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

• ClinicalTrials.gov Identifier: NCT01335087
• Recruitment Status: Completed
• First Posted: April 14, 2011
• Last Update Posted: October 29, 2018
• Sponsor: Sociedad Española de Neumología y Cirugía Torácica
• Collaborators: ResMed; Fondo de Investigacion Sanitaria; EsteveTeijin Healthcare; Societat Catalana de Cardiologia; Sociedad Madrileña de Neumologia
• Information provided by (Responsible Party): Ferran Barbe, Sociedad Española de Neumología y Cirugía Torácica

Study Description

Brief Summary:

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:

1. Determine the prevalence of OSA in patients who have suffered an episode of ACS.

2. 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).
3. To establish the relationship between the severity and phenotype of patients with OSA and clinical outcomes of ACS.
4. To establish the relationship between CPAP compliance and CV events incidence.
5. To identify biological risk markers that allow us to establish the most important mechanisms involved in cardiovascular complications in these patients.
6. To conduct a cost-effectiveness analysis of the diagnosis and CPAP treatment of patients with ACS who have obstructive sleep apnea.

Condition or disease	Intervention/treatment	Phase
Acute Coronary Syndrome; Obstructive Sleep Apnea	Other: Standard care; Device: continuous positive airway pressure	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1864 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: 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
• Study Start Date: April 2011
• Actual Primary Completion Date: September 2018
• Actual Study Completion Date: September 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Lifestyle; Standard care for OSA: lifestyle, and sleep hygiene counselling	Other: Standard care; 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.
Experimental: Continuous positive airway pressure CPAP; CPAP treatment every night plus standard care for OSA: lifestyle, and sleep hygiene counselling	Other: Standard care; 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.; Device: continuous positive airway pressure; 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.
No Intervention: Reference; This group will be followed according to cardiovascular protocols and will be evaluated as a reference group.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Men and women over 18 years old.
2. 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 .
3. Patients with and Epworth Sleep Scale score ≤ 10 (patients without excessive daytime sleepiness).
4. Written informed consent signed.

Exclusion Criteria:

1. Previous CPAP treatment for OSA diagnosis
2. Psycho-physical inability to complete questionnaires.
3. Presence of any previously diagnosed sleep disorders: narcolepsy, insomnia, chronic sleep deprivation, regular use of hypnotic or sedative medications and restless leg syndrome
4. Patients with > 50% of central apneas or the presence of Cheyne-Stokes Respiration (CSResp)
5. Patients with chronic diseases: neoplasia, renal failure (GFR<30 ml/min), severe chronic obstructive pulmonary disease, chronic depression and other very limiting chronic diseases.
6. A medical history that may interfere with the study objectives or, in the opinion of the investigator, compromise the conclusions.
7. 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).
8. Any process, cardiovascular or otherwise, that limits life expectancy to less than one year.
9. Patients in cardiogenic shock who have poor expectations for short-term outcomes.

Contacts and Locations

Locations

Spain

Spanish Respiratory Society

Barcelone, Spain, 08009

Sponsors and Collaborators

Sociedad Española de Neumología y Cirugía Torácica

ResMed

Fondo de Investigacion Sanitaria

EsteveTeijin Healthcare

Societat Catalana de Cardiologia

Sociedad Madrileña de Neumologia

Investigators

• Principal Investigator: Ferran Barbe, MD; Spanish Respiratory Sociey

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Sanchez-de-la-Torre M, Gracia-Lavedan E, Benitez ID, Zapater A, Torres G, Sanchez-de-la-Torre A, Aldoma A, de Batlle J, Targa A, Abad J, Duran-Cantolla J, Urrutia A, Mediano O, Masdeu MJ, Ordax-Carbajo E, Masa JF, De la Pena M, Mayos M, Coloma R, Montserrat JM, Chiner E, Minguez O, Pascual L, Cortijo A, Martinez D, Dalmases M, Lee CH, McEvoy RD, Barbe F; Spanish Sleep Network. Long-Term Effect of Obstructive Sleep Apnea and Continuous Positive Airway Pressure Treatment on Blood Pressure in Patients with Acute Coronary Syndrome: A Clinical Trial. Ann Am Thorac Soc. 2022 Oct;19(10):1750-1759. doi: 10.1513/AnnalsATS.202203-260OC.

Reynor A, McArdle N, Shenoy B, Dhaliwal SS, Rea SC, Walsh J, Eastwood PR, Maddison K, Hillman DR, Ling I, Keenan BT, Maislin G, Magalang U, Pack AI, Mazzotti DR, Lee CH, Singh B. Continuous positive airway pressure and adverse cardiovascular events in obstructive sleep apnea: are participants of randomized trials representative of sleep clinic patients? Sleep. 2022 Apr 11;45(4):zsab264. doi: 10.1093/sleep/zsab264.

Sanchez-de-la-Torre M, Sanchez-de-la-Torre A, Bertran S, Abad J, Duran-Cantolla J, Cabriada V, Mediano O, Masdeu MJ, Alonso ML, Masa JF, Barcelo A, de la Pena M, Mayos M, Coloma R, Montserrat JM, Chiner E, Perello S, Rubinos G, Minguez O, Pascual L, Cortijo A, Martinez D, Aldoma A, Dalmases M, McEvoy RD, Barbe F; Spanish Sleep Network. Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial. Lancet Respir Med. 2020 Apr;8(4):359-367. doi: 10.1016/S2213-2600(19)30271-1. Epub 2019 Dec 12.

Bauca JM, Barcelo A, Fueyo L, Sanchis P, Pierola J, de la Pena M, Arque M, Gomez C, Morell-Garcia D, Sanchez-de-la-Torre A, Sanchez-de-la-Torre M, Abad J, Duran-Cantolla J, Mediano O, Masdeu MJ, Urrutia-Gajate A, Masa JF, Barbe F; Spanish Sleep Group. Biomarker panel in sleep apnea patients after an acute coronary event. Clin Biochem. 2019 Jun;68:24-29. doi: 10.1016/j.clinbiochem.2019.03.015. Epub 2019 Mar 28.

Bauca JM, Yanez A, Fueyo L, de la Pena M, Pierola J, Sanchez-de-la-Torre A, Mediano O, Cabriada-Nuno V, Masdeu MJ, Teran-Santos J, Duran-Cantolla J, Masa JF, Abad J, Sanchez-de-la-Torre M, Barbe F, Barcelo A; Spanish Sleep Network. Cell Death Biomarkers and Obstructive Sleep Apnea: Implications in the Acute Coronary Syndrome. Sleep. 2017 May 1;40(5). doi: 10.1093/sleep/zsx049.

Barcelo A, Bauca JM, Yanez A, Fueyo L, Gomez C, de la Pena M, Pierola J, Rodriguez A, Sanchez-de-la-Torre M, Abad J, Mediano O, Amilibia J, Masdeu MJ, Teran J, Montserrat JM, Mayos M, Sanchez-de-la-Torre A, Barbe F; Spanish Sleep Group. Impact of Obstructive Sleep Apnea on the Levels of Placental Growth Factor (PlGF) and Their Value for Predicting Short-Term Adverse Outcomes in Patients with Acute Coronary Syndrome. PLoS One. 2016 Mar 1;11(3):e0147686. doi: 10.1371/journal.pone.0147686. eCollection 2016.

Torres G, Sanchez-de-la-Torre M, Barbe F. Relationship Between OSA and Hypertension. Chest. 2015 Sep;148(3):824-832. doi: 10.1378/chest.15-0136.

Barbe F, Sanchez-de-la-Torre A, Abad J, Duran-Cantolla J, Mediano O, Amilibia J, Masdeu MJ, Flores M, Barcelo A, de la Pena M, Aldoma A, Worner F, Valls J, Castella G, Sanchez-de-la-Torre M; Spanish Sleep Network. Effect of obstructive sleep apnoea on severity and short-term prognosis of acute coronary syndrome. Eur Respir J. 2015 Feb;45(2):419-27. doi: 10.1183/09031936.00071714. Epub 2015 Jan 8.

Esquinas C, Sanchez-de-la Torre M, Aldoma A, Flores M, Martinez M, Barcelo A, Barbe F; Spanish Sleep Network. Rationale and methodology of the impact of continuous positive airway pressure on patients with ACS and nonsleepy OSA: the ISAACC Trial. Clin Cardiol. 2013 Sep;36(9):495-501. doi: 10.1002/clc.22166. Epub 2013 Jul 10.

• Responsible Party: Ferran Barbe, MD, Sociedad Española de Neumología y Cirugía Torácica
• ClinicalTrials.gov Identifier: NCT01335087
• Other Study ID Numbers: PI10/02763
• First Posted: April 14, 2011
• Last Update Posted: October 29, 2018
• Last Verified: October 2018

Keywords provided by Ferran Barbe, Sociedad Española de Neumología y Cirugía Torácica:

sleep apnea; secondary prevention; cardiovascular endpoint

Additional relevant MeSH terms:

Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Acute Coronary Syndrome; Syndrome; Disease; Pathologic Processes; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases