Cardiovascular benefit of continuous positive airway pressure according to high-risk obstructive sleep apnoea: a multi-trial analysis

Ali Azarbarzin¹, Daniel Vena¹, Neda Esmaeili¹, Andrew Wellman¹, Lucía Pinilla^{2

3}, Ludovico Messineo¹, Andrey Zinchuk⁴, Raichel Alex¹, Mathias Baumert⁵, Kelly A Loffler², Craig S Anderson^{6

7

8}, David P White¹, Susan Redline¹, Daniel J Gottlieb¹, Ferran Barbé^{3

9}, Yuksel Peker^{10

11

12

13}, Manuel Sánchez-de-la-Torre^{3

14}, Doug McEvoy², Scott A Sands¹

Affiliations

¹ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Boston, MA 02115, USA.
² Flinders Health and Medical Research Institute: Sleep Health, College of Medicine and Public Health, Flinders University, Level 2, Building A, Mark Oliphant Building, 5 Laffer Drive, Bedford Park, South Australia 5042, Australia.
³ Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Av. Monforte de Lemos, 3-5, Pavilion 11, Ground Floor, 28029 Madrid, Spain.
⁴ Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, 300 Cedar Street TAC - 441 South, New Haven, CT 06520, USA.
⁵ Discipline of Biomedical Engineering, School of Electrical and Mechanical Engineering, The University of Adelaide, Level 3, Ingkarni Wardli Building, Adelaide, South Australia 5005, Australia.
⁶ The George Institute for Global Health, University of New South Wales, Level 18, International Towers 3, 300 Barangaroo Ave, Sydney, New South Wales 2000, Australia.
⁷ Institute for Science and Technology for Brain-Inspired Intelligence, Fudan University, 220 Handan Road, Shanghai 200433, China.
⁸ Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown, New South Wales 2050, Australia.
⁹ Group of Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa María, University of Lleida, IRBLleida, Av. Rovira Roure, 80, 25198 Lleida, Spain.
¹⁰ Department of Pulmonary Medicine, Koc University, Davutpasa cad, No 4 TR-34010 Zeytinburnu, Istanbul, Turkey.
¹¹ Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Göteborg, Sweden.
¹² Department of Clinical Sciences, Respiratory Medicine and Allergology, Faculty of Medicine, Lund University, Wigerthuset, Remissgatan 4, plan 2, SUS, 221 85 Lund, Sweden.
¹³ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, NW 628 UPMC Montefiore, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA.
¹⁴ Group of Precision Medicine in Chronic Diseases, Hospital Nacional de Parapléjicos, IDISCAM, Department of Nursing, Physiotherapy and Occupational Therapy, Faculty of Physiotherapy and Nursing, University of Castilla-La Mancha, Carretera Finca la Peraleda, sn, 45071 Toledo, Spain.

PMID: 40794640
PMCID: PMC12874658
DOI: 10.1093/eurheartj/ehaf447

Cardiovascular benefit of continuous positive airway pressure according to high-risk obstructive sleep apnoea: a multi-trial analysis

Ali Azarbarzin et al. Eur Heart J. 2025.

. 2025 Aug 5:ehaf447.

doi: 10.1093/eurheartj/ehaf447. Online ahead of print.

Authors

Affiliations

¹ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Boston, MA 02115, USA.
² Flinders Health and Medical Research Institute: Sleep Health, College of Medicine and Public Health, Flinders University, Level 2, Building A, Mark Oliphant Building, 5 Laffer Drive, Bedford Park, South Australia 5042, Australia.
³ Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Av. Monforte de Lemos, 3-5, Pavilion 11, Ground Floor, 28029 Madrid, Spain.
⁴ Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, 300 Cedar Street TAC - 441 South, New Haven, CT 06520, USA.
⁵ Discipline of Biomedical Engineering, School of Electrical and Mechanical Engineering, The University of Adelaide, Level 3, Ingkarni Wardli Building, Adelaide, South Australia 5005, Australia.
⁶ The George Institute for Global Health, University of New South Wales, Level 18, International Towers 3, 300 Barangaroo Ave, Sydney, New South Wales 2000, Australia.
⁷ Institute for Science and Technology for Brain-Inspired Intelligence, Fudan University, 220 Handan Road, Shanghai 200433, China.
⁸ Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown, New South Wales 2050, Australia.
⁹ Group of Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa María, University of Lleida, IRBLleida, Av. Rovira Roure, 80, 25198 Lleida, Spain.
¹⁰ Department of Pulmonary Medicine, Koc University, Davutpasa cad, No 4 TR-34010 Zeytinburnu, Istanbul, Turkey.
¹¹ Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Göteborg, Sweden.
¹² Department of Clinical Sciences, Respiratory Medicine and Allergology, Faculty of Medicine, Lund University, Wigerthuset, Remissgatan 4, plan 2, SUS, 221 85 Lund, Sweden.
¹³ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, NW 628 UPMC Montefiore, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA.
¹⁴ Group of Precision Medicine in Chronic Diseases, Hospital Nacional de Parapléjicos, IDISCAM, Department of Nursing, Physiotherapy and Occupational Therapy, Faculty of Physiotherapy and Nursing, University of Castilla-La Mancha, Carretera Finca la Peraleda, sn, 45071 Toledo, Spain.

PMID: 40794640
PMCID: PMC12874658
DOI: 10.1093/eurheartj/ehaf447

Abstract

Background and aims: Randomized trials of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnoea (OSA) in patients with cardiovascular disease have not detected reduced risk of major adverse cardiovascular and cerebrovascular events (MACCEs). This study tested whether the cardiovascular benefit of CPAP occurs preferentially in high-risk OSA, characterized by greater OSA-related heart rate acceleration or hypoxaemia.

Methods: In a post hoc analysis of pooled Randomized Intervention with Continuous Positive Airway Pressure in Coronary Artery Disease and Obstructive Sleep Apnoea, Impact of Continuous Positive Airway Pressure on Patients with Acute Coronary Syndrome and Nonsleepy Obstructive Sleep Apnoea, and Sleep Apnoea Cardiovascular Endpoints Study randomized trials; outcomes were stratified by high-risk OSA status, defined by heart rate response following OSA respiratory events >9.4 b.p.m. (third tertile) or oxygen desaturation area under baseline (hypoxic burden) > 87.1% min/h (third tertile). Cox mixed models quantified the CPAP treatment effect on MACCE (including cardiovascular mortality, myocardial infarction, and stroke) within high-risk OSA and the difference vs low-risk status (primary test). Secondary analyses examined participants without excessive sleepiness (Epworth <11 points) or without increased blood pressure (systolic/diastolic <140/90 mmHg).

Results: In 3549 participants, 16.6% and 16.3% reached the MACCE endpoint with CPAP (n = 1778) and usual care (n = 1771), respectively. The CPAP treatment effect was greater in participants with vs without high-risk OSA [interaction hazard ratio (iHR) .69, 95% confidence interval (CI) .50-.95, Pinteraction = .024; Nhigh-risk = 1832]. The differential effect was stronger in those without excessive sleepiness (iHR .59, 95% CI .41-.84; Nhigh-risk = 1509), or without increased blood pressure (iHR .54, 95% CI .36-.81; Nhigh-risk = 1244). Continuous positive airway pressure benefits in high-risk OSA were observed alongside harm in low-risk OSA.

Conclusions: Continuous positive airway pressure preferentially improves cardiovascular outcomes in high-risk OSA, while harm in low-risk OSA may counteract this effect. These findings provide a pathway to identify patients likely to benefit.

Keywords: Heart rate response; Hypoxic burden; MACCE; Obstructive sleep apnoea; Phenotype; Precision medicine.

© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Figures

**Figure 1**
Flow diagram presenting ascertainment of the study sample. CPAP, continuous positive airway pressure; ISAACC, Impact of Continuous Positive Airway Pressure on Patients with Acute Coronary Syndrome and Nonsleepy Obstructive Sleep Apnoea; RICCADSA, Randomized Intervention with Continuous Positive Airway Pressure in Coronary Artery Disease and Obstructive Sleep Apnoea; SAVE, Sleep Apnoea Cardiovascular Endpoints Study; SpO₂, oxygen saturation

**Figure 2**
Kaplan–Meier survival curves showing the effect of continuous positive airway pressure on major adverse cardiovascular and cerebrovascular events in al-comers (*A, D, G*, and J), in those with high-risk (*C, F, I*, and L) and low-risk (*B, E, H*, and K) obstructive sleep apnoea in all participants (first row), in those without excessive sleepiness (Epworth sleepiness scale < 11; second row), without increased blood pressure (systolic/diastolic <140/90 mmHg; third row), and those without increased blood pressure or excessive sleepiness (bottom row). MACCE, major adverse cardiovascular and cerebrovascular events

See this image and copyright information in PMC

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Cardiovascular benefit of continuous positive airway pressure according to high-risk obstructive sleep apnoea: a multi-trial analysis

Affiliations

Cardiovascular benefit of continuous positive airway pressure according to high-risk obstructive sleep apnoea: a multi-trial analysis

Authors

Affiliations

Abstract

Figures

References

Grants and funding

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Full Text Sources