Adaptive servo-ventilation is not beneficial and may even be harmful for patients who have predominantly central sleep apnea accompanying heart failure with reduced ejection fraction, Dr. Martin R. Cowie reported at the annual congress of the European Society of Cardiology.
The noninvasive therapy did control central sleep apnea in a large international randomized controlled trial, but nevertheless did not affect the composite end point of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening HF. Moreover, it unexpectedly raised the risk of cardiovascular death by 34%, and significantly increased all-cause mortality as well, said Dr. Cowie of Imperial College London.
Dr. Martin R. Cowie
Adaptive servo-ventilation delivers servo-controlled inspiratory pressure on top of expiratory positive airway pressure during sleep, to alleviate central sleep apnea. This form of sleep-disordered breathing, which may manifest as Cheyne-Stokes respiration in patients who have HF with reduced ejection fraction, is reported to affect up to 40% of this patient population. Its prevalence rises as the severity of HF increases, and it is an independent risk marker for poor prognosis and death in HF.
A recent trial showed that continuous positive airway pressure (CPAP) did not improve morbidity or mortality in patients who had HF with central sleep apnea, but suggested that a treatment that could reduce the apnea-hypopnea index (AHI) – the number of apnea or hypopnea events per hour of sleep – to below 15 might be effective. Adaptive servo-ventilation can accomplish this, and small studies and meta-analyses have shown that the treatment improves surrogate markers including plasma concentration of brain natriuretic peptide, left ventricular ejection fraction (LVEF), and functional outcomes in heart failure.
Dr. Cowie and his associates conducted the SERVE-HF trial, assessing the effect of adding adaptive servo-ventilation to guideline-based medical therapy on survival and cardiovascular outcomes. He presented the trial results at the meeting, and they were simultaneously published online (N Engl J Med. 2015 Sep 1. doi:10.1056/NEJMoa1506459).
The industry-sponsored study comprised 1,325 patients aged 22 and older treated and followed at 91 medical centers for a median of 31 months (range, 0-80 months). They were randomly assigned to receive medical therapy plus adaptive servo-ventilation delivered through a face mask for at least 5 hours every night (666 intervention subjects) or medical therapy alone (659 control subjects).
Central sleep apnea was well controlled only in the intervention group. At 1 year, their mean AHI was 6.6 events per hour, and the oxygen desaturation index – the number of times per hour that the blood oxygen level dropped by 3 or more percentage points from baseline level – was 8.6.
Yet the primary composite end point was not significantly different between the two study groups: The rate of death from any cause, lifesaving cardiovascular intervention, and unplanned hospitalization for worsening HF was 54.1% with adaptive servo-ventilation and 50.8% without it. The treatment also had no significant effect on a broad spectrum of secondary measures such as symptoms and quality of life. Six-minute walk distance gradually declined in both groups, but that decline was significantly more pronounced in the intervention group, the investigator said.
Even more worrisome was the significant increase in mortality associated with adaptive servo-ventilation. Cardiovascular mortality was 29.9% with the treatment, compared with 24.0% without it, for a hazard ratio of 1.34. All-cause mortality was 34.8% with the treatment and 29.3% without it, for an HR of 1.28.
The reason for this unexpected result is not yet known. One explanation is that central sleep apnea may be a compensatory mechanism with potentially beneficial effects in patients who have HF. Attenuating those effects with adaptive servo-ventilation may then have been detrimental. For example, central sleep apnea, and particularly Cheyne-Stokes breathing, may beneficially activate the respiratory muscles, increase sympathetic nervous system activity, induce hypercapnic acidosis, increase end-expiratory lung volume, and raise intrinsic positive airway pressure.
Another possibility is that applying positive airway pressure with adaptive servo-ventilation may impair cardiac function in at least a portion of patients who have HF by decreasing cardiac output and stroke volume during treatment.
ResMed, maker of the AutoSet adaptive servo-ventilator, sponsored SERVE-HF, which was also supported by the National Institute for Health Research and the National Institutes of Health. Dr. Cowie disclosed ties with Servier, Novartis, Pfizer, St. Jude Medical, Boston Scientific, Respicardia,Medtronic, and Bayer; his associates reported ties to numerous industry sources.