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

Abstract

Aims

To describe the baseline characteristics of the participants in the VICTOR (Vericiguat Global Study in Patients with Chronic Heart Failure; NCT05093933) trial and compare them to recent trials in patients with heart failure and reduced ejection fraction (HFrEF).

Methods and results

Baseline characteristics were evaluated in 6105 patients randomized to vericiguat or placebo. The mean age of the participants was 67 ± 11 years, 23.6% were women, 64.4% were White, and 10.7% were self‐identified Black. Overall, 29.1% of participants were enrolled in Latin and South America, 27.8% and 18.5% in Eastern and Western Europe, 14.0% in Asia‐Pacific and 10.6% in North America. The mean left ventricular ejection fraction was 30 ± 7% and 79% had New York Heart Association class II symptoms. Mean estimated glomerular filtration rate was 70.9 ± 24.0 ml/min/1.73 m². Median N‐terminal pro‐B‐type natriuretic peptide level was 1476 (970–2495) pg/ml and 47.5% of participants had no prior hospitalization for heart failure. Baseline therapy included 94.4% beta‐blockers, 94.3% renin–angiotensin system modulation (including 56.0% on an angiotensin receptor–neprilysin inhibitor), 77.7% mineralocorticoid receptor antagonists, 59.1% sodium–glucose cotransporter 2 inhibitors, and 32.9% implantable cardioverter‐defibrillators. Overall characteristics were relatively similar to other recent HFrEF trials but the VICTOR trial enrolled a higher proportion of participants receiving contemporary drug and device therapy.

Conclusion

The VICTOR trial enrolled the most optimally treated population in a phase III heart failure trial. These features will facilitate assessment of the benefit of vericiguat and elucidate the outcomes of patients on up‐to‐date medical therapy.

Introduction

Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with a high risk for morbidity and mortality, reduced functional capacity, and poor health status. ¹ , ² , ³ , ⁴ Despite development of effective therapies, patients with HFrEF face considerable residual risk for adverse outcomes, necessitating the need for novel interventions. ⁵ , ⁶ Vericiguat is a soluble guanylate cyclase stimulator approved for the treatment of patients with worsening HFrEF, characterized by recent hospitalization for HF or need for an urgent outpatient visit requiring intravenous diuretic therapy. This indication was based on the results of the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, in which vericiguat was shown to reduce the risk of cardiovascular (CV) death or hospitalization for HF in patients with HFrEF who were hospitalized within 6 months or required outpatient intravenous diuretic therapy within 3 months prior to randomization. ⁷

Oxidative stress and perturbed nitric oxide bioavailability in HF have been well described, ⁸ and are associated with disease progression across the spectrum of severity. ⁹ This suggests a potential for benefit with therapies targeting oxidative stress across the risk spectrum as well. Prior analysis of the VICTORIA trial showed that patients with lower natriuretic peptides had greater benefit from vericiguat. ¹⁰ , ¹¹ To assess the benefit of vericiguat across the risk spectrum, the VICTOR trial (Vericiguat in Adults with Chronic Heart Failure and Reduced Ejection Fraction; NCT05093933) was designed to assess the effect of vericiguat on the risk of CV death or hospitalization for HF in a broader group of patients with HFrEF who have not experienced recent worsening HF. ¹² Moreover, the standard therapy for HFrEF has evolved in recent years with the introduction of angiotensin receptor–neprilysin inhibitor (ARNI) and sodium–glucose cotransporter 2 inhibitors (SGLT2i). ¹³ , ¹⁴ , ¹⁵ It is important to assess the benefit of novel therapies incremental to contemporary background therapy. The VICTOR trial will assess the benefit of vericiguat in patients with HFrEF without recent worsening on top of contemporary medical therapy. Herein, we describe the baseline characteristics of patients enrolled in the VICTOR trial and compare these with recent contemporary large Phase III HF trials.

Methods

Study design

VICTOR (protocol MK‐1242‐035) is a double‐blind, placebo‐ controlled, parallel group, 1:1 randomized, event‐driven trial testing the effects of vericiguat (target dose 10 mg) versus placebo in ambulatory patients with HFrEF and no recent worsening HF. The study design for the VICTOR trial has been previously published. ¹² Briefly, the key entry criteria include history of HF with left ventricular ejection fraction ≤40%, New York Heart Association class II–IV symptoms on optimally tolerated guideline‐directed medical therapy and no recent hospitalization for HF within 6 months or urgent outpatient intravenous diuretic use within 3 months before randomization. N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels within 30 days prior to randomization were required to be elevated (600–6000 pg/ml for sinus rhythm and 900–6000 pg/ml for atrial fibrillation). Patients with estimated glomerular filtration rate (eGFR) ≥15 ml/min/1.73 m² based on Chronic Kidney Disease Epidemiology Collaboration criteria were included. ¹⁶

Outcomes

The primary endpoint is time from randomization to first event of CV death or hospitalization for HF. Secondary efficacy endpoints include: (i) time to individual components of the primary endpoint, (ii) time to total hospitalizations for HF (first and recurrent), (iii) time to first event of all‐cause death or hospitalization for HF, and (iv) time to all‐cause mortality.

Participant characteristics

Baseline characteristics and treatment of participants in the VICTOR trial are presented and compared with those of the VICTORIA trial, and the recent trials in patients with HFrEF including PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor with Angiotensin‐Converting Enzyme Inhibitor to Determine the Impact on Global Mortality and Morbidity in Heart Failure), ¹³ EMPEROR‐Reduced (EMPagliflozin outcomE tRial in patients with chrOnic heaRt Failure with Reduced Ejection Fraction), ¹⁴ DAPA‐HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure), ¹⁵ and GALACTIC‐HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure). ¹⁷ The data from these trials were extracted from baseline characteristics publications. ¹⁸ , ¹⁹ The criteria for selection of the trials that were compared was large Phase III drug‐based outcomes trials in HFrEF within the past decade.

Statistical analysis

Patient characteristics including concomitant medications available at baseline are presented as counts (percentages) for categorical variables and as medians (25th–75th percentiles) or mean (standard deviation) for continuous variables. The proportion of missing values was reported for the eGFR and ejection fraction at screening. All analyses were performed using SAS (version 9.4; SAS Institute Inc., Cary, NC, USA). The analysis of VICTOR was based on data available on 22 May 2024.

Results

Baseline characteristics

A total of 10 923 participants were screened and 6107 were randomized between November 2021 and December 2023. Two duplicate randomizations were excluded. Overall, 6105 participants were evaluated for the baseline characteristics. The reasons for non‐randomization are described in Table  1 . The baseline characteristics of participants randomized are described in Table  2 . The mean age was 67 ± 11 years, 23.6% were women, 64.4% were White, 12.2% were Asian, and 10.7% self‐identified as Black or were multiracial inclusive of Black. Regional enrolment included 29.1% from Latin and South America, 27.8% from Eastern Europe, 18.5% from Western Europe, 14.0% from Asia‐Pacific, and 10.6% from North America. The mean left ventricular ejection fraction was 30 ± 7% and 38.1% had left ventricular ejection fraction <30%, mean time since HF diagnosis was 6.1 ± 6.4 years, and 79% had New York Heart Association class II symptoms.

Table 1.

VICTOR participant screening summary

Participants screened	10 923 (100)
Participants randomized	6105 (55.9)
Participants not randomized	4816 (44.1)
Participants not randomized who did not meet inclusion criteria or did meet exclusion criteria	4807 (44.0)
Reasons for non‐randomization
Inclusion criteria not met a
Have N‐terminal pro‐B‐type natriuretic peptide levels within range within 30 days prior to randomization	3563 (74.1)
Have left ventricular ejection fraction <40% assessed within 12 months prior to randomization	464 (9.7)
Provide written informed consent for the trial	248 (5.2)
History of chronic heart failure (New York Heart Association class II–IV) on HF guideline‐directed medical therapy, and no previous HF hospitalization within 6 months prior to randomization or intravenous diuretic treatment for HF within 3 months prior to randomization	121 (2.5)
At least 18 years of age at the time of providing informed consent	41 (0.9)
Meet one of reproductive criteria	28 (0.6)
Exclusion criteria present
Clinically unstable at the time of randomization	304 (6.3)
Medical disorder, condition, or history impairing ability to participate	98 (2.0)
Discontinuation or modification of guideline‐directed medical therapy or vericiguat within 30 days prior to randomization	71 (1.5)
Severe hepatic insufficiency	68 (1.4)
Primary valvular heart disease requiring surgery or intervention, or within 3 months after valvular surgery or intervention	51 (1.1)
Estimated glomerular filtration rate <15 ml/min/1.73 m2 or chronic dialysis	26 (0.5)
Acute coronary syndrome (unstable angina, non‐ST‐elevation myocardial infarction, ST‐elevation myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention)	21 (0.4)
Miscellaneous	135 (0.3)

Values are given as n (%).

HF, heart failure.

^a Participants have more than one reason for not meeting entry criteria.

Table 2.

Participant baseline characteristics

Participants in population a	6105 (100)
Men	4665 (76.4)
Women	1440 (23.6)
Age, years, mean ± SD	67 ± 11
≤50	451 (7.4)
51–60	1029 (16.9)
61–70	2111 (34.6)
71–80	1987 (32.5)
≥81	527 (8.6)
Race
American Indian or Alaska Native	301 (4.9)
Asian	746 (12.2)
Black	469 (7.7)
Black (expanded) b	656 (10.7)
Multiracial	643 (10.5)
Native Hawaiian or Pacific Islander	11 (0.2)
Not reported	1 (0)
White	3934 (64.4)
Region
Eastern Europe	1700 (27.8)
Western Europe	1127 (18.5)
Asia‐Pacific	854 (14.0)
Latin and South America	1775 (29.1)
North America	649 (10.6)
Glomerular filtration rate, ml/min/1.73 m2, mean ± SD	70.9 ± 24.0
<15	7 (0.1)
≥15–<30	243 (4.0)
≥30–<60	1860 (30.5)
≥60	3874 (63.5)
New York Heart Association class
II	4823 (79.0)
III	1267 (20.8)
IV	15 (0.2)
Left ventricular ejection fraction, %, mean ± SD	30.4 ± 7.0
<30%	2319 (38.1)
≥30%–<35%	1491 (23.4)
≥35%–≤40%	2287 (37.5)
>40%	4 (0.1)
Smoking history
Current	666 (10.9)
Former	2554 (41.8)
Never	2885 (47.3)
Systolic blood pressure, mmHg, mean ± SD	121.1 ± 16.1
Diastolic blood pressure, mmHg, mean ± SD	72.5 ± 10.6
Heart rate, bpm, mean ± SD	69.9 ± 11.3
Haemoglobin, g/dl, mean ± SD	14.2 ± 2.5
Comorbidities
Hypertension	4327 (70.9)
Anaemia	736 (12.1)
History of atrial fibrillation	2315 (37.9)
Atrial fibrillation on baseline electrocardiogram	1248 (20.4)
Chronic obstructive pulmonary disease	669 (11.0)
Type 2 diabetes	2580 (42.3)
Coronary artery disease	3741 (61.3)
Stroke	565 (9.3)
Peripheral arterial disease	476 (7.8)
Myocardial infarction	2817 (46.1)
Baseline therapy
Beta‐blockers	5762 (94.4)
Angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker	2336 (38.3)
Angiotensin receptor–neprilysin inhibitor	3417 (56.0)
Mineralocorticoid receptor antagonist	4743 (77.7)
Sodium–glucose cotransporter 2 inhibitor	3608 (59.1)
Any diuretic c	4375 (71.7)
Loop diuretics	4243 (69.5)
Implantable cardioverter‐defibrillator	2009 (32.9)
Cardiac resynchronization therapy	902 (14.8)

Values are given as n (%), unless otherwise specified.

SD, standard deviation.

^a Two randomized participants were excluded due to duplicate participation.

^b Includes participants who self‐identified as Black, or multiracial including Black.

^c Loop diuretic plus other class of diuretics.

The mean Kansas City Cardiomyopathy Questionnaire overall summary score and clinical summary score were 70.1 ± 20.2 and 73.3 ± 20.1, respectively. Mean eGFR was 70.9 ± 24.0 ml/min/1.73 m² and 4.0% of participants had an eGFR between 15 and 30 ml/min/1.73 m². Median NT‐proBNP was 1476 (970–2495) pg/ml, including 1314 (872–2262) pg/ml in patients without and 1759 (1146–2839) pg/ml in those with a history of atrial fibrillation. Mean systolic blood pressure was 121.1 ± 16.1 mmHg, mean diastolic blood pressure was 72.5 ± 10.6 mmHg, and mean heart rate was 69.9 ± 11.3 bpm. Mean haemoglobin was 14.2 ± 2.5 g/dl.

Common comorbidities included history of hypertension (70.9%), coronary artery disease (61.3%), type 2 diabetes (42.3%), atrial fibrillation (37.9%), and chronic obstructive pulmonary disease (11%). Hospitalization periods for HF greater than 6 months and urgent intravenous diuretic use in the outpatient setting greater than 3 months before randomization were reported in 52.5% and 5.6% of the participants, respectively.

Use of guideline‐directed medical therapy

Use of drug therapy at baseline is presented in Table  2 . Overall, 94.4% of participants were on beta‐blockers, 94.3% on renin–angiotensin system modulation (including 56.0% on ARNIs), 77.7% on mineralocorticoid receptor antagonists (MRAs), and 59.1% on SGLT2is. An implantable‐cardioverter defibrillator was present in 32.9% and cardiac resynchronization therapy in 14.8% of participants. Quadruple drug therapy with any renin–angiotensin system modulator was present in 44.2% and with ARNI therapy specifically in 32% of participants.

Comparison between VICTOR and VICTORIA

In contrast to VICTORIA, patients included in the VICTOR trial were more diverse (4.9% vs. 1% American Indian or Alaskan, 10.5% vs. 7.2% multiracial, and 7.7% vs. 4.9% Black). VICTOR recruited more patients from Latin and South America (29.1% vs. 14.3%) and fewer European participants (46.3% vs. 51.1%). Patients in VICTOR less frequently had a history of atrial fibrillation (37.9% vs. 45%) and higher eGFR (70.9 vs. 61.5 ml/min/1.73 m²). Overall, 47.5% of participants had no past history of hospitalization for HF (Figure  1 ) whereas all patients in VICTORIA had a prior worsening HF event. VICTOR participants had lower median NT‐proBNP (1476 vs. 3377 pg/ml) and a higher proportion of New York Heart Association class II (79.0% vs. 58.9%) symptoms. The use of guideline‐directed medical therapy was higher in the VICTOR trial with 56.0% versus 14.5% ARNI, 77.7% versus 70.4% MRA, and 59.1% versus 3.1% SGLT2i use. Device therapy was also higher in VICTOR (implantable cardioverter‐defibrillator 32.9% vs. 27.8%).

Figure 1.

History of hospitalization for heart failure.

Comparison with previous trials

Comparison of VICTOR with other HFrEF trials is presented in Table  3 . The demographic characteristics of the participants in VICTOR were generally similar to other trials. The VICTOR trial has enrolled a higher proportion of Black patients and those with New York Heart Association class II symptoms. The VICTOR trial included the second largest proportion of participants from Latin and South America, had the highest use of contemporary guideline‐directed drug and implanted device use, and had the best use of contemporary guideline‐directed medical therapy, with a similar use of beta‐blockers and MRAs to other trials but with the highest use ever reported of sacubitril/valsartan (56%) and SGLT2is (59.1%) (Figure  2 ). The use of devices (implantable cardioverter‐defibrillator and cardiac resynchronization therapy) was also higher in VICTOR than in other trials.

Table 3.

Comparison between contemporary heart failure with reduced ejection fraction clinical trials

Characteristics	VICTOR	VICTORIA	PARADIGM‐HF	DAPA‐HF	EMPEROR‐ Reduced	GALACTIC‐HF
No. of participants randomized	6105	5050	8442	4744	3730	8256
Age, years, mean (SD)	67.0 (11)	67.3 (12.2)	63.8 (11.4)	66.4 (11.0)	66.9 (11.0)	64.5 (11.3)
Female, %	23.6	23.9	22.0	23.4	23.9	21.3
Male, %	76.4	76.1	78.0	76.6	76.1	78.7
Race, %
Asian	12.2	22.4	17.9	23.5	18.0	8.6
Black	7.7	4.9	5.1	4.8	6.9	6.8
White	64.4	64.2	65.7	70.3	70.5	77.8
American Indian or Alaskan	4.9	1.0	–	–	–	–
Native Hawaiian or Pacific Islander	0.2	0.3	–	–	–	–
Multiracial	10.5	7.2	–	–	–	–
Other	–	–	10.9	1.5	–	6.8
Region, %
Asia Pacific	14.0	23.4	17.6	23.1	13.2	8.1
Europe	46.3	51.1	57.7	45.4	36.3	55.9
Eastern Europe	27.8	33.5	33.5	33.8	–	32.8
Western Europe	18.5	17.6	24.3	11.6	–	23.3
Latin and South America	29.1	14.3	17.0	17.2	34.5	19.1
North America	10.6	11.1	7.1	14.3	11.4	16.8
Comorbidities, %
Diabetes	42.3	47.1	34.9	41.8	49.8	40.1
Atrial fibrillation	37.9	45.0	37.0	38.3	35.6	42.1
Body mass index, kg/m2, mean (SD)	28.4 (5.7)	27.8 (5.9)	28.2 (5.5)	28.2 (6.0)	28.0 (5.5)	28.5 (6.2)
No prior hospitalization for heart failure, %	47.5	N/A a	37.8	52.6	69	0
Prior hospitalization for heart failure, %	52.5	83.9 a	62.2	47.4	31	100
NT‐proBNP, pg/ml, median (IQR)	1476 (970–2495)	3377 b (1992–6380)	1608 (886–3221)	1437 (857–2649)	1887 (1077–3429)	1971 (962–4033) b
New York Heart Association class, %
I	0	0	4.7	–	–	–
II	79	58.9	70.9	67.5	75.1	53.2
III–IV	21	41	24.8	32.5	24.9	46.8
Left ventricular ejection fraction, %, mean (SD)	30.4 (7.0)	28.9 (8.3)	29.5 (6.2)	31.1 (6.8)	27.5 (6.1)	26.6 (6.3)
eGFR, ml/min/1.73 m2, mean (SD)	70.9 (24.0)	61.5 (27.2)	70.0 (20)	65.8 (19.4)	62.0 (21.6)	60.3 (21.8)
Medical therapy, %
Beta‐blockers	94.4	93.1	93.6	96.1	94.7	94.0
Angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker	38.3	73.5	100	83.6	70.5	67.4
Angiotensin receptor–neprilysin inhibitor	56.0	14.5	–	10.7	18.3	19.3
Mineralocorticoid receptor antagonist	77.7	70.4	55.3	71.0	71.3	77.0
Sodium–glucose cotransporter 2 inhibitor	59.1	3.1	–	–	–	2.6
Implantable cardioverter‐defibrillator	32.9	27.8	14.9	26.2	31.4	31.7
Cardiac resynchronization therapy	14.8	14.7	6.8	7.5	11.8	14.0

DAPA‐HF, Dapagliflozin And Prevention of Adverse outcomes in Heart Failure; eGFR, estimated glomerular filtration rate; EMPEROR‐Reduced, EMPagliflozin outcomE tRial in patients with chrOnic heaRt Failure with Reduced Ejection Fraction; GALACTIC‐HF, Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure; IQR, interquartile range; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PARADIGM‐HF, Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor with Angiotensin‐Converting Enzyme Inhibitor to Determine the Impact on Global Mortality and Morbidity in Heart Failure; SD, standard deviation; VICTOR, Vericiguat in Adults with Chronic Heart Failure and Reduced Ejection Fraction; VICTORIA, Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction.

^a All VICTORIA participants had either a hospitalization for heart failure within 6 months or an urgent heart failure visit with 3 months of randomization.

^b At screening visit.

Figure 2.

Proportion of guideline‐directed drug and device therapy across contemporary heart failure with reduced ejection fraction trials. ARNI, angiotensin receptor–neprilysin inhibitor; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter‐defibrillator; MRA, mineralocorticoid receptor antagonist; RASi, renin–angiotensin system inhibitor; SGLT2i, sodium–glucose cotransporter 2 inhibitor.

Discussion

The VICTOR trial represents a large and well‐characterized contemporary population of patients with HFrEF with no prior hospitalization for HF within 6 months or urgent outpatient intravenous diuretic use within 3 months before randomization. This randomized cohort characterizes a population with the highest use of ARNIs and SGLT2is and implantable devices for HFrEF compared to any previous trial. The high prevalence of ARNI use at baseline corresponds with the lower use of angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers. Recent trials continue to show substantial suboptimal use of ARNI and SGLT2is in patients with HFrEF. ¹³ , ¹⁴ , ¹⁵ Moreover, device‐based therapies in global trials have also lagged behind, in large part due to cost and accessibility. In that respect, though not necessarily a feature of the VICTOR trial design per se, the high baseline use of guideline‐directed medical therapy provided a unique opportunity in VICTOR to understand the contemporary epidemiology and outcomes of HFrEF and to appropriately assess the incremental value of a novel intervention.

All four components of standard guideline‐directed medical therapy for HFrEF have been shown to improve the risk for CV mortality or hospitalization for HF. In the context of a clinical trial, it is important to assess the incremental benefits and safety of a novel intervention in addition to standard of care treatments as recommended by guidelines. ²⁰ , ²¹ No previous trial has as large a proportion of patients receiving guideline‐directed medical therapy including ARNI and SGLT2is as in the VICTOR trial, which provides a unique opportunity to study the contemporary natural history of HF as well as the incremental value of vericiguat.

Even in the setting of optimal guideline‐directed medical therapy implementation, the residual risk for patients with HFrEF remains high. ²² For example, in the treatment arm of DAPA‐HF, the annualized event rate for CV death or hospitalization for HF was 11.6 per 100 person‐years in the dapagliflozin arm, ¹⁵ and in the EMPEROR‐Reduced trial, it was 15.8 per 100 person‐years in the empagliflozin arm, despite excellent background medical therapy. ¹⁴ Data from these trials emphasize that despite the availability of multiple HF therapies, additional interventions are needed due to the high residual risk, highlighting the importance of the VICTOR trial.

The risk of sudden cardiac death was ~2–3% in the earlier trials and ~1% in the recent HFrEF trials, illustrating the cumulative benefit of modern medical therapy on sudden cardiac death. ²³ The benefit of implantable cardioverter‐defibrillators in reducing sudden cardiac death risk is well established. ²⁴ , ²⁵ , ²⁶ While traditionally sudden cardiac death has represented a large proportion of CV mortality in HFrEF trials, including a higher proportion of those with New York Heart Association class II versus III–IV symptoms, with the higher use of guideline‐directed medical therapy and implantable cardioverter‐defibrillators in the VICTOR trial, the importance of sudden cardiac death in the contemporary HFrEF population will represent a valuable addition to our understanding of the epidemiology, pathophysiology, and mode of death in patients with HFrEF. VICTOR will add information regarding the risk of CV death, including sudden death in a contemporary population of patients with the highest use of contemporary HF drug and device‐based therapies.

VICTOR trial results will complete the prior knowledge from the VICTORIA trial about the efficacy and safety of vericiguat across the entire risk spectrum of patients with HFrEF, including those with and without a recent episode of worsening HF. ⁷ Considerable effort was made to balance recruitment across geographical regions, with particularly strong enrolment from Latin America. These results will help establish the role of vericiguat in a global and diverse population of patients with HFrEF. Diversity in the VICTOR trial is notable, with the higher proportion of Black (23.6% in North America), American Indian or Alaskan, and multiracial patients. From an ethnicity perspective, almost one third of the population was Hispanic or Latino. Racial and ethnic minorities have the highest incidence and prevalence of hospitalizations for HF. With genetic, lifestyle, environmental, clinical, and baseline medical care variations among the different race‐ and ethnic‐based populations, it is imperative to understand the impact of pharmacotherapies and interventions across all populations. ²⁷ , ²⁸ Representation of women, however, was similar to prior HFrEF trials and less than ideal, although recruitment was encouraged since the beginning of the trial. Overall, the proportion of women enrolled in HF trials has remained stagnant at ~20–30% over the past decades, and further efforts are clearly needed. ²⁹ One third of the population from the VICTOR trial was older than 70 years of age, which will facilitate generalizability of the data to real‐world populations.

The NT‐proBNP threshold was a major reason for screened patients not meeting the eligibility criteria. The natriuretic peptide inclusion criteria are a source of discussion in all clinical trial designs, as one tries to balance between enriching the population for reasonable event rate to ensure the trial's logistic feasibility on one hand and avoiding including too high‐risk a population to avoid futility of any treatment on the other. ³⁰ The clinical application of results in light of the eligibility criteria, like all approved therapies, is then driven by the clinician's assessment, individualized to the particular patient that is being treated.

In conclusion, the VICTOR trial recruited a contemporary HFrEF population with high use of guideline‐directed medical therapy that will facilitate assessment of outcomes and the incremental benefit of vericiguat in a contemporary cohort of patients with HFrEF. Between the VICTORIA and VICTOR trials, the role of vericiguat in a global and diverse population of patients with HFrEF across the spectrum of disease severity with and without worsening HF will be elucidated.

Funding

The VICTOR trial is supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and Bayer AG, Wuppertal, Germany.

Conflict of interest: C.I.S. reports consulting fees from Bayer, Merck, and Novo Nordisk; payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Novartis, AstraZeneca, Boehringer Ingelheim, Bayer, Merck, Servier, Sanofi, Pfizer, Novo Nordisk, Eli Lilly, Viatris, and Medtronic; travel support for attending meetings from Bayer, Servier, Pfizer, Novartis, and Boehringer Ingelheim. F.Z. reports personal fees from 89bio, Applied Therapeutics, Bayer, Betagenon, Biopeutics, Boehringer, BMS, CVRx, Cardior, Cambrian, Cereno pharmaceutical, Cellprothera, CEVA, Merck, Northsea, Novartis, Novo Nordisk, Otsuka, Owkin, and Salubri; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Boehringer, CVRx, Cellprothera, CEVA, and Merck; participates in a Data Safety Monitoring Board or Advisory Board for Merck/Acceleron; equities at G3Pharmaceutical, Cereno, Cardiorenal, and Eshmoun Clinical Research; and is founder of CVCT. C.J.M., A.X., D.G., and M.P. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. K.J.A. has received research grants from Merck and the National Institutes of Health and participates in several Data Safety Monitoring Boards outside of the heart failure disease area. M.P.B. is the Executive Director of CPC, a non‐profit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between August 2021 and present from Abbott Laboratories, Agios Pharmaceuticals, Inc., Alexion Pharma, Alnylam Pharmaceuticals, Inc., Amgen Inc., Angionetics, Inc., Anthos Therapeutics, ARCA Biopharma, Inc., Array BioPharma, Inc., AstraZeneca and Affiliates, Atentiv LLC, Audentes Therapeutics, Inc., Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Inc., Boston Clinical Research Institute, Bristol‐Myers Squibb Company, Cambrian Biopharma, Inc., Cardiol Therapeutics Inc., CellResearch Corp., Cleerly Inc., Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics, Inc., EP Trading Co. Ltd., EPG Communication Holdings Ltd., Epizon Pharma, Inc., Esperion Therapeutics, Inc., Everly Well, Inc., Exicon Consulting Pvt. Ltd., Faraday Pharmaceuticals, Inc., Foresee Pharmaceuticals Co. Ltd., Fortress Biotech, Inc., HDL Therapeutics Inc., HeartFlow Inc., Hummingbird Bioscience, Insmed Inc., Ionis Pharmaceuticals, IQVIA Inc., Janssen and Affiliates, Kowa Research Institute, Inc., Kyushu University, Lexicon Pharmaceuticals, Inc., Medimmune Ltd., Medpace, Merck & Co., Inc., Rahway, NJ, USA, Nectero Medical Inc., Novartis Pharmaceuticals Corp., Novo Nordisk, Inc., Osiris Therapeutics Inc., Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PPD Development, LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc., Regio Biosciences, Inc., Saint Luke's Hospital of Kansas City, Sanifit Therapeutics S.A., Sanofi‐Aventis Groupe, Silence Therapeutics PLC, Silence, Smith & Nephew plc, Stanford Center for Clinical Research, Stealth BioTherapeutics Inc., State of Colorado CCPD Grant, The Brigham & Women's Hospital, Inc., The Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, Worldwide Clinical Trials Inc., WraSer, LLC, and Yale Cardiovascular Research Group; and receives support from the AHA SFRN under award numbers 18SFRN3390085 (BWH‐DH SFRN Center) and 18SFRN33960262 (BWH‐DH Clinical Project). S.C. is an employee of Bayer AG. J.A.E. has received research grants and consulting fees from AstraZeneca, Bayer, BI‐Lilly, Merck, Amgen, CSL‐Vifor, Carduirion, American Regent, Otsuka, Novo Nordisk, and Applied Therapeutics. C.S.P.L. has received research grants from National Medical Research Council of Singapore, Novo Nordisk, and Roche Diagnostic; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; has patent PCT/SG2016/050217 pending and patent US Patent No. 10702, 247; is a co‐founder and non‐executive director of Us2.ai; and has received stock or stock options from Us2.ai. E.F.L. reports grants or contracts from Merck, the American Heart Association, and the NHLBI; consulting fees from Akebia, AstraZeneca, Dal‐Cor, Intellia, and Merck; and a leadership or fiduciary role with the American Heart Association. J.L. is receiving research support from AstraZeneca and Volumetrix and consulting fees from Abbott, Adonis, Alleviant, AstraZeneca, Axon, Boston Scientific, Cordio, CVRx, Edwards Lifesciences, Intershunt, Merck, Medtronic, Orchestra Biomed, Whiteswell, Vascular Dynamics, and VWave. R.J.M. has received research support and honoraria from Bayer and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; and consulting fees from Abbott, Alleviant Medical, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Lexicon, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Reprieve Cardiovascular, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree Therapeutics, and Zoll. C.O. has received consulting fees from Abiomed, Merck, and Zealcare. P.P. has received support for the current work from Bayer; grants or contracts from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Novartis, Bayer, Abbott Vascular, Novo Nordisk, Pharmacosmos, and Moderna; consulting fees from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, Abbott Vascular; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, and Abbott Vascular; support for attending meetings and/or travel from Boehringer Ingelheim, Vifor Pharma; and has participated in a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim, Vifor Pharma, Novo Nordisk, Pharmacosmos, and Moderna. Y.N.V.R. is supported by grants from NHLBI (K23HL164901), Sleep Number, Bayer, Merck, United Pharmaceuticals and the Earl Wood Career Development Award from Mayo Clinic; and reports consulting fees from Edwards Life Sciences. G.M.C.R. reports consulting fees from Anlylam, AstraZeneca, Servier, and Vifor Pharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Anlylam, AstraZeneca, Boehringer Ingelheim, Medtronic, Servier, Viatris, and Vifor Pharma. M.S. reports consultancy fees, support for attending meetings and/or travel, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck. J.U. reports support for the current work from Merck, is a member of the steering and executive committees for the VICTOR trial; consulting fees from FIRE‐1 and Reprieve CV; and participation in Data Safety Monitoring Boards or Advisory Boards for Merck, Medtronic, and Alleviant. A.A.V. has received grants or contracts from AnaCardio, Bayer, BMS, Boehringer Ingelheim, Corteria, Cytokinetics, Eli Lilly, Merck, Novartis, Novo Nordisk, Roche Diagnostics, Pfizer, and Moderna; and consulting fees from AnaCardio, Bayer, BMS, Boehringer Ingelheim, Corteria, Cytokinetics, Eli Lilly, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. J.B. has received consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, Cardiorem, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Pfize, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, Boehringer Ingelheim‐Lilly, AstraZeneca, Impulse Dynamics, and Vifor.