Vericiguat in patients with chronic heart failure and reduced ejection fraction (VICTOR): a double-blind, placebo-controlled, randomised, phase 3 trial
Javed ButlerCiaran J. McMullanKevin J. AnstromIrina BarashMarc P. BonacaMaria BorentainStefano CordaJustin A. EzekowitzG. Michael FelkerDavis GatesCarolyn LamEldrin F. LewisJoAnn LindenfeldRobert J. MentzChristopher M. O’ConnorPiotr PonikowskiYogesh N.V. ReddyGiuseppe M.C. RosanoMichele SenniLilin ShePedro Pinto TeixeiraJames E. UdelsonAlessia UrbinatiVanja VlajnicAdriaan A. VoorsAiwen XingMahesh J. PatelFaı̈ez ZannadAlberto CadenaLuis Eduardo EcheverríaYüksel ÇavuşoğluHans ProzeskyFabio SilveriaAleksander ŻurakowskiJose F. Kerr SaraivaAldo Edwin Rodriguez EscuderoElias TsougosJosé AcciniFerenc LakatosAguinaldo Figueiredo FreitasEbrahim NooriTrevor J. GouldLaura ScelsiImran Zainal AbidinA. Shekhar PandeyBéla MerkelyTheema NunkooCamilo AranaVojtěch MelenovskýZ ZilahiGilbert GosselinHerrera E. LópezKrzysztof CymermanMiguel HominalPercy BerrospiKheng Leng David SimM.B. Vidal DíazEric KlugOscar MontañaDiego ArakakiRichard W. TroughtonAttila KónyiLidia PawłowiczMarie-Claude ParentGil MoravskyJanusz ProkopczukAna Belén FernándezMaría G. Crespo‐LeiroPatricio YovaninizRaúl MorenoWeimin LiJacek GniotEzequiel Hector VotteroDiego AizenbergMichele SenniJuan Esteban Gómez‐MesaAntoni Bayés‐GenísCraig BarrUsman QayyumMiguel Moncada CorredorGustavo C MachadoCihan AltınJ L Delgado PrietoJameel MohsenTomasz ŁugowskiTayfun Şahı̇nAijie Hou
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Key result
Vericiguat shows no benefit over placebo for major events in HFrEF without recent worsening.
- HR 0.93
- 95% CI 0.83-1.04
- P=0.22
- n=6,105
Why the study?
Vericiguat is indicated in HFrEF following a recent worsening event, but its effect in patients with HFrEF without recent heart failure worsening was unassessed.
Does vericiguat reduce the composite of cardiovascular death or heart failure hospitalization in ambulatory patients with HFrEF without recent worsening?
Study Design
Type
RCT (n=6,105)
Blinding
Double-blind
Randomization
1:1
Multicenter
Yes
Structured PICO
Does vericiguat reduce the composite of cardiovascular death or heart failure hospitalization in ambulatory patients with HFrEF without recent worsening?
P
Population
6,105 adults (median age 68.0, 23.6% female) with chronic heart failure and reduced ejection fraction without recent worsening, followed for a median of 18.5 months.
I
Intervention
Oral vericiguat once daily (initial dose 2.5 mg, titrated to 5 mg at day 14, and target 10 mg at day 28) added to guideline-directed medical therapy.
C
Comparator
Matching placebo added to guideline-directed medical therapy.
O
Outcome
Composite of time from randomisation to the first occurrence of cardiovascular death or hospitalisation for heart failure.composite
Main Result
Hazard Ratio: 0.93 (95% CI 0.83–1.04)
Absolute Event Rate: 18% vs 19.1%
p-value: p=0.22
In ambulatory patients with HFrEF without recent worsening, vericiguat did not significantly reduce the composite of cardiovascular death or heart failure hospitalization, though it was associated with a nominal reduction in cardiovascular death.
Limitations
- Neutral result for the primary endpoint limits interpretation of secondary endpoints.
- Exclusion of patients with NT-proBNP concentrations greater than 6000 pg/mL at screening might limit generalisability to patients with more advanced disease.
- Subgroup analyses are exploratory in nature and were not powered to detect interaction effects.
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“By studying patients without recent heart failure hospitalizations, the phase 3 VICTOR trial expands our understanding of Verquvo across the full spectrum of chronic heart failure patients with reduced ejection fraction. Together with the previously communicated results in VICTORIA in patients with worsening chronic heart failure and ejection fraction less than 45% following a worsening heart failure event, the results today provide valuable information and add to our understanding of heart failure and Verquvo.”
JMJohn McMurrayCardiologist, University of Glasgow
“When I first saw [VICTOR], I thought, 'Oh my goodness, this looks like an ICD trial,' because the only treatment I can think of that reduces death but doesn't reduce heart failure hospitalizations is an ICD.”
FZFaiez ZannadCardiologist, Université de Lorraine/INSERM
“They had the best possible guideline-directed medical therapy so far compared to any HFrEF trial.”
Implication
Vericiguat should not be used in stable HFrEF; extends prior evidence by confirming benefit requires recent worsening.
Abstract
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.
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Cite This Study
Butler et al. (2025) conducted an RCT in Chronic heart failure and reduced ejection fraction (HFrEF) (n=6,105). Vericiguat vs. Placebo was evaluated on Composite of time to cardiovascular death or heart failure hospitalisation (HR 0.93, 95% CI 0.83-1.04, p=0.22). Vericiguat did not significantly reduce the risk of cardiovascular death or heart failure hospitalisation compared to placebo in patients with chronic heart failure and reduced ejection fraction without recent worsening (HR 0.93).
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