European Sleep Apnea and Sudden CArdiac Death ProjEct
European Sleep Apnea and Sudden CArdiac Death ProjEct
The objective of ESCAPE-SCD Study is assessment of the effect of sleep apnea on sudden
 cardiac death risk and cardiovascular outcomes in patients with ischemic cardiomyopathy. The
 ESCAPE - SCD Study will address following specific study questions:

 -  Is obstructive sleep apnea (OSA) and/or central sleep apnea (CSA) an independent risk
 factor of sudden cardiac death (SCD) in patients with ischemic cardiomyopathy (ICM)
 indicated for ICD/CRT-D implant based on current European Society of Cardiology (ESC)
 Guidelines for primary prevention of sudden cardiac death?

 -  Can treatment of predominant (>50%) obstructive sleep apnea by appropriate Positive
 Airway Pressure (PAP) therapy decrease risk of sudden cardiac arrhythmic death in ICM
 patients?

 -  Can treatment of predominant (>50%) obstructive sleep apnea by appropriate PAP therapy
 improve cardiovascular outcomes in ICM patients indicated for ICD/CRT-D implant?

 -  Does obstructive sleep apnea represent a novel factor that may improve risk
 stratification of sudden cardiac death and advance identification of those patients that
 will benefit from ICD/CRT-D therapy?
Detailed Study Description

 Purpose:

 There is strong evidence that patients with ischemic cardiomyopathy have high cardiovascular
 mortality, including high risk of sudden cardiac death. Sleep apnea is frequently present in
 patients after myocardial infarction/with ischemic cardiomyopathy (approximately in 50% of
 patients).

 Both central and obstructive sleep apnea are considered as independent risk factors of
 worsened prognosis in patients with heart failure with reduced ejection fraction (HFrEF).
 However, there is no evidence from randomized trials yet providing evidence that sleep apnea
 is an independent risk factor leading to an increase in cardiovascular mortality, including
 increased risk of sudden cardiac arrhythmic death in patients with ischemic cardiomyopathy.
 There are also no data from randomized trials assessing if treatment of sleep apnea by
 positive airway pressure therapy may improve cardiovascular outcomes in these patients,
 including reduced risk of sudden cardiac death.

 Rationale:

 ICD therapy decreases risk of sudden cardiac death in patients with HFrEF, including patients
 with ICM with left ventricular ejection fraction of <35%. Current ESC Guidelines for
 implantable cardioverter defibrillator (ICD) therapy for primary prevention of sudden cardiac
 death in patients with ischemic cardiomyopathy have high sensitivity and high positive
 predictive value. A limitation of current guidelines is low specificity and low negative
 predictive value. In real clinical practice, it means that less than 1/3 of patients with
 heart failure with reduced ejection fraction who get the ICD device for an indication of
 primary prevention of sudden cardiac death will receive appropriate ICD discharge. The
 remaining 2/3 of patients have no benefit from ICD implantation, and are exposed to risks of
 complications resulting from ICD implant, such as inappropriate ICD discharges, lead
 dislocation, or even life-threatening complications such as infectious endocarditis or
 myocardial perforation.

 Therefore, improvements of stratification criteria allowing better identification of those
 patients with ICM that will have real benefit from ICD therapy, and improvement of long-term
 outcomes and cost-benefit of ICD therapy, represent one of the major challenges of modern
 cardiology.

 Previous studies show that sleep apnea increases the risk of sudden cardiac death in the
 population. In other words, sleep apnea represents a treatable condition which is also a
 potential risk factor of sudden cardiac death. Some previously non-randomized studies showed
 that in patients with HFrEF, both obstructive and central sleep apnea may increase risk of
 sudden cardiac arrhythmic death. Contrary to these observations, recently released
 preliminary data from the SERVE-HF trial indicate that in patients with HFrEF, treatment of
 central sleep apnea by adaptive servo-ventilation therapy increases cardiovascular mortality,
 and responsible mechanisms might include increased risk of sudden cardiac death.

 There are several pathophysiological mechanisms by which both obstructive and central sleep
 apnea may increase risk of sudden cardiac arrhythmic death in ICM patients. Considering the
 high prevalence of sleep disordered breathing in patients with ICM, sleep apnea represents a
 modifiable risk factor, where proper treatment may decrease risk of sudden cardiac death
 and/or improve cardiovascular outcomes in ICM patients. However, randomized studies
 specifically addressing the role of sleep apnea in risk of sudden cardiac arrhythmic death in
 ICM patients are needed to clarify the existing controversy and provide information highly
 needed for routine clinical practice.

 Objective

 The ESCAPE - SCD Study will address following specific study questions:

 -  Is obstructive sleep apnea and/or central sleep apnea an independent risk factor of
 sudden cardiac death (SCD) in patients with ICM indicated for ICD/CRT-D implant based on
 current ESC Guidelines for primary prevention of sudden cardiac death?

 -  Can treatment of predominant (>50%) obstructive sleep apnea by appropriate Positive
 Airway Pressure (PAP) therapy decrease risk of sudden cardiac arrhythmic death in ICM
 patients?

 -  Can treatment of predominant (>50%) obstructive sleep apnea by appropriate PAP therapy
 improve cardiovascular outcomes in ICM patients indicated for ICD/CRT-D implant?

 -  Does obstructive sleep apnea represent a novel factor that may improve risk
 stratification of sudden cardiac death and advance identification of those patients that
 will benefit from ICD/CRT-D therapy?

 Study Design:

 Prospective, randomized, international multi-centric study.

 Study Population:

 900 patients with ICM indicated for ICD/CRT-D implant based on 2012 and 2013 ESC Guidelines
 for primary prevention of sudden cardiac death (see Section: "References") will be enrolled
 in this study. A sleep study will be performed in each of the subjects and based on results
 patients will be divided to 4 Groups.

 • No or Mild Sleep Apnea Group (Group 1): Patients with no or mild sleep apnea will continue
 with standard therapy (ICD/CRT-D implant + maximal medical therapy).

 Patients with moderate and severe predominant obstructive sleep apnea (AHI >15) will be
 randomized in 1:1 ratio to

 -  Obstructive Sleep Apnea - Control Group (Group 2) - patients with predominant
 obstructive sleep apnea that will receive standard therapy (ICD/CRT-D implant + maximal
 medical therapy), but no PAP therapy for sleep apnea treatment and to

 -  Obstructive Sleep Apnea - Active Group (Group 3) - patients with predominant obstructive
 sleep apnea that will receive standard therapy (ICD/CRT-D implant + maximal medical
 therapy), plus, as intervention, sleep apnea treatment by using PAP therapy.

 -  Central Sleep Apnea Group (Group 4) - patients with predominant central sleep apnea that
 will receive standard therapy (ICD/CRT-D implant + maximal medical therapy). Because the
 SERVE-HF Trial demonstrated a negative effect of predominantly central sleep apnea
 treatment on cardiovascular mortality in patients with HFrEF by using adaptive
 servo-ventilation therapy, patients in Group 4 will not receive any PAP therapy for
 treatment of sleep disordered breathing and will be followed.

 Distribution of Patient Population among Study Group:

 Based on data derived from our pilot study, approximately 60% of patients with ischemic
 cardiomyopathy indicated for ICD/CRT-D implant for primary prevention of sudden cardiac death
 have undiagnosed moderate or severe sleep apnea. Therefore, we expect the following
 distribution of patients among patients' groups: Group 1: n=400 patients; Group 2: n=200
 patients; Group 3: n=200, Group 4: n=100 patients.

 Primary and secondary goals:

 Primary goal:

 -  Assessment of sleep apnea and its treatment on risk of sudden cardiac arrhythmic death
 by assessing the number of appropriate ICD/CRT-D discharges for each of the groups

 Secondary goals:

 -  Assessment of the effect of sleep apnea and OSA treatment on cardiovascular mortality
 and morbidity by assessing MACE (Major Adverse Cardiovascular Events)

 -  Assessment of incidence of complications resulting from ICD/CRT-D therapy among study
 groups

 -  Assessment of sleep apnea as a novel factor that may improve risk stratification of
 sudden cardiac death and advance identification of those patients that will benefit from
 ICD/CRT-D therapy.

 -  Assessment of sleep apnea treatment on systolic and diastolic functions and neurohumoral
 profile

 -  Assessment of prevalence of sleep apnea and its severity among study population

 Eligibility

 Ages Eligible for Study: 18 Years and older Genders Eligible for Study: Both Accepts Healthy
 Volunteers: No

 Technologies used for sleep apnea treatment It is planned to use the Airsense 10 Autoset
 (AutoCPAP) and Aircurve 10 CS Pacewave (AutoASV) RESMED devices for sleep disordered
 breathing treatment in Group 3 with sleep apnea treatment telemonitoring option.

 Technologies used for detection of life-threatening ventricular arrhythmias:

 Most advanced ICD/CRT-D technologies allowing telemonitoring detection of cardiac arrhythmias
 will be used in as many patients as possible who are enrolled into this study.

 Study Timeline:

 -  Study initiation: January 2016

 -  Patient enrollment: March 2016 - December 2017

 -  Average follow-up: 36 months

 -  End of follow-up: December 2019

 -  Data analysis: January-December 2021

 -  Estimated publication of final results: 2022

 Study Co-Principal Investigators (listed alphabetically): Assoc. Prof. Tomas Kara, MD, PhD,
 Prof. Virend K. Somers, MD, DPhil., Prof. Milos Taborsky, MD, PhD

 Study sponsors:

 Investigator Initiated Trial.

 Contacts and locations:

 Coordinating center:

 Department of Cardiovascular Diseases University Hospital Olomouc I.P. Pavlova 6 779 00
 Olomouc, Czech Republic Phone.: +420 58 588 3201 Fax: +420 58 588 2500

 Summary:

 This would be the very first randomized study assessing the effect of predominantly
 obstructive sleep apnea treatment on risk of sudden cardiac death and cardiovascular outcomes
 in patients with ischemic cardiomyopathy. The study will also address important questions
 related to improvement of selection of patients that may benefit from ICD/CRT-D therapy. We
 have solid evidence from our pilot data that addition of sleep disordered breathing screening
 and treatment may improve the selection of patients with ischemic cardiomyopathy that can
 benefit from ICD therapy, including improvement their long-term outcomes. Use of technologies
 for telemonitoring of efficiency of sleep disordered breathing treatment and occurrence of
 cardiac arrhythmias will increase the scientific strength of the study and will explore the
 benefit of use of telemonitoring technologies in daily clinical practice.
Inclusion Criteria:

 Patients with ICM indicated for ICD/CRT-D implant based on current ESC Guidelines for
 primary prevention of sudden cardiac death

 Exclusion Criteria:

 -  Previously diagnosed sleep apnea CPAP, BiPAP or ASV treatment

 -  Patients with previously implanted ICD/CRT-D device indicated for device replacement

 -  Uncontrolled hypertension

 -  Severe valvular heart disease/dysfunction with exception of ischemic and functional
 mitral regurgitation

 -  Acute coronary syndrome or acute cardiac decompensation in 4 weeks before ICD/CRT-D
 implant

 -  Expected indication of heart transplant in period of 12 months or less after ICD/CRT-D
 implant

 -  Expected cardiac surgery or percutaneous coronary intervention in period of 12 months
 or less after ICD/CRT-D implant

 -  Severe pulmonary diseases

 -  Rejection of participation in the study

 -  Pregnancy

 -  Age of 80 years and higher in time of ICD/CRT-D implant