Medical Policy: 07.01.77
Original Effective Date: October 2018
Reviewed: October 2019
Revised:
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Patients with high-level vertebrae C1-C3 spinal cord injuries typically experience respiratory muscle paralysis leading to chronic ventilatory insufficiency. The standard therapy for these patients is chronic mechanical ventilation via tracheostomy.
Non-invasive ventilation (NIV) such as positive ventilation or bilevel positive airway pressure is currently the first line treatment for amyotrophic lateral sclerosis (ALS) patients experiencing symptoms of respiratory insufficiency. At some point ALS affects the respiratory muscles so severely that bulbar paresis is combined with severe expiratory and inspiratory muscle weakness. There is a significant risk of impending respiratory failure or death and invasive ventilation becomes the only option for survival.
Diaphragmatic/phrenic nerve stimulation, is an alternative to mechanical ventilation for a select subgroup of patients. Diaphragmatic/phrenic nerve stimulation, also referred to phrenic pacing, phrenic nerve stimulation, diaphragm pacing, or electrophrenic respiration, is the electrical stimulation of the diaphragm via the phrenic nerve, the major nerve supply to the diaphragm that controls breathing. Patients with partial or complete respiratory insufficiency who have an intact phrenic nerve and diaphragm may be eligible for diaphragmatic/phrenic nerve stimulation. The patient should be alert, mentally competent, motivated and able to complete the training and rehabilitation needed for a successful outcome. Prior to implantation patients may undergo diaphragm electromyography, pulmonary function studies and/or polysomnograpy (i.e. sleep study). Common indications include patients with high quadriplegia (spinal cord injury) at or above C-3, chronic central alveolar hypoventilation syndrome, and amyotrophic lateral sclerosis ALS.
The Avery Breathing Pacemaker System (that is, the Mark IV™ Avery Biomedical Device, Inc., Commack, NY), surgically implanted (i.e. thoracotomy approach) by placing an electrode behind the phrenic nerve, either in the neck or in the chest. The electrode is connected to a radiofrequency receiving (generator) which is implanted just under the skin which are connected to an external transmitter and antennas to send radiofrequency energy to the implanted receivers. The receivers then convert the radio waves into stimulation pulses. These pulses are then sent down the electrodes to the phrenic nerves, causing the diaphragm to contract. This contraction causes the patient to inhale. When the pulses stop, the diaphragm relaxes and the patient exhales. Repetition of this series of pulses produces a normal breathing pattern.
Nonrandomized comparative studies, prospective case series and retrospective reviews have reported that the Mark IV device is a safe and effective alternative to invasive mechanical ventilation and is considered an established alternative therapy in appropriate candidates (upper motor neuron respiratory muscle paralysis [spinal cord injury]; central alveolar hypoventilation). Clinical trials with up to ten years follow-up reported success rates of 73%-94% in patients with spinal cord injuries.
The NeuRx system (NeuRx DPS and NeuRx DPS RA/4) (Synapse Biomedical, Inc., Oberlin, OH) is performed laparoscopically to avoid the need for cervical or thoracic access to the phrenic nerve and potential risks of phrenic nerve damage. The system includes four electrodes implanted in the diaphragm to provide muscle stimulation, a fifth electrode implanted under the skin which grounds the system and completes the circuit, an electrode connector which groups the five electrodes exiting the skin into a socket, an external pulse generator (EPG) and removal cable to connect the electrode socket to the EPG. The NeuRx EPG sends electrical signals to the diaphragm i.e. inhalation upon electrical stimulation and exhalation on cessation of stimulation.
The NeuRx DPS received FDA approval under an HDE (Humanitarian Device Exemption) application for use in amyotrophic lateral sclerosis (ALS) patients (see regulatory information below) and NeuRx DPS RA/4 received FDA approval under an HDE (Humanitarian Device Exemption) for use in patients with stable, high spinal cord injuries (see regulatory information below). In order to receive HDE approval, a manufacturer must first be granted a Humanitarian Use Device (HUD) exemption by demonstrating that the device is designed to treat or diagnose a disease or condition that affects fewer than 4,000 people in the U.S. per year. Although data demonstrating the safety and probable clinical benefit are required for HDE approval, clinical trials evaluating the effectiveness of the device are not required. Following HDE approval, the hospital or health care facility institutional review board (IRB) must also approve the use of the device at the institution before the device may be used in the patient.
The Remede system (Respicardia, Inc., Minneapolis, MN) is an implanted nerve stimulator used to treat moderate to severe central sleep apnea (CSA) in adults. The system includes a battery powered pulse generator that is implanted under the skin in the upper chest and thin wire leads that are threaded through veins (transvenous) near the nerve that stimulates breathing (phrenic nerve). The system is programmed using an external system programmer and programming wand. The Remede system delivers a small electrical stimulus to the phrenic nerve while a patient is asleep. This stimulus makes the diaphragm muscle contract, which causes the patient to take a breath. The Remede system has 2 modes, it can be set to generate pulses at a fixed rate (asynchronous therapy) or it can deliver a pulse only when it detects a pause in breathing (synchronous therapy). The physician is able to set the stimulator to deliver the most appropriate therapy for the patient. The system has safeguards to make sure that therapy is only delivered during sleep, for example it works only at the time of day when the patient is expected to be sleeping and it turns on only when the patient is inactive and lying down.
The FDA approval of the Remede system is based on an industry-supported, multicenter, prospective, randomized controlled sham study that aimed to determine the safety and effectiveness for treatment central sleep apnea (CSA) (Costanza et. al., 2016). A total of 151 adult subjects were randomized to receive either medical management and the Remede system (n=73),or medical management and inactive sham Remede system (n=78). The subjects in the study were an average of 65 years old and predominately Caucasian (95%) and males (89%). The primary endpoint was a 50% or greater reduction in AHI from baseline at 6 months, and the AHI was determined using polysomnography. Subjects were evaluated regularly until the end of the trial. After 6 months, the Remede system was activated in the sham group. Effectiveness was based on modified intention to treat (ITT) data at 6 months (n=141). A significant higher number of subjects in the active Remede system group had a 50% or better reduction in AHI from baseline to 6 months post-procedure (p<0.0001). The success rate for the active Remede system group was 51% compared to 11% in the sham group for a total difference of 41% (95% CI, 25% to 51%; p<0.0001). A total of 76% of subjects in the Remede system group reported improvement in quality of life. Safety results were based on intention to treat (ITT) data for 12 months (n=151). There were 7 deaths but none found to be related to the device or treatment. The number of subjects free from serious adverse events (AEs) was 91% (95% CI, 86% to 95%); however, 13 subjects had serious AEs including impending pocket erosion, implant site infection, lead dislodgement, concomitant device interaction, elevated transaminase, extra-respiratory stimulation, implant site hematoma, lad component failure, lead displacement, and non-cardiac chest pain. The number of subjects who experienced non-serious AEs were 48%. Implants were unsuccessful in 5 subjects, and the rate of explants was 5.3% (8/151). The authors concluded that transvenous neurostimulation could provide a treatment option for central sleep apnea. Limitations of the study included low percentage of female subjects and potential referral bias.
In 2015, Abraham et. al. evaluated transvenous unilateral phrenic nerve stimulation to treat central sleep apnea (CSA) in a prospective, multicenter, nonrandomized study. Fifty-seven patients with CSA underwent baseline polysomnography followed by transvenous phrenic nerve stimulation system implantation and follow-up. Feasibility was assessed by implantation success rate and therapy delivery. Safety was evaluated by monitoring of device- and procedure-related adverse events. Efficacy was evaluated by changes in the apnea-hypopnea index at 3 months. Quality of life at 6 months was evaluated using a sleepiness questionnaire, patient global assessment, and, in patients with heart failure at baseline, the Minnesota Living With Heart Failure Questionnaire. The study met its primary end point, demonstrating a 55% reduction in apnea-hypopnea index from baseline to 3 months (49.5 ± 14.6 episodes/h vs. 22.4 ± 13.6 episodes/h of sleep; p < 0.0001; 95% confidence interval for change: -32.3 to -21.9). Central apnea index, oxygenation, and arousals significantly improved. Favorable effects on quality of life and sleepiness were noted. In patients with heart failure, the Minnesota Living With Heart Failure Questionnaire score significantly improved. Device- or procedure-related serious adverse events occurred in 26% of patients through 6 months post therapy initiation, predominantly due to lead repositioning early in the study. Therapy was well tolerated. Efficacy was maintained at 6 months. The authors concluded, transvenous unilateral phrenic nerve stimulation appears safe and effective for treating CSA, and these findings should be confirmed in a prospective randomized, controlled trial (NCT01124370).
In 2016, Jagielski et. al. evaluated the 12 month clinical outcomes of patients with central sleep apnea (CSA) treated with unilateral transvenous phrenic nerve stimulation in the prospective, multi-center, non-randomized Remede system pilot study. Forty-seven patients with CSA were treated with the Remede system for a minimum of 3 months. Sleep disordered breathing parameters were evaluated by polysomnography (PSG) as 3, 6 and 12 month follow-up. Sleep symptoms and quality of life were also evaluated, Forty-one patients completed all follow-up PSGs and were included in the analysis. At 12 months, there was sustained improvement compared with baseline in the apnea-hypopnea index, central apnea index and there was sustained improvement in the oxygen desaturation index, rapid eye movement sleep and sleep efficiency. There were continued favorable effects on sleepiness and quality of life. Three deaths unrelated to Remede system therapy and five serious adverse events occurred over 12 months of follow-up. The authors noted the main limitations of the study were the non-randomized, open-label nature of the trial, the small sample size, the small number of women enrolled in the study, and the fact that many of the parameters studied were only exploratory and hypothesis-generating and the results should be confirmed with future larger, randomized, controlled studies.
In 2018, Costanza et. al. reported the 12 month results from Remede system pivotal trial (see above) to evaluate the benefits of this therapy for central sleep apnea (CSA). Reproducibility of treatment effect was assessed in the former control group in whom the implanted device was initially inactive for the sixth month and subsequently activated when the randomized control assessments were complete. Patients with moderate-to-severe central sleep apnea implanted with the Remede system were randomized to therapy activation at 1 month (treatment) or after 6 months (control). Sleep indices were assessed from baseline to 12 months in the treatment group and from 6 to 12 months in former controls. In the treatment group, a ≥50% reduction in apnea-hypopnea index occurred in 60% of patients at 6 months (95% confidence interval [CI] 47% to 64%) and 67% (95% CI 53% to 78%) at 12 months. After 6 months of therapy, 55% of former controls (95% CI 43% to 67%) achieved ≥50% reduction in apnea-hypopnea index. Patient Global Assessment was markedly or moderately improved at 6 and 12 months in 60% of treatment patients. Improvements persisted at 12 months. A serious adverse event within 12 months occurred in 13 patients (9%). Phrenic nerve stimulation produced sustained improvements in sleep indices and quality of life to at least 12 months in patients with central sleep apnea. The similar improvement of former controls after 6 months of active therapy confirms benefits are reproducible and reliable.
Based on review of the peer reviewed medical literature the evidence to date is insufficient regarding the safety and effectiveness of the Remede system for the treatment of central sleep apnea (CSA) with only 12 months of outcome data available from single randomized controlled sham study. The device has also not been compared with CPAP or other therapies for central sleep apnea (CSA). Further large, randomized, comparative, controlled studies are needed to determine the safety and efficacy, and the further studies also need to help define optimal patient selection and assess-long term outcomes. The evidence is insufficient to determine the effects of this technology on net health outcomes.
In 2009 (reaffirmed in 2017), the American Academy of Neurology (AAN) issued a practice parameter update on the care of the patient with amyotrophic lateral sclerosis (ALS): drug, nutritional and respiratory therapies an evidence based review. The recommendations in this practice parameter update does not mention diaphragmatic/phrenic nerve stimulation or diaphragm pacing as a treatment.
In 2010, the American Thoracic Society clinical policy statement on congenital central hypoventilation syndrome in their discussion of the diagnosis and management of children with congenital central hypoventilation syndrome (CCHS) which states: diaphragm pacers can be used for daytime support of ambulatory children who require full-time ventilator support, in combination with positive pressure ventilation at night.
In 2016, the American Academy of Sleep Medicine (AASM) issued an updated guideline on the treatment of central sleep apnea syndromes in adults with an evidence based literature review and meta-analysis. This guideline does not include diaphragmatic/phrenic nerve stimulation or diaphragm pacing as a recommended treatment for this condition.
In 2017, ACC/AHA/HFSA issued a focused update of the 2015 ACCP/AHA guideline for the management of heart failure which includes the following recommendations regarding sleep disordered breathing:
This guideline does not include diaphragmatic/phrenic nerve stimulation or diaphragm pacing as a recommended treatment for heart failure management.
The Avery Breathing Pacemaker System (that is, the Mark IV™ Avery Biomedical Device, Inc., Commack, NY) is the only other diaphragmatic/phrenic stimulator system cleared for use by the FDA in the United States for ventilator-dependent individuals. The pacemaker is classified as a Class III neurologic therapeutic device requiring premarket approval (PMA). The device is approved “for persons who require chronic ventilatory support because of upper motor neuron respiratory muscle paralysis (RMP) or because of central alveolar hypoventilation (CAH) and whose remaining phrenic nerve, lung, and diaphragm function is sufficient to accommodate electrical stimulation” (FDA, 2003). Clinical trials that have studied the efficacy of this device have been very limited and included small numbers of subjects.
FDA clearance for distribution of the NeuRx DPS RA/4 Respiratory Stimulation System was granted under a Humanitarian Device Exemption (HDE) on June 17, 2008. The FDA-approved indications are:
This FDA approval is subject to the manufacturer developing “an acceptable method of tracking device implantation to individual patient recipients” (FDA, 2008).
FDA clearance of the NeuRx device was primarily based on a prospective, nonrandomized, multicenter clinical trial that included 50 subjects throughout the U.S. and Canada (Onders, 2009). In the clinical trial, 98% of subjects with spinal cord injury were able to breathe normally for at least 4 hours following implantation of the device, while 50% have been able to completely eliminate their need for mechanical ventilation.
The study inclusion criteria were:
Exclusion criteria were:
On September 28, 2011, the FDA issued an approval under an HDE application for use of the NeuRx DPS Diaphragm Pacing System in:
This approval was based on results of a multicenter, prospective study of the NeuRx Diaphragm Pacing Stimulation (DPS) System of motor-point stimulation for conditioning the diaphragm of subjects with ALS which showed the probable benefit to health from use of the device outweighed the risks of injury or illness from its use (FDA/HDE; SSPB, 2011).
The Remede System was approved by the FDA on October 6, 2017 for the treatment of moderate to severe central sleep apnea in adult individuals. The manufacturer describes the device as:
Not applicable
Diaphragmatic/phrenic nerve stimulation with the Mark IV system as an alternative to mechanical ventilation is considered medically necessary when all of the following criteria is met:
The NeuRx DPS RA/4 Respiratory Stimulation System as an alternative to mechanical ventilation is considered medically necessary when provided in accordance with the Humanitarian Device Exemption (HDE) specifications of the U.S. Food and Drug Administration when all of the following criteria is met:
The NeuRx DPS Diaphragm Pacing System as an alternative to mechanical ventilation is considered medically necessary when provided in accordance with the Humanitarian Device Exemption (HDE) specifications of the U.S. Food and Drug Administration when all of the following criteria is met:
Replacement or revisions of diaphragm/phrenic nerve stimulation and diaphragm pacing systems (generator and/or leads) is considered medically necessary if the individual meets the above criteria, and is no longer under warranty or cannot be repaired.
Diaphragm/phrenic nerve stimulation and diaphragm pacing systems are considered investigational for all other indications including but not limited to the following:
Based on review of the peer reviewed medical literature the evidence is insufficient to determine the effects of this technology on net health outcomes for indications other than the ones listed above. Further large, randomized, comparative, controlled studies are needed to determine the safety and efficacy, and the further studies also need to help define optimal patient selection and assess-long term outcomes.
Diaphragm Fluoroscopy (Sniff Test): a diaphragm fluoroscopy (sniff test) checks how the diaphragm (the muscle that controls breathing) moves when an individual breathes normally and when they inhale quickly. The diaphragm normally moves down when a person inhales, and up when a person exhales. Both the right and left sides of the diaphragm should move in the same direction at the same time. This test shows if there are problems with the phrenic nerve, which controls movement of the diaphragm.
Stimulation of the phrenic nerve may be performed by percutaneously stimulating the phrenic nerve in the neck and assessing diaphragmatic movements.
A provider may utilize electromyography (EMG) or nerve conduction studies to assess phrenic nerve function.
To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.
Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc. They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.
*CPT® is a registered trademark of the American Medical Association.