Starting two heart failure medications together for better outcomes

Initiation of Angiotensin Receptor-neprilysin Inhibitor (ARNi) and Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF): the INITIATE-HFrEF Randomized Open-label Trial

This study tests whether starting two heart failure medications at the same time can help people with reduced heart function feel better and avoid hospital visits.

Quick facts

• Phase: Phase 4
• Study type: Interventional
• Enrollment: 172 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Universidade do Porto (Academic / other)
• Locations: 5 sites (Porto and 4 other locations)
• Trial ID: NCT05989503 on ClinicalTrials.gov

What this trial studies

This study investigates the simultaneous or sequential initiation of sacubitril/valsartan and SGLT2 inhibitors in patients with heart failure and reduced ejection fraction (HFrEF). It aims to address the uncertainty clinicians face regarding the timing of these therapies due to concerns about potential adverse events. By evaluating the safety and efficacy of starting both medications at once, the study seeks to provide clearer guidance for treatment decisions. Participants will be monitored for clinical outcomes, including hospitalizations and mortality rates.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with symptomatic heart failure and a left ventricular ejection fraction of 49% or less.

Not a fit: Patients who have been treated with ARNi or SGLT2i within the past month may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved treatment protocols that enhance survival and quality of life for patients with HFrEF.

How similar studies have performed: Other studies have shown positive outcomes with similar therapeutic approaches, but this specific combination and timing is being explored for the first time.

Eligibility criteria

Inclusion Criteria:

1. Age ≥ 18 years
2. Heart failure symptoms (NYHA II, III or IV)
3. Left ventricle ejection fraction ≤ 49% (assessed by transthoracic echocardiogram)
4. Glomerular filtration rate ≥ 25 ml/min/1.73m2 (CKD-EPI formula)
5. Serum potassium (K+) ≤ 5.4 mmol/L
6. Systolic blood pressure ≥ 100 mmHg
7. Not treated with ARNi nor with SGLT2i within the previous month (30 days before inclusion, except if initiated 5 days before randomization)
8. If female, she must not be a woman of childbearing potential. That is, she must be:

   1. Surgically sterilized (e.g., underwent hysterectomy, bilateral salpingectomy or bilateral oophorectomy)
   2. Clinically diagnosed infertile
   3. In a post-menopausal state, defined as no menses for 12 months without an alternative medical cause
9. If female patient of childbearing potential, she must have a negative serum pregnancy test at Visit 1 (Day 0) and must agree to consistently and correctly use (from 28 days prior to first study treatment administration until at least 7 days after last study treatment administration) one of the following highly effective methods of contraception:

   1. Abstinence of heterosexual intercourse (when this is in line with preferred and usual lifestyle of the subject)
   2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
   3. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
   4. Intrauterine device
   5. Intrauterine hormone-releasing system
   6. Bilateral tubal occlusion
   7. Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
2. Participation in another clinical study with an investigational product during the last month
3. Unwilling to sign inform consent
4. Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any of the excipients of the products
5. Hospitalization due to non-cardiovascular causes, surgical procedure, coronary, cerebral or peripheral vascular events or sepsis in the prior month
6. Cancer (life limiting with an estimated life expectancy of less than 2 years based on investigator's judgement)
7. Previously confirmed cardiac amyloidosis
8. History of angioedema
9. Implantable cardioverter-defibrillators or cardiac resynchronization therapy within 3 months prior to screening or if there is an intent to implant either device in the 3 months following screening
10. Female patients currently pregnant (confirmed by a positive pregnancy test) or intent to become pregnant or breast feeding
11. Severe valvulopathy according to the echocardiogram report
12. Previous history of ketoacidosis due to SGLT2i

Where this trial is running

Porto and 4 other locations

• Centro Hospitalar Universitário de Santo António — Porto, Portugal (Recruiting)
• Centro Hospitalar Universitário São João — Porto, Portugal (Recruiting)
• Faculty of Medicine (FMUP) — Porto, Portugal (Recruiting)
• Centro Hospitalar Vila Nova de Gaia/Espinho — Porto, Portugal (Recruiting)
• Unidade Local de Saúde de Matosinhos - Hospital Pedro Hispano — Porto, Portugal (Recruiting)

Study contacts

• Principal investigator: João P. Ferreira, MD, PhD — Universidade do Porto
• Study coordinator: João P. Ferreira, PhD

Conditions Heart Failure With Reduced Ejection Fraction