Background The VITALITY-HFpEF trial (Evaluate the Efficacy and Safety of the 
Oral sGC Stimulator Vericiguat to Improve Physical Functioning in Daily Living 
Activities of Patients With Heart Failure and Preserved Ejection Fraction) is 
designed to determine the efficacy and safety of a novel oral soluble guanylate 
cyclase stimulator, vericiguat, on quality of life and exercise tolerance in 
heart failure patients with preserved ejection fraction (HFpEF). Impaired 
physical functioning reduces the quality of life in patients with HFpEF. The 
primary goal of HF treatment along with improving survival is to improve 
function, reduce symptoms, and maximize quality of life. Abnormal cyclic 
guanosine monophosphate signaling may contribute to physical limitations in 
patients with HFpEF via central and peripheral mechanisms. Exploratory post hoc 
analyses from a prior trial showed that vericiguat can improve patient-relevant 
domains of the Kansas City Cardiomyopathy Questionnaire, especially the physical 
limitation score. Methods and Results VITALITY-HFpEF is a placebo-controlled, 
double-blind, multi-center, phase IIb trial of ≈735 patients, ≥45 years with 
HFpEF and ejection fraction ≥45% who will be randomized 1:1:1 to placebo, 10 mg, 
or 15 mg vericiguat. The primary end point is change in Kansas City 
Cardiomyopathy Questionnaire physical limitation score from baseline to week 24 
and change in 6-minute walk test from baseline to week 24 is the secondary end 
point. Conclusions VITALITY-HFpEF is the first trial designed to assess the 
efficacy of vericiguat in patients with HFpEF using the Kansas City 
Cardiomyopathy Questionnaire physical limitation score as a novel primary end 
point. This study will also extend the prior dosing experience with vericiguat 
in HF by studying the safety and efficacy of a 15 mg dose. Clinical Trial 
Registration URL: https://www.clinicaltrials.gov . Unique identifier: 
NCT03547583.