| Coverage Policy Manual | |
| Policy #: | 2019002 |
| Category: | Medicine |
| Initiated: | May 2019 |
| Last Review: | May 2023 |
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| Phrenic Nerve Stimulation for Central Sleep Apnea | |
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| Description: |
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 Cheyne-Stokes breathing, a medical condition, drugs, or high altitude breathing. Cheyne-Stokes breathing is common among patients with heart failure or who have had strokes, and accounts for about half of the population with CSA. CSA is less common than obstructive sleep apnea (OSA). Based on analyses of a large community-based cohort in the Sleep Heart Health Study, the estimated prevalences of CSA and OSA are 0.9% and 47.6%, respectively (Donovan, 2016). Risk factors for CSA include age (>65 years), male gender, history of heart failure, 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.
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 heart failure 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 heart failure and with an ejection fraction >45% and who are not responding with CPAP and oxygen therapy, may consider bilevel positive airway pressure (BPAP) or adaptive servo-ventilation (ASV) as second-line therapy. BPAP devices have 2 pressure settings, 1 for inhalation and 1 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 heart failure and with an ejection fraction<45%, and therefore, ASV is not recommended for this group (Cowie, 2015).
For patients with hypoventilation-related CSA, first-line therapy is BPAP.
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
Currently, there is one phrenic nerve stimulation device approved by the Food and Drug Administration (FDA), the remedē® System (Respicardia, Inc.). The remedē® System is an implantable device that stimulates the phrenic nerve in the chest which sends signals to the diaphragm to restore a normal breathing pattern. A cardiologist implants the battery powered device under the skin in the right or left pectoral region. The procedure is conducted using local anesthesia. The device has 2 leads, 1 to stimulate a phrenic nerve (either the left pericardiophrenic or right brachiocephalic vein) and 1 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 granted approval for the remedē® System (Respicardia, Inc; Minnetonka, MN) through the premarket approval application process. The approved indication is for treatment of moderate to severe central sleep apnea in adults.
Coding
The following Category III CPT codes related to neurostimulator systems for treatment of central sleep apnea will be used to report this service:
0424T Insertion or replacement of neurostimulator system for treatment of central sleep apnea; complete system (transvenous placement of right or left stimulation lead, sensing lead, implantable pulse generator)
0425T Insertion or replacement of neurostimulator system for treatment of central sleep apnea; sensing lead only
0426T Insertion or replacement of neurostimulator system for treatment of central sleep apnea; stimulation lead only
0427T Insertion or replacement of neurostimulator system for treatment of central sleep apnea; pulse generator only
0428T Removal of neurostimulator system for treatment of central sleep apnea; pulse generator only
0429T Removal of neurostimulator system for treatment of central sleep apnea; sensing lead only
0430T Removal of neurostimulator system for treatment of central sleep apnea; stimulation lead only
0431T Removal and replacement of neurostimulator system for treatment of central sleep apnea, pulse generator only
0432T Repositioning of neurostimulator system for treatment of central sleep apnea; stimulation lead only
0433T Removal of neurostimulator system for treatment of central sleep apnea; sensing lead only
0434T Interrogation device evaluation implanted neurostimulator pulse generator system for central sleep apnea
0435T Programming device evaluation of implanted neurostimulator pulse generator system for central sleep apnea; single session
0436T Programming device evaluation of implanted neurostimulator pulse generator system for central sleep apnea; during sleep study
The following HCPCS code, may also be billed in relation to this service:
C1823 Generator, neurostimulator (implantable), non-rechargeable, with transvenous sensing and stimulation leads
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Policy/ Coverage: |
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of phrenic nerve stimulation for central sleep apnea does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, the use of phrenic nerve stimulation for central sleep apnea is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
This evidence review was created in April 2019 with searches of the MEDLINE database. The most recent literature update was performed through April 2020.
Costanzo et al (2015) provided background and methodologic details of the remedē® System Pivotal Trial (Costanzo, 2015). 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. 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 1 month after implantation to allow for lead healing. The primary efficacy endpoint is percentage of patients achieving a reduction in Apnea-Hypopnea Index (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, OD14, and Epworth Sleepiness Scale. Quality of life is measured by Patient Global Assessment (PGA), which consists of a 7-point scale (1="markedly improved" to 7="markedly worsened"). Of the 151 patients in the trial, 64% had heart failure, 42% had atrial fibrillation, and a mean left ventricular ejection fraction of 39.6. Six-month per protocol comparative results for the treatment and control groups were published in 2016 by Costanzo et al (Costanzo, 2016). 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.
Costanzo et al (2018) provided 12 months followup results for the intervention arm (Costanzo, 2018). At 6 months followup, 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 12 months followup, an additional 4 patients were lost due to unrelated death, device explant, patient refusal, and missed visit. 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, heart failure (yes/no), defibrillator (yes/no), AHI severity (moderate/severe), and atrial fibrillation (yes/no).
Costanza et al (2018) provided 12-months followup results for the subgroup of patients in the Pivotal Trial who had heart failure (Costanzo, 2018). Pooling of results was possible by using 6 and 12 month data from the intervention group and 12 and 18 month data from the control group (the phrenic nerve stimulator was activated in the control group 6 months after implantation). At baseline, 96 of the patients in the trial had heart failure. By the 6-month followup, there had been 4 deaths, 1 explant, and 5 withdrew from the study. By the 12-month followup, there had been an additional 5 deaths, 1 implant, and 1 withdrawal, as well as 4 missing the final visit.
Abraham et al and Jagielski et al presented 6-month and 12 month results from a cohort of 47 patients with CSA of various etiologies who received phrenic nerve stimulation with the remedē® System (Abraham, 2015; Jagielski, 2016). 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 heart failure (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 month followup (pocket perforation and lead failure).
Fox et al (2017) presented data on long term durability of remedē® System, measuring battery lifetime, device exchangeability, lead position stability, and surgical accessibility (Fox, 2017). Three consecutive patients, mean age 75.7 years, with CSA and HF with preserved ejection fraction were implanted with remedē® System phrenic nerve stimulation device due to intolerability of conventional mask therapy. Implantation occurred in 2011 and the patients were followed for 4 years. Mean battery life duration was 4.2+ 0.2 years. Therapy was well tolerated by the patients, with improvements sustained in AHI, oxygen desaturation index, and quality of life (measured by ESS). Mean device replacement procedure time was 23 minutes, under local anesthesia, with a 2 day hospital stay.
Evidence for the use of phrenic nerve stimulation therapy for the treatment of central sleep apnea consists of 1 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 heart failure, 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 heart failure showed significant improvements in sleep metrics and quality of life at 12 months. No RCTs were identified which compared phrenic nerve stimulation with the current standard treatment for patients with CSA, positive airway pressure of respiratory stimulation medication.
For individuals with central sleep apnea who receive phrenic nerve stimulation, the evidence includes 1 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 central sleep apnea 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 1 month after implantation to allow for lead healing. At 6 months followup, the patients with the activated device experienced significant improvements in several sleep metrics and quality of life measures. At 12 months followup, 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. No RCTs were identified in which phrenic nerve stimulation was compared with 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.
PRACTICE GUIDELINES AND POSITION STATEMENTS
American Academy of Sleep Medicine
In 2012, the American Academy of Sleep Medicine (AASM) published a guideline on the treatment of CSA, based on results of a literature review and meta-analysis (Aurora, 2012). Moderate evidence supported the use of CPAP or adaptive servo-ventilation (ASV) to treat CSA related to congestive heart failure (CHF). Limited evidence was available for the use of positive airway pressure therapy (CPAP, BPAP, ASV) 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 adjusted the previous guideline, to warn that ASV is not recommended for individuals with CSA related to CHF with ejection fraction<45% (Aurora, 2012). The use of phrenic nerve stimulation as a treatment option was not addressed in the guideline.
ONGOING AND UNPUBLISHED CLINICAL TRIALS
A currently ongoing trial that might influence this review is listed below.
NCT03238937 Treatment of Central Sleep Apnea in Patients with Heart Failure with a cervically Implanted Phrenic Nerve Stimulator
Planned Enrollment: 40 Completion Date: Jul 2022
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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 (Fox, 2019). 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.
There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers. A 2019 review by National Government Services, Inc concluded that there is insufficient evidence to show that transvenous phrenic neurostimulation is reasonable and necessary for the treatment of CSA in the Medicare population (L37929) (CMS, 2020).
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
At the 5-year follow-up(N=52) of the remedē System Pivotal Trial, AHI events remained low (median=17 events/hour), and ESS improved by a median of 3 points (Costanzo, 2021). A total of 14%of patients reported a serious adverse event, but no long-term harm or device-related death occurred.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement.
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| References: |
Abraham, WW, Jagielski, DD, Oldenburg, et al.(2015) Phrenic nerve stimulation for the treatment of central sleep apnea. JACC Heart Fail, 2015 Mar 17;3(5). PMID 25770408. Aurora, RR, Bista, SS, Casey, KK, et al.(2012) Updated Adaptive Servo-Ventilation Recommendations for the 2012 AASM Guideline. 2012 AASM Guideline. Aurora, RR, Chowdhuri, SS, Ramar, et al.(2012) The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep, 2012 Jan 5;35(1). PMID 22215916. Centers for Medicare and Medicaid Services (CMS).(2019) 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 Costanzo MR, Javaheri S, Ponikowski P, et al.(2021) Transvenous Phrenic Nerve Stimulation for Treatment of CentralSleep Apnea: Five-Year Safety and Efficacy Outcomes. Nat Sci Sleep. 2021; 13: 515-526. PMID 33953626 Costanzo, MM, Augostini, RR, Goldberg, LL, et al.(2015) Design of the remedÄ“ System Pivotal Trial: A Prospective, Randomized Study in the Use of Respiratory Rhythm Management to Treat Central Sleep Apnea. J. Card. Fail., 2015 Oct 4;21(11). PMID 26432647. Costanzo, MM, Ponikowski, PP, Coats, AA, et al.(2018) Phrenic nerve stimulation to treat patients with central sleep apnoea and heart failure. Eur. J. Heart Fail., 2018 Oct 12;20(12). PMID 30303611. Costanzo, MM, Ponikowski, PP, Javaheri, SS, et al.(2016) Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial. Lancet, 2016 Sep 7;388(10048). PMID 27598679. Costanzo, MM, Ponikowski, PP, Javaheri, SS, et al.(2018) Sustained 12 Month Benefit of Phrenic Nerve Stimulation for Central Sleep Apnea. Am. J. Cardiol., 2018 May 8;121(11). PMID 29735217. Cowie, MM, Woehrle, HH, Wegscheider, KK, et al.(2015) Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. N. Engl. J. Med., 2015 Sep 2;373(12). PMID 26323938. Donovan LM, Kapur VK.(2016) Prevalence and characteristics of central compared to obstructive sleep apnea: analyses from the Sleep Heart Health Study cohort. Sleep 2016;39(7):1353-9. PMID: 27166235. Fox H, Oldenburg O, Javaheri S, et al.(2019) Long-term efficacy and safety of phrenic nerve stimulation for the treatment of central sleep apnea. Sleep. Oct 21 2019; 42(11). PMID 31634407 Fox, HH, Bitter, TT, Horstkotte, DD, et al.(2017) Long-Term Experience with First-Generation Implantable Neurostimulation Device in Central Sleep Apnea Treatment. Pacing Clin Electrophysiol, 2017 Feb 18;40(5). PMID 28211952. Jagielski, DD, Ponikowski, PP, Augostini, et al.(2016) Transvenous stimulation of the phrenic nerve for the treatment of central sleep apnoea: 12 months' experience with the remedÄ“® System.. Eur. J. Heart Fail., 2016 Nov 5;18(11). PMID 27373452. |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |
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