Substudy on the Mechanistic Plausibility of the Clinical Benefits of Adaptive Servo-ventilation

This substudy is performed within the SERVE-HF Study, a randomised, multi-centre,international trial with parallel group design, with patients randomised to either control (optimal medical management) or active treatment (optimal medical treatment plus use of adaptive servoventilation) in a 1:1 ratio. The randomization will be the same as in the parent study. For this purpose, the randomization of the parent study will be stratified as to whether a patient is included in the substudy or not. 300 patients will be recruited for the substudy overall.

For the purpose of this substudy, patients will be followed up for a period of 12 months.

The following extra tests will be performed at the baseline visit, the 3 months follow up and the 12 months follow up:

• Echocardiogram (for both groups)
• cMRI (for both groups)
• PSG (at the baseline visit only for patients in the treatment group and at 3 months follow up and the 12 months follow up for all patients)
• 4 questionnaires (for both groups)
• Additional blood testing (for both groups)

The inclusion and exclusion criteria are mainly those applicable for the parent study; SERVE-HF. The inclusion and exclusion criteria are listed here.

Inclusion criteria

FOR SERVE-HF STUDY:

• Over 22 years of age
• Severe Chronic Heart Failure (CHF) with NYHA class III-IV or NYHA class II with at least one hospitalisation for HF within the last 24 months
• Left ventricular ejection fraction (LVEF) less than or equal to 45% by means of echocardiography, radionucleotide angiography, left ventriculography or cardiac MRI documented less than 12 weeks before randomisation
• Diagnosis of sleep disordered breathing (SDB) with an apnoea-hypopnoea-index (AHI) of >15/hr with at least 50% central events and a central AHI of at least 10/hr
• Clinically stable with no change in medication and no unplanned hospitalisation for heart failure in preceding month
• Optimised medical treatment according to the applicable guidelines
• Able to provide informed consent

ADDITIONAL INCLUSION CRITERIA FOR THE SUBSTUDY

• Predominant central sleep apnoea (apnoea hypopnoea index > 15/hour with ≥ 50% central events and a central AHI ≥10/hour, derived from full polysomnography (based on total sleep time), documented less than 4 weeks before randomization. Flow measurements have to be performed with nasal cannula

Exclusion criteria

FOR THE SERVE-HF STUDY:

• Significant chronic obstructive pulmonary disease (COPD) with Forced Expiratory Volume within one second (FEV1)<50% predicted
• Oxygen saturation at rest during the day 90% at the time of inclusion
• Current use of Positive Airway Pressure (PAP) therapy
• Life expectancy < 1 year for diseases unrelated to chronic heart failure
• Cardiac surgery, Percutaneous coronary intervention (PCI), Myocardial Infarction (MI) or unstable angina within 6 months prior to randomisation
• Implantation of ICD (implanted cardiodefibrillator) or CRT (cardiac resynchronisation therapy) 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)
• Pregnancy

ADDITIONAL EXCLUSION CRITERIA FOR THE SUBSTUDY

• Amyloidosis, hypertrophic obstructive cardiomyopathy or arteriovenous fistulas
• Dosage changes of diuretics more than doubled within the last 4 weeks prior to randomisation