Treatment of Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients With Heart Failure (Serve-HF)

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:

1. all cause mortality or unplanned hospitalisation/prolongation of hospitalisation for worsening heart failure 2. cardiovascular mortality or unplanned hospitalisation/prolongation of hospitalisation for worsening heart failure. 3. 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.