What is the recommended use and dosage of Vericiguat (vericiguat) for patients with heart failure?

Vericiguat for Heart Failure with Reduced Ejection Fraction

Vericiguat is recommended for high-risk patients with symptomatic chronic HFrEF (LVEF <45%) who have experienced recent worsening heart failure (hospitalization within 6 months or need for outpatient IV diuretics) despite guideline-directed medical therapy, to reduce cardiovascular death and heart failure hospitalization. 1

Mechanism of Action

• Vericiguat directly stimulates soluble guanylate cyclase (sGC), increasing cyclic guanosine monophosphate (cGMP) production, which leads to vasodilation, improved endothelial function, and decreased cardiac fibrosis and remodeling 1, 2
• Unlike inotropic agents (dobutamine, milrinone), vericiguat does not directly enhance myocardial contractility, making it safer for long-term use 3, 4
• The drug works both by sensitizing sGC to low levels of nitric oxide and by directly stimulating sGC independent of endogenous nitric oxide 2

Specific Patient Selection Criteria

Inclusion criteria based on VICTORIA trial: 1

• LVEF <45% 1, 5
• NYHA class II to IV symptoms 1, 5
• Recent heart failure worsening: hospitalization within 6 months OR recent outpatient IV diuretic therapy 1, 5
• Elevated natriuretic peptides: BNP ≥300 pg/mL or NT-proBNP ≥1000 pg/mL (higher cutoffs with atrial fibrillation) 1, 3
• Already on guideline-directed medical therapy 1, 5

Absolute contraindications: 1, 2

• Systolic blood pressure <100 mmHg 1, 3, 5
• Severe renal impairment (eGFR <15 mL/min/1.73 m²) 1, 3, 2
• Concomitant use with long-acting nitrates 1

Clinical Efficacy Data

The VICTORIA trial demonstrated: 1, 6

• 10% relative risk reduction in the primary composite outcome of cardiovascular death or heart failure hospitalization (35.5% vs 38.5%, HR 0.90,95% CI 0.82-0.98, p=0.019) 1, 3, 5
• Reduction in any-cause death or heart failure hospitalization (HR 0.90,95% CI 0.83-0.98, p=0.02) 1, 3, 5
• Non-significant trend toward reduced all-cause mortality (20.3% vs 21.2%, HR 0.95% CI 0.84-1.07, p=0.38) 1, 3

Important limitation: Patients with extremely elevated NT-proBNP levels (>5314 pg/mL, highest quartile) did not demonstrate benefit from vericiguat compared to placebo 1, 3

Dosing Protocol

Per FDA labeling: 2

• Starting dose: 2.5 mg once daily with food
• Titration: Double the dose every 2 weeks as tolerated
• Target dose: 10 mg once daily
• Mean dose achieved in trials: 9.2 mg daily 5

Administration specifics: 2

• Must be taken with food (increases AUC by 44% and reduces PK variability compared to fasted state) 2
• Can be administered as whole tablet or crushed in water with comparable bioavailability 2
• Absolute bioavailability is 93% when taken with food 2

Safety Profile and Monitoring

Common adverse effects: 1, 6

• Symptomatic hypotension (9.1% vs 7.9% placebo, p=0.12) 1, 3
• Syncope (4.0% vs 3.5% placebo, p=0.30) 1, 3
• Mean systolic blood pressure reduction of approximately 1-2 mmHg greater than placebo 2

Blood pressure monitoring: Patients with baseline SBP ≥110 mmHg may experience more pronounced initial decline in SBP over the first 16 weeks before returning to baseline 3, 4

Drug interactions: 2

• Concomitant use with sildenafil (25-100 mg) caused additional seated BP reduction of up to 5.4 mmHg; limited experience with PDE-5 inhibitors in heart failure patients 2
• Short-acting nitrates were well tolerated, but limited experience exists with long-acting nitrates 2
• No clinically significant interactions with aspirin, warfarin, or sacubitril/valsartan 2

Renal and Hepatic Considerations

Renal impairment: 2

• Mild, moderate, and severe renal impairment (not requiring dialysis) increased vericiguat exposure by 5%, 13%, and 20% respectively—not considered clinically relevant 2
• No dose adjustment required for eGFR ≥15 mL/min/1.73 m² 2
• Not studied in patients on dialysis 2

Hepatic impairment: 2

• Mild and moderate hepatic impairment (Child-Pugh A-B) increased exposure by 21% and 47% respectively—no dose adjustment required 2

Place in Heart Failure Treatment Algorithm

Vericiguat represents an additional therapeutic option for patients who remain symptomatic despite optimized GDMT (ACE inhibitors/ARBs or sacubitril-valsartan, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors). 1, 3

• The 2022 ACC/AHA/HFSA guidelines give vericiguat a Class 2b recommendation for this specific high-risk population 1
• It should be considered particularly in patients with recent or recurrent hospitalizations despite full background medication 7
• The drug has a different mechanism of action from traditional neurohormonal blockade, targeting the NO-sGC-cGMP pathway 1

Critical Clinical Pearls

Patient selection pitfalls: 1

• Do not use in patients with NT-proBNP >5314 pg/mL (highest quartile), as no benefit was demonstrated in this subgroup 1, 3
• Ensure SBP is consistently ≥100 mmHg before initiation 1, 5
• Verify eGFR is ≥15 mL/min/1.73 m² 1, 2

Timing considerations: The VICTORIA trial enrolled patients who were particularly vulnerable, with 84% hospitalized for heart failure in the previous 6 months, making this a therapy specifically for high-risk, recently decompensated patients 7

Regulatory status: Vericiguat has limited regulatory approval and its place in GDMT remains uncertain compared to more established therapies like SGLT2 inhibitors and sacubitril-valsartan 1