Vericiguat in Heart Failure with a Reduced Ejection Fraction: Patient Selection and Special Considerations

Figures & data

Figure 1 Cyclic guanosine monophosphate (cGMP) pathway.

Abbreviations: eNOS, endothelial nitric oxide synthase; NO, nitric oxide; sGC, soluble guanylate cyclase; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate.

Table 1 sGC Stimulators and Activators

	Mechanism of Action	Maximum Dosing	Adverse Effects	Indications
Stimulators
Riociguat	Binds to the heme-Fe^2+ beta subunit of soluble guanylate cyclase (native form of sGC)	2.5 mg PO TID	Hypotension anemia GERD	PAH CTEPH
Vericiguat	Synergistic with endogenous NO	10 mg PO daily	Hypotension anemia	HFrEF
Activators
Cinaciguat	Binds to dysfunctional heme-free-Fe^3+ sGC regardless of endogenous NO availability	600 mcg/hr IV infusion	Hypotension	Experimental drug, most potent sGC activator

Abbreviations: sGC, soluble guanylate cyclase, NO, nitric oxide; TID, three times daily; PO, orally; GERD, gastroesophageal reflux disease; PAH, pulmonary arterial hypertension; CTEPH, chronic thromboembolic pulmonary hypertension; HFrEF, heart failure with reduced ejection fraction; IV, intravenous.

Table 2 Clinical Trials Evaluating Soluble Guanylate Cyclase Stimulators or Activators in Heart Failure with a Reduced Ejection Fraction

Trial Name (Year of Publication)	Trial Design	Sample Size	Inclusion Criteria	Primary Outcomes	Results
COMPOSE programme (2013)^Citation13	Placebo-controlled, phase 2b, randomized dose ranging study	N=139	Current HFH, PCWP >18 mm Hg, LVEF <40%	Change in PCWP at 8 hours	Significant reduction in mean PCWP vs placebo (mean PCWP −7.7 mm Hg with cinaciguat vs −3.7 mm Hg with placebo [p < 0.0001]). High incidence of hypotension with cinaciguat (73%)
LEPHT (2013)^Citation30	Placebo-controlled, phase 2b, randomized dose ranging study	N=201	LVEF ≤40% and mPAP ≥25mm Hg	Placebo-corrected change from baseline at week 16 in mPAP	No significant difference in mPAP change between riociguat group (−6.1±1.3 mm Hg) vs placebo (−4.0±1.2 mm Hg (p = 0.10)
SOCRATES-REDUCED (2015)^Citation14	Placebo-controlled, phase 2b, dose ranging study	N=456	LVEF <45%, a recent worsening HF event, and elevated natriuretic peptide levels	Reduction in NT-proBNP values at 12 weeks	No significant difference in primary end point between pooled vericiguat group and placebo (p = 0.15). Vericiguat 10 mg dose group had a significant reduction in NT-proBNP values compared to placebo group in exploratory secondary analysis (p = 0.048). Rates of adverse events similar between placebo and vericiguat groups
VICTORIA (2020)^Citation9	Phase 3 randomized, placebo-controlled, double blind study	N=5050	LVEF <45%, NYHA class II–IV symptoms, elevated natriuretic peptide levels, and worsening HF event	Composite CV death or first HFH	Significant reduction in primary end point with vericiguat group (35.5%) versus placebo (38.5%, HR 0.90, p = 0.019). Vericiguat group had fewer total hospitalizations for heart failure (38.3 events per 100 patient-years) compared to placebo (42.4 events per 100 patient-years; HR 0.91; 95% CI 0.84–0.99; p = 0.02) No significant difference between treatment groups for CV or all-cause mortality. Similar rates of serious AEs between treatment groups (32.8% with vericiguat group and 34.8% with placebo group) with higher rates of anemia in the vericiguat group.

Abbreviations: HFH, heart failure hospitalization; LVEF, left ventricular ejection fraction; PCWP, pulmonary capillary wedge pressure; HF, heart failure; mPAP, mean pulmonary arterial pressure, NYHA, New York Heart Association; NT-proBNP, N-terminal pro-B-type natriuretic peptide; HR, hazard ratio; CI, confidence interval; CV, cardiovascular; AE, adverse event.

Figure 2 Place in therapy for vericiguat according to progression through the ACC/AHA stages B and C of heart failure.

Abbreviations: BB, beta blocker; ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; GDMT, guideline-directed medical therapy; ARNI, angiotensin receptor-neprilysin inhibitor; SGLT-2, sodium-glucose cotransporter-2; MRA, mineralocorticoid receptor antagonist.

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