Clinical trial NCT02916160: Sacubitril-valsartan and Heart Failure Patients : the ENTRESTO-SAS Study
Official title: Evaluation in Real Life Conditions of Sacubitril-valsartan Combination in Patients With Chronic Heart Failure and Sleep Apnea Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Heart Failure
Sleep Apnea Syndrome
Keywords: Chronic Heart failure
Sleep Apnea Syndrome
Continuous Positive Airways Pressure
SACUBITRIL - VALSARTAN
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
First posted: 2016-09-27
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in Apnea-Hypopnea Index as compared to baseline
timeFrame: 0 month to 3 months
Secondary outcomes:
measure: Subject Global Assessment
timeFrame: 0 month to 3 months
measure: NYHA Functional Class
timeFrame: 0 month to 3 months
measure: Heart Rhythm
timeFrame: 0 month to 3 months
measure: Systolic and diastolic Blood Pressure
timeFrame: 0 month to 3 months
measure: Renal function as compared to baseline (Estimated GFR (eGFR) will be calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula
timeFrame: 0 month to 3 months
measure: BNP (B-type Natriuretic Peptide) rates
timeFrame: 0 month to 3 months
measure: Subject medications
timeFrame: 0 month to 3 months
measure: Quality of life as measured by Minnesota Living with Heart Failure Questionary
timeFrame: 0 month to 3 months
measure: Quality of life as measured by EQ-5D-3L Questionary
timeFrame: 0 month to 3 months
measure: Epworth Sleepiness Scale
timeFrame: 0 month to 3 months
measure: Pichot Fatigue Scale
timeFrame: 0 month to 3 months
measure: Type of device used in group 2 patients
timeFrame: 0 month to 3 months
measure: CPAP/ASV compliance in group 2 patients
timeFrame: 0 month to 3 months
measure: Historical of CPAP/ASV compliance in group 2 patients
timeFrame: 0 month to 3 months
measure: Settings of CPAP/ASV device used in group 2 patients
timeFrame: 0 month to 3 months
measure: Type of mask used in group 2 patients
timeFrame: 0 month to 3 months
measure: Historical use of mask in group 2 patients
timeFrame: 0 month to 3 months
measure: Changes in AHI compared to Baseline in group 2 patients
timeFrame: 0 month to 3 months
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU Bordeaux
state: Pessac
city: Béziers
country: France
facility: Pôle médical spécialisé MSP
city: Béziers
country: France
facility: CHU Béziers
city: Montpellier
country: France
facility: Centre Hospitalier Universitaire de Montpellier
city: Nimes
country: France
facility: CHU Nimes
city: Toulouse
country: France
facility: CHU Toulouse
Study officials:
affiliation: University Hospital, Montpellier
name: Arnaud BOURDIN, MD,PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.