Initiation of ARNi and SGLT2i in Patients With HFrEF

Study Overview
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Brief Summary
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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. 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.

Detailed Description
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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.

Official Title
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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

Conditions
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Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Drug: Sacubitril-valsartan
* Drug: SGLT2 inhibitor


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Pragmatic study to be conducted in real-life routine practice conditions with a two-arm open randomization, to evaluate the efficacy (on surrogate markers) and safety of ARNi and SGLT2i combination in patients with HFrEF/HFmrEF and the doses of ARNi. initiation of ARNi and SGLT2i simultaneously (same day or within ± 5 days); initial SGLT2i initiation followed by ARNi between week 4 and 12 after randomization.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Simultaneous initiation<br>ARNi (initial dose 24/26mg b.i.d. or 49/51mg b.i.d. titrated to 97/103mg b.i.d. preferably in the first 3-6 weeks, up to 3 months of follow-up) and SGLT2i (10mg q.d.) on the same day or within ± 5 days. | Drug: Sacubitril-valsartan<br>* Sacubitril-valsartan titration at the discretion of the treating physician<br>Drug: SGLT2 inhibitor<br>* Either empagliflozin or dapagliflozin 10 mg/day<br>|
| Active Comparator: Sequential initiation<br>Initial (at randomization day) SGLT2i prescription (either empagliflozin or dapagliflozin, 10 mg q.d.) followed by an ARNi initiated between weeks 4 and 12 after randomization (sacubitril/valsartan at an initial dose of 24/26mg b.i.d. or 49/51mg b.i.d., and titrated to 97/103mg b.i.d. if tolerated, according to assistant physician decision) | Drug: Sacubitril-valsartan<br>* Sacubitril-valsartan titration at the discretion of the treating physician<br>Drug: SGLT2 inhibitor<br>* Either empagliflozin or dapagliflozin 10 mg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite outcome (time-to-first event' occurrence during the 6 months of follow-up): | Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion); Hyperkalaemia (serum potassium >6.0 mmol/L); Hypokalemia (serum potassium <3.0 mmol/L); eGFR drop ≥50% from baseline or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis; Increase in diuretic dose due to worsening heart failure; Use of intravenous diuretics for worsening heart failure; Heart failure hospitalization; Death from cardiovascular causes. | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion) | Time to event' occurrence during the 6 months of follow-up | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Hyperkalaemia (serum potassium >6.0 mmol/L) | Time to event' occurrence during the 6 months of follow-up | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Hypokalemia (serum potassium <3.0 mmol/L) | Time to event' occurrence during the 6 months of follow-up | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| eGFR drop ≥50% from baseline or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis | Time to event' occurrence during the 6 months of follow-up | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Increase in diuretic dose due to worsening heart failure | Time to event' occurrence during the 6 months of follow-up | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Use of intravenous diuretics for worsening heart failure | Time to event' occurrence during the 6 months of follow-up | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Heart failure hospitalization | Time to event' occurrence during the 6 months of follow-up | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Death from cardiovascular causes | Time to event' occurrence during the 6 months of follow-up | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| NT-pro BNP or BNP (log) | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| High sensitivity C-reactive protein | Concentration measured in blood samples | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| Atrial fibrillation/flutter | Electrocardiogram (yes/no) | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Systolic and diastolic blood pressure | Measure in the clinical appointments | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| High sensitivity Troponin | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Left atrial volume | Transthoracic echocardiogram | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| Left ventricular systolic volume | Transthoracic echocardiogram | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| Left ventricular diastolic volume | Transthoracic echocardiogram | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| LV mass | Transthoracic echocardiogram | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| LV ejection fraction | Transthoracic echocardiogram | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| Pulmonary artery systolic pressure | Transthoracic echocardiogram | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| Serum sodium | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Serum potassium | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Serum creatinine | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Glomerular filtration rate (eGFR) | Calculated from the serum creatinine using the 2021 CKD-EPI creatinine-based formula | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Urinary sodium | Spot urine sample | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Urinary potassium | Spot urine sample | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Microalbuminuria | Spot urine sample | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Total Cholesterol | Concentration measured in blood samples | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| LDL Cholesterol | Concentration measured in blood samples | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| HDL Cholesterol | Concentration measured in blood samples | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| Triglycerides | Concentration measured in blood samples | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| Glucose | Measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Glycated hemoglobin (HbA1C) | Concentration measured in blood samples | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| Uric acid | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| TSH | Concentration measured in blood samples | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| Free thyroxin | Concentration measured in blood samples | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | 
| ALAT | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| ASAT | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Gamma-GT | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Alkaline Phosphatase | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Total bilirubin | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Serum iron | Concentration measured in blood samples | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Ferritin | Concentration measured in blood samples | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Transferrin saturation | Concentration measured in blood samples | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Functional class (NYHA, New York Heart Association) | Assessed by the medical doctors in the clinical appointments (I / II / III / IV) | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Quality of life (KCCQ, Kansas City Cardiomyopathy Questionnaire) | HR-QoL assessed by the Kansas City Cardiomyopathy Questionnaire a 12-item instrument. All items are measured on a Likert scale with 5-7 response options. KCCQ scores are scaled from 0 to 100 and summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | 
| Dosage titration of sacubitril/valsartan up to the dose 97/103 mg (b.i.d.) at 3 months | Assessed by the medical doctors in the clinical appointments | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days) |