Sedative Use During Continuous Positive Airway Pressure Titration Improves Subsequent Compliance. A Randomized, Double-Blind, Placebo-Controlled Trial

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1 CHEST Sedative Use During Continuous Positive Airway Pressure Titration Improves Subsequent Compliance A Randomized, Double-Blind, Placebo-Controlled Trial Christopher J. Lettieri, MD, FCCP; Jacob F. Collen, MD; Arn H. Eliasson, MD, FCCP; and Timothy M. Quast, MD Original Research SLEEP MEDICINE Background: The initial experience with continuous positive airway pressure (CPAP) may predict subsequent compliance. In a retrospective study, we found that premedication with nonbenzodiazepine sedative-hypnotic agents during CPAP titration polysomnography independently predicted short-term compliance. To validate these findings, we conducted a prospective clinical trial to assess whether premedication with eszopiclone prior to CPAP titration would improve short-term CPAP compliance. Methods: Subjects in this randomized, double-blind, placebo-controlled trial received 3 mg of eszopiclone or matching placebo prior to undergoing CPAP titration polysomnography. We compared the quality of CPAP titrations and objective measures of compliance during the first 4 to 6 weeks of therapy between the two groups. Results: We enrolled 117 subjects, and 98 subjects completed the protocol (eszopiclone, 50 subjects; placebo, 48 subjects). Other than there being more women in the eszopiclone group, the groups were similar at baseline. Compared with placebo, premedication with eszopiclone significantly improved mean ( SD) sleep efficiency ( % vs %, respectively; p 0.002) and mean total sleep time ( min vs min, respectively; p 0.007). A trend toward improved sleep latency ( min vs min, respectively; p 0.08) and the number of residual obstructive events observed at the final CPAP pressure (6.4 7 events/h vs events/h, respectively; p 0.08) during polysomnography was found. Eszopiclone significantly improved CPAP compliance. Among subjects premedicated with eszopiclone, CPAP was used on a higher percentage of nights ( % vs %, respectively; p 0.005) and for more hours per night ( h vs h, respectively; p 0.03). Conclusions: Premedication with eszopiclone on the night of CPAP titration improved the quality of CPAP titration and led to significantly greater short-term compliance. Trial registration: ClinicalTrials.gov Identifier: NCT (CHEST 2009; 136: ) Abbreviations: AHI apnea-hypopnea index; CPAP continuous positive airway pressure; OSA obstructive sleep apnea; TST total sleep time; WASO wake after sleep onset Continuous positive airway pressure (CPAP) has been shown to reduce symptoms and adverse health effects of obstructive sleep apnea (OSA), 1 5 and CPAP remains the treatment of choice for most patients. 6,7 Despite its benefits, many patients have Manuscript received April 1, 2009; revision accepted May 26, Affiliations: From Pulmonary, Critical Care & Sleep Medicine (Drs. Lettieri, Collen, Eliasson, Quast), Walter Reed Army Medical Center, Washington, DC; and the Department of Medicine (Drs. Lettieri and Eliasson), Uniformed Services University of the Health Sciences, Bethesda, MD. Funding/Support: Study medications were provided by Sepracor Inc (Marlborough, MA). No other financial support was provided. difficulty initiating therapy because of discomfort with CPAP. Intolerance may establish poor compliance patterns or may cause patients to abandon therapy. Conversely, patients who have positive ini- Correspondence to: Christopher J. Lettieri, MD, FCCP, Pulmonary, Critical Care & Sleep Medicine, Walter Reed Army Medical Center, 6900 Georgia Ave NW, Washington, DC 20307; christopher.lettieri@us.army.mil 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( misc/reprints.xhtml). DOI: /chest CHEST / 136 / 5/ NOVEMBER,

2 tial experiences with CPAP may show greater use. Compliance patterns may be established very early in the course of treatment, and initial exposure to CPAP, therefore, may have a tremendous impact on subsequent use. Previous studies have found that long-term adherence to therapy can be predicted within the first few days of CPAP use Similarly, short-term compliance is influenced by the quality of the CPAP titration study. 11 In two retrospective studies, 12,13 we assessed the impact of sedative-hypnotic agent use on CPAP titration study quality and short-term compliance. The first study 12 found that nonbenzodiazepine sedative-hypnotic agents improved the diagnostic yield of polysomnography and the quality of CPAP titration. The second study 13 showed that the only clinical or polysomnographic variable that predicted improved short-term CPAP compliance was whether the patient received premedication with a sedative-hypnotic agent during CPAP titration. We hypothesized that premedication with a sedative-hypnotic agent would promote a better titration study and improve the initial experience with CPAP, subsequently improving therapeutic adherence. To validate these findings, we performed a twophase clinical trial to assess sedative use on the quality of CPAP titration and the impact on subsequent adherence to CPAP therapy. The first phase 14 of the current prospective trial found that premedication with eszopiclone improved the quality of polysomnography and CPAP titration. The objective of this second phase was to assess the impact of a one-time dose of eszopiclone prior to CPAP titration adherence with CPAP therapy. Study Design Materials and Methods We conducted a randomized, double-blind, placebo-controlled trial to assess the impact of therapy with nonbenzodiazepine sedative-hypnotic agents on the diagnosis of and therapy for sleep-disordered breathing. Subjects enrolled in the study were randomized to receive premedication with either 3 mg of eszopiclone or matching placebo at the time of their CPAP titration polysomnography. Study medication was administered 30 min before the start of the sleep study (at lights out). Other than the administration of study medication, enrollment in this protocol did not alter the methods used to conduct polysomnography. The protocol was approved by the Department of Clinical Investigation (Scientific Review Committee, Human Use Committee, and Institutional Review Board) at our hospital. This trial was registered with the National Clinical Trials Registry (identifier NCT ). The study medication and matching placebo were provided to the investigational pharmacy at our hospital by Sepracor Inc (Marlborough, MA). Subjects All subjects were recruited from a single, accredited sleep disorders center (Walter Reed Army Medical Center; Washington, DC). Consecutive patients undergoing an attended, overnight, level I CPAP titration polysomnogram were approached for enrollment. We included patients 18 to 64 years of age with OSA (determined according to a level I polysomnogram) who had not previously used CPAP. All patients initiating CPAP therapy met the diagnostic criteria for OSA syndrome per the American Academy of Sleep Medicine. Individuals with mild OSA (apneahypopnea index [AHI], 5 to 15 events/h) had to exhibit symptoms of OSA, such as excessive daytime somnolence Women of child-bearing age who consented to study enrollment underwent a pregnancy screening test. Those women found to be pregnant were excluded from participation in this trial. We also excluded patients with known sensitivity to eszopiclone; patients with significant hepatic dysfunction or a history of alcohol abuse; patients who had consumed alcohol within 12 h prior to polysomnography; and patients who reported long-term use of sleep aids, such as benzodiazepines, narcotics, barbiturates, or other prescribed or over-thecounter agents with sedative or hypnotic effects. All subjects underwent attended overnight polysomnography for CPAP titration. Enrolled subjects received study medications approximately 30 min prior to the start of the polysomnogram. Per protocol, CPAP pressures were incrementally increased to ablate obstructive respiratory events and minimize respiratory effort-related arousals. For all subjects, we sought to determine the lowest pressure required to ablate these events and promote sleep continuity, preferably with the subject in the supine position during rapid eye movement sleep. No auto-adjusting CPAP devices were used. All polysomnograms were interpreted and scored by the study investigators in accordance with guidelines published by the American Academy of Sleep Medicine. 16,17 Following their CPAP titration polysomnography, subjects were educated regarding OSA and the proper use of CPAP. They underwent formal mask fitting by a respiratory therapist trained in the care of patients with OSA and the use of CPAP, and used the same model of CPAP device (Respironics Remstar M series with C-FLEX and integrated heated humidifiers; Respironics, Inc; Murrysville, PA). There were no auto-adjustable positive airway pressure devices used in this trial. The subsequent use of sedative-hypnotic agents was monitored, and those subjects who required these agents were disenrolled from the study. All individuals received a follow-up telephone call at 2 weeks to ensure proper fitting of the mask and to identify potential barriers to adherence. Those persons still experiencing difficulties were instructed to call back for more assistance or were offered earlier clinic follow-up appointments. All subjects were instructed to return for follow-up consultation after 4 to 6 weeks of CPAP therapy. During this follow-up evaluation, CPAP compliance was measured objectively with a downloadable smart card compliance monitoring device (Encore Pro compliance card; Respironics, Inc). The data used in this analysis were obtained from the initial sleep consultation, follow-up evaluation, and polysomnographic studies. Demographic data included age, gender, and body mass index. Degree of somnolence was assessed with the Epworth sleepiness scale 18 and visual analog fatigue scale. Polysomnographic data included wake after sleep onset (WASO), total sleep time (TST), total arousal index, sleep latency, sleep efficiency, and AHI. Compliance data included the average number of hours CPAP was used per night for all nights, the average number of hours CPAP was used per night on the nights it was used, and the percentage of nights CPAP was used during the study period. We also recorded the percentage of nights CPAP was used for 4h Original Research

3 PATIENT ENROLLMENT Assessed for Eligibility (n=168) Enrollment Excluded (n = 51) Not mee ng inclusion criteria (n=8) Refused to par cipate (n=30) Other reasons (n=13) Randomized (n=117) Allocation Allocated to eszopiclone (n=60) Received interven on (n=60) Did not receive interven on (n=0) Allocated to placebo (n=57) Received interven on (n=57) Did not receive interven on (n=0) Follow-up Lost to follow-up (n=10) Discon nued interven on (n=0) Lost to follow-up (n=9) Discon nued interven on (n=0) Analysis Analyzed (n=50) Excluded from analysis (n=0) Analyzed (n=48) Excluded from analysis (n=0) Figure 1. Consort flow diagram. Randomization Subjects were randomized to receive either 3 mg of eszopiclone or matching placebo. Study medications were administered by the Investigational Pharmacy at our hospital and distributed to the subjects at the beginning of the polysomnogram. The referring physician, polysomnography technician, scoring technician, investigators, and the patient were blinded to the randomization order and treatment group (eszopiclone or placebo). Randomization was implemented using a computerized randomization program and was maintained by our Investigational Pharmacy. End Points The primary end point was CPAP compliance during the initial 4 to 6 weeks of therapy. We compared the percentage of nights CPAP was used and the average number of hours used per night between subjects receiving eszopiclone and those receiving placebo. We also compared good compliance between the groups, which we defined as the use of CPAP for 4 h per night on 70% of nights, similar to that used in prior studies. 19 Differences in the quality of CPAP titration between subjects receiving eszopiclone and those receiving placebo served as the secondary end point. To determine CPAP titration quality, we compared the mean sleep latency, sleep efficiency, WASO, TST, and residual AHI on the prescribed level of CPAP between the two groups. Statistical Analysis Differences between groups were examined using the independent samples t test for continuous variables and the 2 test for categorical data. The data are presented as the mean SD. All tests were two tailed, and p values 0.05 were assumed to represent statistical significance. All correlations were performed using the Spearman correlation coefficient. Data were analyzed using a statistical software package (SPSS, version 13.0; SPSS Inc; Chicago, IL). Results We approached 168 individuals for study enrollment, and 138 persons agreed to participate. Eight persons did not meet our inclusion criteria. Thirteen subjects refused to initiate CPAP therapy following their titration polysomnography, including 8 subjects in the placebo group and 5 subjects in the eszopiclone group (p 0.38). Therefore, we enrolled 117 subjects. Sixty subjects received eszopiclone, and 57 subjects received placebo (Fig 1). Nineteen subjects (10 in the eszopiclone arm, 9 in the placebo arm) did not return for follow-up evaluation. Our final cohort consisted of 98 subjects (eszopiclone group, 50 subjects; placebo group, 48 subjects). In the cohort, 78.6% were men (mean age, years). The majority of subjects had moderate-to-severe OSA, with a mean AHI of events/h among subjects in the cohort. Specifically, 24.1% of subjects had mild OSA, 26.5% had moderate OSA, and 49.4% had severe OSA. Despite randomization, there were more women in the eszopiclone group. Other than gender, the two groups were similar at baseline (Table 1). To account for the impact of gender discrepancy in our study, we CHEST / 136 / 5/ NOVEMBER,

4 Table 1 Baseline Characteristics Table 3 CPAP Compliance* Characteristics Eszopiclone (n 50) Placebo (n 48) p Value Variables Eszopiclone (n 50) Placebo (n 48) p Value Male gender, % Age, yr Epworth sleepiness scale score Visual analog fatigue scale score Spo 2 nadir, % Nights with Spo 2 90%, % AHI, events/h Diagnostic polysomnography Sleep latency, min Sleep efficiency, % TST, min Values are given as the mean SD, unless otherwise indicated. Spo 2 pulse oximetric saturation. performed a two-way analysis of variance that compared placebo vs study medication and male vs female subjects. With regard to CPAP use, statistical significance was only noted for study medication. Gender did not have a significant impact on CPAP use. Specifically, among those meeting our definition of good compliance, 67.5% had been premedicated with eszopiclone, compared with 42.9% in the noncompliant group (p 0.01). In contrast, among subjects meeting our criteria for good compliance, 82.5% were women, compared with 76.6% in the noncompliant group (p 0.47). Premedication with eszopiclone improved the quality of CPAP titration polysomnography (Table 2). Subjects receiving eszopiclone fell asleep sooner, slept longer, had less sleep fragmentation, and achieved a more complete ablation of obstructive events. Specifically, when compared with placebo, eszopiclone shortened sleep latency ( min vs min, respectively; p 0.08), improved Variables Table 2 CPAP Titration Quality* Eszopiclone (n 50) Placebo (n 48) p Value Sleep latency, min Sleep efficiency, % WASO, min TST, min Total arousal index, events/h AHI at highest CPAP, events/h CPAP prescription, cm H 2 O Values are given as the mean SD, unless otherwise indicated. Days of CPAP use, % CPAP use per night on all nights, h CPAP use per night on nights used, h Nights with 4hof CPAP use, % Good compliance, % *All values are given as the mean SD, unless otherwise indicated. CPAP used for 4 h/night on 70% of nights. sleep efficiency ( % vs %, respectively; p 0.002), expanded the TST ( min vs min, respectively; p 0.007), and decreased WASO ( min vs min, respectively; p 0.009). The residual AHI tended to be lower following eszopiclone premedication ( events/h vs events/h, respectively; p 0.08). During the initial 4 to 6 weeks of therapy, CPAP was used on 68% of all nights for h per night for the entire cohort. CPAP use was significantly greater among subjects who received premedication with eszopiclone during their CPAP titration study than for those who received the placebo (Table 3). CPAP was used on a higher percentage of nights in the eszopiclone group than in the control group ( % vs %, respectively; p 0.005). The average nightly use of CPAP also was greater in this group. Eszopiclone was associated with more hours of use per night during nights used ( h vs h, respectively; p 0.03) and for more hours per night for all nights of the study period ( h vs h, respectively; p 0.03). The percentage of days with 4 h of use also was greater among the eszopiclone group ( % vs %, respectively; p 0.007). More subjects receiving premedication with eszopiclone met our definition of good compliance ( 4 h of use per night on 70% of nights). Specifically, good compliance was observed in those subjects who were pretreated with eszopiclone compared with placebo (53.1% vs 27.1%, respectively; p 0.009). Because several subjects did not return for follow-up evaluation, we performed an intention-totreat analysis to reincorporate these individuals into the data analysis. We reanalyzed the compliance data with the assumption that all individuals who did not return for follow-up had zero use of CPAP. CPAP compliance still tended to be greater among subjects premedicated with eszopiclone compared with pla Original Research

5 cebo. Specifically, in subjects receiving eszopiclone compared with placebo, CPAP tended to be used on a higher percentage of nights ( % vs %, respectively; p 0.06) and for more hours per night on all nights ( h vs h, respectively; p 0.05). Subjects receiving eszopiclone also tended to use CPAP for more hours per night on the nights it was used ( h vs h, respectively; p 0.09). The percentage of CPAP use for 4 h per night was significantly greater among the eszopiclone group (46.9% vs 29.9%, respectively; p 0.03). The percentage of subjects meeting our definition for good compliance remained significantly greater in those subjects premedicated with eszopiclone (44.1% vs 22.8%, respectively; p 0.01). Discussion We found that premedication with eszopiclone during CPAP titration polysomnography significantly improved short-term CPAP compliance. Premedication also improved sleep continuity during the titration polysomnogram, and titrations tended to be more complete within this group. In a retrospective study 13 assessing potential clinical and polysomnographic predictors of CPAP compliance, we found that the only variable that affected therapeutic adherence was premedication with a sedative-hypnotic agent during the titration polysomnogram. Titration quality, as measured by sleep continuity and the ablation of obstructive events, was significantly improved among subjects who received premedication. No other variable was associated with improved use of CPAP in this study. We theorized that the improvements in compliance observed in these individuals reflected an improved initial experience with CPAP. Similarly, Drake et al 11 found that the quality of CPAP titration predicted short-term compliance. They concluded that compliance may be influenced by how well patients slept during their CPAP titration. Other studies 8 10,20 have shown that compliance patterns may be established very early in the course of therapy. In fact, CPAP use during the first few days of therapy may be predictive of longer term compliance. As such, it appears that the initial experience with CPAP may have a profound influence on the subsequence adherence to therapy. Nonbenzodiazepine sedative-hypnotic agents have been shown to be safe in patients with OSA, and may enhance the yield and quality of polysomnography. These agents do not disrupt sleep architecture, increase obstructive respiratory events, or significantly reduce oxygenation In addition, Berry and Patel 21 found that zolpidem did not diminish the efficacy of CPAP. In a previous review and subsequent validating clinical trial, 12,14 we found that nonbenzodiazepines significantly improved the diagnostic yield of polysomnography and quality of CPAP titrations without worsening the underlying sleepdisordered breathing. Nonbenzodiazepine sedative-hypnotic agents are effective in inducing sleep onset and improving sleep continuity, which may facilitate improved CPAP titrations by providing more time to determine the optimal pressure needed to ablate respiratory events. Furthermore, they may improve the patient s overall experience in the sleep laboratory setting and the initial comfort with CPAP, which has been shown previously to improve short-term compliance. 11 Our study has several limitations. We did not assess for other potential confounders that may have influenced compliance. However, other than for gender, the two groups studied were similar at baseline, all subjects received the same degree of counseling and follow-up, and all were issued the same CPAP device. Despite randomization, significantly more women received eszopiclone. Previous reports have shown conflicting results regarding the impact of gender on CPAP compliance. McArdle et al 26 found that CPAP compliance was greater among men, whereas Sin et al 27 found that women used CPAP more frequently. We previously found 13 that gender did not significantly affect CPAP compliance. In the present study, we attempted to account for the impact of our gender discrepancy on CPAP compliance by performing a two-way analysis of variance and found that compliance was not significantly affected by gender. Finally, a large number of subjects refused therapy after CPAP titration or were lost to follow-up. We attempted to mitigate this effect by performing an intent-totreat analysis. In conclusion, we found that a one-time use of eszopiclone as pretreatment during CPAP titration polysomnography significantly improved short-term compliance. This study validates our prior retrospective review showing similar results. Given the difficulties with CPAP compliance and potential adverse health consequences of inadequately treated OSA, the routine use of these agents as premedication for CPAP titration should be considered as a method to improve the initial experience with CPAP and potentially improve therapeutic adherence. Acknowledgments Author contributions: All of the authors participated equally in study design, data acquisition and analysis, and preparation of the manuscript. CHEST / 136 / 5/ NOVEMBER,

6 Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: Sepracor Inc was not involved in the design, subject enrollment, or data acquisition for this study, or in the preparation of this manuscript. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the US Government. Other contributions: We thank Ms. Rachel Massey for her assistance in participant recruitment and data collection. References 1 Drager LF, Bortolotto LA, Figueiredo AC, et al. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007; 176: Duran J, Esnaola S, Rubio R, et al. 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