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Novel direct soluble guanylate cyclase stimulators did not improve markers of physical function in heart failure with preserved ejection fraction (HFpEF) in two randomized trials.

In the , mean 24-week change in the physical limitation score of the Kansas City Cardiomyopathy Questionnaire was actually numerically better with placebo than a 15 or 10 mg daily dose of vericiguat (6.9 vs 5.5 and 6.5 points on the 100-point scale). Neither dose differed significantly from placebo, reported Paul Armstrong, MD, of the University of Alberta in Edmonton, and colleagues.

In the , peak rate of oxygen consumption (VO₂) decreased by 0.26 mL/kg/min with daily praliciguat whereas placebo patients improved by 0.04 mL/kg/min from baseline to week 12, reported James Udelson, MD, of Tufts Medical Center in Boston, and colleagues.

By contrast, vericiguat had been heralded for reducing mortality and hospitalizations in recently decompensated heart failure with reduced ejection fraction (HFrEF) in the VICTORIA trial reported at the American College of Cardiology meeting in March.

A significant proportion of HFpEF may be driven by an abnormal vascular response involving endothelial dysfunction and problems with nitric oxide signaling soluble guanylate cyclase, its key target, noted an .

But it's too soon to abandon targeting this pathway for HFpEF, argued editorialists Katherine Clark, MD, MBA, and Eric Velazquez, MD, both of Yale School of Medicine in New Haven, Connecticut.

"[D]ue to the approaches for patient selection, the length of follow-up, and the end points chosen, these studies do not negate the potential that these agents may have to improve outcomes," they wrote. "Future studies should select patients with HFpEF based on demonstrable endothelial dysfunction, and patients should be followed up longer for an end point such as a reduction in HF hospitalization."

The phase IIb VITALITY-HFpEF trial included 789 patients with chronic HFpEF with an EF of at least 45% and New York Heart Association class II-III symptoms, within 6 months of a recent decompensation event (HF hospitalization or IV diuretics for HF without hospitalization), and with elevated natriuretic peptides. Participants received randomly assigned, double-blind treatment with vericiguat, up-titrated to 15 mg or 10 mg daily, or placebo.

Six-minute walking distance improved by a mean 5.0, 8.7, and 10.5 m, with 15 mg vericiguat, 10 mg vericiguat, and placebo, respectively, with neither placebo comparison significant.

Among adverse events, symptomatic hypotension occurred in 6.4% and 4.2% of the 15 mg and 10 mg vericiguat groups, and in 3.4% of the placebo group, and syncope in 1.5%, 0.8%, and 0.4%, respectively.

The phase II CAPACITY HFpEF trial included 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak VO₂, and multiple conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). They were randomized double-blind to 12 weeks of treatment with placebo or three different praliciguat doses, but those were "refocused early to a comparison of the 40-mg praliciguat dose vs placebo," according to the researchers.

No significant differences between the two groups emerged in secondary end points of change from baseline in 6-minute walk test distance or ventilatory efficiency.

Treatment-emergent adverse events seen more often with praliciguat than placebo included dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%). Serious events were similar between groups.

"It is also possible that abnormalities in nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling are present in patients with HFpEF, but are more of a marker of the comorbidities than a mediator of the complex pathophysiology that results in functional impairment," Udelson's group noted.

"Previous trials that addressed this pathway failed to show improvements in exercise tolerance or other end points," they added. "The only strategies that have improved functional status have been exercise and caloric restriction, interventions that would have multifaceted effects across many pathophysiologic pathways."