Continuous Positive Airway Pressure (CPAP) in Patients With Acute Coronary Syndrome and Obstructive Sleep Apnea (OSA)

Study Overview
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Brief Summary
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OSA may be a modifiable risk factor for cardiovascular disease due to its association with hypertension, stroke, heart attack and sudden death. The standard therapy for symptomatic OSA is continuous positive airway pressure (CPAP). CPAP has been shown to effectively reduce snoring, obstructive episodes and daytime sleepiness and to modestly reduce blood pressure and other risk factors for cardiovascular disease. The overall aim of ISAACC is to determine if CPAP can reduce the risk of heart attack, stroke or heart failure for people with OSA admitted in a hospital for an acute coronary syndrome. Overall objective: To assess the impact of obstructive sleep apnea (OSA) and its treatment on the clinical evolution of patients with acute coronary syndrome (ACS). Primary objectives: 1. To determine if continuous positive airway pressure (CPAP) treatment will reduce the rate of cardiovascular events (cardiovascular (CV) death, non-fatal events (acute myocardial infarction (AMI), non-fatal stroke, hospital admission for heart failure, and new hospitalizations) for unstable angina or transient ischaemic attack (TIA)) in patients with ACS and co-occurring sleep apnea. Secondary objectives: Determine the prevalence of OSA in patients who have suffered an episode of ACS. Other secondary objectives will include the effects of CPAP on: To evaluate a composite of CV death, myocardial infarction (MI) and ischaemic stroke. Components of primary composite endpoints Re-vascularization procedures To evaluate all-cause death To evaluate new onset, ECG-confirmed atrial fibrillation or other arrhythmias To evaluate newly diagnosed diabetes mellitus, according to standard definitions To evaluate OSA symptoms (Epworth Sleepiness Scale (ESS)) To evaluate quality of life in patients with ACS (Test EuroQol (EQ-5D). To establish the relationship between the severity and phenotype of patients with OSA and clinical outcomes of ACS. To establish the relationship between CPAP compliance and CV events incidence. To identify biological risk markers that allow us to establish the most important mechanisms involved in cardiovascular complications in these patients. To conduct a cost-effectiveness analysis of the diagnosis and CPAP treatment of patients with ACS who have obstructive sleep apnea.

Detailed Description
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Methods: Study design: multi-centre, open label, parallel, prospective, randomised, controlled trial. Patients: We will include consecutive patients with an ACS diagnosis evaluated in participating Coronary Care Unit. Study sites: IRB Lleida (Lleida), Hospital Son Dureta (Palma de Mallorca), Hospital Clínic (Barcelona), Hospital Germans Tries i Pujol (Barcelona), Hospital de Bellvitge (Barcelona), Hospital Sant Pau (Barcelona), Hospital Txagorritxu (Vitoria), Hospital de Cruces (Bilbao), Hospital San Pedro de Alcántara (Cáceres), Hospital Parc Taulí (Barcelona) and Hospital de Guadalajara (Guadalajara), Hospital de Vallecas (Madrid), Hospital de Yagüe (Burgos), Hospital de Requena (Valencia), Hospital San Juan, (Alicante), Hospital Central de Asturias (Oviedo). Duration of the study: 3 years. Methodology: During a hospital stay we will assess the degree of daytime sleepiness (Epworth Scale) in patients treated at the Coronary Care Unit with a diagnosis of ACS. The results of this evaluation will define the inclusion of the patient in the study. Patients with and ESS score ≤ 10 will be included in the study and will undergo a cardio-respiratory polygraphy. Patients with an AHI ≥ 15 h-1 will be randomized to CPAP treatment or conservative. Patients with and AHÍ < 15 h-1 will be followed as standard management according to cardiovascular protocols and will be evaluated as a reference group. Therefore, the study will have three groups, with a total of 1,864 patients, as follows: patients with an AHI ≥ 15 h-1 will be randomized to CPAP treatment (Group 1) (n=632) or conservative treatment (Group 2) (n=632). Patients with an AHI < 15 h-1 that will be followed as a reference group (Group 3) (n=600). Patients with an ESS score higher than 10 will be excluded of the study and referred to the sleep unit of each participating center for evaluation. Patients included in the study will be monitored and followed for a minimum of one year and a maximum of three years. Patients will be examined at the time of inclusion (T0), after one month (T1), three months (T2), six months (T3), 12 months (T4) and every six months thereafter, if applicable, during the follow-up period. Evaluations will include; i)new episodes of ACS, stroke, TIA, heart failure, hospitalization for cardiovascular causes and cardiovascular mortality, ii) biological risk markers involved in cardiovascular complications, iii) an evaluation of the cost-effectiveness of diagnosis and CPAP treatment in patients with ACS who have obstructive sleep apnea.

Official Title
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Impact of Sleep Apnea Syndrome in the Evolution of Acute Coronary Syndrome. Effect of Intervention With Continuous Positive Airway Pressure (CPAP). A Prospective Randomized Study. ISAACC Study

Conditions
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Acute Coronary Syndrome, Obstructive Sleep Apnea

Intervention / Treatment
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* Other: Standard care
* Device: continuous positive airway pressure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women over 18 years old. Patients admitted for documented symptoms of ACS with or without T segment elevation and have an hospital stay between 24h and 72 h in the moment to perform polygraphy . Patients with and Epworth Sleep Scale score ≤ 10 (patients without excessive daytime sleepiness). Written informed consent signed. Exclusion Criteria: Previous CPAP treatment for OSA diagnosis Psycho-physical inability to complete questionnaires. Presence of any previously diagnosed sleep disorders: narcolepsy, insomnia, chronic sleep deprivation, regular use of hypnotic or sedative medications and restless leg syndrome Patients with > 50% of central apneas or the presence of Cheyne-Stokes Respiration (CSResp) Patients with chronic diseases: neoplasia, renal failure (GFR<30 ml/min), severe chronic obstructive pulmonary disease, chronic depression and other very limiting chronic diseases. A medical history that may interfere with the study objectives or, in the opinion of the investigator, compromise the conclusions. Any medical factor, social or geographical, that may jeopardize patient compliance.(e.g., alcohol consumption (more 80 gr/day in men and more than 60 gr / day in women), no fixed address, disorientation, or a history of non-compliance). Any process, cardiovascular or otherwise, that limits life expectancy to less than one year. Patients in cardiogenic shock who have poor expectations for short-term outcomes.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lifestyle<br>Standard care for OSA: lifestyle, and sleep hygiene counselling | Other: Standard care<br>* Patients with conservative treatment: (Group 2). This group will also be instructed in hygienic-dietary measures, standard care of cardiovascular risk factors and sleep hygiene counselling.<br>|
| Experimental: Continuous positive airway pressure CPAP<br>CPAP treatment every night plus standard care for OSA: lifestyle, and sleep hygiene counselling | Other: Standard care<br>* Patients with conservative treatment: (Group 2). This group will also be instructed in hygienic-dietary measures, standard care of cardiovascular risk factors and sleep hygiene counselling.<br>Device: continuous positive airway pressure<br>* Patients with CPAP treatment (Group 1): CPAP pressure titration will be performed by automated equipment before discharge. It will follow the methodology described by our group (Mass et al. Alternative Methods of titrating continuous positive airway pressure: a large multicentre study. American Journal of Respiratory and Critical Care Medicine (2004) vol. 170 (11) pp. 1218-1224). This group will also be instructed in hygienic-dietary measures recommended for all patients, standard care of cardiovascular risk factors and sleep hygiene counselling.<br>|
| No Intervention: Reference<br>This group will be followed according to cardiovascular protocols and will be evaluated as a reference group. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of cardiovascular events in patients with acute coronary syndrome and co-occurring sleep apnea. | Cardiovascular events are: cardiovascular death, non-fatal AMI, non-fatal stroke, hospital admission for heart failure, and new hospitalization for unstable angina or TIA. | 12 month after the inclusion of the last patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of OSA in patients who have suffered an episode of ACS. | Determined at the inclusion of the patient | 24 month (inclusion period) | 
| Composite of major CV events | CV death, myocardial infarction (MI) and ischaemic stroke. | 12 month after the inclusion of the last patient | 
| Components of primary composite endpoints separately. | Cardiovascular events are: cardiovascular death, non-fatal AMI, non-fatal stroke, hospital admission for heart failure, and new hospitalization for unstable angina or TIA. | 12 month after the inclusion of the last patient | 
| Number of re-vascularization procedures. | Revascularisation procedures, including PCI, CABG, peripheral arterial revascularisation and intra-cerebral stent insertion | 12 month after the inclusion of the last patient | 
| All-cause mortality. | All-cause mortality. | 12 month after the inclusion of the last patient | 
| New onset of ECG-confirmed atrial fibrillation or other arrhythmias. | ECGs were performed at baseline and during the follow-up period; ECG and medical records were collected tovconfirm a hospitalization for atrial fibrillation event | 12 month after the inclusion of the last patient | 
| Newly diagnosed diabetes mellitus, according to standard definitions. | Newly diagnosed diabetes mellitus, according to standard definitions | 12 month after the inclusion of the last patient | 
| Epworth Sleepiness Scale (ESS) and Test EuroQol (EQ-5D). | OSA symptoms: Epworth Sleepiness Scale (ESS). Quality of life: Test EuroQol (EQ-5D). | 12 month after the inclusion of the last patient | 
| Severity and phenotype of patients with OSA and clinical outcomes of ACS. | To establish the relationship between the severity and phenotype of patients with OSA and clinical outcomes of ACS. | 12 month after the inclusion of the last patient | 
| CPAP compliance and CV events incidence. | To establish the relationship between CPAP compliance and CV events incidence. | 12 month after the inclusion of the last patient | 
| Biological risk markers related to mechanisms involved in cardiovascular complications in these patients. | To identify biological risk markers that allow us to establish the most important mechanisms involved in cardiovascular complications in these patients. | 12 month after the inclusion of the last patient | 
| Cost-effectiveness analysis (Qualys) of the diagnosis and CPAP treatment of patients with ACS who have obstructive sleep apnea. | Cost-effectiveness analysis (Qualys) of the diagnosis and CPAP treatment of patients with ACS who have obstructive sleep apnea | 12 month after the inclusion of the last patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sleep apnea, secondary prevention, cardiovascular endpoint