Sacubitril-valsartan and Heart Failure Patients : the ENTRESTO-SAS Study (ENTRESTO696)

Evaluation in Real Life Conditions of Sacubitril-valsartan Combination in Patients With Chronic Heart Failure and Sleep Apnea Syndrome

Chronic Heart Failure (CHF) is a frequent pathology burdened with mortality and significant morbidity. Sleep apnea syndrome (SAS) is frequently associated with CHF in 20% to 75% of cases. Treatment of SAS is however inconsistently associated with a decline in the morbidity and mortality. To date, the CHF medical treatments have been reported to be inconsistently efficient in the treatment of SAS.

SACUBITRIL-VALSARTAN (ENTRESTO®) is a new treatment of CHF recently indicated class I, level B in the recent European Society of Cardiology (ESC) guidelines 2016 on CHF. PARADIGM-HF trial demonstrated that morbidity and mortality can be improved with SACUBITRIL-VALSARTAN. In comparison to enalapril, it reduced the occurrence of cardiovascular death or hospitalisation for CHF by 20% with a 16% reduction in all-cause mortality.

The purpose of the research is the evaluation of SACUBITRIL-VALSARTAN combination in CHF patients presenting sleep apnea syndrome. A three months real life observational trial is performed. A measure of the Apnea Hypopnea Index is realised before and after 3 months of SACUBITRIL-VALSARTAN treatment. A concomitant evaluation of cardiological and quality of life parameters is realized.

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure; Sleep Apnea Syndrome
• Intervention / Treatment: Drug: SACUBITRIL - VALSARTAN (formerly LCZ696, ENTRESTO®)

Detailed Description

The Chronic Heart Failure (CHF) is a frequent pathology burdened with mortality and significant morbidity. Chronic HF provides almost 2% of health expenditure in developed countries, it is the largest expenditure item in the USA (34.8 billion dollars). In most developed countries, including France, mortality 1 year after diagnosis of chronic HF is 40%, it is 50% at 2 years, and over 70% at 4.5 years.

Sleep apnea syndrome (SAS) is frequently associated with HF in 20% to 75% of cases. The presence of an apnea syndrome is associated with a greater morbidity and mortality. Treatment of SAS is however inconsistently associated with a decline in the morbidity and mortality. To date, the CHF medical treatments have been reported to be inconsistently efficient in the treatment of SAS : 6 studies corresponding to a total of 67 patients and 5 types of molecules reported an incomplete effect on the central component of the Apnea Hypopnea Index (AHI) for these patients.

SACUBITRIL - VALSARTAN (ENTRESTO®) is a new treatment of HF recently indicated class I, level B in the recent ESC guidelines 2016 on HF. It combines inhibitory prodrug neprilysin and valsartan. After initial failures with neprilysin inhibition alone or dual neprilysin-angiotensin converting enzyme (ACE) inhibition, the PARADIGM-HF trial demonstrated that morbidity and mortality can be improved with the SACUBITRIL - VALSARTAN combination (formerly LCZ696). In comparison to the ACE inhibitor enalapril, sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality. These findings suggest that sacubitril/valsartan should replace an ACE inhibitor or angiotensin receptor blocker as the foundation of treatment of symptomatic patients (NYHA II-IV) with HF and a reduced ejection fraction.

The purpose of the research is the evaluation of SACUBITRIL-VALSARTAN in CHF patients presenting sleep apnea syndrome. We speculate that synchronously of a beneficial effect on heart failure, the SACUBITRIL-VALSARTAN combination could improve an associated SAS and in particular the central component of the AHI index.

After an exhaustive initial pre-therapeutic evaluation, the SACUBITRIL-VALSARTAN combination treatment is initiated for 3 months.

The pre-therapeutic evaluation includes cardiological and biological exams, quality of life questionaries and nocturnal ventilatory polygraphy.

Considering the results of the polygraphy, three groups of patients are identified:

• group 1 patients, characterized by a central AHI ≥5 / h and an obstructive AHI <15 / h,
• group 2 patients, characterized by an obstructive AHI ≥15 / h whatever is the central component. In this group of patient, a ventilator treatment with constant positive airway pressure or auto-servoventilation is started.
• group 3 patients, characterized by a central AHI < 5 / h and an obstructive AHI <15 / h.

After three months of treatment, the final evaluation includes cardiological and biological exams, quality of life questionaries for all the patient included in the trial. A nocturnal polygraphy is performed only in group 1 and 2 patients. For group 2 patients treated with a device, the observance to the device, the residual AHI device and the pressure device is measured.

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Béziers, France, 34500
    • Pôle médical spécialisé MSP
  • Béziers, France, 34525
    • CHU Béziers
  • Montpellier, France, 34295
    • Centre Hospitalier Universitaire de Montpellier
  • Nimes, France, 30029
    • CHU Nîmes
  • Toulouse, France, 31059
    • Chu Toulouse
  • Pessac
    • Bordeaux, Pessac, France, 33604
      • CHU Bordeaux

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age is greater than or equal to 18 years
• Patient with chronic heart failure (LVEF ≤ 45%).
• Written informed consent

Exclusion Criteria:

• Renal insufficiency (GF<30 milliliters/min)
• Pregnancy
• Allergy to one compound
• Personal history of angiooedema
• Hemodynamical instability
• Severe hepatopathy
• Current and not treated hyperkaliemia
• Prognosis < 6months
• Current CPAP or ASV treatment for Sleep Apnea Syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SACUBITRIL - VALSARTAN; SACUBITRIL - VALSARTAN (formerly LCZ696, ENTRESTO®) is a new treatment of HF recently indicated class I, level B in the recent ESC guidelines 2016 on HF. It combines inhibitory prodrug neprilysin and valsartan.	Drug: SACUBITRIL - VALSARTAN (formerly LCZ696, ENTRESTO®); SACUBITRIL - VALSARTAN (formerly LCZ696, ENTRESTO®) is a new treatment of HF recently indicated class I, level B in the recent ESC guidelines 2016 on HF. It combines inhibitory prodrug neprilysin and valsartan.; Other Names: LCZ696, ENTRESTO®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Apnea-Hypopnea Index as compared to baseline	Changes in AHI as compared to baseline Measure of the apnea hypopnea index by a polygraphy performed before and after 3 months of treatment. The 2012 American Academy of Sleep Medicine recommendations are utilized in order to characterized apnea and hypopnea events, the central or obstructive or mixed phenotype	0 month to 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subject Global Assessment		0 month to 3 months
NYHA Functional Class		0 month to 3 months
Heart Rhythm	physiological parameter	0 month to 3 months
Systolic and diastolic Blood Pressure	physiological parameter	0 month to 3 months
Renal function as compared to baseline (Estimated GFR (eGFR) will be calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula	CKD-EPI formula	0 month to 3 months
BNP (B-type Natriuretic Peptide) rates	Biological parameter	0 month to 3 months
Subject medications		0 month to 3 months
Quality of life as measured by Minnesota Living with Heart Failure Questionary	Questionaries	0 month to 3 months
Quality of life as measured by EQ-5D-3L Questionary	Questionaries	0 month to 3 months
Epworth Sleepiness Scale	Questionary	0 month to 3 months
Pichot Fatigue Scale	Questionary	0 month to 3 months
Type of device used in group 2 patients	CPAP or ASV device CPAP/ASV : continuous positive airway pressure / adaptive servo ventilation	0 month to 3 months
CPAP/ASV compliance in group 2 patients	CPAP/ASV compliance. Unit : number of hour per day using CPAP/ASV device	0 month to 3 months
Historical of CPAP/ASV compliance in group 2 patients	CPAP/ASV compliance. Unit : number of day with ≥3 hours in the past 6 months	0 month to 3 months
Settings of CPAP/ASV device used in group 2 patients	Settings of device	0 month to 3 months
Type of mask used in group 2 patients	Type of mask	0 month to 3 months
Historical use of mask in group 2 patients	Historical use of mask	0 month to 3 months
Changes in AHI compared to Baseline in group 2 patients	Changes in AHI compared to Baseline	0 month to 3 months

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier
• Investigators: Study Director: Arnaud BOURDIN, MD,PhD, University Hospital, Montpellier

Publications and helpful links

General Publications

• Jaffuel D, Molinari N, Berdague P, Pathak A, Galinier M, Dupuis M, Ricci JE, Mallet JP, Bourdin A, Roubille F. Impact of sacubitril-valsartan combination in patients with chronic heart failure and sleep apnoea syndrome: the ENTRESTO-SAS study design. ESC Heart Fail. 2018 Jun;5(3):222-230. doi: 10.1002/ehf2.12270. Epub 2018 Feb 22.
• Jaffuel D, Nogue E, Berdague P, Galinier M, Fournier P, Dupuis M, Georger F, Cadars MP, Ricci JE, Plouvier N, Picard F, Puel V, Mallet JP, Suehs CM, Molinari N, Bourdin A, Roubille F. Sacubitril-valsartan initiation in chronic heart failure patients impacts sleep apnea: the ENTRESTO-SAS study. ESC Heart Fail. 2021 Aug;8(4):2513-2526. doi: 10.1002/ehf2.13455. Epub 2021 Jun 8.

Study record dates

Study Major Dates

• Study Start (Actual): September 22, 2016
• Primary Completion (Actual): February 27, 2020
• Study Completion (Actual): February 27, 2020

Study Registration Dates

• First Submitted: September 9, 2016
• First Submitted That Met QC Criteria: September 23, 2016
• First Posted (Estimate): September 27, 2016

Study Record Updates

• Last Update Posted (Actual): June 15, 2021
• Last Update Submitted That Met QC Criteria: June 10, 2021
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Sleep Apnea Syndrome; Chronic Heart failure; Continuous Positive Airways Pressure; SACUBITRIL - VALSARTAN
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Disease; Signs and Symptoms, Respiratory; Heart Failure; Sleep Apnea Syndromes; Syndrome; Apnea; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: UF 9703

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided