Initiation of ARNi and SGLT2i in Patients With HFrEF

Universidade do Porto62 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (5)

Centro Hospitalar Universitário de Santo António

Porto, Porto District, Portugal

Centro Hospitalar Universitário São João

Porto, Portugal

Faculty of Medicine (FMUP)

Porto, Portugal

Centro Hospitalar Vila Nova de Gaia/Espinho

Porto, Portugal

Unidade Local de Saúde de Matosinhos - Hospital Pedro Hispano

Porto, Portugal

Outcomes

Primary Outcomes

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.

Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)

Secondary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

Atrial fibrillation/flutter

Electrocardiogram (yes/no)

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

Left ventricular systolic volume

Transthoracic echocardiogram

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

Left ventricular diastolic volume

Transthoracic echocardiogram

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

LV mass

Transthoracic echocardiogram

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

LV ejection fraction

Transthoracic echocardiogram

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

Pulmonary artery systolic pressure

Transthoracic echocardiogram

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

Serum sodium

Concentration measured in blood samples

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)

Urinary potassium

Spot urine sample

Time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)

Microalbuminuria

Spot urine sample

Time frame: 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

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

LDL Cholesterol

Concentration measured in blood samples

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

HDL Cholesterol

Concentration measured in blood samples

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

Triglycerides

Concentration measured in blood samples

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

Glucose

Measured in blood samples

Time frame: 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

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

Uric acid

Concentration measured in blood samples

Time frame: 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

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

Free thyroxin

Concentration measured in blood samples

Time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)

ALAT

Concentration measured in blood samples

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days)

Initiation of ARNi and SGLT2i in Patients With HFrEF

Overview

Conditions

Interventions

Eligibility

Locations (5)

Outcomes

Primary Outcomes

Secondary Outcomes