Health Policy Advisory Committee on Technology

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1 Health Policy Advisory Committee on Technology Technology Brief Update Upper Airway Stimulation for Moderate-to-Severe Sleep Apnoea March 2015

2 State of Queensland (Queensland Department of Health) 2015 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division Department of Health, Queensland Level 2, 15 Butterfield St HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD [email protected] Telephone: For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, [email protected], phone (07) Electronic copies can be obtained from: DISCLAIMER: This Brief is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Brief is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health ( Queensland Health ) does not guarantee the accuracy, currency or completeness of the information in this Brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This Brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Brief was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers Advisory Council (AHMAC), reporting to AHMAC s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This brief was prepared by Robbie James from the Centre for Applied Health Economics, Griffith University.

3 TECHNOLOGY BRIEF UPDATE 2015 Technology, Company and Licensing Register ID WP097 Technology name Upper airway stimulation (UAS) Patient indication Patients with moderate-to-severe sleep apnoea Stage of development in Australia Yet to emerge Established Experimental Established but changed indication or modification of technique Investigational Should be taken out of use Nearly established Australian Therapeutic Goods Administration approval Yes ARTG number (s) No Not applicable In 2014, the FDA approved Inspire UAS system for use in a subset of patients with moderate-to-severe obstructive sleep apnoea, who were unable to use or maintain first-line therapy with continuous positive airways pressure. 1 International utilisation Country Level of Use Trials underway or completed Limited use Widely diffused Belgium France Germany Netherlands United States 2015 Cost infrastructure and economic consequences According to the national hospital cost data for (round 16), the Australian refined diagnosis-related group (AR-DRG) for sleep apnoea is E63Z. In summary the: - total average cost per DRG is equal to $1,612; - number of separations (complete episode of care) was 6,223; and average length of stay was 1.41 days; 2 and Upper airway stimulation for obstructive sleep apnoea Update: March

4 - using the National Efficient Price weight for the DRG E63Z (inlier = ), the price per separation is $1, The DRG reflects the casemix of the population, derived from diagnostic and procedure related activity Evidence and Policy Since the technology brief in 2012, one systematic review with meta-analysis conducted by Certal et al. (2014) 3 and one withdrawal randomised controlled trial by Woodson et al. (2014) 4 have been published. The systematic review included published results from the pivotal Stimulation Therapy for Apnoea Reduction (STAR) trial, 5 and the two other key caseseries studies used for clinical evidence in , 7 From the systematic review, study results from three studies that were not available for the 2012 technology brief are presented in this 2015 technology brief update: STAR trial reported in Strollo et al. (2014); 5 Kezirian et al. (2014); 8 and Mwenge et al. (2013). 9 The key new clinical evidence is the results from the: - systematic review with meta-analysis; 3 - three case series included in the systematic review; 5, 8, 9 and - a randomised controlled withdrawal trial. 4 In this brief, the term UAS is synonymous with hypoglossal nerve stimulation used in the 2012 technology brief (located at the end of this document). Safety and effectiveness Certal et al. (2014) 3 This systematic review included six prospective trials 5-10 with a total of 200 patients. The aim of the review was to systematically assess the short-term clinical efficacy and safety of all UAS systems in the treatment of obstructive sleep apnoea. The six included studies were prospective case series (level IV intervention evidence). Therapy for all patients was activated one month post-surgery, allowing the subject to become acclimatised to the newly implanted device. The baseline study characteristics for the studies published since the 2012 technology brief that were included in the systematic review are presented in Table 1 below. Upper airway stimulation for obstructive sleep apnoea Update: March

5 Table 1 Key baseline characteristics of new studies since 2012 Study Device N, Study duration Mean age (SD) Inclusion criteria Exclusion criteria Key outcomes Strollo et al (2014) Inspire UAS medical system months 54.5 years (11.8) 20<AHI<50 on PSG screen BMI>32; endoscopy screen showed anatomical variants ie. enlarged tonsils (grade 3 or 4); neuromuscular disease; severe cardiac diseases; psychiatric disorders AHI, ODI, ESS, FOSQ Kezirian et al (2014) HGNS system months 45.4 years (17.5) Age: years; BMI < 40 and 20<AHI<100 on PSG screen Prior surgery on palate; endoscopy screen showed anatomical variants ie. enlarged tonsils; severe retrognathia; incomplete treated sleep apnoea; severe cardiac diseases AHI, ESS, FOSQ Mwenge et al (2013) ImThera Aura 6000 system months 45.2 years (17.8) Age: years; AHI>20 on PSG screen; 25<BMI<40 Central sleep apnoea; endoscopy screen showed anatomical variants ie. enlarged tonsils (grade 3 or 4); insomnia; psychiatric disorders; pregnancy AHI, ODI, ESS Source: Certal et al. (2014). Abbreviations: AHI; apnoea-hypopnoea index; BMI: body mass index; ESS: Epworth sleepiness scale; FOSQ: functional outcomes of sleep questionnaire; HGNS: hypoglossal nerve stimulation; ODI: oxygen desaturation index; PSG: polysomnography; SD: standard deviation; UAS: upper airway stimulation. All studies enrolled patients with moderate-to-severe obstructive sleep apnoea a who were noncompliant to continuous positive airways pressure. The mean age of these patients was 53.9 ± 10.1 years, with all studies excluding patients with Body Mass Index above 40 and patients identified on endoscopy with abnormal anatomical variants that could interfere with UAS therapy. Study duration ranged from 6 b to 12 months. Blinding was not possible due to the electrical stimulation therapy inducing a physiological response in the patient. The primary outcomes, measured by polysomnographic device, were the Apnoea Hypopnoea Index (AHI) c and Oxygen Desaturation Index (ODI). d These objective sleep and respiratory parameters provide the impact of change in severity of obstructive sleep apnoea. The other primary outcome used; the subjective Epworth Sleepiness Scale (ESS), e was a disease specific quality-of-life variable, that evaluated daytime sleepiness as selfreported by the patient. The study group comprised of all three types of hypoglossal nerve UAS systems identified in the 2012 brief: the hypoglossal nerve stimulation (HGNS ); Aura6000 TM and Inspire UAS systems. a The American Academy of Sleep Medicine (AASM) classifies the severity of obstructive sleep apnoea by the hourly AHI events; AHI between 5 and 15 is mild; AHI between 15 and 30 is moderate and AHI > 30 is severe. b Eastwood et al. (2010), Eastwood et al. (2011) and van de Heyning et al. (2012) followed patients for 6 months. c AHI is the frequency of apnoeas and hypopnoeas per hour of sleep. d ODI is the number of times per hour of sleep that the blood oxygen level drops by 4 percentage points from baseline. e ESS is measured by short questionnaire on daytime sleepiness. The scores range from 0.0 to 24.0, with higher scores indicating more daytime sleepiness. A score of less than 10.0 was considered normal. Upper airway stimulation for obstructive sleep apnoea Update: March

6 Safety All adverse events were recorded despite severity and whether the event was related to device or therapy. These results are summarised in Table 2 below. Table 2 Safety results of three new studies since 2012 Complications Strollo et al (2014) Kezirian et al (2014) Mwenge et al (2013) Therapy related SAE 2 (2%) 3 (10%) 2 (15%) Types of SAE Devices repositioned due to patient discomfort. This resolved the discomfort. 1 patient acquired an infection with the device removed; 2 patients had lead dislodgement and had replacement surgery; 3 leads broke in 2 patients with 1 case requiring reimplantation <1 Device-related non-sae; n (%) 70 (56%) 10 (32%) NS <1 Procedure-related non-sae; n (%) 72 (57%) 22 (71%) NS Main types of non- SAE; n (%) -40% discomfort due to electrical stimulation -25% pain at incision site -21 % tongue soreness -17 (55%) tongue abrasions -11 (31%) pain at incision site -2 (15%) transient tongue paresis with full recovery -1 post-op swelling for 2 weeks -18% tongue weakness Source: Certal et al. (2014). Abbreviations: NS: not specified; SAE: serious adverse event No serious adverse events, defined as any complication that resulted in life-threatening illness, injury or permanent impairment of body structure or function and deaths related to treatment were reported. All of the studies reported similar minor complications, such as tongue weakness and pain or swelling related to surgical procedure. Most of these complications were temporary resolving in the 1 month post-operative period before device activation. Within the longer 12 month follow-up period, 93 per cent of procedure related and 68 per cent of device-related adverse events were fully resolved without intervention. Despite some patient s unresolved adverse events, 88 per cent continued nightly UAS therapy. 5 Overall, the combined rate for serious adverse events that led to device removal was 4.5 per cent (9/200 patients). All of these serious adverse events were resolved when re-operated on. The safety profile from the largest and most reliable study (STAR trial) reported the lowest rate (<2%) for incidence of serious adverse events. 5 It is difficult to determine the longevity and long-term safety of UAS systems within the current published clinical evidence limited to 12 months. Upper airway stimulation for obstructive sleep apnoea Update: March

7 Effectiveness The primary effectiveness endpoints were the mean change from baseline in AHI, ODI and ESS over 12 months. A summary of the component studies before meta-analysis can be seen below in Table 3. Table 3 Study effectiveness results of new studies since 2012 AHI mean (SD) ODI mean (SD) ESS mean (SD) Study Baseline 12 month % reduct Baseline 12 month % reduct Baseline 12 month % reduct Strollo et al (2014) (11.8) 15.3 (16.1) 52 % 28.9 (12.0) 13.9 (15.7) 52% 11.6 (5.0) 7.0 (4.2) 40% Kezirian et al (2014) (17.5) 25.3 (17.6) 44% 20.9 (17.3) 10.7 (17.1) 49% 12.1 (4.6) 8.3 (3.6) 31% Mwenge et al (2013) (17.8) 21.0 (16.5) 54% 29.2 (19.6) 15.3 (16.2) 48% 10.8 (6.2) 7.9 (4.2) 27% Source: Certal et al. (2014). Abbreviations: AHI: apnoea-hypopnoea index; ESS: epworth sleepiness scale; ODI: oxygen desaturation index; reduct: reduction; SD: standard deviation. Results are consistent across studies supporting an improvement in severity of sleep apnoea; evidenced by decreased mean AHI, ODI and ESS from baseline to 12 months (32.0 to 15.3; 28.9 to 13.9 and 11.6 to 7.0 respectively). The most appropriate definition of surgical success is the postoperative reduction of AHI by at least 50 per cent and AHI score less than 20 events per hour. By these clinically meaningful AHI criteria, 66 per cent of patients were classified as responders within the STAR trial. 5 The reductions in ESS scores were also clinically meaningful, evident by the 12 month score for all trials below the 10.0 threshold value for upper limit of normal. The evidence for reduced sleepiness and improvements in quality-of-life measures at 12 months were similar to previously reported effects of alternative continuous positive airways pressure therapy, 5 without the adherence issues. The study results were than pooled for all 200 viable patients for meta-analysis. Due to the variation in follow-up-length of all 6 included studies, subgroup analyses was performed at three, six and 12 month study duration. These results that describe the impact of change in severity of sleep apnoea across all patients and UAS systems are summarised in Table 4 below. Upper airway stimulation for obstructive sleep apnoea Update: March

8 Table 4 Subgroup duration Pooled Results of all mean difference in AHI, ODI and ESS at 3, 6 and 12 months AHI a ODI a ESS a Mean difference [95% CI] % reduction Mean difference [95% CI] % reduction Mean difference [95% CI] 3 month I 2 (%) b [-31.45, ] (0%) 54% [-16.31, -3.78] (0%) 52% [-6.45, -1.90] (0%) 6 month I 2 (%) [-31.18, ] (0%) 57% [-17.16, -6.9] (26%) 52% [-5.37, -2.27] (0 %) 12 month I 2 (%) [-20.69, ] (0%) 50% [-16.87, ] (54%) 48% [-5.39, -3.44] (0%) Source: Certal et al. (2014). Abbreviations: AHI: apnoea-hypopnoea index; CI: confidence interval; ESS: epworth sleepiness scale; ODI: oxygen desaturation index; bold indicates statistically significant; a fixed effects models used as no heterogeneity found; b heterogeneity was assessed by means of Cochran s Q test. All results demonstrated statistically significant reductions in mean difference of AHI, ODI and ESS through all time periods. At conclusion of 12 months, the pooled fixed effects were: mean difference of (95% CI [-20.69, ]); (95% CI [-16.87, ]) and (95% CI [-5.39, -3.44]), respectively. These results were similar to the preceding three and six month time periods. However, the impact on AHI did worsen slightly between the three and 12 month period (AHI reduction: 54% vs. 50%, respectively). These pooled results for UAS efficacy met predefined clinically meaningful criteria of 50 per cent reduction of AHI events. The clinical evidence supports UAS therapy in a selective group of patients, can reduce the severity of sleep apnoea. No significant heterogeneity, defined as test statistic I 2 greater than 75 per cent, was reported. This could imply equivalent efficacy across all three types of UAS systems, for the treatment of moderate-tosevere sleep apnoea. There are several limitations to this systematic review. These are the: - applicability concerns regarding results from a highly specific study population and therefore unlikely representative of the broader Australian population with sleep apnoea. - likely high bias regarding studies that lacked randomisation and blinding of participants; - clinical evidence is based on case/series with no control or matched group which does not allow appropriate treatment of possible confounding variables; - lack of a generic multi-attribute utility instrument (ie. QALYs) to measure outcomes, as opposed to disease specific outcomes (AHI, ODI) and self-assessed ESS; - short duration of clinical follow-up limited to 12 months; and The main advantage of this systematic review was it looked to overcome the weakness of prior effectiveness data that was based on small (N<30), low-quality studies with differing UAS systems. Upper airway stimulation for obstructive sleep apnoea Update: March

9 Woodson et al. (2014) 4 Woodson et al. (2014) was a randomised controlled therapy withdrawal study (Level II intervention evidence). After completion of the 12-month follow up in the STAR trial, 5 46 consecutive patients classified as responders f were selected and were randomly allocated to either one week therapy-withdrawal subgroup or therapy-maintenance subgroup. The therapy-withdrawal subgroup ceased nightly treatment for 1 week during this phase. Following the RCT, patients resumed routine nightly treatment for six months, totalling an 18 month follow-up period. The primary aim of the study was to assess the short-term RCT withdrawal effect and durability of UAS systems over the entire 18 month trial period. The patient demographics for each RCT trial arm can be seen in Table 5 below. Table 5 Patient demographics of the randomised controlled withdrawal study Trial arm / parameter Therapy-maintenance Therapy-withdrawal p value N 23 Age, year 57.1 ± 10.0 Gender (% male) ± Mean BMI kg/m 2 : baseline 28.4 ± 2.4 Mean BMI kg/m 2 : 18 months 28.1 ± ± ± Source: Woodson et al. (2014). Abbreviations: BMI: body mass index; RCT: randomised controlled therapy. No differences in patient demographics were observed between the therapy-withdrawal and therapy-maintenance subgroups (p > 0.05). No participants were lost to follow-up during RCT, but one patient did not complete the 18 month study duration. Overall, risk of bias is low. The polysomnographic outcomes, AHI and ODI, are presented in Table 6 below. The patientreported subjective outcomes; ESS and the functional outcomes of sleep questionnaire (FOSQ) g are presented in Table 7. f Response classified as 50 per cent reduction in AHI from baseline and AHI less than 20 events/hour; similar to earlier definition of surgical success. g FOSQ is a disease specific quality-of-life questionnaire that measures the effect of excessive sleepiness on everyday living. Upper airway stimulation for obstructive sleep apnoea Update: March

10 Table 6 Results for RCT polysomnographic outcomes: AHI and ODI through RCT and 18 month period AHI ODI Study duration Mean difference, [95% CI] Therapymaintenance Therapywithdrawal Therapymaintenance Therapywithdrawal Mean difference, [95% CI] Baseline 31.3 ± ± [-5.8, 8.3] 26.7 ± ± [-7.0, 6.9] 12 m 7.2 ± ± [-3.1, 2.3] 6.3 ± ± [-2.4, 3.1] RCT (13 m) 8.9 ± ± [-24.7, -9.0] 8.0 ± ± [-22.7, -7.5] 18 m 9.6 ± ± [-6.9, 4.7] 8.6 ± ± [-5.9, 5.0] Change (12 m-rct) Change (12-18) m 1.7 ± ± [9.2, 23.7] -2.0 ± ± [-5.1, 5.4] 1.6 ± ± [8.7, 22.1] -1.9 ± ± [-4.1, 4.8] Source: Woodson et al. (2014). Abbreviations: AHI: apnoea-hypopnoea index; CI: confidence interval; m: month; ODI: oxygen desaturation index; RCT: randomised controlled trial; bold: statistically significant. Table 7 Self-reported quality-of-life outcomes ESS and FOSQ through RCT and 18 month period ESS FOSQ Study duration Mean difference, [95% CI] Therapymaintenance Therapywithdrawal Therapymaintenance Therapywithdrawal Mean difference, [95% CI] Baseline 11.2 ± ± [-2.8, 3.6] 15.1 ± ± [-0.4, 3.0] 12 m 5.9 ± ± [-3.4, ± ± [-1.0, 2.8] RCT (13 m) 5.6 ± ± [-7.5, -1.4] 17.9 ± ± [0.8, 5.0] 18 m 6.0 ± ± [-4.5, 0.5] 18.0 ± ± [-0.8, 5.0] Change (12 m-rct) 0.3 ± ± [2.0, 6.4] 0.0 ± ± [-3.8, -0.9] Change (12-18) m -0.1 ± ± [-1.0, 3.5] -0.1 ± ± [-1.3, 1.1 Source: Woodson et al. (2014). Abbreviations: CI: confidence interval; ESS: epworth sleepiness scale; FOSQ: functional outcomes of sleep questionnaire; m: month; bold: statistically significant. The withdrawal of therapeutic UAS within the one week RCT phase resulted in a worsening of both objective and subjective measures of sleep and breathing. This was demonstrated by the statistically significant differences from Therapy-maintenance to Therapy-withdrawal in AHI: (95%CI [-24.7, -9.0]); ODI: (95% CI [-22.7, -7.5]); ESS: -4.5 (95% CI [-7.5, - 1.4]) and FOSQ h : 2.9 (95% CI [0.8, 5.0]). When therapy was resumed, all outcomes converged back to Therapy-maintenance arm levels at 18 months. Therefore, the reduction h FOSQ: a change of >2.0 is considered clinically meaningful improvement in daily functioning; a higher score indicated an improvement in sleep apnoea. Upper airway stimulation for obstructive sleep apnoea Update: March

11 of sleep apnoea events and improvements to quality-of-life measures appeared to be attributable to the UAS therapy. There are several key limitations to this study. The main criticism is the short one week off therapy period, which does not allow long-term efficacy and safety to be assessed. The other concerns are the bias associated with selecting patients classified as responders only for the trial population and the inherent lack of blinding of UAS therapy Economic evaluation Pietzsch et al. (2014) 11 A recent cost-effectiveness analysis conducted by Pietzsch et al. (2014) 11 compared UAS versus no treatment. Continuous positive airways pressure was not considered a comparator as UAS therapy is indicated only in those who are intolerant to its first-line use. The results from the STAR trial 5 were used to populate the five-state Markov model. The device used was the Inspire UAS system. The outcomes used were the rates of: cardiovascular events (myocardial infarction, stroke, and hypertension); motor vehicle collisions; mortality; quality-adjusted life years (QALYs) and costs. The utility estimates used to calculate the QALYs were sourced from the wider literature. The lifetime of the model was 10 years, with the assumption that the 12 month mean reduction seen in STAR trial (AHI: 32.0 to 15.3 events/hour: Table 3) was maintained throughout. The setting was the U.S. healthcare system, with a U.S. payer perspective adopted. Both costs and effects were discounted at 3 per cent. The results of the analysis were that the Inspire UAS system reduced event probabilities and therefore health outcomes (relative risks: myocardial infarction = 0.63; stroke = 0.75 and motor vehicle collisions = 0.34), over the 10 year analysis period. The incremental QALYs and costs were 1.09 QALYs and USD $42, 953 respectively, which resulted in a lifetime incremental cost-effectiveness ratio (ICER) of USD $39,471 (approximately AUD $49,000) per QALY. To put this ICER in perspective, the same author reported an ICER of $15,915 per QALY (lifetime horizon) for the comparator, first-line CPAP therapy 12. Again, the weakness of this study is that the clinical evidence is from the industry-sponsored STAR trial, with likely high bias with single-arm evidence. The assumption that AHI effectiveness is maintained for 10 years is also unconfirmed and implies extrapolation issues within the model. The study also used U.S cost data and may not be applicable to the Australian context Ongoing research A post approval study is proposed by the manufacturer to follow all STAR participants through a five year follow-up period. 1 On the Clinical Trials Registry, NCT is listed for a total enrolment of 929, with published results currently existing for 126 Upper airway stimulation for obstructive sleep apnoea Update: March

12 participants. 5 There are several other key trials identified for future completion. All trials use the same study population; adults diagnosed with moderate-to-severe sleep apnoea who failed continuous positive airways pressure therapy. These trials are: - NCT : This is a prospective, open-label, single group study (N=15). The aim of this study is to assess the safety and performance of the Nyxoah SAT system for the treatment of obstructive sleep apnoea. The estimated primary completion date is August The trial is listed to recruit participants in Belgium and Germany. This new technology is discussed in the next section of this brief update. - NCT : Is a randomised, open-label, parallel assignment trial. The estimated enrolment is 141 participants with a 12 month follow-up period. The aim of this trial is to assess the benefits and risks of the ImThera Medical aura6000 system as a potential therapeutic option. This study will be the first to use a multiattributable utility index, the EuroQol 5 dimensions (EQ-5D), over a 4 month period. The start date was estimated to be November 2014 with primary completion in May Longer term data may become available, as final completion is listed for May NCT : This is a phase IV, multi-centre, prospective, single-arm study (n=60). This German post-market study is due for completion in April The aim of this study is to update additional safety and efficacy data for the Inspire UAS system after market introduction. In 2013, Apnex Medical Inc. sponsor of the HGNS system ceased operations. The final completion results for NCT in October 2017 are therefore unknown. This is unfortunate as the study was a RCT (with separate treatment and control arms) with longterm follow up data expected Other issues The Nyxoah SAT system 18 represents a new type of UAS system. The device, like its predecessor systems, works by stimulating the hypoglossal nerves causing the tongue muscles to contract and maintain an open airway during sleep. This ultra-small neurostimulator, measuring 20mm in diameter and 2.5mm thick (16 times smaller than competitor systems), is designed to be implanted close to the nerves of the tongue muscle. The implantable component requires a single surgical incision only. A small disposable patch (55mm by 90mm) positioned under the chin powers the implant for appropriate nightly therapy. This product claims to overcome the prior weaknesses of predecessor UAS systems (Active systems: aura6000 ; Inspire UAS). The manufacturer proposes the device will be: Upper airway stimulation for obstructive sleep apnoea Update: March

13 - less invasive as the device is now controlled by an adhesive disposable patch as opposed to a generator and long electrode inserted into neck and upper chest region; - reduced risk of post-surgical infections, scarring and pain; - less risk of migration away from the defined implantation site. This brief reported device complications that required re-implantation to be a moderate 4.5 per cent; - battery-less, allowing device to be wirelessly powered. Product life is also proposed to increase from 3-5 years to 12 years; - less complex to implant. The manufacturer proposes a 15 minute implantation process, compared to previous recorded procedural times to be up to 3 hours in Australian study; 6 - more comfortable during therapy and as a result expected improvements to sleep related quality-of-life. 18 Currently, there is no clinical evidence to substantiate these product-sponsored claims. There are also key generalisability concerns with the European study population used and the open-label trial design, with small sample size (n=15) Summary of findings The results from the systematic review and RCT show support for short-term effectiveness for first generation UAS systems. Overall, UAS can improve the management of patients diagnosed with obstructive sleep apnoea by reducing its severity, as measured by sleep- related health measurements. However, clinical feedback indicates that there is a persisting issue, discrepancy between symptomatic improvement (which seems to occur in just about 100% of patients) and the improvement in AHI (between 30-60% shows a clinically significant improvement). This could imply caution with using AHI as the main primary outcome. UAS systems do not offer a cure for the patient from the disease. The incidence of device-related serious adverse events was 4.5 per cent. These results were aligned with clinical feedback, In general the device/procedure has a good safety profile. Long-term safety and effectiveness was difficult to establish with the current level of clinical evidence present. Bias was also a concern for most studies, due to the clinical evidence produced from case-series studies without concomitant control arms. Despite these concerns, the short-term randomised controlled withdrawal study results did appear to attribute the clinical benefits to UAS therapy. No Australian cost-effectiveness evidence was found HealthPACT assessment The evidence-base supporting the use of upper airway stimulation to treat obstructive sleep apnoea was weak, consisting of case series and one study where patients were randomised to a withdrawal of treatment. This latter study demonstrated a worsening of both objective and subjective measures of sleep and breathing after treatment withdrawal. However, the Upper airway stimulation for obstructive sleep apnoea Update: March

14 study was small and participants were recruited from the industry-sponsored, uncontrolled STAR study and, therefore, highly selective and not representative of the target population. Based on the lack of safety and clinical effectiveness evidence in the appropriate population, it is unlikely this device will diffuse into the jurisdictions within the next one to three years. It is therefore recommended that no further research on behalf of HealthPACT is warranted at this time. Number of studies included All evidence included for assessment in this Technology Brief has been assessed according to the revised NHMRC levels of evidence. A document summarising these levels may be accessed via the HealthPACT web site. Total number of studies 3 Total number of Level II Studies 1 Total number of Level IV studies 4 (1 Systematic review) Other (cost-effectiveness) 1 Search criteria to be used (MeSH terms) MeSH: sleep apnea, obstructive/ AND hypoglossal nerve/ OR electric stimulation therapy/ OR electric stimulation Keyword: hypoglossal nerve stimulation and obstructive sleep apnoea (limited to humans) 2015 References 1. Aaberg, J. (2014). Inspire Upper Airway Stimulation PMA: P [Internet]. Sponsor: Inspire UAS. Available from: medicaldevices/medicaldevicesadvisorycommittee/anesthesiologyandrespiratorythe rapydevicespanel/ucm pdf [Accessed ]. 2. (IHPA), I. H. P. A. (2014). Appendix B: Cost Weights (actual) for AR-DRG version 6.0x, Round 16 ( ). Available from: round16-html~appendices~appendix-b [Accessed ]. 3. Certal, V. F., Zaghi, S. et al (2014). 'Hypoglossal nerve stimulation in the treatment of obstructive sleep apnea: A systematic review and meta-analysis'. Laryngoscope. 4. Woodson, B. T., Gillespie, M. B. et al (2014). 'Randomized controlled withdrawal study of upper airway stimulation on OSA: short- and long-term effect'. Otolaryngol Head Neck Surg, 151 (5), Strollo, P. J., Jr., Soose, R. J. et al (2014). 'Upper-airway stimulation for obstructive sleep apnea'. N Engl J Med, 370 (2), Eastwood, P. R., Barnes, M. et al (2011). 'Treating obstructive sleep apnea with hypoglossal nerve stimulation'. Sleep, 34 (11), Van de Heyning, P. H., Badr, M. S. et al (2012). 'Implanted upper airway stimulation device for obstructive sleep apnea'. Laryngoscope, 122 (7), Upper airway stimulation for obstructive sleep apnoea Update: March

15 8. Kezirian, E. J., Goding, G. S., Jr. et al (2014). 'Hypoglossal nerve stimulation improves obstructive sleep apnea: 12-month outcomes'. J Sleep Res, 23 (1), Mwenge, G. B., Rombaux, P. et al (2013). 'Targeted hypoglossal neurostimulation for obstructive sleep apnoea: a 1-year pilot study'. Eur Respir J, 41 (2), Eastwood, P. R., Walsh, J. H. et al (2010). 'Treatment of Obstructive Sleep Apnea with Unilateral Hypoglossal Nerve Stimulation'. American Journal of Respiratory and Critical Care Medicine, 181, A Pietzsch, J. B., Liu, S. et al (2014). 'Long-Term Cost-Effectiveness of Upper Airway Stimulation for the Treatment of Obstructive Sleep Apnea: A Model-Based Projection Based on the STAR Trial'. Sleep. 12. Pietzsch, J. B., Garner, A. et al (2011). 'An integrated health-economic analysis of diagnostic and therapeutic strategies in the treatment of moderate-to-severe obstructive sleep apnea'. Sleep, 34 (6), Inspire Medical Systems, I. Stimulation Therapy for Apnea Reduction ( Nyxoah, S. A. Safety and Performance Study of the Nyxoah SAT System for Treating OSA ImThera Medical, I. Targeted Hypoglossal Neurostimulation Study # Inspire Medical Systems, I. Inspire Upper Airway Stimulation (UAS) System German Post-Market Study Apnex Medical, I. Apnex Clinical Study of the Hypoglossal Nerve Stimulation (HGNS ) System to Treat Obstructive Sleep Apnea Nyxoah (2013). Obstructive Sleep Apnoea Solved. Available from: [Accessed ]. Upper airway stimulation for obstructive sleep apnoea Update: March

16 TECHNOLOGY BRIEF Register ID Name of technology Purpose and target group WP097 Hypoglossal nerve stimulation Patients with sleep apnoea Stage of development in Australia Yet to emerge Established Experimental Established but changed indication or modification of technique Investigational Should be taken out of use Nearly established Australian Therapeutic Goods Administration approval Yes ARTG number No Not applicable International utilisation Country United States France Germany Netherlands Belgium Israel Trials underway or completed Level of use Limited use Widely diffused Impact summary Hypoglossal nerve stimulation technology has been developed with the aim to treat obstructive sleep apnoea (OSA). The technology utilises an implantable device that electrically stimulates the hypoglossal nerve, leading to the contraction of the genioglossus muscle, the major muscle responsible for tongue protrusion. This prevents airway collapse and the development of upper airway obstruction during sleep. The technology is not currently registered on the Australian Register of Therapeutic Goods (ARTG), but has approval for use in clinical trials. The technology would be made available through hospitals via implantation by surgeons. The most common treatment for OSA, continuous positive airway pressure (CPAP), has been Hypoglossal nerve stimulation for sleep apnoea: August

17 associated with poor patient compliance. 1 Hypoglossal nerve stimulation technology may provide patients with an alternative, more palatable, treatment option. Background OSA is characterised by repeated episodes of pharyngeal obstruction during sleep, including airway collapse (apnoea) or narrowing (hypopnoea), resulting in recurrent airflow cessation. 1 Immediate symptoms of OSA include loud snoring, choking and gasping, and disrupted sleep. OSA is also associated with excessive daytime sleepiness, cognitive impairment, and cardiovascular and metabolic morbidities, resulting in a significant increase in mortality. 2, 3 Possible risk factors for OSA include obesity, gender (higher risk for males), craniofacial and upper airway abnormalities, alcohol consumption prior to sleep and night-time nasal congestion. Age is also a risk factor, with a higher prevalence between years of age. 2 Diagnosis and severity of OSA is based on polysomnography (PSG; overnight monitoring of breathing abnormalities), which can detect apnoea or hypopnoea events. One common severity index of sleep disordered breathing is the apnoeahypopnoea index (AHI), which is the number of events per hour of sleep. Mild OSA is defined as an AHI , moderate OSA , and severe OSA >30. An additional severity indicator used is the oxygen desaturation index (ODI), which is the number of events per hour of sleep where there is a greater than or equal to four per cent decrease in oxygen saturation. The subjective effects of OSA can be determined by patient questionnaires, including the Epworth Sleepiness Scale (ESS), a selfadministered questionnaire that measures daytime sleepiness; and the Functional Outcomes of Sleep Questionnaire (FOSQ), a self-administered questionnaire that assesses the impact of excessive sleepiness on daily living activities. 1 Treatment options for OSA include CPAP, the delivery of air by a mask to maintain a constant pressure along the upper airway, preventing narrowing or collapse; use of oral appliances to stabilise the mandible and/or pull the tongue forward; and surgical options that target the upper airway. 4, 5 During deep sleep, the muscles of the throat relax, leading to a reduction in airflow. In OSA, complete relaxation of these muscles may cause the tongue to prolapse into the throat, causing the cessation of airflow. Tongue prolapse may be due to diminished neuromuscular activity in the genioglossus muscle. 6 Therefore, the genioglossus muscle is a potential therapeutic target for OSA, as electrical stimulation can cause the protrusion of the tongue, stiffening of the anterior pharyngeal wall and prevention of upper airway blockage. Devices developed to stimulate this muscle directly were associated with improvements in the severity of the disease; however, these stimulation techniques would often arouse the patient, limiting the effectiveness of the treatment. 1 Hypoglossal nerve stimulation for sleep apnoea: August

18 The genioglossus muscle can alternatively be targeted through the electrical stimulation of its motor nerve, the hypoglossal nerve. The branches of this nerve that innervate the genioglossus are predominantly motor fibres, and as such, stimulation of this nerve has the ability to activate the muscle with minimal sensory feedback. 1 Hypoglossal nerve stimulation systems: the HGNS System (Apnex Medical, Inc., St. Paul, MN, USA); the aura6000 system (ImThera Medical, Inc., San Diego, CA, USA) and the Inspire Upper Airway Stimulation (Inspire Medical Systems, Inc., Maple Grove, MN, USA) consist of an implantable neurostimulator that delivers an electrical current to the hypoglossal nerve by a stimulation lead. Stimulation is synchronised with respiration sensing leads that measure changes in breathing. The neurostimulator is programmable through a computer interface and programmer head, with limited additional patient control (Figure 1). The device is surgically implanted under general anaesthesia, with the stimulating lead placed on the main trunk of the hypoglossal nerve. The neurostimulator is implanted in an infraclavicular subcutaneous pocket, and the respiratory sensing lead(s) are placed between the external and internal intercostal muscle (Figure 2). 1, 4 Clinical trials for the use of hypoglossal nerve stimulation therapy are being undertaken in the USA and Europe. The USA Food & Drug Administration (FDA) has granted investigational devices exception (for use in clinical trials only) for all three systems, with CE Mark approval in Europe granted to the Apnex HGNS System and the ImThera aura6000 System. Clinical trials for the Inspire Upper Airway Stimulation system are underway in Europe. Figure 1 The ImThera aura6000 hypoglossal nerve stimulation components (printed with permission of ImThera Medical, Inc.) 7 Hypoglossal nerve stimulation for sleep apnoea: August

19 Figure 2 Hypoglossal nerve stimulation system (printed with permission of Apnex Medical Inc.) 8 Clinical need and burden of disease The characteristic episodes of OSA lead to intermittent hypoxemia and the frequent interruption of sleep, which may result in long-term neurocognitive, metabolic and cardiovascular issues. 9 Left untreated, patients with OSA are at increased risk of sudden death, hypertension, stroke, coronary artery disease, congestive heart failure, type II diabetes, depression, and decreased quality of life. 1 OSA affects millions of people worldwide, and prevalence is increasing with a greater incidence of obesity and an ageing population. 1 In Australia, OSA is the most common chronic primary sleep disorder, affecting approximately 775,000 people in 2010 (4.7% of the population). 10 Hospital separations for OSA (mainly overnight stays in sleep centres) have increased by 35 per cent between and In , private hospitals provided 86 per cent of hospital separations for sleep apnoea. 12 Recent evidence from New Zealand indicates that Māori people have a higher prevalence of OSA than non-māori, and that this population often presents with more severe forms of the disease. Obesity, one of the risk factors for OSA, is additionally higher in the Māori population than non-māori. 13 Hypoglossal nerve stimulation for sleep apnoea: August

20 In 2010, it was estimated that sleep disorders cost the Australian hospital system $96.2 million. Of this amount, 59.6 per cent has been attributed to OSA. The out-ofhospital cost of OSA was estimated to be $96.6 million. The cost to the health system for conditions attributed to OSA (cardiovascular disease, depression and anxiety, motor-vehicle and workplace injuries) was an estimated $408.5 million in Diffusion of technology in Australia While hypoglossal nerve stimulation devices are not registered on the ARTG, clinical trials using the Apnex device have been undertaken at four clinical trial sites in Australia (Austin Health in VIC, St. Charles Gardner Hospital in WA, Repatriation General Hospital in SA and Westmead Hospital in NSW), with participation in a worldwide RCT at Austin Health and Westmead Hospital. 1, 14 ImThera Medical, Inc. plans to submit an application to the TGA later in Comparators CPAP is currently the universally-accepted gold standard treatment for OSA. The CPAP machine delivers a positive stream of air pressure that acts as a pneumatic splint to maintain the opening of the airway during sleep. 5 The intervention requires patients to wear a nasal mask whilst sleeping. Compliance in the home setting is often poor, with only per cent of patients using the treatment long-term or as prescribed. 1 A variety of upper airway surgical procedures are options for patients with severe OSA who do not respond to CPAP. One of the more commonly performed procedures in Australia is uvulopalatopharyngoplasty (UPPP), a highly invasive procedure wherein the uvula, a portion of the soft palate, and tonsils (if present) are removed in order to enlarge the airway. 5 Medicare Benefits Schedule (MBS) claims for UPPP (item number 41486) have remained constant over the past five years, with approximately 1200 claims per year. 15 Long-term follow-up studies have suggested that the initial effect of surgery may lessen over time. 16 Due to the limited effectiveness of treatment alternatives, Eastwood et al (2011) suggested that patients may not be seeking the required medical advice. 1 Consequently, the number of patients who report for sleep investigations may be an underestimation of the true burden of disease. Safety and effectiveness Four studies assessing hypoglossal nerve stimulation were included in this brief: two case-series studies that examined safety and preliminary effectiveness; 1, 4 and two additional studies that used the same patient pool as one of the case-series, Eastwood et al (2011) 1, with an aim to characterise physiological changes in response to therapy. 9, 17 All studies were manufacturer-sponsored. Hypoglossal nerve stimulation for sleep apnoea: August

21 Van de Heyning et al (2012) 4 Study description This prospective multi-centre case-series study (level IV intervention evidence) aimed to examine the safety and preliminary effectiveness of the Inspire Upper Airway Stimulation system. The study was conducted in two stages: in the first stage, patients were enrolled based on broad selection criteria (n=22); while additional patients were recruited for the second stage based on the outcomes of stage one (n=9). Patients who met the inclusion criteria (stage one: moderate to severe OSA, failure of or intolerance to CPAP treatment, body mass index (BMI) <35 kg/m² and AHI 25 events/h; stage two: as in stage one but BMI 32 kg/m² and AHI 50/h) underwent surgical implantation of the hypoglossal nerve stimulation system, under general anaesthesia. Nine patients were implanted with the Inspire Upper Airway Stimulation system in phase two of the study; however, one patient was excluded from the analysis within the period of six months post-implantation due to the inability to activate the tongue with amplitude within the allowable range. Therapy was activated four weeks post-implant, at which point the device was adjusted to produce optimal results. Therapeutic titration was made at 2- and 4- month post-implant sleep studies if necessary. Study (effectiveness) data were recorded at baseline and six months post-implant. Three participants were excluded from the effectiveness analysis, two had explantation of the device (see Safety section below), and one was lost to follow-up. Responders were predefined as those with an AHI reduction of at least 50 per cent from baseline, and an AHI less than 20 at six months post-implant. Safety Two (6.4%) serious device-related adverse events were reported during the 6-month post-implant period. One participant experienced pain and swelling immediately post-implant which resolved with antibiotic treatment. The other experienced a delayed device-related post-implant infection and required device explantation. One (3.2%) additional participant had the device removed due to inadequate tongue response. The majority of non-serious adverse events were due to postoperative pain and stiffness (7/31) and sore throat (4/31). All non-serious events resolved without intervention. Effectiveness The effectiveness of the therapy was assessed during in-laboratory polysomnography (PSG) and the completion of the ESS and FOSQ questionnaires. In the first stage of the study, there was no change in baseline AHI when all patients were considered. Of the 20 patients who were assessed at six months, six (30%) met the responder definition, with significant reduction in AHI and ODI compared to Hypoglossal nerve stimulation for sleep apnoea: August

22 baseline (p<0.001; note that 14 patients did not meet the responder definition). It was identified that the responders had significantly lower AHI (26.1 ± 5.0 for responders compared to 51.1 ± 16.8 for non-responders, p<0.01) and BMI (27.8 ± 1.8 responders, 30.7 ± 2.6 non-responders, p<0.05) levels at baseline. Statistical analyses determined the predictors of therapy to be a combined criteria of AHI less than 50/h and BMI of less than 32 kg/m² (p=0.01). Of the 11 participants who met this criteria, six (55%) were responders. Additional participants were recruited for the second stage of the study on the basis of this new criteria (n=9). Placement of the stimulating electrode changed between the stages: placement in the second stage was only around the medial division of XII hypoglossal nerve branch, which innervates the genioglossus muscle. In the first stage, the electrode was placed prior to the branching of the XII branch into its medial and lateral parts; the latter innervates other muscles of the tongue. One participant was excluded from 6-month assessment due to explantation of the device (see Safety section above). In the eight participants assessed at six months, AHI was reduced significantly from 38.9 at baseline to 10 (-74%; p<0.01). A significant improvement in ODI was also observed (p<0.01). In total, seven of eight (87.5%) participants met the responder definition. Of the participants who were followed up at six months (n=28), ESS improved from 11.0 at baseline to 7.6 after six months (p<0.01), and FOSQ score improved from 89.1 to (p=0.02). Eastwood et al (2011) 1 Study description The aim of this single-arm, open-label case-series study (level IV intervention evidence) at four clinical sites in Australia was to examine the safety and effectiveness of the Apnex HGNS System in the treatment of OSA, with long-term follow-up to three years; the publication reports data to six months. Patients (n=21) who met the inclusion criteria (moderate to severe OSA, failure of or intolerance to CPAP treatment, age 21 to 70 years, BMI 40 kg/m² and AHI between 20 and 100/h with 15 events/h occurring in non-rapid eye movement sleep with a predominance of hypopnoeas) underwent surgical implantation of a hypoglossal nerve stimulation system. Only 21 of 33 patients assessed for eligibility were enrolled and all patients were overweight or obese (mean BMI 32.7 kg/m 2, range ). The surgery took a mean of three hours (189 ± 58 minutes). Therapy was initiated 30 days post-implant, with daytime and overnight studies used to determine the effectiveness in reducing OSA severity. Baseline data were recorded one month post-implant, with sleep studies repeated again at three and six months. The severity of OSA was defined by AHI at baseline (one month) and three and six months post-implant. Participants additionally completed five questionnaires at these time points, including the FOSQ, ESS and others relating to changes in Hypoglossal nerve stimulation for sleep apnoea: August

23 quality of life, measures of sleep quality and levels of depression. It appears that the study used a shortened version of the FOSQ questionnaire (range 0-20 compared to for the full version); however, this was not explicitly reported. Data to 12 months have recently been presented that show efficacy is maintained. Safety All adverse events were reported regardless of severity or whether the event was device or therapy-related. The primary safety endpoint was the rate of freedom from serious adverse events at implant and at three and six months. Adverse events were considered serious if they resulted in patient death, life-threatening illness or injury, permanent impairment of body structure or function (including medical or surgical intervention to prevent), or in-patient hospitalisation (> 24 h). There were no deaths in the study, nor were there any unanticipated adverse effects related to the device. Two serious adverse events were observed (9.5%): the device was explanted in one participant due to a procedure-related haematoma and infection while the second required an additional procedure for lead replacement due to a cuff dislodgment (considered both a procedural- and device-related event). A third patient elected for explantation of the device in order to proceed with an alternative surgical treatment. Numbness and pain at the incision site were the most common procedure-related adverse events, with five (23%) and three (14%) respective reports. Of the therapyrelated adverse events, eight patients (38%) had abrasions on the ventral surface of the tongue due to movement over the lower incisors. These were short in duration and treated with plastic guards placed over the mandibular teeth. Resolution occurred in all cases. The rate of freedom from serious adverse events at three months was 90.2 per cent (19/21) and at six months, 85.2 per cent (18/21). Effectiveness The primary effectiveness endpoints were the mean change from baseline in the AHI and FOSQ score at three and six months post-implant. The most common definition of surgical success includes the postoperative reduction of AHI to less than 20 events/h and a greater than 50% postoperative reduction of AHI. Twelve of 21 participants (57%) met these criteria after six months of therapy. Overall, AHI decreased from 43.1 at baseline to 19.1 (-56%) at three months (p<0.001), and 19.5 (-55%) at six months (p<0.001). Additionally, participants with BMI less than 35 kg/m² were observed to have a lower AHI at six months post-implant, compared to those with a BMI greater than 35 kg/m². The total FOSQ score changed from 14.4 at baseline to 17.0 at three months (p<0.001), and 16.7 at six months (p<0.001). FOSQ scores that exceed a 2-point change were considered to be clinically meaningful improvements in daily life activities. Hypoglossal nerve stimulation for sleep apnoea: August

24 The secondary effectiveness endpoints included therapy utilisation, changes from baseline measurement of other PSG-based measures that relate to sleep disordered breathing and sleep architecture, and changes in the questionnaire scores. Compliance with the therapy was high, with use on 89 ± 15 per cent of nights, at an average of 5.8 ± 1.6 hours per night. The ESS score changed from an abnormal sleepiness baseline score of 12.0 to 7.9 and 8.1 at three and six months respectively (p<0.001). These scores are within the normal range on the ESS. Changes in the other sleep-related questionnaire scores reflected some improvement in sleep, but restoration to normal range was not observed for all cases. Schwartz et al (2012) 9 Study description The aim of this study (level IV intervention evidence) was to characterise airflow responses to hypoglossal nerve stimulation therapy. Participants who met the eligibility criteria (AHI 20) underwent surgical implantation of the device (n=30, a number of these participants were reported in the Eastwood et al (2011) 1 study but it was unclear how many). The differences between alternating stimulated and unstimulated breaths during sleep were analysed. Therapy was also applied with increasing amplitudes. Effectiveness Therapy was observed to increase maximal inspiratory airflow relative to unstimulated adjacent breaths at mid- and high-level amplitudes. At the mid-level, inspiration was observed to be flow limited, with flow limitation abolished at the high-level amplitude. The airflow response increased from 215 ± 21 ml/s without stimulation to 509 ± 37 ml/s upon stimulation. The authors concluded that the therapy produced marked dose-related increases in airflow without arousing patients from sleep. Increases in airflow were of sufficient magnitude to eliminate inspiratory airflow limitation in most patients suggesting potential efficacy across a broad range of OSA severity. Goding et al (2012) 17 Study description The aim of this study (level IV intervention evidence) was to characterise the changes in the airway spaces of the pharynx during hypoglossal nerve stimulation. Participants who met the inclusion criteria (moderate to severe OSA, failure or intolerance of CPAP treatment, BMI 40 kg/m² and AHI events/h) underwent surgical implantation of the device (n=26, 17 participants were in the Eastwood et al (2011) 1 study). Cinefluoroscopy image acquisition started and stopped approximately one second before and one second after stimulation in participants under general Hypoglossal nerve stimulation for sleep apnoea: August

25 anaesthesia. Measurements of the pharyngeal lucency at the inferior and superior borders of the mandibular body were recorded (PLIMB and PLSMB). Effectiveness Prior to stimulation, PLIMB and PLSMB were not visible in any of the participants. The average width of the PLIMB with stimulation was 9 ± 3 mm, with a width of 13 ± 5 mm for PLSMB. The presence of PLIMB and PLSMB indicate an increase in the amount of total airway available. The authors concluded, In a majority of subjects examined, hypoglossal nerve stimulation resulted in opening of the retropalatal space. Hypoglossal nerve stimulation produced pharyngeal opening in the retrolingual area and anterior to the palate independent of BMI. Cost impact The manufacturers of the hypoglossal nerve stimulation systems have been contacted regarding the costs of the device; with the cost of the aura6000 system indicated to be US$30,000, with a 15 year estimated lifetime. 7 Other costs related to the therapy include the costs of the surgery, anaesthesia and postoperative and follow-up sleep studies. During the Australian clinical trial, the average surgery time was three hours; however, two manufacturers have indicated an estimated surgery time of approximately 90 minutes; 1, 7 with an overnight hospital stay at the discretion of the physician. 7 Clinical advise suggests that with experience and expertise in implantation of the device, surgical time would be expected to decrease, and most patients would be discharged on the same day, given the completion of surgery by mid-afternoon. In comparison, the average cost of a CPAP machine, accessories and spare parts in Australia in 2010 was $ These can be purchased or rented at the patient s expense; some states may offer subsidies for CPAP treatment, and some private health insurance companies assist with the cost of the machine. 18 A cost-utility analysis performed by one of the manufacturers has concluded that the therapy is a highly cost effective intervention for OSA from a health system perspective and dominant from a societal perspective. 7 The incremental cost effectiveness ratios (ICERs) were calculated for both the hypoglossal nerve stimulation therapy and CPAP in comparison to no treatment, and were based on the assumption that the therapy is approximately as effective as CPAP. As the therapy consists of an implantable device, with no tubes, noise or need for a mask, the added convenience of the therapy has been estimated to lead to higher compliance, resulting in improved cost effectiveness. 7 The cost-utility analysis may be highly optimistic, and premature given the limitations of the evidence base. Implantation of the device requires no special instrumentation, and can be performed by surgeons familiar with the surgical techniques and neuroanatomy of Hypoglossal nerve stimulation for sleep apnoea: August

26 the upper neck, which are typically ear, nose and throat, maxillofacial and neurosurgeons. 7 Ethical, cultural or religious considerations Access to surgeons and surgical lists in the public sector may be a limiting factor. Other issues All studies included in this brief were manufacturer-sponsored. Training techniques for optimal placement of the electrode around the hypoglossal nerve must be developed for better effectiveness and to avoid nerve injury. Upcoming manufacturer-sponsored clinical trials: ImThera Medical, Inc. has conducted a safety and effectiveness study for the aura6000 system, which was scheduled for completion at the end of Safety and effectiveness results at 12 months have been published during the completion of this brief. The study included 14 participants and observed significant reductions in the AHI and ODI indices. Device-related faults that resulted in re-operation were reported, in addition to two cases of transient tongue paresis. 19 Inspire Medical Systems, Inc. has a large (n=900) randomised Phase III trial underway with a 12-month follow-up period. The estimated study completion date is March Details specifying the type of intervention and the nature of the control group were not provided. 20 Longer term follow-up of the HGNS System from the Eastwood et al (2011) 1 study is estimated for completion in May The safety and effectiveness trial for the same device conducted in the USA is due for completion in Apnex Medical, Inc. is also recruiting for a Phase III randomised clinical trial undertaken predominantly in Australia and the US (estimated n=132, completion in 2017). 22 Summary of findings The use of hypoglossal nerve stimulation devices in the treatment of OSA appears to be relatively safe; however, the effectiveness data are based on small, low-quality studies. Study participants who exhibited positive treatment effects were observed to have lower AHI and BMI levels at baseline, and as such, may not be representative of the population with moderate to severe OSA. Therefore, large randomised controlled trials are required in order to adequately determine the effectiveness, in terms of clinical response rates; and safety, including the rate of explantation and infection. As the included studies were small with relatively short follow-up, clinician advice indicated that the rate of these complications is likely to increase. Hypoglossal nerve stimulation for sleep apnoea: August

27 Consequently, should the therapy be introduced, a record of the implanted devices should be maintained on a central registry. Evidence to date only supports the use of the technology for the treatment of mild to moderate (not severe) OSA, and that at the quoted price, is unlikely to be offered to patients in the public sector. Compared to the non-invasive comparator CPAP, use of the technology may pose great harm at considerable cost for benefit which is not currently proven. HealthPACT assessment: Based on the low level, small feasibility studies included in this brief and the use of the device at an experimental level only, HealthPACT recommended that the technology be monitored for 24 months. Number of studies included All evidence included for assessment in this Technology Brief has been assessed according to the revised NHMRC levels of evidence. A document summarising these levels may be accessed via the HealthPACT web site. Total number of studies 4 Total number of level IV studies 4 References 1. Eastwood, P. R., Barnes, M. et al (2011). 'Treating obstructive sleep apnea with hypoglossal nerve stimulation', Sleep, 34 (11), Young, T., Skatrud, J. & Peppard, P. E. (2004). 'Risk factors for obstructive sleep apnea in adults', JAMA, 291 (16), Levy, P., Tamisier, R. et al (2011). 'Sleep apnoea syndrome in 2011: current concepts and future directions', Eur Respir Rev, 20 (121), Van de Heyning, P. H., Badr, M. S. et al (2012). 'Implanted upper airway stimulation device for obstructive sleep apnea', Laryngoscope, 122 (7), Rosario, I. C. (2011). 'Obstructive sleep apnea: a review and update', Minn Med, 94 (11), Eisele, D. W., Smith, P. L. et al (1997). 'Direct hypoglossal nerve stimulation in obstructive sleep apnea', Arch Otolaryngol Head Neck Surg, 123 (1), ImThera Medical Inc. (2012). Cost Utility Analysis of the aura6000 TM targeted Hypoglossal Nerve Stimulation System. ImTherma Medical Inc., San Diego. 8. Apnex Medical Inc. (2011). Apnex Medical Inc. Newsroom [Internet]. Available from: =91747FCE78AB427CAD868A3662A99326 [Accessed 17 May 2012]. 9. Schwartz, A. R., Barnes, M. et al (2012). 'Acute upper airway responses to hypoglossal nerve stimulation during sleep in obstructive sleep apnea', Am J Respir Crit Care Med, 185 (4), Hypoglossal nerve stimulation for sleep apnoea: August

28 10. Deloitte Access Economics (2011). Re-awakening Australia: the economic costs of sleep disorders in Australia, Commissioned by the Sleep Health Foundation. Available from: Australian Institute of Health and Welfare (2011). Separation statistics by principal diagnosis in ICD-10-AM, Australia, to , Separation statistics by principal diagnosis in ICD-10-AM, Australia, to [Internet]. AIHW. Available from: [Accessed 7 May 2012]. 12. Australian Institute of Health and Welfare (2011). Australian hospital statistics , Canberra. Report No.: Health services series no. 43. Cat. no. HSE 117 [Internet]. Available from: &tab= Paine, S. J., Harris, R. B. & Mihaere, K. M. (2011). 'Managing obstructive sleep apnoea and achieving equity: implications for health services', N Z Med J, 124 (1334), ClinicalTrials.gov (2011). Australian Clinical Study of the Apnex Medical HGNS System to Treat Obstructive Sleep Apnea. Trial Identifier: NCT [Internet]. Available from: [Accessed 31 May 2012]. 15. Medicare Australia (2012). Medicare Benefits Schedule item statistics [Internet]. Available from: [Accessed 7 May 2012]. 16. Sundaram, S., Bridgman, S. A. et al (2005). 'Surgery for obstructive sleep apnoea', Cochrane Database Syst Rev, (4), CD Goding, G. S., Jr., Tesfayesus, W. & Kezirian, E. J. (2012). 'Hypoglossal nerve stimulation and airway changes under fluoroscopy', Otolaryngol Head Neck Surg, 146 (6), Australian Lung Foundation (2011). Obstructive Sleep Apnoea [Internet]. Available from: [Accessed 7 May 2012]. 19. Mwenge, G. B., Rombaux, P. et al (2012). 'Targeted hypoglossal neurostimulation for obstructive sleep apnoea. A 1 year pilot Study', Eur Respir J. doi: / ClinicalTrials.gov (2012). Stimulation Therapy for Apnea Reduction ( Trial Idenitifier: NCT [Internet]. Available from: [Accessed 7 May 2012]. 21. ClinicalTrials.gov (2011). US Clinical Study of the Apnex Medical Hypoglossal Nerve Stimulation (HGNS) System to Treat Obstructive Sleep Apnea. Trial identifer: NCT [Internet]. Available from: /NCT [Accessed 7 May 2012]. 22. ClinicalTrials.gov (2011). Apnex Clinical Study of the Hypoglossal Nerve Stimulation (HGNS ) System to Treat Obstructive Sleep Apnea. Trial Identifier: Hypoglossal nerve stimulation for sleep apnoea: August

29 NCT [Internet]. Available from: [Accessed 7 May 2012]. Search criteria to be used Hypoglossal nerve stimulation, obstructive sleep apnoea Hypoglossal nerve stimulation for sleep apnoea: August