Verquvo (Vericiguat) in Heart Failure: Evidence from Clinical Trials
VICTORIA Trial: The Pivotal Evidence
Vericiguat demonstrated a modest but statistically significant 10% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization in high-risk HFrEF patients with recent worsening events. 1, 2
Primary Trial Results
The VICTORIA trial enrolled 5,034 patients with symptomatic chronic heart failure and LVEF <45% who had experienced recent worsening (hospitalization within 6 months or outpatient IV diuretics). 1, 2
Key outcomes:
- Primary composite endpoint (CV death or HF hospitalization): 35.5% with vericiguat vs 38.5% with placebo (HR 0.90, p=0.019) 1
- All-cause mortality or HF hospitalization: HR 0.90 (95% CI 0.83-0.98, p=0.02) 1
- All-cause mortality alone: No significant reduction (20.3% vs 21.2%, HR 0.95, p=0.38) 1
- Cardiovascular death alone: Showed a trend but was not the primary endpoint 1
Critical Patient Selection Factors
Biomarker levels significantly influenced treatment response. Patients with extremely elevated NT-proBNP levels (>5,314 pg/mL) showed no benefit from vericiguat, while those with lower natriuretic peptide levels demonstrated greater benefit. 3, 1
Optimal candidates for vericiguat include: 1, 4
- LVEF <45%
- NYHA class II-IV symptoms
- Recent worsening event (hospitalization within 6 months OR outpatient IV diuretics within 3 months)
- Elevated natriuretic peptides (BNP ≥300 pg/mL or NT-proBNP ≥1,000 pg/mL in sinus rhythm)
- Critically: NT-proBNP should NOT be grossly elevated (avoid if >5,314 pg/mL) 1
LVEF Subgroup Analysis
Lower LVEF was associated with higher event rates but no significant heterogeneity in treatment effect across LVEF tertiles (≤24%, 25-33%, >33%), though the numerically largest benefit was observed in the lowest tertile (LVEF ≤24%, HR 0.79). 5
VICTOR Trial: The Negative Study
In the more recent VICTOR trial (2025), vericiguat failed to reduce the primary composite endpoint in patients WITHOUT recent heart failure worsening. 6
VICTOR Trial Results
Among 6,105 patients with HFrEF (LVEF ≤40%) but no hospitalization within 6 months or outpatient IV diuretics within 3 months: 6
- Primary endpoint (CV death or HF hospitalization): 18.0% vericiguat vs 19.1% placebo (HR 0.93, p=0.22) - NOT significant 6
- Cardiovascular death (nominal): 9.6% vs 11.3% (HR 0.83,95% CI 0.71-0.97) 6
- All-cause death (nominal): 12.3% vs 14.4% (HR 0.84,95% CI 0.74-0.97) 6
This negative trial reinforces that vericiguat's benefit is specifically in patients with recent worsening events, not stable chronic HFrEF. 6
FDA-Approved Indication and Dosing
FDA approval is specifically limited to: Reducing risk of CV death and HF hospitalization following a hospitalization for heart failure OR need for outpatient IV diuretics, in adults with symptomatic chronic HF and LVEF <45%. 4
Dosing Protocol 4
- Starting dose: 2.5 mg orally once daily with food
- Titration: Double dose every 2 weeks as tolerated
- Target dose: 10 mg once daily
- Tablets may be crushed and mixed with water for patients unable to swallow whole tablets
Safety Profile and Contraindications
Absolute Contraindications 4
- Pregnancy (boxed warning for embryo-fetal toxicity)
- Concomitant use of other soluble guanylate cyclase stimulators
Practical Contraindications 1, 4
- Systolic blood pressure <100 mmHg
- Severe renal impairment (eGFR <15 mL/min/1.73 m²)
- Concomitant long-acting nitrates (not recommended)
Common Adverse Events 4, 2
- Hypotension: 16% with vericiguat vs 15% with placebo
- Anemia: 10% with vericiguat vs 7% with placebo
- Symptomatic hypotension: 9.1% vs 7.9% (not statistically significant)
- Syncope: 4.0% vs 3.5% (not statistically significant)
Blood Pressure Monitoring 7, 1
Patients with baseline SBP ≥110 mmHg may experience a more pronounced initial decline in SBP over the first 16 weeks before returning to baseline levels. This is a hemodynamic effect, not an inotropic effect—vericiguat does NOT enhance myocardial contractility like dobutamine or milrinone. 7
Place in Guideline-Directed Medical Therapy
Vericiguat has limited regulatory approval and its place in GDMT remains uncertain. 3 Current guidelines prioritize a 4-drug class approach for HFrEF: beta-blockers, RAS inhibitors/ARNI (preferred), mineralocorticoid receptor antagonists, and SGLT2 inhibitors. 3
Vericiguat should be considered as an additional therapy for patients who remain symptomatic despite optimized GDMT with the above four drug classes and who meet the specific criteria from VICTORIA. 1 It represents a novel mechanism (soluble guanylate cyclase stimulation) distinct from traditional HF medications. 1, 8
Critical Clinical Pearls
The benefit of vericiguat is modest (10% relative risk reduction) even in the high-risk VICTORIA population. 1 This is substantially less than the benefits seen with SGLT2 inhibitors, ARNI, or beta-blockers in their respective landmark trials. 3
Do not confuse vericiguat with inotropic agents. It does not increase cardiac contractility and should not be used for acute decompensated heart failure requiring inotropic support. 7
Patient selection is paramount: The drug only works in patients with recent worsening events (VICTORIA-positive population), not stable chronic HFrEF (VICTOR-negative population). 6
Pregnancy testing is mandatory in females of reproductive potential before initiating treatment, with effective contraception required during treatment and for one month after discontinuation. 4