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A Paradigm Shift in the Treatment of Central Sleep Apnea in Heart FailureCentral Apnea and Heart Failure FREE TO VIEW

Reena Mehra, MD, FCCP; Daniel J. Gottlieb, MD, MPH, FCCP
Author and Funding Information

From the Cleveland Clinic (Dr Mehra), Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; VA Boston Healthcare System (Dr Gottlieb); and Division of Sleep Medicine (Dr Gottlieb), Harvard Medical School.

CORRESPONDENCE TO: Reena Mehra MD, FCCP, Sleep Disorders Research, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: mehrar@ccf.org


CONFLICT OF INTEREST: R. M. has received honoraria from the American Academy of Sleep Medicine, positive airway pressure machines and equipment for research from Philips Respironics (Koninklijke Philips NV), and funding from the National Institutes of Health. D. J. G. has served as a consultant for VIVUS Inc and has received research support from Jazz Pharmaceuticals plc.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(4):848-851. doi:10.1378/chest.15-1536
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Periodic breathing with central sleep apnea (CSA), known as Hunter-Cheyne-Stokes respiration, is among the first recognized sleep-related breathing disorders, described in the early 19th century, and is now recognized to be quite common in patients with chronic heart failure (HF). It remains uncertain whether CSA is simply a marker of underlying cardiac dysfunction or, alternatively, whether CSA exerts a detrimental effect on the failing heart (eg, via hypoxia, arousal, and their associated sympathoexcitation) or if it is a beneficial compensatory mechanism (eg, via increased end-expiratory lung volumes improving oxygenation or via promotion of cardioprotective alkalosis).1 Reports that CSA is associated with increased risk for mortality in patients with HF, along with preliminary findings of improved cardiac function and reduced mortality when CSA was treated with CPAP,2-4 prompted a multicenter randomized controlled trial to investigate the effect of CPAP on transplant-free survival in patients with HF with CSA. This trial was prematurely terminated because of low recruitment, reduced mortality due to secular trends in the medical treatment of HF, and early divergence of the survival curves in favor of the control group (hazard ratio [HR] in first 18 months, 1.5; P = .02).5 Beyond 18 months, survival favored the CPAP arm, but the overall difference between treatment groups was not statistically significant, despite sustained improvement in intermediate measures (left ventricular ejection fraction [LVEF], plasma norepinephrine level, 6-min walk distance).5 The power of this study was limited, CPAP had suboptimal effectiveness in reducing CSA burden, and secondary analysis suggested that survival was improved in those in whom CSA was suppressed,6 leading to the design and initiation of two larger, more adequately powered trials using adaptive servoventilation (ASV), a bilevel positive airway pressure modality that is more effective in reversing CSA in patients with HF.7 These include an ongoing trial enrolling patients with either obstructive or central sleep apnea (Effect of Adaptive Servo Ventilation on Survival and Hospital Admissions in Heart Failure [ADVENT-HF])8 and a completed trial enrolling only patients with predominantly CSA (Treatment of Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure [SERVE-HF]),9 with recently publicized results.

SERVE-HF is a multicenter randomized controlled trial designed to compare the effect of standard medical management plus ASV vs medical management alone in patients with symptomatic chronic HF (class III or IV, or class II with at least one hospitalization for HF over the preceding 24 months), LVEF ≤ 45%, and predominant CSA (apnea-hypopnea index ≥ 15/h, > 50% central events, and central apnea-hypopnea index ≥ 10). The primary end point was all-cause mortality or unplanned hospitalization for HF.10 A total of 1,325 patients were randomized and followed for a mean of 3.5 years. Preliminary results were made public by the sponsor, ResMed Inc, in May 2015, with an urgent Field Safety Notice, which reported that there was no statistically significant difference in the primary end point, with a trend favoring the control (non-ASV) condition (HR, 1.14; 95% CI, 0.97-1.33; P = .10). There was, however, a statistically significant increased risk for cardiovascular mortality in patients treated with ASV compared with control subjects: 10%/y in ASV compared with 7.5%/y in control subjects (HR, 1.34; 95% CI, 1.07-1.67; P = .01).11,12 Moreover, as there was no offsetting improvement noted in HF symptoms or functional status, clinicians were advised that ASV would now be contraindicated for treatment of CSA in patients with symptomatic HF and reduced LVEF and were urged to contact patients in this group already receiving ASV “to discuss with them immediate discontinuation of ASV treatment.”11,12

How are we to interpret and respond to these unanticipated findings? It is important to note that despite the Field Safety Notice and limited data presentation at the SLEEP 2015 conference, the results of this study have not yet been subjected to peer review and publication; interpretation, therefore, is provisional. It is tempting to consider that this might reflect a type 1 statistical error, as cardiovascular mortality was not one of the three prespecified primary end points but was among > 20 prespecified secondary end points.9 Given the large magnitude of the effect on cardiovascular mortality, however, it would be imprudent to dismiss this finding. Certainly ample precedent exists in other disciplines of interventions that improve surrogate or intermediate end points, yet in subsequent trials cause no improvement or even harm with respect to “hard” clinical outcomes.13-15 Thus, although trials that focus on surrogate end points are shorter and more efficient, a major challenge includes inability to effectively ascertain the potential of the intervention to cause adverse events.16

The excess cardiovascular mortality observed with ASV use in the SERVE-HF trial is reportedly out-of-hospital death without preceding symptoms of decompensated HF, without change in the usual temporal pattern of mortality in HF, and is presumed to reflect arrhythmic sudden cardiac death. A number of potential mechanisms merit consideration. Increased intrathoracic pressure reduces both preload and afterload; while these effects may be beneficial in acute decompensated HF,17 reduction of preload in a euvolemic or volume-depleted state, as is likely to be present in aggressively managed severe HF, may move patients to a more unfavorable position on the pressure-volume curve and may result in hypotension. In a study of patients with LVEF < 40% and New York Heart Association class II-III HF, however, hemodynamics were not appreciably altered with incremental CPAP increases from 0 to 10 cm H2O.18 Reduced preload might also result in reduction of atrial natriuretic peptide, leading to reduction of water and sodium excretion, potentially worsening HF. Increased ventilation due to pressure support from ASV might worsen respiratory alkalosis, with a consequent increase in potassium excretion, thus predisposing to fatal arrhythmia. Although this is not supported by data demonstrating that ASV acutely improves alkalosis7 and reduces appropriate defibrillator shocks,19 ASV has been shown to increase alkalosis during wakefulness,20 and the long-term effects of ASV on alkalosis and electrolyte balance in patients whose CSA is chronically suppressed is not clear. Unfavorable hemodynamics in those with pulmonary hypertension and right ventricular dysfunction, device-patient dyssynchrony with increased sleep fragmentation, or adverse effects of positive pressure on cardiac remodeling are also possible. A beneficial effect of ASV on symptoms might plausibly lead to reduced adherence to HF medications or to increased physical activity triggering fatal arrhythmias, although the reported lack of symptomatic or functional improvement in the ASV-treated group argues against these mechanisms. Finally, we cannot entirely discount the possibility that CSA serves a beneficial, adaptive function in severe HF, as Naughton1 has long advocated.

As the results of the SERVE-HF study are further analyzed and presented, extensive data already collected by this study may shed light on these potential mechanisms. Additional studies focusing in more detail on physiologic parameters such as intravascular volume status, loop gain, electrolyte values, CO2 levels, cardiac electrical stability, and lung compliance may also be helpful. Understanding the mechanism of increased mortality in patients treated with ASV is critical to clinical decision-making. If positive airway pressure per se is detrimental in this patient population, risk may extend to all positive airway pressure modalities. If CSA is, in fact, a beneficial compensatory mechanism, a major paradigm shift is needed, as treatment of CSA by any means other than improving cardiac function may be inappropriate.

Given the limitations of current knowledge, clinical recommendations should be narrowly focused. SERVE-HF findings are not generalizable to patients with HF who have normal LVEF, to those with predominantly OSA regardless of LVEF (a population being studied in the ongoing ADVENT-HF study), or to patients treated with ASV for reasons other than HF-related CSA. Although ASV devices from different manufacturers use different algorithms, at this point they should be treated as equivalent from the standpoint of risk. Given the results of SERVE-HF and the impending contraindication labeling, it would be imprudent to start ASV in patients with HF, LVEF ≤ 45%, and predominant CSA. Patients with reduced LVEF already using ASV for this indication should be notified of the SERVE-HF findings; although the manufacturer has recommended immediate discontinuation of therapy in these patients, we believe it is more appropriate for clinicians to discuss the risks with their patients in the context of whatever benefit they may have obtained from ASV and alternative treatment options. What are these alternatives? For the many patients in whom CSA is asymptomatic, no specific treatment is indicated, given equipoise as to whether any treatment offers cardiac benefits. For patients who are deemed to be symptomatic from CSA, currently favored options include nocturnal supplemental oxygen or CPAP, each of which has been shown to control CSA in a substantial number of patients.21 Positional therapy, acetazolamide, leg compression stockings, cardiac resynchronization therapy, and transvenous phrenic-nerve pacing, a modality that shows promise in the treatment of CSA,22 may also play a role in appropriate patients.

As a community of sleep medicine practitioners, we should be humbled by the unexpected results of the SERVE-HF trial. While these results should be applied narrowly, they should have a broad impact on our discussions of sleep apnea treatment for cardiovascular risk reduction in general and reinforce the need for a culture of evidence-based treatment guided by well-designed and well-executed clinical trials.

References

Naughton MT. Cheyne-Stokes respiration: friend or foe? Thorax. 2012;67(4):357-360. [CrossRef] [PubMed]
 
Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med. 1996;153(1):272-276. [CrossRef] [PubMed]
 
Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol. 2007;49(20):2028-2034. [CrossRef] [PubMed]
 
Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation. 2000;102(1):61-66. [CrossRef] [PubMed]
 
Bradley TD, Logan AG, Kimoff RJ, et al; CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353(19):2025-2033. [CrossRef] [PubMed]
 
Arzt M, Young T, Finn L, Skatrud JB, Bradley TD. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med. 2005;172(11):1447-1451. [CrossRef] [PubMed]
 
Teschler H, Döhring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med. 2001;164(4):614-619. [CrossRef] [PubMed]
 
Effect of adaptive servo ventilation (ASV) on survival and hospital admissions in heart failure (ADVENT-HF). NCT01128816. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2010. https://clinicaltrials.gov/ct2/show/NCT01128816. Last updated October 6, 2014.
 
Tescher H, Cowie M. Treatment of predominant central sleep apnea by adaptive servo ventilation in patients with heart failure (Serve-HF). NCT00733343. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2008. https://clinicaltrials.gov/ct2/show/NCT00733343. Last updated September 18, 2014.
 
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. Eur J Heart Fail. 2013;15(8):937-943. [CrossRef] [PubMed]
 
ResMed provides update on phase IV SERVE-HF study of adaptive servo-ventilation (ASV) therapy in central sleep apnea and chronic heart failure. ResMed Inc website. http://www.resmed.com/us/en/consumer/newsandinformation/news- releases/2015/resmed-provides-update-on-phase-iv-serve-hf-study-of-adaptive-servo-ventilation-therapy.html. Accessed June 26, 2015.
 
The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321(6):406-412. [CrossRef] [PubMed]
 
Barter PJ, Caulfield M, Eriksson M, et al; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109-2122. [CrossRef] [PubMed]
 
Manson JE, Hsia J, Johnson KC, et al; Women’s Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523-534. [CrossRef] [PubMed]
 
Croswell JM, Kramer BS. Clinical trial design and evidence-based outcomes in the study of liver diseases. J Hepatol. 2009;50(4):817-826. [CrossRef] [PubMed]
 
Naughton MT, Rahman MA, Hara K, Floras JS, Bradley TD. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation. 1995;91(6):1725-1731. [CrossRef] [PubMed]
 
Schroll S, Sériès F, Lewis K, et al. Acute haemodynamic effects of continuous positive airway pressure in awake patients with heart failure. Respirology. 2014;19(1):47-52. [CrossRef] [PubMed]
 
Bitter T, Gutleben KJ, Nölker G, et al. Treatment of Cheyne-Stokes respiration reduces arrhythmic events in chronic heart failure. J Cardiovasc Electrophysiol. 2013;24(10):1132-1140. [PubMed]
 
Spießhöfer J, Heinrich J, Lehmann R, et al. Respiratory effects of adaptive servoventilation therapy in patients with heart failure and Cheyne-Stokes respiration compared to healthy volunteers. Respiration. 2015;89(5):374-382. [CrossRef] [PubMed]
 
Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep. 2012;35(1):17-40. [PubMed]
 
Abraham WT, Jagielski D, Oldenburg O, et al; remedē Pilot Study Investigators. Phrenic nerve stimulation for the treatment of central sleep apnea. JACC Heart Fail. 2015;3(5):360-369. [CrossRef] [PubMed]
 

Figures

Tables

References

Naughton MT. Cheyne-Stokes respiration: friend or foe? Thorax. 2012;67(4):357-360. [CrossRef] [PubMed]
 
Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med. 1996;153(1):272-276. [CrossRef] [PubMed]
 
Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol. 2007;49(20):2028-2034. [CrossRef] [PubMed]
 
Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation. 2000;102(1):61-66. [CrossRef] [PubMed]
 
Bradley TD, Logan AG, Kimoff RJ, et al; CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353(19):2025-2033. [CrossRef] [PubMed]
 
Arzt M, Young T, Finn L, Skatrud JB, Bradley TD. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med. 2005;172(11):1447-1451. [CrossRef] [PubMed]
 
Teschler H, Döhring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med. 2001;164(4):614-619. [CrossRef] [PubMed]
 
Effect of adaptive servo ventilation (ASV) on survival and hospital admissions in heart failure (ADVENT-HF). NCT01128816. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2010. https://clinicaltrials.gov/ct2/show/NCT01128816. Last updated October 6, 2014.
 
Tescher H, Cowie M. Treatment of predominant central sleep apnea by adaptive servo ventilation in patients with heart failure (Serve-HF). NCT00733343. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2008. https://clinicaltrials.gov/ct2/show/NCT00733343. Last updated September 18, 2014.
 
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. Eur J Heart Fail. 2013;15(8):937-943. [CrossRef] [PubMed]
 
ResMed provides update on phase IV SERVE-HF study of adaptive servo-ventilation (ASV) therapy in central sleep apnea and chronic heart failure. ResMed Inc website. http://www.resmed.com/us/en/consumer/newsandinformation/news- releases/2015/resmed-provides-update-on-phase-iv-serve-hf-study-of-adaptive-servo-ventilation-therapy.html. Accessed June 26, 2015.
 
The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321(6):406-412. [CrossRef] [PubMed]
 
Barter PJ, Caulfield M, Eriksson M, et al; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109-2122. [CrossRef] [PubMed]
 
Manson JE, Hsia J, Johnson KC, et al; Women’s Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523-534. [CrossRef] [PubMed]
 
Croswell JM, Kramer BS. Clinical trial design and evidence-based outcomes in the study of liver diseases. J Hepatol. 2009;50(4):817-826. [CrossRef] [PubMed]
 
Naughton MT, Rahman MA, Hara K, Floras JS, Bradley TD. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation. 1995;91(6):1725-1731. [CrossRef] [PubMed]
 
Schroll S, Sériès F, Lewis K, et al. Acute haemodynamic effects of continuous positive airway pressure in awake patients with heart failure. Respirology. 2014;19(1):47-52. [CrossRef] [PubMed]
 
Bitter T, Gutleben KJ, Nölker G, et al. Treatment of Cheyne-Stokes respiration reduces arrhythmic events in chronic heart failure. J Cardiovasc Electrophysiol. 2013;24(10):1132-1140. [PubMed]
 
Spießhöfer J, Heinrich J, Lehmann R, et al. Respiratory effects of adaptive servoventilation therapy in patients with heart failure and Cheyne-Stokes respiration compared to healthy volunteers. Respiration. 2015;89(5):374-382. [CrossRef] [PubMed]
 
Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep. 2012;35(1):17-40. [PubMed]
 
Abraham WT, Jagielski D, Oldenburg O, et al; remedē Pilot Study Investigators. Phrenic nerve stimulation for the treatment of central sleep apnea. JACC Heart Fail. 2015;3(5):360-369. [CrossRef] [PubMed]
 
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