Dapagliflozin Improves Heart Failure Symptoms and Physical Limitations Across the Full Range of Ejection Fraction: Pooled Patient-Level Analysis from DEFINE-HF and PRESERVED-HF Trials

• Type of Material: Article
• Authors: Michael E Nassif, University of Missouri-Kansas City; Sheryl L Windsor, Mid America Heart Institute - Kansas City; Kensey Gosch, Mid America Heart Institute - Kansas City; Barry A Borlaug, Mayo Clinic, Rochester; Mansoor Husain, University of Toronto; Silvio E Inzucchi, Yale School of Medicine; Dalane W Kitzman, Wake Forest School of Medicine; Darren K McGuire, University of Texas; Bertram Pitt, University of Michigan; Benjamin M Scirica, Harvard Medical School; Sanjiv J Shah, Northwestern University Feinberg; Guillermo Umpierrez, Emory University; Bethany A Austin, Mid America Heart Institute - Kansas City; Sumant Lamba, First Coast Cardiovascular Institute, Jacksonville; Taiyeb Khumri, University of Missouri-Kansas City; Kavita Sharma, Johns Hopkins University; Mikhail N Kosiborod, University of Missouri-Kansas City
• Language: English
• Date: 2023-07-01
• Publisher: Wolters kluwer health inc
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCHEARTFAILURE.122.009837
• Title of Journal or Parent Work: Circulation: Heart Failure
• Volume: 16
• Issue: 7
• Start Page: E009837
• End Page: E009837
• Grant/Funding Information: The DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) and PRESERVED-HF (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) studies were investigator-initiated trials funded by AstraZeneca and conducted by Saint Luke’s Mid America Heart Institute independent of the funding source.
• Keywords: Quality of Life; Humans; health status; quality of life; Stroke Volume; Biomarkers; Ventricular Dysfunction, Left; ejection fraction; heart failure; Heart Failure; Diabetes Mellitus, Type 2; Kansas City Cardiomyopathy Questionnaire; dapagliflozin; SGLT2 inhibitors
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

BACKGROUND: Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. METHODS: Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. RESULTS: Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6-7.5]; P<0.001). This was consistent in participants with EF≤40 (4.6 points [95% CI, 1.0-8.1]; P=0.01), >40 to ≤60 (4.9 points [95% CI, 0.8-9.0]; P=0.02) and >60% (6.8 points [95% CI, 1.5-12.1]; P=0.01; Pinteraction=0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously (Pinteraction=0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all Pinteractionvalues nonsignificant). CONCLUSIONS: In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02653482 and NCT03030235.