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Comparative effectiveness research in obstructive sleep apnea: bridging gaps between efficacy studies and clinical practice Comparative effectiveness research encompasses research that compares two interventions to each other, and takes place in real-world settings without strict inclusion and exclusion criteria, according to the established standard of care. There is a need for comparative evaluations of the treatments for obstructive sleep apnea, a disease associated with increased cardiovascular risk, stroke and metabolic derangement. This article reviews the recent, representative literature that addresses obstructive sleep apnea intervention and treatment, paradigms for diagnosis and randomized control trials addressing the efficacy of interventions, in an effort to demonstrate examples of both traditional observational and randomized control trials, as well as to illustrate the considerable overlap between some traditional studies and comparative effectiveness research. Despite methodological challenges, the potentially large clinical and public health impact of obstructive sleep apnea, accompanied by considerable cost, mandates that randomized controlled trials and comparative effectiveness research be systematically applied to identify both the efficacy and effectiveness of alternative diagnosis and treatment strategies.

Tanya G Weinstock* & Susan Redline Programs in Sleep & Cardiovascular Medicine & Sleep Medicine Epidemiology, Division of Sleep Medicine, Brigham & Women’s Hospital & Beth Israel Deaconess Medical Center, Boston, MA, USA *Author for correspondence: [email protected]

Keywords: cardiovascular disease n comparative effectiveness research n continuous positive airway pressure n heart failure n obstructive sleep apnea

Comparative effectiveness research (CER) has been defined by the Federal Coordinating Council (FCC) for CER as “the conduct and synthesis of research comparing the benefits and harms of different interventions and strategies to prevent, diagnose, treat and monitor health conditions in ‘real world’ settings. The purpose of this research is to improve health outcomes by developing and disseminating evidence-based information to patients, clinicians and other decision-makers, responding to their expressed needs, about which interventions are most effective for which patients under specific circumstances…” [1,2] . CER is a rapidly developing area of research, and in part, a response to a national imperative to develop evidence-based data to guide the allocation of medical resources to improve health outcomes and reduce unnecessary costs. With the recent designation by the Obama Administration of almost US$1 billion towards CER through both the Health Information Technology for Economic and Clinical Health (HITECH) Act and the Patient Protection and Affordable Care Act (PPACA), this alternative mode of clinical research has received much more attention, not only with an eye towards which fields would benefit significantly by its less rigorous inclusion criteria and as a result its more generalizable applicability, but also to scrutinize well-established interventions with new and other alternatives, focusing on the highest quality, most cost-effective treatments [3] .

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1(1), 83–105 (2012)

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CER, in its most basic design, encompasses research that compares two interventions to each other, and takes place in real-world settings without strict inclusion and exclusion criteria, according to standard of care. Most of the intervention research that exist today focus on the effects of medications or procedural interventions compared with a placebo, and are designed to evaluate efficacy, and thus, often utilize strict eligibility criteria in an effort to hone in on and isolate the intervention’s impact on the outcome being measured, while limiting bias. With placebocontrolled trials we learn about the efficacy of an intervention compared with no therapy, which is appropriate for the evaluation of new therapies. However, critics often point out the difficulty in generalizing these outcomes to more representative groups of patients. Once there are several reasonable alternative treatments to offer a patient, there exists the opportunity to study them side by side, evaluating their comparative impact on outcomes, cost or side effects, or combinations of these. Furthermore, there is a need to study these interventions in realistic settings that reflect clinical practice better than the constrained conditions typical of traditional clinical trial efficacy studies. The data from such assessments have substantial implications for guiding both best practice and payer disbursement. Despite these distinctions, there may be substantial overlap between trials conducted under the framework of traditional randomized controlled trials (RCTs) and those that meet the criteria for CER. In this article of obstructive sleep apnea (OSA) research, we review literature with an eye towards identifying where such overlaps in trial design and comparator arms exist while identifying future research challenges and opportunities. Within the field of sleep medicine, there is a need for comparative evaluations of treatments of common conditions with potential high levels of morbidity, including OSA, central sleep apnea, insomnia and periodic leg movement disorder, as well as for disorders of hypersomnolence, including narcolepsy. Of these disorders, OSA is the one that has most rapidly grown in recognition, and has contributed most to increased healthcare expenditures in the area of sleep medicine, and therefore, will be the focus of this article. For example, between 2004 and 2007, Medicare reimbursement for continuous positive airway pressure (CPAP) machines increased from US$291 to $571 million. It is also a disorder with substantial potential impact

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on health and quality of life, and thus its appropriate recognition and treatment are of great importance. This article will first outline the clinical aspects of OSA and discuss the areas that need further evidence to guide clinical practice. We will highlight the overlap as well as unique aspects of CER in OSA as compared with the traditional placebo-controlled RCTs. We will review the recent, representative literature that addresses the following areas: OSA intervention and treatment, paradigms for diagnosis, RCTs addressing the efficacy of interventions on specific subgroups of patients and studies that have addressed the impact of OSA interventions on cardiovascular and neurobehavioral outcomes. Studies will be identified according to their main outcomes. A comparison of different study designs will be made, including, when available, examples of placebo-controlled trials, controlled trials with a conservative measures group and comparative effectiveness-type studies, including comparisons of two or more variables. This article is not intended as a systematic review of the literature and will not specifically address the literature comparing similar types of equipment, clinical prediction rules or issues surrounding the patient with OSA in the ­preoperative setting. Clinical aspects of OSA

OSA is a form of sleep-disordered breathing that is characterized by repeated obstruction of the upper airway during sleep, despite continued respiratory efforts, resulting in periods of apnea or hypopnea, and intermittent hypoxemia. The diagnosis of OSA is made by polysomno­g raphy (PSG) and supported by symptoms such as excessive daytime sleepiness, unrefreshed sleep, disruptive snoring, frequent awakenings and fatigue. PSG, which requires overnight monitoring of multiple physiologic signals, measures the number of apneic and hypopneic events per hour of sleep, which is referred to as the apnea–hypopnea index (AHI). The normal threshold of the AHI in adults is less than five events/h. OSA severity is typically categorized by severity of AHI, with five to less than 15 events/h considered mild OSA, 15 to less than 30 events/h considered moderate and >30 events/h considered severe [4] . Apnea is usually defined as a period of breathing cessation for a minimum of 10 s. Hypopnea is a period of shallow breathing (i.e., reduced airflow amplitude) for a minimum of 10 s with either

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Comparative effectiveness research in obstructive sleep apnea 

a neurological arousal on EEG or an oxygen desaturation of 3–4% or greater, or both [4] . It was estimated that one in five adults have at least mild OSA, and one in 15 adults have ­moderate-to-severe OSA [5] . Obesity is a major risk factor for OSA [5] and with more than two-thirds of the American population either overweight or obese, the incidence of OSA is expected to climb significantly in the next 10 years. Additional risk factors for OSA include male gender, older age and craniofacial dysmorphology. There also are data demonstrating familial clustering of OSA, suggesting a genetic basis for disease, independent of craniofacial or upper airway structural abnormalities. Patients with diabetes, hyper­tension and cardiovascular disease also have a high prevalence of OSA [5,6] . The primary treatment for OSA is use of a device, CPAP, which is prescribed for nightly use. The CPAP machine delivers compressed air at a determined pressure via a nose/mouth interface, which serves to stent open the airway, maintaining unobstructed airflow. In doing so, it abates or eliminates the pharyngeal collapsibility that precipitates obstructive apnea and hypopneas. Traditionally, the level of continuous airway pressure prescribed is determined after a titration PSG study, which is either conducted overnight as a therapeutic study, or performed in the second half of an initial (diagnostic) PSG (split-night study), or more recently, with use of at-home monitoring with devices that automatically titrate pressures in response to sensors detecting airflow limitation (auto-titrating positive airway pressure [APAP]). The latter devices, which are more expensive and complex than CPAP devices, can be prescribed for chronic OSA, or the data from these devices can be reviewed after a brief period (3–7 days) of use, identifying the pressure level that obliterated the majority of apneas and hypopneas, and inform the prescription of a fixed level of support delivered using a traditional CPAP device. Other available devices for the treatment of OSA include oral appliances (OAs) that either advance the mandible (mandibular advancement device [MAD]), or push the tongue forward (tongue retaining device). There are many brands of these devices, and often they are individually tailored to optimize patient comfort and fit [7] . Other approaches in the treatment of OSA include a variety of surgical procedures, such as uvulopalatopharyngoplasty, genioglossus advancement, hyoid

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advancement, maxillo­m andibular advancement or expansion, and temperature-controlled radiofrequency tongue base reduction. Uvulopalatopharyngoplasty has been the most common surgical procedure performed in the treatment of OSA [8] , with a primary purpose of removing redundant tissue from the posterior oropharynx in an effort to reduce the degree of obstruction from the ­collapsible upper airway during sleep. The role of RCTs in OSA research

Most OSA outcomes studies have used uncontrolled cross-sectional or prospective observational study designs. The initial clinical trials in OSA were designed largely to evaluate acute physiological sleep-related outcomes, such as AHI. Assessment of changes in AHI does not directly address the impact of the intervention on patient-related outcomes or morbidities. However, although the use of AHI as a physio­ logical target in efficacy studies is supported by data from observational studies demonstrating a dose-response between AHI and overall mortality [9] and mortality from stroke [10] , dimensions other than mortality, including symptoms such as quality of life and sleepiness, have only been modestly associated with AHI [11] , and support the need for measures in addition to the AHI for capturing all relevant health outcomes. Assumptions that improvements in a physio­ logical parameter predict improved health outcomes have been used to justify early efficacy studies of other conditions, such as chronic obstructive pulmonary disease (where therapeutic interventions aimed at improving forced expiratory volume in 1 s were initially informed by observational data showing an association between forced expiratory volume in 1 s, mortality and healthcare utilization) [12] . Nonetheless, data are needed to define if lowering the AHI either to normal levels or in increments would significantly impact health status. In contrast to studies that have evaluated the AHI as an outcome, there have been relatively few large-scale studies that have compared the effects of OSA interventions on health-related outcomes such as hypertension and cardiovascular events. Most of the trials conducted so far meet traditional criteria for efficacy studies: they have had rigid inclusion and exclusion criteria and tended to focus on subpopulations of subjects, such as patients with heart failure, or those with mild-to-moderate OSA and minimal

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sleepiness. These were largely designed with moderate control of the conditions in the treatment arms, recruited from sleep referral centers, and had interventions supervised by specialists [13] . Although data reported over the last 10 years clearly support the treatment of sleepiness, the impact of OSA intervention on cardio­vascular and neuro­c ognitive outcomes and glucose homeostasis remains unclear due to a lack of data from large RCTs. Whereas most of the RCTs conducted to evaluate OSA interventions have enrolled less than 150 subjects, studies in other disorders, such as cardiovascular disease interventions, have shown the need to enroll sample sizes an order of magnitude higher in order to detect intervention effects, identify subgroup differences and avoid spurious inferences. There is a critical need for data from RCTs conducted with large sample sizes and using the rigorous study design features typical of the RCT to establish efficacy of OSA intervention on influencing cardiovascular, neurological and metabolic outcomes. In general, with regard to these outcomes, efficacy should be demonstrated prior to ­addressing effectiveness in real-world settings. Why have large-scale traditional RCTs lagged in OSA? To some extent, the paucity of largescale studies reflects the inherent challenges of implementing rigorous intervention studies for a disease whose main intervention is a device rather than a medication. Unlike a placebo in the form of a pill, OSA efficacy studies are limited by the difficulty in establishing a control intervention that appropriately emulates the active intervention being studied, whether it is CPAP, an OA or a surgical intervention, and effectively blinds the study subject and/or investigator. Many prior OSA efficacy studies have not used a placebo per se, but have used conservative measures, such as sleep hygiene and weight loss counseling, as a control arm. Whether these comparators are alternative treatments (as would be used in CER) or represent placebos is debatable. The difficulty in using a true placebo may be one reason that it may be more feasible to conduct future CER than efficacy trials in OSA. Review of previous literature ■■ Studies on diagnostic interventions

A number of studies have compared the use of questionnaires and self-reported symptoms to traditional PSG in their effectiveness to diagnose OSA. In general, these studies were designed to examine a new diagnostic tool as compared with

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a previously validated diagnostic tool, thus meeting some criteria for CER. Although the subjects were generally recruited from subspecialty clinics and not the population at large, the entry criteria were minimal. Questionnaires that have been evaluated include the Berlin questionnaire, STOP (snoring, tiredness during daytime, observed apnea and high blood pressure), the STOP-Bang (STOP with BMI, age, neck circumference and gender variables), the American Society of Anesthesiologists (ASA) screening checklist for OSA in surgical patients, and the Hawaii sleep questionnaire. The comparator was sleep center-based PSG (in three studies) [13–15] , homebased PSG (in one) [16] and PSG performed in a hospital (in one) [17] . These studies varied with regard to where the study subjects were recruited from, but none were community based. Rather, recruitment was through subspecialty clinics. Overall, these studies showed variable results according to the thresholds used for defining positivity (Table  1) . Another example was the study by Gurubhagavatula et al. that evaluated an algorithm to establish risk stratification, with an aim of identifying patients who may have such a low risk for OSA that PSG would be unnecessary, while trying to identify those patients at high risk for severe OSA who should receive early PSG screening [18] . Among 359 patients studied with both a questionnaire and continuous overnight oximetry, the algorithm yielded a sensitivity of 95% and specificity of 86% in identifying all cases of OSA, and a specificity of 97% with a positive predictive value of 94% in identifying severe apneics [19] . To date, there has been no question or series of questions that alone provide sufficient diagnostic accuracy to replace objective monitoring. A more detailed discussion of the studies evaluating the efficacy of screening questionnaires can be found in the Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review of the Diagnosis and Treatment of OSA in Adults 2011 publication [20] . ■■ Studies comparing types of monitoring & monitoring devices

Although there are many different variations in monitoring equipment, the studies comparing alternative devices will not be discussed here, but for detailed discussion, please refer to AHRQ’s Comparative Effectiveness Review of the Diagnosis and Treatment of OSA in Adults

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Cross-sectional N/A

Cross-sectional N/A

Chung et al. (2008), STOP

Sharma et al. (2006)

2467 screened, of those with high risk on screens, 177 had PSG

2467 screened, of those with high risk on screens, 177 had PSG

n

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No

No

No

Control group?

Retrospective: No subjects underwent PSG and took questionnaire

Referral center

Recruitment from preop setting

Recruitment from preop setting

Recruitment strategy

Sensitivity, specificity

Sensitivity and specificity of a modified Berlin questionnaire

Sensitivity of STOP in screening for high-risk OSA patients

Validation of Berlin as compared with STOP and ASA

Major outcomes

Sensitivity of 95% and specificity of 86% in identifying all cases of OSA, and a specificity of 97% with a positive predictive value of 94% in identifying severe apneics

Simplified tool was validated to detect high-risk individuals for OSA

STOP had moderate sensitivity for screening for high-risk OSA patients. Was highest for severe OSA when combined with BMI, age, gender and neck circumference. Simple tool

Can use Berlin to screen OSA patients with similar sensitivity to previous tools

Clinical relevance

Apnea and High Blood Pressure Questionnaire.

ASA: American Society of Anesthesiologists; hx: History; N/A: Not applicable; OSA: Obstructive sleep apnea; Preop: Preoperative; PSG: Polysomnography; STOP: Snoring, Tiredness During Daytime, Observed

359

Middle-aged 180 screened, 104 had PSG

Preop; age >18 years; No prior hx of OSA

Preop; age >18 years; No prior hx of OSA

Eligibility criteria

Questionnaire Age + oximetry >18 years → sensitivity/ specificity to identify at-risk patients with OSA

Cross-sectional N/A

Chung et al. (2008), Berlin

Gurubhagavatula Cohort et al. (2001)

Design

Study (year)

Arms

Table 1. Comparison of screening studies for obstructive sleep apnea.

[18]

[17]

[14]

[15]

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2011 publication [20] . As healthcare costs come to the forefront of political and economic discussions, attempts to limit the expense of PSG have directed increased attention to the role of portable home PSG monitoring, with a particular emphasis on evaluating this potentially less costly diagnostic modality in terms of noninferiority. A number of studies have compared hometo laboratory-based PSG. There are multiple home-based monitors, which fall into four categories. Briefly, type I machines are used in traditional PSG monitoring and are used only in a laboratory setting with a technician present. Type II is the same as type I, except it can be run outside the laboratory without a technician. These machines monitor, among other parameters, EEG, eye movements (electrooculography), and submental electromyography to assess sleep stage, respiratory effort, oximetry, airflow, electrocardio­graphy, body position and limb movements. Type III machines are portable and monitor respiratory effort, airflow, either heart rate or electrocardio­g raphy, and oximetry. Notably, type III machines may underestimate the AHI given that they are not designed to monitor sleep stages and arousals related to respiratory efforts. Furthermore, the denominator in the portable studies is the total test time, rather than the exact sleep time. Type IV devices are portable machines that only measure one or two metrics, such as oximetry and airflow [19] . The 2007 Technology Assessment of Home Diagnosis of OSA-Hypopnea Syndrome report evaluated over 20 studies of different home monitoring devices compared with traditional PSG. The report found variable discrepancies in AHI between both the type III and type IV machines [19] . Several additional studies published since 2007 continue to point to this ongoing issue, which can affect clinical interpretation and ­management in some patients. A study from Spain evaluated the diagnostic efficacy as well as cost–effectiveness of home sleep studies as compared with in-hospital PSG [21] . A total of 366 subjects were randomized to either home PSG or in-hospital PSG, with the same monitoring machine used in both settings. Diagnostic efficacy, as defined by receiver operator curve analysis and using different PSG cut-off points (AHI ≥5, ≥10 and ≥15) for OSA diagnosis, was shown to be highly comparable across study arms despite the lower mean AHI level recorded in-home than in-hospital, which was attributed to longer recording times and a

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more accurate ‘real world’ study environment. The cost analysis showed that the expense of the home studies was less than half that of the traditional in-hospital PSG [22] . Kuna et al. conducted a study based at a US Veteran’s Administration medical center comparing the use of an in-home sleep study with APAP titration to an in-laboratory split-night sleep study in 296  men [22] . This study was designed to test for noninferiority over 3 months in regards to the study outcomes of functional status and CPAP adherence. The mean AHI derived for each group were similar and there was no difference between the two groups in time to initiation of CPAP therapy after diagnosis. The quality of life scores were significantly improved in both groups. CPAP adherence was not significantly different between the two groups. Because this was a study within the Veteran’s Administration system, which is a largely male study population, its extrapolation to other settings may be limited [23] . The Portable Monitoring for Diagnosis and Management of Sleep Apnea (HomePAP) Study is a recently completed comparative effectiveness trial that was designed to test the utility of an integrated clinical pathway for OSA diagnosis and CPAP titration using home-based portable monitoring devices as compared with standard in-laboratory PSG [Rosen C, Submitted] . Patients with consecutive new sleep center referrals, who were ≥18 years with a high probability of ­moderate-to-severe OSA with sleepiness were included in the study and underwent either home-based testing followed by 1 week of APAP compared with in-laboratory PSG for diagnosis and titration. CPAP acceptance, time to treatment, adherence at 1 and 3 months, changes in subjective sleepiness and functional outcomes were recorded. As in the Veteran’s Administration study, outcomes improved in both groups and there was no evidence of lack of noninferiority in this home-based strategy for diagnosis and treatment compared with in-laboratory PSG as measured by acceptance of therapy, time to treatment and sleepiness improvement. In fact, adherence was somewhat better in the home as compared with the laboratory-based arm. In each of these studies, it can be argued that there are features of comparative effectiveness trial design. For example, each compares two different types of treatment interventions with effectiveness measures as outcomes. Features of the first two studies that make them less

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Comparative effectiveness research in obstructive sleep apnea 

characteristic of CER include closely monitored intervention arms, especially for the intervention that was intended to be the controlled setting, as well as recruitment from population subsets. Therapeutic intervention studies ■■ OA versus placebo

OAs for OSA treatment are designed to increase upper airway patency by use of a nightly device, usually through advancing the jaw (MADs). There are multiple OAs and studies have compared the efficacy of MADs to inactive oral devices [23–28] , compared different MADs to each other [29–32] , and compared different degrees of mandibular advancement [31] . These studies will not be detailed. However, in brief, they have not demonstrated evidence to indicate the superiority of one type of OA over other such devices in regards to AHI or sleepiness [29–31] , sleep quality or nocturnal oxygen saturation [30,32] . There are several studies comparing MADs to no treatment [33–35] , and several using a sham OA as a control [25–28,36] . Barnes et al. conducted a crossover efficacy study comparing MADs to a placebo, in the form of an oral tablet, as well as to CPAP, in a group of 80 patients with mild-to-moderate OSA (AHI between 5 and 30) [37] . Compared with placebo, MADs resulted in improved AHI and sleep hypoxemia, both markers of efficacy. Specifically, MADs resulted in a reduction in AHI from a mean of 21 to 14 while the AHI in the placebo group did not change. The long-term clinical significance of an improvement in AHI, but not a complete ­normalization of AHI, is unclear. Petri et al. compared MAD to a sham OA (nonadvancing mandibular device) and to findings in a group receiving no treatment in a group of 93 patients. Subjects were obese and had, on average, fairly severe OSA (mean AHI: 35) [35] . The primary outcome was change in AHI from baseline. AHI dropped significantly from 39 to 25 in the MAD group, with no AHI decline observed in either the sham MAD or the no intervention group. Approximately half of the MAD patients had a >50% reduction in the AHI, with 40% achieving an AHI 15). The study participants will be followed for 2 years, with primary outcome measures including time to composite outcome of death or first hospital admission for a cardiovascular cause. SERVE-HF plans to study the long-term effects and cost–­effectiveness of adaptive servo-ventilation on survival and other cardiovascular outcomes of patients who have both stable heart failure and predominantly central sleep apnea over a 2-year period. Patients will be randomized to either adaptive servo-ventilation with optimal medical management or medical management alone and inclusion criteria require both an AHI ≥15 and central AHI ≥10. The Sleep Apnea Cardiovascular End points (SAVE) trial is another active international multi­c enter randomized trial [203] . The trial plans to enroll 5000 subjects to be followed over 4 years (making it the largest study with the longest ­follow-up), and will examine the effects of CPAP plus standard care versus standard care alone in subjects with coexisting cardiovascular disease and moderate-to-severe OSA and the effect on cardiovascular morbidity and mortality. Neurocognition: CPAP versus placebo

A focus of many studies has been to address changes in neurocognition among patients with mild OSA, for whom treatment with CPAP is especially controversial. Engleman et  al.

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Comparative effectiveness research in obstructive sleep apnea 

conducted a prospective placebo-controlled randomized crossover pilot study evaluating the effect of CPAP on daytime functioning in patients with mild OSA (AHI 5–15) [125] . The 16 subjects spent 4 weeks on CPAP and then 4 weeks using ranitidine 300 mg, an oral H2 blocker used in the treatment of heartburn, and not known to affect sleep-disordered breathing. Primary outcomes were symptoms score, mental flexibility and depression rating, and objective and subjective sleepiness. All of these categories other than sleepiness significantly improved with CPAP compared with placebo. A later prospective placebo-controlled crossover trial of 34 subjects with mild OSA (AHI 5–15) with daytime sleepiness was also conducted [126] . The results were similar, although in this larger sample, subjective sleepiness also significantly improved. Objective sleepiness remained unchanged, however. Neurocognition: CPAP versus sham CPAP

The Apnea Positive Pressure Long-Term Efficacy Study (APPLES) was a large multicenter RCT examining the relationship between OSA and neurocognitive performance before and after either CPAP or sham CPAP [53] . The study included 1204 subjects that had an AHI ≥10 and generally excluded those patients who had obvious attention deficits or other mental status compromise. Neurocognitive function, which was assessed by tests of attention and psychomotor function, short- and long-term memory, and executive function, was tested before and after a 6-month intervention with either CPAP or sham CPAP. The major outcomes from the study are not yet published. However, the baseline data showed low correlations among indices of OSA severity and neurocognitive function. Of all measures, the severity of oxygen desaturation was weakly but significantly associated with tests measuring intelligence, attention and processing speed. Study subjects had relatively severe OSA (with a mean AHI of 38) and 28% of subjects had severe OSA. Stratifying the neuro­c ognitive performance outcomes by preintervention OSA severity did not alter the cross-sectional associations. Neurologic outcomes after stroke: standard care versus standard care & CPAP

The Spanish Sleep and Breathing Group’s study of early intervention with CPAP in stroke patients

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is a RCT of 126 subjects with acute ischemic stroke (but without deficits of consciousness) and moderate-to-severe OSA [127] . Within the first 3–6 days of stroke onset, subjects were randomized to conventional stroke therapy plus CPAP or conventional therapy without CPAP. Follow-up continued for 2 years. Primary outcomes were neurological scales (Barthel, Canadian and Rankin). The study found that the CPAP group performed significantly better on the Canadian and Rankin scales, but similarly on the Barthel index. Over the 2 years, there were no significant differences in occurrence of stroke or other cardiovascular events between the two groups. Glucose metabolism & CPAP: uncontrolled trials

In contrast to the studies demonstrating crosssectional associations between OSA and glucose metabolism, there has been a paucity of intervention studies evaluating the impact of CPAP on metabolic control. One study of ten subjects with both T2DM and OSA showed improved insulin resistance after CPAP treatment [128] ; however, another study did not demonstrate such an association [129] . Another study of 31 patients with moderate-to-severe OSA and without T2DM who were compliant with CPAP showed an improvement in circulating leptin that correlated with significant improvements in the homeostasis model of assessment – insulin resistance (HOMA-IR) from baseline, but change in the HOMA-IR was not associated with OSA severity [130] . A similar study showed improvements in the HOMA-IR in 32 patients, but only in those subjects who were compliant with CPAP [131] . Several small studies have shown that acute or short periods of CPAP use improved levels of inflammatory or oxidative stress markers [131–135] . Other uncontrolled studies of patients with T2DM have demonstrated improved glucose control during sleep with CPAP use [136] and after long-term CPAP use [137] . Harsch et  al. examined insulin sensitivity in 40 patients with OSA, most of whom were men, and only a small proportion of whom had impaired glucose tolerance (none had T2DM) [138] . In this uncontrolled study, an immediate improvement in measures of insulin sensitivity with CPAP therapy was reported in the group as a whole, with the largest improvements occurring in the patients with a BMI 30.

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Glucose metabolism & CPAP: CPAP versus placebo

Coughlin et al. conducted a randomized placebocontrolled blinded crossover trial of 34 patients with newly diagnosed OSA and without diabetes recruited from a sleep clinic, who received either CPAP or sham CPAP for 6 weeks [65] . There was no evidence of a change in metabolic para­ meters in this time frame. In contrast to Harsch et al. [138] , this study did not stratify by BMI, so it was unclear whether improvement may have occurred in less obese subjects. West et  al. studied 42  men recruited from a sleep clinic with known T2DM and newly diagnosed OSA who were randomized to either CPAP or sham CPAP for 3 months [71] . Measures of glucose metabolism and insulin resistance did not change significantly with CPAP as compared with sham CPAP. Again in this study, the mean BMI was >30, and a post-hoc BMI stratification was not performed. Lam et  al. evaluated insulin sensitivity in 61 men with moderate-to-severe OSA without previous evidence of impaired glucose tolerance [139] . The subjects were randomized to CPAP or sham CPAP for 1 week and then reassessed. At that time, there was a significant change in measures of insulin sensitivity. Those on therapeutic CPAP were reassessed after 3 months. Overall, there was no significant change in insulin sensitivity, but when stratified by BMI, improved insulin sensitivity was reported among subjects in the higher BMI group, a finding which contrasted to that of Harsch et al. [138] . A recent small randomized placebo-controlled crossover study of 13 subjects with moderateto-severe OSA showed no changes in insulin sensitivity [73] . Summary: traditional RCTs versus CER in OSA

Although most studies reviewed in this article were designed as traditional RCTs, many meet the CER criterion that the study compares two acceptable alternative interventions [140] . These studies include ones that compared different devices to one another or compared CPAP to OAs or to surgery. Due to problems in identifying an appropriate placebo for a device-based intervention such as CPAP or for surgery, and ongoing variability in equipoise in the community, some OSA trials have also compared accepted therapies such as CPAP to more conservative interventions such as nightly use of

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nasal dilator strips and education regimens (Table  2) . Those studies may qualify as CER when the alternative interventions are considered to be reasonable, such as in patients with minimal symptoms. Areas where most existing OSA trials do not meet criteria for CER are in the application of inclusion and exclusion criteria (studies have generally applied fairly strict eligibility criteria), and in the settings in which the studies were conducted, which were largely in academic ­medical centers and often in subspecialty practices. Newly initiated CER OSA trials

Since 2009, three recent pilot studies were initiated under the framework of CER: the Comparative Outcomes Management with Electronic Data Technology (COMET) study [204] , the Heart Biomarkers in Apnea Treatment study (HeartBEAT) [205] and the Randomized Trial of Bariatric Surgery for Treatment of Sleep Apnea (ABC) [206] . COMET is designed to compare an OA to CPAP in an overweight/obese hypertensive population recruited from academic sleep centers, with 24-h blood pressure as the study outcome. The CER features of this study include its focus on comparing two active intervention arms, each of which will be implemented in clinical settings allowing local variability in treatment approaches. The HeartBEAT study similarly addresses 24-h blood pressure as its primary outcome and recruited subjects from a wide variety of cardiology, rather than sleep medicine clinics, including community-based locations. Three intervention arms will be compared, all of which include a healthy lifestyle education program, one also includes supplemental nocturnal oxygen administration and the other CPAP. The ABC trial is designed to compare the role of bariatric surgery to standard CPAP plus weight loss counseling in patients with both OSA and class II obesity. In contrast to the prior studies, its primary outcome is change in AHI, which arguably may be most relevant to a CER design given the relatively weak efficacy data showing blood pressure improvement with the current active interventions. Secondary outcomes of this study include subjective sleepiness, changes in adiposity, and various physiologic outcomes such as 24-h blood pressure, markers of systemic inflammation and oxidative stress, insulin resistance, lipid metabolism, hemostasis and

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Parra et al. (SSBG), 2011 (stroke)

Eligibility criteria

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CPAP vs HF and CSA standard of care

RCT

RCT

RCT

RCT

Arzt et al. (CANPAP), 2007

Barbé et al., 2010

MOSAIC, 2010

ADVENT-HF

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N/A

391

374

258

258

126

n

Standard medical care

Standard medical care

Standard medical care

Standard medical care

2 years

Standard medical care

6 months Standard medical care

1 year

2 years

2 years

2 years

Duration Control group?

Major outcomes [127]

Ref.

CPAP reduced study subjects’ daytime sleepiness, but not vascular risk score

Small but significant decrease in diastolic BP; trend to decrease in systolic BP in CPAP group

There was a correlation between efficacy of AHI change and survival

UA: Unstable angina.

End Points trial; SERVE‑HF: Treatment of Sleep-Disordered Breathing by Adaptive Servo-Ventilation in Heart Failure Patients study; SSBG: Spanish Sleep and Breathing Group; TIA: Transient ischemic attack;

Obstructive Sleep Apnoea Interventional Cardiovascular trial; N/A: Not applicable; OA: Oral appliance; OSA: Obstructive sleep apnea; RCT: Randomized controlled trail; SAVE: Sleep Apnea Cardiovascular

CSA: Central sleep apnea; CV: Cardiovascular; EF: Ejection fraction; HeartBEAT: Heart Biomarkers in Apnea Treatment study; HF: Heart failure; HTN: Hypertension; MI: Myocardial infarction; MOSAIC: Multicentre

Central Sleep Apnea and Heart Failure; CER: Comparative effectiveness research; COMET: Comparative Outcomes Management with Electronic Data Technology study; CPAP: Continuous positive airway pressure;

Admissions in Patients with Heart Failure and Sleep Apnea trial; AHI: Apnea–hypopnea index; ASV: Adaptive servo-ventilation; BP: Blood pressure; CANPAP: Canadian Continuous Positive Pressure for Patients with

[201]

[124]

[123]

[122]

[121] Transplant-free survival did not differ between groups; significant increase in EF and 6MWT, and decrease in hypoxemia and circulating norepinephrine in CPAP group

CPAP group performed significantly better on the Canadian and Rankin scales, and similarly on the Barthel index. No other CV outcome differences between groups

Clinical relevance

Controlled by Time to death or Ongoing standard of care first admission for CV cause

Controlled by Change in standard of care subjective sleepiness, vascular risk score

Controlled by Change in standard of care 24‑h BP

Controlled by Transplant-free standard of care survival

Controlled by Transplant-free standard of care survival

Controlled by Neurocognitive standard of care outcomes

Rigidity of intervention

6MWT: 6 min walk test; ABC: Randomized trial of Bariatric Surgery for Treatment of Sleep Apnea; ADVENT-HF: Effects of Adaptive Servo-Ventilation on Survival and Frequency of Cardiovascular Hospital

Standard of HF and moderatecare vs standard to-severe OSA of care + ASV

CPAP vs Mild OSA without standard of care significant sleepiness

CPAP vs HTN (could be standard of care already treated) and moderate-tosevere OSA

CPAP vs HF and CSA standard of care

Bradley et al. RCT (CANPAP), 2005

CPAP plus Acute ischemic standard of care stroke, moderatevs standard of to-severe OSA care

Design Arms

Study, year

Table 2. Representative trials evaluating alternative strategies for obstructive sleep apnea treatment.

Comparative effectiveness research in obstructive sleep apnea 

Review

97

98

CER

CER

COMET

HeartBEAT

Symptoms of heart disease, moderate-tosevere OSA

Overweight/obese with HTN

Bariatric surgery Overweight/obese vs CPAP with moderate-tosevere OSA

Education vs education + O2 vs education + CPAP

OA vs CPAP

Standard of CV disorders and care vs standard moderate-toof care + CPAP severe OSA

N/A

354

N/A

N/A

N/A

n

Standard medical care

Standard medical care

18 months

No

3 months No

9 months No

4 years

2 years

Duration Control group?

Major outcomes

Not rigid, patients treated according to local care standards

Not rigid, patients treated according to local care standards

Not rigid, local variability present

Change in AHI

24‑h BP, other biomarkers of CV risk

24‑h BP

Controlled by Sudden death, standard of care MI, stroke, UA, TIA, HF

Controlled by Cost– standard of care effectiveness of ASV, long-term survival and CV outcomes

Rigidity of intervention

Actively enrolling

Actively enrolling

Not yet enrolling

Longest follow-up for CV outcomes so far – ongoing

Ongoing

Clinical relevance

[206]

[205]

[204]

[203]

[202]

Ref.

J. Compar. Effect. Res. (2012) 1(1)

UA: Unstable angina.

End Points trial; SERVE‑HF: Treatment of Sleep-Disordered Breathing by Adaptive Servo-Ventilation in Heart Failure Patients study; SSBG: Spanish Sleep and Breathing Group; TIA: Transient ischemic attack;

Obstructive Sleep Apnoea Interventional Cardiovascular trial; N/A: Not applicable; OA: Oral appliance; OSA: Obstructive sleep apnea; RCT: Randomized controlled trail; SAVE: Sleep Apnea Cardiovascular

CSA: Central sleep apnea; CV: Cardiovascular; EF: Ejection fraction; HeartBEAT: Heart Biomarkers in Apnea Treatment study; HF: Heart failure; HTN: Hypertension; MI: Myocardial infarction; MOSAIC: Multicentre

Central Sleep Apnea and Heart Failure; CER: Comparative effectiveness research; COMET: Comparative Outcomes Management with Electronic Data Technology study; CPAP: Continuous positive airway pressure;

Admissions in Patients with Heart Failure and Sleep Apnea trial; AHI: Apnea–hypopnea index; ASV: Adaptive servo-ventilation; BP: Blood pressure; CANPAP: Canadian Continuous Positive Pressure for Patients with

6MWT: 6 min walk test; ABC: Randomized trial of Bariatric Surgery for Treatment of Sleep Apnea; ADVENT-HF: Effects of Adaptive Servo-Ventilation on Survival and Frequency of Cardiovascular Hospital

CER

RCT

SAVE

ABC

RCT

SERVE-HF

Stringency of eligibility

Standard of Stable HF and CSA care vs standard of care + ASV

Design Arms

Study

Table 2. Representative trials evaluating alternative strategies for obstructive sleep apnea treatment (cont.).

Review   Weinstock & Redline

future science group

Comparative effectiveness research in obstructive sleep apnea 

vascular function. An interesting feature of the ABC trial is that it systematically assesses the equipoise of both patients and physicians in enrolling in a study where randomization will result in either a surgical versus a nonsurgical intervention. Future perspective

RCTs have established that CPAP is efficacious for improving AHI, oxygen desaturation, sleep quality and sleepiness. However, adherence is variable across different settings and the longterm effectiveness of CPAP for these physio­ logical and sleepiness outcomes are unclear. Side effects of CPAP include disrupted sleep, claustro­phobia, nasal stuffiness, dry mouth and sore throat [141] . Typical adherence in many clinical trials averages approximately 50–70% of prescribed nights [48] . Alternatives such as use of OAs and surgical interventions of the upper airway generally have had lower success rates except in highly selected patients, but OAs may be better tolerated than CPAP [36–38] . Bariatric surgery has been reported to be highly successful in improving OSA in morbidly obese patients, but these data are of variable quality and much of the existing literature have relied on self-reported improvement in OSA symptoms rather than objective measures or have had limited follow-up times [142–144] . Therefore, there is a strong role for CER in identifying the comparative effectiveness of these alternative interventions in real-world settings in relation to improving sleep disturbances as study outcomes. Since OSA, which is defined using minimal criteria, affects a very large proportion of the population, CER for OSA also provides important opportunities to evaluate methods for identifying those patients most likely to benefit from a given intervention. Several trials have also established the comparability of diagnosing and treating OSA in inhome as well as in-laboratory settings. However, because these studies have had follow-up periods of less than 1 year and had therapies administered largely by highly trained personnel, CER may help to further evaluate the longer term effectiveness of alternative diagnosis/treatment care paths, including interventions designed to improve adherence once out of a highly monitored setting. For example, across clinical settings there is a wide variety of CPAP support systems, ranging from little support to support by trained respiratory therapists and behavioral

future science group

Review

medicine specialists who assist the patient with adapting to their devices and improving their sleep hygiene with cognitive behavioral therapy, motivational enhancement, and close monitoring of adherence and troubleshooting. CER is needed to define the roles of these alternative support systems given their variable costs, and potential large benefits, and to evaluate the impact of use of sleep medicine compared with other practices. Despite a large body of observational data showing that OSA is linked to hypertension and to cardiovascular, metabolic and neurological outcomes, there are relatively scant data from controlled trials that have addressed the influence of OSA interventions on these health outcomes. Data from RCTs are not only important to clarify the role of OSA treatment on health outcomes, but also to define which patients are most likely to benefit from alternative interventions. The challenges specific to implementing RCTs for OSA include: use of nonpharmacological interventions (e.g., devices and surgery) that are less amenable to placebo controls; challenges in reliably defining patient populations and outcomes that require complex overnight physiological monitoring; and variability in clinical practice and equipoise, resulting in uneven acceptance of randomized trials in some settings. It may be argued that some of these limitations are less relevant for CER where the focus is more geared to evaluating alternative interventions in real-world settings, usually using less strict study designs and applying looser inclusion and exclusion criteria, and without requiring a placebo control. However, to move research on OSA diagnosis and management firmly into the CER framework, we will continue to need evidence demonstrating that the available interventions improve not just sleep quality and quality of life, but chronic health outcomes as well. Novel study designs will assist in overcoming the barriers in recruitment and patient identification. In addition, given potential gender and age modification of the relationship between OSA and cardiovascular disease, sufficiently large studies are needed to better understand subgroup d­i fferences in treatment responses Although this article focused on OSA, other areas in sleep medicine that require additional study with RCTs and CER include central sleep apnea, insomnia, periodic limb movements and narcolepsy.

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99

Review  

Weinstock & Redline

Financial & competing interests disclosure S Redline discloses the following conflicts of interest: receipt of continuous positive airway pressure units from PhilipsRespironics and Resmed Inc. for use in NIH-funded studies; receipt of a grant from Dymedix Inc. for conducting a sensor validation study; appointment as the first incumbent of an endowed professorship donated to the Harvard Medical School by Dr P Farrell, the founder and Board Chairman of Resmed, through a charitable trust instrument, with

equal support equivalent to the endowment payout provided to HMS during Dr Farrell’s lifetime by the Resmed Co. through an irrevocable gift agreement. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials ­discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary Comparative effectiveness research (CER) encompasses research that compares two interventions to each other, and takes place in real-world settings without strict inclusion and exclusion criteria, according to routine standard of care. ■■ The rising cost of healthcare coupled with other economic pressures requires evidence-based research that informs strategies for reducing costs while improving health outcomes. ■■ Obstructive sleep apnea (OSA) is an area for which evidence-based research is needed to address the impact of alternative interventions on a potentially wide range of outcomes, including: patient-related outcomes such as sleepiness, functional status, mood and cognitive function; healthcare utilization; and effects on cardiovascular events, heart failure, hypertension, stroke and diabetes mellitus. Some outcomes may be best initially addressed with efficacy studies establishing their responsiveness to OSA interventions. ■■ One area amenable to CER of major interest to healthcare delivery systems and payers is the use of in-laboratory as compared with in-home diagnosis and treatment care pathways. In-laboratory approaches have been considered the gold standard for many years but require patients to spend a night in an attended setting, which can be burdensome and expensive. Devices are now available that can be used in-home for both diagnosis and titration, and could reduce costs if unaccompanied by high failure rates or equivocal results that would necessitate repeating studies. Comparing those alternatives thus requires a comprehensive assessment of a variety of costs and patient outcomes. ■■ Another challenging area relates to comparing markedly different treatment modalities, such as assessments of the role of surgical interventions for OSA, (e.g., craniofacial surgery or gastric surgery [to achieve weight loss]) compared with nightly use of a device (e.g., continuous positive airway pressure or an oral device). These different intervention modalities present markedly different cost and side effect profiles and also different trajectories of response. For example, surgery may have higher ‘up-front’ costs, but if ‘curative’ may be less costly than a device prescribed indefinitely for disease management. Further efficacy data, however, are needed to better identify the impact of OSA treatment on clinical outcomes. ■■ Despite methodological challenges, the potentially large clinical and public health impact of OSA accompanied by considerable costs mandates that randomized controlled trials and CER be systematically applied to identify both the efficacy and effectiveness of alternative diagnosis and treatment strategies. ■■

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Comparative effectiveness research in obstructive sleep apnea: bridging gaps between efficacy studies and clinical practice.

Comparative effectiveness research encompasses research that compares two interventions to each other, and takes place in real-world settings without ...
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