Treatment of Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients With Heart Failure

Study Overview
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Brief Summary
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The purpose of this trial is to evaluate the long-term effects and cost-effectiveness of adaptive servo-ventilation (ASV) on the mortality and morbidity of patients with stable heart failure due to left ventricular systolic dysfunction, already receiving optimal medical therapy, who have sleep disordered breathing (SDB) that is predominantly central sleep apnea. Assumptions: the intervention reduces the hazard rate by 20%. The event rate in the control group is 35% in the first year. It is assumed that the hazard rate is constant over time.

Detailed Description
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Objective: The purpose of this trial is to evaluate the long-term effects and cost-effectiveness of adaptive servo-ventilation (ASV) on the mortality and morbidity of patients with stable heart failure due to left ventricular systolic dysfunction, already receiving optimal medical therapy, who have sleep disordered breathing (SDB) that is predominantly central sleep apnea. Study Design: Randomized, multicentre, international trial with parallel group design, with patients randomized to either control (optimal medical management) or active treatment (optimal medical treatment plus use of adaptive servoventilation) in a 1:1 ratio. There will be no sham-positive airway pressure treatment in the control arm. Assumptions: the intervention reduces the hazard rate by 20%. The event rate in the control group is 35% in the first year. It is assumed that the hazard rate is constant over time. The trial is an event driven design: the final analysis is to be performed latest when 651 events have been observed. The primary analysis is in the intention-to-treat population that consists of all patients randomized. Number of Patients: 1116 patients will be randomly assigned to one of the two treatment groups. A 20% drop out rate is estimated. Selection criteria: Patients at the age of or over 22 years with severe chronic heart failure (chronic HF), New York Heart Association (NYHA) class III-IV or NYHA class II with at least one hospitalization for HF within the last 24 months, with Left Ventricular Ejection Fraction (LVEF) less or equal 45% by means of echocardiography, radionuclide ventriculography or cardiac MRI and Sleep Disordered Breathing (SDB) (apnoea-hypopnoea-index (AHI > 15/h) with 50% central events and a central AHI ≥ 10/h, no change of medication and no hospitalization for more than 1 month before randomization and medical therapy according to the applicable guidelines (European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) respectively). Primary Endpoints: Time to first event of: all cause mortality or unplanned hospitalisation/prolongation of hospitalisation for worsening heart failure cardiovascular mortality or unplanned hospitalisation/prolongation of hospitalisation for worsening heart failure. all cause mortality or all cause unplanned hospitalisation/prolongation of hospitalisation Heart transplantation, appropriate shock from implantable cardioverter-defibrillator (ICD), long term assist device (LTAD) insertion and survived resuscitation of sudden cardiac arrest are counted as cardiovascular death, survived resuscitation for other reasons is counted as all cause death. The three combinations are not tested in parallel but in this hierarchical order. Secondary Endpoints : Time until death, non cardiovascular death, cardiovascular death, hospitalization due to deterioration of heart failure or cardiovascular death, hospitalization for other reasons or death, hospitalization for cardiovascular cause or cardiovascular death, percent of follow-up (FU) days which patient survives and is not hospitalized for cardiovascular cause, percent of follow up days which patient survives and is not hospitalized for other reason, time to first adequate shock (in patients with ICD, evaluation of appropriateness will also be made by the ERC) or cardiovascular death, changes in NYHA class as compared to baseline, changes in difference in health costs between the two treatment groups, changes in QoL (Minnesota, Euroqol 5D (EQ5D)) as compared to baseline, changes in renal function (based on serum creatinine) as compared to baseline, changes in result of Six Minute Walking Test (6MWT) (50) as compared to baseline,changes of AHI and oxygen desaturation index compared to baseline, AHI below 10 per hour at twelve months and Oxygen desaturation index (ODI) below 5 per hour at twelve months, atrial fibrillation at follow-up visits. Number and cost of hospitalizations (with tariff/diagnostic-related Group (DRG), diagnoses and procedures for calculating DRG or length of stay and level of care provided), cost of care (technology and service, nursing, physicians visit) related to ventilation, difference in utilities / QoL (Minnesota and EQ5D) compared to control arm, difference in cost of resources consumed, cost-efficacy, cost-utility. Secondary target parameters will be measured at the last follow up or at the last available observation within FU. Scheduled follow up : Minimum follow up time will be 24 months, maximum about 70 months. There will be a final assessment for each patient at the end of the study.

Official Title
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Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure

Conditions
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Heart Failure, Sleep Disordered Breathing

Intervention / Treatment
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* Device: Europe: AutoSet CS (USA: VPAP Adapt SV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be at least 22 years old Chronic heart failure (at least 12 weeks since diagnosis) according to the current applicable guidelines (ESC, ACC/AHA) Left ventricular systolic dysfunction (LVEF ≤45% by imaging method such as echocardiography, radionuclide angiography, left ventriculography, or cardiac magnetic resonance imaging) documented less than 12 weeks before randomisation NYHA class III or IV at the time of inclusion or NYHA class II with at least one hospitalisation for HF in the last 24 months No hospitalisation for heart failure for at least 4 weeks prior to inclusion Optimised medical treatment according to applicable guidelines with no new class of disease modifying drug for more than 4 weeks prior to randomisation. In case of no beta blockers or ACE (angiotensin converting Enzyme) inhibitors/ ARB (angiotensin receptor blocker) antagonists the reasons must be documented SDB (AHI > 15/h with ≥ 50% central events and a central AHI ≥ 10/h, derived from polygraphy or polysomnography (based on total recording time (TRT)), documented less than 4 weeks before randomisation. Flow measurement has to be performed with nasal cannula Patients for whom the use of AutoSet CS2 (TM)/VPAP Adapt may be contra-indicated because of symptomatic hypotension or significant intravascular volume depletion or pneumothorax or pneumomediastinum Patient is able to fully understand study information and signed informed consent Exclusion Criteria: Significant COPD (chronic obstructive pulmonary disease) with Forced Expiratory Volume within one second (FEV1) <50% (European Respiratory Society criteria) in the last four weeks before randomisation Oxygen saturation at rest during the day ≤ 90% at inclusion Current use of Positive Airway Pressure (PAP) - therapy Life expectancy < 1 year for diseases unrelated to chronic HF Cardiac surgery, Percutaneous coronary intervention (PCI), Myocardial Infarction (MI) or unstable angina within 6 months prior to randomisation CRT (cardiac resynchronisation therapy)-implantation or ICD-implantation scheduled or within 6 months prior to randomisation Transient ischemic attack (TIA) or Stroke within 3 months prior to randomisation Primary hemodynamically significant uncorrected valvular heart disease, obstructive or regurgitant, or any valvular disease expected to lead to surgery during the trial Acute myocarditis/pericarditis within 6 months prior to randomisation Untreated or therapy refractory Restless legs-Syndrome (RLS) according to criteria listed in Appendix IX at the time of study entry Pregnancy

Ages Eligible for Study
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Minimum Age: 22 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Group<br>treatment with Adaptive Servoventilation (Europe: AutoSet CS (USA: VPAP (Variable Positive Airway Pressure) Adapt SV)) + standard medical therapy according to applicable guidelines (ESC, ACC/AHA) | Device: Europe: AutoSet CS (USA: VPAP Adapt SV)<br>* At least 3 hours average daily usage time<br>|
| No Intervention: Control Group<br>standard medical therapy according to applicable guidelines (ESC, ACC/AHA) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cause Mortality or Unplanned Hospitalisation/Prolongation of Hospitalisation for Worsening Heart Failure |  | time to first event, assessed for up to 70 weeks | 
| Cardiovascular Mortality or Unplanned Hospitalisation/Prolongation of Hospitalisation for Worsening Heart Failure |  | time to first event, assessed for up to 70 weeks | 
| All Cause Mortality or All Cause Unplanned Hospitalisation/Prolongation of Hospitalisation |  | time to first event, assessed for up to 70 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death From Any Cause |  | the last follow up or at the last available observation within Follow Up (FU), assessed for up to 70 weeks | 
| Non-cardiovascular Death |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Cardiovascular Death |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Unplanned Hospitalisation/Prolongation of Hospitalisation Due to Worsening of Heart Failure |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Unplanned Hospitalisation/Prolongation of Hospitalisation for Other Reasons or Death |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Adequate Shock in Patients With ICD (Evaluation of Appropriateness Will Also be Made by the Endpoint Review Committee, ERC), Long-Term Atrial Defibrillator Insertion or Cardiovascular Death |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| First Survived Resuscitation for Any Reason (Evaluation Will Also be Made by the ERC) |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| First Survived Resuscitation of Sudden Cardiac Arrest (Evaluation Will Also be Made by the ERC) |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Age Baseline |  | 1 x at Baseline | 
| Body Weight Baseline |  | 1 x at baseline | 
| Body Mass Index (BMI) Baseline |  | 1 x baseline | 
| Left Ventricular Ejection Fraction at Baseline |  | 1x at baseline | 
| Blood Pressure Systolic Baseline |  | 1 x at baseline | 
| Blood Pressure Diastolic Baseline |  | 1 x at baseline | 
| Hemoglobine Baseline |  | 1 x at baseline | 
| Creatinine Baseline |  | 1 x at baseline | 
| Glomerular Filtration Rate Baseline |  | 1 x at baseline | 
| 6-Min Walk Distance |  | 1 x at baseline | 
| Epworth Sleepiness Scale (ESS) | Measure Description: ESS is a self-administered questionnaire. It contains 8 questions. Questions are rated on a 4-point Likert scale (0-3); 0= would never doze, 3=high Chance of dozing. Range of scores 0-24. Global score= sum of all item scores. Copyright (c)MW Johns | 1 x at baseline | 
| Apnoea-Hypopnea-Index (AHI) at Baseline | Measure Description: The AHI is an index to describe the severity of Sleep Apnea. Apnea is cessation of breathing during sleep. Hypopnea is diminished breathing during sleep. The number of Apneas and Hypopneas are added up and divided by hours of sleep (Apneas + Hypopneas per hour). An AHI ranging from 5-15 describes mild Sleep Apnea. AHI 15-30 describes moderate Sleep Apnea. AHI >30 describes severe Sleep Apnea. | 1 x at baseline | 
| Central Apnoea Index/Total AHI | Measure Description: Central apneas are partial or complete cessations of airflow caused by reduced or stopped neural Stimulation of the breathing muscles. For comparison: In obstructive apneas are caused by blocked airways that shut off the air although the breathing Stimulus is working. | 1 x at baseline | 
| Central AHI/Total AHI at Baseline |  | 1 x at baseline | 
| Oxygen Desaturation Index (ODI) at Baseline | Number of oxygen desaturations per hour at baseline | 1 x at baseline | 
| Oxygen Saturation Baseline |  | 1 x at baseline | 
| Time With Oxygen Saturation Below 90% |  | 1 x at baseline | 
| Time Until Unplanned Hospitalisation/Prolongation of Hospitalisation for Cardiovascular Cause or Cardiovascular Death/ Time Frame |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Percent of Follow up Days Which Patient Survives and is Not Hospitalized/Hospital Stay is Not Prolonged for Cardiovascular Cause |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Changes in NYHA Classification as Compared to Baseline |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Changes in QoL (Minnesota) as Compared to Baseline |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Changes in Renal Function (Based on Serum Creatinine) as Compared to Baseline |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Changes in Six Minute Walking Distance (6MWD) as Compared to Baseline |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Changes of AHI and Oxygen Desaturation Index Compared to Baseline |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| AHI Below 10 Per Hour at Twelve Months and ODI Below 5 Per Hour at Twelve Months |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Atrial Fibrillation at Follow-up Visits |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Number and Cost of Hospitalisations (With Tariff/DRG, Diagnoses and Procedures for Calculating DRG or Length of Stay and Level of Care Provided) |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Difference in Utilities / QoL (Minnesota and EQ5D) Compared to Control Arm |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Difference in Cost of Resources Consumed |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Incremental Cost-efficacy Ratio |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 
| Incremental Cost-utility Ratio |  | the last follow up or at the last available observation within FU, assessed for up to 70 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure (HF), sleep disordered breathing (SDB), sleep apnea, left ventricular systolic dysfunction