Comparison of Health Outcomes of CPAP versus Oral Appliance Treatment for

Transcription

1 ONLINE DATA SUPPLEMENT Comparison of Health Outcomes of CPAP versus Oral Appliance Treatment for Obstructive Sleep Apnea: A Randomised Controlled Trial Authors: Craig L Phillips Ronald R Grunstein M. Ali Darendeliler Anastasia S Mihailidou Vasantha K Srinivasan Brendon J Yee Guy B Marks Peter A Cistulli

2 METHODS Design Overview.A randomised crossover open label study design was used to compare the health effects of 1 month of optimal treatment of OSA with CPAP versus MAD therapy. Optimal treatment was defined as attaining the highest compliance and best efficacy with each treatment under standard clinical practices during each 4-6 week acclimatisation period.recruitment and follow up of patients occurred between June 2007 and December The trial was registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) at trial number ACTRN Setting and participants. The study was conducted between the Woolcock Institute of Medical Research, Royal North Shore and Royal Prince Alfred hospitals in Sydney, Australia. Patients with newly diagnosed OSA by overnight polysomnography were recruited from these and other affiliated sleep clinics. Selection criteria included adults aged 20 years, an apnea-hypopnea index (AHI) >10 /hr of sleep, >=2 symptoms of OSA (snoring, fragmented sleep, witnessed apneas, or daytime sleepiness), and a willingness to use both treatments. Recruitment was enriched for moderate-severe OSA. Patients were excluded for any of the following reasons: previous OSA treatmentor a need for immediate treatment based on clinical judgement, central sleep apnea, a co-existing sleep disorder, regular use of sedatives or narcotics, pre-existing lung or psychiatric disease and any contra-indication for oral appliance therapy (eg periodontal disease or insufficient dentition). Dental eligibility was assessed by an orthodontist at the Sydney Dental Hospital. All study procedures, were approved by the site-specific Institutional Human Research Ethics Committees (Sydney Southwest Area Health

3 Service Protocol X ). Prior to consenting, patients were told they would be compensated for participating in the study by receiving the treatment device recommended by their sleep physician at no cost. Randomisation and Interventions. Patients who met all eligibility criteria were randomised to both the treatment acclimatisation and treatment arm orders. This was to minimise any bias related to treatment preference based upon the order of treatment exposure and resulted in 4 randomised sequences for MAD (M) and CPAP (C) as follows: MCMC, MCCM, CMMC and CMCM. Each sequence was generated by a computer program using random permuted blocks. The acclimatisation periods for each treatment were generally between 4-8 weeks. Treatment periods were for 1 month each. CPAP.The CPAP device used was the ResMedAutoset S8 (ResMed, Bella Vista, Australia). Prior to CPAP acclimatisation, patients were fitted with an appropriate mask interface. All patients received CPAP education including instruction on CPAP machine operation by a trained therapist. The machines were initially set in auto- CPAP mode for home use and patients were asked to return the device after they had reported >4 hours/nightusage during sleep. This usually occurred within 1 week. The optimum fixed pressure was then set to the 95 th percentile pressure that controlled most of the OSA events, as routinely used in clinical practice. This approach to CPAP titration has been shown to produce similar outcomes to inlaboratory titration. 1 Patients were then asked to use the device each night for as long as they could tolerate it. Both face-to-face and telephone support from a CPAP therapist was available during this acclimatisation period. Pressures were

4 occasionally altered by 1-2 cmh20 to overcome any residual OSA detected by the device and at the same time, to maximise usage and comfort as well as to minimise mask leak. Once the usage pattern had stabilised, treatment was considered to be optimised and patients were asked to surrender the machine until the CPAP treatment phase of the study. MAD. The mandibular advancement splint (Somnodent, SomnoMed Ltd Australia) is a custom fitted and titratable two-piece device. Individual dental impressions for manufacture of the device were taken at a mandibular protrusive bite of 60% of maximum protrusion. The mechanical operation of this device and its effectiveness in treating OSA, including comparison to placebo, has been reported previously. 2-4 Once fitted with the device, patients underwent acclimatisation during which they incrementally advanced the device until the maximum comfortable limit of advancement was achieved. Patients were asked to use the device each night for as long as they could tolerate it. Both face-to-face and telephone orthodontic support was available during acclimatisation. The advancements were recorded in a diary and the final position was verified by the orthodontist, after which the device was surrendered until the MAD treatment phase of the study. Outcomes and Follow-up. All outcomes were assessed on three occasions, at baseline prior to treatment acclimatisation and then at the end of each of the 1 month treatment arms. Polysomnography(E-Series, Compumedics, Melbourne, Australia, Alice 5, Philips Respironics, Andover, MA, USA or Sandman Elite, Nellcor Puritan Bennett, Pleasanton,CA, USA) and scoring were conducted using standard techniques. 5 Recordings included 4 channels ofelectroencephalogram (EEG), 2

5 channels of elecro-oculogram (EOG), chin electromyogram (EMG), electrocardiogram (ECG), anterior tibial EMG, nasal pressure, chest and abdomen movements, body position and arterial oxygen saturation (SpO2). Office BP was assessed in duplicate in the seated position after 5-min rest by conventional sphygmomanometry. Twenty-four hour ambulatory BP monitoring was performed using the Spacelabs monitor. BP was measured at 30-min intervals during the day (06:00-20:00) and every 60-min at night (20:00-06:00). Participants were instructed to undertake their usual daily activity and maintain a diary to note their activity at each recording, and their sleep time. Minimal editing of data and criteria according to the modified Casadei method were used to eliminate artefact 6. Central BP and arterial stiffness were assessed after 10-min rest in the supine position using pulse wave analysis as previously described (SphymoCor, AtCor Medical, Ryde, Australia). 7 Daytime functioning was measured with a sleep-related QOL questionnaire, the Functional Outcomes of Sleep Questionnaire (FOSQ) 8, a general QOL questionnaire, the Short Form 36 (SF36) 9 and a subjective sleepiness questionnaire, the Epworth Sleepiness Score (ESS) 10. Patients also underwent a computer-based driving simulator performance assessment (AusEd, Australasian Sleep Trials Network, Australia) 11 with a 10-min practice period preceding each 30- min drive. Patients were also asked to complete a daily diary recording details of treatment usage and side-effects. Diaries were used to compile subjective compliance data. Compliance was determined by dividing the total hours of reported use each night by the number of nights with access to treatment. After completing the trial but before knowledge of their results, patients reported their treatment preference (CPAP, MAD, either, or neither).

6 Statistical analysis We selected the difference in 24-hour mean arterial pressure (24MAP) between CPAP and MAD as the primary outcome. The analysis was designed to establish non-inferiority of MAD compared with CPAP for this outcome. A previous study showed that OSA treatment with therapeutic CPAP lowered 24MAP by 3.3mmHg relative to sham CPAP. 12 This study did not select patients on the basis of their hypertensive status. Therefore, we assumed that by using similar selection criteria we could establish non-inferiority of MAD to CPAP for control of 24MAP with a noninferiority margin of 1.6mmHg. An analysis of variance with the 4 randomised groups was used to establish that no acclimatisation or treatment arm order effects occurred in the 24MAP, ESS, FOSQ or SF36 component responses after MAD and CPAP (all p>0.39). The primary hypothesis was tested by comparing the upper limit of the 95% confidence interval for the MAD-CPAP difference in 24MAP with the a priori non-inferiority margin using the paired t-test. All other health outcomes including subjective sleepiness (ESS), quality of life (FOSQ, SF-36), driving simulator performance and arterial stiffness were assessed withthe repeated measures analysis of variance. This approach alloweddirect between-treatment comparisonsas well as post-hoc comparisons between each treatment and baseline.we limited the analysis to the 108 subjects who completed the trial, regardless of compliance with their assigned treatment. Compared with an intention-to-treat analysis, this was a more conservative approach that would reduce the likelihood of falsely claiming (1) non-inferiority for the primary outcome 13 and (2) no between-treatment differences for other outcomes.

7 Sample size and study power In order to ensure an adequate sample size to assess multiple unrelated health outcomes, we powered the study on a blood pressure outcome 24 hour Mean Arterial Pressure (24MAP). Based on our own data, 4 we estimated a within-subject mean square error of 3.9 for 24MAP. Hence, in order to detect non-inferiority of this outcome with 90% power, using a non-inferiority margin of 1.6mmHg and assuming a true difference between treatment means of 0, a sample size of 108 completers was required. Power analysis was performed using PASS software version 11 (NCSS Inc, Kaysville Utah). All other analyses were made using the PASW statistical software version 17 (SPSS Inc., Chicago, IL).

8 References for Online Supplement E1. Duran-Cantolla J, Aizpuru F, Montserrat JM, Ballester E, Teran-Santos J, Aguirregomoscorta JI, et al. Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial. BMJ 2010;341:c5991. E2. Mehta A, Qian J, Petocz P, Darendeliler MA, Cistulli P. A Randomized, Controlled Study of a Mandibular Advancement Splint for Obstructive Sleep Apnea. American Journal of Respiratory and Critical Care Medicine 2001;163: E3. Gotsopoulos H, Chen C, Qian J, Cistulli PA. Oral Appliance Therapy Improves Symptoms in Obstructive Sleep Apnea: A Randomized, Controlled Trial. Am J Respir Crit Care Med 2002;166: E4. Gotsopoulos H, Kelly JJ, Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. Sleep 2004;27: E5. Anonymous. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force.[see comment]. Sleep 1999;22: E6. Winnicki M, Canali C, Mormino P, Palatini P. Ambulatory blood pressure monitoring editing criteria. Am J Hypertens 1997;10: E7. Phillips CL, Yee B, Yang Q, Villaneuva AT, Hedner J, Berend N, et al. Effects of Continuous Positive Airway Pressure Treatment and Withdrawal in Patients With Obstructive Sleep Apnea on Arterial Stiffness and Central BP. Chest 2008;134:

9 E8. Weaver TE, Laizner AM, Evans LK, Maislin G, Chugh DK, Lyon K, et al. An instrument to measure functional status outcomes for disorders of excessive sleepiness. Sleep 1997;20: E9. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical care 1992;30: E10. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14: E11. Desai AV, Wilsmore B, Bartlett DJ, Unger G, Constable B, Joffe D, et al. The utility of the AusEd driving simulator in the clinical assessment of driver fatigue. Behav Res Methods 2007;39: E12. Pepperell JCT, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson C, Stradling JR, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. The Lancet 2002;359: E13. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA : the journal of the American Medical Association 2006;295:

10 Table E1: 24hr BP in All (n=108: top panel) and Hypertensive Completers (n= 45: bottom panel) Variable Mean (SE) Baseline CPAP MAD Mean Baseline - CPAP Difference(95% CI) Mean Baseline - MAD Difference (95% CI) Mean CPAP - MAD Difference (95% CI) All Completers Office SBP (mmhg) (1.4) (1.3) (1.1) -0.2 (-2.4 to 2.0) -0.3 (-2.3 to 1.8) (-2.1 to 2.0) Office DBP (mmhg) 80.6 (0.9) 79.6 (0.9) 79.7 (0.8) 1.1 (-0.5 to 2.6) 1.0 (-0.4 to 2.4) (-1.5 to 1.4) 24 hr ABPM SBP (mmhg) (1.2) (1.0) (1.1) -0.5 (-2.0 to 0.9) -0.0 (-1.5 to 1.5) 0.5 (-0.7 to 1.8) DBP (mmhg) 77.3 (0.8) 77.2 (0.7) 77.1 (0.7) 0.1 (-0.9 to 1.1) 0.2 (-0.7 to 1.1) 0.2 (-0.7 to 1.0) MBP (mmhg) 92.7 (0.8) 92.7 (0.7) 92.5 (0.7) 0.0 (-1.0 to 1.0) 0.3 (-0.8 to 1.3) 0.2 (-0.7 to 1.1) Wake SBP (mmhg) (1.1) (1.1) (1.1) -0.8 (-2.4 to 0.9) -0.2 (-1.7 to 1.4) 0.6 (-0.8 to 2.0) Wake DBP (mmhg) 81.6 (0.8) 81.4 (0.8) 81.1 (0.8) 0.2 (-0.8 to 1.2) 0.5 (-0.5 to 1.5) 0.3 (-0.6 to 1.2) Wake MBP (mmhg) 96.9 (0.8) 97.0 (0.8) 96.5 (0.8) -0.0 (-1.1 to 1.1) 0.4 (-0.7 to 1.5) 0.4 (-0.5 to 1.1) Sleep SBP (mmhg) (1.3) (1.1) (1.2) 0.0 (-1.7 to 1.8) 0.4 (-1.3 to 2.2) 0.4 (-1.3 to 2.1) Sleep DBP (mmhg) 68.1 (0.9) 68.1 (0.8) 67.9 (0.8) 0.0 (-1.5 to 1.6) 0.2 (-1.1 to 1.5) 0.2 (-1.1 to 1.5) Sleep MBP (mmhg) 83.3 (0.9) 83.3 (0.8) 82.7 (0.9) 0.1 (-1.4 to 1.5) 0.7 (-0.8 to 2.1) 0.6 (-0.7 to 1.9) Nocturnal Dipping SBP Dip (%) 13.3 (0.6) 13.7 (0.6) 13.5 (0.6) -0.4 (-1.7 to 1.0) -0.2 (-1.5 to 1.2) 0.2 (-1.1 to 1.5) DBP Dip (%) 16.6 (0.7) 16.2 (0.8) 16.1 (0.8) 0.4 (-1.4 to 2.2) 0.5 (-1.2 to 2.2) 0.1 (-1.4 to 1.6) Hypertensive Completers Office SBP (mmhg) (1.9) (1.9) (1.7) 2.7 (-1.0 to 6.3) 4.7 (-1.4 to 8.0) 2.0 (-1.5 to 5.6) Office DBP (mmhg) 87.3 (1.4) 84.5 (1.5) 83.7 (1.2) 2.8 (-0.0 to 5.7) 3.6 (1.3 to 5.9)** 0.8 (-1.8 to 3.4) 24 hr ABPM SBP (mmhg) (1.4) (1.3) (1.6) 3.0 (0.6 to 5.4)* 2.9 (0.3 to 5.4)* -0.2 (-2.3 to 2) DBP (mmhg) 83.6 (1.1) 81.2 (1.1) 81.5 (1.2) 2.4 (0.9 to 3.9)** 2.1 (0.4 to 3.7)* -0.3 (-1.8 to 1.1) MBP (mmhg) 99.8 (0.9) 97.4 (1.0) 97.6 (1.2) 2.5 (0.9 to 4.1)** 2.2 (0.4 to 4.0)* -0.3 (-1.9 to 1.3) Wake SBP (mmhg) (1.4) (1.4) (1.6) 2.3 (-0.5 to 5.1) 2.5 (-0.1 to 5.1) 0.2 (-2.0 to 2.5) Wake DBP (mmhg) 87.4 (1.2) 85.2 (1.3) 85.0 (1.3) 2.1 (0.7 to 3.6)** 2.4 (0.8 to 3.9)** 0.2 (-1.1 to 1.5) Wake MBP (mmhg) (1.0) (1.1) (1.2) 2.1 (0.4 to 3.7)* 2.4 (0.5 to 4.2)* 0.3 (-1.2 to 1.7) Sleep SBP (mmhg) (1.7) (1.6) (1.9) 4.1 (1.7 to 6.5)** 3.4 (0.6 to 6.3)* -0.7 (-3.5 to 2.2) Sleep DBP (mmhg) 75.2 (1.3) 72.1 (1.1) 73.3 (1.3) 3.1 (0.7 to 5.5)* 1.9 (-0.4 to 4.2) -1.1 (-3.5 to 1.1) Sleep MBP (mmhg) 91.1 (1.3) 88.1 (1.1) 88.1 (1.4) 3.0 (0.8 to 5.2)** 3.0 (0.3 to 5.7)* 0.0 (-2.3 to 2.4) Nocturnal Dipping SBP Dip (%) 11.6 (0.9) 13.0 (1.1) 12.5 (1.0) -1.4 (-3.3 to 0.4) -0.8 (-2.7 to 0.9) 0.6 (-1.4 to 2.5) DBP Dip (%) 13.9 (1.1) 15.0 (1.3) 13.6 (1.2) -1.1 (-3.6 to 1.4) 0.3 (-2.2 to 2.8) 1.4 (-3.6 to 0.8)

11 ** p<0.01, * p< 0.05 Table E2 Pulse Wave Analysis results Variable Mean (SE) Baseline CPAP MAD Mean Baseline - CPAP Difference(95% CI) Mean Baseline - MAD Difference (95% CI) Mean CPAP - MAD Difference (95% CI) PWA PSBP (mmhg) (1.2) (1.2) (1.3) 0.1 ( ) -0.9 ( ) -0.9 ( ) PDBP (mmhg) 77.3 (0.9) 75.9 (0.9) 77.2 (1.0) 1.3 ( ) 0.1 ( ) -1.2 ( ) MAP (mmhg) 93.9 (1.0) 92.8 (0.9) 94.0 (1.0) 1.1 ( ) -0.1 ( ) -1.2 ( ) CSBP (mmhg) (1.3) (1.2) (1.3) 1.0 ( ) -0.2 ( ) -1.2 ( ) CPP (mmhg) 35.9 (0.9) 36.1 (0.8) 36.2 (0.8) -0.2 ( ) -0.2 ( ) -0.1 ( ) AIx (%) 23.6 (1.2) 21.7 (1.2) 22.4 (1.2) 1.8 ( )** 1.2 ( )* -0.7 ( ) AIx 75 (%) 16.9 ( (1.2) 15.8 (1.2) 1.3 ( )* 1.1 ( )* -0.2 ( ) ** p<0.01 * p<0.05 PSBP = Peripheral SBP PDBP = Peripheral DBP MAP = Mean Arterial Pressure CSBP = Central SBP CPP = Central Pulse Pressure AIx = Augmentation Index AIx 75 = Augmentation Index corrected to a heart rate of 75bpm AP = Augmentation Pressure

12 LEGEND FOR ONLINE DATA SUPPLEMENT FIGURES Figure E1 Intention-to-treat AHI (±SEM) according to baseline OSA severity Closedsymbols = CPAP, Open symbols = MAD. The AHI was lower on CPAP thanmadfor patients withmild,moderate and severe OSA at baseline All p< 0.05 (WilcoxinSigned Rank Test) Figure E2 Subjective compliance (±SEM) according to baseline OSA severity where compliance = total hours of reported use over all nights of the treatment period Closedsymbols = CPAP, Open symbols = MAD. The compliancewas lower on CPAP thanmad for patients withmild,moderate and severe OSA at baseline (all p < 0.05) Figure E3 24-hour blood pressure profiles during CPAP and MAD treatment showing blood pressure dipping during the sleep period. Data are means (SEM)

13 Figure E1 Figure E2

14 Figure E3