Eszopiclone Improves Overnight Polysomnography and Continuous ...

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registry (NCT00507117). The study medication and matching placebo were provided to our institution's Investigational Phar- macy by Sepracor Inc, Marlborough ...

Eszopiclone during CPAP titration

Eszopiclone Improves Overnight Polysomnography and Continuous Positive Airway Pressure Titration: A Prospective, Randomized, Placebo-Controlled Trial Christopher J. Lettieri, MD1,2; Timothy N. Quast, MD1; Arn H. Eliasson, MD1,2; Teotimo Andrada, MS1 Pulmonary, Critical Care and Sleep Medicine Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC; 2Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 1

Study Objectives: To assess whether premedication with eszopiclone would improve sleep duration and continuity during polysomnography, thereby improving the quality of diagnostic and CPAP titration studies. Design: Prospective, double-blinded, placebo-controlled trial Setting: Academic, multidisciplinary sleep center. Patients: 226 adult subjects undergoing polysomnography for suspected sleep disordered breathing; 113 received eszopiclone and 113 received placebo. Interventions: Subjects received eszopiclone 3 mg or matching placebo before polysomnography. We compared sleep latency, efficiency, total sleep time, and apnea-hypopnea index between these groups. We also compared rates of inadequate studies, defined as insufficient sleep time (< 120 min or sleep efficiency ≤ 70%) or incomplete CPAP titrations (≥ 5 events/h on the highest CPAP or complete intolerance). Measurements and Results: Eszopiclone premedication significantly improved a number of measured variables. Eszopiclone reduced sleep latency (21.7 ± 27.1 vs. 32.6 ± 38.2 min, P = 0.014), improved sleep efficiency (87.6% ± 10.8% vs. 78.1% ± 15.6%, P < 0.001), reduced wake after sleep onset (39.2 ± 31.9 vs. 64.5 ± 45.4 min, P < 0.001) and prolonged sleep time (346.5 ± 53.1 vs. 312.2 ± 64.2 min, P < 0.001).

Sleep efficiencies ≤ 70% were more common with placebo than medication (21.2% vs. 7.1%, P = 0.004). Eszopiclone facilitated improved CPAP titrations with fewer residual events (5.7 ± 10.3 vs. 11.9 ± 19.6, P = 0.02) and fewer incomplete titrations (31.1% vs. 48.0%, P = 0.04). Poor quality studies (46.0% vs. 26.5%, P = 0.004) were more common with placebo than with eszopiclone. There was a trend for more nonusable studies with placebo (7.1% vs. 2.7%, P = 0.22). Side effects were uncommon and did not differ between groups. Conclusion: Pretreatment with eszopiclone improves the quality of polysomnography and CPAP titration and decreases the need to repeat studies. Given the ever-growing demand for polysomnography and the need to improve efficiency, the routine use of nonbenzodiazepines as premedication for polysomnography should be considered. Keywords: Eszopiclone, polysomnography, sleep study, sleep latency, sleep efficiency, CPAP titration, quality Citation: Lettieri CJ; Quast TN; Eliasson AH; Andrada T. Eszopiclone improves overnight polysomnography and continuous positive airway pressure titration: a prospective, randomized, placebo-controlled trial. SLEEP 2008;31(9):1310-1316.

THE INCREASING AWARENESS OF SLEEP DISORDERED BREATHING HAS CREATED A GROWING DEMAND FOR POLYSOMNOGRAPHY, RESULTING IN EXCESSIVE waiting times in many sleep laboratories.1 Sleep centers, therefore, need to develop methods to improve efficiency, streamline the evaluation process, increase access to care, and reduce costs. Unfortunately, many patients find it difficult to fall asleep in the unfamiliar environment of a laboratory setting (the first-night effect), which may prolong sleep latency and decrease sleep efficiency.2 Likewise, intolerance of continuous positive airway

pressure (CPAP) in those initially treated or being titrated to higher levels may disrupt sleep continuity and reduce the quality of polysomnography. Poor quality studies may lead to an inability to establish a diagnosis or titrate CPAP therapy adequately. Unsatisfactory studies may need to be repeated, further adding to the demand for polysomnography. Nonbenzodiazepine hypnotics are commonly used to treat both acute and chronic insomnia. They are effective at reducing sleep latency, increasing total sleep time, and improving sleep efficiency.3-5 These agents have minimal side effects and do not disrupt normal sleep architecture or alter respiratory events.3,5-7 These attributes make these agents ideal for use during polysomnography and, theoretically, could enhance the efficiency of sleep centers. In a recent retrospective review, we found that the use of a nonbenzodiazepine hypnotic prior to polysomnography resulted in significantly shorter sleep latency, improved sleep efficiency, and improved patient tolerance of CPAP titration.8 We concluded that prestudy sedation resulted in improved quality and greater yield of polysomnography. Although promising, these results required validation with a prospective, randomized, placebo-controlled trial. Eszopiclone is a new non-narcotic, nonbenzodiazepine hypnotic agent approved for the treatment of acute and chronic insomnia.9 Clinical trials have found that eszopiclone decreases sleep latency and reduces wake time after sleep onset (WASO), thereby improving sleep efficiency.10-12 Eszopiclone achieves

Disclosure Statement This study was conducted using study medications and an unrestricted research grant given by Sepracor Inc to The Henry M. Jackson Foundation for the Advancement of Military Medicine and the United States Army Clinical Investigation Regulatory Office. The authors have indicated no other financial conflicts of interest. The opinions expressed herein are those of the authors and should not be construed as official or as reflecting the policies of either the Department of the Army or the Department of Defense. Submitted for publication January, 2008 Accepted for publication May, 2008 Address correspondence to: Christopher J. Lettieri, MD, Pulmonary and Critical Care Medicine, Walter Reed Army Medical Center, 6900 Georgia Ave., NW, Washington, DC 20307; Tel: (202) 782-5720; Fax: (202) 7829032; E-mail: [email protected] SLEEP, Vol. 31, No. 9, 2008

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peak plasma levels within 1 hour and has a duration of action of 6-7 h.9,13 Because of its efficacy in promoting sleep onset and sleep maintenance and its favorable safety profile, this agent may be beneficial as a prestudy sedative. Furthermore, its duration of action would be ideal for polysomnography as it would continue to be effective throughout the study period. This would be especially helpful during split-night and CPAP titration studies, in which crucial adjustments in CPAP pressure occur towards the end of the sleep period. We hypothesized that the use of a short-acting hypnotic agent would improve the yield and quality of diagnostic polysomnography and CPAP titration and reduce the rate of studies needing to be repeated.

patients with significant hepatic dysfunction or a history of alcohol abuse; those who consumed alcohol within 12 hours prior to polysomnography; and those who were concomitantly using benzodiazepines, trazodone, narcotics, barbiturates, or other prescribed or over-the-counter agents with sedative or hypnotic effects. We also excluded patients with decompensated medical conditions, severe dementia, or decompensated psychiatric disorders. For patients undergoing a diagnostic study, we excluded any who had had a prior polysomnogram. For those undergoing CPAP titration, we excluded any subjects who previously used CPAP or had an overnight study other than the diagnostic study leading to this titration. We did not offer enrollment for the CPAP arm of the protocol to any subject previously enrolled in our protocol for diagnostic study. We chose to impose these exclusions to ensure that prior experience with overnight testing in a sleep laboratory environment was similar between groups. All studies were performed in accordance with guidelines published by the American Academy of Sleep Medicine. Enrolled patients underwent an attended, overnight polysomnogram using a 16-channel montage (Sensormedics Alpha Somnostar system, Sensormedics, Yorba Linda, CA). Polysomnography consisted of continuous recordings of central and occipital electroencephalograms, bilateral electrooculograms, submental and bilateral tibial electromyograms, and electrocardiogram. Nasal and oral airflow were measured using both thermocouple sensors and pressure transducer airflow (PTAF) monitoring devices. Tracheal sounds were monitored using an acoustic microphone. Thoracic and abdominal excursions were measured using inductance plethysmography. Continuous oxygen saturation was assessed using noninvasive pulse oximetry. Body positioning was verified by infrared video recording. Studies were scheduled to last between 6 and 8 h and were terminated following the final wakening. Polysomnograms were scored in 30-sec epochs, following criteria of Rechtschaffen and Kales for sleep staging.14 All studies were scored by a registered polysomnography technician. In addition, all studies were reviewed and interpreted by a physician board certified in sleep medicine. CPAP titrations were conducted using the same monitoring devices as described in diagnostic studies with the addition of the delivery of positive air pressure via a nasal or full face mask according to patient preference. Patients were fitted for the masks at the beginning of the study, prior to lights out. During the study, detections of leaks, oral breathing, or patient complaints of mask discomfort prompted a switch to a full face mask. The studies were attended by a certified sleep technician. CPAP pressures were incrementally increased to ablate observed respiratory events and minimize respiratory effort-related arousals. For all subjects, we sought to determine the lowest pressure needed to adequately ablate these events and promote sleep continuity, preferably in the supine position during REM sleep. No autoadjusting CPAP devices were used. When applicable (i.e., for central apneic events or complex sleep apnea), bilevel PAP titrations were performed according to our laboratory procedures, as directed by the American Academy of Sleep Medicine. Split-night studies were performed in accordance with standard operating procedures of our laboratory, as outlined by the American Academy of Sleep Medicine.15 Patients undergoing a diagnostic polysomnogram for suspected sleep apnea who exhibited more than 40 apneic events in the first 120 min of

METHODS Study Design We conducted a prospective, double-blinded, randomized, placebo-controlled trial assessing the effect of eszopiclone on the quality of polysomnography. Consecutive patients meeting inclusion criteria who presented to the sleep laboratory for an attended, overnight polysomnogram were approached for enrollment into the study. Enrolled subjects were randomized to receive either eszopiclone 3 mg or matching placebo prior to polysomnography. There were 3 study arms correlating with the type of polysomnography being conducted: diagnostic polysomnography, split-night polysomnography, and CPAP titration polysomnography. The protocol was designed to achieve an equal distribution of subjects in each arm. Eszopiclone or placebo was taken within 60 min prior to the start of the sleep study. 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 our institution’s Scientific Research Review Committee and Department of Clinical Investigation. This trial was registered in the National Clinical Trials registry (NCT00507117). The study medication and matching placebo were provided to our institution’s Investigational Pharmacy by Sepracor Inc, Marlborough, Massachusetts. This study was, in part, conducted using funds derived from an unrestricted research grant given by Sepracor Inc to The Henry M. Jackson Foundation for the Advancement of Military Medicine and the United States Army Clinical Investigation Regulatory Office. Patients All subjects were recruited from a single center. Our sleep center is part of an academic, military referral hospital, which serves military service members, retired military members, and their civilian dependents. Our patient population, therefore, is comprised of both men and women of all ages from a wide spectrum of ethnic backgrounds. The sleep laboratory is accredited by the American Academy of Sleep Medicine. We included patients 18 to 64 years old undergoing a diagnostic polysomnogram for suspected sleep disordered breathing or a CPAP titration study to treat sleep disordered breathing previously diagnosed by polysomnography. We excluded patients younger than 18 years or older than 65 years of age; pregnant women; those with known sensitivity to eszopiclone; SLEEP, Vol. 31, No. 9, 2008

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Table 1—Baseline Characteristics Eszopiclone (N = 113) Age 43.5 ± 10.0 % Male 68.1 BMI (kg/m2) 29.6 ± 4.5 Epworth Sleepiness Scale 12.9 ± 5.2 TAI (diagnostic – PSGs and Split Studies) 21.7 ± 13.6 AHI (diagnostic – PSGs and Split Studies) 27.0 ± 28.0

Table 2—Effects of Sleep Quality – All Studies Placebo (N = 113) 45.1 ± 10.0 76.9 31.0 ± 5.2 12.9 ± 4.9

P 0.23 0.11 0.03 0.99

27.7 ± 17.7

0.03

31.6 ± 28.7

0.17

Sleep latency (min) Sleep efficiency (%) Total sleep time (min) WASO (min) Less than 120 min TST Sleep efficiency ≤ 70% Non-usable studies Poor quality studies

Eszopiclone Placebo P (N = 113) (N = 113) 21.7 ± 27.1 32.6 ± 38.2 0.014 87.6 ± 10.8 78.1 ± 15.6 < 0.001 346.5 ± 53.1 312.2 ± 64.2 < 0.001 39.2 ± 31.9 64.5 ± 45.4 < 0.001 2 (1.8%) 4 (3.5%) 0.41 8 (7.1%) 24 (21.2%) 0.004 3 (2.7%) 8 (7.1%) 0.22 30 (26.5%) 52 (46.0%) 0.004

BMI (body mass index), AHI (apnea-hypopnea index), WASO (wake after sleep onset), TAI (total arousal index), CPAP (continuous positive airway pressure), PSG (polysomnography)

BMI (body mass index), AHI (apnea-hypopnea index), WASO (wake after sleep onset), TAI (total arousal index), CPAP (continuous positive airway pressure), PSG (polysomnography)

sleep (AHI >20/h) were placed on CPAP and titrated to ablate respiratory events for the remainder for the study, provided ≥ 3 h of test time remained for CPAP titration. Although we could not stratify for split-night studies a priori, evaluation of prior patterns of sleep studies in our laboratory showed that approximately half of those undergoing a diagnostic study would meet criteria for a split-night study. Therefore, we anticipated balanced enrollment of subjects for diagnostic and split-night studies.

by the total time in bed. The AHI reflected the average number of respiratory events per hour of sleep. Respiratory events were defined as apneic episodes lasting > 10 sec or hypopneas (> 50% reduction in airflow lasting > 10 sec) associated with either an EEG arousal lasting ≥ 3 sec or a desaturation of ≥ 4% by noninvasive pulse oximetry. We compared measured variables between those receiving eszopiclone to those receiving placebo. For subjects in the splitnight and CPAP titration arms, we also compared the quality of CPAP titration. We utilized the residual AHI on the highest level of CPAP attained during the study as a marker of titration quality. All subjects completed a post-polysomnography questionnaire to assess subjective somnolence following the overnight study and to evaluate possible adverse side effects of eszopiclone. This assessment included subjective reports of headaches, nausea, and confusion. Subjects were asked if they felt safe to drive themselves home following the overnight polysomnography. Additionally, subjects were asked to rate their degree of sleepiness at the time they were released from the sleep center using an analogue scale from 1-10, with 10 being significantly sleepy.

Randomization Subjects were randomized to receive either eszopiclone 3 mg or matching placebo. Study drug and placebo were identical in appearance and were administered to the patient by our institution’s Investigational Pharmacy. The referring physician, the polysomnography technician, the scoring technician, the investigators, and the patient were blinded to the randomization order and treatment group (eszopiclone or placebo). Randomization was implemented using a computerized randomization program to generate random tables for each stratified group. Using the table, subjects within each stratum were assigned with an equal number to one of the treatment groups. Study medications were administered by our research pharmacy and distributed to subjects at the beginning of the polysomnogram. All patients gave written consent for this protocol and their sleep study.

Endpoints The primary endpoint was the rate of non-usable and poor quality polysomnograms. Non-usable polysomnograms were defined as studies with less than 120 min of total sleep time (does not meet criteria for a diagnostic study) or complete CPAP intolerance. Poor quality polysomnograms were defined as studies with less than 120 min of TST, sleep efficiency less than or equal to 70%, or an incomplete CPAP titration. We defined incomplete CPAP titrations as those with a residual AHI ≥ 5 on the highest level of CPAP achieved, or complete CPAP intolerance. CPAP intolerance was defined as the patient’s complete inability to sleep on CPAP or their request to end the study prematurely due to CPAP discomfort. Secondary endpoints included mean sleep latency, mean sleep efficiency, mean WASO, mean TST, and residual AHI >10 on the highest level of CPAP achieved. We also assessed the rate of unwanted side effects related to eszopiclone. All comparisons were made between those receiving eszopiclone and those receiving placebo.

Data Demographic and polysomnographic data were recorded for analysis. Demographic data included age, gender, and body mass index (BMI). The degree of sleepiness, as measured by the Epworth Sleepiness Scale (ESS), was recorded in each patient.16 Data derived from polysomnography included sleep latency, sleep efficiency, wake after sleep onset (WASO), total sleep time (TST), total arousal index (TAI), and the apneahypopnea index (AHI). Sleep latency was defined as the time, in min, from the start of the study (lights out) to the onset of sleep. Sleep onset was determined by 3 consecutive epochs of stage 1 sleep or one epoch of any other sleep stage. Sleep efficiency was defined as the percentage of the total time with electroencephalographic (EEG) confirmation of sleep divided SLEEP, Vol. 31, No. 9, 2008

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Table 3—Diagnostic Polysomnograms Eszopiclone Placebo (N = 39) (N = 40) Age 42.9 ± 42.4 44.9 ± 44.5 % Male 64.1 64.1 BMI (kg/m2) 28.1 ± 27.4 30.9 ± 29.8 TAI 18.1 ± 13.1 24.6 ± 15.8 AHI 12.6 ± 12.3 17.5 ± 17.6 Sleep latency (min) 21.4 ± 31.2 30.1 ± 26.4 Sleep efficiency (%) 88.4 ± 0.9 75.3 ± 17.5 Total sleep time (min) 345.3 ± 35.4 303.3 ± 62.9 WASO (min) 37.4 ± 30.8 68.8 ± 48.8 Less than 120 min TST 0 (0%) 2 (5%) Sleep efficiency ≤ 70% 2 (5.1%) 10 (25%) Non-usable studies 0 (0%) 2 (5%) Poor quality studies 2 (5.1%) 12 (30.0%)

Table 4—Split-Night Polysomnograms P

Eszopiclone Placebo (N = 30) (N = 37) Age 44.3 ± 9.0 46.3± 9.4 % Male 80.0 88.2 BMI (kg/m2) 31.6 ± 5.4 31.1 ± 5.1 TAI 26.3 ± 13.0 34.3 ± 17.2 AHI 45.7 ± 25.5 51.0 ± 28.2 Sleep latency (min) 21.4 ± 0.6 39.7 ± 46.6 Sleep efficiency (%) 88.1 ± 0.0 78.3 ± 13.3 Total sleep time (min) 353.1 ± 41.9 310.6 ± 61.9 WASO (min) 44.4 ± 34.0 70.0 ± 42.9 Less than 120 min TST 0 0 Sleep efficiency ≤ 70% 1 (3.3%) 6 (16.2%) AHI on final CPAP pressure 3.8 ± 4.2 16.5 ± 23.9 Residual AHI ≥ 5 10 18 Residual AHI ≥ 10 3 14 Complete CPAP intolerance 0 2 (5.4%) Non-usable studies 0 2 (5.4%) Poor quality studies 10 (33.3%) 24 (64.9%)

0.53 0.93 0.02 0.09 0.16 0.15 < 0.001 < 0.001 0.002 0.16 0.01 0.16 0.003

BMI (body mass index), AHI (apnea-hypopnea index), WASO (wake after sleep onset), TAI (total arousal index), CPAP (continuous positive airway pressure), PSG (polysomnography)

Safety Measures

0.21 0.35 0.90 0.04 0.47 0.05 0.01 0.002 0.01 n/a 0.08 0.006 0.21 0.008 0.20 0.20 0.009

BMI (body mass index), AHI (apnea-hypopnea index), WASO (wake after sleep onset), TAI (total arousal index), CPAP (continuous positive airway pressure), PSG (polysomnography)

The guidelines for conducting research on human subjects mandated by the Department of Clinical Investigation (DCI) were strictly followed. These guidelines included the timely notification of DCI and other regulatory bodies of poor outcomes and unforeseen ill events when applicable. The primary investigator was updated on all enrolled subjects and unusual events on a daily basis. If encountered, potentially serious events were discussed with the primary investigator immediately and reviewed by the Sleep Center’s Quality Assurance Committee as soon as possible. The protocol’s appointed medical monitor was contacted by the primary investigator no less than weekly with updates regarding subject enrollment, post-polysomnography somnolence and any potential complications.

Continuous variables were analyzed using the Student’s t test and categorical variables were compared using a chi-squared analysis. All tests were two-tailed, and P values < 0.05 were assumed to represent statistical significance. Data are presented as mean ± standard deviation. All analyses were performed using the Statistical Package for the Social Sciences 12.0 (SPSS Inc, Chicago, IL). Results During the study period, we approached 642 consecutive patients presenting for polysomnography. We excluded 37 individuals who underwent prior polysomnography; 77 who had previously enrolled in this trial during their diagnostic study; 36 individuals were not eligible by age criteria; and 6 who used hypnotics chronically for long-standing insomnia. Participation was declined by 260 individuals. We enrolled 226 subjects: 113 received eszopiclone and 113 received placebo. No subjects were lost to follow-up, no enrolled subjects withdrew from the study and there were no protocol violations. There were 79 diagnostic studies, 67 split-night studies, and 80 CPAP titration studies during this trial. Among the cohort, the average age was 44.3 ± 10.0 years and 72.6% were men. Body mass index (BMI) was higher among those receiving placebo, but otherwise demographics and the degree of somnolence did not differ between groups. The severity of sleep disordered breathing did not differ between those receiving eszopiclone and those receiving placebo. Among those undergoing diagnostic polysomnography, the AHI was 12.6 ± 11.3 in the eszopiclone group versus 17.5 ± 17.6 in the placebo group (P = 0.16). The AHI was also similar between groups for the diagnostic portion of split-night studies. (45.7 ± 25.5 vs. 51.0 ± 22.7, P = 0.47). Combining the

Statistical Analysis and Sample Size Determination The sample size estimation was based upon the proposed study design for comparing two proportions, specifically the anticipated percentages of subjects who cannot sleep well during polysomnography. From a pre-study assessment of the experience in our laboratory, we conservatively estimated that subjects receiving placebo would not sleep well (prolonged sleep latency, poor sleep efficiency) in 20% of instances. We estimated that study subjects receiving eszopiclone would not sleep well in 5% of instances. Data analysis was performed using a two-tailed test with the type I error set at 5% and the assumption of no baseline difference between the 2 treatment groups (drug and placebo). In order to detect this estimated difference in treatment effect, a total of 120 subjects would need to be enrolled in each arm of the study, for a total of 360 subjects. An interim analysis was scheduled after greater than 60% of subjects completed the study to determine if significance was achieved regarding the protocol’s hypothesis. We performed a univariate analysis using Student’s t tests, chi-squared analysis, and Fisher exact tests as appropriate. SLEEP, Vol. 31, No. 9, 2008

P

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Table 5—CPAP Titration Polysomnograms Eszopiclone Placebo (N = 44) (N = 36) Age 44.1 ± 8.8 46.3± 9.4 % Male 64.6 88.2 BMI (kg/m2) 29.6 ± 3.7 31.1 ± 5.1 TAI 14.1 ± 10.5 34.3 ± 17.2 Sleep latency (min) 18.6 ± 24.9 39.7 ± 46.6 Sleep efficiency (%) 86.5 ± 13.5 78.3 ± 13.3 Total sleep time (min) 343.1 ± 60.9 324.1 ± 67.8 WASO (min) 37.7 ± 31.7 54.8 ± 43.7 Less than 120 min TST 2 (4.5%) 2 (5.6%) Sleep efficiency ≤ 70% 1 (2.3%) 6 (16.7%) AHI on final CPAP pressure 4.0 ± 6.2 16.5 ± 23.9 Residual AHI ≥ 5 12 (27.3%) 15 (41.7%) Residual AHI ≥ 10 11 (25.0%) 11 (30.6%) Complete CPAP intolerance 1 (2.3%) 2 (5.6%) Non-usable studies 3 (6.8%) 4 (11.1%) Poor quality studies 18 (40.9%) 24 (66.7%)

Table 6—CPAP Titration (Split-Night and CPAP Titration Polysomnography)

P

Eszopiclone (N=74) Sleep latency (min) 21.9 ± 24.9 Sleep efficiency (%) 87.1 ± 11.8 Total sleep time (min) 347.1 ± 60.6 WASO (min) 40.2 ± 32.6 Sleep efficiency ≤ 70% 4 (5.4%) AHI on final CPAP pressure 5.7 ± 10.3 Residual AHI ≥ 5 22 (29.7%) Residual AHI ≥ 10 14 (18.9%) Complete CPAP intolerance 1 (1.4%)

0.87 0.17 0.42 0.50 0.12 0.10 0.18 0.05 0.84 0.02 0.09 0.18 0.58

P 0.04 0.001 0.003 0.001 0.02

11.9 ± 19.6 33 (44.6%) 25 (33.8%)

0.02 0.06 0.04

4 (5.4%)

0.37

BMI (body mass index), AHI (apnea-hypopnea index), WASO (wake after sleep onset), TAI (total arousal index), CPAP (continuous positive airway pressure), PSG (polysomnography)

0.45 0.50 0.02

0.22). Using our definition, eszopiclone was associated with a relative risk reduction (RRR) of 62%, an absolute risk reduction (ARR) of 4.4%, and a number needed to treat (NNT) of 23 to prevent one non-usable sleep study. Poor quality studies (non-usable studies plus incomplete CPAP titrations plus sleep efficiency ≤ 70%) were significantly more common in the placebo group (46.0% vs. 26.5%, P = 0.004). Using this definition, eszopiclone was associated with a RRR of 42.3%, an ARR of 19.5%, and an NNT of only 5 to prevent one poor quality sleep study. Significantly fewer individuals receiving placebo were able to undergo a split-night polysomnogram because of prolonged sleep latencies. Despite meeting criteria (>40 events within the first 2 h of sleep), 6 (15.0%) individuals receiving placebo could not initiate CPAP titration (undergo a split-night study) because of an insufficient amount of remaining test time, compared with only one (2.6%) subject receiving eszopiclone (P = 0.05). Side effects were uncommon among the cohort and did not differ between groups (Table 6). After a scheduled interim analysis, the monitoring committee stopped the study early because eszopiclone demonstrated a clear benefit when used as a premedication for polysomnography.

BMI (body mass index), AHI (apnea-hypopnea index), WASO (wake after sleep onset), TAI (total arousal index), CPAP (continuous positive airway pressure), PSG (polysomnography)

AHI for both diagnostic polysomnograms and the diagnostic portion of split-night studies did not differ between the groups (27.0 ± 28.0 vs. 33.6 ± 28.7, P = 0.17). The TAI during diagnostic studies was also similar between groups (18.1 ± 13.1 vs. 21.6 ± 15.8, P = 0.30). Comparisons between the 2 groups are depicted in Tables 1-5. Premedication with eszopiclone resulted in improved sleep quality during polysomnography. Those receiving eszopiclone experienced a shorter sleep latency (21.7 ± 27.1 vs. 32.6 ± 38.2 min, P = 0.014), improved sleep efficiency (87.6% ± 10.8% vs. 78.1% ± 15.6%, P < 0.001), less WASO (39.2 ± 31.9 vs. 64.5 ± 45.4 min, P < 0.001), and greater TST (346.5 ± 53.1 vs. 312.2 ± 64.2 min, P < 0.001). Sleep efficiencies ≤ 70% were significantly more common in the placebo group (21.2% vs. 7.1%, P = 0.004). Eszopiclone produced better sleep quality regardless of the type of study conducted (diagnostic, split-night, and CPAP titrations, Tables 3-5). Among those undergoing CPAP titrations (split-night and dedicated CPAP titrations studies, N = 149), eszopiclone allowed greater ablation of respiratory events (Tables 5 and 6). The residual AHI on the final level of CPAP achieved was significantly lower in those receiving eszopiclone (5.7 ± 10.3 vs. 11.9 ± 19.6, P = 0.02). This effect was even greater among those who underwent split-night studies (3.8 ± 4.2 vs. 16.5 ± 23.9, P = 0.006, Table 4). Incomplete CPAP titrations were less frequent among the eszopiclone group. Specifically, 23/74 (31.1%) of eszopiclone patients versus 36/75 (48.0%) of placebo patients were intolerant of CPAP or had an AHI ≥ 5 at the highest setting (P = 0.04). Similar improvements were seen when the definition of incomplete titrations was changed to an AHI ≥ 10 at the highest level of CPAP achieved (20.3% vs. 36.0%, P = 0.05). Overall, non-usable studies were uncommon but tended to occur more with those receiving placebo (7.1% vs. 2.7%, P = SLEEP, Vol. 31, No. 9, 2008

Placebo (N=75) 33.7 ± 43.0 79.5 ± 14.1 315.9 ± 64.3 63.0 ± 43.3 14 (18.7%)

Discussion In this study, pretreatment with eszopiclone 3 mg prior to polysomnography significantly improved the quality of polysomnography by shortening sleep latency, improving sleep continuity, and increasing the total amount of sleep obtained. This improved sleep quality facilitated better CPAP titrations, allowing greater ablation of respiratory events. Eszopiclone was associated with fewer non-usable or poor quality studies. Use of a nonbenzodiazepine hypnotic could significantly reduce the total number of studies needing to be performed, which may result in greater efficiencies for sleep laboratories. This, in turn, could improve access to care and allow greater numbers of patients to be studied. Furthermore, premedication with a nonbenzodiazepine hypnotic allowed more patients to 1314

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treatment for acute insomnia.3,18,19 When hypnotic agents are used as a pretreatment for polysomnography, they can provide greater total sleep time allowing for more data collection. Additionally, they can assist with initial tolerance of CPAP therapy. CPAP tolerance, combined with greater total sleep time and better sleep continuity, can facilitate better, more effective CPAP titrations. Our study has several limitations. While eszopiclone did not appear to worsen sleep-disordered breathing or alter sleep architecture when compared to the placebo group, individuals were not studied both with and without this agent. Therefore, our study does not directly address the question of whether or not eszopiclone has these effects in individual patients. However, our data agree with findings of previous investigations that have shown that eszopiclone does not impair airway stability or alter sleep architecture.17 Subjects were not matched for age, gender, or BMI at the time of randomization, and those receiving placebo had a higher BMI. This may explain the nonsignificant trend towards the higher AHIs seen in the placebo group. It may also have contributed to the insufficient CPAP titrations seen more commonly in this group. Residual somnolence in the morning following polysomnography poses both driving risks to patients and potential liability to sleep laboratories. However, in this and other studies, side effects were uncommon. Among our cohort, no subject reported concerns over driving home the next day and subjective reports of somnolence were not different between patients receiving medication or placebo. Although side effects were uncommon, it should be noted that individuals only received one dose of medication and these effects may differ from those seen with more prolonged use. Individuals undergoing polysomnographic evaluation commonly report excessive daytime somnolence (EDS). It may be expected that EDS along with counseling to avoid naps or stimulant use preceding the study would promote adequate sleep, even in a laboratory environment. However, we have observed in both our clinical experience and a recently published retrospective study that many individuals have a difficult time sleeping in the laboratory setting.8 Predicting who will have difficulty sleeping in the lab setting is unreliable. Transient insomnia in the sleep lab may be due to the “first-night” effect, which is a form of environmental and/or adjustment insomnia. Patients with sleep disordered breathing may also experience concomitant chronic insomnia, which would also diminish sleep quality in the laboratory environment. We did not evaluate for insomnia or other pretreatment variables as part of this protocol. However, patients using chronic sleep aids were excluded from enrollment, minimizing this effect. The goal of our study was to evaluate the utility of nonbenzodiazepine hypnotics as a means to overcome the potential for environmentally induced insomnia. In conclusion, our study suggests that eszopiclone premedication may improve the quality of polysomnography. This study validates our prior retrospective study showing similar results. Eszopiclone was not associated with significant side effects, and it did not appear to worsen the severity of sleep apnea. Nonbenzodiazepine hypnotics are safe and relatively inexpensive and have the potential to improve the quality of polysomnograms or prevent studies from needing to be repeated. Given the ever-growing demand for polysomnography and the need

Table 7—Adverse Events Post-PSG somnolence Headaches Nausea Confusion Feels safe to drive

Eszopiclone (N = 79) 2.94 ± 2.92 12 (15.2%) 4 (5.1%) 0 (0%) 73 (92.4%)

Placebo (N = 83) 3.29 ± 2.96 18 (21.7%) 1 (1.2%) 1 (1.2%) 79 (95.2%)

P 0.45 0.29 0.16 0.33 0.47

BMI (body mass index), AHI (apnea-hypopnea index), WASO (wake after sleep onset), TAI (total arousal index), CPAP (continuous positive airway pressure), PSG (polysomnography)

qualify for split-night studies that would not have met criteria due to poor sleep quality and prolonged sleep latencies. The ability to both obtain a diagnosis and titrate CPAP during one study (split-night polysomnogram) will decrease the number of seep studies needed. Given the increasing prevalence of sleep disordered breathing, the need for improved sleep lab efficiency and increased access to care cannot be overemphasized. The findings of this study are similar to a retrospective review we conducted comparing the quality of polysomnograms between patients receiving pretreatment with a nonbenzodiazepine hypnotic and those who did not.8 Eszopiclone did not appear to worsen the severity of sleep disordered breathing. In this study, we showed that the AHI was similar between those receiving eszopiclone and those receiving placebo. Similarly, the TAI was the same or lower among those receiving eszopiclone. The fact that both indices tended to be lower among those receiving eszopiclone suggests that eszopiclone does not cause instability of the upper airway. The subtle difference seen in AHI likely reflects the increased number of subjects who were unable to receive a split-night study because of prolonged sleep latency. Our findings are similar to other studies, which have not found an association between nonbenzodiazepine hypnotics and worsening or precipitation of apneas or hypopneas.3-7,17 Unlike other classes of sedative-hypnotics, nonbenzodiazepine have not been shown to worsen underlying sleep disordered breathing. In a prospective study specifically looking at the effects of eszopiclone on upper airway patency during sleep, Rosenberg and colleagues demonstrated that eszopiclone did not worsen respiratory events (apneas and hypopneas) in patients with mild to moderate obstructive sleep apnea syndrome.16 Several prior publications have shown that nonbenzodiazepine hypnotics, unlike other classes of hypnotics, have minimal to no effect on sleep architecture, sleep apnea, or airway patency.3,5-7,17 Nonbenzodiazepine hypnotics appear safe to use even in patients with underlying sleep disordered breathing and should not alter the results of polysomnography. Similar to previous reports, side effects, in particular residual somnolence, headaches or nausea, were not commonly seen among our cohort and did not differ between those receiving eszopiclone or placebo.2,3 Our data showed that eszopiclone significantly shortened sleep latency, improved sleep efficiency, expanded total sleep time, and enhanced sleep continuity (reduced WASO). Nonbenzodiazepine hypnotics have been previously shown to improve both objective and subjective sleep quality and are an effective SLEEP, Vol. 31, No. 9, 2008

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to improve efficiency and reduce costs, the routine use of these agents as premedication for polysomnographic studies should be considered.

9.

Acknowledgments

10.

National Clinical Trials Registry: NCT00507117

11.

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Eszopiclone Improves Polysomnography—Lettieri et al

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