Initiation of ARNi and SGLT2i in Patients With HFrEF

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 beforeinclusion, except if initiated 5 days before randomization; patients treated with anACEi or ARB can be included and maintain their therapy until the switch to an ARNiis performed)

8. If female, she must not be a woman of childbearing potential. That is, she must be:

9. Surgically sterilized (e.g., underwent hysterectomy, bilateral salpingectomy orbilateral oophorectomy)

10. Clinically diagnosed infertile

11. In a post-menopausal state, defined as no menses for 12 months without analternative medical cause

12. If female patient of childbearing potential, she must have a negative serumpregnancy 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 daysafter last study treatment administration) one of the following highly effectivemethods of contraception:

13. Abstinence of heterosexual intercourse (when this is in line with preferred andusual lifestyle of the subject)

14. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)

15. Combined (estrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation (oral, intravaginal, transdermal)

16. Intrauterine device

17. Intrauterine hormone-releasing system

18. Bilateral tubal occlusion

19. Vasectomized partner, who has received medical assessment of the surgicalsuccess, or clinically diagnosed infertile partner

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to bothInvestigator staff and/or staff at the study site)

2. Participation in another clinical study with an investigational product during thelast month

3. Unwilling to sign inform consent

4. Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any ofthe 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 basedon 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) orintent to become pregnant or breast feeding

11. Severe valvulopathy according to the echocardiogram report

12. Previous history of ketoacidosis due to SGLT2i