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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Chronic Heart Failure, Sleep Apnea Syndrome

Intervention / Treatment
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* Drug: SACUBITRIL - VALSARTAN (formerly LCZ696, ENTRESTO®)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SACUBITRIL - VALSARTAN<br>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®)<br>* 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.<br>* Other names: LCZ696, ENTRESTO®;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Heart failure, Sleep Apnea Syndrome, Continuous Positive Airways Pressure, SACUBITRIL - VALSARTAN