Soluble guanylate cyclase stimulators in patients with heart failure with reduced ejection fraction across the risk spectrum

Abstract Patients with heart failure with reduced ejection fraction (HFrEF) have a high residual risk of adverse outcomes, even when treated with optimal guideline‐directed medical therapy and in a clinically stable state. Soluble guanylate cyclase (sGC) stimulators have the potential to lower this risk by modifying the nitric oxide–sGC–cyclic guanosine monophosphate cascade – a pathophysiological pathway that has been targeted with limited success in HFrEF previously. Vericiguat, an sGC stimulator, was shown to improve outcomes in patients with HFrEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. However, this trial included patients with recently worsening disease. In this brief review, we discuss the rationale of evaluating sGC stimulators in lower‐risk HFrEF patients. First, all key HFrEF medications have been evaluated in both higher‐ and lower‐risk populations, and the treatment effect is not always consistent across the risk spectrum. Second, pre‐clinical studies and post‐hoc studies of the VICTORIA trial have suggested that sGC stimulators may have cardioprotective effects – these effects may be more apparent when the medication is initiated earlier in the disease process. Third, the effect of vericiguat on cardiovascular mortality remains uncertain and a trial with a longer follow‐up in a lower‐risk population may allow better assessment of its effect on cardiovascular mortality. Therefore, there is a pertinent need to investigate the effects of vericiguat in optimally treated, low‐risk HFrEF patients (i.e. those without recently worsening heart failure).