Systolic Heart Failure Mortality Elevated with Sleep Apnea Treatment

The mechanism accounting for negative outcomes with ASV treatment in patients with systolic heart failure and central sleep apnea remains poorly understood.

Top-line results from the SERVE-HF trial data first reported in May 2015 that suggested unexpected mortality in patients with systolic heart failure who underwent central sleep apnea treatment have now been confirmed, study data published in the New England Journal of Medicine indicate.

Not only were trial results negative – indicating no benefit with adaptive servo-ventilation (ASV) on the composite primary endpoint of all-cause death, life-saving cardiovascular intervention, or unplanned HF hospitalization (54.1% in the ASV group vs 50.8% in the control group; hazard ratio 1.13; P=.10) – treatment with ASV actually increased the risk of cardiovascular death (HR 1.34; P=.006).

“This study has changed our understanding of sleep-disordered breathing in systolic heart failure – the text books will have to be rewritten,” study investigator Martin R. Cowie, MD, of Imperial College London and Royal Brompton Hospital said in a press release. “[Clinicians] now know that treatment of central sleep-disordered breathing by mask therapy is not helpful for these patients and might be harmful.”

In the SERVE-HF trial (The Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure), 1325 patients who had chronic HF with reduced left ventricular ejection fraction (45% or less) and predominantly central sleep apnea were randomly assigned to treatment with ASV (recommended 5 hours per night, 7 days a week; n=666) or to a control group that received guideline-based medical treatment alone (n=659).

Although ASV effectively treated central sleep apnea at median 31-month follow-up, it had no effect on the primary endpoint or functional measures including quality-of-life, six-minute walk distance, or symptoms.

Furthermore, both all-cause (34.8% vs 29.3%; HR 1.28; P=.01) and cardiovascular mortality (29.9% vs 24%; HR 1.34; P=.006) were elevated in the ASV group compared with the control group.

It is not certain why ASV therapy appeared to worsen conditions associated with systolic HF, but the study researchers presented some hypotheses. Possible explanations included that central sleep apnea might compensate for HF by allowing respiratory muscles to rest, modulating excessive sympathetic nervous system activity, avoiding hypercapnic acidosis, increasing hyperventilation-related end-expiratory lung volume, and allowing intrinsic positive airway pressure.

“By diminishing this effect ASV may be detrimental for patients with heart failure,” said Dr Cowie. “The pathophysiological features of this effect remain to be elucidated.”

The researchers emphasized the study was conducted in patients who had HF with reduced ejection fraction and central sleep apnea, so the results cannot be generalized to patients with heart failure and preserved ejection fraction or those with predominately obstructive sleep apnea.


  1. Cowie MR, Woehrle H, Wegscheider K et al. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. New Engl J Med. 2015; doi:10.1056/NEJMoa1506459.