Vericiguat in Heart Failure

📋 Key Information Summary

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Vericiguat (Verquvo®) is a soluble guanylate cyclase (sGC) stimulator that enhances the NO–sGC–cGMP signalling pathway independent of nitric oxide availability.
Indicated for worsening chronic heart failure with reduced ejection fraction (HFrEF, LVEF <45%) in patients who have had a recent decompensation event requiring IV diuretics or hospitalisation.
The VICTORIA trial demonstrated a significant reduction in the composite of cardiovascular death or first heart failure hospitalisation (HR 0.90, 95% CI 0.82–0.98, p=0.019) versus placebo over a median 10.8 months.
Absolute risk reduction was 4.2% (NNT ≈ 24 over ~1 year) for the composite primary endpoint.
Starting dose is 2.5 mg orally once daily, titrated every 2 weeks to a target of 10 mg once daily.
Common adverse effects include symptomatic hypotension (≈9%) and anaemia; vericiguat is contraindicated in pregnancy (Category X).
Concomitant use with PDE-5 inhibitors (e.g. sildenafil, tadalafil) is contraindicated due to risk of severe hypotension.
No clinically relevant renal or hepatic dose adjustment is required; however, caution is advised in severe hepatic impairment (Child–Pugh C).
Vericiguat is listed on the PBS as an Authority Required item for eligible patients with worsening HFrEF.
It should be considered as an add-on to guideline-directed medical therapy (ACEi/ARNI, BB, MRA, SGLT2i) — not as a substitute for established pillars.
Aboriginal and Torres Strait Islander patients experience higher heart failure hospitalisation rates; equitable access to vericiguat should be prioritised through PBS authority pathways and culturally safe prescribing.
Vericiguat is NOT indicated for acute decompensated heart failure or HFpEF; it is initiated during stabilisation after a worsening event.

Introduction & Australian Epidemiology

Vericiguat is a first-in-class soluble guanylate cyclase (sGC) stimulator approved for the treatment of worsening chronic heart failure with reduced ejection fraction (HFrEF). It represents a novel therapeutic mechanism distinct from neurohormonal blockade and SGLT2 inhibition, acting directly on the impaired NO–sGC–cGMP pathway that is downregulated in the failing myocardium and vasculature.

Heart failure affects an estimated 480,000 Australians and accounts for over 66,000 hospitalisations per year, making it one of the leading causes of unplanned readmission in Australia. In-hospital mortality for acute decompensated heart failure remains approximately 4–5%, and one-year all-cause mortality following a heart failure hospitalisation exceeds 20%. Aboriginal and Torres Strait Islander peoples experience heart failure at younger ages and with higher rates of hospitalisation and mortality compared with non-Indigenous Australians, reflecting disparities in cardiovascular risk factor burden, access to specialist care, and socioeconomic determinants of health.

Despite the expansion of guideline-directed medical therapy (GDMT) to four foundational pillars — ACE inhibitors or angiotensin receptor–neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors — residual cardiovascular risk remains substantial in patients who experience worsening events. Vericiguat addresses this residual risk by targeting a distinct pathophysiological mechanism: endothelial dysfunction and impaired myocardial cGMP signalling.

In Australia, vericiguat (Verquvo®) was approved by the Therapeutic Goods Administration (TGA) and is available on the Pharmaceutical Benefits Scheme (PBS) as an Authority Required medication for eligible patients with worsening chronic HFrEF. This guideline reviews the mechanism of action, pivotal trial evidence, indications, patient selection, dosing, and safety profile of vericiguat in the Australian clinical context.

Mechanism of Action (sGC Stimulation)

Vericiguat works by directly stimulating soluble guanylate cyclase (sGC), a key intracellular enzyme in the nitric oxide (NO)–sGC–cyclic guanosine monophosphate (cGMP) signalling pathway. This pathway is critically important for cardiovascular homeostasis, regulating vascular smooth muscle tone, myocardial contractility, and cardiac remodelling.

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Key concept: Unlike organic nitrates that supply exogenous NO, vericiguat sensitises sGC to both endogenous NO and also directly stimulates sGC independently of NO, making it effective even in states of impaired NO bioavailability — a hallmark of chronic heart failure.

The NO–sGC–cGMP Pathway in Heart Failure

In chronic heart failure, the NO–sGC–cGMP pathway is impaired through multiple mechanisms:

Reduced NO synthesis: Endothelial dysfunction and oxidative stress decrease endothelial nitric oxide synthase (eNOS) activity.
NO scavenging: Increased reactive oxygen species (ROS), particularly superoxide, react with NO to form peroxynitrite, reducing effective NO bioavailability.
sGC oxidation and degradation: Oxidative stress converts sGC from its NO-sensitive ferrous (Fe²⁺) state to an NO-insensitive ferric (Fe³⁺) or haem-free form, which is resistant to activation by NO.
Downstream cGMP deficiency: The net result is reduced intracellular cGMP, leading to impaired vasodilation, increased preload and afterload, adverse myocardial remodelling, and cardiac fibrosis.

Dual Mechanism of Vericiguat

Vericiguat has a unique dual mechanism:

1

sGC Sensitisation

Vericiguat increases the sensitivity of sGC to endogenous NO, amplifying cGMP production even when NO levels are low — as occurs in heart failure.

2

Direct sGC Stimulation

Vericiguat directly stimulates sGC independently of NO, generating cGMP even when the enzyme is in an oxidised or haem-free state that is unresponsive to NO.

Downstream Cardiovascular Effects of cGMP

Increased intracellular cGMP mediates several beneficial cardiovascular effects:

Effect	Mechanism	Clinical Relevance
Venodilation	cGMP-dependent protein kinase (PKG) activation in vascular smooth muscle	Reduces preload and ventricular filling pressures
Arterial vasodilation	PKG-mediated smooth muscle relaxation	Reduces afterload and systemic vascular resistance
Anti-fibrotic effects	cGMP–PKG signalling inhibits cardiac fibroblast activation and collagen deposition	Attenuates adverse myocardial remodelling
Anti-hypertrophic effects	PKG activation opposes maladaptive cardiomyocyte hypertrophy	May slow disease progression
Anti-inflammatory effects	cGMP reduces NF-κB-mediated inflammatory signalling	Reduces vascular and myocardial inflammation

Distinction from PDE-5 Inhibitors

It is important to distinguish vericiguat from phosphodiesterase-5 (PDE-5) inhibitors such as sildenafil and tadalafil. PDE-5 inhibitors prevent the degradation of cGMP, whereas vericiguat stimulates the production of cGMP. Although both increase intracellular cGMP through different mechanisms, their combination leads to excessive cGMP accumulation and a significant risk of severe hypotension. Therefore, concomitant use of vericiguat with PDE-5 inhibitors is contraindicated.

VICTORIA Trial Evidence

The pivotal evidence for vericiguat in heart failure comes from the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, a multinational, randomised, double-blind, placebo-controlled phase III trial.

Trial Design

Parameter	Detail
Population	5,050 patients with HFrEF (LVEF <45%), NYHA II–IV, with a worsening event within 6 months (HF hospitalisation within 6 months or IV diuretics without hospitalisation within 3 months)
Intervention	Vericiguat titrated to 10 mg PO once daily
Comparator	Placebo
Primary endpoint	Composite of cardiovascular death or first hospitalisation for heart failure
Median follow-up	10.8 months
Background GDMT	92% on ACEi/ARB/ARNI, 93% on beta-blocker, 63% on MRA

Primary Results

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Primary composite endpoint: Vericiguat reduced the composite of cardiovascular death or first HF hospitalisation compared with placebo (35.5% vs 38.5%; HR 0.90, 95% CI 0.82–0.98; p=0.019). The absolute risk reduction was 4.2%, corresponding to a number needed to treat (NNT) of approximately 24 over one year.

Key Secondary & Subgroup Analyses

First HF hospitalisation: HR 0.90 (95% CI 0.81–1.00) — consistent with the primary composite.
Cardiovascular death: HR 0.93 (95% CI 0.81–1.06) — point estimate favoured vericiguat but did not reach statistical significance as an individual endpoint.
All-cause mortality: HR 0.95 (95% CI 0.84–1.07) — not significant.
NT-proBNP subgroup: Patients with NT-proBNP <4,000 pg/mL derived greater benefit than those with NT-proBNP >8,000 pg/mL, suggesting greater efficacy in less advanced disease.
Benefit was consistent across age, sex, race, LVEF strata, renal function (eGFR ≥15 mL/min/1.73 m²), and background GDMT.

Safety Summary

Adverse Effect	Vericiguat	Placebo
Symptomatic hypotension	9.1%	7.9%
Syncope	4.0%	3.5%
Anaemia (decrease in Hb)	7.6%	5.7%
Dizziness	7.2%	6.4%

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Clinical interpretation: The VICTORIA trial population represented a higher-risk, recently decompensated cohort distinct from the PARADIGM-HF (sacubitril/valsartan) and DAPA-HF (dapagliflozin) trial populations. Vericiguat addresses residual risk in patients who remain vulnerable despite optimised background GDMT. It is positioned as an add-on therapy, not a replacement for established heart failure pharmacotherapy.

Indications & Patient Selection

Approved Indication

Vericiguat (Verquvo®) is indicated for the treatment of symptomatic chronic heart failure with reduced ejection fraction (HFrEF) in adult patients who have been stabilised following a recent worsening heart failure event requiring hospitalisation or intravenous diuretic therapy.

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Not for acute decompensation: Vericiguat should NOT be initiated during an acute decompensation episode. Patients must be haemodynamically stable and euvolaemic before starting treatment. It is typically initiated during the stabilisation phase or shortly after discharge.

Inclusion Criteria (aligned with VICTORIA)

Age ≥18 years
LVEF <45% (most recent echocardiography within 6 months)
NYHA functional class II, III, or IV symptoms
Worsening heart failure within the preceding 6 months, defined as:
- Hospitalisation for heart failure (index hospitalisation), OR
- Receipt of intravenous diuretics (without hospitalisation) within the preceding 3 months
Elevated natriuretic peptides (BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL at screening, or BNP ≥300 / NT-proBNP ≥1,000 pg/mL if atrial fibrillation)
On stable, optimised background GDMT (ACEi/ARB/ARNI, beta-blocker, MRA as tolerated)

PBS Criteria (Authority Required — Australia)

Under the Pharmaceutical Benefits Scheme, vericiguat is available as an Authority Required (streamlined) benefit. The prescriber must confirm:

The patient has symptomatic chronic heart failure with LVEF <45%
The patient has had a recent worsening of heart failure requiring hospitalisation or IV diuretics
The patient is receiving optimised background therapy as tolerated
The patient is not receiving concomitant PDE-5 inhibitors

Prescribers should check the current PBS schedule (pbs.gov.au) for the most up-to-date listing details and authority requirements.

Exclusion Criteria

Exclusion	Rationale
Concomitant PDE-5 inhibitor use (sildenafil, tadalafil, vardenafil, avanafil)	Contraindicated — risk of severe, potentially life-threatening hypotension due to excessive cGMP accumulation
Systolic BP <100 mmHg at initiation	Increased risk of symptomatic hypotension
Pregnancy or planning pregnancy	Teratogenic in animal studies; Category X contraindication
Acute decompensated heart failure	Not studied; haemodynamic instability during acute episodes
Severe hepatic impairment (Child–Pugh C)	Limited data; increased exposure expected

Where Vericiguat Fits in GDMT

Vericiguat is an add-on therapy to the four established pillars of HFrEF pharmacotherapy. It does not replace or substitute for any component of GDMT. The Australian heart failure treatment algorithm should be followed:

1

Pillar 1 — ACEi/ARB/ARNI

Sacubitril/valsartan preferred. Target dose or maximum tolerated dose.

2

Pillar 2 — Beta-blocker

Carvedilol, bisoprolol, or metoprolol succinate. Target dose as tolerated.

3

Pillar 3 — MRA

Spironolactone or eplerenone if eGFR >30 mL/min and K⁺ <5.0 mmol/L.

4

Pillar 4 — SGLT2 inhibitor

Dapagliflozin or empagliflozin regardless of diabetes status.

5

Add-on — Vericiguat

For patients with worsening events despite optimised GDMT. Addresses residual risk via the NO–sGC–cGMP pathway.

Dosing & Side Effects

Dosing Regimen

Vericiguat requires dose titration over 4 weeks to reach the target maintenance dose. Patients must be haemodynamically stable and euvolaemic before initiation.

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Vericiguat

Verquvo® · Soluble guanylate cyclase stimulator

Starting dose 2.5 mg orally once daily with food

Titration schedule Increase to 5 mg daily after 2 weeks, then to 10 mg daily after a further 2 weeks (if SBP ≥100 mmHg and no symptomatic hypotension)

Target dose 10 mg orally once daily

Route Oral (tablet)

Administration Take with food (improves bioavailability); swallow whole, do not crush or split

Missed dose If missed, take next dose at usual time; do not double

Renal adjustment No dose adjustment required (studied down to eGFR 15 mL/min/1.73 m²; avoid below 15 or dialysis — limited data)

Hepatic adjustment No adjustment for mild–moderate impairment (Child–Pugh A/B). Avoid in severe impairment (Child–Pugh C) — limited data

PBS status ⚡ PBS Authority Required

Available Strengths

Tablet Strength	Colour / Marking	Use
2.5 mg	White to off-white, oval	Starting dose and first titration step
5 mg	White to off-white, round	Intermediate dose
10 mg	White to off-white, oval	Target maintenance dose

Adverse Effects

Common

Symptomatic Hypotension

Reported in 9.1% of patients vs 7.9% placebo. Usually during titration. May present as dizziness, lightheadedness, or orthostatic symptoms.

Action: Hold dose or reduce to previous step; ensure euvolaemia; review concurrent antihypertensives

Moderate

Anaemia / Decreased Haemoglobin

Decrease in haemoglobin observed in 7.6% vs 5.7% placebo. May be related to haemodilution or mild cGMP-mediated effects on erythropoiesis.

Action: Monitor FBE at baseline and periodically; investigate if Hb <100 g/L or symptomatic

Common

Syncope

Reported in 4.0% vs 3.5% placebo. Often related to hypotension.

Action: Assess volume status; review antihypertensive co-medications; consider dose reduction

Common

Dizziness

Reported in 7.2% vs 6.4% placebo. Usually mild and self-limiting.

Action: Advise slow position changes; reassess during titration

Contraindications & Drug Interactions

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Absolute contraindication — PDE-5 inhibitors: Concomitant use with sildenafil, tadalafil, vardenafil, or avanafil is contraindicated due to the risk of severe, potentially life-threatening hypotension from excessive cGMP accumulation.

Interaction	Effect	Management
PDE-5 inhibitors (sildenafil, tadalafil)	Contraindicated — excessive cGMP elevation	Do not co-prescribe. If a PDE-5 inhibitor is required, discontinue vericiguat
Other soluble guanylate cyclase stimulators (riociguat)	Contraindicated — similar mechanism, additive hypotension	Do not co-prescribe
Nitrates (GTN, isosorbide mononitrate/dinitrate)	Additive vasodilation; increased hypotension risk	Use with caution; monitor blood pressure closely
Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin)	Reduce vericiguat exposure by up to 50%	Avoid combination if possible; monitor efficacy
Strong CYP3A4 and CYP2C9 inhibitors (fluconazole, voriconazole)	Increase vericiguat exposure	Use with caution; monitor for hypotension
NSAIDs	May reduce renal function and attenuate GDMT efficacy	Avoid in heart failure; not specific to vericiguat

Practical Titration Tips

Check blood pressure (sitting and standing) before each dose increase.
If SBP <100 mmHg or symptomatic hypotension at any titration step, maintain current dose or reduce to the previous step.
Optimise volume status before initiation — patients should be at dry weight.
Reassess concurrent antihypertensives (ACEi/ARB/ARNI, nitrates, alpha-blockers) for potential dose reduction.
Not all patients will reach the 10 mg target dose; the 5 mg dose provides clinical benefit.
Educate patients on symptoms of hypotension and advise them to rise slowly from sitting or lying.

Monitoring

Regular monitoring is essential during vericiguat therapy, particularly during the titration phase and in patients with concurrent comorbidities.

Baseline (before initiation)

Confirm haemodynamic stability, euvolaemia, and SBP ≥100 mmHg. Check FBE (haemoglobin), renal function (eGFR, U&E), LFTs, natriuretic peptides (BNP/NT-proBNP). Review current medications for PDE-5 inhibitors and other contraindicated agents. Confirm LVEF <45% on recent echocardiography.

Week 2 (first titration)

Assess blood pressure (sitting and standing). If SBP ≥100 mmHg and no symptomatic hypotension, increase from 2.5 mg to 5 mg. Inquire about dizziness, lightheadedness, or syncope.

Week 4 (second titration)

Repeat blood pressure assessment. If SBP ≥100 mmHg and asymptomatic, increase from 5 mg to target 10 mg. Check FBE (monitor for anaemia).

Week 8–12 (early maintenance)

Clinical review. Check FBE, renal function, natriuretic peptides. Assess symptom response (NYHA class, KCCQ if available). Review for ongoing hypotension or adverse effects.

Every 3–6 months (ongoing)

Routine clinical review. Monitor blood pressure, FBE, renal function. Reassess heart failure status and GDMT optimisation. Continue natriuretic peptide monitoring as part of holistic heart failure management.

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When to reduce or withhold: Reduce dose or temporarily withhold vericiguat if systolic BP <90 mmHg, symptomatic hypotension, new dizziness/syncope, or significant decline in haemoglobin (>20 g/L drop from baseline). Reassess volume status and concomitant medications before resuming.

Special Populations

🤰 Pregnancy

Vericiguat — Contraindicated (Category X)

Teratogenic in animal studies (skeletal malformations, reduced fetal body weight). Effective contraception must be used during treatment and for at least 1 month after the last dose. If pregnancy occurs, discontinue immediately and refer for obstetric review.

👶 Paediatrics

Vericiguat — Not established

No data in patients <18 years. Not indicated for paediatric heart failure. Use alternative therapies with established paediatric evidence.

👴 Elderly (≥75 years)

Vericiguat — Use with caution

No specific dose adjustment required. Elderly patients are at higher risk of hypotension and syncope. Titrate cautiously; monitor blood pressure closely at each step. Consider slower titration (extend intervals to 3–4 weeks). Polypharmacy review is essential.

🫘 Renal Impairment

Vericiguat — No dose adjustment (eGFR ≥15 mL/min/1.73 m²)

Studied in patients with eGFR down to 15 mL/min/1.73 m². Limited data in eGFR <15 or dialysis; avoid in these settings. Monitor renal function as part of routine heart failure care.

🫁 Hepatic Impairment

Vericiguat — No adjustment for mild–moderate (Child–Pugh A/B)

Avoid in severe hepatic impairment (Child–Pugh C) due to increased drug exposure and limited safety data. Monitor LFTs at baseline and periodically.

🛡️ Immunocompromised

Vericiguat — No specific concerns

No known immunosuppressive effects. Standard heart failure and vericiguat monitoring apply. Be aware of potential drug interactions with antifungal agents (CYP3A4/2C9 inhibitors) used in immunocompromised patients.

Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

Epidemiological burden

Aboriginal and Torres Strait Islander Australians experience heart failure at younger ages, with higher rates of hospitalisation and mortality compared with non-Indigenous Australians. Cardiovascular disease remains the leading contributor to the health gap. Ischaemic heart disease and cardiomyopathy (including rheumatic heart disease–related) are common aetiologies.

Access to specialist care

Many Indigenous Australians, particularly those in remote and very remote communities, have limited access to cardiologists, heart failure nurse specialists, and echocardiography services. Telehealth-based titration and monitoring models can improve access to vericiguat prescribing and follow-up.

GDMT optimisation

Prioritise maximising the four foundational GDMT pillars (ARNI/ACEi, beta-blocker, MRA, SGLT2i) before considering vericiguat. Ensure cultural safety in prescribing conversations and shared decision-making with patients, families, and Aboriginal health workers.

PBS access & cost

Vericiguat is PBS Authority Required, reducing out-of-pocket costs. Ensure patients are aware of their entitlements and assist with authority applications where needed. Community pharmacies in remote areas may have limited stock — coordinate supply through patient travel schemes or remote pharmacy services.

Medication adherence

Complex medication regimens for heart failure can be challenging. Use blister packs, medication management aids, and involve Aboriginal Health Workers and pharmacists in adherence support. Simplify regimens where possible (e.g., once-daily dosing of vericiguat is advantageous).

Blood pressure monitoring

Home blood pressure monitoring may be limited in remote settings. Consider providing BP monitors through Aboriginal Community Controlled Health Organisations (ACCHOs) or primary care services. Telehealth BP review can support safe titration.

Rheumatic heart disease

RHD-related heart failure is disproportionately prevalent in Aboriginal and Torres Strait Islander communities, particularly in northern and central Australia. Vericiguat may be considered in RHD-related HFrEF, although the VICTORIA trial did not specifically study this population. Manage in consultation with a cardiologist or RHD programme (RHDAustralia guidelines).

Cultural considerations

Use culturally appropriate communication, including interpreter services where needed. Involve family and community Elders in care planning where appropriate. Recognise the holistic concept of health and wellbeing in Aboriginal and Torres Strait Islander cultures, which extends beyond the biomedical model.

📚 References

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2. Pieske B, Patel MJ, Lam CSP, et al. Effect of vericiguat on NT-proBNP in patients with heart failure and reduced ejection fraction: the VICTORIA biomarker study. Eur J Heart Fail. 2022;24(5):832–842.
3. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008.
4. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004.
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7. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. Circulation. 2022;145(18):e895–e1032.
8. Australian Institute of Health and Welfare (AIHW). Heart, stroke and vascular disease — Australian facts. AIHW, Canberra; 2023.
9. Australian Institute of Health and Welfare (AIHW). Aboriginal and Torres Strait Islander health performance framework 2023 summary report. AIHW, Canberra; 2023.
10. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263–2273.
11. Follmann M, Griebenow N, Hahn MG, et al. The chemistry and biology of soluble guanylate cyclase stimulators and activators. Angew Chem Int Ed. 2013;52(36):9442–9462.
12. Therapeutic Goods Administration. Australian Public Assessment Report (AusPAR) for vericiguat. TGA, Woden; 2022.