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Treatment of Adult Obstructive Sleep Apnea With Positive Airway Pressure: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment

2019; American Academy of Sleep Medicine; Volume: 15; Issue: 02 Linguagem: Inglês

10.5664/jcsm.7638

1550-9397

Susheel P. Patil, Indu Ayappa, Sean M. Caples, R. John Kimoff, Sanjay R. Patel, Christopher G. Harrod,

Sleep and Wakefulness Research

Free AccessSurgery - CPAP - BPAP - APAP - Positive Airway Pressure - Treatment-Emergent Central Sleep Apnea - Obstructive Sleep Apnea - Central Sleep Apnea - Sleep Quality - Sleep Latency - Systematic Review - Clinical Practice Guideline - Women - Quality of Life - Policy - Depression - Anxiety - Obesity - Diabetes - Stroke - Resistant Hypertension - Hypertension - Congestive Heart Failure - Atrial Fibrillation - Cardiovascular Disease - Noise - Light - Education - Memory - Cognition - Behavior - Review ArticlesTreatment of Adult Obstructive Sleep Apnea With Positive Airway Pressure: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment Susheel P. Patil, MD, PhD, Indu A. Ayappa, PhD, Sean M. Caples, DO, R. John Kimoff, MD, Sanjay R. Patel, MD, Christopher G. Harrod, MS Susheel P. Patil, MD, PhD Address correspondence to: Susheel P. Patil, MD, PhD; 2510 N. Frontage Road, Darien, IL(630) 737-9700(630) 737-9790 E-mail Address: [email protected] Johns Hopkins University, Baltimore, Maryland , Indu A. Ayappa, PhD Icahn School of Medicine at Mount Sinai, New York, New York , Sean M. Caples, DO Mayo Clinic, Rochester, Minnesota , R. John Kimoff, MD McGill University Health Centre, Montreal, Quebec, Canada , Sanjay R. Patel, MD University of Pittsburgh, Pittsburgh, Pennsylvania , Christopher G. Harrod, MS American Academy of Sleep Medicine, Darien, Illinois Published Online:February 15, 2019https://doi.org/10.5664/jcsm.7638Cited by:111SectionsAbstractPDFSupplemental Material ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTIntroduction:The purpose of this systematic review is to provide supporting evidence for the clinical practice guideline for the treatment of obstructive sleep apnea (OSA) in adults using positive airway pressure (PAP).Methods:The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine. A systematic review was conducted to identify studies that compared the use of PAP with no treatment as well as studies that compared different PAP modalities. Meta-analyses were performed to determine the clinical significance of using PAP in several modalities (ie, continuous PAP, auto-adjusting PAP, and bilevel PAP), to treat OSA in adults. In addition, meta-analyses were performed to determine the clinical significance of using an in-laboratory versus ambulatory strategy for the initiation of PAP, educational and behavioral interventions, telemonitoring, humidification, different mask interfaces, and flexible or modified pressure profile PAP in conjunction with PAP to treat OSA in adults. Finally, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence for making recommendations.Results:The literature search resulted in 336 studies that met inclusion criteria; 184 studies provided data suitable for meta-analyses. The data demonstrated that PAP compared to no treatment results in a clinically significant reduction in disease severity, sleepiness, blood pressure, and motor vehicle accidents, and improvement in sleep-related quality of life in adults with OSA. In addition, the initiation of PAP in the home demonstrated equivalent effects on patient outcomes when compared to an in-laboratory titration approach. The data also demonstrated that the use of auto-adjusting or bilevel PAP did not result in clinically significant differences in patient outcomes compared with standard continuous PAP. Furthermore, data demonstrated a clinically significant improvement in PAP adherence with the use of educational, behavioral, troubleshooting, and telemonitoring interventions. Systematic reviews for specific PAP delivery method were also performed and suggested that nasal interfaces compared to oronasal interfaces have improved adherence and slightly greater reductions in OSA severity, heated humidification compared to no humidification reduces some continuous PAP-related side effects, and pressure profile PAP did not result in clinically significant differences in patient outcomes compared with standard continuous PAP.Citation:Patil SP, Ayappa IA, Caples SM, Kimoff RJ, Patel SR, Harrod CG. Treatment of adult obstructive sleep apnea with positive airway pressure: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2019;15(2):301–334.INTRODUCTIONObstructive sleep apnea (OSA) is a common sleep disorder affecting 26% of the United States adult population1 and is associated with adverse health outcomes including excessive sleepiness, impaired quality of life (QOL), increased motor vehicle crashes (MVC), and cardiovascular events.2,3 Despite the advent of an array of treatment options, positive airway pressure (PAP) remains the primary treatment modality for OSA since the approach was introduced in 1981.4 Since the publication of the previous American Academy of Sleep Medicine (AASM) PAP practice parameters,5–7 the scientific literature on the effects of PAP on clinical outcomes in adults with OSA has grown substantially. Research on improving PAP adherence, a major barrier to maximizing the effectiveness of PAP therapy, and advancements in device technology to improve patient comfort have continued to evolve. The objective of this systematic review is to examine the clinical utility of PAP to treat OSA in adults given these recent advancements in technology and knowledge. The AASM commissioned a task force (TF) of content experts to conduct this review. This review is intended to provide supporting evidence for the new clinical practice guideline on the use of PAP for the treatment of OSA in adults,8 and to replace the previously published AASM systematic review on the use of PAP treatment for sleep-related breathing disorders.9 This review addresses the initial management of patients with OSA without major medical comorbidities. This review does not address the initiation and management of PAP in patients with obesity hypoventilation syndrome, sleep-related hypoventilation, or those with concurrent forms of OSA and central sleep apnea. Prior reviews provided evidence in support of previously published AASM practice parameters regarding the efficacy of various modes of PAP therapy for central sleep apnea and hypoventilation syndromes,10,11 and are not considered in the scope of this review.BACKGROUNDOSA is a common sleep disorder affecting 26% of adults, with 10% estimated to have moderate to severe disease.1 Untreated OSA is associated with multiple adverse health outcomes including daytime sleepiness and decreased QOL as well as increased risk of MVC, systemic hypertension, diabetes, coronary artery disease, stroke, atrial fibrillation, congestive heart failure, and mortality.1 OSA is defined by repetitive upper airway collapse and arousals from sleep, traditionally quantified with testing during sleep by the apnea-hypopnea index (AHI), respiratory disturbance index (RDI) or respiratory event index (REI). Common risk factors for OSA include obesity, advanced age, male gender, post-menopausal status in women, race, and craniofacial dysmorphisms.1 Obesity is a prominent risk factor for OSA as demonstrated by reductions in OSA severity with weight loss interventions12,13 and the concurrent rise in the prevalence of OSA as obesity rates have risen.1 Specifically, recent data from the Wisconsin Sleep Cohort estimate that 17% of men and 9% of women aged 50 to 70 years have at least moderate to severe OSA.1 Furthermore, individuals of African American, Asian, or Hispanic race/ethnicity are at higher risk for OSA compared with similarly-aged Caucasians.14,15An important and well-recognized direct consequence of OSA is excessive daytime sleepiness, which can interfere with productivity both at home and in the workplace, and has been associated with an increased risk of MVC.16 OSA has been associated with QOL impairment, based upon global questionnaires like the Short Form of the Medical Outcomes Survey (SF-36), as well as those more specific to sleep-related domains, such as the Functional Outcomes of Sleep Questionnaire (FOSQ), Quebec Sleep Questionnaire (QSQ), and the Calgary Sleep Apnea Quality of Life Index (SAQLI). Although results have varied, studies have also found associations between OSA and impaired cognition, with more consistent deficits in executive function and vigilance.17OSA is also associated with a number of systemic disorders. It is strongly linked with cardiovascular diseases such as congestive heart failure, stroke, atrial fibrillation and ischemic heart disease, and may have a causal role in the development of systemic hypertension.18 Although the evidence is conflicting and sometimes confounded by obesity, OSA has been shown to impair insulin sensitivity and predict incident type 2 diabetes mellitus (T2DM).19The pathogenic role of upper airway collapse was initially described in the 1960's,20,21 and for more than a decade tracheostomy was the only effective treatment. PAP has become the primary therapy used to treat adult OSA across the spectrum of disease severity. Continuous positive airway pressure (CPAP) therapy as a treatment modality was first described in 1981.4 This form of treatment applied a constant pressure throughout the respiratory cycle to splint the airway open. Subsequently, bilevel PAP (BPAP), a modality which delivers a higher inspiratory PAP (IPAP) relative to the expiratory PAP (EPAP) was also found to be effective in the treatment of OSA. A theoretical advantage of BPAP was that a lower EPAP could be applied that would increase tolerance to PAP treatment of OSA. With advancements in technology, flow sensors were integrated into PAP devices to assess the presence of obstructive breathing events. Computer algorithms were then developed and incorporated into CPAP devices to dynamically increase CPAP when obstructive breathing events were detected, and to periodically reduce the delivered pressure when no events were detected for some period of time, ie auto-adjusting PAP (APAP). Auto-adjusting computer algorithms were subsequently developed for BPAP (auto-BPAP). APAP in the ambulatory setting is increasingly being utilized as an alternative to traditional in-laboratory PAP titrations for the initiation and continued treatment of OSA.Regardless of these technological advancements, the continuous application of PAP during sleep when the airway is vulnerable to collapse is critical. To maximize clinical benefit, most clinicians recommend utilization of PAP therapy for the entire sleeping period, though lesser utilization may have benefits for some individuals. Although PAP use for at least 4 hours during sleep per a 24-hour period is commonly used to clinically define minimal acceptable levels of adherence, current evidence suggests a continuous dose-response relationship between hours of use and therapeutic response.22,23Given challenges in optimizing PAP adherence, approaches to making PAP more comfortable are desirable. Technological advances in PAP therapy have occurred over time to promote patient comfort and potentially improve adherence to treatment. A variety of mask interfaces available continues to evolve with design advances in nasal masks, nasal pillows, full face masks, and oral masks. This greater variety of mask configurations has allowed for better individualization of the interface to a patient to reduce leak and improve comfort. PAP manufacturers have also addressed the common side effect of nasal dryness by designing in-line humidifiers, which were first passive but now include heated systems. These have become standard to include with PAP therapy in many markets. The current generation of PAP devices also integrates modified pressure profiles and is offered as a standard feature. This option transiently lowers the treatment pressure during expiration, with some systems also modifying the inspiratory pressure profile, to increase patient comfort without compromising airway patency. Prior to the development of modified pressure profile technologies, BPAP was and continues to be used for similar reasons.Given evidence that patients overestimate their usage of PAP, objective adherence monitoring has been another major advance in PAP technology. Initially, based on a meter built into the machine,24 the development of removable cards to record PAP usage increased the ability of providers to track patient adherence. Internet-based applications combined with built-in modems now allow for remote monitoring of usage. The adoption of adherence requirements for insurance coverage by many payors has made objective adherence monitoring a standard of care in the United States.Because device improvements have only had a modest impact on adherence,25 more attention is being given to educational and behavioral interventions to improve patient adherence. Observational data have demonstrated that increased knowledge of OSA and its long-term impacts, as well as the beneficial effects of PAP predict adherence, raising interest in educational interventions.26 Similar data suggest that decisions about PAP usage are made very early after treatment initiation suggesting any such intervention needs to be delivered early to maximize effect.27 Based on efficacy in changing behaviors in other conditions and settings such as sleep behaviors in insomnia, abstinence in addiction disorders, and medication adherence in chronic medical diseases, there has been interest in developing behavioral interventions such as cognitive behavioral therapy or motivational enhancement to improve PAP adherence. A major challenge, however, has been developing an intervention intensive enough to be effective, but not so expensive as to reduce feasibility in clinical practice. In this milieu, the use of telemonitoring of adherence has gained substantial interest. By identifying those patients who are having the greatest difficulties in real-time, interventions can be individually tailored and quickly deployed to those who will benefit the most.Finally, the overall concerns of rising healthcare costs have impacted the delivery of OSA care. More patients are being diagnosed based on home sleep apnea tests and in this setting the use of APAP has the potential to allow for rapid initiation of treatment at lower costs in the uncomplicated patient. These devices detect flow and/or impedance and based on manufacturer-specific algorithms, adjust pressure in real-time in an effort to deliver the lowest pressure needed to maintain airway patency.28,29 While originally developed to improve comfort, the technology has increasingly been utilized as an alternative to in-laboratory PAP titration. Long-term use of APAP has the potential benefit of obviating adjustments in pressure settings over time in response to changes in OSA severity. However, as the algorithms are designed to continually lower pressure until respiratory events return, there is the potential for incomplete treatment of OSA.29With these key issues in mind, this systematic review provides a comprehensive update of the latest evidence for the use of PAP to treat adult patients with OSA.METHODSExpert Task ForceThe AASM commissioned a TF composed of both board-certified sleep medicine specialists and experts with proficiency in the use of PAP in adults with OSA to develop this systematic review. The TF was required to disclose all potential conflicts of interest (COI) per the AASM's COI policy prior to being appointed to the TF, and throughout the research and writing of this paper. In accordance with the AASM's COI policy, TF members with a Level 1 conflict were not allowed to participate. TF members with a Level 2 conflict were required to recuse themselves from any related discussion or writing responsibilities. All relevant COI are listed in the disclosure statement.PICO QuestionsPICO (Patient, Population or Prob lem, Intervention, Comparison, and Outcomes) questions were developed based on a review of the existing AASM practice parameters on the use of PAP and a review of systematic reviews, meta-analyses, and guidelines published since 2005. The AASM Board of Directors approved the final list of PICO questions presented in Table 1 before the literature search was performed. To develop the PICO questions, the TF identified commonly used PAP interventions and alternative approaches and strategies for the implementation of PAP in the treatment of adults with OSA. The TF then developed a list of patient-oriented, clinically relevant outcomes to determine whether CPAP, compared to no treatment, alternative PAP modes, and concurrent strategies designed to enhance acceptance and use of PAP for OSA treatment should be recommended for clinical practice. The TF rated the relative importance of each outcome to determine which outcomes were critical for decision-making. A summary of these "critical" outcomes by PICO is presented in Table 2. Several additional clinical outcomes considered of importance for the clinical management of OSA and related comorbidities were also examined including the AHI/RDI/REI, hemoglobin A1c, fasting glucose, blood pressure, left ventricular ejection fraction (LVEF), neurocognitive function, MVC, hospitalizations, cardiovascular events, and mortality.Table 1 PICO questions.Table 1 PICO questions.Table 2 Critical outcomes by PICO question.Table 2 Critical outcomes by PICO question.The TF set a clinical significance threshold for each outcome to determine whether the mean changes in the outcomes assessed were clinically significant. The clinical significance threshold was defined as the minimum level of improvement in the outcome of interest that would be considered clinically important to clinicians and patients. Outcomes which met the clinical significance threshold but were not statistically significant resulted in reductions in the grading of the evidence quality and reduced the strength of the recommendation. A summary of the clinical significance thresholds for the clinical outcome measures is presented in Table 3. Clinical significance thresholds were determined based on a TF literature review of commonly used thresholds. Where no clearly established threshold values could be determined, the TF used the literature review, clinical judgment, and experience to establish a clinical significance threshold based on consensus.Table 3 Summary of clinical significance thresholds for outcome measures.Table 3 Summary of clinical significance thresholds for outcome measures.Literature Searches, Evidence Review and Data ExtractionThe TF performed an extensive review of the scientific literature to retrieve articles that addressed the PICO questions. Separate literature searches were performed by the AASM research staff for each PICO question using the PubMed and Embase databases (see Figure 1). The key terms, search limits, and inclusion/exclusion criteria specified by the TF are detailed in the supplemental material. Randomized controlled trials (RCTs) and observational studies that were cited in the prior AASM PAP practice parameters5,7 were included for data analysis only if they met the current inclusion criteria.Figure 1: Evidence base flow diagram.CPAP = continuous positive airway pressure, OSA = obstructive sleep apnea, PICO = Patient, Population or Problem, Intervention, Comparison, and Outcomes, RCT = randomized controlled trial.Download FigureThe initial literature search of English publications in PubMed and Embase was performed in October 2013 and was limited to RCTs. A second literature search was performed in April 2015 using broader search terms to identify additional articles in PubMed and Embase from October 2013 to April 2015 (see supplemental material). This search was conducted using broader search terms in an effort to capture more relevant articles than the initial PICO-targeted searches. In addition, for PICO questions 1 (MVC only), 3, and 8, where the evidence based on RCTs was low or not available, the TF also searched for observational studies with both an intervention and control group relevant to the specific PICO. A third literature search limited to PubMed was performed in September 2016 to identify studies that were published since the second literature search to update the body of evidence for the review. A fourth search also limited to PubMed was conducted in February 2018 to update the evidence prior to publication. These searches identified a total of 1,447 unique articles. Lastly, the TF reviewed previously published guidelines, systematic reviews, and meta-analyses to spot check for references that may have been missed during the prior searches. The TF identified 65 additional articles for a total of 1,512 articles that were screened for inclusion/exclusion in the guideline.The TF set inclusion and exclusion criteria, which are presented in the supplemental material and summarized in Figure 1. All abstracts were reviewed based on inclusion/ exclusion criteria by two TF members. Any discrepancies between the reviewers were discussed and resolved by the Chair. A total of 184 studies were determined to be suitable for meta-analysis and/or grading.Meta-AnalysisMeta-analysis was performed on outcomes of interest, when possible, for each PICO question. Comparisons of CPAP to no treatment and the comparative efficacy of alternative types of PAP devices used to treat OSA in adult patients were performed. For the purposes of our analyses, PAP devices were categorized into the following categories: CPAP, APAP, BPAP, and modified pressure profile PAP. Mask interfaces were categorized as nasal PAP, nasal pillow PAP, oral PAP, and oronasal PAP. Education and behavioral interventions were categorized as education, education plus troubleshooting, and behavioral interventions. Telemonitoring was defined as the remote monitoring of PAP parameters such as PAP usage, residual OSA severity, excessive mask leaks, and PAP settings, during treatment initiation and follow-up. Treatment delivery strategies were categorized as home APAP-initiated (ambulatory) or in-laboratory initiated CPAP and treatment with APAP or fixed CPAP. There was insufficient evidence to perform meta-analyses for some outcome measures and comparisons within some of the PICO questions, including side effects data.Meta-analysis was performed using Review Manager 5.3 software by pooling data across studies for each outcome measure. Posttreatment data were used for meta-analysis, except where change values were determined to be more meaningful to the reader (eg, blood pressure [BP], LVEF, neurocognitive outcomes, and driving proficiency). Standardized mean differences (SMD) were used for outcomes when the TF determined interpretation of effect size would be more clinically meaningful than posttreatment or change values (eg, combined Maintenance of Wakefulness Test [MWT] and Oxford Sleep Resistance Test [OSLER], combined FOSQ, QSQ, and SAQLI, neurocognitive measures, and driving simulator outcomes). The pooled results for each continuous outcome measure are expressed as the mean difference or standardized mean difference between the intervention and comparator. The pooled results for dichotomous outcome measures are expressed as the odds ratio or risk ratio between the intervention and comparator. All analyses were performed using a random effects model with results displayed as a forest plot. Interpretation of clinical significance for the outcomes of interest was conducted by comparing the mean difference in effect of each treatment approach to the clinical significance threshold (see Table 3).GRADE Assessment for Developing RecommendationsThe assessment of evidence quality was performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process.60 The TF assessed the following four components to determine the direction and strength of a recommendation: quality of evidence, balance of beneficial and harmful effects, patient values and preferences, and resource use, as described below. Quality of evidence – based on an assessment of the overall risk of bias (randomization, blinding, allocation concealment, selective reporting), imprecision (95% confidence interval relative to the clinical significance threshold), inconsistency (I2 cutoff of 50%), indirectness (study population), and risk of publication bias (funding sources), the TF determined their overall confidence that the estimated effect found in the body of evidence was representative of the true treatment effect that typical adult patients with OSA would see. The overall quality of the evidence was based on outcomes that the TF deemed critical for decision making.Benefits versus harms – based on the meta-analysis (if data were available), analysis of any harms/side effects reported within the accepted literature, and the clinical expertise of the TF, the TF determined if the beneficial outcomes of the intervention outweighed any harmful side effects.Patient values and preferences – based on the clinical expertise of the TF members and any data published on the topic relevant to patient preferences, the TF determined if patient values and preferences would be generally consistent across the majority of patients, and if patients would use the intervention based on the relative harms and benefits identified.Resource use – based on the clinical expertise of the TF members, the TF judged resource use to be important for determining whether to recommend the use of a specific PAP device type or approach to patient care over another for the treatment of adults with OSA. A summary of each GRADE domain is provided after the detailed evidence review. As this guideline focuses on providing recommendations on the indications for PAP therapy in adult patients with OSA, rather than the use of specific components or accessories of the PAP device, recommendations for PICOs 7–9 (Table 1) were not included. A summary of the systematic review and meta-analyses of the evidence for these PICO questions can be found in the "Additional Considerations" section, as these factors are still important for clinicians to consider in the context of their individual patient's circumstances when initiating PAP therapy.Public Comment and Final ApprovalA draft of the guideline and systematic review was made available for public comment for a two-week period on the AASM website. The TF took into consideration all the comments received and made decisions about whether to revise the draft based on the comments. The revised guideline and systematic review were submitted to the AASM Board of Directors for subsequent approval. This review reflects the state of knowledge at the time of publication and will be reviewed and updated as new information becomes available.THE USE OF POSITIVE AIRWAY PRESSUREThe aims of the current literature reviews and data analyses were focused on addressing 11 questions pertaining to the use of PAP to treat OSA in adults. Below are detailed summaries of the evidence identified in the literature searches and the statistical analyses performed by the TF. Each evidence summary is accompanied by a discussion of the quality of evidence, balance of benefits and harms, patient values and preferences, and resource use considerations that contributed to the development of the recommendations provided in the accompanying clinical practice guideline.8Continuous Positive Airway Pressure Therapy Versus No TherapyThis section addresses PICO questions 1–3 (see Table 1) and resulted in three recommendations (see Recommendations 1–3 in the companion clinical practice guideline).8 A total of 80 RCTs34,36,61–132 and 15 non-randomized studies133–152 investigated the use of PAP to improve one or more of the following outcomes: OSA severity, sleepiness, QOL, sleep quality, mood, neurocognitive function, MVC, blood pressure, left ventricle ejection fraction, fasting glucose, hemoglobin A1c, incident cardiovascular events, and incident mortality. Participants in the studies were from clinic-based populations and were predominantly male, obese, with moderate to severe OSA and self-reported sleepiness. RCTs were reviewed for all outcomes with the exception of MVC, for which non-randomized studies were reviewed. Both RCTs and non-randomized studies were reviewed for the outcomes of incident cardiovascular events and incident mortality. For the RCTs, participants were randomized to a control intervention utilizing sham CPAP, conservative measures or no intervention, sham surgery, placebo tablet, or nasal dilator strips. For each outcome, important differences in patient population or study design from the general description above are noted below. Several meta-analyses were performed to assess the efficacy of PAP for the treatment of OSA in adults as compared with no therapy. The meta-analyses are provided in the supplemental material, Figure S1 through Figure S57. Summary of Findings tables are provided in the supplemental material, Table S1 through Table S3. A summary of the evidence for each outcome is provided below.OSA SeverityThe efficacy of PAP in reducing OSA severity in adults was evaluated using a meta-analysis of studies that reported on the AHI or RDI. For this analysis, the two measures were considered equivalent. All studies were RCTs, with 3 studies using a randomized, cross-over design.61,65,84 Participants were randomized to CPAP or a control intervention. The control interventions utilized included sham CPAP (n = 5),34,66,74,84,93 conservative measures (advice on weight loss or good sleep habit counseling), no intervention (n = 3),78,82,92 sham surgery (n = 1),90 placebo tablet (n = 1),65 and nasal dilator strips (n = 1)61. The duration of intervention was at least 1 month (range: 1–6 months).A meta-analysis of 11 RCTs34,6