Summary of Evidence

Hypoglossal nerve stimulation (HNS) uses an implantable pacemaker-like device which stimulates the nerve strongly enough to evoke a response of keeping the airway open, but without disturbing sleep. Patients control the therapy start and stop times with a handheld controller. The pulse generator processes information from the sensor and determines the most beneficial time to deliver the stimulation. The single-lead pressure sensor provides real-time breathing cycle data throughout the night. The evidence in support of HNS for the treatment of OSA includes systematic reviews, a meta-analysis, randomized controlled trials, comparative studies, nonrandomized studies with historical controls, and prospective single-arm studies. 

Rationale

Kim et al (2024) compared hypoglossal nerve stimulation (HNS) to other obstructive sleep apnea treatments in a systematic review and meta-analysis. A total of 10 studies with 2209 patients (mean BMI ≤30 kg/m2 in every study) who were treated with HNS or alternative interventions were included. Compared to other airway surgeries (i.e., uvulopalatopharyngoplasty, expansion sphincterpharyngoplasty, or tongue-based surgery) the rates of post-treatment apnea-hypopnea index (AHI) < 10 and < 15 events/hour were significantly lower in the HNS group (odds ratio [OR] 5.33, 95% confidence interval [CI] 1.21–23.42; and 2.73, 95% CI 1.30–5.71, respectively). Postoperative AHI was significantly lower in the HNS group than in all other airway surgery groups (AHI: mean difference [MD] -8.00, 95% CI -12.03 to -3.97 events/hour). HNS is determined to be an effective option for selected patients with moderate to severe OSA with CPAP intolerance.

Patel et al (2024) conducted a retrospective cohort study at a single academic institution evaluating the effects of BMI on response to HNS. A total of 76 patients with an average age of 61 years and a median BMI of 28.9 kg/m2 were identified. Treatment response was defined as 50% reduction or greater in preimplantation AHI score and postimplantation AHI of less than 15 events per hour. Of 76 patients, 59 (78%) achieved a treatment response. There was a clinically meaningful reduction in median (IQR) AHI, from 29.3 (23.1-42.8) events per hour preimplantation to 5.3 (2.6-12.3) events per hour postimplantation (Hodges-Lehman difference of 23.0; 95% CI, 22.6-23.4). In adjusted analyses, patients with BMI of 32 to 35 had 75% lower odds of responding to HGNS compared with those with a BMI of 32 or less (odds ratio, 0.25; 95% CI, 0.07-0.94). In adjusted analysis, BMI was associated with lower odds of responding to HGNS with supine AHI treatment response (odds ratio, 0.39; 95% CI, 0.04-2.59), but the imprecision of the estimate prevents making a definitive conclusion.

Schwartz et al (2023) published the results of a randomized controlled trial which investigated the efficacy and safety of targeted HNS of the proximal hypoglossal nerve in patients (N=138) with moderate-to-severe OSA (AHI 20-60 events per hour). All patients were implanted with the HNS system (aura6000; ImThera Medical), and randomly assigned 2:1 to HNS device activation at 1 or 4 months after implant for the treatment and control groups, respectively. Efficacy was measured at month 4, as well as after 11 months of therapy (study months 12 and 15 for treatment and control groups, respectively). The study included mostly males (86.2%) and White individuals (91.3%). The results demonstrated that at month 4, the treatment group had significantly better outcomes compared to the control group for AHI and ODI scores. However, after 11 months of active therapy, the difference between the treatment and control groups was not statistically significant for AHI (RR, -7.5; 95% CI, -16 to 1.4) but remained significant for ODI (RR, 10.4; 95% CI, 1.6 to 18.8).

Heiser et al (2021) published the results of a multi-center, randomized controlled, double-blind, crossover design study in adult patients with moderate-to-severe OSA (defined as AHI >15) who could not tolerate CPAP. All patients received implantation of HNS device (Inspire Medical Solutions) at least 6 months prior to enrollment. Baseline AHI before implantation was 32.2 events/h; after implantation, baseline AHI was approximately 8.3 events/h. All participants received therapeutic stimulation during the baseline visit. Patients were then randomized to 1 of 2 treatment groups: HNS-Sham (n=45) or Sham-HNS (n=44). After randomization, the HNS-Sham group received therapeutic stimulation and the Sham-HNS received sham stimulation for 1 week. During the second week, the HNS-Sham group received sham stimulation while the Sham-HNS group received therapeutic stimulation. Changes in AHI over time showed a statistically significant decrease in AHI with stimulation compared to sham stimulation during the baseline, week 1, and week 2 visits. This meant that during week 1 when the HNS-Sham group received stimulation, they had significantly lower AHI; during week 2, when the Sham-HNS group received stimulation, they had significantly lower AHI. Similarly, participants reported a lower ESS with stimulation compared to sham stimulation during all visits. The change of AHI and ESS from baseline to the 1-week and 2-week visits was analyzed between the groups and investigators found no evidence of a carryover effect for AHI or ESS.

Soose et al (2016) evaluated the results of the prospective multi-center cohort study (STAR) of 126 patients with moderate to severe OSA who reported difficulty adhering to CPAP and received the surgically implanted upper airway stimulation. 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). Investigators found significant improvement in mean FOSQ scores from baseline (14.3) to 12 months (17.2), with maintenance of the effect at 24 months (17.2). Subjective daytime sleepiness, as measured by mean ESS, improved significantly from baseline (11.6) to 12 months (7.0) and 24 months (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. Upper airway stimulation (UAS) demonstrated large effect size (> 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.

In 2016, Woodson et al reported on the 36-month clinical and polysomnography (PSG) outcomes on the OSA cohort treated with hypoglossal cranial nerve upper airway stimulation. 116 subjects from a cohort of 126 participated. Of those, 98 participants agreed additionally to a voluntary 36-month PSG. Self-report daily device usage was 81%. In the PSG group, 74% met the a priori 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. Investigators concluded that long-term 3-year improvements in respiratory and quality-of-life outcomes are maintained, and that upper airway stimulation is an appropriate long-term treatment. 

Woodson et al again in 2018 published 5-year outcomes of a multi-center, prospective cohort study (STAR trial) (N = 126) of patients with obstructive sleep apnea treated with upper airway stimulation via hypoglossal nerve. Outcomes included apnea-hypopnea index (AHI), oxygen desaturation index, and adverse events, as well as measures of sleepiness, quality of life, and snoring. Improvement in sleepiness (via 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 <20 events per hour and >50% reduction) was 75% (n = 71). Investigators concluded that upper airway stimulation “is a nonanatomic surgical treatment with long-term benefit for individuals with moderate to severe OSA who have failed nasal continuous positive airway pressure."

Kompelli et al (2018) published a meta-analysis of available studies on hypoglossal nerve stimulation to analyze objective and subjective outcomes. 16 studies were found that included analysis of 381 patients. At 6 months (p = 0.008), mean Sleep Apnea Quality of Life Index (SAQLI) improved by 3.1 (95% CI, 2.6 - 3.7). At 12 months (p < 0.0001), mean AHI was reduced by 21.1 (95% CI, 16.9 - 25.3), mean ODI was reduced by 15.0 (95% CI, 12.7-17.4), mean Epworth Sleepiness Scale (ESS )was reduced by 5.0 (95% CI, 4.2 - 5.8), mean FOSQ improved by 3.1 (95% CI, 2.6 - 3.4). Pain (6.2%: 0.7 -16.6), tongue abrasion (11.0%: 1.2 - 28.7), and internal (3.0%: 0.3 - 8.4)/external device (5.8%: 0.3 -17.4) malfunction were common adverse events. Authors concluded that hypoglossal nerve stimulation is a safe and effective treatment for CPAP refractory OSA. 

Costantino et al (2019) published a systematic review and meta-analysis evaluating hypoglossal nerve stimulation clinical outcomes in the treatment of moderate to severe obstructive sleep apnea. A total of 350 patients (median age 54.3) from 12 publications of 8 studies were included. Six of the 8 studies assessed Inspire (N = 239). At 12 months, the apnea-hypopnea index (AHI) mean differences was − 17.50 for Inspire. The AHI mean reduction after 5 years was − 18.00 (− 22.38 to − 13.62, P < 0.001). Epworth Sleepiness Scale (ESS) mean reduction was − 5.27 at 12 months and − 4.40 at 5 years. 6% of patients reported serious device-related adverse events after 1- and 5-year follow-up. Authors concluded that “HNS has obtained a high surgical success rate with reasonable long-term complication rate related to the device implanted. The procedure represents an effective and safe surgical treatment for moderate-severe OSA in selected adult patients who had difficulty accepting or adhering to CPAP treatment.”

In May 2020, Thaler et al reported on the outcomes of the ongoing ADHERE registry. This observational study followed the outcomes of UAS therapy in patients who have failed PAP therapy and enrolled adults who meet the approved indications for UAS. The registry enrolled 1,017 patients from October 2016 through February 2019. The registry enrolled adult participants who meet the approved indications of UAS including AHI between 15 to 65 events per hour inclusive, who are intolerant to CPAP, and who are free of complete concentric collapse during sedated endoscopy. Average age was 60 years. After 12 months, median AHI was reduced from 32.8 (interquartile range [IQR], 23.6–45.0) to 9.5 (IQR, 4.0–18.5); mean, 35.8 ± 15.4 to 14.2 ± 15.0, P < .0001. Epworth Sleepiness Scale was similarly improved from 11.0 (IQR, 7–16) to 7.0 (IQR, 4–11); mean, 11.4 ± 5.6 to 7.2 ± 4.8, P < .0001. Therapy usage was 5.6 ± 2.1 hours per night after 12 months. Conclusion drawn was that, across a multi-institutional study, the therapy shows significant improvement in outcomes. The analysis demonstrated that the therapy effect is durable with high adherence. When using the Sher definition of surgical outcome (AHI < 20 and reduction of the AHI of at least 50%), female sex and lower baseline BMI are positive predictors of therapy.

In 2018, Diercks et al published a case series of 6 adolescents with Down Syndrome that underwent hypoglossal nerve stimulator implantation. Ages ranged from 12 – 18 and participants had a diagnosis of severe OSA with AHI > 10/events/hour despite prior adenotonsillectomy. In all participants, HNS was well tolerated (mean use, 5.6 – 10.0 hours per night) and effective, resulting in significant improvements in OSA. At 6 -12 months follow-up, patients demonstrated a 56% to 85% reduction in AHI, with an overall AHI of less than 5 events/hour in 4 children and less than 10 events/h in 2 children. Children also demonstrated a clinically significant improvement (mean [SD] overall change score, 1.5 [0.6]; range, 0.9-2.3) on the OSA-18, a validated quality-of-life instrument.

Caloway et al (2019) reported on a case series of 20 children and adolescents, aged 10 – 21 years, with Down Syndrome and severe OSA (apnea-hypopnea index [AHI] >10 and <50 events/hr) despite prior adenotonsillectomy. All participants had failed a trial of CPAP and had undergone sleep endoscopy confirming surgical candidacy. Primary outcome was to assess safety and monitor for adverse events. Secondary outcomes included efficacy in reducing AHI, adherence to therapy, and change in a validated quality-of-life instrument OSA-18 survey). All participants (median age = 16.0 years [interquartile range = 13-17 years], 13 male) were implanted with no long-term complications. All participants completed the 2-month polysomnogram, with median percent reduction in titration AHI of 85% (interquartile range = 75%-92%). The median nightly usage for these children was 9.21 hours/night. There was a median change in the OSA-18 score of 1.15, indicating a moderate, yet significant, clinical change. Two minor complications were corrected surgically. 

Liu et al (2022) published a systematic review of the investigation of HNS in adolescents with Down Syndrome and OSA. Nine studies were included with a follow-up period ranging from 2 to 58 months. Six studies had sample sizes fewer than 10 patients. The largest was a prospective cohort study by Yu et al (2022) (below). In an analysis that included 104 patients, AHI scores were significantly reduced in patients after HNS (mean AHI reduction, 17.43 events/h; 95% CI, 13.98 to 20.88 events/h; p<.001). Similarly, in an analysis that included 88 patients, OSA-18 survey scores were significantly reduced after HNS (mean OSA-18 reduction, 1.67; 95% CI, 1.27 to 2.08; p<.001). Authors concluded that HNS significantly reduces AHI and improves quality of life and may be a potential alternative therapy for OSA in adolescents with Down Syndrome.

Yu et al (2022) reported on the safety and effectiveness of HNS in 42 adolescents with Down Syndrome and severe OSA (AHI or 10 or greater). This was a single-group, multicenter, cohort study with a 1-year follow-up that included non-obese (BMI <95%) children and adolescents aged 10 to 21 years who were refractory to adenotonsillectomy and unable to tolerate CPAP. Patients who were included had an AHI between 10 and 50 on baseline PSG; the mean baseline AHI was 23.5 (SD, 9.7). All patients included tolerated HNS without any intraoperative complications. The most common complication was tongue or oral discomfort or pain, which occurred in 5 (11.9%) patients and was temporary, lasting weeks or rarely, months. Four patients (9.5%) had device extrusion resulting in readmissions to replace the extruded device. At 12 months, there was a mean decrease in AHI of 12.9 (SD, 13.2) events per hour (95% CI, -17.0 to -8.7 events/h). At the 12-month PSG, 30 of 41 patients (73.2%) had an AHI of less than 10 events/h, 14/41 patients (34.1%) had an AHI of less than 5 events/h, and 3/41 patients (7.3%) had an AHI of less than 2 events/h. There was also a significant improvement in quality of life outcomes. The mean improvement in the OSA-18 total score was 34.8 (SD, 20.3; 95% CI, -42.1 to -27.5) and the ESS improved by 5.1 (SD, 6.9; 95% CI, -7.4 to -2.8). Investigators concluded that HNS appears safe and effective 2for adolescent patients with Down Syndrome who are unable to tolerate positive pressure.

The American Academy of Otolaryngology – Head and Neck Surgery considers upper airway stimulation via the hypoglossal nerve for the treatment of obstructive sleep apnea (OSA) to be a safe and effective second-line treatment for moderate to severe OSA. 

Effective April 1, 2020, National Government Services (NGS), the local contractor for Medicare, published a Local Coverage Determination (LCD), L38387, which established medical necessity criteria for the use of hypoglossal nerve stimulation for the treatment of obstructive sleep apnea. 

Reference List

1. American Academy of Otolaryngology – Head and Neck Surgery. Position Statement: Hypoglossal Nerve Stimulation for Treatment of Obstructive Sleep Apnea (OSA). Revised April 2021.
2. Caloway CL, Diercks GR, Keamy D, et al. Update on Hypoglossal Nerve Stimulation in Children With Down Syndrome and Obstructive Sleep Apnea. Laryngoscope. 2020 Apr;130(4):E263-E267.
3. Constantino A, Rinaldi V, Moffa A, et al. Hypoglossal Nerve Stimulation Long-Term Clinical Outcomes: A Systematic Review and Meta-Analysis. Sleep Breath. 2020 Jun;24(2):399-411.
4. Diercks GR, Wentland C, Keamy D. Hypoglossal Nerve Stimulation in Adolescents with Down Syndrome and Obstructive Sleep Apnea. JAMA Otolaryngol Head Neck Surg. 2018 Jan 1;144(1):37-42.
5. Heiser C, Steffen A, Hofauer B, et al. Effect of Upper Airway Stimulation in Patients with Obstructive Sleep Apnea (EFFECT): A Randomized Controlled Crossover Trial. J Clin Med. Jun 29 2021; 10(13).
6. Kim DH, Kim SW, Han JS, et al. Comparative effectiveness of hypoglossal nerve stimulation and alternative treatments for obstructive sleep apnea: a systematic review and meta-analysis. J Sleep Res. May 2024; 33(3): e14017.
7. Kompelli AR, Ni JS, Nguyen SA, et al. The outcomes of hypoglossal nerve stimulation in the management of OSA: A systematic review and meta-analysis. World J Otorhinolaryngol Head Neck Surg
8. Liu P, Kong W, Fang C, et al. Hypoglossal nerve stimulation in adolescents with down syndrome and obstructive sleep apnea: A systematic review and meta-analysis. Front Neurol. 2022; 13: 1037926.
9. National Government Services (NGS). Local Coverage Determination (LCD) Hypoglossal Nerve Stimulation for the Treatment of Obstructive Sleep Apnea L38387. April 1, 2020. Available at https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38387&ver=7&bc=0 
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12. Soose RJ, Woodson BT, Gillespie MB, et al. Upper airway stimulation for obstructive sleep apnea: Self-reported outcomes at 24 months. J Clin Sleep Med. 2016 Jan;12(1):43-48.
13. Thaler E, Schwab R, Maurer J, et al. Results of the ADHERE Upper Airway Stimulation Registry and Predictors of Therapy Efficacy. Laryngoscope. 2020 May;130:1333-1338. 
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