Clinical trial NCT01261390: Sleep Apnea Intervention for Cardiovascular Disease Reduction
Official title: A Planning Study: Sleep Apnea Intervention for Cardiovascular Disease Reduction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obstructive Sleep Apnea
Keywords: Sleep Apnea
Heart Disease
Risk factors for heart disease
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Beth Israel Deaconess Medical Center
First posted: 2010-12-16
Enrollment: 169
Sex: ALL
Minimum age (years): 45
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Moderate to severe sleep apnea (a high number of breathing pauses on a sleep study) is a common health problem that is often associated with loud snoring and sleepiness.The medical term for this problem is obstructive sleep apnea (OSA). People with OSA often have an increased risk for developing heart disease or may already have a diagnosis of heart disease.

A clinical research study is being conducted at Brigham and Women's Hospital (BWH) and Beth Israel Deaconess Medical Center (BIDMC) to compare the effects of continuous positive airway pressure (CPAP) to conservative medical therapy with participation in one of four groups:

1. Active-PAP Therapy Group (Active-Beh or Active+Beh): Will receive standard medical treatment for sleep apnea with active-PAP. Participants will be randomized to either:

   1. Active-Pap with respiratory therapist visits only
   2. Active-Pap with respiratory therapist visits and cognitive behavioral therapist visits.
2. Alternative PAP Group (Sham): Will receive lower air delivery level than active-PAP therapy group. Will also have meetings with respiratory therapist.
3. Conservative Medical Therapy Group (CMT)\*: Will receive a free supply of nasal strips for the duration of their treatment period (either 6 months or 12 months) and follow healthy sleep hygiene guidelines for how to change sleep habits to minimize incidences of apneas (breathing disturbances during sleep). Frequent follow-up support with research coordinator.

A sleep doctor or cardiologist will have indicated that a potential participant is an appropriate candidate to receive PAP or CMT as acceptable approaches to treat his/her sleep apnea. Participants will be recruited between the ages of 45-75 years who have diagnosed heart disease or between 55-75 years for those who have risk factors for developing heart disease.

This is a 6-12 month study\*\* to evaluate alternative ways to address the potential for OSA treatment to reduce heart disease and to identify those features that would strengthen a later, large-scale randomized controlled trial.

We will test the hypothesis that active treatment for OSA with CPAP reduces CVD morbidity and mortality.

\*All randomized participants will be given conservative medical therapy (CMT).

\*\*For those randomized after December 31, 2012, follow-up assessment will only be 6 months long

Detailed description: In this pilot randomized controlled trial, we will assess the effectiveness of CPAP therapy to reduce the burden of cardiovascular disease (CVD) and CVD risk factors in patients with moderate to severe obstructive sleep apnea (OSA) presenting to a sleep disorders clinic. A total of 700 patients with a new diagnosis of moderate to severe OSA will be recruited from BWH-affiliated sleep disorder clinics, BWH, Massachusetts General Hospital (MGH), and Faulkner Hospital Cardiology Clinics (and similar specialized clinics seeing patients with cardiovascular risk factors, such as endocrinology and hypertensive clinics), Beth Israel Deaconess Medical Center and Joslin Diabetes Center. After completing a 2 week run-in period, randomized participants (approximately 150 participants will be randomized) will undergo baseline and 6 month assessments of key study exposure and outcome variables.

Participants will be randomized after completion of Baseline visit. The treatment arms are as follows:

The active arms are:

1. Active-PAP treatment delivered using standard respiratory therapist (RT) adherence education and support. (Active-Beh)
2. Active-PAP treatment administered using adherence education and support delivered by a RT and enhanced by a behavioral promotion intervention. (Active+Beh)

The control arms are:

1. Conservative Medical Therapy (CMT)
2. Sham-PAP (Sham)

Participants randomized before December 31, 2012 (n=108) also will undergo 12 month follow-up assessments. Participants will be offered a 12 month supervised conservative medical therapy (CMT) program for OSA over the duration of the study intervention. Subjects would be contacted at bimonthly intervals by alternating phone and office visits to assess safety, identify adverse events, identify health care utilization, and reinforce protocol adherence. At 6 and 12 months, study outcomes will be reassessed by collecting data from sources.

Patients randomized after December 31, 2012 (n=61) will undergo only 6 months of follow-up assessment. Participants will be offered a 6 month supervised conservative medical therapy (CMT) program for OSA over the duration of the study intervention. Subjects would be contacted at bimonthly intervals by alternating phone and office visits to assess safety, identify adverse events, identify health care utilization, and reinforce protocol adherence. At 6 months, study outcomes will be reassessed by collecting data from sources.

Eligibility criteria: Inclusion Criteria:

* Obstructive apnea hypopnea index (AHI) ≥ 15
* Age 45-75 years, or 55 to 75 yrs if without established Cardiovascular Disease (CVD)
* Ability to provide informed consent, with the patient and physician acknowledging accepting uncertainty on the role of PAP in CVD prevention.
* Established CVD,or having diabetes mellitus, defined by one or more of the following:

  1. Prior myocardial infarction
  2. Coronary artery revascularization procedure (≥4 months before study entry)
  3. Angiographically documented stenosis (\>70%) of a major coronary artery
  4. Prior ischemic stroke without major functional impairment
  5. Diabetes mellitus treated with medication or ≥ 2 fasting glucose levels ≥ 126 mg/dl

OR

Three or more of the following established CVD risk factors:

1. Hypertension treated with medications or systolic BP \> 140 or diastolic BP \> 90 on ≥ 2 occasions
2. Male sex
3. BMI ≥ 30
4. Total cholesterol \> 240 mg/dl or LDL cholesterol \> 160 mg/dl or HDL \< 45 mg/dl
5. \> 10 pack years of smoking

Exclusion Criteria:

* Diagnosed heart failure with known cardiac ejection fraction of \< 35% or New York Heart Association (NYHA) class 3 or 4 status
* Less than 4 months since myocardial infarction (MI), stroke or revascularization procedure
* Poorly controlled hypertension (\>170/\>100)
* Prior stroke with functional impairment interfering with ability to complete the protocol
* Severe uncontrolled medical problems or medications that may influence measurements or impair ability to participate in the study exams (e.g. oral steroids; chronic opioid use; self- reported chronic kidney disease or, if measured, creatinine \> 2.5 mg/dl or glomerular filtration rate (GFR) \< 30; anemia with Hgb \< 10, etc.)
* Resting oxygen saturation \< 90% or nocturnal oxygen saturation \<85% for \> 10% of the sleep period;
* Use of prescribed PAP for sleep apnea within the prior 2 years
* Report of inability to spend \>6 hrs in bed
* Any use of prescribed PAP for sleep apnea
* Severe sleepiness defined by an Epworth Sleepiness Score of \>14 or report of falling asleep driving in the prior 2 years
* Working as a professional driver
* Low risk related to having sleep apnea defined by a Berlin Score \< 2
* Central sleep apnea, with \>50% of respiratory events classified as central apneas
* Refusal to consider PAP use after an initial split-night PAP study (pre-randomization)
* Concurrent involvement in another research study that will result in a conflict as determined by study doctors

Primary outcomes:
measure: Change From Baseline in 24-hour Blood Pressure at Months 6 and 12 by Pooled Arms
timeFrame: Mean of 6- and 12-months
measure: Difference in CPAP Adherence by Active Treatment Arm
timeFrame: 6-months
measure: Change From Baseline in 24-hour Blood Pressure at Months 6 and 12 (4 Arms)
timeFrame: Mean of 6- and 12-months
measure: Change From Baseline in 24-hour Blood Pressure at Month 12 by Pooled Arms
timeFrame: 12-months
measure: Change From Baseline in 24-hour Blood Pressure at Month 6 by Pooled Arms
timeFrame: 6-months
measure: Change From Baseline in 24-hour Blood Pressure at Month 12 (4 Arms)
timeFrame: 12-months
measure: Change From Baseline in 24-hour Blood Pressure at Month 6 (4 Arms)
timeFrame: 6-months
Secondary outcomes:
measure: Change in 36-Item Short Form Survey (SF-36) Measures (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Epworth Sleepiness Scale (ESS) (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Patient Health Questionnaire (PHQ8) (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in the Calgary Sleep Apnea Quality of Life Index (SAQLI) (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in C-Reactive Protein at Months 6 and 12 (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Lipid Panel at 6 and 12 Months (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Glucose, Fibrinogen, Creatinine and BNP at Months 6 and 12 (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change From Baseline in Hemoglobin A1c Percentage at Months 6 and 12 (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change From Baseline in Fasting Insulin at Months 6 and 12 (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Interleukin 6 (IL-6) at Months 6 and 12 (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Glomerular Filtration Rate (GFR) at Months 6 and 12 (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Urine Microalbumin at Months 6 and 12 (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Urinary Albumin Creatinine Ratio at Months 6 and 12 (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Plasminogen Activator Inhibitor-1 (PAI-1) at Months 6 and 12 (4 Arm)
timeFrame: Mean of 6- and 12-months
measure: Change in Pulse Wave Velocity (PWV) at Months 6 and 12 (4 Arms)
timeFrame: Mean of 6- and 12-months
measure: Change in Augmentation Index at Months 6 and 12 (4 Arms)
timeFrame: Mean of 6- and 12-months
measure: Left Ventricular (LV) Mass Index (4 Arm) - Baseline
timeFrame: 12-months
measure: Left Atrial (LA) Volume Index (4 Arm) - Baseline
timeFrame: 12-months
measure: End-Diastolic Volume (4 Arm) - Baseline
timeFrame: 12-months
measure: Ejection Fraction (4 Arm) - Baseline
timeFrame: 12-months
measure: Right Ventricular Fractional Area Change (4 Arm) - Baseline
timeFrame: 12-months
measure: Tricuspid Annular Peak Systolic Myocardial Velocity (4 Arm) - Baseline
timeFrame: 12-months
measure: Pulmonary Vascular Resistance (4 Arm) - Baseline
timeFrame: 12-months
measure: E/Em Lateral Ratio (4 Arm) - Baseline
timeFrame: 12-months
measure: Peak Tricuspid Regurgitation Velocity (4 Arm) - Baseline
timeFrame: 12-months
measure: Left Ventricular Mass Index (4 Arm) - 12 Month
timeFrame: 12-months
measure: Left Atrial Volume Index (4 Arm) - 12 Month
timeFrame: 12-months
measure: End-Diastolic Volume (4 Arm) - 12 Month
timeFrame: 12-months
measure: Ejection Fraction (4 Arm) - 12 Month
timeFrame: 12-months
measure: Right Ventricular Fractional Area Change (4 Arm) - 12 Month
timeFrame: 12-months
measure: Tricuspid Annular Peak Systolic Myocardial Velocity (4 Arm) - 12 Month
timeFrame: 12-months
measure: Pulmonary Vascular Resistance (4 Arm) - 12 Month
timeFrame: 12-months
measure: E/Em Lateral Ratio (4 Arm) - 12 Month
timeFrame: 12-months
measure: Peak Tricuspid Regurgitation Velocity (4 Arm) - 12 Month
timeFrame: 12-months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Susan Redline, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Beth Israel Deaconess Medical Center
name: Murray Mittleman, MD, DrPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhao YY, Wang R, Gleason KJ, Lewis EF, Quan SF, Toth CM, Song Y, Morrical M, Rueschman M, Mittleman MA, Redline S. Effect of continuous positive airway pressure treatment on ambulatory blood pressures in high-risk sleep apnea patients: a randomized controlled trial. J Clin Sleep Med. 2022 Aug 1;18(8):1899-1907. doi: 10.5664/jcsm.10012.
citation: Reid ML, Gleason KJ, Bakker JP, Wang R, Mittleman MA, Redline S. The role of sham continuous positive airway pressure as a placebo in controlled trials: Best Apnea Interventions for Research Trial. Sleep. 2019 Aug 1;42(8):zsz099. doi: 10.1093/sleep/zsz099.
citation: Bakker JP, Wang R, Weng J, Aloia MS, Toth C, Morrical MG, Gleason KJ, Rueschman M, Dorsey C, Patel SR, Ware JH, Mittleman MA, Redline S. Motivational Enhancement for Increasing Adherence to CPAP: A Randomized Controlled Trial. Chest. 2016 Aug;150(2):337-45. doi: 10.1016/j.chest.2016.03.019. Epub 2016 Mar 24.
citation: Yaggi HK, Mittleman MA, Bravata DM, Concato J, Ware J, Stoney CM, Redline S. Reducing cardiovascular risk through treatment of obstructive sleep apnea: 2 methodological approaches. Am Heart J. 2016 Feb;172:135-43. doi: 10.1016/j.ahj.2015.07.033. Epub 2015 Sep 11.