efigure 1. Network map showing the number of trials and patients in which CPAP, mandibular advancement devices and inactive controls were compared

Transcription

1 Supplementary Online Content Bratton DJ, Gaisl T, Wons AM, Kohler M. CPAP vs mandibular advancement devices and blood pressure in patients with obstructive sleep apnea: a systematic review and meta-analysis. JAMA. doi:1.11/jama emethods. Search strategy efigure 1. Network map showing the number of trials and patients in which CPAP, mandibular advancement devices and inactive controls were compared efigure 2. Comparison-adjusted funnel plots efigure 3. Association between the length of follow-up in each study and the reported effect of CPAP on BP vs inactive control efigure 4. Association between the reported average baseline BP in each study and the corresponding reported effect of CPAP on BP vs inactive control efigure 5. Association between the reported mean baseline apnea-hypopnea index (AHI) and the reported effect of CPAP on BP vs inactive control efigure 6. Association between the reported mean baseline oxygen desaturation index (ODI) and the reported effect of CPAP on BP vs inactive control efigure 7. Summary of proportion of trials at low, unclear and high risk of bias in each domain of the Cochrane Collaboration s tool for assessing risk of bias (N=51) etable 1. Sensitivity analysis of the network meta-analysis on systolic blood pressure (SBP) etable 2. Sensitivity analysis of the network meta-analysis on diastolic blood pressure (DBP) etable 3. Results of the network meta-analysis common-heterogeneity model etable 4. Difference in the reported effects of CPAP vs inactive control on BP in trials using sham CPAP and any other placebo compared to trials using no placebo etable 5. Difference in the reported effects of CPAP vs inactive control on BP in trials from which morning, office or 24h BP data were extracted compared to studies from which daytime BP was extracted etable 6. Risk of bias of included trials evaluated using the Cochrane Risk of Bias tool ereferences

2 emethods. Search strategy 1) (apnea or apnoea or OSA or OSAS or SAHS or hypopnoea or hypopnea or obstructive sleep apnea or obstructive sleep apnoea).af. 2) blood pressure.af. 3) (randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or trial.ti. or clinical trials as topic.sh. or randomly.ab. 4) (oral appliance or mandibular advancement or dental appliance or mandibular device or dental device or oral device).af. 5) (CPAP or continuous positive airway pressure).af 6) 1 AND 2 AND 3 AND (4 OR 5) Key: af = all fields, pt = publication type, ab = abstract, ti = title, sh = medical subject headings, OSA = obstructive sleep apnea, OSAS = obstructive sleep apnea syndrome, SAHS = sleep apnea/hypopnea syndrome, CPAP = continuous positive airway pressure.

3 efigure 1. Network map showing the number of trials and patients in which CPAP, mandibular advancement devices and inactive controls were compared The middle triangle represents the number of 3-arm studies in which all three treatments are directly compared. Line widths are roughly proportional to the number of trials of the comparison that they represent. Numbers in brackets indicate the total number of participants randomized in each comparison. CPAP = continuous positive airway pressure, MAD = mandibular advancement device.

4 efigure 2. Comparison-adjusted funnel plots Standard error of SBP effect size Standard error of DBP effect size SBP effect size centred at comparison-specific pooled effect DBP effect size centred at comparison-specific pooled effect CPAP vs Inactive (N = 47) MAD vs Inactive (N = 6) CPAP vs MAD (N = 4) CPAP vs Inactive (N = 46) MAD vs Inactive (N = 6) CPAP vs MAD (N = 4) Treatment effect standard error vs. comparison adjusted reported treatment effect for SBP (left figure) and DBP (right figure). The solid vertical line represents the shifted pooled treatment difference estimate for each treatment comparison. N = number of studies for each comparison. SBP = systolic blood pressure, DBP = diastolic blood pressure, CPAP = continuous positive airway pressure, MAD = mandibular advancement device.

5 efigure 3. Association between the length of follow-up in each study and the reported effect of CPAP on BP vs inactive control 1 1 Reported treatment difference on SBP (CPAP - inactive control), mmhg Reported treatment difference on DBP (CPAP - inactive control), mmhg Individual trial Meta-regression line & 95% CI Overall difference Length of follow-up (weeks) SBP slope =.2mmHg (95% CI.1,.3), p =.3, (N = 45) Length of follow-up (weeks) DBP slope =.1mmHg (95% CI.,.2), p =.6, (N = 44) Association between the length of follow-up (weeks) in each study and the reported effect of CPAP on SBP (left figure) and DBP (right figure) vs inactive control. Circles represent individual results for each trial with the size of the circle being proportional to its weight in the random-effects meta-analysis. Each regression line and its 95% CI were estimated using a random-effects linear meta-regression model with length of follow-up as the covariate. Two studies 1,2 with a follow-up length of one year or more were considered outliers and excluded from the analysis. N, number of studies included in each analysis.

6 efigure 4. Association between the reported average baseline BP in each study and the corresponding reported effect of CPAP on BP vs inactive control 1 1 Reported treatment difference on SBP (CPAP - inactive control), mmhg Reported treatment difference on DBP (CPAP - inactive control), mmhg Individual trial Meta-regression line & 95% CI Overall difference Mean baseline SBP (mmhg) SBP slope = -.2mmHg (95% CI -.3,-.), p =.42, (N = 43) Mean baseline DBP (mmhg) DBP slope = -.2mmHg (95% CI -.4,-.), p =.14, (N = 42) Association between the reported average baseline BP (mmhg) in each study and the corresponding reported effect of CPAP on SBP (left figure) and DBP (right figure) vs inactive control. Circles represent individual results for each trial with the size of the circle being proportional to its weight in the random-effects meta-analysis. Each regression line and its 95% CI were estimated using a random-effects linear meta-regression model with the corresponding mean BP measurement as the covariate. N, number of studies included in each analysis.

7 efigure 5. Association between the reported mean baseline apnea-hypopnea index (AHI) and the reported effect of CPAP on BP vs inactive control 1 1 Reported treatment difference on SBP (CPAP - inactive control), mmhg Reported treatment difference on DBP (CPAP - inactive control), mmhg Individual trial Meta-regression line & 95% CI Overall difference Mean baseline AHI (/h) SBP slope = -.mmhg (95% CI -.1,.), p =.24, (N = 42) Mean baseline AHI (/h) DBP slope = -.mmhg (95% CI -.1,.), p =.17, (N = 41) Association between the reported average baseline apnea-hypopnea index (AHI, /h) in each study and the reported effect of CPAP on SBP (left figure) and DBP (right figure) vs. inactive control. Circles represent individual results for each trial with the size of the circle being proportional to its weight in the random-effects meta-analysis. Each meta-regression line and its 95% CI were estimated using a random-effects linear meta-regression model with mean AHI as the covariate. N, number of studies included in each analysis.

8 efigure 6. Association between the reported mean baseline oxygen desaturation index (ODI) and the reported effect of CPAP on BP vs inactive control 1 1 Reported treatment difference on SBP (CPAP - inactive control), mmhg Reported treatment difference on DBP (CPAP - inactive control), mmhg Individual trial -15 Meta-regression line & 95% CI Overall difference Mean baseline ODI (dips/h) SBP slope = -.1mmHg (95% CI -.3,.), p =.17, (N = 14) Mean baseline ODI (dips/h) DBP slope = -.1mmHg (95% CI -.2,.), p =.7, (N = 14) Association between the reported average baseline oxygen desaturation index (ODI, dips /h) in each study and the reported effect of CPAP on SBP (left figure) and DBP (right figure) vs. inactive control. Circles represent individual results for each trial with the size of the circle being proportional to its weight in the random-effects meta-analysis. Each meta-regression line and its 95% CI were estimated using a random-effects linear meta-regression model with mean ODI as the covariate. Ten 2-11 out of the 14 studies defined ODI as the number of dips in oxygen saturation 4% from baseline per hour, two 12,13 used 3% and in two 14,15 studies this information was unavailable. N, number of studies included in each analysis.

9 efigure 7. Summary of proportion of trials at low, unclear and high risk of bias in each domain of the Cochrane Collaboration s tool for assessing risk of bias (N=51) Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) % of trials Low risk Unclear risk High risk

10 etable 1. Sensitivity analysis of the network meta-analysis on systolic blood pressure (SBP) Comparison CPAP v control MAD v control CPAP v MAD Correlation estimate Difference in SBP (mmhg) 95% CI p-value Min , -1.4 <.1 Mean , -1.5 <.1 Max , -1.6 <.1 Min , Mean , Max , Min , Mean , Max ,.5.2 Results of the network meta-analysis of SBP when using the minimum (r=.47), mean (r=.69, primary analysis) or maximum (r=.89) estimated between-visit correlation to impute the treatment effect standard error in studies in which it could not be obtained or was not reported.

11 etable 2. Sensitivity analysis of the network meta-analysis on diastolic blood pressure (DBP) Comparison CPAP v control MAD v control CPAP v MAD Correlation estimate Difference in DBP (mmhg) 95% CI p-value Min , -1.3 <.1 Mean , -1.3 <.1 Max , -1.4 <.1 Min , -1.1 <.1 Mean , Max , -..4 Min ,.9.86 Mean , Max ,.9.37 Results of the network meta-analysis of DBP when using the minimum (r=.53), mean (r=.74, primary analysis) or maximum (r=.85) estimated between-visit correlation to impute the treatment effect standard error in studies in which it could not be obtained or was not reported.

12 etable 3. Results of the network meta-analysis common-heterogeneity model Outcome Comparison Difference (SE), mmhg 95% CI p-value Between- study variance, τ 2 SBP CPAP vs control -2.5 (.5) -3.4, -1.5 <.1 MAD vs control -1.8 (1.) -3.7,.1.59 CPAP vs MAD -.6 (1.) -2.6, DBP CPAP vs control -2.1 (.3) -2.7, -1.4 <.1 MAD vs control -1.4 (.7) -2.7, CPAP vs MAD -.6 (.7) -2.,

13 etable 4. Difference in the reported effects of CPAP vs inactive control on BP in trials using sham CPAP and any other placebo compared to trials using no placebo Outcome SBP DBP Difference (mmhg) vs Type of Number of Sample studies using no placebo comparator studies size Difference 95% CI p-value Sham CPAP 3,6-9, , Other placebo 5,1,11, , Sham CPAP 3,6-9, , Other placebo 5,1,11, , Global test p-value studies 1,2,4,33-47 (total sample size 2585) reported the effect of CPAP vs. no placebo on SBP and 17 studies 1,2,4,33-37,39-46 (total sample size 254) reported the effect of CPAP vs. no placebo on DBP. In those studies the pooled association of CPAP in the meta-regression was -1.8mmHg (95% CI -3.4, -.2; p=.3) on SBP and -2.mmHg (95% CI -3.1, -.8; p=.1) on DBP.

14 etable 5. Difference in the reported effects of CPAP vs inactive control on BP in trials from which morning, office or 24h BP data were extracted compared to studies from which daytime BP was extracted Outcome SBP DBP Type of BP measurement Number of studies Sample size Difference (mmhg) vs. studies reporting daytime measurements Difference 95% CI p- value Morning 1,7,1,14,19,25,39,46, , Office 2,6,12,2,26-28,33,38,42, , hour 3,5,8,9,11, , Morning 1,7,1,14,19,25,39,46, ,.3.9 Office 2,6,12,2,26-28,33,42, , hour 3,5,8,9,11, , Global test p-value studies 4,13,15-18,21,22,24,29-32,35-37,4,41,43,45 (total sample size 2129) compared CPAP vs. inactive control on ambulatory daytime BP. In those studies, the estimated association of CPAP vs. inactive control in the meta-regression was -2.4mmHg (95% CI -3.9, -1.; p=.1) on SBP and -2.2mmHg (95% CI -3.1, -1.3; p<.1) on DBP. Type of BP measurement could not be obtained from one study. 23

15 etable 6. Risk of bias of included trials evaluated using the Cochrane Risk of Bias tool Selection bias Performance bias Detection bias Attrition bias Reporting bias Study Random sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data Selective reporting CPAP vs Inactive control Arias Unclear Unclear Low Low High Low Barbe Low Unclear Low Low Low Low Barbe Low Low Low Low Low Low Barnes Low High Low Low Low Low Becker Unclear Low Low Low Unclear Low Campos- 3 Rodriguez 26 Unclear Unclear Low Low Low Low Comondore Low Unclear Low Low Unclear Low Coughlin Low Low Low Unclear Low Low Craig Low Low Low Low Low Low Cross 28 2 Unclear Unclear Low Low Low Low de Oliveira Unclear Unclear Low Low Low Low Drager Low Unclear Low Low Low Low Drager Low Unclear Low Low Low Low Duran-Cantolla Low Low Low Low Low Low Egea Unclear Unclear Low Unclear Low Low Engleman Unclear Unclear Low Low Low Low Faccenda 21 5 Unclear Unclear Low Low Low Low Gottlieb Low Unclear Low Low Low Low Hall Low High Low Unclear Low High Hoyos Low Unclear Low Low Low Low Hoyos Low Low Low Low Unclear Low Huang Low Low Low Low High Low Hui Unclear Unclear Low Low Low Low Ip Unclear Unclear Unclear Unclear Low Low Jones Low Unclear Low Low Low Low Kohler Low Unclear Low Low Low Low Lam Low High Low Low Low Low Litvin Unclear Unclear Low Low Low Low Lozano 21 4 Low Unclear Low Low Low Low Martinez-Garcia Low Low Low Low Low Low McMillan Low Low Low Low Low Low Monasterio Low Unclear Low Unclear Unclear Low Muxfeldt Low Low Low Low Low Low

16 Selection bias Performance bias Detection bias Attrition bias Reporting bias Study Random sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data Selective reporting Nguyen Unclear Unclear Low Unclear Low Low Noda Unclear Unclear Low Unclear Low Low Norman Unclear Unclear Low Low Low Low Pamidi Low Unclear Low Low Low Low Pedrosa Unclear Unclear Low Low Low Low Pepperell 22 8 Unclear Low Low Low Low Low Robinson 26 9 Low Low Low Low Low Low Rossi Low Low Low Unclear Low Low Ruttanaumpawan Unclear Unclear Low Unclear Low Low Takaesu Low Unclear Low Unclear Low Low Weaver Low Low Low Low High Low MAD vs Inactive control Andren Low High Low Low Low Low Gotsopoulos Low Low Low Low Low Low Quinnell Low Low Low Unclear Low Low CPAP vs MAD Phillips Unclear Unclear Low Low Low Low CPAP vs MAD vs Inactive control Barnes Low High Low Low Low Low Dal-Fabbro Unclear Unclear Low Low High Low Lam Unclear Unclear Unclear Unclear Low Low

17 ereferences 1. Huang Z, Liu Z, Luo Q, et al. Long-term effects of continuous positive airway pressure on blood pressure and prognosis in hypertensive patients with coronary heart disease and obstructive sleep apnea: a randomized controlled trial. Am J Hypertens. 215;28(3): McMillan A, Bratton DJ, Faria R, et al. Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial. Lancet Respir Med. 214;2(1): Campos-Rodriguez F, Grilo-Reina A, Perez-Ronchel J, et al. Effect of continuous positive airway pressure on ambulatory BP in patients with sleep apnea and hypertension: a placebo-controlled trial. Chest. 26;129(6): Craig SE, Kohler M, Nicoll D, et al. Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial. Thorax. 212;67(12): Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med. 21;163(2): Jones A, Vennelle M, Connell M, et al. The effect of continuous positive airway pressure therapy on arterial stiffness and endothelial function in obstructive sleep apnea: a randomized controlled trial in patients without cardiovascular disease. Sleep Med. 213;14(12): Kohler M, Stoewhas AC, Ayers L, et al. Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med. 211;184(1): Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet. 22;359(932): Robinson GV, Smith DM, Langford BA, Davies RJ, Stradling JR. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur Respir J. 26;27(6): Rossi VA, Winter B, Rahman NM, et al. The effects of Provent on moderate to severe obstructive sleep apnoea during continuous positive airway pressure therapy withdrawal: a randomised controlled trial. Thorax. 213;68(9): Barnes M, McEvoy RD, Banks S, et al. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med. 24;17(6): Hoyos CM, Killick R, Yee BJ, Phillips CL, Grunstein RR, Liu PY. Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study. Thorax. 212;67(12): Norman D, Loredo JS, Nelesen RA, et al. Effects of continuous positive airway pressure versus supplemental oxygen on 24-hour ambulatory blood pressure. Hypertension. 26;47(5): Hoyos CM, Yee BJ, Wong KK, Grunstein RR, Phillips CL. Treatment of Sleep Apnea With CPAP Lowers Central and Peripheral Blood Pressure Independent of the Time-of-Day: A Randomized Controlled Study. Am J Hypertens. 215;1.193/ajh/hpv Weaver TE, Mancini C, Maislin G, et al. Continuous positive airway pressure treatment of sleepy patients with milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP) randomized clinical trial. Am J Respir Crit Care Med. 212;186(7): Arias MA, Garcia-Rio F, Alonso-Fernandez A, Mediano O, Martinez I, Villamor J. Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation. 25;112(3): Barbe F, Mayoralas LR, Duran J, et al. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern Med. 21;134(11): Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation. 23;17(1): Coughlin SR, Mawdsley L, Mugarza JA, Wilding JP, Calverley PM. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J. 27;29(4): Cross MD, Mills NL, Al-Abri M, et al. Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a randomised controlled trial. Thorax. 28;63(7): de Oliveira AC, Martinez D, Massierer D, et al. The antihypertensive effect of positive airway pressure on resistant hypertension of patients with obstructive sleep apnea: a randomized, double-blind, clinical trial. Am J Respir Crit Care Med. 214;19(3):

18 22. Duran-Cantolla J, Aizpuru F, Montserrat JM, et al. Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial. BMJ. 21;341:c Egea CJ, Aizpuru F, Pinto JA, et al. Cardiac function after CPAP therapy in patients with chronic heart failure and sleep apnea: a multicenter study. Sleep Med. 28;9(6): Hui DS, To KW, Ko FW, et al. Nasal CPAP reduces systemic blood pressure in patients with obstructive sleep apnoea and mild sleepiness. Thorax. 26;61(12): Lam JC, Lam B, Yao TJ, et al. A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea. Eur Respir J. 21;35(1): Litvin AY, Sukmarova ZN, Elfimova EM, et al. Effects of CPAP on "vascular" risk factors in patients with obstructive sleep apnea and arterial hypertension. Vasc Health Risk Manag. 213;9: Nguyen PK, Katikireddy CK, McConnell MV, Kushida C, Yang PC. Nasal continuous positive airway pressure improves myocardial perfusion reserve and endothelial-dependent vasodilation in patients with obstructive sleep apnea. J Cardiovasc Magn Reson. 21;12: Takaesu Y, Inoue Y, Komada Y, Kagimura T, Iimori M. Effects of nasal continuous positive airway pressure on panic disorder comorbid with obstructive sleep apnea syndrome. Sleep Med. 212;13(2): Barnes M, Houston D, Worsnop CJ, et al. A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Respir Crit Care Med. 22;165(6): Engleman HM, Gough K, Martin SE, Kingshott RN, Padfield PL, Douglas NJ. Ambulatory blood pressure on and off continuous positive airway pressure therapy for the sleep apnea/hypopnea syndrome: effects in "non-dippers". Sleep. 1996;19(5): Pamidi S, Wroblewski K, Stepien M, et al. Eight Hours of Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea Improves Glucose Metabolism in Patients with Prediabetes. A Randomized Controlled Trial. Am J Respir Crit Care Med. 215;192(1): Dal-Fabbro C, Garbuio S, D'Almeida V, Cintra FD, Tufik S, Bittencourt L. Mandibular advancement device and CPAP upon cardiovascular parameters in OSA. Sleep Breath. 214;18(4): Barbe F, Duran-Cantolla J, Sanchez-de-la-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA. 212;37(2): Comondore VR, Cheema R, Fox J, et al. The impact of CPAP on cardiovascular biomarkers in minimally symptomatic patients with obstructive sleep apnea: a pilot feasibility randomized crossover trial. Lung. 29;187(1): Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi GF. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med. 27;176(7): Drager LF, Pedrosa RP, Diniz PM, et al. The effects of continuous positive airway pressure on prehypertension and masked hypertension in men with severe obstructive sleep apnea. Hypertension. 211;57(3): Gottlieb DJ, Punjabi NM, Mehra R, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med. 214;37(24): Hall AB, Ziadi MC, Leech JA, et al. Effects of short-term continuous positive airway pressure on myocardial sympathetic nerve function and energetics in patients with heart failure and obstructive sleep apnea: a randomized study. Circulation. 214;13(11): Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med. 24;169(3): Lozano L, Tovar JL, Sampol G, et al. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens. 21;28(1): Martinez-Garcia MA, Capote F, Campos-Rodriguez F, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA. 213;31(22): Monasterio C, Vidal S, Duran J, et al. Effectiveness of continuous positive airway pressure in mild sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med. 21;164(6): Muxfeldt ES, Margallo V, Costa LM, et al. Effects of continuous positive airway pressure treatment on clinic and ambulatory blood pressures in patients with obstructive sleep apnea and resistant hypertension: a randomized controlled trial. Hypertension. 215;65(4): Noda A, Nakata S, Koike Y, et al. Continuous positive airway pressure improves daytime baroreflex sensitivity and nitric oxide production in patients with moderate to severe obstructive sleep apnea syndrome. Hypertens Res. 27;3(8):

19 45. Pedrosa RP, Drager LF, de Paula LK, Amaro AC, Bortolotto LA, Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial. Chest. 213;144(5): Ruttanaumpawan P, Gilman MP, Usui K, Floras JS, Bradley TD. Sustained effect of continuous positive airway pressure on baroreflex sensitivity in congestive heart failure patients with obstructive sleep apnea. J Hypertens. 28;26(6): Lam B, Sam K, Mok WY, et al. Randomised study of three non-surgical treatments in mild to moderate obstructive sleep apnoea. Thorax. 27;62(4): Andren A, Hedberg P, Walker-Engstrom ML, Wahlen P, Tegelberg A. Effects of treatment with oral appliance on 24-h blood pressure in patients with obstructive sleep apnea and hypertension: a randomized clinical trial. Sleep Breath. 213;17(2): Gotsopoulos H, Kelly JJ, Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. Sleep. 24;27(5): Quinnell TG, Bennett M, Jordan J, et al. A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO). Thorax. 214;69(1): Phillips CL, Grunstein RR, Darendeliler MA, et al. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med. 213;187(8):