Effect of Vericiguat vs Placebo on Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The VITALITY-HFpEF Randomized Clinical Trial

Abstract

Importance: Patients with heart failure and preserved ejection fraction (HFpEF) are at high risk of mortality, hospitalizations, and reduced functional capacity and quality of life.

Objective: To assess the efficacy of the oral soluble guanylate cyclase stimulator vericiguat on the physical limitation score (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ).

Design, setting, and participants: Phase 2b randomized, double-blind, placebo-controlled, multicenter trial of 789 patients with chronic HFpEF and left ventricular ejection fraction 45% or higher with New York Heart Association class II-III symptoms, within 6 months of a recent decompensation (HF hospitalization or intravenous diuretics for HF without hospitalization), and with elevated natriuretic peptides, enrolled at 167 sites in 21 countries from June 15, 2018, through March 27, 2019; follow-up was completed on November 4, 2019.

Interventions: Patients were randomized to receive vericiguat, up-titrated to 15-mg (n = 264) or 10-mg (n = 263) daily oral dosages, compared with placebo (n = 262) and randomized 1:1:1.

Main outcomes and measures: The primary outcome was change in the KCCQ PLS (range, 0-100; higher values indicate better functioning) after 24 weeks of treatment. The secondary outcome was 6-minute walking distance from baseline to 24 weeks.

Results: Among 789 randomized patients, the mean age was 72.7 (SD, 9.4) years; 385 (49%) were female; mean EF was 56%; and median N-terminal pro-brain natriuretic peptide level was 1403 pg/mL; 761 (96.5%) completed the trial. The baseline and 24-week KCCQ PLS means for the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 60.0 and 68.3, 57.3 and 69.0, and 59.0 and 67.1, respectively, and the least-squares mean changes were 5.5, 6.4, and 6.9, respectively. The least-squares mean difference in scores between the 15-mg/d vericiguat and placebo groups was -1.5 (95% CI, -5.5 to 2.5; P = .47) and between the 10-mg/d vericiguat and placebo groups was -0.5 (95% CI, -4.6 to 3.5; P = .80). The baseline and 24-week 6-minute walking distance mean scores in the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 295.0 m and 311.8m , 292.1 m and 318.3 m, and 295.8 m and 311.4 m, and the least-squares mean changes were 5.0 m, 8.7 m, and 10.5 m, respectively. The least-squares mean difference between the 15-mg/d vericiguat and placebo groups was -5.5 m (95% CI, -19.7 m to 8.8 m; P = .45) and between the 10-mg/d vericiguat and placebo groups was -1.8 m (95% CI, -16.2 m to 12.6 m; P = .81), respectively. The proportions of patients who experienced symptomatic hypotension were 6.4% in the 15-mg/d vericiguat group, 4.2% in the 10-mg/d vericiguat group, and 3.4% in the placebo group; those with syncope were 1.5%, 0.8%, and 0.4%, respectively.

Conclusions and relevance: Among patients with HFpEF and recent decompensation, 24-week treatment with vericiguat at either 15-mg/d or 10-mg/d dosages compared with placebo did not improve the physical limitation score of the KCCQ.

Trial registration: ClinicalTrials.gov Identifier: NCT03547583.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Armstrong reported receiving personal fees from Merck and Bayer during the conduct of the study as well as grants from Sanofi-Aventis Recherche & Developpement, Boehringer Ingelheim, and CSL Limited and personal fees from AstraZeneca and Novartis. Dr Lam reported receiving personal fees from Bayer during the conduct of the study as well as grants from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma and personal fees from Abbott Diagnostics, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Biofourmis, Boehringer Ingelheim, Boston Scientific, Corvia Medical, Cytokinetics, Darma, Eko.ai, JanaCare, Janssen Research & Development, Medtronic, Menarini Group, Merck, MyoKardia, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Stealth BioTherapeutics, The Corpus, Vifor Pharma, and WebMD. In addition, Dr Lam has a patent pending on a method for diagnosis and prognosis of chronic heart failure (PCT/SG2016/050217) and a patent issued for a clinical workflow that recognizes and analyses 2D and Doppler echocardiogram images for automated cardiac measurements and diagnosis, prediction, and prognosis of heart disease (16/216,929). Dr Lam is also cofounder and nonexecutive director of EKo.ai Pte Ltd. Dr Ezekowitz reported receiving personal fees from Bayer and Merck during the conduct of the study as well as grants and personal fees from American Regent, Novartis, AstraZeneca, Boehringer Ingelheim, Amgen, and Cytokinetics (additional disclosures available online at https://thecvc.ca). Dr Hernandez reported receiving personal fees from Bayer and Merck during the conduct of the study as well as grants and personal fees from AstraZeneca and Novartis and personal fees from Amgen and Cytokinetics. Dr O’Connor reported receiving consulting for Bayer, Bristol Myers Squibb Foundation, and Dey. Dr Pieske reported receiving personal fees from Merck and Bayer during the conduct of the study as well as personal fees from Novartis, Servier, Medscape, and Bristol Myers Squibb. Dr Ponikowski reported receiving personal fees from Merck during the conduct of the study as well as receiving personal fees from and participating in clinical trials for Amgen, Boehringer Ingelheim, Servier, AstraZeneca, RenalGuardSolution, and Cibiem; receiving grants and personal fees from and participating in clinical trials for Vifor Pharma; and receiving personal fees from Pfizer and Respicardia. Dr Shah reported receiving personal fees from Bayer during the conduct of the study as well as grants and personal fees from Actelion, AstraZeneca, Novartis, and Pfizer; grants from Corvia; and personal fees from Cyclerion, Amgen, Boehringer Ingelheim, Cardiora, Cytokinetics, MyoKardia, Merck, Shifamed, Eisai, Ionis, Novo Nordisk, Sanofi, and Tenax. Dr Solomon reported receiving personal fees from Bayer during the conduct of the study as well as grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, Neurotronik, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Respicardia, Sanofi Pasteur, and Theracos and personal fees from Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Sanofi Pasteur, Tenaya, Dinaqor, Tremeau, CellProThera, and Moderna. Dr Voors reported receiving personal fees from Merck and Bayer during the conduct of the study as well as personal fees from AstraZeneca, Cytokinetics, Novartis, and MyoKardia and grants and personal fees from Boehringer Ingelheim, Novo Nordisk, and Roche Diagnostics. Ms Vlajnic is an employee of Bayer. Dr Carvalho is an employee of Bayer. Mr Bamber is an employee of Bayer. Dr Blaustein reported receiving personal fees from Merck during the conduct of the study and is an employee of Merck. Dr Roessig is an employee of Bayer. Dr Butler reported receiving personal fees from Bayer and Merck during the conduct of the study as well as personal fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Limited, and Vifor. No other disclosures were reported.

Figures

Figure 1.. Participant Flow in the VITALITY-HFpEF Randomized Clinical Trial

KCCQ PLS indicates physical limitation score of the Kansas City Cardiomyopathy Questionnaire. aIncludes participants who did not meet 1 or more inclusion/exclusion criteria, so numbers add to more than total. Details of failure to meet screening criteria are provided in eAppendix 2 in Supplement 3. bRandomization was stratified according to region and heart rhythm.

Figure 2.. Primary Outcome: Kansas City Cardiomyopathy Questionnaire Physical Limitation Score (KCCQ PLS)

A, Box plots for KCCCQ PLS. Center bars are medians; box tops and bottoms are interquartile ranges; and whiskers, fifth and 95th percentiles. Solid circles inside boxes are means; open circles are data that fall outside of the fifth and 95th percentiles. B, Changes in KCCQ PLS. Left, least-squares means of the changes from baseline to week 24 for the 3 treatment groups (imputed data); error bars indicate 95% CIs. Right, difference between least-squares mean changes from baseline to week 24 for placebo vs 10-mg/d and 15-mg/d vericiguat dosages; error bars indicate 95% CIs. Positive scores favor vericiguat over placebo. The KCCQ PLS is one of the 6 domains of the KCCQ that measures patients’ functional capacity in activities of daily life. Scores are calculated by summing patients’ responses on 6 domain questions and transforming scores to a 0- to 100-point scale. Higher numbers on the KCCQ PLS indicate better health status.

Figure 3.. Secondary Outcome: 6-Minute Walking Distance

A, Box plots for 6-minute walking distances. Center bars are medians; box tops and bottoms are interquartile ranges; and whiskers, fifth and 95th percentiles. Solid circles inside boxes are means; open circles are data that fall outside of the fifth and 95th percentiles. B, Changes in 6-minute walking distance. Left, least-squares means of the changes from baseline to week 24 for the 3 treatment groups (imputed data); error bars indicate 95% CIs. Right, difference between least-squares mean changes from baseline to week 24 for placebo vs 10-mg/d and 15-mg/d vericiguat dosages; error bars indicate 95% CIs. Positive scores favor vericiguat over placebo.