Central Sleep Apnea Therapy Neutral on Outcomes but Hints at Increased Mortality

Deborah Brauser

September 01, 2015

LONDON, UK — Researchers are urging clinicians to stop the use in clinical practice of adaptive servo ventilation (ASV) for central sleep apnea (CSA) in HF patients with reduced ejection fraction because of a new neutral outcome study that saw increases on the secondary end point of mortality[1].

The large Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE-HF) trial enrolled 1300 participants. It showed no significant differences at 60 months between those who did and did not receive ASV for time to first event of all-cause death, CV intervention (such as heart transplant or an appropriate ICD shock), or unplanned hospitalization—the primary end point.

However, both all-cause and CV death were significantly increased in the ASV group (by 28% and 34%, respectively).

"These results were completely unexpected and important for both respiratory physicians and cardiologists," Dr Martin Cowie (Imperial College London, UK) told heartwire from Medscape, noting this was the world's largest sleep-apnea trial ever conducted. "This is a complete about-turn in the field. The textbooks may need to be changed," he added.

Cowie presented results today at a press conference here at the European Society of Cardiology (ESC) 2015 Congress, with the findings simultaneously published in the New England Journal of Medicine. "In my opinion, ASV shouldn't be used in this group of patients," he said to attendees.

However, he stressed that the findings only apply to the study's very specific population—and shouldn't be generalized to patients with predominant obstructive sleep apnea or in those with HF and preserved EF.

CSA in 25% to 40% of HF Patients

Dr Martin Cowie

CSA, "which may manifest as Cheyne-Stokes respiration," is found in 25% to 40% of HF patients with reduced EF, note the investigators.

Unlike CPAP, ­­­ASV provides controlled end-expiratory pressure at a fixed or variable expiratory positive airway pressure to these patients. "Although different ASV devices use slightly varying algorithms, the principal is the same, consisting of backup rate ventilation with adaptive pressure support," explained Cowie.

For the study, 1325 patients with chronic stable HF and LVEF <45% were enrolled at 91 centers in 11 countries. All were randomly assigned to receive "guideline-based medical management" alone (control group, n=659; 90% men; mean age 69.3 years) or with ASV (AutoSet CS, ResMed, n=666; 89.9% men; mean age 69.6 years).

General quality-of-life (QoL) changes were measured using the EuroQol Group 5-Dimension Self-Report Questionnaire, whereas disease-specific QoL changes were measured with the Minnesota Living with Heart Failure Questionnaire. A total of 60% of the ASV group used the device for an average of 3 hours per nights.

Sleep-disordered breathing was "controlled beautifully" for the ASV group, with a decrease in mean apnea-hypopnea index from 31.2 events per hour at baseline to 6.2 to 6.9 events/hour at the 48-month point (P<0.001). Mean oxygen desaturation index declined from 32.1 events/hour to 8.6 to 9.9 events/hour during the same time-period (P<0.001).

The primary composite end point was 54.1% and 50.8% in those who did and did not receive ASV, respectively (hazard ratio [HR] 1.13). "These results were neutral. We made no difference at all for this," said Cowie.

The HR was 1.28 for all-cause death at 60 months for the group receiving ASV vs the control group (95% CI 1.06–1.55, P=0.01) and was 1.34 for CV death (95% CI 1.09–1.65, P=0.006).

A Game-Changer?

There were no significant between-group differences for symptoms, QoL scores, or change in NYHA class. Although the 6-minute-walk distance decreased in both treatment groups, exercise capacity declined more prominently for those receiving ASV (P=0.04).

In summary, "addition of ASV to guideline-based medical management does not improve outcomes in patients with HFrEF and predominant CSA, despite effective control of CSA," said Cowie.

He speculated that Cheyne-Stokes respiration, although it can act as a marker of HF severity, "may actually be a compensatory mechanism to help the whole body to survive the heart failure. And getting rid of it may not be such a good idea," said Cowie.

"Or applying positive airway pressure to at least some of these patients may be harmful." But that doesn't fit with findings from past studies, he said. "So further work needs to be done."

Dr Salim Yusuf

He noted that although one door has now closed with these findings, more have opened. "This trial was disappointing. But it's just as important to know what doesn't work as what does."

Session comoderator Dr Salim Yusuf (McMaster University, Hamilton, Ontario) told heartwire that this was "a remarkable study" that really could be a game-changer.

"As with anything, you want confirmation; but I think we should stop using this in central sleep apnea as a clinical tool. However, in the context of a carefully conducted study, we should continue to investigate emerging data," said Yusuf, who is also the current president of the World Heart Federation.

Questions Remain

In an accompanying editorial[2], Dr Ulysses J Magalang (Ohio State University Wexner Medical Center, Columbus) and Dr Allan I Pack (University of Pennsylvania Perelman School of Medicine, Philadelphia) note that with this study, "the plot thickens," especially with such unexpected results.

Regarding the two possibilities raised by the investigators as to why all this happened, the editorialists note that if positive airway pressure (PAP) therapy might lead to adverse CV events, perhaps the effect of PAP on cardiac function should be measured before being started in these patients. "Such assessment, however, is not currently the standard of care."

As for eliminating Cheyne-Stokes respiration leading to the removal of a compensatory mechanism in HF, they note that more information is needed, including about the deaths that occurred in this study. Also, the trial doesn't answer whether the findings generalize to all ASV devices.

"Until other studies clarify whether the results seen in the SERVE-HF trial are a consequence of the specific device that was used, we recommend that adaptive servo ventilation not be used outside clinical trials in patients with heart failure who have predominantly [CSA]," write Magalang and Pack.

They add that this study brings up major questions, "and further investigation of this important topic is required."

The study was funded by ResMed. Cowie reports receiving research funding and consultancy fees from ResMed, as well as consulting fees from Servier, Novartis, Pfizer, St Jude Medical, Boston Scientific, Respicardia, and Medtronic and grant support from Bayer. Disclosures for the coauthors are listed in the article. Magalang reports receiving grant support from the National Institutes of Health, the Rudi Schulte Family Foundation, Hill-Rom, and the Tzagournis Medical Research Endowment. Pack is the holder of the endowed chair for sleep medicine from the Respironics Foundation at the University of Pennsylvania.

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