Editor's Note: Commentary based on Cowie MR, Woehrle H, Wegscheider K et al. Rationale and design of the SERVE-HF study: treatment of sleep-disordered breathing with predominant central sleep apnoea with adaptive servo-ventilation in patients with chronic heart failure. European Journal of Heart Failure 2013;15:937-43.

Background

Sleep disordered breathing is common in patients with heart failure (HF) and is subtyped into obstructive and central sleep apnea.^1-3 Polysomnography testing revealing at least 10 to 15 apneas and hypopneas per hour of sleep is consistent with a diagnosis of sleep apnea.^4,5 Continuous positive airway pressure (CPAP) in the general population improves daytime blood pressure measurements and quality of life through metrics of daytime sleepiness and sleep quality.^6,7 Central sleep apnea (CSA) occurs in 25-40% of patients with HF with reduced ejection fraction (HFrEF) and often may manifest with Cheyne-Stokes respiration.⁸ However, sleep apnea-targeted therapies have not previously been shown to improve cardiovascular outcomes in patients with HF. The Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) study demonstrated no benefit from CPAP use in patients with CSA and HFrEF.⁹ Exploratory post-hoc findings suggested that patients who experienced a reduction in the apnea-hypopnea index had a reduction in mortality. Adapative servo-ventilation (ASV) is a distinct noninvasive pressure support therapy that delivers servo-controlled inspiratory pressure on top of expiratory positive airway pressure with the potential to reduce Cheyne-Stokes respiration in patients with CSA. The Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE-HF) trial assessed the hypothesis that ASV would improve clinical outcomes in HFrEF patients with predominant CSA.

Methods

In SERVE-HF, 1325 patients with New York Heart Association class II-IV symptoms and an ejection fraction less than 45% with predominantly central apopnea events were randomized to guideline-directed medical therapy with or without ASV.¹⁰ The primary end point was the composite of all-cause mortality, lifesaving cardiovascular intervention or unplanned worsening heart failure requiring hospitalization.

Results

The study patients were mostly men (90%), overweight (median BMI 28+), largely NYHA class II (29%) and class III (69%) with most patients prescribed guideline-directed medical therapy (91% ACE inhibitor/ARB, 92% beta-blocker, 47% aldosterone antagonist). There was no difference in the primary outcome between groups with 54.1% of patients in the ASV treatment group experiencing an event compared with 50.8% in the control group (hazard ratio [HR] 1.13, 95% CI 0.97 to 1.31, p=0.10). However, all-cause mortality and cardiovascular mortality were significantly higher in the ASV treated group compared with the control group (HR 1.28, 95% CI 1.06 to 1.55, p-value =0.01 and 1.34, 95% CI 1.09 to 1.65, p-value = 0.006, respectively). Cardiovascular mortality was largely driven by sudden death with absolute annual risk of 10% in the ASV group versus 7.5% in the control group.¹¹

Conclusion

Continued management of patients with ongoing CSA is challenging. Abrupt withdrawal of ASV may be harmful but ASV therapy cessation should be carefully considered in patients with HFrEF. Outcomes associated with ASV use in patients with HFpEF are unknown. However, CSR may also be an important compensatory process in HFpEF and caution should be used when considering use of ASV in these patients. It remains unknown if patients with HFrEF and OSA should continue ASV or be transitioned to CPAP.

Commentary/Perspective

The findings of the SERVE-HF trial are particularly relevant given the increased recognition of the adverse effects of SDB in HF patients in recent years and the limited data empirically evaluating treatment strategies. Multiple theories are plausible for the negative findings seen with ASV therapy in patients with HFrEF and predominant CSA. The SERVE-HF investigators focus on two potential mechanisms: increased positive airway pressure leading to adverse changes in cardiac function and the removal of potential compensatory mechanisms of Cheyne-Stokes respiration¹². ASV suppresses CSR through use of bilevel positive airway pressure that increases pressure support during apneic or hyponeic periods and decreases airway support during regular breathing. In this way, ASV may have direct cardiovascular effects through positive airway pressures leading to a drop in cardiac output or reflex sympathetic nervous system responses leading to dysrhythmias. Other modes of assisted ventilation may not be harmful in patients with HFrEF; the CANPAP trial of CPAP therapy demonstrated no increase in mortality (nor benefit) compared to usual care in patients with HFrEF.

The results of SERVE-HF may not translate to other disease states. Although providers for patients with HFrEF who are currently using ASV should strongly consider the risks of ongoing ASV use, shared decision-making using an open dialogue will best individualize each patient's scenario. If ASV cessation is decided, potential risks of abrupt withdrawal of ASV may be avoided through transitioning to therapies including CPAP, nocturnal oxygen, and/or acetazolamide that improve nocturnal desaturation ¹³.

Although the results of SERVE-HF do not support the use of ASV for CSA, many questions remain regarding the safety and efficacy of other modes of noninvasive nocturnal ventilation in patients with OSA and HFrEF (as well as HFpEF). The CAT-HF (Cardiovascular Improvements With Minute Ventilation-targeted ASV Therapy in Heart Failure (CAT-HF) trial was design to evaluate minute ventilation targeted ASV therapy in patients following stabilization during acute heart failure (ClinicalTrials.gov Identifier: NCT01953874). Although CAT-HF stopped enrollment following the SERVE-HF results, follow-up is ongoing, the inclusion of patients with HFpEF and HFrEF with OSA and CSA will add further insight into patients with HF and sleep disordered breathing.

Sleep disordered breathing is a common comorbidity in patients with HF and therapies that improve quality of life and clinical outcomes continue to be lacking. Future studies are needed to explore potential therapies that may improve quality of life and outcomes in these patients.

References

1. Bradley TD, Floras JS. Sleep apnea and heart failure: Part I: obstructive sleep apnea. Circulation 2003;107:1671-8.
2. Bradley TD, Floras JS. Sleep apnea and heart failure: Part II: central sleep apnea. Circulation 2003;107:1822-6.
3. Mentz RJ, Fiuzat M. Sleep-disordered breathing in patients with heart failure. Heart failure clinics 2014;10:243-50.
4. Javaheri S, Parker TJ, Liming JD et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998;97:2154-9.
5. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. The New England journal of medicine 1993;328:1230-5.
6. Engleman HM, Martin SE, Deary IJ, Douglas NJ. Effect of continuous positive airway pressure treatment on daytime function in sleep apnoea/hypopnoea syndrome. Lancet 1994;343:572-5.
7. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002;359:204-10.
8. Lévy P PJ-L, Tamisier R, Neuder Y, Baguet J-P, Javaheri S. Prevalence and impact of central sleep apnea in heart failure. Sleep Med Clin 2007;2:615-621.
9. Bradley TD, Logan AG, Kimoff RJ et al. Continuous positive airway pressure for central sleep apnea and heart failure. The New England journal of medicine 2005;353:2025-33.
10. Cowie MR, Woehrle H, Wegscheider K et al. Rationale and design of the SERVE-HF study: treatment of sleep-disordered breathing with predominant central sleep apnoea with adaptive servo-ventilation in patients with chronic heart failure. European journal of heart failure 2013;15:937-43.
11. Malhotra A, Patil S, Sands S, Ayas N. Central sleep apnoea in congestive heart failure. The Lancet Respiratory medicine 2015;3:507-8.
12. Magalang UJ, Pack AI. Heart Failure and Sleep-Disordered Breathing--The Plot Thickens. The New England journal of medicine 2015;373:1166-7.
13. Edwards BA, Connolly JG, Campana LM et al. Acetazolamide attenuates the ventilatory response to arousal in patients with obstructive sleep apnea. Sleep 2013;36:281-5.

Keywords: Acetazolamide, Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Apnea, Sleep Apnea Syndromes, Sleep Apnea, Central, Blood Pressure, Body Mass Index, Cardiac Output, Cheyne-Stokes Respiration, Comorbidity, Continuous Positive Airway Pressure, Control Groups, Death, Sudden, Follow-Up Studies, Heart Failure, Hospitalization, Mineralocorticoid Receptor Antagonists, Overweight, Oxygen, Polysomnography, Quality of Life, Reflex, Research Personnel, Respiration, Artificial, Sleep, Sympathetic Nervous System

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