Vericiguat for Heart Failure

From 1 December 2022, vericiguat was made available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of symptomatic heart failure.

The criteria for initial PBS supply requires patients to:

• Have a left ventricular ejection fraction (LVEF) of less than 45%;
• New York Heart Association (NYHA) class II, III, or IV;
• No clinical signs of fluid overload and not have received intravenous treatment for fluid overload in the preceding 24 hours;
• Systolic blood pressure ≥ 100mmHg;
• Be receiving optimal standard therapy for chronic heart failure that includes a beta-blocker (unless contraindicated or not tolerated); and
• Be receiving optimal standard therapy that includes either an angiotensin converting enzyme (ACE) inhibitor, angiotensin II antagonist, or angiotensin receptor with neprilysin inhibitor combination (unless contraindicated or not tolerated).

Vericiguat is a stimulator of soluble guanylate cyclase (sGC), a receptor normally activated by nitric oxide (NO). Stimulation of sGC leads to the synthesis of cyclic guanosine monophosphate (cGMP), a signalling molecule that is essential for the normal functioning of the cardiovascular system. This system plays an important role in regulating cardiac contractility, vascular tone, and cardiac remodelling. The synthesis of NO and the activity of sGC are both reduced in heart failure.

Efficacy

The safety and efficacy of vericiguat were evaluated in the VICTORIA trial. This double-blind study randomly assigned patients with chronic heart failure (NYHA class II-IV) and LVEF of less than 45% to receive vericiguat or placebo, in addition to standard guideline-based therapy. Over 5,000 adult patients participated in this study over a median follow-up period of 10.8 months. The primary outcome was a composite of death from cardiovascular causes or first hospitalisation for heart failure.

Some of the main findings of the study include the following:

• A primary-outcome event occurred in 35.5% of the vericiguat group and 38.5% of the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.02);
• Hospitalisation for heart failure occurred in 27.4% of the vericiguat group and 29.6% of the placebo group (hazard ratio, 0.90; 95% CI, 0.81 to 1.00);
• Death from cardiovascular causes occurred in 16.4% of the vericiguat group and 17.5% of the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06); and
• The composite of death from any cause or hospitalisation for heart failure occurred in 37.9% of the vericiguat group and 40.9% of the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P=0.02).

Safety

There was a slight reduction in systolic blood pressure noted in each group over the first 16 weeks of the VICTORIA study (greater effect in the vericiguat group than in the placebo group). However, readings returned to baseline by week 32. Patients with a systolic blood pressure of less than 100mmHg or symptomatic hypotension at treatment initiation were excluded from the study.

Symptomatic hypotension and syncope were prespecified adverse events of clinical interest in the VICTORIA trial. Symptomatic hypotension was more commonly reported in the vericiguat group (9.1% versus 7.9%), as was syncope (4.0% versus 3.5%).

The manufacturer advises that if symptomatic hypotension occurs, prescribers should consider dose adjustment of concomitant diuretics and treatment of other causes of hypotension. If symptomatic hypotension continues, a temporary reduction or interruption of vericiguat dosing should be considered.

Anaemia was also more commonly reported in the vericiguat group (7.6% versus 5.7%). While anaemia was common at baseline (35.7% of patients met the World Health Organization criteria for anaemia), vericiguat was associated with a modest reduction in haemoglobin at week 16. This reduction did not progress further over the 96 weeks of follow-up. Analysis demonstrates that patients with lower baseline haemoglobin levels were at higher risk for the primary end point of death from cardiovascular causes or hospitalisation for heart failure.

Reduced haemoglobin is a finding similar to studies conducted with riociguat, another sGC stimulator. The mechanism of this adverse effect is currently unknown. It has been postulated that anaemia could be a result of vasodilator effects that could lead to bleeding from unidentified sources. Alternatively, animal models suggest there may be a link between haemoglobin and the sGC pathway.

Contraindications and precautions

Vericiguat is contraindicated with other sGC stimulators. The other sGC stimulator available in Australia is riociguat, which is approved for the treatment of pulmonary hypertension.

Although not contraindicated, combined use with phosphodiesterase 5 inhibitors (e.g. sildenafil, tadalafil) is not recommended. This combination of medications has not been studied in patients with heart failure, and it may increase the risk of symptomatic hypotension.

Administration

Vericiguat has a longer half-life (around 30 hours in heart failure patients) than riociguat and can be administered as a single daily dose. Dosing is usually initiated at 2.5mg daily. This can be doubled every two weeks to a target maintenance dose of 10mg once daily, or as tolerated. Tablets are available in 2.5mg, 5mg, and 10mg strengths to facilitate titration.

The manufacturer does not recommend dose adjustments for patients with mild or moderate hepatic impairment or severe renal impairment (eGFR ≥ 15 mL/min/1.73 m² without dialysis). However, vericiguat is not recommended for use in patients with severe hepatic impairment or an eGFR <15 mL/min/1.73 m^2, as it has not been studied in these populations.

For optimal bioavailability, vericiguat tablets should be taken with food. For patients who have difficulty swallowing, tablets may be crushed and mixed with water immediately before administration. This provides comparable bioavailability and peak plasma levels to swallowing a whole tablet.

When given with food, vericiguat exposure is not affected by coadministration with medications that increase gastric pH. This includes proton pump inhibitors, H₂ receptor antagonists, and antacids.

Place in therapy

Vericiguat is indicated as an adjunct to standard of care therapy for symptomatic chronic heart failure with reduced ejection fraction (HFrEF). The National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand recommend the following medications for all patients with HFrEF: an ACE inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist.

In the VICTORIA trial, more than 99% of patients were treated with other heart failure therapies at baseline. This included beta-blockers (93%), ACE inhibitors or angiotensin II receptor blockers (73%), and a mineralocorticoid receptor antagonist (70%). The majority of patients (91%) were taking two or more heart failure medications, and 60% were receiving triple therapy (i.e. a beta-blocker, any renin-angiotensin system inhibitor, and a mineralocorticoid antagonist.

Patients were also included who were taking an angiotensin receptor and neprilysin inhibitor (ARNI) combination (15%) or ivabradine (6%), or had an implantable cardiac defibrillator (28%) or biventricular pacemaker (15%).

Only 3% of patients were on a sodium glucose co-transporter 2 (SGLT2) inhibitor. Therefore, the study authors declined to comment on any potential additional benefit of vericiguat to SGLT2 inhibitor therapy. The SGLT2 inhibitors approved for the treatment of heart failure are empagliflozin and dapagliflozin.