Central Sleep Apnea
Central sleep apnea (CSA) is characterized by repetitive cessation or decrease in both airflow and ventilatory effort during sleep. CSA may be idiopathic or secondary (associated with a medical condition such as congestive heart failure, drugs, or high altitude breathing). Apneas associated with Cheyne-Stokes respiration are common among patients with heart failure (HF) or who have had strokes, and accounts for about half of the population with CSA. CSA is less common than obstructive sleep apnea. Based on analyses of a large community-based cohort of participants 40 years of age and older in the Sleep Heart Health Study, the estimated prevalence of CSA and obstructive sleep apnea are 0.9% and 47.6%, respectively.^1, Risk factors for CSA include age (>65 years), male gender, history of HF, history of stroke, other medical conditions (acromegaly, renal failure, atrial fibrillation, low cervical tetraplegia, and primary mitochondrial diseases), and opioid use. Individuals with CSA have difficulty maintaining sleep and therefore experience excessive daytime sleepiness, poor concentration, morning headaches, and are at higher risk for accidents and injuries.

Treatment

The goal of treatment is to normalize sleep-related breathing patterns. Because most cases of CSA are secondary to an underlying condition, central nervous system pathology, or medication side effects, treatment of the underlying condition or removal of the medication, may improve CSA. Treatment recommendations differ depending on the classification of CSA as either hyperventilation-related (most common, including primary CSA and those relating to HF or high altitude breathing) or hypoventilation-related (less common, relating to central nervous system diseases or use of nervous system suppressing drugs such as opioids).

For patients with hyperventilation-related CSA, continuous positive airway pressure (CPAP) is considered first-line therapy. Due to CPAP discomfort, patient compliance may become an issue. Supplemental oxygen during sleep may be considered for patients experiencing hypoxia during sleep or who cannot tolerate CPAP. Patients with CSA due to HF and with an ejection fraction > 45% and who are not responding with CPAP and oxygen therapy, may consider bilevel positive airway pressure or adaptive servo-ventilation (ASV) as second-line therapy. Bilevel positive airway pressure devices have two pressure settings, one for inhalation and one for exhalation. ASV uses both inspiratory and expiratory pressure, and titrates the pressure to maintain adequate air movement. However, a clinical trial reported increased cardiovascular mortality with ASV in patients with CSA due to HF and with an ejection fraction <45%,^2, and therefore, ASV is not recommended for this group,

For patients with hypoventilation-related CSA, first-line therapy is bilevel positive airway pressure.

Pharmacologic therapy with a respiratory stimulant may be recommended to patients with hyper- or hypoventilation CSA who do not benefit from positive airway pressure devices, though close monitoring is necessary due to the potential for adverse effects such as rapid heart rate, high blood pressure, and panic attacks.

Phrenic Nerve Stimulation

Several phrenic nerve stimulation systems are available for patients who are ventilator dependent. They stimulate the phrenic nerve in the chest which sends signals to the diaphragm to restore a normal breathing pattern. Currently, there is one phrenic nerve stimulation device approved by the U.S. Food and Drug Administration (FDA) for CSA, the remede System (Respicardia, Inc.). A cardiologist implants the battery powered device under the skin in the right or left pectoral region using local anesthesia. The device has two leads, one to stimulate a phrenic nerve (either the left pericardiophrenic or right brachiocephalic vein) and one to sense breathing. The device runs on an algorithm that activates automatically at night when the patient is in a sleeping position, and suspends therapy when the patient sits up. Patient-specific changes in programming can be conducted externally by a programmer.

Regulatory Status

In October 2017, the FDA approved the remede System (Respicardia, Inc; Minnetonka, MN) through the premarket approval application process. The approved indication is for treatment of moderate to severe CSA in adults. Follow-up will continue for 5 years in the post-approval study. FDA product code: PSR.

Related Policies

• None

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function - including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Phrenic Nerve Stimulation for Central Sleep Apnea
Clinical Context and Therapy Purpose

The purpose of phrenic nerve stimulation (PNS) in patients who have central sleep apnea (CSA) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does the use of PNS improve the net health outcome in patients with CSA compared with positive airway pressure or respiratory stimulation medication?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with CSA. CSA is characterized by repetitive cessation or decrease in both airflow and ventilatory effort during sleep. Individuals with CSA have difficulty maintaining sleep and therefore experience excessive daytime sleepiness, poor concentration, morning headaches, and are at higher risk for accidents and injuries.

Interventions

The therapy being considered is PNS. The System stimulates the phrenic nerve in the chest which sends signals to the diaphragm to restore a normal breathing pattern. The device activates automatically when the patient is in a sleeping position, and suspends therapy when the patient sits up.

Comparators

Current first-line therapy is positive airway pressure. There are several devices providing positive airway pressure (Table 1):

Table 1: Description of Positive Airway Pressure Devices

Device	Description	Comments
CPAP	continuous positive airway pressure	Considered first line therapy for patients with hyperventilation-related CSA.
BPAP	bilevel positive airway pressure (2 pressure settings - 1 for inhalation and 1 for exhalation)	Considered first line therapy for patients with hypoventilation-related CSA
ASV	adaptive servo-ventilation (titrates the inspiratory and expiratory pressure)	Not recommended for patients with CSA with heart failure and left ventricular ejection fraction <45%

For patients who do not benefit from positive airway pressure devices, pharmacologic therapy with a respiratory stimulant may be recommended. Close monitoring is necessary due to the potential of adverse effects such as rapid heart rate, high blood pressure, and panic attacks.

Outcomes

Outcomes of interest include sleep quality metrics and quality of life measures. The Apnea-Hypopnea Index (AHI) is the number of apnea and hypopnea (events per hour of sleep, in which the apnea events last at least ten seconds and are associated with decreased blood oxygenation. In adults, the AHI scale is: < 5 AHI (normal); 5 > AHI < 15 (mild); 15 ≥ AHI < 30 (moderate); and ≥ 30 AHI (severe) per hour of sleep. Additional sleep metrics include central apnea index (CAI, number of central apnea events per hour of sleep) and obstructive apnea index (OAI, number of obstructive apnea events per hour of sleep).

Subjective sleepiness can be measured by the Epworth Sleepiness Scale (ESS).The ESS is a short self-administered questionnaire that asks patients how likely they are to fall asleep (0 = "no chance" to 3 = "high chance") in eight different situations (eg, watching TV, sitting quietly in a car, or sitting and talking to someone). The scores are added, ranging from 0 to 24, with scores over 10 indicating excessive sleepiness and recommendation to seek medical attention. quality of life can be measured by Patient Global Assessment, which consists of a 7-point scale (1 = "markedly improved" to 7 = "markedly worsened").

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;
• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;
• Studies with duplicative or overlapping populations were excluded.

Costanzo et al (2015) provided background and methodologic details of the remede System Pivotal Trial.^3, The trial is a prospective, multicenter, randomized, open-label controlled trial comparing transvenous unilateral phrenic nerve stimulation with no stimulation in patients with CSA of various etiologies (Table 2). All patients received implantation of the phrenic nerve stimulation system, with activation of the system after 1 month in the intervention group (n=73) and activation after 6 months in the control group (n=78). Activation is delayed one month after implantation to allow for lead healing. The primary efficacy endpoint is percentage of patients achieving a reduction in AHI of 50%, as interpreted from polysomnography by an assessor blinded to treatment arm. The reduction of 50% was based on assessments showing that a 50% reduction in AHI is associated with reduced mortality risk and is therefore clinically meaningful. Secondary endpoints include mean reductions in CAI, AHI, arousal index, oxygen desaturation index, and ESS. Of the 151 patients in the trial, 64% had heart failure (HF), 42% had atrial fibrillation, and a mean left ventricular ejection fraction of 39.6.

Costanzo et al (2016) reported the 6-month per protocol comparative results for the treatment and control groups (Table 3).^4, Twelve, 24, and 36 month results for the intervention group are shown in Table 4. Adverse events were reported in 9% of the intervention group and 8% of the control group (for example, implant site infection, implant site hematoma, and lead dislodgement). Non-serious therapy-related discomfort was reported in 27 (37%) of the intervention group, with all but 1 case resolved by system reprogramming. At 6 months follow-up, 15 of the 73 (21%) in the treatment group were excluded due to no 6-month data (n=9: unrelated death, device explant, missed visit, study exit), failed inclusion criteria (n=3), unsuccessful implant (n=2), therapy programmed off (n=1).

At the 12-month follow-up, an additional 4 patients were lost due to unrelated death, device explant, patient refusal, and missed visit. Results from the remaining 54 patients in the intervention group at 12 months are summarized in Table 4.^5, Subgroup analyses showed consistent improvements in percent experiencing > 50% AHI reductions from treatment across all of the following subgroups: age (< 65, 65 to < 75, and > 75), gender, HF (yes/no), defibrillator (yes/no), AHI severity (moderate/severe), and atrial fibrillation (yes/no). Follow-up at 24 months was available for 42 patients in the treatment group, while 22 patients in the treatment group and 28 patients in the control arm had reached 36 month follow-up at the time of study closure.^6, Central apnea events remained low throughout follow-up with a median time to battery depletion of 39.4 months. Serious adverse events related to the implant procedure, device, or delivered therapy occurred in 10% of patients through the 24-month visit. All were reported to be resolved with remedē System revisions or programming. Safety data will be collected through 5 years as part of the post-approval study.

Table 2. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Intervention	Control
Costanzo (2015)3,	Germany, Poland, United States	31	2013 - 2015	Adult patients with moderate to severe CSA of various etiologies confirmed by PSGa and medically stableb	Implanted phrenic nerve stimulator (remede system) activated at 1 month postprocedure (n=73, 58 analyzed)	Implanted phrenic nerve stimulator (remede system) activated at 6 months postprocedure (n=78, 73 analyzed)

AHI: apnea-hypopnea index; CSA: central sleep apnea; PSG: polysomnography; RCT: randomized controlled trial.

a AHI >20 events/hr; CAI >50% of all apneas, with >30 central apnea events; OAI <20% of all AHI
b For 30 days prior to baseline testing: no hospitalizations for illness, no breathing mask-based therapy, and on stable medications and therapies.

Study	Baseline	6-Month	Change from Baseline	Between Group Difference
Costanzo (2018)4,
>50% AHI reduction
Treatment	NA	51% (39% to 64%)	NA
Control	NA	11% (5% to 20%)	NA	41% (25% to 54%)
AHI
Treatment	49.7 + 18.9	25.9 + 20.5	-23.9 + 18.6
Control	43.9 + 17.3	45.0 + 20.3	1.1 + 17.6	-25.0 + 18.1
CAI
Treatment	31.7 + 18.6	6.0 + 9.2	-25.7 + 18.0
Control	26.2 + 16.2	23.3 + 17.4	-2.9 + 17.7	-22.8 + 17.8
PGAb
Treatment	NA	60% (47% to 73%)	NA
Control	NA	6% (2% to 14%)	NA	55% (40% to 68%)
ESS
Treatment	10.7 + 5.3	7.1 + 4.1	-3.6 + 5.6
Control	9.3 + 5.7	9.4 + 6.1	0.1 + 4.5	-3.7 + 5.0

a Data are presented as either % (95% confidence intervals) or mean (standard deviation)
b Patients with marked or moderate improvement in 7-point quality of life scale

Table 4. Summary of Treatment Arm Results at Follow-up

	Baseline	6-Month	12-Month	24-Month Median [IQR]	36-Month Median [IQR]	Paired Change, Baseline to 12-Month Mean (95% CI)
Costanzo (2018)5,6,
Treatment arm alone, N	58	58	54	42	22a	54
AHI	49.7 + 18.9	25.9 + 20.5	23.0 + 21.9	16 [7, 37]	13 [8, 37]	-25.4 (-44.4 to -11.4)
CAI	31.7 + 18.6	6.0 + 9.2	3.4 + 6.9	0 [0, 3]	1 [0, 3]	-26.0 (-40.2 to -14.6)
OAI	2.1 + 2.2	6.3 + 7.0	4.5 + 5.1	3 [0, 8]	4 [1, 11]	0.9 (-0.5 to 4.4)
PGAb	NA	60% (47% to 72%)	60% (47% to 72%)			NA
ESS	10.7 + 5.3	7.1 + 4.1	6.5 + 3.5			-4.0 (-7.0 to -1.0)
Costanzo (2018)7,
Pooled HF subgroup, N	96	86	75			79
>50% AHI reduction	NA	53% (42% to 64%)	57% (45% to 68%)			NA
AHI	47.1 + 18.5	25.2 + 14.2	3.5 + 6.5			-19.9 (-34.6 to -11.8)
CAI	26.2 + 17.7	4.1 + 6.0	3.4 + 6.9			-26.0 (-40.2 to -14.6)
PGAb	NA	58% (NR)	55% (NR)			NA
ESS	8.9 + 5.1	6.2 + 4.1	6.1 + 3.7			-2.0 (-5.0 to 0.0)

AHI: Apnea-Hypopnea Index; CAI: central apnea index; CI: confidence interval; ESS: Epworth Sleepiness Scale; IQR; iinterquartile range; HF: heart failure; NA: not applicable; NR: not reported; OAI: obstructive apnea index; PGA: Patient Global Assessment; RCT: randomized controlled trial.

a Patients in the treatment group who had reached 36 months of follow-up prior to study closure
b Patients with marked or moderate improvement in 7-point quality of life scale

Abraham et al (2015)^8, and Jagielski et al (2016)^9, presented 6-month and 12-month results from a U.S. Food and Drug Administration regulated feasibility study of 47 patients with CSA of various etiologies who received phrenic nerve stimulation with the remede system (Table 5). Sleep disorder parameters were measured by polysomnography, through 12 months, with an optional sleep testing at 18 months. quality of life was measured on a 7-point scale, with patients answering the question, "How do you feel today compared with how you felt before having your device implanted?" CSA etiologies included HF (79%), other cardiac (13%), and opiate use (4%). Three deaths occurred during the study period, none attributed to the intervention. Five experienced serious adverse events, 3 at the beginning of the study (2 [hematoma, migraine] due to implantation procedure and 1 chest pain), and 2 during 12-months follow-up (pocket perforation and lead failure). A summary of sleep metric and quality of life results are presented in Table 6.

Table 5. Summary of Non-Comparative Study Characteristics

Study	Country	Participants	Follow-Up
Abraham (2015)8, and Jagielski (2016)9,	Germany, Italy, Poland, United States	Adult patients with a history of sleep apnea, predominantly CSA rather than OSA, and an AHI >20 events/hour	12 months (optional 18 months)

AHI: Apnea-Hypopnea Index; CSA: central sleep apnea; OSA: obstructive sleep apnea.

Table 6. Summary of Non-Comparative Study Results^8,9,

Outcome	Baseline(n=47) mean + SD	3 months(n=47) mean + SD	6 months(n=41) mean + SD	12 months (n=41) mean + SD	18 months (n=17) mean + SD
AHI, events/hour	49.9 + 14.6	22.4 + 13.6	23.8 + 13.1	27.5 + 18.3b	24.9 + 13.5b
CAI, events/hour	28.0 + 14.2	4.7 + 8.6	4.6 + 7.4	6.0 + 9.2b	4.8 + 5.8b
OAI, events/hour	3.0 + 2.9	3.9 + 4.7	3.9 + 5.4	4.5 + 6.0	5.6 + 6.2
4% ODI, events/hour	45.2 + 18.7	21.6 + 13.7	23.1 + 13.1	26.9 + 18.0b	25.2 + 13.7b
Arousal index, events/hour	36.2 + 18.8	23.7 + 10.6	25.1 + 12.5	32.1 + 15.2	26.8 + 9.2
QOL, % improvement from baselinea	NA	70.8%	75.6%	83.0%	NR

AHI: Apnea-Hypopnea Index; CAI: central apnea index; NA: not applicable; NR: not reported; OAI: obstructive apnea index; ODI: oxygen desaturation index; QOL: quality of life; RCT: randomized controlled trial; SD: standard deviation.

a Patients with marked or moderate improvement in 7-point quality of life scale
b p<0.006 compared to baseline

Section Summary: Phrenic Nerve Stimulation for Central Sleep Apnea

Evidence for the use of phrenic nerve stimulation therapy for the treatment of CSA consists of one RCT and observational studies. In the RCT, all patients were implanted with the phrenic nerve stimulation device, with the device activated in the intervention group at 1 month postimplantation and activated in the control group at 6 months postimplantation. The RCT provided 6 month comparative analyses showing significant improvements in sleep metrics as well as quality of life measures among patients with the activated stimulation device compared with patients receiving the inactivated device. Patients in the activated device arm were followed for 12 months, with analyses showing sustained significant improvements from baseline in sleep metrics and quality of life. A subgroup analyses was conducted on the subgroup of patients with HF, combining 6 and 12 month data from patients in the intervention group and 12 and 18 month data from the control group. Results from the subgroup analyses of patients with HF showed significant improvements in sleep metrics and quality of life at 12 months. An invasive procedure would typically be considered appropriate only if non-surgical treatments had failed, but there is very limited data in which phrenic nerve stimulation was evaluated in patients who had failed the current standard of care, positive airway pressure or respiratory stimulant medication.

Summary of Evidence

For individuals with CSA who receive phrenic nerve stimulation, the evidence includes one randomized controlled trial (RCT) and observational studies. Relevant outcomes are change in disease status, functional outcomes, and quality of life. The RCT compared the use of phrenic nerve stimulation to no treatment among patients with CSA of various etiologies. All patients received implantation of the phrenic nerve stimulation system, with activation of the system after 1 month in the intervention group and activation after 6 months in the control group. Activation is delayed one month after implantation to allow for lead healing. At 6 months follow-up, the patients with the activated device experienced significant improvements in several sleep metrics and quality of life measures. At 12 months follow-up, patients in the activated device arm showed sustained significant improvements from baseline in sleep metrics and quality of life. A subgroup analysis of patients with heart failure combined 6 and 12 month data from patients in the intervention group and 12 and 18 month data from the control group. Results from this subgroup analyses showed significant improvements in sleep metrics and quality of life at 12 months compared with baseline. Results from observational studies supported the results of the RCT. An invasive procedure would typically be considered only if non-surgical treatments had failed, but there is limited data in which phrenic nerve stimulation was evaluated in patients who had failed the current standard of care, positive airway pressure or respiratory stimulant medication. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
American Academy of Sleep Medicine

The American Academy of Sleep Medicine (2012) published a guideline on the treatment of central sleep apnea (CSA), based on results of a literature review and meta-analysis.^11, Moderate evidence supported the use of continuous positive airway pressure or adaptive servo-ventilation to treat CSA related to congestive heart failure. Limited evidence was available for the use of positive airway pressure therapy (continuous positive airway pressure, bilevel positive airway pressure, adaptive servo-ventilation) to treat primary CSA; however, there is potential for ameliorating central respiratory events, risks are low, and the therapies are readily available. The use of phrenic nerve stimulation devices were not discussed in the guideline. An update to the guideline, published in 2016,^12, adjusted the previous guideline, to warn that adaptive servo-ventilation is not recommended for individuals with CSA related to congestive heart failure with ejection fraction <45%. The use of phrenic nerve stimulation as a treatment option was not addressed in the guideline.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in March 2020 did not identify any ongoing or unpublished trials that would likely influence this review.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Phrenic Nerve Stimulation for Central Sleep Apnea
Central Sleep Apnea, Phrenic Nerve Stimulation
Apnea, Central Sleep, Phrenic Nerve Stimulation
remede System (Respicardia, Inc; Minnetonka, MN)
Respicardia, Inc remede System

References:
1. Donovan LM, Kapur VK. Prevalence and Characteristics of Central Compared to Obstructive Sleep Apnea: Analyses from the Sleep Heart Health Study Cohort. Sleep. Jul 01 2016; 39(7): 1353-9. PMID 27166235

2. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. N Engl J Med. Sep 17 2015; 373(12): 1095-105. PMID 26323938

3. Costanzo MR, Augostini R, Goldberg LR, et al. Design of the remede System Pivotal Trial: A Prospective, Randomized Study in the Use of Respiratory Rhythm Management to Treat Central Sleep Apnea. J Card Fail. Nov 2015; 21(11): 892-902. PMID 26432647

4. Costanzo MR, Ponikowski P, Javaheri S, et al. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial. Lancet. Sep 03 2016; 388(10048): 974-82. PMID 27598679

5. Costanzo MR, Ponikowski P, Javaheri S, et al. Sustained 12 Month Benefit of Phrenic Nerve Stimulation for Central Sleep Apnea. Am J Cardiol. Jun 01 2018; 121(11): 1400-1408. PMID 29735217

6. Fox H, Oldenburg O, Javaheri S, et al. Long-term efficacy and safety of phrenic nerve stimulation for the treatment of central sleep apnea. Sleep. Oct 21 2019; 42(11). PMID 31634407

7. Costanzo MR, Ponikowski P, Coats A, et al. Phrenic nerve stimulation to treat patients with central sleep apnoea and heart failure. Eur J Heart Fail. Dec 2018; 20(12): 1746-1754. PMID 30303611

8. Abraham WT, Jagielski D, Oldenburg O, et al. Phrenic nerve stimulation for the treatment of central sleep apnea. JACC Heart Fail. May 2015; 3(5): 360-369. PMID 25770408

9. Jagielski D, Ponikowski P, Augostini R, et al. Transvenous Stimulation of the Phrenic Nerve for the treatment of Central Sleep Apnoea: 12 Months' Experience with the Remede System. Eur J Heart Fail. 2016 Nov; 18(121): 1386-1393.

10. Fox H, Bitter T, Horstkotte D, et al. Long-Term Experience with First-Generation Implantable Neurostimulation Device in Central Sleep Apnea Treatment. Pacing Clin Electrophysiol. May 2017; 40(5): 498-503. PMID 28211952

11. 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. Jan 01 2012; 35(1): 17-40. PMID 22215916

12. 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. May 15 2016; 12(5): 757-61. PMID 27092695

13. Centers for Medicare and Medicaid Services. Local Coverage Determination: Transvenous Phrenic Nerve Stimulation in the Treatment of Central Sleep Apnea (A57548) 2019 https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=37929. Last Accessed April 2, 2020

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