pii: jc- 00477-14
http://dx.doi.org/10.5664/jcsm.5390
S CI E NT IF IC IN VES TIGATIONS
Upper Airway Stimulation for Obstructive Sleep Apnea: Self-Reported Outcomes at 24 Months Ryan J. Soose, MD1; B. Tucker Woodson, MD2; M. Boyd Gillespie, MD3; Joachim T. Maurer, MD4; Nico de Vries, MD5; David L. Steward, MD6; Kingman P. Strohl, MD7; Jonathan Z. Baskin, MD7; Tapan A. Padhya, MD8; M. Safwan Badr, MD9; Ho-sheng Lin, MD9; Olivier M. Vanderveken, MD, PhD10; Sam Mickelson, MD11; Eileen Chasens, PhD12; Patrick J. Strollo Jr, MD1; On Behalf of STAR Trial Investigators University of Pittsburgh School of Medicine, Pittsburgh, PA; 2Medical College of Wisconsin, Milwaukee, WI; 3Medical University of South Carolina, Charleston, SC; 4University Hospital Mannheim, Mannheim, Germany; 5Saint Lucas Andreas Hospital, Amsterdam, Netherlands; 6University of Cincinnati Medical Center, Cincinnati, OH; 7Case Western Reserve University, Cleveland, OH; 8University of South Florida College of Medicine, Tampa, FL; 9Wayne State University, Detroit, MI; 10Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; 11Advanced ENT, Atlanta, GA; 12University of Pittsburgh School of Nursing, Pittsburgh, PA 1
Objectives: To evaluate the long-term (24-mo) effect of cranial nerve upper airway stimulation (UAS) therapy on patient-centered obstructive sleep apnea (OSA) outcome measures. Methods: 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 mo and 24 mo, 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. Results: Significant improvement in mean FOSQ score was observed from baseline (14.3) to 12 mo (17.3), and the effect was maintained at 24 mo (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 mo (7.0) and 24 mo (7.1). Self-reported snoring severity showed increased percentage of “no” or “soft” snoring from 22% at baseline to 88% at 12 mo and 91% at 24 mo. UAS demonstrated large effect size (> 0.8) at 12 and 24 mo for overall ESS and FOSQ measures, and the effect size compared favorably to previously published effect size with other sleep apnea treatments. Conclusions: In a selected group of patients with moderate to severe OSA and body mass index ≤ 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-y follow-up period. Keywords: sleep apnea, surgery, neurostimulation, hypoglossal nerve, cranial nerve stimulation Citation: Soose RJ, Woodson BT, Gillespie MB, Maurer JT, de Vries N, Steward DL, Strohl KP, Baskin JZ, Padhya TA, Badr MS, Lin H, Vanderveken OM, Mickelson S, Chasens E, Strollo Jr PJ, STAR Trial Investigators. Upper airway stimulation for obstructive sleep apnea: self-reported outcomes at 24 months. J Clin Sleep Med 2016;12(1):43–48.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: Hypoglossal cranial nerve stimulation therapy consists of a surgically implantable and medically titratable second-line treatment option for obstructive sleep apnea (OSA), and was previously shown to provide safe and effective short-term management for patients who meet specific clinical and anatomical inclusion criteria. Since OSA represents a chronic condition requiring longitudinal care, this study was undertaken to examine the durability of effect of the therapy on patient-centered outcome measures at 24 months after implantation. Study Impact: This study demonstrates long-term clinically meaningful improvement in snoring, daytime alertness, and sleeprelated quality of life with hypoglossal cranial nerve stimulation therapy. The treatment effect size is large and is maintained across a 2 year follow-up period, providing support for consideration of this therapeutic option in selected patients who are unable to adhere to positive pressure therapy.
Patients suffering from moderate to severe obstructive sleep apnea (OSA) commonly report symptoms consistent with excessive daytime sleepiness, neurocognitive dysfunction, and impaired quality of life.1 Although the underlying pathophysiologic mechanisms of OSA are complex, multifactorial, and variable among patients, the goals of any longitudinal care model are generally consistent across all patients and fall into two categories: (1) to improve sleep related symptoms and quality-of-life measures, and (2) to reduce cardiovascular and related health risks. Continuous positive airway pressure (CPAP) therapy has a wealth of data on safely and effectively accomplishing these goals and remains the standard first-line therapy.2,3 Despite the low morbidity and high effectiveness of CPAP, long-term adherence and acceptance rates are suboptimal and necessitate consideration of alternative treatment options in many patients.4–6 A variety of interface-related or pressure-related side effects as well as psychosocial barriers frequently preclude
adequate use. Recent multicenter trials reported 6-mo adherence rates of only 39% to 50%.5,6 A universally accepted second-line therapy does not exist; however, oral appliance 43
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therapy, upper airway reconstructive surgery, weight loss, positional therapy, and more recently, hypoglossal cranial nerve upper airway stimulation (UAS) therapy can provide effective management in patients with OSA who have certain clinical, polysomnographic, and anatomical characteristics. In a prospective multicenter trial, UAS therapy has been shown to provide safe and effective short-term management in a cohort of patients with moderate to severe OSA who were unable to achieve benefit with positive pressure therapy.7 The randomized withdrawal portion of the study demonstrated that withdrawal of therapy leads to recurrence of OSA and that resumption of nightly therapy restores subjective and objective benefits.8 These observations emphasize the need to monitor durability of effect over time, particularly because OSA is most commonly a chronic long-term condition that requires effective management throughout the lifespan. The subjective sleep related symptoms and quality-of-life effects of OSA constitute the patient-centered experience of disease presentation, cost-benefit assessment, and treatment outcomes.9 Excessive daytime sleepiness and impairment of daytime functioning, for example, are consequences of the disease that prompt patients to seek care and are associated with an increased motor vehicle accident risk and increased health care utilization.10 These important outcome measures are not adequately represented on objective sleep laboratory testing. As previously stated by Flemons,11 for the majority of patients without significant medical comorbidities, “the primary reason to test for and treat sleep apnea is the potential to improve the quality of life. Clinicians do not make decisions about treatment on the basis of the apnea–hypopnea index alone because it correlates poorly with the quality of life and the severity of symptoms.”11 The aim of this study was to evaluate the long-term (24-mo) effect of UAS therapy on (1) intrusive snoring as measured by self- and bedpartner-report, (2) the propensity for waketime sleepiness as measured by the Epworth Sleepiness Scale (ESS), and (3) daytime functioning as measured by the Functional Outcomes of Sleep Questionnaire (FOSQ) including subscale analysis.
lead that was placed on the distal medial branch of the right hypoglossal nerve to recruit protrussor muscles of the tongue; a pressure sensing lead placed within the intercostal muscles; and an implantable pulse generator placed in the midinfraclavicular region that delivers electrical stimulation to the twelfth cranial nerve, synchronous with the respiratory cycle.
Subjective Outcomes
Self-reported outcomes were collected at baseline, 12 mo, and 24 mo. Subjective daytime sleepiness was measured with the ESS, which is a validated eight-item instrument assessing the propensity to fall asleep.12 Sleep related quality of life was measured with the FOSQ, a validated self-reported measure designed to assess the effect of disorders of excessive sleepiness on daily functional status.13 Additional analysis included the five FOSQ subscales: activity level, general productivity, social outcome, intimacy and sexual relationships, and vigilance, as well as the FOSQ-10, a shorter version of the original 30-item FOSQ with potential for easier and improved clinical applicability.14 Snoring intensity was reported by the participant and by the bed partner on a categorical scale (no snoring, soft snoring, loud snoring, very intense snoring, or bed partner leaves room).
Statistical Analysis
All results of continuous variables are expressed as mean ± standard deviation (SD). A paired t-test was used to evaluate the difference of between baseline and 12 mo, between baseline and 24 mo, and between 12 mo and 24 mo to detect at the 5% significance level. The mean change with associated 95% confidence limits was calculated. Effect size was calculated as (posttreatment mean – baseline mean)/(baseline SD) as per Kazis et al.15 An effect size between 0.2 to 0.5 is considered small, 0.5 to 0.8 is considered moderate, and greater than 0.8 is considered large. R ES U LT S
Demographics
The study cohort consisted of 126 participants--mostly Caucasian (97%), male (83%), middle aged (54.5 ± 10.2 y, ranged from 31 to 80 y), and overweight (BMI of 28.4 ± 2.6 kg/m2, ranged from 18.4 to 32.5 kg/m 2). A total of 124 participants completed follow-up at 12 mo (one participant died due to an unrelated cardiac cause, and one participant requested elective explantation due to lack of satisfaction with therapy response). A total of 111 participants (88% of 126) completed all followup questionnaires at 24 mo. Three participants were lost to long-term follow up and 10 participants missed the data collection during the 24-mo visit window. The mean BMI was 28.5 ± 2.7 at 12 mo and 28.5 ± 3.2 at 24 mo, both unchanged from baseline.
METHODS
Study Design
The Stimulation Treatment for Apnea Reduction (STAR) trial was a multicenter, prospective trial with 126 participants serving as their own control. The primary assessments were safety and effectiveness of UAS therapy at 12 mo. Long-term follow-up visits were performed every 6 mo, including report of adverse events, and assessment of quality of life using standardized questionnaires. The current report aims to summarize the patient-centered outcomes of UAS therapy at 24 mo postimplantation. Key selection criteria of the STAR trial included a history of moderate to severe OSA, nonadherence to CPAP, BMI equal to or less than 32 kg/m2, and absence of complete concentric collapse at the level of the soft palate during sedated endoscopy. Qualified participants received an implanted device that consists of three parts: a stimulation Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016
Epworth Sleepiness Scale
There was a significant decrease in self-reported daytime sleepiness measured by the mean ESS score from baseline to 12 mo (p < 0.01), as well as at 24 mo (p < 0.01). Mean ESS 44
RJ Soose, BT Woodson, MB Gillespie et al. Upper Airway Stimulation for OSA
Table 1—ESS and FOSQ. Variables ESS FOSQ Activity Productivity Social Intimacy Vigilance
Baseline mean (SE) 11.6 (0.4) 14.3 (0.3) 2.7 (0.1) 3.0 (0.1) 3.1 (0.1) 2.7 (0.1) 2.7 (0.1)
12-mo mean (SE) 7.0 (0.4) 17.3 (0.3) 3.4 (0.1) 3.3 (0.1) 3.6 (0.1) 3.3 (0.1) 3.4 (0.1)
24-mo mean (SE) 7.1 (0.4) 17.2 (0.3) 3.4 (0.1) 3.6 (0.1) 3.7 (0.1) 3.3 (0.1) 3.3 (0.1)
Mean Baseline – 12-mo difference (95% CI) 4.7 (3.8 to 5.6)* −2.9 (−3.5 to −2.4)* −0.7 (−0.8 to −0.5)* −0.5 (−0.6 to −0.4)* −0.5 (−0.7 to −0.3)* −0.6 (−0.8 to −0.4)* −0.7 (−0.8 to −0.5)*
Mean Baseline – 24-mo difference (95% CI) 4.4 (3.4 to 5.4)* −3.0 (−3.5 to −2.4)* −0.7 (−0.9 to −0.6)* −0.5 (−0.6 to −0.4)* −0.5 (−0.7 to −0.4)* −0.6 (−0.8 to −0.4)* −0.7 (−0.8 to −0.5)*
Mean 12 mo – 24-mo difference (95% CI) 0.0 (−0.6 to 0.6) 0.2 (−0.5 to 0.1) 0.0 (−0.1, 0.02) −0.0 (−0.1, −0.04) −0.0 (−0.2, 0.03) 0.0 (−0.3, 0.07) 0.1 (−0.12, 0.04)
*P < 0.01. ESS, Epworth sleepiness scale; FOSQ, Functional Outcomes of Sleep Questionnaire; SE, standard error.
Figure 1—Significant improvement in short version Functional Outcomes of Sleep Questionnaire (FOSQ-10) at 12 months is maintained at 24 months after implant.
Table 2—Effect size of upper airway stimulation on ESS FOSQ, and FOSQ subscales. Variables ESS FOSQ Activity Productivity Social Intimacy Vigilance
Effect Size at 12 mo 0.94 0.91 0.87 0.74 0.57 0.62 0.88
Effect Size at 24 mo 0.87 1.00 0.94 0.77 0.66 0.66 0.95
ESS, Epworth Sleepiness Scale; FOSQ, Functional Outcomes of Sleep Questionnaire. Reported as mean and standard deviation in error bar.
of effect was seen in the shorter version FOSQ-10 (Figure 1). Compared to baseline, the percentage of participants reporting a clinically significant improvement (increase ≥ 2) in FOSQ was 53% at 12 mo and 59% at 24 mo. The percentage of participants reporting a significant reduction (decrease ≥ 2) in FOSQ was 3.3% at 12 mo and 5.4% at 24 mo.
remained unchanged from 12 to 24 mo (Table 1). The report of ESS score < 10, often considered acceptable daytime alertness, increased from 32.5% at baseline, to 74.8% at 12 mo, and 77.5% at 24 mo among all participants. Compared to baseline, the percentage of participants with a significant reduction (change of 2 or more) in ESS score was 72% at 12 mo and 70% at 24 mo. The percentage of participants with an increase in ESS score (change of 2 or more) was 7% at 12 mo and 9% at 24 mo.
Effect Size
UAS showed large effect size (> 0.8) at 12 and 24 mo for overall ESS and FOSQ measures. Moderate (> 0.5) to large effect size was also observed among all individual subscales of FOSQ measures (Table 2).
Functional Outcome of Sleep Questionnaire
Self-reported Snoring
Self-reported daytime functioning as measured by the FOSQ improved from baseline to 12 mo (p < 0.01), and maintained improvement at 24 mo (p < 0.01) (Table 1). The mean change from baseline to 12 mo was 2.9 ± 0.3 (standard error [SE]), and 2.7 ± 0.3 (SE) from baseline to 24 mo. There were consistent and significant improvements (p < 0.01) in all five subscales of the FOSQ (activity level, general productivity, social outcomes, intimacy and sexual relationships, and vigilance) from baseline to 12 mo, as well as from baseline to 24 mo. There were no changes of FOSQ and its subscales from 12 mo to 24 mo. The percentage of participants who reported a FOSQ score of > 17.9 (generally considered consistent with normal sleep related quality of life) increased from 15.9% at baseline to 54.5% at 12 mo, and 53.2% at 24 mo. Similar change and durability
Snoring severity based on participant self-report showed increased percentage of “no” or “soft” snoring from baseline of 22% to 88% at 12 and 91% at 24 mo. Reports collected from bed partners supported participant self-report with overall reduced snoring level with therapy use. The percent of “bed partner leaves room” reduced from 30% at baseline to 3% at 12 and 24 mo (Figure 2). D I SCUS S I O N The goal of this study was to examine the durability of treatment effect of upper airway cranial nerve stimulation therapy 45
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Figure 2—Self-reported and bed partner-reported snoring intensity on a 5-item analog scale as measured at baseline, 12 months, and 24 months.
Percentage of participants reporting “no” or “soft” snoring increased from 22% at baseline to 88% at 12 months and 91% at 24 months.
over a 2-y period using validated questionnaires of patientcentered outcome measures that reflect the sleep related symptoms and quality-of-life components of the disease. The major findings of the study were: (1) UAS therapy provides clinically meaningful and statistically significant improvements in key patient-centered OSA outcome measures, including snoring, daytime sleepiness, and sleep related quality of life, and (2) the beneficial effect on subjective sleep outcomes is maintained through the first 2 y of treatment. This sustainability is critical in a chronic condition such as OSA that requires long-term management and has not been previously demonstrated in other surgical studies. The detrimental effect of OSA on activities of daily living and quality-of-life measures contributes significantly to the disease morbidity as well as the financial burden of patients with OSA on the health care system. Untreated moderatesevere OSA has been associated with increased health care costs and physician visits, increased motor vehicle accidents, increased workplace errors, and loss of work productivity.16,17 Although CPAP, the standard first-line therapy, is highly effective, suboptimal patient acceptance and adherence frequently limit long-term results.18–20 As such, alternative medical or surgical therapies are required to effectively manage a large portion of the OSA population. Numerous upper airway reconstructive surgical procedures have been described to reduce OSA severity by improving the anatomical and structural vulnerability of the upper airway. The routine use of many upper airway surgical procedures is limited by increased risk and morbidity as well as a relative lack of high-quality data on the consistency of results. Most surgical studies are also limited by a lack of long-term followup and sustainability of effect, which is important because OSA is chronic condition requiring ongoing reevaluation and management as part of a longitudinal care model. UAS therapy differs markedly from traditional OSA surgery in many respects. In patients with moderate to severe OSA and specific clinical and anatomical characteristics, UAS therapy has previously been shown to provide multilevel (retropalatal and retrolingual) improvement in airway dimension and airflow by augmenting neuromuscular function of Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016
specific upper airway muscles while avoiding anatomy-altering surgery – dramatically reducing side effects, recovery, and risk.21–23 Prior reports have also demonstrated significant and sustained reductions in polysomnographic measures of OSA severity over a 12- to 18-mo follow-up period.7,8 At 18 mo, the median apnea-hypopnea index (AHI) was reduced by 67.4% from the baseline of 29.3 to 9.7/h, and the median 4% oxygen desaturation index (ODI) was reduced by 67.5% from 25.4 to 8.6/h. A treatment AHI of less than 15/h was achieved in 69% of participants at 18 mo. Although patient-reported outcome measures are subjective, multifaceted, and variable among certain subpopulations, it is precisely these self-reported symptoms that often drive patients to seek care from health care professionals. Polysomnography measures alone do not capture important aspects of OSA disease burden and treatment outcomes.24,25 Subjective measures of patients’ daytime sleepiness state, and how the sleepiness affects daily function and quality of life, are likely to contribute significantly to the long-term disease morbidity as well as direct and indirect health care costs. A large retrospective OSA cohort rated snoring as the OSA symptom of highest importance and magnitude from the patient’s perspective.26 With increasing emphasis on quality outcomes relative to health care cost, the long-term qualityof-life outcome measures for OSA treatment have clinical and economic relevance. This study demonstrated that UAS therapy provides clinically and statistically significant improvements in self-reported quality of life, daytime alertness, and snoring; and the treatment effect was maintained over the first 2 y of treatment. Improvement in the FOSQ-30 and subscale analysis was similar to improvement observed in the FOSQ-10 supporting the notion that the shorter FOSQ-10 accurately reflects the original longer version and may be easier to implement in the clinical setting and in future studies. Although the reliability of self-report and bed partner-report of snoring intensity may be questioned, there is currently no accepted standard objective measure of snoring, and it is precisely this subjective report that often drives evaluation and management. The majority of participants in this cohort achieved successful reduction 46
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in their snoring from loud or disruptive levels to soft or no snoring. In this study, UAS therapy demonstrated large effect size (> 0.8) in quality-of-life measures as assessed by ESS and FOSQ. Cohort studies have been previously shown to provide reliable data with a large effect size (i.e., > 0.5). When effect sizes are small (i.e., < 0.3), the amount of uncontrolled data and uncontrollable confounding inherent to such designs is as large as the postulated effect size.27 In a comparison between multilevel temperature-controlled radiofrequency tissue ablation and CPAP for treatment of mild to moderate OSA, the effect size of ESS was 0.5 for ablation and 0.4 for CPAP, and the effect size of FOSQ was 0.66 for ablation and 0.6 for CPAP.28 Thus, the effect size results suggest that, in the setting of an uncontrolled prospective cohort study, UAS therapy convincingly provides strong improvement in daytime sleepiness and sleep related quality of life, and the effect compares favorably to CPAP as well as other second-line therapies. To our knowledge, this is the first study of a surgical intervention for OSA that evaluated quality of life outcome measures 2 y postoperatively. The strengths of this study include the large prospective cohort and high percentage of available long-term follow-up data. Limitations relate to the lack of a control group and the highly selected patient population based on clinical, polysomnographic, and endoscopic/anatomical screening criteria, which may limit generalizability of these findings to other OSA populations. Such limitations of the current uncontrolled study design may also introduce the possibility that a placebo effect could have contributed, at least in part, to the study findings. To corroborate these improvements in quality- of-life measures, long-term sleep laboratory data and other objective outcome measures, in conjunction with responder versus nonresponder analysis, are also needed to further demonstrate therapy effectiveness across a longitudinal care model.
SE, standard error STAR trial, Stimulation Treatment for Apnea Reduction trial UAS, upper airway stimulation S TA R T R I A L I N V ES T I G ATO RS Study Center/ Facility Name
Location
Investigators
Study Staff
Advanced ENT
Atlanta, GA
Sam Mickelson, MD
Faraa Mobini
Borgess Research Institute
Kalamazoo, MI
Mark Goetting, MD L. Steven Szeles, MD
Rebecca Timpe,
Hôpital de Pellegrin
Bordeaux, France
Piérre Philip, MD Piérre-Jean Monteyrol, MD
Céderic Valtat
University Hospitals Cleveland
Cleveland, OH
Kingman Strohl, MD Jonathan Baskin, MD
Mary Andrews Julie Heald
California Sleep Institute
Palo Alto, CA
Joseph Roberson, MD Don Sesso, MD
Jokasta Cordon
Hôpital Foch
Suresnes, France
Frédéric Chabolle, MD Marc Blumen, MD
Lia Guileré
INTERSOM Köln & St. Franziskus Hospital
Köln, Germany
Lennart Knaack, MD Jaroslaw Janicki, MD Christoph Möckel, MD Christian Tholen, MD
Sabine Schäfer
Medical College of Wisconsin Otolaryngology and Communication Sciences
Milwaukee, WI
B. Tucker Woodson, MD
Lauren Markowski, Sue Vacula, Christy Erbe
Charleston, SC
M. Boyd Gillespie, MD Shaun Nguyen, MD
Colin Fuller, MD Shivangi Lohia, MD Ryan Reddy, MD Alex Murphy, MD
North Memorial Sleep Center
Maple Grove, MN
Jason Cornelius, MD Oleg Froymovich, MD
Cindy Stein Jamie Witt
Clinical Research Group of St. Petersburg, Inc.
St. Petersburg, FL
Neil Feldman, MD Tapan Padhya, MD
Mary O’Brien
Sint Lucas Andreas Ziekenhuis
Amsterdam, Netherlands
Nico de Vries, MD Faiza Safiruddin, MD Linda Benoist, MD
Tinneke De Bleser
Sleep Med. Assoc. of TX
Dallas, TX
Andrew Jamieson, MD Neil Williams, MD
Chris Hassell
St. Cloud Hospital Sleep Center
St. Cloud, MN
Ronald D. Hanson, MD Troy Payne, MD
Emily Jacobs Kathy Gerads
Sleep Medicine Associates
Seattle, WA
Sarah Stolz, MD Chris Yang, MD
Jeremy Gillis Deb Tinlin
UC Physicians
Cincinnati, OH
David Steward, MD Victoria Surdulescu, MD
Jessica Keller
Universitäts Medizin Mannheim
Mannheim, Germany
Joachim T. Maurer, MD Clemens Anders, MD
Oliver Schmidt
University of Pittsburgh Medical Center
Pittsburgh, PA
Ryan Soose, MD Patrick Strollo, MD Charles Atwood, MD
Tina Harrison John McCormick
University of South Florida - Tampa General Hospital
Tampa, FL
Tapan Padhya, MD Mack Anderson, MD
Laurie Joughlin
Universitair Ziekenhuis Antwerpen
Edegem, Belgium
Paul H. Van de Heyning, MD, PhD Olivier M. Vanderveken, MD, PhD Wilfried A. De Backer, MD, PhD Johan Verbraecken, MD, PhD
Marijke Dieltjens Marc Willemen Wim D’Hondt
Medical University of South Carolina -Otolaryngology
CO N CLUS I O N S In a selected group of patients with moderate to severe OSA and BMI ≤ 32 kg/m2 who are unable to achieve benefit with CPAP, 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-y follow-up period. A B B R E V I AT I O N S AHI, apnea-hypopnea index BMI, body mass index CPAP, continuous positive airway pressure ESS, Epworth Sleepiness Scale FOSQ, Functional Outcomes of Sleep Questionnaire (30-item) FOSQ-10, Functional Outcomes of Sleep Questionnaire (10-item) OSA, obstructive sleep apnea SD, standard deviation 47
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Solingen, Germany
Winfried Randerath, MD Christina Priegnitz, MD Winfried Hohenhorst, MD
Marcel Treml, MD
Wayne State University - Detroit Medical Center
Detroit, MI
M. Safwan Badr, MD Ho-sheng Lin, MD
Nicole Nickert Anita D’Souza
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Inspire Medical Systems (Sponsor): Quan Ni, PhD, Kris Selander Medical Research Biostatistician: Teri Yurik (Namsa, Inc) Clinical Events Committee: Kent Wilson, MD, Markus Gapany, MD, Sandra M Skovlund, MD, Erik St. Louis, MD
R E FE R E N CES 1. Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ 2009;108:246–9. 2. Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep 2007;30:711–9. 3. McDaid C, Durée KH, Griffin SC, et al. A systematic review of continuous positive airway pressure for obstructive sleep apnoea-hypopnoea syndrome. Sleep Med Rev 2009;13:427–36. 4. Richard W, Venker J, den Herder C, et al. Acceptance and long-term compliance of nCPAP in obstructive sleep apnea. Eur Arch Otorhinolaryngol 2007;264:1081–6. 5. Kushida CA, Nichols DA, Holmes TH, et al. Effects of CPAP on neurocognitive function in OSA patients: the APPLES. Sleep 2012;36:1593–602. 6. Rosen CL, Auckley D, Benca R, Foldvary-Schaefer N, Iber C, Kapur V, et al. A multisite randomized trial of portable sleep studies and PAP autotitration vs laboratory based PSG for the diagnosis and treatment of OSA: the Home-PAP study. Sleep 2012;36:757–67. 7. Strollo PJ, Soose RJ, Maurer JT, et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med 2014;370:139–49. 8. Woodson BT, Gillespie MB, Soose RJ, et al. Randomized controlled withdrawal study of upper airway stimulation on OSA: short-term and longterm effect. Otolaryngol Head Neck Surg 2014;151:880–7. 9. Kapur VK. Obstructive sleep apnea: diagnosis, epidemiology, and economics. Respir Care 2010;55:1155–67. 10. Ronksley PE, Hemmelgarn BR, Heitman SJ, et al. Excessive daytime sleepiness is associated with increased health care utilization among patients referred for assessment of OSA. Sleep 2011;34:363–70. 11. Flemons WW. Clinical practice. Obstructive sleep apnea. N Engl J Med 2002;15;347:498–504. 12. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540–5. 13. Weaver TE, Laizner AM, Evans LK, et al. An instrument to measure functional status outcomes for disorders of excessive sleepiness. Sleep 1997;20:835–43. 14. Chasens ER, Ratcliffe SJ, Weaver TE. Development of the FOSQ-10: a short version of the Functional Outcomes of Sleep Questionnaire. Sleep 2009;32:915–9. 15. Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. Med Care 1989;27:S178–89. 16. Guglielmi O, Jurado-Gámez B, Gude F, Buela-Casal G. Occupational health of patients with obstructive sleep apnea syndrome: a systematic review. Sleep Breath 2015;19:35–44. 17. Kapur VK. Obstructive sleep apnea: diagnosis, epidemiology, and economics. Respir Care 2010;55:1155–67. 18. Campos-Rodriguez F, Pena-Grinan N, Reyes-Nunez N, et al. Mortality in obstructive sleep apnea-hypopnea patients treated with positive airway pressure. Chest 2005;128:624.
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SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication December, 2014 Submitted in final revised form July, 2015 Accepted for publication July, 2015 Address correspondence to: Ryan J. Soose, MD, UPMC Mercy, Building B, Suite 11500, 1400 Locust Street, Pittsburgh, PA 15219; Tel: (412) 232-8989; Fax: (412) 232-8525; Email: [email protected]
D I SCLO S U R E S TAT E M E N T Funding source for this study was Inspire Medical Systems. Dr. Soose: Inspire Medical Systems–study investigator, consultant; Philips Respironics–consultant. Dr. Woodson: Inspire Medical Systems–study investigator, consultant; Medtronic– consultant, royalty; Siesta Medical–consultant. Dr. Gillespie: Inspire Medical Systems–study investigator, consultant, research support; Medtronic, Olympus, Arthrocare–consultant; Surgical Specialties–consultant, research support. Dr. Maurer: Inspire Medical Systems–study investigator, consultant; personal fees from GlaxoSmithKline, Weinmann, Olympus, ResMed, Neuwirth, Medtronic, and Heinen & Lo¨wenstein, outside the submitted work. Dr. de Vries: Inspire Medical Systems– study investigator, consultant; Philips, Olympus–consultant; Night Balance/ReVent– medical advisor, shareholder, funding from company. Dr. Steward: Inspire Medical Systems–study investigator, consultant. Dr. Strohl: Inspire Medical Systems–study investigator (site principal investigator for Phase III study), consultant. Dr. Baskin: Inspire Medical Systems–study investigator, consultant. Dr. Padhya: Inspire Medical Systems–study investigator, consultant, grant funding. Dr. Badr: Inspire Medical Systems–study investigator, consultant. Dr. Lin: Inspire Medical Systems–study investigator, consultant; Intuitive Surgical–proctor. Dr. Vanderveken: Inspire Medical Systems–study investigator; SomnoMed–research grant. Dr. Mickelson: Inspire Medical Systems–study investigator, consultant. Dr. Strollo Jr.: Inspire Medical Systems–study investigator, consultant, research grant; ResMed–scientific advisory board, research grant; Philips Respironics–research grant. Dr. Chasens has indicated no financial conflicts of interest.
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http://dx.doi.org/10.5664/jcsm.5390
S CI E NT IF IC IN VES TIGATIONS
Upper Airway Stimulation for Obstructive Sleep Apnea: Self-Reported Outcomes at 24 Months Ryan J. Soose, MD1; B. Tucker Woodson, MD2; M. Boyd Gillespie, MD3; Joachim T. Maurer, MD4; Nico de Vries, MD5; David L. Steward, MD6; Kingman P. Strohl, MD7; Jonathan Z. Baskin, MD7; Tapan A. Padhya, MD8; M. Safwan Badr, MD9; Ho-sheng Lin, MD9; Olivier M. Vanderveken, MD, PhD10; Sam Mickelson, MD11; Eileen Chasens, PhD12; Patrick J. Strollo Jr, MD1; On Behalf of STAR Trial Investigators University of Pittsburgh School of Medicine, Pittsburgh, PA; 2Medical College of Wisconsin, Milwaukee, WI; 3Medical University of South Carolina, Charleston, SC; 4University Hospital Mannheim, Mannheim, Germany; 5Saint Lucas Andreas Hospital, Amsterdam, Netherlands; 6University of Cincinnati Medical Center, Cincinnati, OH; 7Case Western Reserve University, Cleveland, OH; 8University of South Florida College of Medicine, Tampa, FL; 9Wayne State University, Detroit, MI; 10Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; 11Advanced ENT, Atlanta, GA; 12University of Pittsburgh School of Nursing, Pittsburgh, PA 1
Objectives: To evaluate the long-term (24-mo) effect of cranial nerve upper airway stimulation (UAS) therapy on patient-centered obstructive sleep apnea (OSA) outcome measures. Methods: 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 mo and 24 mo, 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. Results: Significant improvement in mean FOSQ score was observed from baseline (14.3) to 12 mo (17.3), and the effect was maintained at 24 mo (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 mo (7.0) and 24 mo (7.1). Self-reported snoring severity showed increased percentage of “no” or “soft” snoring from 22% at baseline to 88% at 12 mo and 91% at 24 mo. UAS demonstrated large effect size (> 0.8) at 12 and 24 mo for overall ESS and FOSQ measures, and the effect size compared favorably to previously published effect size with other sleep apnea treatments. Conclusions: In a selected group of patients with moderate to severe OSA and body mass index ≤ 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-y follow-up period. Keywords: sleep apnea, surgery, neurostimulation, hypoglossal nerve, cranial nerve stimulation Citation: Soose RJ, Woodson BT, Gillespie MB, Maurer JT, de Vries N, Steward DL, Strohl KP, Baskin JZ, Padhya TA, Badr MS, Lin H, Vanderveken OM, Mickelson S, Chasens E, Strollo Jr PJ, STAR Trial Investigators. Upper airway stimulation for obstructive sleep apnea: self-reported outcomes at 24 months. J Clin Sleep Med 2016;12(1):43–48.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: Hypoglossal cranial nerve stimulation therapy consists of a surgically implantable and medically titratable second-line treatment option for obstructive sleep apnea (OSA), and was previously shown to provide safe and effective short-term management for patients who meet specific clinical and anatomical inclusion criteria. Since OSA represents a chronic condition requiring longitudinal care, this study was undertaken to examine the durability of effect of the therapy on patient-centered outcome measures at 24 months after implantation. Study Impact: This study demonstrates long-term clinically meaningful improvement in snoring, daytime alertness, and sleeprelated quality of life with hypoglossal cranial nerve stimulation therapy. The treatment effect size is large and is maintained across a 2 year follow-up period, providing support for consideration of this therapeutic option in selected patients who are unable to adhere to positive pressure therapy.
Patients suffering from moderate to severe obstructive sleep apnea (OSA) commonly report symptoms consistent with excessive daytime sleepiness, neurocognitive dysfunction, and impaired quality of life.1 Although the underlying pathophysiologic mechanisms of OSA are complex, multifactorial, and variable among patients, the goals of any longitudinal care model are generally consistent across all patients and fall into two categories: (1) to improve sleep related symptoms and quality-of-life measures, and (2) to reduce cardiovascular and related health risks. Continuous positive airway pressure (CPAP) therapy has a wealth of data on safely and effectively accomplishing these goals and remains the standard first-line therapy.2,3 Despite the low morbidity and high effectiveness of CPAP, long-term adherence and acceptance rates are suboptimal and necessitate consideration of alternative treatment options in many patients.4–6 A variety of interface-related or pressure-related side effects as well as psychosocial barriers frequently preclude
adequate use. Recent multicenter trials reported 6-mo adherence rates of only 39% to 50%.5,6 A universally accepted second-line therapy does not exist; however, oral appliance 43
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therapy, upper airway reconstructive surgery, weight loss, positional therapy, and more recently, hypoglossal cranial nerve upper airway stimulation (UAS) therapy can provide effective management in patients with OSA who have certain clinical, polysomnographic, and anatomical characteristics. In a prospective multicenter trial, UAS therapy has been shown to provide safe and effective short-term management in a cohort of patients with moderate to severe OSA who were unable to achieve benefit with positive pressure therapy.7 The randomized withdrawal portion of the study demonstrated that withdrawal of therapy leads to recurrence of OSA and that resumption of nightly therapy restores subjective and objective benefits.8 These observations emphasize the need to monitor durability of effect over time, particularly because OSA is most commonly a chronic long-term condition that requires effective management throughout the lifespan. The subjective sleep related symptoms and quality-of-life effects of OSA constitute the patient-centered experience of disease presentation, cost-benefit assessment, and treatment outcomes.9 Excessive daytime sleepiness and impairment of daytime functioning, for example, are consequences of the disease that prompt patients to seek care and are associated with an increased motor vehicle accident risk and increased health care utilization.10 These important outcome measures are not adequately represented on objective sleep laboratory testing. As previously stated by Flemons,11 for the majority of patients without significant medical comorbidities, “the primary reason to test for and treat sleep apnea is the potential to improve the quality of life. Clinicians do not make decisions about treatment on the basis of the apnea–hypopnea index alone because it correlates poorly with the quality of life and the severity of symptoms.”11 The aim of this study was to evaluate the long-term (24-mo) effect of UAS therapy on (1) intrusive snoring as measured by self- and bedpartner-report, (2) the propensity for waketime sleepiness as measured by the Epworth Sleepiness Scale (ESS), and (3) daytime functioning as measured by the Functional Outcomes of Sleep Questionnaire (FOSQ) including subscale analysis.
lead that was placed on the distal medial branch of the right hypoglossal nerve to recruit protrussor muscles of the tongue; a pressure sensing lead placed within the intercostal muscles; and an implantable pulse generator placed in the midinfraclavicular region that delivers electrical stimulation to the twelfth cranial nerve, synchronous with the respiratory cycle.
Subjective Outcomes
Self-reported outcomes were collected at baseline, 12 mo, and 24 mo. Subjective daytime sleepiness was measured with the ESS, which is a validated eight-item instrument assessing the propensity to fall asleep.12 Sleep related quality of life was measured with the FOSQ, a validated self-reported measure designed to assess the effect of disorders of excessive sleepiness on daily functional status.13 Additional analysis included the five FOSQ subscales: activity level, general productivity, social outcome, intimacy and sexual relationships, and vigilance, as well as the FOSQ-10, a shorter version of the original 30-item FOSQ with potential for easier and improved clinical applicability.14 Snoring intensity was reported by the participant and by the bed partner on a categorical scale (no snoring, soft snoring, loud snoring, very intense snoring, or bed partner leaves room).
Statistical Analysis
All results of continuous variables are expressed as mean ± standard deviation (SD). A paired t-test was used to evaluate the difference of between baseline and 12 mo, between baseline and 24 mo, and between 12 mo and 24 mo to detect at the 5% significance level. The mean change with associated 95% confidence limits was calculated. Effect size was calculated as (posttreatment mean – baseline mean)/(baseline SD) as per Kazis et al.15 An effect size between 0.2 to 0.5 is considered small, 0.5 to 0.8 is considered moderate, and greater than 0.8 is considered large. R ES U LT S
Demographics
The study cohort consisted of 126 participants--mostly Caucasian (97%), male (83%), middle aged (54.5 ± 10.2 y, ranged from 31 to 80 y), and overweight (BMI of 28.4 ± 2.6 kg/m2, ranged from 18.4 to 32.5 kg/m 2). A total of 124 participants completed follow-up at 12 mo (one participant died due to an unrelated cardiac cause, and one participant requested elective explantation due to lack of satisfaction with therapy response). A total of 111 participants (88% of 126) completed all followup questionnaires at 24 mo. Three participants were lost to long-term follow up and 10 participants missed the data collection during the 24-mo visit window. The mean BMI was 28.5 ± 2.7 at 12 mo and 28.5 ± 3.2 at 24 mo, both unchanged from baseline.
METHODS
Study Design
The Stimulation Treatment for Apnea Reduction (STAR) trial was a multicenter, prospective trial with 126 participants serving as their own control. The primary assessments were safety and effectiveness of UAS therapy at 12 mo. Long-term follow-up visits were performed every 6 mo, including report of adverse events, and assessment of quality of life using standardized questionnaires. The current report aims to summarize the patient-centered outcomes of UAS therapy at 24 mo postimplantation. Key selection criteria of the STAR trial included a history of moderate to severe OSA, nonadherence to CPAP, BMI equal to or less than 32 kg/m2, and absence of complete concentric collapse at the level of the soft palate during sedated endoscopy. Qualified participants received an implanted device that consists of three parts: a stimulation Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016
Epworth Sleepiness Scale
There was a significant decrease in self-reported daytime sleepiness measured by the mean ESS score from baseline to 12 mo (p < 0.01), as well as at 24 mo (p < 0.01). Mean ESS 44
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Table 1—ESS and FOSQ. Variables ESS FOSQ Activity Productivity Social Intimacy Vigilance
Baseline mean (SE) 11.6 (0.4) 14.3 (0.3) 2.7 (0.1) 3.0 (0.1) 3.1 (0.1) 2.7 (0.1) 2.7 (0.1)
12-mo mean (SE) 7.0 (0.4) 17.3 (0.3) 3.4 (0.1) 3.3 (0.1) 3.6 (0.1) 3.3 (0.1) 3.4 (0.1)
24-mo mean (SE) 7.1 (0.4) 17.2 (0.3) 3.4 (0.1) 3.6 (0.1) 3.7 (0.1) 3.3 (0.1) 3.3 (0.1)
Mean Baseline – 12-mo difference (95% CI) 4.7 (3.8 to 5.6)* −2.9 (−3.5 to −2.4)* −0.7 (−0.8 to −0.5)* −0.5 (−0.6 to −0.4)* −0.5 (−0.7 to −0.3)* −0.6 (−0.8 to −0.4)* −0.7 (−0.8 to −0.5)*
Mean Baseline – 24-mo difference (95% CI) 4.4 (3.4 to 5.4)* −3.0 (−3.5 to −2.4)* −0.7 (−0.9 to −0.6)* −0.5 (−0.6 to −0.4)* −0.5 (−0.7 to −0.4)* −0.6 (−0.8 to −0.4)* −0.7 (−0.8 to −0.5)*
Mean 12 mo – 24-mo difference (95% CI) 0.0 (−0.6 to 0.6) 0.2 (−0.5 to 0.1) 0.0 (−0.1, 0.02) −0.0 (−0.1, −0.04) −0.0 (−0.2, 0.03) 0.0 (−0.3, 0.07) 0.1 (−0.12, 0.04)
*P < 0.01. ESS, Epworth sleepiness scale; FOSQ, Functional Outcomes of Sleep Questionnaire; SE, standard error.
Figure 1—Significant improvement in short version Functional Outcomes of Sleep Questionnaire (FOSQ-10) at 12 months is maintained at 24 months after implant.
Table 2—Effect size of upper airway stimulation on ESS FOSQ, and FOSQ subscales. Variables ESS FOSQ Activity Productivity Social Intimacy Vigilance
Effect Size at 12 mo 0.94 0.91 0.87 0.74 0.57 0.62 0.88
Effect Size at 24 mo 0.87 1.00 0.94 0.77 0.66 0.66 0.95
ESS, Epworth Sleepiness Scale; FOSQ, Functional Outcomes of Sleep Questionnaire. Reported as mean and standard deviation in error bar.
of effect was seen in the shorter version FOSQ-10 (Figure 1). Compared to baseline, the percentage of participants reporting a clinically significant improvement (increase ≥ 2) in FOSQ was 53% at 12 mo and 59% at 24 mo. The percentage of participants reporting a significant reduction (decrease ≥ 2) in FOSQ was 3.3% at 12 mo and 5.4% at 24 mo.
remained unchanged from 12 to 24 mo (Table 1). The report of ESS score < 10, often considered acceptable daytime alertness, increased from 32.5% at baseline, to 74.8% at 12 mo, and 77.5% at 24 mo among all participants. Compared to baseline, the percentage of participants with a significant reduction (change of 2 or more) in ESS score was 72% at 12 mo and 70% at 24 mo. The percentage of participants with an increase in ESS score (change of 2 or more) was 7% at 12 mo and 9% at 24 mo.
Effect Size
UAS showed large effect size (> 0.8) at 12 and 24 mo for overall ESS and FOSQ measures. Moderate (> 0.5) to large effect size was also observed among all individual subscales of FOSQ measures (Table 2).
Functional Outcome of Sleep Questionnaire
Self-reported Snoring
Self-reported daytime functioning as measured by the FOSQ improved from baseline to 12 mo (p < 0.01), and maintained improvement at 24 mo (p < 0.01) (Table 1). The mean change from baseline to 12 mo was 2.9 ± 0.3 (standard error [SE]), and 2.7 ± 0.3 (SE) from baseline to 24 mo. There were consistent and significant improvements (p < 0.01) in all five subscales of the FOSQ (activity level, general productivity, social outcomes, intimacy and sexual relationships, and vigilance) from baseline to 12 mo, as well as from baseline to 24 mo. There were no changes of FOSQ and its subscales from 12 mo to 24 mo. The percentage of participants who reported a FOSQ score of > 17.9 (generally considered consistent with normal sleep related quality of life) increased from 15.9% at baseline to 54.5% at 12 mo, and 53.2% at 24 mo. Similar change and durability
Snoring severity based on participant self-report showed increased percentage of “no” or “soft” snoring from baseline of 22% to 88% at 12 and 91% at 24 mo. Reports collected from bed partners supported participant self-report with overall reduced snoring level with therapy use. The percent of “bed partner leaves room” reduced from 30% at baseline to 3% at 12 and 24 mo (Figure 2). D I SCUS S I O N The goal of this study was to examine the durability of treatment effect of upper airway cranial nerve stimulation therapy 45
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Figure 2—Self-reported and bed partner-reported snoring intensity on a 5-item analog scale as measured at baseline, 12 months, and 24 months.
Percentage of participants reporting “no” or “soft” snoring increased from 22% at baseline to 88% at 12 months and 91% at 24 months.
over a 2-y period using validated questionnaires of patientcentered outcome measures that reflect the sleep related symptoms and quality-of-life components of the disease. The major findings of the study were: (1) UAS therapy provides clinically meaningful and statistically significant improvements in key patient-centered OSA outcome measures, including snoring, daytime sleepiness, and sleep related quality of life, and (2) the beneficial effect on subjective sleep outcomes is maintained through the first 2 y of treatment. This sustainability is critical in a chronic condition such as OSA that requires long-term management and has not been previously demonstrated in other surgical studies. The detrimental effect of OSA on activities of daily living and quality-of-life measures contributes significantly to the disease morbidity as well as the financial burden of patients with OSA on the health care system. Untreated moderatesevere OSA has been associated with increased health care costs and physician visits, increased motor vehicle accidents, increased workplace errors, and loss of work productivity.16,17 Although CPAP, the standard first-line therapy, is highly effective, suboptimal patient acceptance and adherence frequently limit long-term results.18–20 As such, alternative medical or surgical therapies are required to effectively manage a large portion of the OSA population. Numerous upper airway reconstructive surgical procedures have been described to reduce OSA severity by improving the anatomical and structural vulnerability of the upper airway. The routine use of many upper airway surgical procedures is limited by increased risk and morbidity as well as a relative lack of high-quality data on the consistency of results. Most surgical studies are also limited by a lack of long-term followup and sustainability of effect, which is important because OSA is chronic condition requiring ongoing reevaluation and management as part of a longitudinal care model. UAS therapy differs markedly from traditional OSA surgery in many respects. In patients with moderate to severe OSA and specific clinical and anatomical characteristics, UAS therapy has previously been shown to provide multilevel (retropalatal and retrolingual) improvement in airway dimension and airflow by augmenting neuromuscular function of Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016
specific upper airway muscles while avoiding anatomy-altering surgery – dramatically reducing side effects, recovery, and risk.21–23 Prior reports have also demonstrated significant and sustained reductions in polysomnographic measures of OSA severity over a 12- to 18-mo follow-up period.7,8 At 18 mo, the median apnea-hypopnea index (AHI) was reduced by 67.4% from the baseline of 29.3 to 9.7/h, and the median 4% oxygen desaturation index (ODI) was reduced by 67.5% from 25.4 to 8.6/h. A treatment AHI of less than 15/h was achieved in 69% of participants at 18 mo. Although patient-reported outcome measures are subjective, multifaceted, and variable among certain subpopulations, it is precisely these self-reported symptoms that often drive patients to seek care from health care professionals. Polysomnography measures alone do not capture important aspects of OSA disease burden and treatment outcomes.24,25 Subjective measures of patients’ daytime sleepiness state, and how the sleepiness affects daily function and quality of life, are likely to contribute significantly to the long-term disease morbidity as well as direct and indirect health care costs. A large retrospective OSA cohort rated snoring as the OSA symptom of highest importance and magnitude from the patient’s perspective.26 With increasing emphasis on quality outcomes relative to health care cost, the long-term qualityof-life outcome measures for OSA treatment have clinical and economic relevance. This study demonstrated that UAS therapy provides clinically and statistically significant improvements in self-reported quality of life, daytime alertness, and snoring; and the treatment effect was maintained over the first 2 y of treatment. Improvement in the FOSQ-30 and subscale analysis was similar to improvement observed in the FOSQ-10 supporting the notion that the shorter FOSQ-10 accurately reflects the original longer version and may be easier to implement in the clinical setting and in future studies. Although the reliability of self-report and bed partner-report of snoring intensity may be questioned, there is currently no accepted standard objective measure of snoring, and it is precisely this subjective report that often drives evaluation and management. The majority of participants in this cohort achieved successful reduction 46
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in their snoring from loud or disruptive levels to soft or no snoring. In this study, UAS therapy demonstrated large effect size (> 0.8) in quality-of-life measures as assessed by ESS and FOSQ. Cohort studies have been previously shown to provide reliable data with a large effect size (i.e., > 0.5). When effect sizes are small (i.e., < 0.3), the amount of uncontrolled data and uncontrollable confounding inherent to such designs is as large as the postulated effect size.27 In a comparison between multilevel temperature-controlled radiofrequency tissue ablation and CPAP for treatment of mild to moderate OSA, the effect size of ESS was 0.5 for ablation and 0.4 for CPAP, and the effect size of FOSQ was 0.66 for ablation and 0.6 for CPAP.28 Thus, the effect size results suggest that, in the setting of an uncontrolled prospective cohort study, UAS therapy convincingly provides strong improvement in daytime sleepiness and sleep related quality of life, and the effect compares favorably to CPAP as well as other second-line therapies. To our knowledge, this is the first study of a surgical intervention for OSA that evaluated quality of life outcome measures 2 y postoperatively. The strengths of this study include the large prospective cohort and high percentage of available long-term follow-up data. Limitations relate to the lack of a control group and the highly selected patient population based on clinical, polysomnographic, and endoscopic/anatomical screening criteria, which may limit generalizability of these findings to other OSA populations. Such limitations of the current uncontrolled study design may also introduce the possibility that a placebo effect could have contributed, at least in part, to the study findings. To corroborate these improvements in quality- of-life measures, long-term sleep laboratory data and other objective outcome measures, in conjunction with responder versus nonresponder analysis, are also needed to further demonstrate therapy effectiveness across a longitudinal care model.
SE, standard error STAR trial, Stimulation Treatment for Apnea Reduction trial UAS, upper airway stimulation S TA R T R I A L I N V ES T I G ATO RS Study Center/ Facility Name
Location
Investigators
Study Staff
Advanced ENT
Atlanta, GA
Sam Mickelson, MD
Faraa Mobini
Borgess Research Institute
Kalamazoo, MI
Mark Goetting, MD L. Steven Szeles, MD
Rebecca Timpe,
Hôpital de Pellegrin
Bordeaux, France
Piérre Philip, MD Piérre-Jean Monteyrol, MD
Céderic Valtat
University Hospitals Cleveland
Cleveland, OH
Kingman Strohl, MD Jonathan Baskin, MD
Mary Andrews Julie Heald
California Sleep Institute
Palo Alto, CA
Joseph Roberson, MD Don Sesso, MD
Jokasta Cordon
Hôpital Foch
Suresnes, France
Frédéric Chabolle, MD Marc Blumen, MD
Lia Guileré
INTERSOM Köln & St. Franziskus Hospital
Köln, Germany
Lennart Knaack, MD Jaroslaw Janicki, MD Christoph Möckel, MD Christian Tholen, MD
Sabine Schäfer
Medical College of Wisconsin Otolaryngology and Communication Sciences
Milwaukee, WI
B. Tucker Woodson, MD
Lauren Markowski, Sue Vacula, Christy Erbe
Charleston, SC
M. Boyd Gillespie, MD Shaun Nguyen, MD
Colin Fuller, MD Shivangi Lohia, MD Ryan Reddy, MD Alex Murphy, MD
North Memorial Sleep Center
Maple Grove, MN
Jason Cornelius, MD Oleg Froymovich, MD
Cindy Stein Jamie Witt
Clinical Research Group of St. Petersburg, Inc.
St. Petersburg, FL
Neil Feldman, MD Tapan Padhya, MD
Mary O’Brien
Sint Lucas Andreas Ziekenhuis
Amsterdam, Netherlands
Nico de Vries, MD Faiza Safiruddin, MD Linda Benoist, MD
Tinneke De Bleser
Sleep Med. Assoc. of TX
Dallas, TX
Andrew Jamieson, MD Neil Williams, MD
Chris Hassell
St. Cloud Hospital Sleep Center
St. Cloud, MN
Ronald D. Hanson, MD Troy Payne, MD
Emily Jacobs Kathy Gerads
Sleep Medicine Associates
Seattle, WA
Sarah Stolz, MD Chris Yang, MD
Jeremy Gillis Deb Tinlin
UC Physicians
Cincinnati, OH
David Steward, MD Victoria Surdulescu, MD
Jessica Keller
Universitäts Medizin Mannheim
Mannheim, Germany
Joachim T. Maurer, MD Clemens Anders, MD
Oliver Schmidt
University of Pittsburgh Medical Center
Pittsburgh, PA
Ryan Soose, MD Patrick Strollo, MD Charles Atwood, MD
Tina Harrison John McCormick
University of South Florida - Tampa General Hospital
Tampa, FL
Tapan Padhya, MD Mack Anderson, MD
Laurie Joughlin
Universitair Ziekenhuis Antwerpen
Edegem, Belgium
Paul H. Van de Heyning, MD, PhD Olivier M. Vanderveken, MD, PhD Wilfried A. De Backer, MD, PhD Johan Verbraecken, MD, PhD
Marijke Dieltjens Marc Willemen Wim D’Hondt
Medical University of South Carolina -Otolaryngology
CO N CLUS I O N S In a selected group of patients with moderate to severe OSA and BMI ≤ 32 kg/m2 who are unable to achieve benefit with CPAP, 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-y follow-up period. A B B R E V I AT I O N S AHI, apnea-hypopnea index BMI, body mass index CPAP, continuous positive airway pressure ESS, Epworth Sleepiness Scale FOSQ, Functional Outcomes of Sleep Questionnaire (30-item) FOSQ-10, Functional Outcomes of Sleep Questionnaire (10-item) OSA, obstructive sleep apnea SD, standard deviation 47
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RJ Soose, BT Woodson, MB Gillespie et al. Upper Airway Stimulation for OSA Krankenhaus Bethanien Solingen / Klinik Vogelsangstrasse Wuppertal
Solingen, Germany
Winfried Randerath, MD Christina Priegnitz, MD Winfried Hohenhorst, MD
Marcel Treml, MD
Wayne State University - Detroit Medical Center
Detroit, MI
M. Safwan Badr, MD Ho-sheng Lin, MD
Nicole Nickert Anita D’Souza
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Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication December, 2014 Submitted in final revised form July, 2015 Accepted for publication July, 2015 Address correspondence to: Ryan J. Soose, MD, UPMC Mercy, Building B, Suite 11500, 1400 Locust Street, Pittsburgh, PA 15219; Tel: (412) 232-8989; Fax: (412) 232-8525; Email: [email protected]
D I SCLO S U R E S TAT E M E N T Funding source for this study was Inspire Medical Systems. Dr. Soose: Inspire Medical Systems–study investigator, consultant; Philips Respironics–consultant. Dr. Woodson: Inspire Medical Systems–study investigator, consultant; Medtronic– consultant, royalty; Siesta Medical–consultant. Dr. Gillespie: Inspire Medical Systems–study investigator, consultant, research support; Medtronic, Olympus, Arthrocare–consultant; Surgical Specialties–consultant, research support. Dr. Maurer: Inspire Medical Systems–study investigator, consultant; personal fees from GlaxoSmithKline, Weinmann, Olympus, ResMed, Neuwirth, Medtronic, and Heinen & Lo¨wenstein, outside the submitted work. Dr. de Vries: Inspire Medical Systems– study investigator, consultant; Philips, Olympus–consultant; Night Balance/ReVent– medical advisor, shareholder, funding from company. Dr. Steward: Inspire Medical Systems–study investigator, consultant. Dr. Strohl: Inspire Medical Systems–study investigator (site principal investigator for Phase III study), consultant. Dr. Baskin: Inspire Medical Systems–study investigator, consultant. Dr. Padhya: Inspire Medical Systems–study investigator, consultant, grant funding. Dr. Badr: Inspire Medical Systems–study investigator, consultant. Dr. Lin: Inspire Medical Systems–study investigator, consultant; Intuitive Surgical–proctor. Dr. Vanderveken: Inspire Medical Systems–study investigator; SomnoMed–research grant. Dr. Mickelson: Inspire Medical Systems–study investigator, consultant. Dr. Strollo Jr.: Inspire Medical Systems–study investigator, consultant, research grant; ResMed–scientific advisory board, research grant; Philips Respironics–research grant. Dr. Chasens has indicated no financial conflicts of interest.
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