Vericiguat addresses unmet needs in worsening HFrEF

Heart failure (HF) is a complicated clinical syndrome that is inherently progressive. In HF with reduced ejection fraction (HFrEF), the left ventricular ejection fraction (LVEF) is ≤40 percent and accompanied by progressive LV dilatation and adverse cardiac remodeling. [Eur J Heart Fail 2021;23:352-380]

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors, β-blockers, mineralocorticoid receptor antagonists, and diuretics form the basis of first-line pharmacological management of HFrEF. However, despite guideline-directed medical therapy (GDMT), many patients still experience repetitive worsening HF events, characterized by the development of progressively escalating signs and symptoms requiring intravenous (IV) diuretics or hospitalizations, and with markedly worse prognosis (Figure 1).

In a real-world study, 1 in 6 patients with HFrEF developed worsening HF within 18 months of HF diagnosis. The two-year mortality rate was 22.5 percent, and 56 percent of patients were rehospitalized within 30 days of a worsening HF event. [J Am Coll Cardiol 2019;73:935-944]

In another study in the US, approximately 50 percent of patients hospitalized for HF were readmitted within 6 months of discharge, and almost 30 percent died within a year. [J Am Coll Cardiol 2009;54:1703-1705; Am Heart J 2007;154:260-266]

In the ASIAN-HF multinational registry which included HF patients in Singapore,  one-year, crude, all-cause mortality was 10.6 percent among Asians with HFrEF. Cardiovascular (CV) death was the most common cause of death in this high-risk group. [J Am Heart Assoc 2020;9:e012199]

Importantly, the risk of HF rehospitalization or CV death was greater in patients with previous hospitalization for HF. [Circulation 2020;141:e139-e596]

Impaired NO-sGC-cGMP pathway signalling in HF
In HF, endothelial dysfunction and reactive oxygen species reduce nitric oxide (NO) bioavailability, resulting in a relative deficiency in soluble guanylate cyclase (sGC) and reduced cyclic guanosine monophosphate (cGMP) generation. [J Med Chem 2017;60:5146-5161]

By directly stimulating sGC in a manner similar to, but independent of, endogenous NO, cGMP levels will likely increase, and its protective effects (regulation of cardiac contractility, vascular tone, and cardiac remodelling) can be restored.

However, the low levels of sGC in HFrEF remain unaddressed by current medical therapies, many of which merely block the harmful effects of the natural neurohormonal systems activated by myocardial and vascular dysfunction.

With this high unmet need, novel treatment options are warranted, particularly in patients with worsening HFrEF.

Vericiguat for worsening HFrEF
Vericiguat, a novel oral sGC stimulator, offers a novel treatment mechanism for worsening HFrEF.

Instead of targeting compensatory mechanisms to adjust for the primary deficit in cardiac output, vericiguat enhances the cGMP pathway by directly stimulating the sGC through a binding site independent of NO and sensitizing sGC to endogenous NO. [Circulation 2011;123:2263-2273]

By increasing cGMP production, vericiguat decreases arterial constriction and arterial stiffness.

Vericiguat is approved by the Singapore Health Sciences Authority (HSA) for the treatment of symptomatic chronic HF in adult patients with reduced EF, who are stabilized after a recent decompensation event requiring IV therapy.

Administered in combination with other HF therapies, vericiguat is both US FDA- and EMA-approved.

VICTORIA a win for patients with worsening HFrEF
In the phase III, randomized, double-blind, placebo-controlled trial, vericiguat reduced the primary endpoint of combined risk of CV death and hospitalization for HF following a worsening HF event. [N Engl J Med 2020;382;1883-1893]

From a trial perspective, what was interesting was the picking out of patients with a recent HF hospitalization, which constituted a high-risk group – 5,050 patients with chronic HF (New York Heart Association class II, III, or IV) and an EF of <45 percent. Patients were randomly assigned to receive vericiguat 2.5 mg daily, titrated to a target dose of 10 mg once daily, or placebo against a background of GDMT.

Sixty percent of the patients were on triple therapy, 90 percent were on double therapy, and 32 percent had devices. The primary endpoint was a composite of CV death and first hospitalization for HF.

At a median follow-up of 10.8 months, there was a 10 percent relative risk reduction (RRR) in CV death or hospitalization with vericiguat — importantly, this translated into an absolute event-rate reduction (ARR) of 4.2 events per 100 patient-years. The number needed to treat (NNT) with vericiguat for 1 year to prevent CV death or HF hospitalization is 24 patients (Figure 2).

KOL perspectives
“Readmission for HF continues to pose a significant burden for both mortality and morbidity,” commented Clinical Associate Professor David Sim, Deputy Head and Senior Consultant, Department of Cardiology and Director of Heart Failure Programme, National Heart Centre Singapore. “The use of vericiguat in this group of patients with worsening HF has been shown to reduce the composite endpoint of CV death or hospitalization for HF, in addition to current proven therapy for HFrEF.”

Despite excellent GDMT, one in four patients with HFrEF will be hospitalized for worsening HF, said VICTORIA lead investigator Professor Paul Armstrong from the University of Alberta and Director of the Canadian VIGOUR Centre in Alberta, Canada, during his presentation at the American College of Cardiology 2020 Meeting. “This is where vericiguat adds value. We can say with assurance that we made a difference in a new population with a new drug.”

In the 2021 ESC guidelines for the treatment and management of acute and chronic HF, vericiguat was the only therapy recommended as an add-on therapy for HFrEF patients (NYHA class II-IV) who had a worsening HF despite treatment with an ACE inhibitor or an ARNI, a β-blocker, and an MRA to reduce the risk of CV mortality or HF hospitalization. [Eur Heart J 2021;42:3599-3726]

Vericiguat therefore offers a new treatment mechanism for this high-risk population with worsening HFrEF who previously had very limited treatment options.