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Cardiology

Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular EventsA Meta-Analysis

Educational Objective: To identify the key insights or developments described in this article.

1 Credit CME

JAMA

Published Online: October 3, 2023

Original Investigation

Article Information and Disclosures

Manuel Sánchez-de-la-Torre, PhD^1,2;

Esther Gracia-Lavedan, BSc (Stat)^2,3;

Ivan D. Benitez, BSc (Stat)^1,2;

Alicia Sánchez-de-la-Torre, PhD^1,2;

Anna Moncusí-Moix, MsC^2,3;

Gerard Torres, MD, PhD^1,2;

Kelly Loffler, PhD⁴;

Richard Woodman, PhD⁴;

Robert Adams, MD⁴;

Gonzalo Labarca, MD^5,6;

Jorge Dreyse, MD, PhD⁷;

Christine Eulenburg, PhD⁸;

Erik Thunström, PhD⁹;

Helena Glantz, PhD¹⁰;

Yüksel Peker, MD, PhD^6,9,11,12,13;

Craig Anderson, MD, PhD¹⁴;

Doug McEvoy, MD⁴;

Ferran Barbé, MD^2,3

Author Affiliations

¹Precision Medicine in Chronic Diseases, Hospital Universitari Arnau de Vilanova-Santa Maria, IRB Lleida, Department of Nursing and Physiotherapy, Faculty of Nursing and Physiotherapy, University of Lleida, Lleida, Spain
²Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
³Translation Research in Respiratory Medicine, Hospital Universitari Arnau de Vilanova-Santa Maria, IRBLleida, Lleida, Spain
⁴Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
⁵Laboratorio de Inmunología Traslacional, Departamento de Bioquímica Clínica e Inmunología, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile
⁶Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
⁷Clinica Las Condes, Santiago, Chile
⁸Department for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
⁹Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
¹⁰Department of Internal Medicine, Skarabrg Hospital, Lidköping, Sweden
¹¹Department of Pulmonary Medicine, Koç University School of Medicine, Istanbul, Turkey
¹²Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
¹³Department of Clinical Sciences, Respiratory Medicine, and Allergology, Faculty of Medicine, Lund University, Lund, Sweden
¹⁴The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia

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Key Points

Question Is continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea (OSA) associated with a decreased risk of cardiovascular adverse events in participants with both OSA and established cardiovascular disease?

Findings This systematic review and individual participant data (IPD) meta-analysis of 3 randomized clinical trials including 4186 patients with IPD showed that whereas the IPD meta-analysis based on intention to treat reported no effect of CPAP treatment, the adherent use of CPAP treatment (≥4 hours/day) is associated with a reduced recurrence risk of major adverse cardiac or cerebrovascular events (MACCEs) with a significant hazard ratio of 0.69.

Meaning Patients with established cardiovascular disease and OSA who used CPAP for 4 or more hours per day had a significantly lower risk of MACCEs than those who used CPAP less than 4 hours per day.

Abstract

Importance The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated.

Objective To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials.

Data Sources PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023.

Study Selection For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included.

Data Extraction and Synthesis Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597]).

Main Outcomes and Measures One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day).

Results A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92]).

Conclusions and Relevance Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

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Article Information

Accepted for Publication: August 20, 2023.

Corresponding Author: Ferran Barbé, MD, Translation Research in Respiratory Medicine, Hospital Universitario Arnau de Vilanova-Santa María, IRB Lleida, CIBERes, Avda, Rovira Roure 80, 25198 Lleida, Spain (febarbe.lleida.ics@gencat.cat).

Author Contributions: Dr Barbé had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: M. Sánchez-de-la-Torre, Gracia-Lavedan, Benitez, Adams, Labarca, Eulenburg, Peker, McEvoy, Barbé.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: M. Sánchez-de-la-Torre, Gracia-Lavedan, Benitez, A. Sánchez-de-la-Torre, Moncusí-Moix, Labarca, Barbé.

Critical review of the manuscript for important intellectual content: M. Sánchez-de-la-Torre, Gracia-Lavedan, Benitez, Torres, Loffler, Woodman, Adams, Labarca, Dreyse, Eulenburg, Thunström, Glantz, Peker, Anderson, McEvoy, Barbé.

Statistical analysis: M. Sánchez-de-la-Torre, Gracia-Lavedan, Benitez, Labarca, Dreyse, Eulenburg.

Obtained funding: Adams, McEvoy, Barbé.

Administrative, technical, or material support: M. Sánchez-de-la-Torre, A. Sánchez-de-la-Torre, Moncusí-Moix, Loffler, Labarca, Thunström, Glantz, Peker, Anderson, McEvoy.

Supervision: M. Sánchez-de-la-Torre, Benitez, A. Sánchez-de-la-Torre, Torres, Woodman, Labarca, Peker, Barbé.

Conflict of Interest Disclosures: Dr Adams reported receiving grants from the National Health and Medical Research Institute during the conduct of the study and grants from the National Health and Medical Research Institute, ResMed Foundation, The Hospital Research Foundation, and Flinders Foundation; nonfinancial support from Philips Equipment; and personal fees from SomnoMed outside the submitted work. Dr Labarca reported receiving grants from the National Institutes of Health/National Heart, Lung, and Blood Institute, CHEST Foundation, Sleep Research Society, ResMed Foundation, and American Academy of Sleep Medicine outside the submitted work. Dr Thunström reported receiving lecture fees from ResMed. Dr Peker reported receiving grants from ResMed Foundation for the RICCADSA trial outside the submitted work. Dr Anderson reported receiving grants from National Health and Medical Research Council of Australia and fellowships to his institution during the conduct of the study and grants from Medical Research Council of UK, Penumbra, and Takeda paid to his institution outside the submitted work. Dr McEvoy reported receiving grants from the National Health and Medical Research Council during the conduct of the study. Dr Barbé reported receiving grants from ResMed, the Health Research Fund, Spanish Ministry of Health, Sociedad Española de Neumología y Cirugía Torácica, Societat Catalana de Pneumologia, Esteve Teijin (Spain), Oxigen Salud (Spain), and ALLER during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was funded by the Instituto de Salud Carlos III (PI10/02763, PI10/02745, PI18/00449, PI19/00907, PI21/00337), co-funded by the European Union and FEDER (Una Manera de Hacer Europa), IRBLleida—Fundació Dr Pifarré, SEPAR, ResMed Ltd (Australia), Associació Lleidatana de Respiratori (ALLER), and CIBERES. Dr Sánchez-de-la-Torre received financial support from a Ramón y Cajal grant (RYC2019-027831-I) from the Ministerio de Ciencia e Innovación–Agencia Estatal de Investigación co-funded by the European Social Fund/Investing in Your Future.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The research teams of the current study had full autonomy in all aspects of the study.

Additional Contributions: We thank the individuals who participated in the SAVE, ISAACC, and RICCADSA trials and their families and the clinical and research teams of the various sleep and cardiology departments of the recruiting centers for their work.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.