no recent worsening HF event. This population represents a complementary population to that studied in VICTORIA. Baseline characteristics were evaluated in 6105 patients randomized in the VICTOR trial (Table 1). Key characteristics in the VICTOR population were assessed and compared with other recent HFrEF trials including PARADIGM-HF, DAPA HF, EMPEROR Reduced, VICTORIA and GALACTIC HF. Baseline standard of care HFrEF therapy was notable for the higher incidence of SGLT2i, ARNI, and ICD use in VICTOR compared with other contemporary HFrEF trials. Conclusions The VICTOR trial includes a contemporary HFrEF population with high use of foundational HF therapy and will facilitate assessment of outcomes and the incremental benefit of vericiguat for patients with HFrEF. VICTOR trial will establish the role of vericiguat in a global and diverse population of patients with chronic HFrEF without recent worsening HF.

Randomized controlled clinical trials remain the gold standard for determining efficacy of new heart failure (HF) therapies; however, failure to account for heterogeneity in risk of the primary endpoint(s) may dilute treatment efficacy. The novel 5-step stratified testing and amalgamation routine (5-STAR) methodology addresses these limitations using risk stratification based on treatment-independent associations between baseline covariates and clinical outcomes. We applied the 5-STAR methodology to the original VICTORIA database enriched by relevant ancillary information. Within the 5-STAR analysis, elastic net Cox regression and a conditional inference tree tool blinded to treatment assignment were used to partition the trial population into risk strata for trial endpoints based on baseline covariates determined to be jointly strongly associated with the risk of the outcome. Core laboratory mechanistic biomarkers and baseline electrocardiographic variables were added to the VICTORIA dataset. After unblinding, treatments were compared for the primary composite endpoint of cardiovascular death or HF hospitalization within each risk stratum: stratum-level results were then averaged for overall inference. The 5-STAR analysis showed a greater vericiguat treatment effect on the primary composite endpoint than the original prespecified VICTORIA analysis (5-STAR-averaged HR, 95% CI: 0.85, 0.77–0.94 vs 0.90, 0.82–0.98), and on its components (5-STAR-averaged HR, 95% CI: cardiovascular death: 0.79, 0.67–0.93 vs 0.93, 0.81–1.06; HF hospitalization: 0.89, 0.79–1.00 vs 0.90, 0.81–1.00). Five biomarkers (GDF-15, NT-proBNP, albumin, blood urea nitrogen, urate) determined the risk strata across the 3 endpoints. By developing treatment-independent risk stratification, the 5-STAR methodology attenuates dilution of treatment effects inherent in conventional prognostic risk heterogeneity. This retrospective analysis of VICTORIA revealed greater efficacy of vericiguat on the primary endpoint and its components. GDF-15 was consistently the strongest prognostic risk factor across the composite endpoint and its components of cardiovascular death and HF hospitalization. ClinicalTrials.gov ( NCT02861534 ).

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. METHODS:This prespecified, pooled individual participant-level analysis was conducted on data from two trials: VICTORIA, which was active from Sept 25, 2016, to Sept 2, 2019 in 42 countries, and VICTOR, which was active from Nov 2, 2021, to Feb 5, 2025 in 36 countries. The VICTORIA trial enrolled adult (aged ≥18 years) participants with HFrEF with recent worsening (defined as either hospitalisation for heart failure within the previous 6 months or outpatient use of intravenous diuretics within the previous 3 months) and increased NT-proBNP concentrations; the VICTOR trial had similar eligibility criteria but participants had no recent worsening of heart failure. Participants in both trials received contemporary background guideline-directed heart failure therapy as appropriate. The primary endpoint was a composite endpoint of cardiovascular death or hospitalisation for heart failure (also assessed individually). This study is registered with PROSPERO, CRD420251065636. FINDINGS:Data from 11 155 patients (5050 in the VICTORIA trial and 6105 in the VICTOR trial) were included in the pooled analysis. The primary endpoint of cardiovascular death or hospitalisation for heart failure occurred in 1446 (25·9%) of 5579 patients in the vericiguat group and 1556 (27·9%) of 5576 patients in the placebo group (hazard ratio [HR] 0·91 [95% CI 0·85-0·98]; p=0·0088), with similar reductions in its individual components of cardiovascular death (0·89 [0·80-0·98]; p=0·020) and hospitalisation for heart failure (0·92 [0·84-1·00]; p=0·043) as first events. INTERPRETATION:Vericiguat reduced the risk of hospitalisation for heart failure and cardiovascular death in patients with HFrEF across a broad range of clinical severity, including those receiving contemporary guideline-directed medical therapy. Vericiguat might be suitable as an additional treatment option for selected patients with HFrEF. FUNDING:Merck Sharp & Dohme (a subsidiary of Merck) and Bayer.

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. METHODS AND RESULTS:VELOCITY was a prospective, 2-week, single-arm, open-label phase 2b study that enrolled patients with chronic HF with ejection fraction <45%, with or without a recent (≤6 or >6 months) worsening HF (WHF) event. Patients with systolic blood pressure <100 mmHg, recent symptomatic hypotension, and recent change in background GDMT or diuretic dosing were excluded. Participants were initiated on vericiguat 5 mg daily and followed for the primary endpoint, defined as completion of 2-week period with maximum 1-day interruption and without moderate to severe symptomatic hypotension between Visit 1 (Day 1) and Visit 2 (Day 14). Among 106 study patients (mean age 67 years, 28% female), 50% had recent WHF. Background GDMT included 54% prescribed angiotensin receptor-neprilysin inhibitors and 81% prescribed sodium-glucose cotransporter 2 inhibitors. The primary tolerability endpoint was met in 93.4% of patients, including 90.6% of patients in the WHF group and 96.2% of patients in the non-WHF group. Tolerability of initiating vericiguat 5 mg was generally consistent across the pre-specified sensitivity and secondary endpoints. When comparing patients initiating vericiguat 2.5 mg daily in VICTORIA with those starting vericiguat 5 mg daily in VELOCITY, the proportion meeting the VELOCITY primary tolerability endpoint was 97.2% in VICTORIA versus 93.4% in VELOCITY. CONCLUSIONS:In the prospective VELOCITY study of patients with chronic HF with ejection fraction <45% who were well-treated with background GDMT, >9 of 10 patients safely tolerated initiation of vericiguat at the 5 mg/day dose. Findings were generally consistent regardless of recent history of WHF. In the context of safety and tolerability data from prior vericiguat studies, VELOCITY supports a potential update in clinical guidance to include a 5 mg starting dose of vericiguat among patients without recent hypotension. CLINICAL TRIALS REGISTRATION:ClinicalTrials.gov NCT06195930.

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.

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.

BACKGROUND:Randomized trials remain the standard for evaluating novel therapies. Primary endpoint(s) risk heterogeneity and may dilute treatment efficacy. The 5-step Stratified Testing and Amalgamation Routine (5-STAR) methodology helps to address these limitations. We applied this methodology to the original VICTORIA (VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) database and enriched it by relevant ancillary information. METHODS:Elastic net Cox regression and a conditional inference-tree tool blinded to treatment assignment partitioned the population into risk strata for endpoints based on baseline covariates strongly associated with outcomes. Core laboratory biomarkers and baseline electrocardiographic variables were available covariates. After unblinding, treatments were compared for the primary composite endpoint of cardiovascular death or heart failure hospitalization (HFH) within each risk stratum: stratum-level results were averaged for overall inference. RESULTS:The 5-STAR analysis revealed greater vericiguat efficacy pooled on the primary composite endpoint than the original VICTORIA analysis (5-STAR HR, 95% CI: 0.85, 0.77-0.94 vs 0.90, 0.82-0.98), and its components (5-STAR HR, 95% CI: cardiovascular death: 0.79, 0.67-0.93 vs 0.93, 0.81-1.06; HFH: 0.89, 0.79-1.00 vs 0.90, 0.81-1.00). Five biomarkers (GDF-15, NT-proBNP, albumin, blood urea nitrogen, and uric acid) determined the risk strata across the 3 endpoints. CONCLUSIONS:The 5-STAR methodology attenuates the dilution of treatment effects inherent in conventional prognostic risk heterogeneity. This retrospective analysis of VICTORIA revealed greater efficacy of vericiguat on the primary endpoint and its components. GDF-15 was consistently the strongest prognostic risk factor across the composite endpoint and its components.

BACKGROUND:In the VICTOR (Vericiguat Global Study in Participants With Chronic Heart Failure) 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. OBJECTIVES:This study aimed to determine the effect of vericiguat on the overall risk of worsening HF by incorporating the entire patient experience of worsening outpatient and inpatient HF episodes. METHODS:VICTOR was a phase 3, double-blind, placebo-controlled trial testing the effect of vericiguat in ambulatory patients with HFrEF who had not experienced recent worsening (defined as HHF admission within 6 months or outpatient intravenous diuretic use within 3 months) and were on a background of high use of contemporary guideline therapy. The primary endpoint was a composite of cardiovascular death or HHF. The current analysis provides detailed effects of vericiguat on overall worsening HF in both the inpatient and outpatient settings, including urgent care visits for intravenous diuretics or outpatient oral diuretic initiation or intensification. RESULTS:A total of 6,105 participants were randomized. Outpatient worsening HF was more common as the first worsening HF event (n = 851, 59.3%), compared with HHF (n = 507, 35.4%) or urgent HF visits (n = 76, 5.3%). Outpatient oral diuretic initiation or intensification was associated with increased mortality (RR: 1.69; 95% CI: 1.47-1.94; P < 0.001). Overall worsening HF occurred in 686 participants (22.5%) in the vericiguat group and 748 participants (24.8%) in the placebo group (HR: 0.90; 95% CI: 0.81-1.00; P = 0.047). The composite of all-cause death and overall worsening HF occurred in 917 participants (30.0%) in the vericiguat group and 1,004 participants (32.9%) in the placebo group (HR: 0.90; 95% CI: 0.82-0.98; P = 0.016). CONCLUSIONS:In compensated patients with HFrEF on contemporary guideline therapy, worsening HF in outpatients was more common than HHF and was associated with higher risk of mortality. Exploratory analyses suggested a potential reduction in overall worsening HF events when both inpatient and outpatient settings were considered.

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. The primary composite endpoint was time to cardiovascular death or heart failure hospitalisation. Efficacy endpoints were assessed in the intention-to-treat population. Adverse events were assessed in all randomly assigned patients who received at least one dose of study drug (safety population). This trial is registered with ClinicalTrials.gov, NCT05093933, and is complete. FINDINGS:Between Nov 2, 2021, and Dec 21, 2023, 10 921 patients were screened and 6105 were randomly assigned: 3053 to vericiguat and 3052 to placebo. The median age was 68·0 years (IQR 61·0-75·0), 1440 (23·6%) patients were women, 4665 (76·4%) were men, 3934 (64·4%) were White, and 2899 (47·5%) had no previous hospitalisation for heart failure. During a median follow-up of 18·5 months (IQR 13·6-24·7), primary outcome events occurred in 549 (18·0%) patients in the vericiguat group and 584 (19·1%) patients in the placebo group (hazard ratio [HR] 0·93 [95% CI 0·83-1·04]; p=0·22). As prespecified in the protocol, because the primary endpoint was not statistically significant, all analyses of secondary and exploratory endpoints are considered nominal. Cardiovascular death occurred in 292 (9·6%) patients in the vericiguat group and 346 (11·3%) patients in the placebo group (HR 0·83 [95% CI 0·71-0·97]). Hospitalisation for heart failure occurred in 348 (11·4%) patients in the vericiguat group and in 362 (11·9%) patients in the placebo group (HR 0·95 [95% CI 0·82-1·10]). Serious adverse events occurred in 717 (23·5%) of 3049 patients in the vericiguat group and 751 (24·6%) of 3049 patients in the placebo group. The most common adverse event was symptomatic hypotension (345 [11·3%] patients in the vericiguat group and 281 [9·2%] in the placebo group). All-cause death occurred in 377 (12·3%) patients in the vericiguat group and 440 (14·4%) patients in the placebo group (HR 0·84 [95% CI 0·74-0·97]). INTERPRETATION:Among patients with HFrEF and no recent worsening, vericiguat did not reduce the risk of a composite endpoint of time to cardiovascular death or heart failure hospitalisation. Fewer cardiovascular deaths were observed in the vericiguat group than in the placebo group. FUNDING:Merck Sharp & Dohme (a subsidiary of Merck) and Bayer.

AbstractAimsThe 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.MethodsSubgroups of VICTORIA participants (n = 5050) were generated to simulate PARADIGM‐HF and DAPA‐HF trial populations. The PARADIGM‐HF‐eligible population excluded participants not meeting left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), and minimal dose criteria and those with high predicted probability of run‐in failure. The DAPA‐HF‐eligible population excluded those not meeting LVEF and eGFR criteria or with recent (<30 days) HF hospitalization. The time‐to‐first‐event analysis was performed using an unadjusted Cox proportional hazards model.ResultsA total of 1982 (39.2%) and 2543 (50.4%) VICTORIA participants were respectively deemed eligible for PARADIGM‐HF and DAPA‐HF. Vericiguat was associated with numerically larger reductions in the primary outcome of HF hospitalization or cardiovascular death in populations simulated from PARADIGM‐HF [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.72–0.99] and DAPA‐HF (HR 0.82, 95% CI 0.71–0.94) compared with the overall VICTORIA trial (HR 0.90). Significant reduction in HF hospitalization with vericiguat was also observed in the DAPA‐HF‐eligible population (HR 0.83, 95%CI 0.73–0.95) and with a nominal reduction in the PARADIGM‐HF‐eligible population (HR 0.86, 95% CI 0.74–1.01).ConclusionsA trend towards enhanced efficacy of vericiguat in populations simulated from PARADIGM‐HF and DAPA‐HF was observed. These findings support further exploration of vericiguat in lower‐risk HF populations as is being investigated in the ongoing VICTOR (a study of vericiguat in participants with chronic heart failure with reduced ejection fraction) 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. 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.

Supplementary Figure 7 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity <i>In vitro</i> and <i>In vivo</i>

Supplementary Figure 4 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity <i>In vitro</i> and <i>In vivo</i>

BACKGROUND:We examined whether the primary composite outcome (cardiovascular death or heart failure hospitalization) was related to differences in background use and dosing of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction enrolled in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), a randomized trial of vericiguat versus placebo.METHODS:We evaluated the adherence to guideline use of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. We assessed basic adherence; indication-corrected adherence accounting for guideline indications and contraindications; and dose-corrected adherence (indication-corrected adherence+≥50% of drug dose target). Associations between study treatment and the primary composite outcome according to the adherence to guidelines were assessed using multivariable adjustment; adjusted hazard ratios with 95% CIs and Pinteraction are reported.RESULTS:Of 5050 patients, 5040 (99.8%) had medication data at baseline. For angiotensin-converting enzyme inhibitor, angiotensin-receptor blockers, and angiotensin receptor-neprilysin inhibitors, basic adherence to guidelines was 87.4%, indication-corrected was 95.7%, and dose-corrected was 50.9%. For beta-blockers, basic adherence was 93.1%, indication-corrected was 96.2%, and dose-corrected was 45.4%. For mineralocorticoid receptor antagonists, basic adherence was 70.3%, indication-corrected was 87.1%, and dose-corrected was 82.2%. For triple therapy (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or angiotensin receptor-neprilysin inhibitors+beta-blocker+mineralocorticoid receptor antagonist), basic adherence was 59.7%, indication-corrected was 83.3%, and dose-corrected was 25.5%. Using basic or dose-corrected adherence, the treatment effect of vericiguat was consistent across adherence to guidelines groups, with or without multivariable adjustment with no treatment heterogeneity.CONCLUSIONS:Patients in VICTORIA were well treated with heart failure with reduced ejection fraction medications. The efficacy of vericiguat was consistent across background therapy with very high adherence to guidelines accounting for patient-level indications, contraindications, and tolerance.REGISTRATION:URL: https://www.CLINICALTRIALS:gov; Unique identifier: NCT02861534.

Background: Heart failure (HF) is a leading cause of hospitalizations in the US. While Guideline-Directed Medical Therapy (GDMT) improves outcomes in patients with heart failure with reduced ejection (HFrEF), healthcare resource utilization (HCRU) among patients with worsening heart failure (WHF) has not been well characterized. Aim: We compare HCRU by history of WHF at initiation of “2022 GDMT” (i.e., ARNi+β-blocker+MRA+SGLT2i). Methods: Patients with HFrEF who had concurrent exposure for ARNi, SGLT2i, β-blocker, and MRA between Jan 2020-Jun 2022 were identified using Optum’s deidentified Clinformatics® Data Mart Database. HCRU (i.e., all-cause hospitalizations [ACH] and HF hospitalizations [HFH]) was compared by history of WHF (i.e., HFH or IV diuretic administration) in the prior 12 months. Cox proportional hazard and negative binomial regressions estimated factors independently associated with risk of first and recurrent hospitalizations and their durations, respectively. Results: The analytical cohort included 3,881 HFrEF patients receiving 2022 GDMT, 1,835 (47%) with a prior history of WHF. Patients with and without a history of WHF had similar sociodemographic characteristics. The median (IQR) follow-up time was 352 (244, 544) days for the cohort. Patients with WHF were hospitalized sooner, more frequently, and for a longer duration of time ( Table ) compared to those without. After adjusting for sociodemographic characteristics, WHF was independently associated with longer length of stay of ACH (coefficient, 95% CI: 1.91, 1.59-2.31) and HFH (2.13, 1.74-2.61) and almost three times the risk of first and recurrent ACH (HR, 95% CI: 2.93, 2.64-3.26) and HFH (2.93, 2.61-3.29). Conclusion: Prior history of WHF was associated with clinically meaningful and statistically significant worse HCRU, despite first-line “2022 GDMT”. Additional care strategies and novel therapies are required to further decrease residual risk among these patients.

Supplementary Methods, Figure Legends 1-8 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity <i>In vitro</i> and <i>In vivo</i>