CleteA. Kushida, M.D., Ph.D., [email protected] What …€¦ · Reduction in daytime SBP and DBP...

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Clete A. Kushida, M.D., Ph.D., [email protected] Have Large Trials Taught Us About Treating OSA?

WHAT HAVE LARGE TRIALS TAUGHT US ABOUT TREATING OSA?

Clete A. Kushida, M.D., Ph.D.Professor, Stanford University Medical Center

Medical Director, Stanford Sleep Medicine CenterDirector, Stanford Center for Human Sleep Research

Conflict of Interest DisclosuresClete A. Kushida, M.D., Ph.D., Professor, Stanford University

What Have Large Trials Taught Us About Treating OSA?

Type of Potential Conflict Details of Potential Conflict

Grant/Research Support ResMed, Pacific Medico

Consultant Philips-Respironics

Speakers’ Bureaus

Financial support

Other

Kaplan-Meier Survival Curves Across Sleep Apnea Severity

Marin JM, Lancet, 2005

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Grote L, Hedner J, Peter JH. Mean blood pressure, pulse pressure and grade of hypertension in untreated hypertensive patients with sleep-related breathing disorder. J Hypertens 2001; 19:683–690.

OSA and HTN Severity CPAP and HTN

Sanner BM, Tepel M, Markmann A, et al. Effect of continuous positive airway pressure therapy on 24-hour blood pressure in patients with obstructive sleep apnea syndrome. Am J Hypertens 2002; 15:251–257.

A prospective study with automated ambulatory 24-hour BP monitoring reported a lower mean arterial BP at a 9 month follow-up period than at baseline in 40 of 52 patients with OSA started on CPAP therapy

CPAP and HTN (cont.)

Pepperell JC, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002; 359:204–210.

CPAP and HTN (cont.)

Barbé F. 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, 2012 May 23;307(20):2161-8

Cumulative incidence of hypertension or cardiovascular events for the intervention groups during follow-up, with/without CPAP group stratified according to adherence (<4 vs ≥4 h/night) and the P values for their incidence density ratios in reference to the control group.

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Gotsopoulos H, Kelly JJ, Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. Sleep 2004; 27:934–941.

OA and HTN

Reduction in daytime SBP and DBP and 24-hour DBP after treatment of OSA in 61 patients with a mandibular advancement splint for 4 weeks. MAS reduction in mean 24-hr DBP (1.8 ± 0.5 mmHg) vs. control (P = .001) but not in 24-hour SBP. Awake BP variables reduced with MAS, mean of 3.3 ± 1.1 mmHg SBP (P = .003) and 3.4 ± 0.9 mmHg DBP (P < .0001).

OA vs. CPAP and HTN

Mean differences from baseline in BP variables; CPAP (closed symbols) and MAD (open symbols) for 24-hr wake and sleep periods.

Top = all completers, n = 108; Bottom = HTN completers, n = 45

Phillips CL, Grunstein RR, Darendeliler MA, Mihailidou AS, Srinivasan VK, Yee BJ, Marks GB, Cistulli PA. 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. 2013;187(8):879-87.

Shibata N, Nishimura T, Hasegawa K, et al. Influence of sleep respiratory disturbance on nocturnal blood pressure.Acta Otolaryngol Suppl 2003; 550:32–35.

• A study found an improvement in blood pressure in proportion to the oxygen desaturation time in 31 patients with OSA after surgery.

• After surgery, an improvement in AHI of > 50% was noted in 19/31 patients (61.3%). Improvements in DT and change in BP were > 50% in 21/31 (67.7%) and 14/ 31 (45.2%) patients, respectively.

Surgery and HTN Contrasting Results

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 2001; 134:1015–1023.

A multicenter, randomized, sham CPAP-controlled, parallel-group study of 55 SDB patients with an AHI ≥ 30, ESS ≤ 10, and normal average BP.

No significant effect of CPAP therapy on BP, when used for six weeks, was found.

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• lack of a consistent definition for abnormal breathing events or non-standardized AHI cutoff across studies

• lack of proper randomization or inadequate blinding

• short or inadequate follow-up• Mixing of hypertensive/normotensive subjects

Contrasting Results (cont.)

Several factors may contribute to the contrasting results seen in some of these studies evaluating the effect of OSA treatment on BP:

OSA

C

C

?

?

NCF in OSA PatientsAuthor(Year)

Study Type

nOSA

SeverityConclusions

Barbé(2001)

RCT 29/25 severe no difference in Active vs. Sham CPAP groups for 8 A/P, L/M, and E/F tests

Bédard(1991)

CC 20/10mod-

severedecrease* in 7/9 A/P and 2/4 E/F tests; decrease* in 5/6 L/M tests (only severecases)

Cheshire(1992)

CS 29mod-

severecorrelation* between AHI and 1/2 EF tests and IQ decrease; no correlation in 3 A/P or1 L/M tests

Findley(1986)

CS 26 severedecrease* in 4/8 A/P, L/M, and E/F tests for hypoxemic vs. non-hypoxemic OSAsubjects

Greenberg(1987)

CC 14/14 severe decrease* in 7/14 A/P and E/F tests vs. controls

Ingram(1994)

CC 16/43mild-

severeno difference in OSA vs. controls subjects ≥ 54 yrs for 1 A/P test

Kim(1997)

CH 199/642mild-

severenegative association* between log AHI and psychomotor efficiency in 8 A/P, L/M, orE/F tests

Naëgelé(1995)

CC 17/17 severe decrease* in 1/4 A/P tests, 8/10 L/M tests, and 3/9 E/F tests vs. controls

Presty(1991)

CS 119mild-

severedecrease* in A/P and L/M tests for those OSA patients with severe hypoxia

Redline(1997)

CC 32/20mild-mod

decrease* in 1/4 A/P tests and 1/5 E/F tests; no difference in 3 L/M tests vs. controls

Telakivi(1993)

CS 31mild-

severeno correlation between hypoxia or sleepiness and 7 A/P, L/M, and E/F tests

Verstraeten(1996)

CC 26/22mild-

severeno differences in OSAS vs. insomnia subjects for 6 A/P, L/M, or E/F tests

*Significance Level: p < 0.05; Study Type: RCT = randomized control trial; CC = case-control, CH = cohort; CS = case series; n: cases/controls(if applicable); OSA Severity by average Apnea-Hypopnea Index (AHI), with mild = 5 - 15 events/hr, moderate = 15 - 30 events/hr, and severe> 30 events/hr; Test Type: A/P = tests of attention and psychomotor function, L/M = tests of learning and memory, E/F = tests of executive andfrontal-lobe function

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APPLES

APPLES was a randomized, blinded, sham-controlled, multicenter trial of CPAP therapy, with these specific aims:

• To assess the long-term effectiveness of CPAP therapy on neurocognitive function, mood, sleepiness and quality of life

• To identify specific deficits in neurocognitive function associated with OSA

• To determine which deficits in neurocognitive function in OSA subjects are reversible and most sensitive to the effects of CPAP

• To develop multivariate composite indices to assess the clinical effectiveness of CPAP

• To use functional magnetic resonance imaging (fMRI) on a subset of OSA subjects

NHLBI-AppointedData and Safety

Monitoring Board (DSMB)

Data Coordinating Center

Co-Director, Operations (DO)Co-Director, Biostatistics (DB)

Co-Director, Data Management (DM)Clinical Trialist (CT)

APPLES Coordinator (AC)Quality Assurance/Control Supervisor (QS)

Database Administrator/Data Manager (DD)System Administrator (SA)Chief Neuropsychologist (N)

PSG Scorers (PS)

Clinical Coordinating Center

Principal Investigator (PI)Senior Advisor (SA)

Administrative Director (AD)Procurement Officer (PrO)

NHLBI Program Officer

Clinical Centers (5)

Clinical Center Director (D)Physician-Observer (PO)

Clinical Center Coordinator (C)Data Aide (DA)

PSG Technologists (PSGT)Psychometricians (PM)

Committees

TrainingQuality Assurance/Control

Publication and Presentation

Additional Protocol Review

Consultant Teams

MethodologySleep-Disordered Breathing

EEG/Neurocognitive FunctionMood and Sleepiness

AssessmentQuality of Life Assessment

Secondary Analysis-NC Team

Steering Committee

NHLBI Director

Study Organization

Stanford University, University of Arizona, St. Mary’s Medical Center, St. Luke’s Hospital, Brigham and Women’s Hospital

Inclusion Criteria• OSA as defined by the AASM Task Force OSA diagnostic criteria and a

respiratory disturbance index (RDI) ≥ 10 by polysomnography.

• Male or female gender

• Age ≥ 18 years

Key Exclusion Criteria• Prior treatment for OSA with CPAP or surgery.

• Any individual in the household currently on CPAP or on CPAP in the past.

• An oxygen saturation < 75 percent for > 10 percent of the diagnostic sleep study.

• A near-miss or prior automobile accident due to sleepiness within the past 12 months.

• Conditions, disorders, medications, or substances that could potentially affect neurocognitive function and/or alertness.

• A score ≤ 26 on the Mini Mental State Examination.

Inclusion / Exclusion Criteria

Secondary Outcomes Primary

Outcomes Neurocognitive Function

Daytime Sleepiness Mood Quality

of Life Demographic-

Physical

PN, BSRT, SWMT

SDC, SDCDR, PC, PASAT,

SAT, PVT, VSC, WASI, fMRI

MWT, ESS, SSS, FS

MINI, BDI-I,

POMS, HAM-D

SAQLI, QWB-

SA

age, sex, body mass index, hip,

waist, neck circumference,

pulse, blood pressure

Outcome Measures

PN = Pathfinder Number MWT = Maintenance of Wakefulness TestBSRT = Buschke Selective Reminding Test ESS = Epworth Sleepiness ScaleSWMT = Sustained Working Memory Test SSS = Stanford Sleepiness ScaleSDC = Symbol Digit Coding FS = Fatigue ScaleSDCDR = Symbol Digit Coding Delayed Recall MINI = Mini International Neuropsychiatric InterviewPC = Pathfinder Combined BDI-I = Beck Depression Inventory-IPASAT = Paced Auditory Serial Addition Task POMS = Profile of Mood StatesSAT = Shifting Attention Test HAM-D = Hamilton Rating Scale for DepressionPVT = Psychomotor Vigilance Task SAQLI = Calgary Sleep Apnea Quality of Life IndexVSC = Visual Sequence Comparison QWB-SA = Quality of Well-Being Scale, Self-AdministeredWASI = Wechsler Abbreviated Scale of IntelligencefMRI = Functional Magnetic Resonance Imaging

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• One trial of a 2.5-minute task

• Test of attention, requiring the subject to scan a visual field to locate and connect numbers in sequence

• Measures number sequencing skills, ability to systematically apply an organizing principle, immediate memory, motor coordination, and visual scanning (A/P)

Variables:

PFNRTC, PFNACC, PFNPUT, PFNTOTL, PFNCOOR

CogScreen – PN(Trails A Computer Analogue)

• One trial of a 15-minute task

• Selective reminding test – after 1st trial, only the words not recalled are provided

• A word recalled on 1 trial, but not the next is said to represent “short-term retrieval” (L/M)

• A word remembered on 2 consecutive trials is said to have entered “long-term storage” (L/M)

Variables:

STR, LTR, RLTR, CLTR, LTS, SumRecall, DR TotalRecall

BSRT

• Three 11-minute blocks with 4-minute trials of a 1-back and 2-back working memory task

• Subject compares the spatial position of a stimulus with the position of the stimulus that occurred on a previous trial (E/F)

• Behavioral and EEG data are collected during performance, these measures are combined to yield a composite score indicating degree of change from baseline

Variables:

Activation, Alertness, Behavioral, and Overall Indices x 3

SWMT

456 Completed On-Treatment468 Completed On-Study




102 Dropped for Any Reason9 Disqualified for Any Reason2 Died

126 Dropped for Any Reason11 Disqualified for Any Reason

2 Died

1098 Randomized & Analyzed

1516 Enrolled (CE, TS)

1224 DX PSG Visit

1105 Randomized (CT)

2 Excluded2 AHI <10 post-QC

5 Excluded4 Received both arms1 AHI <10 post-QC

112 Excluded for Any Reason7 Withdrawn for Any Reason

156 Excluded for Any Reason136 Withdrawn for Any Reason

558 Active CPAP 547 Sham CPAP

556 Active CPAP 542 Sham CPAP

2M-CPAP Visit 2M-CPAP Visit

6M-CPAP Visit 6M-CPAP Visit

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Active CPAPMean (SD) or Count (%)

Sham CPAPMean (SD) or Count (%)

Randomization FactorsSex

Male (%) 363 (65.3) 356 (65.7)Female (%) 193 (34.7) 186 (34.3)

RaceWhite (%) 424 (76.3) 411 (75.8)Not White (%) 132 (23.7) 131 (24.2)

OSA SeverityMild OSA (%) 78 (14.0) 71 (13.1)Moderate OSA (%) 174 (31.3) 170 (31.4)Severe OSA (%) 304 (54.7) 301 (55.5)

DemographicsAge (y) 52.2 (12.2)* 50.8 (12.2)*Married (%) 325 (58.5) 309 (57.0)BMI (kg/m2) 32.4 (7.3) 32.1 (7.0)Highest Grade Level (y) 15.50 (2.6) 15.50 (2.6)WASI Full-4 IQ 112.1 (12.7) 112.0 (13.3)WASI Verbal IQ 110.0 (12.8) 110.0 (13.9)WASI Performance IQ 111.6 (13.5) 111.4 (13.0)

Baseline DataActive CPAPMean (SD)

Sham CPAPMean (SD)

Sleep StudyTotal Sleep Time (min) 375.4 (66.6) 378.3 (63.8)Sleep Efficiency (%) 78.2 (13.3) 78.4 (12.2)Sleep Latency (min) 18.8 (22.4) 19.0 (21.4)REM Latency (min) 137.0 (83.6) 137.6 (82.9)Stage 1 (% of TST) 18.8 (14.3) 18.9 (14.6)Stage 2 (% of TST) 60.7 (13.3) 60.3 (13.8)Stage 3 (% of TST) 2.4 (4.6) 2.6 (5.0)Stage 4 (% of TST) 0.5 (2.0) 0.6 (2.0)Stage REM (% of TST) 17.4 (7.2) 17.6 (6.9)

Apnea Hypopnea Index 39.7 (24.9) 40.6 (25.6)

Minimum O2SAT - Sleep (%) 81.0 (7.6) 80.8 (8.5)O2SAT<85% (% of TST) 2.2 (6.1) 2.3 (6.3)

Baseline Data

Active n = 556Sham n = 542p = 0.5122

Active n = 454Sham n = 420p < 0.0001*

Active n = 442Sham n = 398p < 0.0001*

AHI Means

DX 2M 6M

Per-Protocol GEE of PFN

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Covariates

• Gender

• Race (white vs. non-white)

• OSA severity (mild, moderate, severe)

• %TST O2<85

• Age <60 years

• WASI verbal IQ and performance IQ

Visits/OSA SeverityActive CPAP:

Mean Estimate(95% CI LB-UB)

Sham CPAP:Mean Estimate(95% CI LB-UB)

P Value

2M(Active n = 437; Sham n = 394)

0.035(-0.019 – 0.090)

-0.074(-0.133 – -0.015)

0.0074*

6M(Active n = 426; Sham n = 374)

0.072(0.012 – 0.132)

0.018(-0.046 – 0.082)

0.2254

COVARIATE-Adjusted

2M(n = 828)

Mild OSA-0.017

(-0.152 – 0.119)0.011

(-0.135 – 0.157)0.7834

Moderate OSA0.016

(-0.087 – 0.120)-0.032

(-0.128 – 0.064)0.4950

Severe OSA0.054

(-0.017 – 0.125)-0.112

(-0.197 – -0.028)0.0031*

6M(n = 796)

Mild OSA0.023

(-0.132 – 0.177)-0.046

(-0.216 – 0.123)0.5515

Moderate OSA0.017

(-0.086 – 0.121)0.008

(-0.108 – 0.125)0.9101

Severe OSA0.113

(0.031 – 0.195)0.039

(-0.046 – 0.124)0.2176

GLMM: SWMT Overall Mid-Day Index

Sham CPAP = 3.4 Hours

Active CPAP = 4.2 Hours

Mean Hours of Nightly CPAP

P < 0.001*

Active CPAP Sham CPAP76,770 days 69,807 days

Adherence

Baseline features associated with better adherence:

• Increased age

• Higher IQ

• White ethnicity

• Being married

• Poorer sleep quality (e.g., decreased sleep efficiency, longer sleep latency, longer REM latency)

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Variable Category

Number of

VariablesVariables

Demographics 11 Age, BMI, Married, WASI Full-4 IQ, WASI Verbal IQ, WASI Performance IQ,Highest Grade Level, MMSE Total Score, Ethnicity, Study Arm, Site

Health Variables

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Caffeine Servings/Wk, Alcohol Servings/Wk, Current Smoker, CV History, AM Headaches, Dry Mouth/ Throat, Bruxism, Nasal Congestion, Hypertension,

Asthma, COPD, GERD, Chronic Pain Syndrome, Thyroid Disease, Diabetes, Eczema, Anemia, 5 Year

Weight Gain >20 Lbs, Allergic Rhinitis, Depression, Anxiety, Rhinoplasty, Cancer, Smoker, Claustrophobia, Neck Circumference, Nose Exam, Oral/Throat Exam,

Coughing/Wheezing, Shortness of Breath, Pain in Joints/Muscles/Back, Leg Cramps/Jerks, Need to Go to Bathroom

Sleep Variables

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AHI TST, AHI NREM, AHI REM, O2 Sat<85%TST, Avg SpO2 NREM, Avg SpO2REM, Min SpO2, Hrs Sleep/Night, Snore Duration, TIB, TST, Sleep Efficiency, SO after LO, %TSTS3, %TSTS4, %REM, Arousal Index, PLM Index, OA Index, CA

Index, MA Index, Hypopnea Index, Avg SpO2 Wake, Desaturation Index, Number of Awakenings, Naps/Wk, Difficulty

Rising, EDS, Trouble Falling Asleep, Difficulty Falling Back to Sleep at Night, Difficulty Falling Back to Sleep in AM, Pain Affects Sleep, Worry About Sleep,

Unrested During Day, Not Enough Sleep, Noisy Surroundings, MEQ Total Score, MEQ Category

Neurocognitive 3 PVT Median RT, PVT Mean Slowest 10% of RTs, PASAT Total Correct

Mood 9 HAM-D Total Score, POMS TMD, POMS Factor F, POMS Factor T, POMS Factor D, POMS Factor A, POMS Factor C, POMS Factor V, BDI Total Score

Sleepiness 3 MWT Mean Sleep Latency, ESS Total Score, SSS Mean Score

Quality of Life 5 SAQLI Total Score, SAQLI Domain A Mean, SAQLI Domain B Mean, SAQLI Domain C Mean, SAQLI Domain D Mean

Possible Confounders

CPAP Adherence-Adjusted Primary Neurocognitive Outcomes

CPAP Study Arm

NC Mean Estimate (95% CI LB - UB)

Lower 3 Quartiles for %TSTO2 <85

NC Mean Estimate (95% CI LB - UB) Upper Quartile for

%TSTO2 <85

P Value

CogScreen Pathfinder Number Total Time

DXActive CPAP 24.05 (23.46 – 24.64) 26.80 (25.59 – 28.02) <0.0001*Sham CPAP 24.49 (23.83 – 25.15) 24.36 (23.36 – 25.36) 0.9572

2MActive CPAP 24.77 (23.99 – 25.54) 26.78 (25.36 – 28.20) 0.0043*Sham CPAP 24.41 (23.70 – 25.12) 23.70 (22.67 – 24.74) 0.5405

6MActive CPAP 24.19 (23.52 – 24.87) 27.40 (25.85 – 28.95) <0.0001*Sham CPAP 24.40 (23.67 – 25.13) 24.35 (23.01 – 25.69) 0.8879

BSRT Sum Recall

DXActive CPAP 49.93 (49.05 – 50.81) 49.07 (47.52 – 50.62) 0.3357Sham CPAP 50.12 (49.23 – 51.02) 49.09 (47.60 – 50.58) 0.2545

2MActive CPAP 52.87 (52.00 – 53.75) 50.68 (48.92 – 52.43) 0.0208*Sham CPAP 52.10 (51.07 – 53.13) 51.52 (49.90 – 53.14) 0.5561

6MActive CPAP 54.47 (53.56 – 55.38) 52.95 (51.20 – 54.69) 0.1108Sham CPAP 54.31 (53.30 – 55.32) 54.18 (52.63 – 55.73) 0.8928

SWMT Overall Mid-day

2MActive CPAP 0.003 (-0.061 – 0.066) 0.132 (0.023 – 0.242) 0.0448*

Sham CPAP-0.079 (-0.146 – -

0.013)-0.057 (-0.173 –

0.059)0.7411

6MActive CPAP 0.070 (0.001 – 0.139) 0.079 (-0.040– 0.198) 0.9010

Sham CPAP0.005 (-0.069 – 0.078) 0.058 (-0.070 –

0.187)0.4785

Primary NC by O2 Quartiles Secondary NC Variables

SWMT – Mid-day Behavioral Index

Active CPAP Mean Estimate (95% CI LB-UB)

Sham CPAP Mean Estimate (95% CI LB-UB)

P Value

2M (n = 843)

Mild OSA 0.180 (0.006 – 0.355) 0.104 (-0.074 – 0.283) 0.5419Moderate OSA 0.137 (0.035 – 0.238) 0.126 (0.007 – 0.245) 0.8900

Severe OSA 0.205 (0.117 – 0.294) -0.011 (-0.128 – 0.106) 0.0031*

6M (n = 815)Mild OSA 0.143 (-0.072 – 0.357) 0.116 (-0.123 – 0.356) 0.8703

Moderate OSA 0.194 (0.062 – 0.325) 0.314 (0.191 – 0.437) 0.1838Severe OSA 0.321 (0.212 – 0.430) 0.173 (0.052 – 0.295) 0.0739

SWMT – Mid-day Activation Index

2M (n = 815)Mild OSA -0.050 (-0.268 – 0.169) 0.317 (0.031 – 0.603) 0.0450*

Moderate OSA 0.262 (0.084 – 0.440) 0.170 (0.006 – 0.334) 0.4512Severe OSA -0.003 (-0.109 – 0.103) 0.033 (-0.093 – 0.159) 0.6672

6M (n = 787)Mild OSA 0.157 (-0.089 – 0.403) 0.118 (-0.117 – 0.353) 0.8197

Moderate OSA 0.016 (-0.131 – 0.162) 0.014 (-0.188 – 0.216) 0.9890 Severe OSA 0.058 (-0.068 – 0.185) 0.123 (-0.016 – 0.262) 0.5029

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Active CPAP = 79.7%

Sham CPAP = 74.4%

p = 0.0363*

Retention Between Study Arms Participant Guesses

Epworth Sleepiness Scale

DX (n = 1098; Active n = 556; Sham n = 542) 10.07 (4.26) 10.09 (4.39) 0.9291

DX

Mild OSA (n = 149) 10.10 (4.55) 9.73 (4.43) 0.6152

Moderate OSA (n = 344) 9.57 (4.13) 9.75 (4.56) 0.7040

Severe OSA (n = 605) 10.35 (4.24) 10.37 (4.28) 0.9537

2M (n = 875; Active n = 453; Sham n = 422)

7.86 (4.20) 8.89 (4.31) 0.0004*

2M

Mild OSA (n = 111) 8.59 (4.31) 7.90 (4.01) 0.3886

Moderate OSA (n = 261) 7.25 (3.89) 8.39 (4.29) 0.0236*

Severe OSA (n = 503) 8.00 (4.31) 9.34 (4.34) 0.0005*

6M(n = 846; Active n = 443; Sham n = 403)

7.39 (4.21) 8.41 (4.18) 0.0005*

6M

Mild OSA (n = 113) 8.37 (4.64) 7.64 (3.98) 0.3796

Moderate OSA (n = 250) 7.07 (3.87) 8.43 (4.55) 0.0106*

Severe OSA (n = 483) 7.31 (4.25) 8.56 (4.02) 0.0010*

MWT Mean Sleep Latency

p = 0.0052* p = 0.0022*p = 0.6540

n=551 n= 535 n=445 n= 408 n=432 n= 395

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MWT-MSL ≤ 14.5Active CPAP P Value Sham CPAP P Value

CogScreen Pathfinder Number – Total Time

2MSpearman Correlation Coefficient (∆ MWT-MSL vs. ∆ PFN-TOTL)

0.0322n = 101

0.74940.1197n = 85

0.2754

6MSpearman Correlation Coefficient (∆ MWT-MSL vs. ∆ PFN-TOTL)

-0.1629n = 101

0.10350.1239n = 83

0.2643

BSRT – Sum Recall

2MSpearman Correlation Coefficient

(∆ MWT-MSL vs. ∆ BSRT-SR)

-0.0894n = 101

0.37400.0109n = 85

0.9214

6MSpearman Correlation Coefficient

(∆ MWT-MSL vs. ∆ BSRT-SR)

-0.1356n = 101

0.17640.1108n = 82

0.3216

SWMT – Mid-day Overall Index

2MSpearman Correlation Coefficient (∆ MWT-MSL vs. ∆ SWMT-OMD)

0.2084n = 98

0.0395*0.0774n = 80

0.4948

6MSpearman Correlation Coefficient (∆ MWT-MSL vs. ∆ SWMT-OMD)

0.1598n = 95

0.12190.1015n = 78

0.3766

For Participants with MWT-MSL ≤14.5, Correlation between Change in MWT-MSL vs. Change in Primary Neurocognitive Outcome by Visit and Study Arm

?• The detection of CPAP effects for only the primary E/F

variable suggests this test is a more sensitive measure for subtle neurocognitive changes, combining a cognitive task with simultaneous EEG measures of brain function.

• Lower levels of oxygen saturation and increased sleepiness had an association with this primary E/F variable.

• However, these effects were only detected at 2 months and were minor compared to effects of caffeine and diphenhydramine for this measure in other studies.

Individual Variability and Cognitive Reserve

• Individual variability: Deficits in NCF may vary significantly among individuals independent of sleep history and may involve a trait-like differential yet stable vulnerability to impairment from sleep loss, of which the neurobiological correlates are presently unidentified.1

• The concept of cognitive (or brain) reserve may be important; the neural effect of sleep loss may be mediated through cognitive reserve, so that individuals with more reserve are able to withstand a greater insult before performance is detrimentally affected.2

1Van Dongen HPA et al. Systematic interindividual differences in neurobehavioral impairment from sleep loss: Evidence of trait-likedifferential vulnerability. Sleep. 2004; 27(3):423-33. 2Van Dongen HP. Brain activation patterns and individual differences in working memory impairment during sleep deprivation. Sleep. 2005 Apr 1;28(4):386-8.

Limitations

Could these factors collectively result in less susceptibility to the neurocognitive effects of OSA and a subsequent reduced response to treatment?

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Key Issues and Future Research

• OSA is a multifaceted disorder with many comorbidities and outcomes; we believe that the mixed results from prior studies and the limited effect of CPAP on E/F measures of neurocognition in this study suggest the existence of a complex OSA-neurocognitive relationship.

• Clinicians should consider disease severity, sleepiness, and individual differences (variability and cognitive reserve) including treatment adherence in managing their OSA patients with CPAP.

• We need more large-scale studies (e.g., APPLES, CATNAP)

• Sleep-neurocognitive expert teams need to further evaluate these and other test batteries (e.g., CANTAB, Mindstreams, CNS Vital Signs [CNSVS]) to select the most relevant tests and variables for each major sleep area of study

ComparativeOutcomesManagement withElectronic DataTechnology

ACKNOWLEDGEMENTS

APPLES was funded by contract 5UO1-HL-068060 from the National Heart, Lung and Blood Institute. The APPLES pilot studies were supported by grants from the American Academy of Sleep Medicine and the Sleep Medicine Education and Research

Foundation to Stanford University and by the National Institute of Neurological Disorders and Stroke (N44-NS-002394) to SAM Technology. APPLES investigators gratefully recognize the vital input and support of Dr. Sylvan Green who died before the results of

this trial were analyzed, but was instrumental in its design and conduct.

ADMINISTRATIVE COREClete A. Kushida, MD, PhD; Deborah A. Nichols, MS; Eileen B. Leary, BA, RPSGT; Pamela R. Hyde, MA; Tyson H. Holmes, PhD;

Daniel A. Bloch, PhD; William C. Dement, MD, PhD

DATA COORDINATING CENTER Daniel A. Bloch, PhD; Tyson H. Holmes, PhD; Deborah A. Nichols, MS; Rik Jadrnicek, Microflow, Ric Miller, Microflow, Usman Aijaz,

MS; Aamir Farooq, PhD; Darryl Thomander, PhD; Chia-Yu Cardell, RPSGT; Emily Kees, Michael E. Sorel, MPH; Oscar Carrillo, RPSGT; Tami Crabtree, MS; Booil Jo, PhD; Ray Balise, PhD; Tracy Kuo, PhD

CLINICAL COORDINATING CENTERClete A. Kushida, MD, PhD, William C. Dement, MD, PhD, Pamela R. Hyde, MA, Rhonda M. Wong, BA, Pete Silva, Max Hirshkowitz,

PhD, Alan Gevins, DSc, Gary Kay, PhD, Linda K. McEvoy, PhD, Cynthia S. Chan, BS, Sylvan Green, MD

CLINICAL CENTERS

Stanford UniversityChristian Guilleminault, MD; Eileen B. Leary, BA, RPSGT; David Claman, MD; Stephen Brooks, MD; Julianne Blythe, PA-C, RPSGT; Jennifer Blair, BA; Pam Simi, Ronelle Broussard, BA; Emily Greenberg, MPH; Bethany Franklin, MS; Amirah Khouzam, MA; Sanjana

Behari Black, BS, RPSGT; Viola Arias, RPSGT; Romelyn Delos Santos, BS; Tara Tanaka, PhD

University of ArizonaStuart F. Quan, MD; James L. Goodwin, PhD; Wei Shen, MD; Phillip Eichling, MD; Rohit Budhiraja, MD; Charles Wynstra, MBA; Cathy Ward, Colleen Dunn, BS; Terry Smith, BS; Dane Holderman, Michael Robinson, BS; Osmara Molina, BS; Aaron Ostrovsky,

Jesus Wences, Sean Priefert, Julia Rogers, BS; Megan Ruiter, BS; Leslie Crosby, BS, RN

St. Mary Medical CenterRichard D. Simon Jr., MD; Kevin Hurlburt, RPSGT; Michael Bernstein, MD; Timothy Davidson, MD; Jeannine Orock-Takele, RPSGT;

Shelly Rubin, MA; Phillip Smith, RPSGT; Erica Roth, RPSGT; Julie Flaa, RPSGT; Jennifer Blair, BA; Jennifer Schwartz, BA; Anna Simon, BA; Amber Randall, BA

CleteA. Kushida, M.D., Ph.D., [email protected] What …€¦ · Reduction in daytime SBP and DBP...

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