STAR Trial 12 month follow-up:
Strollo, et al. for the STAR Trial Group evaluated the clinical safety and effectiveness of upper-airway stimulation at 12 months for the treatment of moderate-to-severe obstructive sleep apnea1. The study included 126 participants; 83% were men. The mean age was 54.5 years, and the mean BMI was 28.4. Exclusion criteria were a BMI of more than 32.0, neuromuscular disease, hypoglossal-nerve palsy, severe restrictive or obstructive pulmonary disease, moderate-to-severe pulmonary arterial hypertension, severe valvular heart disease, New York Heart Association class III or IV heart failure, recent myocardial infarction or severe cardiac arrhythmias (within the past 6 months), persistent uncontrolled hypertension despite medication use, active psychiatric disease, and coexisting nonrespiratory sleep disorders that would confound functional sleep assessment. The study was designed by the sponsor (Inspire Medical Systems), the investigators, and the FDA as a multicenter, prospective, single-group trial with participants serving as their own controls. The primary outcome evaluation was followed by a randomized, controlled therapy-withdrawal study that included a subgroup of consecutive participants selected from the population that had a response to therapy. The primary outcome measures were assessed by means of overnight polysomnography and scored by an independent core laboratory with the use of standard criteria. The data analysis was performed by the independent statistician.
Participants underwent screening that included polysomnography, medical and surgical consultation, and endoscopy during drug-induced sleep. Participants were excluded if the AHI score from the screening polysomnography was less than 20 or more than 50 events per hour, if central or mixed sleep-disordered breathing events accounted for more than 25% of all apnea and hypopnea episodes, or if the AHI score while the person was not in a supine position was less than 10 events per hour. Participants were also excluded if pronounced anatomical abnormalities preventing the effective use or assessment of upper-airway stimulation were identified during the surgical consultation (e.g., tonsil size of 3 or 4 [tonsils visible beyond the pillars or extending to midline]) or if complete concentric collapse at the retropalatal airway was observed on endoscopy performed during drug-induced sleep. Qualified participants underwent a surgical procedure to implant the upper-airway stimulation system (Inspire Medical Systems). The stimulation electrode was placed on the hypoglossal nerve to recruit tongue-protrusion function; the sensing lead was placed between the internal and external intercostal muscles to detect ventilatory effort; the neurostimulator was implanted in the right ipsilateral mid-infraclavicular region.
The primary outcome was the change in the severity of obstructive sleep apnea in the study population, as assessed by means of the AHI and the oxygen desaturation index (ODI; the number of times per hour of sleep that the blood oxygen level drops by greater than or equal to 4 percentage points from baseline). The co-primary outcome was the proportion of participants with a response from baseline to 12 months with respect to the primary outcome measures of the AHI and ODI scores. A response as measured by means of the AHI was defined as a reduction of at least 50% from baseline in the AHI score and an AHI score on the 12-month polysomnography of less than 20 events per hour. The ODI was chosen as a stable integrative outcome value of all forms of sleep-disordered breathing. A response as measured by means of the ODI was defined as a reduction of at least 25% from baseline in the ODI score. The prespecified primary efficacy objectives were response rates of at least 50%, as assessed by means of the AHI and ODI. All participants who received an implant were included in the primary outcome analysis; participants who did not complete the 12-month visit were considered not to have had a response.
Secondary outcome measures included self-reported sleepiness and disease-specific quality of life as assessed with the use of the Epworth Sleepiness Scale (scores range from 0.0 to 24.0, with higher scores indicating more daytime sleepiness), disease-specific quality of life, as assessed with the use of the Functional Outcomes of Sleep Questionnaire (FOSQ; scores range from 5.0 to 20.0, with higher scores indicating greater functioning), and the percentage of sleep time with the oxygen saturation less than 90%.
At the 12-month visit, the first 46 consecutive participants who met the criterion of having a response to therapy were randomly assigned, in a 1:1 ratio, to the therapy-maintenance group or the therapy-withdrawal group1. This design filtered out persons who had not had a response to therapy. The therapy-withdrawal group had the device turned off for 7 days, whereas the therapy-maintenance group continued with the device turned on. Polysomnography was performed after the randomization period to measure the effects of therapy withdrawal, as compared with continued use of the therapy.
The scores on the AHI and ODI (primary outcome measures) were lower (indicating fewer episodes of sleep apnea) at 12 months than at baseline. The median AHI score decreased 68%, from the baseline value of 29.3 events per hour to 9.0 events per hour. The median ODI score decreased 70%, from 25.4 events per hour to 7.4 events per hour. At the 12-month visit, the criteria for the coprimary outcome of a reduction of at least 50% in the AHI score from baseline and an AHI score of less than 20 events per hour were met by 66% of the participants (83 of 126 participants; lower boundary of the 97.5% confidence interval [CI], 57). The criterion for the coprimary outcome of a reduction of at least 25% in the ODI score from baseline was met by 75% of participants (94 of 126; lower boundary of the 97.5% CI, 66). Both primary efficacy outcomes exceeded the predefined study objectives.
Scores on the FOSQ and Epworth Sleepiness Scale indicated significant improvement at 12 months, as compared with baseline. The median percentage of sleep time with the oxygen saturation less than 90% decreased from a baseline value of 5.4% to 0.9% at 12 months. The average increase in the AHI score in the therapy-withdrawal group was 18.2 events per hour, whereas the average increase in the therapy-maintenance group was 1.7 events per hour (difference in changes in mean scores, 16.4±12.0 events per hour; P less than 0.001). A similar effect was observed with respect to the mean ODI scores.
Two participants had a serious device-related adverse event requiring repositioning and fixation of the neurostimulator to resolve discomfort. No permanent tongue weakness was reported during the study. Most of the device-related events that were not considered to be serious resolved after the participants acclimated to the upper-airway stimulation therapy or after the device was reprogrammed to adjust the stimulation variables.
The daily use of upper-airway stimulation was 86%, as assessed on the basis of self-report. A control group of therapeutic CPAP users (i.e., a comparative-effectiveness design) would be impractical, given the current study design.
The randomized, controlled therapy-withdrawal study in which some participants had the therapy turned off for 1 week provided evidence that the therapeutic effect established at 12 months was attributable to the upper-airway stimulation therapy, rather than variability in the AHI score.
STAR Trial 18 month follow-up:
Dedhia, et al. for the STAR Trial Group evaluated the stability of improvement in polysomnographic measures of sleep disordered breathing, patient reported outcomes, the durability of hypoglossal nerve recruitment and safety at 18 months in the Stimulation Treatment for Apnea Reduction (STAR) trial participants2. This was a prospective multicenter single group trial with participants serving as their own controls. Primary outcome measures were the apnea-hypopnea index (AHI) and the 4% oxygen desaturation index (ODI). Secondary outcome measures were the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire (FOSQ), and oxygen saturation percent time < 90% during sleep. Stimulation level for each participant was collected at three predefined thresholds during awake testing. Procedure- and/or device-related adverse events were reviewed and coded by the Clinical Events Committee.
The median AHI was reduced by 67.4% from the baseline of 29.3 to 9.7/h at 18 months. The median ODI was reduced by 67.5% from 25.4 to 8.6/h at 18 months. The FOSQ and ESS improved significantly at 18 months compared to baseline values. The functional threshold was unchanged from baseline at 18 months. Two participants experienced a serious device-related adverse event requiring neurostimulator repositioning and fixation. No tongue weakness reported at 18 months.
The authors concluded that upper airway stimulation via the hypoglossal nerve maintained a durable effect of improving airway stability during sleep and improved patient reported outcomes (Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire) without an increase of the stimulation thresholds or tongue injury at 18 months of follow-up.
STAR Trial 24 month follow-up:
On behalf of the STAR Trial Investigators evaluated the long-term (24-month) effect of cranial nerve upper airway stimulation (UAS) therapy on patient-centered obstructive sleep apnea (OSA) outcome measures3. This was a prospective, multicenter, cohort study of 126 patients with moderate to severe OSA who had difficulty adhering to positive pressure therapy and received the surgically implanted UAS system. Outcomes were measured at baseline and postoperatively at 12 months and 24 months, and included self- and bedpartner-report of snoring intensity, Epworth Sleepiness Scale (ESS), and Functional Outcomes of Sleep Questionnaire (FOSQ). Additional analysis included FOSQ subscales, FOSQ-10, and treatment effect size.
Significant improvement in mean FOSQ score was observed from baseline (14.3) to 12 month (17.3), and the effect was maintained at 24 month (17.2). Similar improvements and maintenance of effect were seen with all FOSQ subscales and FOSQ-10. Subjective daytime sleepiness, as measured by mean ESS, improved significantly from baseline (11.6) to 12 month (7.0) and 24 month (7.1). Self-reported snoring severity showed increased percentage of "no" or "soft" snoring from 22% at baseline to 88% at 12 months and 91% at 24 mo. UAS demonstrated large effect size (greater than 0.8) at 12 and 24 months for overall ESS and FOSQ measures, and the effect size compared favorably to previously published effect size with other sleep apnea treatments.
The authors concluded that in a selected group of patients with moderate to severe OSA and body mass index less than or equal to 32 kg/m2, hypoglossal cranial nerve stimulation therapy can provide significant improvement in important sleep related quality-of-life outcome measures and the effect is maintained across a 2-year follow-up period.
STAR Trial 36 month follow-up:
On behalf of the STAR Trial Investigators describe the 36-month clinical and polysomnography (PSG) outcomes in an obstructive sleep apnea (OSA) cohort treated with hypoglossal cranial nerve upper airway stimulation (UAS)4.
Of 126 enrolled participants, 116 (92%) completed 36-month follow-up evaluation per protocol; 98 participants additionally agreed to a voluntary 36-month PSG. Self-report daily device usage was 81%. In the PSG group, 74% met the apriori definition of success with the primary outcomes of apnea-hypopnea index, reduced from the median value of 28.2 events per hour at baseline to 8.7 and 6.2 at 12 and 36 months, respectively. Similarly, self-reported outcomes improved from baseline to 12 months and were maintained at 36 months. Soft or no snoring reported by bed partner increased from 17% at baseline to 80% at 36 months. Serious device-related adverse events were rare, with 1 elective device explanation from 12 to 36 months.
The authors concluded that long-term 3-year improvements in objective respiratory and subjective quality-of-life outcome measures are maintained. Adverse events are uncommon. UAS is a successful and appropriate long-term treatment for individuals with moderate to severe OSA.
STAR Trial 48 month follow-up:
On behalf of the STAR Trial Investigators assess patient-based outcomes of participants in a large multicenter prospective cohort study-the STAR trial-48 months after implantation with an upper airway stimulation system for moderate to severe obstructive sleep apnea5.
A total of 91 subjects completed the 48-month visit. Daytime sleepiness as measured by ESS was significantly reduced (P equal to .01), and sleep-related quality of life as measured by FOSQ significantly improved (P equal to .01) when compared with baseline. Soft to no snoring was reported by 85% of bed partners. Two patients required additional surgery without complication for lead malfunction.
The authors concluded that upper airway stimulation maintained a sustained benefit on patient-reported outcomes (ESS, FOSQ, snoring) at 48 months in select patients with moderate to severe obstructive sleep apnea.
STAR Trial 5 year outcomes:
On behalf of the STAR Trial Investigators present 5-year outcomes from a multicenter prospective cohort of patients with obstructive sleep apnea (OSA) who were treated with upper airway stimulation (UAS) via a unilateral hypoglossal nerve implant6. From a cohort of 126 patients, 97 completed protocol, and 71 consented to a voluntary polysomnogram. Those having continuous positive airway pressure failure with moderate to severe OSA, body mass index less than 32 kg/m2, and no unfavorable collapse on drug-induced sleep endoscopy were enrolled in a phase 3 trial. Prospective outcomes included apnea-hypopnea index (AHI), oxygen desaturation index, and adverse events, as well as measures of sleepiness, quality of life, and snoring.
Patients who did and did not complete the protocol differed in baseline AHI, oxygen desaturation index, and Functional Outcomes of Sleep Questionnaire scores but not in any other demographics or treatment response measures. Improvement in sleepiness (Epworth Sleepiness Scale) and quality of life was observed, with normalization of scores increasing from 33% to 78% and 15% to 67%, respectively. AHI response rate (AHI less than 20 events per hour and greater than 50% reduction) was 75% (n equal to 71). When a last observation carried forward analysis was applied, the responder rate was 63% at 5 years. Serious device-related events all related to lead/device adjustments were reported in 6% of patients.
The authors concluded that there were improvements in sleepiness, quality of life, and respiratory outcomes are observed with 5 years of UAS. Serious adverse events are uncommon. UAS is a nonanatomic surgical treatment with long-term benefit for individuals with moderate to severe OSA who have failed nasal continuous positive airway pressure.
Evidence-Based Practice Guidelines and Position Statements
American Academy of Sleep Medicine
The American Academy of Sleep Medicine (AASM) Clinical Practice Guideline for Diagnostic Testing for Adult OSA states that the third edition of the International Classification of Sleep Disorders (ICSD-3) defines OSA as a PSG-determined obstructive respiratory disturbance index (RDI) greater than or equal to 5 events/hour associated with the typical symptoms of OSA (e.g., unrefreshing sleep, daytime sleepiness, fatigue or insomnia, awakening with a gasping or choking sensation, loud snoring, or witnessed apneas), or an obstructive RDI greater than or equal to 15 events/hour (even in the absence of symptoms).
American Academy of Otolaryngology Head and Neck Surgery (AAO-HNS)
In 2016, the American Academy of Otolaryngology Head and Neck Surgery issued a position statement on hypoglossal nerve stimulation for treatment of obstructive sleep apnea (OSA) which states “The American Academy of Otolaryngology Head and Neck Surgery considers upper airway stimulation (UAS) via the hypoglossal nerve for the treatment of adult obstructive sleep apnea syndrome to be an effective second-line treatment of moderate to severe obstructive sleep apnea in patient who are intolerant or unable to achieve benefit with positive pressure therapy (PAP). Not all adult patients are candidates for UAS therapy and appropriate polysomnographic, age, BMI and objective upper airway evaluation measures are required for proper patient selection.”
International Society for Sleep Surgery
International Society for Sleep Surgery states that Cranial nerve (hypoglossal nerve) stimulation is among surgical treatments and procedures that “have been shown to be effective in the treatment of sleep disordered breathing/obstructive sleep apnea syndrome in adults (and/or children) when applied to selected patients based on their anatomy, physiology, body mass index and neck size, prior therapy and co-morbidities. Patient should have undergone an appropriate evaluation(s) prior to treatment which may include polysomnography, home sleep testing, awake or drug induced sleep endoscopy, and possible cephalometric or other radiographic evaluations.”
National Institute for Health and Clinical Excellence (NICE)
In 2017, National Institute for Health and Clinical Excellence (NICE) issued an interventional procedure guidance (IPG598) which states: “Current evidence on the safety and efficacy of hypoglossal nerve stimulation for moderate to severe obstructive sleep apnea is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit for research.”
CAC Advisory Committee (CAC) Evidentiary Summary
After review of the literature, the consensus among the CAC Advisory Committee (CAC) panel was positive for hypoglossal nerve stimulation (HNS) as a viable treatment option for patients with moderate to severe Obstructive Sleep Apnea (OSA). Upper airway stimulation (UAS) compared favorably with sleep surgeries (e.g., uvulopalatopharyngoplasty [UPPP], trans-oral robotic surgery [TORS]) used to treat tongue base obstruction. CAC discussions regarding patient criteria included changing the body mass index (BMI) to <35 based on additional studies that included the higher BMI with successful results, and including expanded descriptions of limitations to clarify the rationale for limiting certain patients from this procedure. Also, based on the CAC panel discussion and the Food and Drug Administration (FDA), it was suggested that the apnea-hypopnea index (AHI) should start at 15 with the upper limit of the AHI being increased to 65. This limit was adopted and the Covered Indications now include patients that have an AHI of 15 to 65 events per hour. In addition, CAC members agree that providers who underwent FDA approved device manufacturer DISE training prior to the date of this LCD, shall be deemed to meet the criteria for satisfactory performance of DISE without further documentation. All such providers shall maintain certification of completion of this training, supply proof of training by manufacturer and DISE results should be made available upon request. Finally, not all adults are candidates for UAS therapy and appropriate polysomnographic, age, BMI and objective upper airway evaluation measures are required for proper patient selection. Overall, this is an appropriate method of treating OSA for the Medicare population.