Mortality benefit and lifetime survival gains with vericiguat in HFrEF: Bayesian and actuarial analyses of the VICTOR trial
Francesco FiorettiFaı̈ez ZannadDerek CyrKevin J AnstromIrina BarashMarc P BonacaStefano CordaAnique DucharmeJustin EzekowitzAnuradha LalaCarolyn S P LamEldrin F LewisJoAnn LindenfeldCiaran J. McMullanRobert J MentzMarco MetraAlanna A. MorrisChristopher M O’ConnorPiotr PonikowskiYogesh N V ReddyGiuseppe RosanoC I SaldarriagaMichele SenniJames UdelsonAdriaan A. VoorsJaved Butler
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Key result
Vericiguat did not significantly reduce the primary composite endpoint of cardiovascular death or heart failure hospitalization (HR 0.93), but Bayesian analyses showed a 98.4% posterior probability of cardiovascular mortality benefit.
Why the study?
The VICTOR trial did not meet its primary composite endpoint but showed a nominally significant reduction in cardiovascular death with vericiguat in HFrEF patients, motivating further analysis of mortality benefit and lifetime survival implications.
Does vericiguat improve cardiovascular mortality and lifetime survival in patients with HFrEF?
Key Points
- To evaluate the probabilistic strength of evidence and lifetime survival implications of cardiovascular mortality reduction with vericiguat in heart failure with reduced ejection fraction using Bayesian and actuarial frameworks.
- Conducted post hoc Bayesian and actuarial analyses of the randomized VICTOR trial, which enrolled 6105 participants (3053 assigned to vericiguat and 3052 to placebo) with a median mortality follow-up of 19.7 months.
- Calculated posterior probabilities of mortality reduction by integrating trial likelihood with sceptical, optimistic (VICTORIA-based), and pessimistic prior distributions.
- Estimated 1- and 2-year event-free survival using restricted mean survival time and projected lifetime survival gains across ages 45 to 80 using age-based Cox proportional hazards modelling.
- In the VICTOR trial, cardiovascular death occurred in 292 participants (9.6%) in the vericiguat group versus 346 (11.3%) in the placebo group (HR 0.83; 95% CI 0.71–0.97), whereas the primary composite endpoint occurred in 549 (18.0%) versus 584 (19.1%) participants (HR 0.93; 95% CI 0.83–1.04).
- Actuarial lifetime projections indicated vericiguat extends overall survival across ages 45 to 80, with the largest gains of ∼1.6 to 1.9 years observed in participants aged 55 to 60 at randomization.
Structured PICO
Does vericiguat improve cardiovascular mortality and lifetime survival in patients with HFrEF?
P
Population
6,105 patients with HFrEF (LVEF ≤ 40%) and no recent worsening heart failure, mean age 67 years, followed for a median of 18.5 months.
I
Intervention
Vericiguat target dose 10 mg daily
C
Comparator
Placebo
O
Outcome
Cardiovascular death or first hospitalization for heart failurecomposite
Main Result
Hazard Ratio: 0.93 (95% CI 0.83–1.04)
Absolute Event Rate: 18% vs 19.1%
Bayesian and actuarial analyses suggest a high probability of cardiovascular mortality benefit and meaningful lifetime survival gains with vericiguat in HFrEF, despite the neutral primary composite endpoint in the VICTOR trial.
Limitations
- Post hoc secondary analyses
- Not prespecified in the trial protocol or the original statistical analysis plan
- post hoc secondary analyses
- not prespecified in the trial protocol or the original statistical analysis plan
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The cumulative evidence from pooling the VICTOR and VICTORIA trials affirms that vericiguat improved outcomes, including mortality, across the broad range of well-treated patients with HFrEF, with the clearest benefit observed in those with NT-proBNP ≤6,000 pg/ml.”
SGStephen GreeneHeart failure cardiologist, Duke University
“VICTOR trial showed that there was benefits on cardiovascular death, all-cause death, heart failure death, and sudden death with vericiguat versus placebo. And again, it showed consistency in these benefits across a spectrum of background medicines, devices, comorbidities, and laboratory findings.”
FZFaiez ZannadHead, Division of Heart Failure, Université de Lorraine
“The totality of evidence indicated that this is a lifesaving medicine [and] should be considered part of standard treatment in heart failure with reduced ejection fraction.”
Implication
Bayesian CV mortality signals in VICTOR may guide future HFrEF trials; leaves open whether vericiguat should enter routine care.
Abstract
BACKGROUND: The VICTOR trial did not meet its primary composite endpoint of cardiovascular death or first hospitalization for heart failure (HF) but demonstrated a nominally significant reduction in the prespecified and powered endpoint of cardiovascular death with vericiguat in patients with HF and reduced ejection fraction (HFrEF). Bayesian and actuarial methods offer complementary frameworks to quantify the probability and lifetime implications of this mortality benefit. METHODS: This post hoc analysis of the VICTOR trial applied Bayesian and actuarial analyses. Bayesian analysis estimated the probability that vericiguat reduces mortality, integrating trial data with prior evidence. Actuarial analysis used restricted mean survival time (RMST) to quantify event-free survival at 1 and 2 years, and age-based Cox proportional hazards modelling to project lifetime survival gains across ages 45-80. RESULTS: Bayesian analyses showed a consistently high probability of mortality benefit with vericiguat, regardless of whether sceptical or optimistic prior evidence was weighted. For cardiovascular mortality, the sceptical prior yielded a 98.4% posterior probability of any benefit, a 77.6% probability of at least a 10% relative reduction, and a 20.4% probability of at least a 20% reduction. The VICTORIA-based optimistic prior yielded 99.1%, 60.7%, and 2.2%, respectively. Similar results were observed for all-cause mortality. Actuarial analyses demonstrated greater event-free survival with vericiguat over 1 and 2 years. Lifetime projections suggested that vericiguat may extend overall survival across a broad age range, with the largest gains observed of ∼1.6 to 1.9 years for those aged 55 to 60 at randomization. CONCLUSION: In this post hoc analysis, Bayesian and actuarial methods provided hypothesis-generating evidence of a cardiovascular mortality benefit with vericiguat in HFrEF, an endpoint for which the trial was prospectively powered, that warrants prospective confirmation.
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Cite This Study
Fioretti et al. (2026) studied Heart failure with reduced ejection fraction (HFrEF) (n=6,105). Vericiguat vs. Placebo was evaluated on Cardiovascular death or first hospitalization for heart failure (HR 0.93, 95% CI 0.83-1.04). Vericiguat did not significantly reduce the primary composite endpoint of cardiovascular death or heart failure hospitalization (HR 0.93), but Bayesian analyses showed a 98.4% posterior probability of cardiovascular mortality benefit.
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