Heart failure (HF) is a condition in which the heart does not contract ("pump") or relax well, leading to insufficient perfusion of vital organs. Ankle swelling, fatigue, and breathlessness are some of the features of this syndrome. There are different causes for HF (e.g., infarct and hypertension) and two distinct types: HFpEF - HF with preserved ejection fraction - the heart "pumps" but does not relax well and HFrEF/HFmrEF - HF with reduced or mildly reduced ejection fraction - where the heart does not "pump" properly, here referred to as having HFrEF.

Patients with HFrEF experience substantially shorter life expectancies compared with people in the general population of similar age. Compared to the different available therapeutics for HFrEF patients, angiotensin receptor-neprilysin inhibitor (ARNi), sacubitril/valsartan, has shown superiority for improving clinical outcomes. Furthermore, the new recently drug sodium-glucose cotransporter 2 inhibitor (SGLT2i) was proven to reduce mortality and morbidity on top of well-adapted background therapy.

This work aims to test the safety of ARNi and SGLT2i initiation by comparing a strategy of simultaneous initiation of ARNi and SGLT2i versus sequential initiation of a SGLT2i first followed by an ARNi.

Sacubitril/valsartan and SGLT2i reduced HF hospitalizations and mortality in patients with heart failure and a reduced ejection fraction with a rapid onset of action, but the timing of initiation of each drug is uncertain. Clinicians may be reluctant to initiate both therapies simultaneously due to fear of adverse events (e.g., hypotension and worsening renal function) which may delay the initiation of (at least one) of these life-saving therapies.

This study aims to fill this gap in knowledge by studying the initiation of sacubitril/valsartan and a SGLT2i simultaneously or in sequence. This study will better inform clinicians on their daily decisions.

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; patients treated with an ACEi or ARB can be included and maintain their therapy until the switch to an ARNi is performed)

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