Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction (VICTORIA)

Authors, Journal, Affiliations, Type, DOI

• Paul W. Armstrong, Burkert Pieske, Kevin J. Anstrom, Justin Ezekowitz, Adrian F. Hernandez, Javed Butler, Carolyn S.P. Lam, Piotr Ponikowski, Adriaan A. Voors, Gang Jia, Steven E. McNulty, Mahesh J. Patel, Lothar Roessig, Joerg Koglin, Christopher M. O'Connor; for the VICTORIA Study Group
• New England Journal of Medicine 2020;382(20):1883–1893
• Canadian VIGOUR Centre (University of Alberta); Charité/German Heart Center Berlin; Duke Clinical Research Institute; University of Mississippi; National Heart Centre Singapore; Wroclaw Medical University; University of Groningen; Merck (Kenilworth NJ); Bayer (Wuppertal); Inova Heart and Vascular Institute
• Phase 3, multinational, randomized, double-blind, placebo-controlled trial
• DOI: https://doi.org/10.1056/NEJMoa1915928
• Funded by Merck Sharp & Dohme and Bayer; independent replication by Duke Clinical Research Institute (DCRI)

Overview

VICTORIA is the pivotal phase 3 RCT establishing vericiguat — the first oral soluble guanylate cyclase (sGC) stimulator — as an outcomes-based therapy for worsening HFrEF. The trial enrolled 5,050 patients on guideline-based medical therapy across 42 countries who had recently experienced HF worsening (hospitalization within 6 months or IV diuretics within 3 months). The population was markedly higher risk than prior pivotal HF trials (PARADIGM-HF, DAPA-HF): median NT-proBNP 2816 pg/mL, 41% NYHA III/IV, mean EF 29%. Vericiguat 10 mg OD significantly reduced the primary composite of CV death or first HF hospitalization (HR 0.90, P=0.02; NNT ~24 for 1 year) on top of background guideline therapy. No all-cause mortality benefit was demonstrated. The sGC mechanism is entirely distinct from the neurohormonal axis, making vericiguat the first novel HF drug class with outcomes evidence since SGLT2i.

Keywords

Heart failure; reduced ejection fraction; soluble guanylate cyclase; cyclic GMP; vericiguat; nitric oxide; worsening heart failure; hospitalization; clinical trial

Key Takeaways

Background and Mechanism

• Vericiguat mechanism: Oral soluble guanylate cyclase (sGC) stimulator with a dual action: (1) directly stimulates sGC via a binding site independent of nitric oxide; (2) sensitizes sGC to endogenous nitric oxide by stabilizing NO binding. Net result: increased cyclic GMP (cGMP) production.
• Pathophysiological rationale in HF: Endothelial dysfunction + reactive oxygen species (ROS) in HF reduce NO bioavailability → relative sGC deficiency → ↓cGMP. Vericiguat corrects this downstream signaling deficit.
• Mechanistic distinction: Different from nitrates (exogenous NO donation) and PDE5 inhibitors (prevent cGMP degradation). Vericiguat directly stimulates sGC regardless of upstream NO availability — relevant when endothelial dysfunction is severe and NO availability is limited.
• Phase 2b (SOCRATES-REDUCED) demonstrated NT-proBNP reduction, supporting phase 3 development.

Trial Design

• Design: Phase 3 randomized, double-blind, placebo-controlled; no run-in period
• Enrollment: September 2016 – December 2018; 5,050 patients at 616 sites in 42 countries
• Randomization: 1:1; vericiguat 2.5 mg → 5 mg → target 10 mg OD (blinded up-titration guided by BP and symptoms); stratified by geographic region and North American race
• Primary outcome: Composite of death from cardiovascular causes or first hospitalization for heart failure
• Follow-up: Median 10.8 months; 99.5–99.6% ascertainment completeness

Inclusion Criteria (High-Risk Population)

• Age ≥18; NYHA Class II, III, or IV
• LVEF <45% within 12 months
• Elevated natriuretic peptides within 30 days (sinus rhythm: BNP ≥300 or NT-proBNP ≥1000 pg/mL; AF: BNP ≥500 or NT-proBNP ≥1600 pg/mL)
• Evidence of worsening HF (3 cohorts): hospitalized within 3 months; hospitalized 3–6 months prior; IV diuretics without hospitalization within 3 months
• eGFR 15–30 ml/min/1.73m² capped at 15% of enrollment

Exclusion Criteria (Key)

• SBP <100 mmHg
• Concurrent long-acting nitrates, sGC stimulators, or PDE5 inhibitors
• IV inotropes or LVAD

Baseline Characteristics

• Mean age 67 years; 24% women; mean EF 29%; 40% NYHA Class III
• Median NT-proBNP 2816 pg/mL (central lab)
• Two-thirds enrolled within 3 months of index HF hospitalization
• Background therapy: 60% triple therapy (BB + MRA + ACEi/ARB/ARNI); 15% sacubitril-valsartan; 32% ICD/CRT/both
• Adherence >80% in 93.8% vericiguat vs 93.4% placebo; 90.3% at target 10-mg dose at ~12 months
• Note: Very few patients receiving SGLT2i (enrolled 2016–2018, before broad SGLT2i adoption)

Primary Results

*n/r = not reported (not controlled for multiple comparisons)

• ARR: ~4.2 events per 100 patient-years
• NNT: ~24 patients treated for 1 year to prevent one primary-outcome event (or ~28 by 12-month Kaplan–Meier)
• Benefit emerged at ~3 months and persisted throughout the trial
• Consistent across prespecified subgroups including patients receiving sacubitril-valsartan
• Exception: Subgroups defined by age and NT-proBNP level (very elevated NT-proBNP may signal HF too advanced for benefit)

Safety

• Symptomatic hypotension: 9.1% vs 7.9% (P=0.12 — not significant)
• Syncope: 4.0% vs 3.5% (P=0.30 — not significant)
• Anemia: 7.6% vs 5.7% (more common with vericiguat; 1.6% vs 0.9% serious); haemoglobin decline −0.38 vs −0.14 g/dL at 16 weeks — class effect of sGC stimulators
• BP decline: slight SBP decrease over first 16 weeks (more in vericiguat group), returned to baseline thereafter
• No significant difference in renal function or electrolyte adverse events
• Serious adverse events: 32.8% vs 34.8%

Contextual Comparisons

• VICTORIA vs PARADIGM-HF / DAPA-HF: VICTORIA enrolled a much sicker population — NYHA III/IV: 41% vs 25%/32%; median NT-proBNP: 2816 vs 1608/1437 pg/mL. Annualised primary event rate 33.6% in VICTORIA vericiguat group vs much lower in comparators. Despite higher absolute risk, annualised absolute risk reductions are similar across trials.
• Benefit demonstrated on top of existing evidence-based therapies including ARNI (15% of trial population)

Limitations of the Document

• Short median follow-up (10.8 months) — insufficient to demonstrate mortality benefit; CV death HR 0.93 is directionally consistent but underpowered
• Events accrued faster than expected, preventing planned interim efficacy analyses and potentially shortening exposure time
• Very few patients receiving SGLT2i at time of enrollment — no data on incremental benefit of vericiguat over contemporary 4-pillar GDMT including SGLT2i
• Industry-funded (Merck + Bayer) with sponsor involvement in design, site selection, and data storage (though independent DCRI replication conducted)
• Subgroup findings (NT-proBNP interaction) are hypothesis-generating only

Key Concepts Mentioned

• entities/HFpEF — trial context (HFrEF focused; contrasted against HFpEF)
• concepts/Titin-PTMs — cGMP-PKG axis mentioned as therapeutic pathway (RELAX, VITALITY, SOCRATES trials cited in context)

Key Entities Mentioned

• entities/Heart-Failure — primary subject; vericiguat as 5th add-on therapy in worsening HFrEF
• entities/Vericiguat — drug entity; full VICTORIA trial data

Wiki Pages Updated

• wiki/sources/vericiguat-victoria-nejm-2020 — created
• wiki/sourceindex.md — entry added
• entities/Vericiguat — created
• entities/Heart-Failure — source_count updated; vericiguat entry enriched with primary VICTORIA data
• wiki/wikiindex.md — Vericiguat entity entry added