Efficacy of Vericiguat by Background Guideline-Directed Medical Therapy in the VICTOR Trial
Abstract
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.
Related
- Evaluating Electronic Health Record Intervention Efficacy in Enhancing Inpatient Initiation of Guideline-Directed Medical Therapy
- Clinical and Social Determinants of Guideline-Directed Medical Therapy Optimization in Heart Failure with Reduced Ejection Fraction
- Digital and algorithmic strategies for guideline-directed medical therapy initiation and up-titration in adults with heart failure with reduced ejection fraction: a systematic review
- Heart Failure Progression in the Setting of Persistent Atrial Fibrillation, Frequent Premature Ventricular Complexes, and Malignancy-Related Limitations to Guideline-Directed Medical Therapy: A Case Report.
- Improving Guideline-Directed Medical Therapy in Hospitalized HFrEF Patients
BibTeX
@article{ezekowitz2026efficacy,
title = {{Efficacy of Vericiguat by Background Guideline-Directed Medical Therapy in the VICTOR Trial}},
author = {Justin A Ezekowitz and Javed Butler and Derek Cyr and Kevin J Anstrom and Irina Barash and Marc P Bonaca and Stefano Corda and Carolyn S P Lam and Eldrin F Lewis and Joann Lindenfeld and Ciaran J Mcmullan and Robert J Mentz and Christopher O’connor and Piotr Ponikowski and Yogesh N V Reddy and Giuseppe Rosano and Clara Saldarriaga and Michele Senni and Stefan Störk and James E Udelson and Adriaan A Voors and Henrik Wiggers and Faiez Zannad},
journal = {European Journal of Heart Failure},
year = {2026},
month = sep,
doi = {10.1093/ejhf/xuag294},
url = {https://hal.univ-lorraine.fr/hal-05742667v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Efficacy of Vericiguat by Background Guideline-Directed Medical Therapy in the VICTOR Trial
AU - Justin A Ezekowitz
AU - Javed Butler
AU - Derek Cyr
AU - Kevin J Anstrom
AU - Irina Barash
AU - Marc P Bonaca
AU - Stefano Corda
AU - Carolyn S P Lam
AU - Eldrin F Lewis
AU - Joann Lindenfeld
AU - Ciaran J Mcmullan
AU - Robert J Mentz
AU - Christopher O’connor
AU - Piotr Ponikowski
AU - Yogesh N V Reddy
AU - Giuseppe Rosano
AU - Clara Saldarriaga
AU - Michele Senni
AU - Stefan Störk
AU - James E Udelson
AU - Adriaan A Voors
AU - Henrik Wiggers
AU - Faiez Zannad
PY - 2026
DA - 2026/09/08
JO - European Journal of Heart Failure
DO - 10.1093/ejhf/xuag294
UR - https://hal.univ-lorraine.fr/hal-05742667v1
AB - 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.
SN - 1388-9842
ER -