Background
Heart failure (HF) is a significant health problem with a prevalence of 4.5% in Singapore, and over 26 million globally. More than half of HF patients are categorised as HF with reduced left ventricular ejection fraction (LVEF ≤ 45%) i.e., HFrEF. Low LVEF in systolic HF as well as hospitalisation for worsening or symptomatic HF are powerful predictors of mortality, with few therapies to date designed to attenuate this risk.
Vericiguat (Verquvo), an oral soluble guanylate cyclase (sGC) stimulator, enhances the cyclic guanosine monophosphate (cGMP) pathway and restores nitric oxide (NO) sensitivity within the dysregulated HF state. This translates to decreased arterial constriction and stiffness as well as reduced myocardial thickening and fibrosis. The novel therapeutic received HSA approval in October 2021 for use in symptomatic chronic HF adult patients with reduced EF, who are stabilised after a recent decompensation event requiring intravenous (IV) therapy. Vericiguat is available in Singapore as 10mg, 5mg and 2.5mg film-coated tablets. The drug, administered in combination with prevailing standard of care HF therapies, is initiated at 2.5mg daily and increased to 5mg daily, then 10mg daily at 2-weekly intervals as tolerated.
Efficacy
Vericiguat’s global registry approvals were based on results from the Phase III VICTORIA study that evaluated the therapeutic (n=2,526) against placebo (n=2,524) in chronic heart failure (NYHA Class II-IV) patients with reduced ejection fraction (mean EF=29%) over a median follow-up period of 11-months. All patients had a recent worsening event, which was defined as hospitalisation for HF/ IV diuretic administration and elevated natriuretic peptides (median NT-proBNP=2,800 pg/mL). Patients with CKD Stage ≥4 or on dialysis were excluded. The study participants were on pharmacologic standard of care at baseline, where 91% of patients were treated with ≥2 HF medications (beta-blocker, any renin angiotensin system (RAAS) inhibitor or mineralocorticoid receptor antagonist (MRA)) and 60% of patients were treated with all three. 3% of all patients were also receiving a sodium glucose co-transporter 2 inhibitor (SGLT2i).
The primary outcome, a composite of cardiovascular (CV) death or HF hospitalisation, occurred in 35.5% of the vericiguat group compared with 38.5% of the placebo group (HR 0.90, p=0.019). In secondary analyses, data demonstrated that the 10% risk reduction was primarily driven by a reduction in HF hospitalisations. When evaluated as standalone secondary outcomes, CV death (16.4% vs 17.5%, p=0.27) and all-cause death (20.3% vs 21.2%, p=0.38) events were numerically lower but not significantly reduced in the vericiguat arm. Separately, there were signals for greater benefit in HFrEF patients aged <75 years (HR 0.83) versus patients aged ≥75 years (HR 1.04; p for interaction =0.030). Patients with chronic renal insufficiency (>40% of patients had CKD Stage 3) and NYHA Class III or IV also appeared to receive further benefit from the therapy.
Safety
After approximately one year, 90% of patients in vericiguat arm received the 10mg target maintenance dose. The mean duration of vericiguat exposure was one year and the maximum duration was 2.6 years. The trial reported a similar adverse event (AE) profile between vericiguat and placebo arms, with comparable rates of severe AEs. Notably, the AEs that occurred more frequently in the vericiguat group were hypotension (16% vs 15%) and anaemia (10% vs 7%). As HF patients frequently have low blood pressure (BP), BP modulation is a perennial problem that plagues HF pharmacotherapy optimization. Vericiguat titration must be closely monitored for hypotension AEs and tolerability. The study found that occurrence of new anemia was more prevalent in patients with baseline lower haemoglobin (Hb) levels (≤ 15g/dl), but the authors demonstrated that the benefit of vericiguat compared with placebo on prevention of AEs was preserved when Hb was considered in a time-updated model. Encouragingly, there were no AEs relating to electrolytes or renal function, minimising the need for regular blood monitoring.
The road ahead
Questions still remain surrounding the optimal treatment strategy for HFrEF patients given the expanse of potential combinations available. Notably, a majority of the VICTORIA population were not in receipt of prevailing guideline-directed “quintuple therapy” i.e. RAAS inhibition, MRA, beta blocker and SGLT2i.
Notwithstanding, clinicians are often faced with limited pharmacologic options in the treatment algorithm specific to VICTORIA’s high-risk population, where optimal medical therapy are oftentimes either exhausted or contraindicated. Vericiguat’s registry trial has thus compellingly demonstrated the safety of a novel sGC modulator in reducing HF outcomes in a high-risk population with recent decompensation.
At the time of writing, the drug makers have also begun recruitment for VICTOR(NCT05093933), a Phase III randomised placebo-controlled trial evaluating vericiguat in chronic HFrEF patients who have not had a recent worsening HF event. The trial is expected to conclude in late 2024 and will provide clinicians information on the drug’s utility in earlier stages of the HF trajectory.
