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NCT Number: NCT05508035

The Effect of Sacubitril/valsartan Versus Ramipril on Left Ventricular Function and Remodeling in Patients with Ischemic Heart Failure with Mid-range Ejection Fraction

Heart failure with moderately reduced ejection fraction (HFmrEF) is a frequent disease associated with significant morbidity and mortality and therefore requires effective therapies that may improve clinical outcomes. The most common reason of HFmrEF is ischemic injury, usually caused by myocardial infarction, that may lead to left ventricular remodeling and systolic dysfunction, accompanied by symptoms of heart failure. Therefore, the anti-remodeling therapies may effectively improve clinical outcomes. Recently, sacubitril/valsartan - the angiotensin receptor neprilysin inhibitor suppressing the renin-angiotensin-aldosterone system and enhancing the effect of natriuretic peptides - has been introduced in the treatment of heart failure. To date, this drug was found to be clinically beneficial in patients with heart failure with reduced ejection fraction (HFrEF), however has not been tested in the group of patients with HFmrEF.

The aim of the study is to evaluate effectiveness of sacubitril/valsartan as compared with ramipril on left ventricular remodeling and function in patients with ischemic HFmrEF.

Patients with ischemic HFmrEF, New York Heart Association class II-IV symptoms, an elevated plasma natriuretic peptide level and the left ventricular ejection fraction (LVEF) of 40-49 % will be enrolled in this prospective, multicenter, randomized, double-blind, active-controlled study. Initially, patients will enter a single-blind ramipril run-in period (titrated to 5 mg bid), followed by a sacubitril/valsartan run-in period (100 mg titrated to 200 mg bid). A total of 666 patients tolerating both periods will be randomized 1:1 to either ramipril 10 mg bid or sacubitril/valsartan 200 mg bid. The primary endpoint will be the change of left ventricular end-systolic volume index within 12-month of treatment as measured by magnetic resonance imaging. The main secondary endpoints include the change of left ventricular end-diastolic volume index within 12-month of treatment, the change of LVEF within 12-month of treatment, 12-month composite endpoint of cardiovascular death or heart failure requiring hospitalization, 12-month cardiovascular death, 12-month heart failure requiring hospitalization, time to death or heart failure requiring hospitalization or mortality rate within 12-month of treatment.

This study may determine the place of sacubitril/valsartan as an alternative to ramipril in the treatment of patients with ischemic HFmrEF in order to prevent further left ventricular remodeling and to improve its systolic function.

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Key information

Conditions

Heart Failure with Moderately Reduced Ejection Fraction Cardiovascular Diseases Heart Diseases Heart Failure

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Krakowski Szpital Specjalistyczny im. św. Jana Pawła II

Krakow, Lesser Poland Voivodeship, 31-202, Poland

Location status: Recruiting

Location contact

CONTACT

[email protected]

+48789459021

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Written consent to participate in the study, expressed prior to any procedures related to the study.
  • Age 18 and over.
  • Symptomatic HF in NYHA class II to IV of ischemic etiology.
  • Left ventricular ejection fraction at screening visit ranged from 40-49%.
  • Elevated concentration of NT-proBNP natriuretic peptide ≥125 pg/ml.
  • Features of a structural / functional disease of the left ventricle.
  • Optimal pharmacotherapy with ACEI or ARB and beta-blocker, unless they are contraindicated.

Exclusion criteria

  • History of hypersensitivity or allergy to any of the drugs tested or drugs of similar chemical class, ACEIs, ARBs or neprilysin inhibitors.
  • Previous history of intolerance to recommended ACEI or ARB target doses.
  • Known history of angioedema.
  • Requirement of simultaneous treatment with ACEI and ARB.
  • Acute decompensated HF within 6 weeks prior to screening visit.
  • Symptomatic hypotension systolic blood pressure <100 mmHg at screening visit.
  • Current or previous treatment with sacubitril / valsartan.
  • Estimated creatinine clearance <30 ml / min / 1.73 m2 at screening visit.
  • Serum potassium >5.2 mmol / L at screening visit.
  • Acute coronary syndrome or elective revascularization within 6 weeks prior to screening.
  • Stroke, transient ischemic attack, carotid angioplasty, heart surgery, or any other major cardiovascular surgery in the 3 months prior to screening.
  • Implantation of a cardioverter defibrillator, pacemaker, or resynchronization therapy device incompatible with MRI.
  • Fixed atrial fibrillation.

Treatment and study plan

Sacubitril / Valsartan

Drug

The participants will be randomized to either ramipril 5 mg twice daily plus placebo for sacubitril / valsartan 200 mg twice daily or sacubitril / valsartan 200 mg twice daily plus placebo for ramipril 5 mg twice daily in 1: 1 ratio using the IT randomization module. All patients eligible for randomization will receive their first dose of double-blind drug plus placebo the day after randomization visit. After assigning a randomized treatment, patients will continue at the target dose and attend a 2-week telephone follow-up followed by site visits after one month, four months, eight months and in the final visit after 12 months.

Ramipril

Drug

The participants will be randomized to either ramipril 5 mg twice daily plus placebo for sacubitril / valsartan 200 mg twice daily or sacubitril / valsartan 200 mg twice daily plus placebo for ramipril 5 mg twice daily in 1: 1 ratio using the IT randomization module. All patients eligible for randomization will receive their first dose of double-blind drug plus placebo the day after randomization visit. After assigning a randomized treatment, patients will continue at the target dose and attend a 2-week telephone follow-up followed by site visits after one month, four months, eight months and in the final visit after 12 months.

Primary outcomes

  1. Change in left ventricular end-systolic volume

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the change in left ventricular end-systolic volume as measured by MRI in patients with ischemic HFmrEF

Secondary outcomes

  1. Change in left ventricular end-diastolic volume

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the change in left ventricular end-diastolic volume as measured by MRI in patients with ischemic HFmrEF

  2. Change in indexed left ventricular end-systolic and end-diastolic volumes

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the change in indexed left ventricular end-systolic and end-diastolic volumes as measured by MRI in patients with ischemic HFmrEF

  3. Change in left ventricular ejection fraction

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the change in left ventricular ejection fraction as measured by MRI in patients with ischemic HFmrEF

  4. Occurrence of the endpoint of death from cardiovascular causes or first hospitalization for HF

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the occurrence of the endpoint of death from cardiovascular causes or first hospitalization for HF in patients with ischemic HFmrEF

  5. Occurrence of the endpoint of death from cardiovascular causes or first or subsequent hospitalization for HF

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the occurrence of the endpoint of death from cardiovascular causes or first or subsequent hospitalization for HF in patients with ischemic HFmrEF

  6. Occurrence of death from cardiovascular causes

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the occurrence of death from cardiovascular causes in patients with ischemic HFmrEF

  7. First hospitalization due to HF

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the first hospitalization due to HF in patients with ischemic HFmrEF

  8. Occurrence of the first or subsequent hospitalization due to HF

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the occurrence of the first or subsequent hospitalization due to HF in patients with ischemic HFmrEF

  9. Time to death from cardiovascular causes or first hospitalization for HF

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the time to death from cardiovascular causes or first hospitalization for HF in patients with ischemic HFmrEF

  10. Occurrence of death from any cause

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the occurrence of death from any cause in patients with ischemic HFmrEF

Other outcomes

  1. Incidence of hypotension

    Time frame: 12 months

    Incidence of symptomatic hypotension and/or hypotension with systolic blood pressure <95 mmHg in patients on sacubitril / valsartan versus in those on ramipril

  2. Occurrence of hyperkalaemia

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the occurrence of hyperkalaemia (>5.4 mmol/L)

  3. Onset or worsening of renal failure

    Time frame: 12 months

    Assessment of the effect of sacubitril / valsartan versus ramipril on the onset or worsening of renal failure (eGFR <30 ml / minute / 1.73 m2 or decrease in eGFR compared to visit W1 or W2 by more than 25%)

Study contacts

Contact information is provided by the study sponsor or research team.

Jadwiga Nessler, professor

CONTACT

[email protected]

+48 12 6142218

Sponsors and collaborators

Lead sponsor

John Paul II Hospital, Krakow

Other

Registry information

Acronym: CRACOVIA-HF

Important dates

Study start
2023
Primary completion
2027
Study completion
2027
First posted
Aug 19, 2022
Registry last updated
Oct 31, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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