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

Abstract

Aims

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

Methods

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

Results

A 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).

Conclusions

A 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.

Introduction

The vericiguat global study in subjects with heart failure with reduced ejection fraction (VICTORIA) trial demonstrated a 10% relative and 4.2 events/100 patient‐years absolute risk reduction in a composite of heart failure (HF) hospitalization (HFH) or cardiovascular death relative to placebo in patients with high‐risk HF. ¹ Differences in patient risk profiles add complexity to comparing the relative efficacy of vericiguat with other approved contemporary HF therapies. ² Thus, we sought to estimate treatment effects of vericiguat in subsets of VICTORIA participants sharing similar baseline characteristics to patients enrolled in the PARADIGM‐HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) ³ and DAPA‐HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trials. ⁴

Methods

The VICTORIA trial was a multinational, randomized, double‐blind, placebo‐controlled trial to investigate the efficacy and safety of vericiguat in patients with chronic HF with reduced left ventricular ejection fraction (LVEF) of <45% and recent worsening HF events (ClinicalTrials.gov number: NCT02861534). ⁵ Institutional review board approval was obtained at all sites, and all patients provided written informed consent.

To simulate PARADIGM‐HF and DAPA‐HF study populations, selected eligibility criteria of each study were applied to the VICTORIA participants. The PARADIGM‐HF‐eligible population included participants receiving angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker with equivalent dose of lisinopril ≥10 mg/day or sacubitril/valsartan at any dose at the time of enrolment. Participants who had LVEF 40%–45% or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² were excluded. To account for the run‐in phase which required tolerability to target doses of both enalapril and sacubitril/valsartan in PARADIGM‐HF, the probability of run‐in failure was estimated using a previously validated predictive model. ⁶ We excluded 19.8% of participants with the highest estimated probability of run‐in failure, which represents the same proportion of participants who failed the run‐in phase in PARADIGM‐HF. The DAPA‐HF eligible population excluded participants who had LVEF 40%–45%, eGFR <30 mL/min/1.73 m², or recent HFH within 30 days.

The primary outcome was a composite of HFH or cardiovascular death. The secondary outcomes were the components of the primary outcome, all‐cause death, and a composite of HFH or all‐cause death. The time‐to‐first‐event analysis was performed using an unadjusted Cox proportional hazards model. Within each outcome, the hazard ratios (HRs) with 95% confidence intervals (CIs) and absolute rate reductions (ARRs) per 100 patient‐years were calculated for the PARADIGM‐HF‐ and DAPA‐HF‐eligible populations. A Normal Approximation of the Poisson distribution was used to estimate 95% CI for the ARR. A two‐sided test result with P value <0.05 was considered statistically significant.

Results

Of 5050 participants, 1982 (39.2%) and 2,543 (50.4%) VICTORIA participants were deemed eligible for PARADIGM‐HF and DAPA‐HF, respectively (Supporting information S1). Participants eligible for both studies were more likely to be younger and Black and have lower New York Heart Association symptom class, LVEF and natriuretic peptide levels but higher eGFR and use of guideline‐directed medical therapy compared with the ineligible populations (Table 1 ). Within the populations simulated from each trial, participants eligible for PARADIGM‐HF tended to have higher body mass index but were less likely to have coronary artery disease or use of cardiac resynchronization therapy, whereas participants eligible for DAPA‐HF were less likely to have hypertension and diabetes.

Table 1.

Baseline characteristics.

Characteristic	Overall (N = 5,050)	PARADIGM‐HF eligible (N = 1982)	PARADIGM‐HF ineligible (N = 3068)	P a	DAPA‐HF eligible (N = 2543)	DAPA‐HF ineligible (N = 2507)	P b
Age, years	69 (60–76)	65 (57–73)	71 (62–78)	<0.01	68 (59–76)	70 (61–77)	<0.01
Female, n (%)	1,208 (23.9)	469 (23.7)	739 (24.1)	0.73	592 (23.3)	616 (24.6)	0.28
Race, n (%)				<0.01			<0.01
White	3,239 (64.2)	1,256 (63.4)	1983 (64.6)		1,600 (62.9)	1,639 (65.4)
Black	249 (4.9)	140 (7.1)	109 (3.6)		156 (6.1)	93 (3.7)
Asian	1,132 (22.4)	367 (18.5)	765 (24.9)		539 (21.2)	593 (23.7)
Index events, n (%)				0.79			<0.01
HFH within 3 months	3,378 (66.9)	1,318 (66.5)	2060 (67.1)		1,178 (46.3)	2,200 (87.8)
HFH within 3–6 months	871 (17.2)	341 (17.2)	530 (17.3)		707 (27.8)	164 (6.5)
Intravenous diuretic use for HF (without HFH) within 3 months	801 (15.9)	323 (16.3)	478 (15.6)		658 (25.9)	143 (5.7)
Medical history
Ejection Fraction, %	30 (23–35)	28 (22–35)	30 (23–37)	<0.01	28 (22–35)	30 (23–38)	<0.01
Body mass index, kg/m2	27 (24–31)	28 (24–32)	26 (23–30)	<0.01	27 (24–31)	27 (24–31)	0.24
NYHA functional class, n (%)				<0.01			<0.01
I/II	2977 (59.0)	1216 (61.4)	1761 (57.5)		1552 (61.0)	1,425 (56.9)
III/IV	2069 (41.0)	766 (38.6)	1303 (42.5)		991 (39.0)	1078 (43.1)
Diabetes, n (%)	2369 (46.9)	908 (45.8)	1461 (47.7)	0.20	1112 (43.7)	1257 (50.2)	<0.01
Hypertension, n (%)	3995 (79.1)	1591 (80.3)	2404 (78.4)	0.11	1967 (77.3)	2028 (81.0)	<0.01
Coronary artery disease, n (%)	2862 (56.7)	970 (48.9)	1892 (61.7)	<0.01	1445 (56.8)	1417 (56.6)	0.86
Previous myocardial infarction, n (%)	2121 (42.0)	721 (36.4)	1400 (45.7)	<0.01	1084 (42.6)	1037 (41.4)	0.38
Vital signs and labs
Systolic blood pressure, mmHg	119 (109–131)	122 (112–135)	117 (107–129)	<0.01	119 (109–131)	118 (109–131)	0.41
Pulse, BPM	72 (64–81)	72 (64–82)	72 (63–81)	0.18	72 (64–81)	72 (63–81)	0.25
NT‐proBNP, pg/mL	2,816 (1,556–5,314)	2,237 (1,261–3,865)	3,434 (1826–6,486)	<0.01	2,654 (1,538–4,855)	3,074 (1,581–5,992)	<0.01
BNP, pg/mL	746 (452–1,342)	639 (384–1,104)	797 (514–1,461)	<0.01	692 (418–1,193)	840 (515–1,502)	<0.01
eGFR, mL/min/m2	58 (41–77)	69 (54–85)	50 (35–71)	<0.01	62 (48–81)	53 (34–74)	<0.01
Potassium, mEq/L	4.5 (4.2–4.8)	4.5 (4.2–4.8)	4.5 (4.2–4.8)	0.31	4.5 (4.2–4.8)	4.5 (4.2–4.9)	0.01
Medications and devices, n (%)
ACEI or ARB	3,700 (73.4)	1,540 (77.7)	2,160 (70.6)	<0.01	1908 (75.0)	1792 (71.8)	<0.01
Sacubitril‐valsartan	731 (14.5)	427 (21.5)	304 (9.9)	<0.01	386 (15.2)	345 (13.8)	0.17
Beta‐blocker	4,691 (93.1)	1863 (94.0)	2,828 (92.5)	0.04	2,373 (93.3)	2,318 (92.8)	0.50
Mineralocorticoid receptor antagonist	3,545 (70.3)	1,523 (76.8)	2022 (66.1)	<0.01	1839 (72.3)	1706 (68.3)	<0.01
Cardiac resynchronization therapy	739 (14.7)	247 (12.5)	492 (16.1)	<0.01	385 (15.1)	354 (14.2)	0.33
Implantable cardioverter defibrillator	1,399 (27.8)	505 (25.5)	894 (29.2)	<0.01	734 (28.9)	665 (26.6)	0.08

Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; HFH, heart failure hospitalization; NYHA, New York Heart Association; NT‐proBNP, N‐terminal pro b‐type natriuretic peptide.

^a P values for comparisons between patients who were eligible and ineligible for PARADIGM‐HF.

^b P‐values for comparisons between patients who were eligible and ineligible for DAPA‐HF

Vericiguat was associated with significantly lower hazards of the primary outcome of HFH or cardiovascular death in populations simulated from PARADIGM‐HF (HR 0.85, 95% CI 0.72–0.99; P = 0.04) and DAPA‐HF (HR 0.82, 95% CI 0.71–0.94; P < 0.01) (Figure  1 ). The ARR of the primary outcome with vericiguat was 5.1 (95% CI 0.6–9.6) events per 100 patient‐years in the PARADIGM‐HF‐eligible population and 6.6 (95% CI 2.4–10.6) events per 100 patient‐years in the DAPA‐HF‐eligible population (Table  2 ).

Figure 1.

Treatment effects of vericiguat in populations simulated from PARADIGM‐HF and DAPA‐HF. The hazard ratios (HR) and event rates for overall VICTORIA population from the primary analysis are shown for reference. The event rates were calculated from total of 1982 patients in PARADIGM‐HF‐eligible cohort and 2543 patients in DAPA‐HF‐eligible cohort. ARR, absolute rate reduction; CI, confidence interval; HFH, heart failure hospitalization.

Table 2.

Comparison of outcomes between trials and populations simulated from trials.

	VICTORIA 5		PARADIGM‐HF 3		PARADIGM‐HF eligible		DAPA‐HF 4		DAPA‐HF eligible
	Vericiguat	Placebo	Sacubitril/valsartan	Enalapril	Vericiguat	Placebo	Dapagliflozin	Placebo	Vericiguat	Placebo
Sample size	2526	2524	4187	4212	988	994	2373	2371	1288	1255
HR (95% CI)
HFH or cardiovascular death	0.90 (0.82–0.98)		0.80 (0.73–0.87)		0.85 (0.72–0.99)		0.74 (0.65–0.85)		0.82 (0.71–0.94)
HFH	0.90 (0.81–1.00)		0.79 (0.71–0.89)		0.86 (0.72–1.03)		0.70 (0.59–0.83)		0.81 (0.69–0.94)
Cardiovascular death	0.93 (0.81–1.06)		0.80 (0.71–0.89)		0.83 (0.64–1.06)		0.82 (0.69–0.98)		0.85 (0.70–1.03)
Annualized event rate, events per 100 patient‐years
HFH or cardiovascular death	33.6	37.8	10.5	13.2	25.8	30.9	11.6	15.6	27.2	33.8
Absolute rate reduction	4.2 (0.9–7.4)		2.7		5.1 (0.6–9.6)		4.0		6.6 (2.4–10.6)
HFH	25.9	29.1	NA	NA	20.6	24.2	6.9	9.8	20.0	25.2
Absolute rate reduction	3.2 (0.3–6.0)		1.6		3.6 (−0.3–7.7)		2.9		5.2 (1.7–8.8)
Cardiovascular death	12.9	13.9	6.0	7.5	8.5	10.3	6.5	7.9	11.1	13.1
Absolute rate reduction	1.0 (−0.8–2.8)		1.5		1.8 (−0.6–4.2)		1.4		2.0 (−0.4–4.4)

Note: The HR and event rates from the primary analysis of VICTORIA, PARADIGM‐HF and DAPA‐HF are shown for reference.

Abbreviation: CI, confidence interval; HFH, heart failure hospitalization; HR, hazard ratio.

Vericiguat was associated with lower HFH in the DAPA‐HF‐eligible population (HR 0.83, 95% CI 0.73–0.95; P < 0.01) but not in the PARADIGM‐HF‐eligible population, although a nominal reduction was observed (HR 0.86, 95% CI 0.74–1.01; P = 0.06). The ARR in HFH with vericiguat was 3.7 (95% CI −0.3 to 7.7) events per 100 patient‐years in the PARADIGM‐HF‐eligible population and 5.2 (95% CI 1.7–8.8) events per 100 patient‐years in the DAPA‐HF‐eligible population. There were no significant differences in the hazards of other secondary outcomes in populations simulated from both studies.

Discussion

In this secondary analysis of the VICTORIA trial, only 39.2% and 50.4% of the overall VICTORIA participants were deemed eligible for PARADIGM‐HF and DAPA‐HF by major eligibility criteria. Vericiguat was associated with significant reductions in the primary outcome of HFH or cardiovascular death and HFH in populations stimulated from PARADIGM‐HF and DAPA‐HF, and the projected treatment effects were numerically greater than those observed in the higher‐risk overall VICTORIA cohort.

VICTORIA participants deemed eligible for PARADIGM‐HF and DAPA‐HF represent a lower‐risk HF population as evidenced by lower natriuretic peptide levels, higher eGFR and higher use of guideline‐directed medical therapy. This is in line with the consistently lower event rates across all outcomes in the placebo arms of populations simulated from both trials compared with the overall VICTORIA population (Table 2). Although previous analyses of VICTORIA suggested greater benefits in patients with some high‐risk features such as lower LVEF and higher biomarkers of myocardial injury, ⁷ , ⁸ greater treatment effects were also observed in patients with lower N‐terminal pro‐b type natriuretic peptide (NT‐proBNP) levels and were no longer evident in in those with NT‐proBNP >8000 pg/mL. ⁹ It remains unclear how each high‐risk characteristic differentially influenced the treatment effects of vericiguat. While the multivariate models might be preferred over the use of any single variable in assessing treatment heterogeneity, ¹⁰ the simulation of trial populations can offer valuable insights.

A nominal trend towards enhanced treatment effects of vericiguat in both the PARADIGM‐HF‐ and DAPA‐HF‐eligible populations compared with the overall VICTORIA trial was observed. The HR associated with vericiguat was lower in populations simulated from PARADIGM‐HF and DAPA‐HF compared with the overall VICTORIA cohort. However, the difference in HR does not typically reflect the magnitude of the relative or absolute risk difference. ¹¹ We also observed numerically higher ARR with vericiguat treatment across all outcomes in populations simulated from PARADIGM‐HF and DAPA‐HF compared with the overall VICTORIA cohort. Notably, in the present simulation, we included less than one‐quarter of the original PARADIGM‐HF trial population and approximately one‐half of the DAPA‐HF population which was also characterized by lower risk. As the DAPA‐HF‐ and PARADIGM‐HF‐eligible populations had less advanced HF as compared with the overall VICTORIA population, the findings support further exploration of the treatment benefits of vericiguat in lower‐risk HF populations in the ongoing VICTOR (A study of vericiguat in participants with chronic heart failure with reduced ejection fraction) trial (ClinicalTrials.gov number: NCT05093933). Compared with VICTORIA, the VICTOR trial specifically aimed to enrol patients with no HFH within 6 months or intravenous diuretic use within 3 months and a lower NT‐proBNP level threshold for inclusion of (600–6000 or 900–6000 pg/mL for sinus rhythm or atrial fibrillation, respectively).

Within each respective trial‐simulated population, vericiguat was associated with more modest reduction in the HR for the primary outcome compared with sacubitril/valsartan (HR: 0.85 vs. 0.80) ³ and dapagliflozin (HR: 0.82 vs. 0.75). ⁴ In contrast, the ARR in the primary outcome of vericiguat in the overall VICTORIA population (4.2 events per 100 patient‐years) was numerically greater than those of sacubitril/valsartan (2.7 events per 100 patient‐years) and dapagliflozin (4.0 events per 100 patient‐year) in PARADIGM‐HF and DAPA‐HF, respectively. A head‐to‐head comparison between vericiguat and other therapies using simulated populations may be restricted by variations in source populations, background therapies, practices of participating sites, event adjudications, and follow‐up duration in the original trials. Nonetheless, in addition to highlighting potentially greater benefits of vericiguat in a less advanced HF population, this simulation analysis provides a more clinically relevant calibration of treatment effects of vericiguat to sacubitril/valsartan and dapagliflozin.

Limitations

Because the trial simulation did not fully incorporate the extensive PARADIGM‐HF and DAPA‐HF eligibility criteria, there was a possibility for inaccurate determination of study eligibility. Furthermore, the simulation of populations was limited by the inherently higher‐risk characteristics of VICTORIA participants, attributed to the prerequisite of worsening HF events. This was demonstrated by heightened event rates of HFH or cardiovascular death in the comparator group of simulated populations (PARADIGM‐HF: simulated 32.6%, original 26.5%; DAPA‐HF: simulated 36.1%, original 20.9%). Moreover, conducting a statistical comparison between the overall and simulated cohorts, including estimated differences or P values for interaction, was not feasible due to overlap in the populations in this analysis.

Conclusions

In this secondary analysis of the VICTORIA trial, a trend for enhanced treatment effects of vericiguat existed in populations simulated from PARADIGM‐HF and DAPA‐HF as compared with the overall VICTORIA population. These findings support further exploration of vericiguat in lower‐risk HF populations such as currently underway in the ongoing VICTOR trial.

Conflict of interest statement

Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics and Zoll. Dr Butler has received consulting fees for Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, 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, Pfizer, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor and Zoll. Dr Ezekowitz has received research grants from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent and Applied Therapeutics; consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent and Applied Therapeutics. Dr Lam has received research grants from Bayer, National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma and AstraZeneca; consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd and Corpus. Patent PCT/SG2016/050217 pending, and a patent 16/216929 pending and co‐founder & non‐executive director of eKo.ai. Dr Ponikowski has received research grant, consulting fees, speaker's bureau for Bayer, MSD, Servier, Novartis, Vifor Pharma Ltd., BMS, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuardSolution and Berlin Chemie. Dr Voors has received research grants from Boehringer Ingelheim and Roche Diagnostics; consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier and Roche Diagnostics. Dr Corda is an employee of Bayer AG. Dr McMullan is an employee of Merck & Co., Inc. Dr O'Connor has received research funding from Merck; consulting fees from Bayer, Dey LP and Bristol Myers Squibb Foundation. Dr Anstrom has received research grants from Merck and NIH. Dr Armstrong has received consulting fees from Merck, Bayer, Boehringer Ingelheim and Novo Nordisk; research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly and CSL Limited. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Funding

The VICTORIA trial was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Company, Inc, and Bayer AG.

Supporting information

Figure S1. Study flow diagram of simulated PARADIGM‐HF cohort

Figure S2. Study flow diagram of simulated DAPA‐HF cohort

Kittipibul, V. , Mentz, R. J. , Young, R. , Butler, J. , Ezekowitz, J. A. , Lam, C. S. P. , Ponikowski, P. , Voors, A. , Corda, S. , McMullan, C. , O'Connor, C. M. , Anstrom, K. J. , Armstrong, P. W. , and for the VICTORIA Study Group (2025) Projecting the benefit of vericiguat in PARADIGM‐HF and DAPA‐HF populations: Insights from the VICTORIA trial. ESC Heart Failure, 12: 1479–1484. 10.1002/ehf2.15134.