What is Veriquat?

What is Vericiguat?

Vericiguat is an oral soluble guanylate cyclase (sGC) stimulator approved for reducing cardiovascular death and heart failure hospitalization in high-risk patients with heart failure with reduced ejection fraction (HFrEF) who have recently experienced worsening heart failure. 1

Mechanism of Action

Vericiguat works by directly stimulating soluble guanylate cyclase in the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway 2, 3:

• Enhances cGMP production independently of nitric oxide while also synergistically amplifying NO effects when present 2
• Restores the NO-sGC-cGMP pathway that becomes deficient in heart failure, contributing to disease progression 4, 3
• Relaxes vascular smooth muscle, leading to hemodynamic improvements 2

Clinical Indication and Patient Selection

Vericiguat is specifically indicated for high-risk patients with HFrEF who have experienced recent worsening heart failure despite being on guideline-directed medical therapy (GDMT). 1

The target population includes patients with 1, 5:

• Heart failure with ejection fraction ≤45% (some sources cite <45%)
• Recent heart failure hospitalization or need for intravenous diuretic therapy
• Already receiving optimized GDMT (sacubitril-valsartan or ACE inhibitors/ARBs, beta-blockers, mineralocorticoid receptor antagonists, SGLT2 inhibitors)

Evidence Base

The VICTORIA trial demonstrated 5, 3:

• 10% relative risk reduction in the composite endpoint of cardiovascular death or heart failure hospitalization
• Number needed to treat of 24 patients to prevent one event
• Benefit was independent of background heart failure therapy
• Well-tolerated with low incidence of symptomatic hypotension and syncope compared to placebo

Dosing and Administration

Standard dosing regimen 2:

• Starting dose: 2.5 mg once daily with food (to maximize absorption)
• Titration: Double dose every 2 weeks as tolerated based on blood pressure
• Target dose: 10 mg once daily
• Food requirement: Must be taken with food for optimal bioavailability (93%)

Pharmacokinetic Profile

Key pharmacokinetic characteristics 2:

• Half-life: approximately 20 hours in healthy volunteers, 30 hours in HFrEF patients
• Metabolism: primarily via glucuronidation (UGT1A1 and UGT1A9)
• Low renal clearance with minimal urinary excretion
• Dose-proportional pharmacokinetics in healthy volunteers; slightly less than dose-proportional in HFrEF patients

Drug Interactions

Vericiguat has minimal clinically significant drug interactions 2, 6:

Safe Combinations (No Dose Adjustment Needed)

• Sacubitril/valsartan: No clinically relevant pharmacodynamic or pharmacokinetic interactions 6
• Warfarin: No effect on anticoagulation 6
• Aspirin: No effect on bleeding time or platelet aggregation 6
• Digoxin: No clinically meaningful interactions 2

Contraindicated Combinations

• Phosphodiesterase type-5 inhibitors (e.g., sildenafil, tadalafil): Not studied in HFrEF patients; avoid due to potential increased risk of symptomatic hypotension 2

Use with Caution

• Long-acting nitrates: Limited experience; ongoing VICTOR trial is evaluating this combination 2

Special Populations

No dose adjustments are required for 2:

• Age
• Sex
• Race
• Body weight
• Hepatic impairment
• Renal impairment

Safety Profile

Vericiguat was well-tolerated in clinical trials 3:

• Low incidence of symptomatic hypotension compared to placebo
• Low incidence of syncope compared to placebo
• No electrophysiological abnormalities observed in preclinical and clinical studies 2
• Most patients achieved the 10 mg target dose using blood pressure-guided titration 2

Clinical Context and Timing

Vericiguat should be initiated during the vulnerable period after worsening heart failure 5:

• Risk is highest in the weeks following a worsening event (up to 10% mortality and 30% rehospitalization risk)
• Early optimization of treatment is critical during this vulnerable period
• Vericiguat addresses residual risk not targeted by standard quadruple therapy

Important Caveats

• Vericiguat is NOT a replacement for GDMT; it is added on top of optimized guideline-directed therapy 1, 3
• Blood pressure monitoring is essential during titration to guide dosing 2
• The drug targets a specific pathophysiologic mechanism (cGMP deficiency) that persists despite standard neurohormonal blockade 3