What is the role of Vericiguat (soluble guanylate cyclase stimulator) in the management of heart failure with reduced left ventricular ejection fraction (HFrEF)?

Role of Vericiguat in Heart Failure with Reduced Ejection Fraction (HFrEF)

Vericiguat should be considered as an additional therapy for high-risk HFrEF patients with recent worsening heart failure who remain symptomatic despite guideline-directed medical therapy (GDMT), but it is not recommended as a first-line treatment for all HFrEF patients. 1, 2

Mechanism of Action and Indication

• Vericiguat is a soluble guanylate cyclase (sGC) stimulator that works by directly stimulating sGC, independently of and synergistically with nitric oxide (NO), augmenting levels of intracellular cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation and vasodilation 2
• FDA approved 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 HF and ejection fraction less than 45% 2
• Heart failure is associated with impaired synthesis of NO and decreased activity of sGC, which may contribute to myocardial and vascular dysfunction 2

Patient Selection Criteria

• Appropriate candidates for vericiguat include patients with:

  • Left ventricular ejection fraction (LVEF) <45% 2
  • NYHA class II-IV symptoms 3
  • Recent heart failure worsening (hospitalization within 6 months or outpatient IV diuretic use within 3 months) 1, 3
  • Elevated natriuretic peptides (BNP ≥300 pg/mL or NT-proBNP ≥1000 pg/mL in sinus rhythm) 3
  • Patients already on optimal GDMT who remain symptomatic 1

• Vericiguat should NOT be used in patients with:

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

Clinical Efficacy

• In the VICTORIA trial, vericiguat demonstrated a 10% relative reduction in the primary composite outcome of cardiovascular death or heart failure hospitalization compared to placebo (HR 0.90, p=0.019) 1, 4
• The benefit was primarily driven by reduction in heart failure hospitalizations rather than cardiovascular death 1
• The benefit was greater in patients with lower N-terminal pro-brain natriuretic peptide levels and less effective in patients with very high NT-proBNP levels (>5314 pg/mL) 1
• In the more recent VICTOR trial, which studied patients with HFrEF without recent worsening, vericiguat did not significantly reduce the primary composite endpoint of cardiovascular death or heart failure hospitalization (HR 0.93 [95% CI 0.83-1.04]; p=0.22) 5
• However, VICTOR did show fewer cardiovascular deaths (HR 0.83 [95% CI 0.71-0.97]) and all-cause deaths (HR 0.84 [95% CI 0.74-0.97]) in the vericiguat group 5

Place in Therapy Algorithm

1. First-line therapies (establish these before considering vericiguat):

   • Beta-blockers 1
   • ACE inhibitors, ARBs, or preferably ARNI (sacubitril/valsartan) 1
   • Mineralocorticoid receptor antagonists (spironolactone, eplerenone) 1
   • SGLT2 inhibitors 1

2. Consider vericiguat when:

   • Patient has had recent worsening heart failure (hospitalization within 6 months or IV diuretic use within 3 months) 1, 2
   • Patient remains symptomatic despite optimal doses of first-line therapies 1
   • LVEF <45% and elevated natriuretic peptides 3, 2
   • Systolic BP ≥100 mmHg 1, 3

3. Dosing and administration:

   • Start at 2.5 mg once daily 1
   • Titrate to target dose of 10 mg once daily 1
   • Average dose in clinical trials was 9.2 mg daily 1

Monitoring and Safety Considerations

• Monitor for symptomatic hypotension, which occurred in 9.1% of patients on vericiguat versus 7.9% on placebo in the VICTORIA trial 1
• In real-world studies, gastrointestinal symptoms were more common with vericiguat (23.62% vs. 2.74%) 6
• No dosage adjustment required in geriatric patients or those with mild to moderate hepatic impairment 2
• No dosage adjustment required in patients with eGFR ≥15 mL/min/1.73m² who are not on dialysis 2
• Vericiguat demonstrated a dose-dependent reduction in NT-proBNP at 12 weeks compared to placebo 2

Clinical Pearls and Caveats

• Vericiguat has a Class 2b recommendation from the American Heart Association, American College of Cardiology, and Heart Failure Society of America, indicating it "may be considered" rather than "should be used" 1, 3
• The drug's place in GDMT is currently uncertain, and it is not expected to be widely used in contemporary trials 1
• Vericiguat appears to have different effects in different patient populations - more benefit in those with recent worsening HF (VICTORIA) than in stable outpatients (VICTOR) 5, 4
• The benefit appears to be greater in patients with lower NT-proBNP levels, suggesting earlier intervention may be more beneficial 1
• Vericiguat may be particularly useful in patients who cannot tolerate other HFrEF therapies due to hypotension, as it causes only a modest reduction in systolic blood pressure (1-2 mmHg greater than placebo) 2