Central Sleep Apnea and Cheyne-Stokes Respiration in heart failure
Central sleep apnea (CSA), often characterized as Cheyne-Stokes Respiration in heart failure (HF) patients, is a common comorbidity, affecting 30-50% of patients with reduced left ventricular ejection fraction (LVEF) and up to 18-30% of patients with preserved LVEF.1 Untreated central sleep apnea has shown to be independently associated with increased mortality and hospitalizations, especially in patients with heart failure.2,3 The symptoms of sleep apnea—fatigue, daytime somnolence, shortness of breath, and nocturnal dyspnea—often overlap with those of heart failure, making it difficult to evaluate the effect of cardiovascular therapies on patient symptoms while the sleep apnea remains untreated.4
Clinicians are commonly presented with complaints of fatigue and problems sleeping. Understanding who to systematically screen and test can be challenging. In addition, heart failure clinicians need to be aware of treatment options for their patients as they may differ from the best options for other sleep apnea patients.
Importance of Distinguishing obstructive versus central sleep apnea in heart failure
Sleep apnea is commonly classified as either obstructive sleep apnea (OSA) or central sleep apnea (CSA). Obstructive apnea results from the muscles in the upper airway relaxing or collapsing during sleep, narrowing the breathing passage, and impeding airflow. Central apnea results from a failure of the brain to send appropriate signals to the respiratory muscles to initiate a breath (independent of whether the airway is open).1 OSA is substantially more prevalent than CSA in the general population and is, therefore, the focus of the majority of sleep-disordered breathing diagnostic and treatment efforts. However, the two types of apnea are nearly equally represented in heart failure, where CSA affects approximately 40% of patients and OSA 36%.5 This presents a major challenge, as many of the diagnostic and treatment advances may not be appropriate for managing patients with central sleep apnea. Indeed, the 2017 ACC/AHA/HFSA guidelines recognize the “clinical necessity to distinguish obstructive versus central sleep apnea” in patients with heart failure.6
Cardiologists confront challenges when trying to diagnose and manage sleep apnea using tools designed with only obstructive apnea in mind. Fortunately, available technology and changes in practice are making it easier to overcome these challenges to clarify which patients have CSA.
Choosing the right heart failure patients to evaluate for sleep apnea
In the general population, clinicians often use screening questionnaires (e.g. ESS, STOP-BANG) to identify OSA patients using externally observable criteria: the presence of snoring, large neck circumference, high BMI, etc. This approach is less helpful within the heart failure population for two reasons. First, the high prevalence of sleep-disordered breathing (76%) in this population establishes a low bar for pre-test probability.5 Second, CSA is approximately equal in prevalence to OSA within this population.5 By definition, CSA is due to a decrease in the drive to breathe. When patients with CSA stop breathing, it is often quiet—patients and bedpartners may not even realize that there is a breathing issue at night unless actively monitoring. The fatigue and lack of sleep often is confused with similar heart failure symptoms, keeping patients from understanding that a lack of quality sleep plays into their overall health.4
Changes in both guidelines and technology have reframed how clinicians may think about screening questionnaires to predict CSA. In 2017, the ACC/AHA/HFSA updated heart failure guidelines to include a IIa recommendation to evaluate NYHA class II-IV HF patients for sleep-disordered breathing where signs or symptoms of sleep disorders are noted.6 The update also specified the need to distinguish between obstructive and central sleep apnea. While there is a yet to be a questionnaire that can rule out sleep apnea in HF patients, there is increased adoption of home sleep test (HST) devices as an effective way to quickly and easily identify sleep-disordered breathing. One HSAT device, the WatchPAT® Central+ (Itamar®), has been FDA cleared as a diagnostic aid that can generate a central Apnea-Hypopnea index, as well as a general measure of AHI.7 Use of HST devices, has allowed some cardiology practices to screen more broadly, and without the wait times associated with overnight polysomnography in a sleep lab.
A novel approach to treating Central Sleep apnea in heart failure: Phrenic Nerve Stimulation
Treatment options for central sleep apnea are limited. While positive airway pressure devices are the most frequently attempted treatment (continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), or adaptive servo-ventilation (ASV)), there are clear limitations to the efficacy and/or safety of all baseline treatment options.4 Compliance remains difficult for patients who are prescribed positive airway pressure devices, 25-50% refuse or are unable to tolerate this therapy, and an additional 40-60% are non-compliant to an even minimal definition of compliance (therapy used an average of 4 hours/night for 5 nights/week).8,9 There have also been safety challenges, particularly in HF patients with reduced cardiac output with these therapies—resulting in more cautious use of CPAP and an explicit, black box warning against ASV for patients with LVEF ≤ 45%.10
A novel therapy designed specifically for central sleep apnea—phrenic nerve stimulation (brand name remedē®, www.respicardia.com)—was FDA-approved in 2017 for moderate to severe CSA in adults.11 The remedē system is a fully implantable, transvenous therapy that activates automatically each night to monitor and stabilize the breathing pattern, restoring restful sleep throughout the night. It is designed to stimulate the phrenic nerve in a way that causes smooth contractions of the diaphragm, similar to natural breathing. The system includes an implantable pulse generator (IPG) and transvenous leads for unilateral stimulation of the phrenic nerve and sensing respiration via transthoracic impedance.11
Unlike other sleep apnea treatments, remedē is programmed to start automatically each night, ensuring therapy compliance. It activates when all the following programmable conditions are met:11
a) Time of day is within the patient’s normal sleeping times; (e.g. 11:00 PM to 6:00 AM)
b) The patient’s activity level is representative of a sleeping or resting condition
c) The patient is in a sleeping posture (for example; a horizontal position)
The remedē System is implanted by an electrophysiologist (EP) under conscious sedation and is typically done on an outpatient basis in the cardiac device suite. The procedure involves the subcutaneous implantation of the pulse generator in the upper chest and the placement of two leads into appropriate veins.11
The remedē system was studied in a prospective, multicenter, randomized Pivotal Trial evaluating the safety and effectiveness of therapy delivered by the remedē System in Treatment subjects with moderate to severe CSA and optimal medical management, compared to Control subjects receiving optimal medical management and an implanted but inactive remedē System.12 As CSA is so common in the heart failure population, 64% of the patients in the clinical trial had comorbid heart failure and 42% had a concomitant cardiac device. The primary effectiveness endpoint and all seven hierarchically tested secondary endpoints demonstrated statistically significant and clinically meaningful improvements in favor of transvenous phrenic nerve stimulation including:13
- Improved oxygenation: Oxygen desaturation index of 4% (ODI4) was improved significantly—with the Treatment group reducing the number of hypoxic events by 19 events per hour from the baseline. This finding was further strengthened by an exploratory analysis of the reduction in time below 90% oxygen saturation. Recent research has suggested that the amount of time during sleep with oxygen saturation <90% is predictive of survival in heart failure patients.14,15 These results demonstrate a statistically significant and clinically meaningful reduction in hypoxia.
- Improved sleep quality: The remedē System Pivotal Trial is the first randomized study in CSA subjects to demonstrate improvements in REM sleep (p<0.0244) and arousals (p<0.0001).
- Improved quality of life: 79% of treatment group subjects reported improved quality of life, demonstrated through the patient-centric Patient Global Assessment (PGA). Subjects were also less sleepy, as evidenced by the significant improvement in the Epworth Sleepiness Scale (ESS) between Treatment and Control groups (Treatment group improved 3.7 points more compared to Control, p<0.0001).
- Safety: Ninety-one percent of subjects did not experience a serious adverse event related to the implant procedure, device, or delivered therapy through 12 months post-implant. Of the nine percent experiencing an event, none of the events led to death and all resolved without sequelae.
- Further, at the request of the FDA and not as a formal endpoint of the study, patients were asked “Based on your experience with the remedē System therapy, would you elect to have this medical device implanted again?” and 95% of the patients in the pivotal trial indicated they would have the system implanted again.
Since the pivotal trial, long term safety and efficacy data have been published in the peer-reviewed The American Journal of Cardiology (12 months)16 and Sleep (24 and 36 months).17 Both safety and efficacy of the therapy remain durable and consistent over this time. Data on long term cardiac outcomes are needed, but the therapy demonstrates strong improvement is quality of life and sleep quality in patients with or without heart failure.
Challenges remain is establishing streamlined approaches to evaluate, diagnose, and treat heart failure patients with central sleep apnea. The requirements of a multi-disciplinary approach are key to understanding the significant impact that sleep apnea has on the HF patient. New diagnostic tools such as the WatchPAT® device allow simple testing and classifying of sleep apnea even when the sleep and cardiology offices are located apart geographically. These tools can help categorize patients early and identify the appropriate treatment pathway. With few treatment options available for patients with CSA, it is important to identify these patients early and identify the treatment pathway. The remedē System now offers treatment for patients with CSA demonstrating significant improvements in sleep and quality of life.
- Javaheri S., Dempsey J.A. (2013) Central sleep apnea. Compr Physiol. 2013; 3:141–163
- Khayat R, Abraham W, Patt B, et al. Central sleep apnea is a predictor of cardiac readmission in hospitalized patients with systolic heart failure. J Card Fail. 2012;18(7):534–540.
- Khayat R, Jarjoura D, Porter K, et al. Sleep-disordered breathing and post-discharge mortality in patients with acute heart failure. European Heart Journal. 2015; 36(23): 463–1469.
- Costanzo M.R., Khayat R., Ponikowski P., et al. Mechanisms and clinical consequences of untreated central sleep apnea in heart failure. J Am Coll Cardiol. 2015; 65:72–84.
- Oldenburg O, et al. Sleep-disordered breathing in patients with symptomatic heart failure: A contemporary study of prevalence in and characteristics of 700 patients Eur J Heart Fail 2007; 9:251-257.
- Yancy et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. JACC 2017; 70(6):776-803
- FDA 510(k) K180775, https://www.accessdata.fda.gov/cdrh_docs/pdf18/K180775.pdf
- Takama N, Kurabayashi M, Effect of adaptive servo-ventilation on 1-year prognosis in heart failure patients. Circulation Jour 2012;76:661-7
- Arzt M, et al., Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP), Circulation 2007; 115:3713-80
- Aurora RN, Bista SR, Casey KR et al. Updated adaptive servo-ventilation recommendations for the 2012 AASM guideline: “the treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses”. J Clin Sleep Med. 2016;12:757–61.
- FDA PMA P160039 https://www.fda.gov/medical-devices/recently-approved-devices/remeder-system-p160039
- Design of the remedē System Pivotal Trial: A Prospective, Randomized Study in the Use of Respiratory Rhythm Mgmt to Treat Central Sleep Apnea Costanzo, Maria Rosa et al. Journal of Cardiac Failure, Volume 21, Issue 11, 892 – 902
- Costanzo M, et al. Transvenous neurostimulation for central sleep apnoea: a randomized controlled trial. The Lancet. 2016; 388: 974–82.
- Oldenburg O, Wellmann B, Buchholz A, Bitter T, Fox H, Thiem U, Horstkotte D, Wegscheider K. Nocturnal hypoxemia is associated with increased mortality in stable heart failure patients. Eur Heart J. 2016;37(21):1695-703.
- Bostanci A, Turhan M, Bozkurt S. Factors Influencing Sleep Time With Oxygen Saturation Below 90% in Sleep-Disordered Breathing. Laryngoscope, 125:1008–1012, 2015.
- Costanzo M, et al. Sustained Twelve Month Benefit of Phrenic Nerve Stimulation for Central Sleep Apnea. Am J Cardiol 2018;121:1400-8. 
- Fox H, et al. remedē® System Pivotal Trial Study Group, Long-term Efficacy, and Safety of Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnea Outcomes of Phrenic Nerve Stimulation for Central Sleep Apnea. Sleep. doi.org/10.1093/sleep/zsz158.