What is the dosing regimen and indications for Vericiguat (vericiguat) in patients with heart failure with reduced ejection fraction?

Vericiguat Dosing Regimen and Indications for HFrEF

Vericiguat is indicated to reduce the risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic heart failure with ejection fraction less than 45%.

Indications

Vericiguat is specifically indicated for patients with:

• Heart failure with reduced ejection fraction (HFrEF) with EF <45%
• Recent worsening heart failure defined as:
  • Hospitalization for heart failure within the past 6 months, OR
  • Need for outpatient IV diuretic therapy without hospitalization
• NYHA class II-IV symptoms
• On background guideline-directed medical therapy (GDMT)
• Elevated natriuretic peptides:
  • BNP ≥300 pg/mL or NT-proBNP ≥1000 pg/mL (in sinus rhythm)
  • Higher cutoffs for patients with atrial fibrillation

Dosing Regimen

The FDA-approved dosing regimen for vericiguat is:

• Starting dose: 2.5 mg orally once daily with food
• Titration: Double the dose approximately every 2 weeks
• Target maintenance dose: 10 mg once daily
• Administration: May be crushed and mixed with water for patients who have difficulty swallowing

Patient Selection Considerations

Vericiguat should not be used in patients with:

• Systolic blood pressure <100 mmHg
• eGFR <15 mL/min/1.73 m²
• Concomitant use of other soluble guanylate cyclase (sGC) stimulators
• Pregnancy (contraindicated due to embryo-fetal toxicity)
• Patients on long-acting nitrates

Clinical Evidence

The VICTORIA trial demonstrated that vericiguat reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared to placebo (35.5% vs 38.5%, HR 0.90, p=0.019) 1. The absolute risk reduction was modest at 4.2 events per 100 patient-years with a number needed to treat of 24 patients 2.

Importantly, patients with extremely elevated NT-proBNP levels (>5314 pg/mL) did not show benefit from vericiguat compared to placebo 1.

Place in Therapy

Vericiguat should be considered after optimization of foundational GDMT for HFrEF, which includes:

1. SGLT2 inhibitors
2. Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol)
3. Renin-angiotensin system inhibitors (preferably ARNi such as sacubitril/valsartan)
4. Mineralocorticoid receptor antagonists

Vericiguat represents an additional option for patients who continue to have symptoms or have recently experienced worsening heart failure despite optimal GDMT 1.

Monitoring and Safety

• Pregnancy testing: Required before initiating treatment in females of reproductive potential
• Contraception: Females of reproductive potential must use effective contraception during treatment and for one month after stopping treatment
• Common adverse effects: Hypotension (16% vs 15% with placebo) and anemia (10% vs 7% with placebo) 3
• Monitor for symptomatic hypotension (9.1% vs 7.9% with placebo) and syncope (4.0% vs 3.5% with placebo) 1

Clinical Pearls

• Vericiguat works through a novel mechanism as a soluble guanylate cyclase stimulator, increasing cGMP production which has beneficial effects including vasodilation, improved endothelial function, and decreased fibrosis and remodeling 1
• The drug can be taken with other heart failure medications but should not be combined with other sGC stimulators or PDE-5 inhibitors 3
• Unlike some other heart failure therapies, vericiguat has been studied specifically in high-risk patients with recent worsening heart failure, making it particularly relevant for this vulnerable population 4
• Approximately 90% of patients in the VICTORIA trial were able to achieve the target dose of 10 mg daily 2

Vericiguat represents an additional therapeutic option for patients with HFrEF who continue to experience symptoms or hospitalizations despite optimal GDMT, particularly targeting those at highest risk with recent worsening heart failure.