SUMMARY

• CHIEF-HF^1-5 (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) was a randomized, double-blind, placebo controlled, decentralized study designed to investigate the effects of INVOKANA 100 mg (n=222) versus placebo (n=226) on health status across the spectrum of heart failure (HF), regardless of ejection fraction (EF) and diabetes status.
  • INVOKANA significantly improved Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at 12 weeks vs. placebo with a difference of 4.3 points at week 12 (95% confidence interval [CI], 0.80-7.80; P = 0.016).
  • Serious adverse events occurred in 12.1% of patients (n=27) in the INVOKANA treatment group and 7.8% of patients (n=18) in the placebo treatment group.
• Additional relevant citations have been identified in the published literature are cited here.⁶

CLINICAL DATA

CHIEF-HF

Study Design/Methods

CHIEF HF^1-5 was a randomized, double-blind, placebo-controlled, parallel-group, interventional, decentralized, participant-centered, superiority study designed to investigate the effects of INVOKANA 100 mg versus placebo on health status across the spectrum of HF, regardless of EF and diabetes status. Participants were randomized in a 1:1 ratio to either INVOKANA 100 mg or placebo for a period of 12 weeks.

• Key inclusion criteria included participants with confirmed HF of any type (based on EHR review), sole access to smartphone compatible with Fitbit device, willingness to wear a Fitbit (Versa 2), and a Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) >40 to <80.
  • The KCCQ is a 23-item, self-administered questionnaire developed to independently measure the participant's perception of their health status over eight domains:
    • Physical Limitation
    • Symptoms Stability
    • Symptom Frequency
    • Symptom Burden
    • Total Symptom
    • Social Limitation
    • Self-Efficacy
    • Quality of Life
  • Participants were stratified based on their baseline EF (HF with reduced EF [HFrEF] or HF with preserved EF [HFpEF]).
    • HFrEF is defined as: (a) EF <40%; or (b) a primary diagnosis of HF or 2 out patient visits for HF in the past 18 months.
    • HFpEF is defined as: (a) EF >40%; or (b) a primary diagnosis of HF or 2 out patient visits for HF; or (c) on a loop diuretic or aldosterone receptor blocker in the past 18 months.
• Key exclusion criteria included:
  • Current or prior (within the past 3 months) treatment with a sodium-glucose cotransporter-2 (SGLT2) inhibitor
  • History of diabetic ketoacidosis or type 1 diabetes, advanced kidney disease (estimated glomerular filtration rate <30 mL/min or on dialysis)
  • Diagnosis of recent (within 30 days) hypotension
  • History of a traumatic amputation or critical limb ischemia
  • Planned major surgery or prior major surgery (within the past 3 months)
  • Left ventricular assist device implantation
  • Pregnant, planning to become pregnant, or breastfeeding during the study
  • Acute decompensated heart failure (exacerbation of symptomatic HF) requiring intravenous diuretics, inotropes, or vasodilators within 4 weeks prior to enrollment were excluded.
• In a decentralized (no face-to-face visits) approach, participants were engaged through a study website, electronic informed consent, direct home delivery of study medication, completion of the primary outcome via a mobile application, and a Fitbit Versa 2 to monitor activity.²
• The primary outcome for the study was the change from baseline to week 12 in Total Symptom Score of the KCCQ (KCCQ-TSS).
  • The KCCQ was collected at baseline, weeks 2, 4, 6, and 12, with the 12-week assessment (duration of randomized, double-blind drug exposure) being the primary outcome.
• Secondary outcomes include:
  • A comparison of daily step counts acquired from the Fitbit,
  • Individual domain scores of the KCCQ: Physical Limitation, Quality of Life, Clinical Summary (the average of Physical Limitation and Total Symptom scores), and Overall Summary (the average of the Physical Limitation, Total Symptom, Social Functioning, and Quality of Life domains) scores.
• Adverse events were also assessed

Results

Baseline Characteristics

• A total of 448 participants were included in the final, intention-to-treat analysis. Two hundred and twenty-two participants were assigned to the INVOKANA treatment arm and 226 to the placebo treatment arm. CHIEF-HF participant characteristics are shown in the below Table: Baseline Characteristics.

Efficacy

• INVOKANA significantly improved KCCQ-TSS at 12 weeks vs. placebo with a difference of 4.3 points at week 12 (95% CI, 0.80-7.80, P = 0.016). Improvement in KCCQ-TSS with INVOKANA was observed as early as 2 weeks.
• These benefits were consistent across the key pre-specified subgroups listed below:
  • HFrEF: difference of 4.0 points (95% CI, -1.0 to 9.0) and HFpEF: difference of 4.5 points (95% CI, -0.3 to 9.4)
    • P value for interaction = 0.35
  • Type 2 Diabetes Mellitus: difference of 6.5 points (95% CI, -0.2 to 13.2) and non-Type 2 Diabetes Mellitus: difference of 3.6 points (95% CI, -0.5 to 7.8)
    • P value for interaction = 0.90
• Improvements in mean scores were also observed in the INVOKANA treatment group for most other KCCQ domains (Overall summary score, Clinical summary score, Physical limitations score, Quality of life score, Social limitations score) but not for changes in step counts, which did not change over 12 weeks in either group (mean difference favoring INVOKANA of 29.8 steps (95% CI, −284 to 344). No P values are reported for the secondary analyses because a smaller-than planned sample size left no room for additional analyses.

Safety

Serious adverse events occurred in 12.1% of patients (n=27) in the INVOKANA treatment group and 7.8% of patients (n=18) in the placebo treatment group. For safety results, please see Table: Post-randomization Adverse Events Through Week 12^a

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 14 August 2024.