Trial Designs Impact of Obstructive Sleep Apnea on Cardiovascular Outcomes in Patients Treated With Percutaneous Coronary Intervention: Rationale and Design of the Sleep and Stent Study
Address for correspondence: Chi-Hang Lee, MD, FRCP Department of Cardiology National University Heart Centre Singapore 1E Kent Ridge Road, NUHS Tower Block Level 9 Singapore 119228
[email protected]
Germaine Loo, Chieh-Yang Koo, MBBS; Junjie Zhang, MD; Ruogu Li, MD; Rithi Sethi, MD; Thun-How Ong, MBBS; Bee-Choo Tai, PhD; Chi-Hang Lee, MD Department of Cardiology (Loo, Koo, Lee), National University Heart Centre, Singapore; Department of Medicine (Loo, Koo, Lee), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Cardiology (Zhang), Nanjing First Hospital, Nanjing, China; Department of Cardiology (Li), Shanghai Chest Hospital, Shanghai, China; Department of Cardiology (Sethi), King George’s Medical University, Lucknow, India; Department of Respiratory and Critical Care Medicine (Ong), Singapore General Hospital, Singapore; Saw Swee Hock School of Public Health (Tai), National University of Singapore, National University Health System, Singapore
Elucidating the effects of obstructive sleep apnea (OSA) on cardiovascular outcomes is crucial in risk assessments and therapeutic recommendations for affected individuals. The Sleep and Stent Study is a multicenter observational study investigating the relationships between OSA and cardiovascular outcomes in patients treated with percutaneous coronary intervention (PCI). Eight centers in 5 countries (Singapore, China and Hong Kong, India, Myanmar, and Brazil) are participating in the study, and the recruitment target is 1600 patients. Adult patients age 18 to 80 years who have undergone successful PCI are eligible. Recruited patients will undergo an overnight sleep study using a level-3 portable diagnostic device before hospital discharge. The sleep tracings will be analyzed by a certified sleep technologist and audited by a sleep physician, both of whom will be blinded to other study data. The patients will be divided into 2 groups based on apnea-hypopnea index (AHI): OSA (AHI ≥15) and non-OSA (AHI 15 million people and constitutes up to 17% of deaths in the adult population.1 Patients presenting with symptomatic CAD are frequently treated with percutaneous coronary intervention (PCI).2 Despite significant advancements in PCI technology and This study is funded by the Investigator-Sponsored Research Program of the Boston Scientific Corporation. The study was designed solely by the investigators. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Received: November 22, 2013 Accepted with revision: January 15, 2014
devices in the past few decades, studies of real-world practice have revealed that the long-term clinical outcomes of patients treated with PCI remain suboptimal.3,4 In the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), which included 28 953 Swedish patients who underwent coronary stent implantation, 19.2% of the patients suffered death or myocardial infarction (MI) at a median follow-up time of 2.7 years.3 There remains an unmet need to further improve the clinical outcomes of patients who undergo PCI for CAD. Obstructive sleep apnea (OSA) is an emerging cardiovascular risk factor that is present in 2% to 7% of the general population.5 OSA is characterized by recurrent episodes of complete or partial upper-airway obstruction Clin. Cardiol. 37, 5, 261–269 (2014) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22261 © 2014 Wiley Periodicals, Inc.
261
due to the collapse of upper-pharyngeal soft tissue during sleep, resulting in intermittent oxygen deprivation. The pathophysiological mechanisms of OSA, including sympathetic activation, production of vasoactive substances, and activation of inflammatory and procoagulant pathways, have been implicated in cardiovascular pathogenesis.6 This is associated with the development of cardiovascular disease, including hypertension, CAD, stroke, and heart failure. In the healthy general population, untreated OSA is independently and strongly associated with adverse long-term cardiovascular outcomes.7,8 It was previously observed that patients with untreated severe OSA had an approximately 3× higher incidence of both fatal and nonfatal cardiovascular events compared with healthy individuals.8 Current data indicate that the prevalence of OSA is greater in patients with CAD compared with the general population.9,10 The estimated prevalence of OSA ranges between 26% and 69% in CAD patients.11 However, whether OSA exerts a deleterious effect on the evolution of patients who have undergone PCI for CAD is yet to be established. Although multiple studies have shown a strong association between OSA and cardiovascular events in the general population, corresponding evidence in patients treated with PCI has been limited. In 105 patients with acute MI treated with PCI, the incidence of major adverse cardiovascular events was significantly higher in OSA patients after 18month follow-up (16% vs 3%; adjusted hazard ratio: 5.02, P = 0.04).12 Similar results were also obtained in another study on 89 acute coronary syndrome (ACS) patients treated with PCI.13 The incidence of cardiac death, reinfarction, and target-vessel revascularization at 8-month follow-up was higher in the OSA group than in the non-OSA group (23.5% vs 5.3%, P = 0.022). Restudy angiography at 6-month follow-up showed that the incidence of restenosis was significantly higher in the OSA group than in the non-OSA group (36.5% vs 15.4%, P = 0.026). However, drug-eluting stents, the state-of-the-art device in PCI, were not used in this study. Finally, it has been proposed that apnea-induced sympathetic activation and hypoxemia could be trigger factors for stent thrombosis.14 Taken together, the aforementioned studies provide preliminary evidence that OSA may lead to adverse cardiovascular outcomes after PCI. However, existing data were generated from small-scale, single-center studies. Therefore, in the Sleep and Stent Study, we aim to conduct a large-scale, multinational cohort study to determine the association between OSA and the incidence of adverse cardiovascular outcomes over a long-term follow-up period. We hypothesize that OSA is an independent risk factor for the development of major adverse cardiovascular and cerebrovascular events (MACCE) in CAD patients treated with PCI. Results from the Sleep and Stent Study will advance the fundamental understanding of the burden and prognostic implications of OSA in patients undergoing PCI for CAD. Study Objectives The main objective of the Sleep and Stent Study is to determine the association between OSA and MACCE after a median of 2 years’ follow-up in patients undergoing clinically
262
Clin. Cardiol. 37, 5, 261–269 (2014) G. Loo et al: Sleep and Stent Study Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22261 © 2014 Wiley Periodicals, Inc.
indicated PCI. MACCE is defined as a composite endpoint of cardiovascular mortality, MI, stroke, and unplanned revascularization. The secondary objectives are to investigate the prevalence of OSA in patients undergoing PCI and to determine if OSA is associated with a higher incidence of the secondary endpoints of all-cause mortality, target-vessel revascularization, stent thrombosis, and hospitalization for heart failure after long-term follow-up.
Methods Study Population and Design The Sleep and Stent Study is a prospective, observational, multinational cohort study of patients undergoing PCI for CAD. A total of 1600 adult patients undergoing clinically indicated PCI for CAD will be enrolled. The study involves 8 medical centers in 5 countries (Singapore, China and Hong Kong, Brazil, Myanmar, India), all with on-site cardiac catheterization facilities and cardiac care units. The study is led by the coordinating center (National University Heart Centre, Singapore), which is responsible for the overall study design and study conduct. The estimated duration of the Sleep and Stent Study is 8 years (2011–2019). Eligible patients (Table 1) who have undergone successful PCI in any of the participating centers during the study period will be approached for recruitment. All subjects and/or their legally authorized representatives must provide written informed consent before any study-related procedure can be conducted. As a standard clinical practice in all participating centers, patients who have undergone PCI will be admitted to the hospital for monitoring. As such, all recruited patients will undergo an overnight sleep study prior to hospital discharge during the index PCI admission. The patients will then be separated into OSA and non-OSA groups based on apnea-hypopnea index (AHI) ≥15. This cutoff is based on epidemiologic studies showing that the risk of adverse cardiovascular events increases particularly in patients with an AHI ≥15.5 The study design is shown in Figure 1. There will be no financial incentive offered to patients who participate in the Sleep and Stent Study. All recruited patients will be treated according to the standard clinical practices of the local institutions, and no clinical privilege will be gained from participation in the Sleep and Stent Study. Percutaneous Coronary Intervention As the Sleep and Stent Study aims to evaluate the prognostic implications of OSA in the clinical setting, there are no restrictions on the presenting indications of patients for PCI (ie, ST-segment elevation myocardial infarction, non–STsegment elevation myocardial infarction, unstable angina, stable CAD silent ischemia, staged PCI) or the usage of pharmacologic and device strategies during PCI. PCI is defined as any intervention to a major epicardial coronary artery with a significant stenosis based on ≥70%-diameter narrowing on visual estimation (≥50% for left main) and/or fulfilling physiological criteria for revascularization (ie, fractional flow reserve ≤0.80). All PCIs will be conducted in accordance to the most up-to-date guidelines.15
Table 1. Inclusion and Exclusion Criteria Inclusion criteria Age ≥18 and
