Initiation of ARNi and SGLT2i in Patients With HFrEF

Phase 4

Recruiting

• Conditions: Heart Failure With Reduced Ejection Fraction
• Interventions: Drug: Sacubitril-valsartan; Drug: SGLT2 inhibitor

• Registration Number: NCT05989503
• Lead Sponsor: Universidade do Porto

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.

Study Timeline

• Status Verified: 2023-06
• Study First Submitted: 2023-07-14
• Study Start: 2023-08-04
• Study First Submitted QC: 2023-08-09
• Study First Posted: 2023-08-14
• Last Update Submitted: 2023-10-18
• Last Update Posted: 2023-10-23
• Primary Completion: 2024-11
• Study Completion: 2025-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 172

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sequential initiation	Sacubitril-valsartan	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)
Sequential initiation	SGLT2 inhibitor	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)
Simultaneous initiation	Sacubitril-valsartan	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.
Simultaneous initiation	SGLT2 inhibitor	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.

Primary Outcome Measures

Name	Time	Method
Composite outcome (time-to-first 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)	* 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.

Secondary Outcome Measures

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

Trial Locations

Locations (5)

Centro Hospitalar Universitário de Santo António; 🇵🇹 Porto, Portugal

Unidade Local de Saúde de Matosinhos - Hospital Pedro Hispano; 🇵🇹 Porto, Portugal

Centro Hospitalar Universitário São João; 🇵🇹 Porto, Portugal

Faculty of Medicine (FMUP); 🇵🇹 Porto, Portugal

Centro Hospitalar Vila Nova de Gaia/Espinho; 🇵🇹 Porto, Portugal