Clinical trial NCT05989503: Initiation of ARNi and SGLT2i in Patients With HFrEF
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Heart Failure With Reduced Ejection Fraction
Lead sponsor: Universidade do Porto
Sponsor class: OTHER
Collaborators: name: Unidade de Investigação e Desenvolvimento Cardiovascular (UnIC)
name: Rede de Investigação em Saúde
First posted: 2023-08-14
Enrollment: 172
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.

1. initiation of ARNi and SGLT2i simultaneously (same day or within ± 5 days);
2. initial SGLT2i initiation followed by ARNi between week 4 and 12 after randomization.
Primary purpose: TREATMENT

Brief summary: 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: 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.

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

Primary outcomes:
measure: Composite outcome (time-to-first event' occurrence during the 6 months of follow-up):
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
Secondary outcomes:
measure: Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion)
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Hyperkalaemia (serum potassium >6.0 mmol/L)
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Hypokalemia (serum potassium <3.0 mmol/L)
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: eGFR drop ≥50% from baseline or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Increase in diuretic dose due to worsening heart failure
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Use of intravenous diuretics for worsening heart failure
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Heart failure hospitalization
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Death from cardiovascular causes
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: NT-pro BNP or BNP (log)
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: High sensitivity C-reactive protein
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: Atrial fibrillation/flutter
timeFrame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Systolic and diastolic blood pressure
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: High sensitivity Troponin
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Left atrial volume
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: Left ventricular systolic volume
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: Left ventricular diastolic volume
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: LV mass
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: LV ejection fraction
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: Pulmonary artery systolic pressure
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: Serum sodium
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Serum potassium
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Serum creatinine
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Glomerular filtration rate (eGFR)
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Urinary sodium
timeFrame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Urinary potassium
timeFrame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Microalbuminuria
timeFrame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Total Cholesterol
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: LDL Cholesterol
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: HDL Cholesterol
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: Triglycerides
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: Glucose
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Glycated hemoglobin (HbA1C)
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: Uric acid
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: TSH
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: Free thyroxin
timeFrame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
measure: ALAT
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: ASAT
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Gamma-GT
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Alkaline Phosphatase
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Total bilirubin
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Serum iron
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Ferritin
timeFrame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Transferrin saturation
timeFrame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Functional class (NYHA, New York Heart Association)
timeFrame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Quality of life (KCCQ, Kansas City Cardiomyopathy Questionnaire)
timeFrame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
measure: Dosage titration of sacubitril/valsartan up to the dose 97/103 mg (b.i.d.) at 3 months
timeFrame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days)
Other outcomes:
Locations:
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário de Santo António
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário São João
city: Porto
country: Portugal
facility: Faculty of Medicine (FMUP)
city: Porto
country: Portugal
facility: Centro Hospitalar Vila Nova de Gaia/Espinho
city: Porto
country: Portugal
facility: Unidade Local de Saúde de Matosinhos - Hospital Pedro Hispano
Study officials:
affiliation: Universidade do Porto
name: João P. Ferreira, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: