The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial

Abstract

Large traditional clinical trials suggest that sodium-glucose co-transporter 2 inhibitors improve symptoms in patients with heart failure and reduced ejection fraction (HFrEF) and in patients with heart failure and preserved ejection fraction (HFpEF). In the midst of the Coronavirus Disease 2019 pandemic, we sought to confirm these benefits in a new type of trial that was patient centered and conducted in a completely remote fashion. In the CHIEF-HF trial ( NCT04252287 ), 476 participants with HF, regardless of EF or diabetes status, were randomized to 100 mg of canagliflozin or placebo. Enrollment was stopped early due to shifting sponsor priorities, without unblinding. The primary outcome was change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at 12 weeks. The 12-week change in KCCQ TSS was 4.3 points (95% confidence interval, 0.8-7.8; P = 0.016) higher with canagliflozin than with placebo, meeting the primary endpoint. Similar effects were observed in participants with HFpEF and in those with HFrEF and in participants with and without diabetes, demonstrating that canagliflozin significantly improves symptom burden in HF, regardless of EF or diabetes status. This randomized, double-blind trial, conducted without in-person interactions between doctor and patient, can serve as a model for future all-virtual clinical trials.

Conflict of interest statement

J.A.S. is the principal investigator of grants from the National Institutes of Health, Abbott Vascular and the American College of Cardiology Foundation; is a consultant to Janssen, Novartis, Amgen, Myokardia/Bristol Myers Squibb, AstraZeneca, Bayer and Merck; serves on the Scientific Advisory Board of United Healthcare and the Board of Directors for Blue Cross Blue Shield of Kansas City; and owns the copyright to the KCCQ, SAQ and PAQ. M.C.B. is an employee of Janssen Scientific Affairs. M.N. is a consultant to Amgen, Roche and Vifor Pharma. C.V.D. is an employee of Janssen Research & Development. A.A. has received research grant support from Janssen, Kiniksa, Novartis, Olatec, R-Pharm, Serpin Pharma and Swedish Orphan Biovitrum; has served as a consultant to Applied Clinical Intel, Cromos Pharma, Implicit Biosciences, Janssen, Kiniksa, Merck, Novartis, Novo Nordisk, Olatec, Serpin Pharma and Swedish Orphan Biovitrum. J.B. is a consultant to Abbott, Adrenomed, Arena Pharma, Array, Amgen, Applied Therapeutics, Astra Zeneca, Bayer, BerlinCures, Boehringer Ingelheim, Corvia, Cardior, CVRx, Eli Lilly, FIRE1, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, SC Pharma, Sanofi, Sequana Medical, V-Wave Limited and Vifor Pharma. D.E.L. has received research grants from NHLBI, Amgen, Bayer, Critical Diagnostics, AstraZeneca, Eli Lilly and Janssen; has participated in collaborative research with Somalogic; is a consultant for Abbott Laboratories, Amgen, Janssen, Ortho Diagnostics, Cytokinetics, Illumina, Vicardia and DCRI (Novartis). I.L. has received research funding, advisory/consulting fees and/or other support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen, Intercept, Intarcia, TARGETPharma, Merck, Pfizer, Novartis, GI Dynamics, Mylan, Mannkind, Valeritas, Zealand Pharma and Bayer. M.N.K. has received research grants from AstraZeneca and Boehringer Ingelheim; is a consultant or advisory board member for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi and Vifor Pharma; and has received honoraria from AstraZeneca, Boehringer Ingelheim and Novo Nordisk. J.L.J. is supported by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; has received grant support from Applied Therapeutics and Novartis; has received consulting income from Abbott, Janssen, Novartis, Pfizer, Merck and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen and Takeda.

© 2022. The Author(s).

Figures

Fig. 1. Study CONSORT diagram showing the process of subject participation.

KCCQ, Kansas City Cardiomyopathy Questionnaire.

Fig. 2. KCCQ TSS over time.

Mean changes in KCCQ TSSs (error bars represent standard errors) at 2, 4, 6 and 12 weeks after randomization.

Fig. 3. Effects of treatment by HF type and diabetes status.

Estimates of the mean difference in KCCQ TSSs by subgroups are stratified by EF and diabetes status. In total, 208 participants were treated with canagliflozin and 206 with placebo. T2DM, type 2 diabetes mellitus.

Extended Data Fig. 1. Distributions of 3-month Changes in KCCQ Total Symptom Scores.

The proportions of patients experiencing the indicated magnitudes of clinical change are shown. KCCQ=Kansas City Cardiomyopathy Questionnaire.