Initiation of ARNi and SGLT2i in Patients With HFrEF (INITIATE)

Inclusion Criteria: Age ≥ 18 years Heart failure symptoms (NYHA II, III or IV) Left ventricle ejection fraction ≤ 49% (assessed by transthoracic echocardiogram) Glomerular filtration rate ≥ 25 ml/min/1.73m2 (CKD-EPI formula) Serum potassium (K+) ≤ 5.4 mmol/L Systolic blood pressure ≥ 100 mmHg Not treated with ARNi nor with SGLT2i within the previous month (30 days before inclusion, except if initiated 5 days before randomization) If female, she must not be a woman of childbearing potential. That is, she must be: Surgically sterilized (e.g., underwent hysterectomy, bilateral salpingectomy or bilateral oophorectomy) Clinically diagnosed infertile In a post-menopausal state, defined as no menses for 12 months without an alternative medical cause 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: Abstinence of heterosexual intercourse (when this is in line with preferred and usual lifestyle of the subject) Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) Intrauterine device Intrauterine hormone-releasing system Bilateral tubal occlusion Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner Exclusion Criteria: Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site) Participation in another clinical study with an investigational product during the last month Unwilling to sign inform consent Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any of the excipients of the products Hospitalization due to non-cardiovascular causes, surgical procedure, coronary, cerebral or peripheral vascular events or sepsis in the prior month Cancer (life limiting with an estimated life expectancy of less than 2 years based on investigator's judgement) Previously confirmed cardiac amyloidosis History of angioedema 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 Female patients currently pregnant (confirmed by a positive pregnancy test) or intent to become pregnant or breast feeding Severe valvulopathy according to the echocardiogram report Previous history of ketoacidosis due to SGLT2i