Initiation of ARNi and SGLT2i in Patients With HFrEF

NCT05989503 | Completed Phase 4

• 2 other identifiers: INITIATE-HFrEF2022-502409-14-00
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 5

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, 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.

Conditions

Heart Failure With Reduced Ejection Fraction

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (46)

• 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)

• 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)

• 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)

• 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)

• 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)

Study Arms (2)

Simultaneous initiation

ACTIVE COMPARATOR

ARNi ((i.e. sacubitril/valsartan, irrespectively of brand name, at an 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 (either empagliflozin or dapagliflozin or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10mg/d) on the same day or within ± 5 days.

Drug: Sacubitril-valsartan; Drug: SGLT2 inhibitor

Sequential initiation

ACTIVE COMPARATOR

Initial (at randomization day) SGLT2i prescription (either empagliflozin or dapagliflozin, or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10 mg/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; Drug: SGLT2 inhibitor

Interventions

Sacubitril-valsartan DRUG

Sacubitril-valsartan titration at the discretion of the treating physician

Sequential initiation; Simultaneous initiation

SGLT2 inhibitor DRUG

Either empagliflozin or dapagliflozin 10 mg/day

Sequential initiation; Simultaneous initiation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Universidade do Porto: lead
• Unidade de Investigação e Desenvolvimento Cardiovascular (UnIC): collaborator
• Rede de Investigação em Saúde: collaborator

Study Sites (5)

Centro Hospitalar Universitário de Santo António

Porto, Porto District, 4099-001, Portugal

Location

Centro Hospitalar Universitário São João

Porto, 4200-319, Portugal

Location

Faculty of Medicine (FMUP)

Porto, 4200-319, Portugal

Location

Centro Hospitalar Vila Nova de Gaia/Espinho

Porto, 4434-502, Portugal

Location

Unidade Local de Saúde de Matosinhos - Hospital Pedro Hispano

Porto, Portugal

Location

MeSH Terms

Interventions

sacubitril and valsartan sodium hydrate drug combination; Sodium-Glucose Transporter 2 Inhibitors

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs

Study Officials

• João P. Ferreira, MD, PhD

  Universidade do Porto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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. Assuming a primary outcome frequency of 30% in the sequential group, if there is a true difference between the intervention groups (simultaneous vs sequential) of 10%, then 62 patients are required to be 80% certain that the upper limit of a one-sided 95% confidence interval will exclude a difference in favour of the sequential group of more than 20%.

Study Record Dates

• First Submitted: July 14, 2023
• First Posted: August 14, 2023
• Study Start: August 4, 2023
• Primary Completion: July 31, 2025
• Study Completion: July 31, 2025
• Last Updated: November 19, 2025

Record last verified: 2025-08

Locations

PT (5)