Incident Cheyne-Stokes respiration occurring in CPAP-treated patients and cardiovascular risk: a 2-years prospective follow-up (The Alertapnee study) (2025)

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  • Arnaud Prigent ORCID: orcid.org/0000-0001-6302-11301,2,8,
  • Joëlle Texereau3,4,
  • Sébastien Bailly5,
  • Renaud Gervais6,
  • Anne-Laure Serandour7,
  • Régis Luraine1,2 &
  • Jean Louis Pépin5

Respiratory Research volume26, Articlenumber:31 (2025) Cite this article

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Abstract

The Alertapnée study followed 555 adults with obstructive sleep apnea treated with CPAP and found that the occurrence of Cheyne-Stokes respiration (CSR) was linked to a 14-fold increase in the risk of significant cardiac events (SCE) after one year. However, the progression and clinical significance of CSR episodes over time remain unclear. This ancillary study aimed to assess CSR progression and clinical outcomes during a second year of follow-up in 66 patients who had experienced at least one CSR episode in the first year. The study focused on the number of nights with CSR, percentage of CSR, SCEs. Results showed that 62 of 66 patients with CSR in the first year also experienced CSR in the second year, with a significant increase in the median number of CSR nights, particularly when CSR was related to cardiovascular conditions (37 vs. 19 nights, p = 0.006). Patients who experienced a SCE in year 2 had significantly more nights with CSR (median 48/90nights; IQR = 35) and a significantly greater mean percentage of CSR (median 13.8%; interquartile range (IQR) = 13.7) as compared with patients free of SCE (median 9.5/90 nights IQR = 27.8 (p = 0.012); 6.1% IQR = 4.5 (p = 0.008), respectively). In conclusion, CSR occurrence and severity depend on the underlying condition. CSR related to cardiovascular aetiology increases over time and is associated with SCEs, whereas CSR linked to non-cardiovascular conditions does not indicate a poor prognosis. Identifying CSR patterns related to cardiovascular aetiologies could enable early detection of SCEs through telemonitoring in CPAP-treated patients.

Introduction

Continuous positive airway pressure (CPAP) telemonitoring platforms collect data on various parameters reflecting treatment efficacy in obstructive sleep apnea (OSA), such as adherence (hours of CPAP usage per night), unintentional leaks, and residual apnea-hypopnea index (rAHI). Integrating data from CPAP telemonitoring in routine care enables early interventions in response to poor adherence or the occurrence of excessive leaks. Abrupt increases and/or night-to-night variability in rAHI could be related to emergent central sleep apnea under CPAP, frequently associated with Cheyne-Stokes respiration (CSR). CSR is typically described as a form of periodic breathing with a crescendo-decrescendo alteration in tidal volume, separated by periods of apnea or hypopneas [1]. In France, a national CPAP telemonitoring scheme was implemented in 2018. The system is applied continuously for the duration of CPAP therapy. In 2023, about 97% of CPAP-treated patient in France were being telemonitored. The Alertapnee study was prospectively conducted in 555 CPAP-treated adults with OSA. After one year follow-up, we have reported that incident CSR was found in 13.3% of patients and associated with a 14-fold increased risk of serious cardiac events, defined as the onset or worsening of cardiac arrhythmias or acute heart failure requiring therapeutic intervention [2]. The aim of the current additional analysis was to compare the number of nights with CSR in the first and second year of follow-up, to characterize underlying conditions associated with CSR, and to assess the two-year cardiovascular morbidity and related hospitalizations.

Methods

The Alertapnee prospective interventional study [2] included 555 adults (412 men; 57% with known cardiovascular comorbidities) with OSA treated with CPAP (AirSense™ 10 AutoSet, RESMED) and telemonitored, with a 1-year follow-up. The study complied with the Declaration of Helsinki and was approved by the French ethics committee ‘Ouest-VI’ (CPP 1083-HPS2). All patients provided written informed consent. Clinical trial registration: NCT03592108 at ClinicalTrials.gov (2018-07-30). According to the protocol, follow-up was continued for a second year for patients having presented with at least one CSR episode during the first year and still on CPAP.

Data collected included CPAP data, occurrence of significant cardiac events (SCE), all-cause hospitalizations, hospitalizations in cardiac units, and outpatient cardiac consultations. A serious cardiac event (SCE) was defined as the onset or worsening of cardiac arrhythmias or acute heart failure requiring therapeutic intervention. A CSR episode was defined as any CSR identified by the Airsense10 software. The ApneaLink Air diagnosis tool and Airsense10 share the same algorithm for respiratory event identification. The RCS detection in the ResMed algorithm is based on specific respiratory patterns, including crescendo-decrescendo tidal volume, cycle length (40 to 120s), and breath amplitude. Detection requires at least 15 consecutive minutes of characteristic variations suggesting CSR. Post-arousal oscillations of limited duration are not considered by the algorithm as Cheyne-Stokes respiration. A robust validation study [3] has demonstrated that this algorithm is reliable for CSR recognition with a sensitivity of 87.1% and a specificity of 94.9%. Using the detailed telemonitoring software report, the number of nights with CSR (regardless of the percentage of CSR per night) was determined over 90 days at the time of the first CSR episode and at the end of the two-year follow-up. The aetiologies of CSR were grouped into five categories: related to a cardiovascular disease (heart failure, rhythm disorders), ventilatory instability induced by residual obstructive events, mask leaks, medications, or other causes (unknown, undetermined, renal insufficiency).

Statistical methods

Data analysis was performed using JMP® software, version 15.0 for Windows (SAS Institute, Inc) and R version 3.4.1 (2017-06-30, R Foundation for Statistical Computing).

Continuous variables are reported as means and standard deviations and categorical variables as numbers and percentages. Independent comparisons were made using a t-test or Welch’s test according to the equality of variance assessed by Fisher’s test, and Chi-square test or Fisher’s exact test for categorical variables. Adherence to CPAP, AHI, leaks, number of nights with CSR, percentage of CSR, number of outpatient visits and hospitalizations were analyzed overall and according to the cause of CSR and, for the number of nights with CSR, compared between year 1 and year 2. The number of nights with CSR and the mean percentage of CSR were assessed over a 90day-period at the end of the second year of follow-up. The mean percentage of CSR was calculated from daily PAP data, considering the nights with CSR. The Kruskal-Walis test was used to determine significant differences between boxplots of the percentage of CSR and the number of nights with CSR across underlying conditions in patients presenting with SCE. Due to the non-normal distribution, the Spearman correlation test was used to assess the relationship between the number of nights with CSR and the percentage of CSR. The Mann-Whitney U test was used to compare the distribution of the number of nights with CSR and the percentage of nights with CSR between patients with CSR without SCE and patients with SCE. A univariate logistic regression model was used, with the qualitative variable (SCE) as the dependent variable and the explanatory variable as either the number of nights with CSR or the percentage of CSR.

Results

Of the 74 patients included in the AlertApnee study and having experienced at least 1 CSR episode during the first year, 66 were included in this ancillary study and 64 completed the 2-year follow-up (Flow chart, Fig.1).

Flowchart

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Patients (n = 66) had a mean age of 73.2 ± 9.3 years, were mostly men (86.4%), obese (mean BMI 30.3 ± 4.1), with a mean AHI at diagnosis of 46.6 ± 14.5 /hour. 62 of 66 patients experienced at least one CSR episode during the second year of follow-up. Characteristics of the CPAP treatment by underlying conditions associated with CSR are presented in Table1. Except for the group with obstructive events associated with CSR, the nasal mask was the most frequently used mask. Fixed pressure mode was less frequent when cardiovascular disease was associated with CSR. Adherence and rAHI remained stable during the two years regardless of the underlying conditions associated with CSR (Table1). Leaks (median and 95th percentile (L/min)) tended to decrease at Y1 and Y2 years, except when obstructive events were associated with CSR (Table1). Overall, the median number of nights with CSR was higher in the second year compared to the first year (8.5 versus 6 nights over a 90-day period, p = 0.025). It was true when CSR was associated with a cardiovascular disease (37 versus 19 nights, p = 0.006), but not for other aetiologies (Fig.2).

Boxplot of number of nights with CSR over 3 months by causes of CSR at the time of the 1st alert and after 2 years of follow-up. Legend: circle: mean; Y1: First alert; Y2: 2 years; P: p value (Wilcoxon test); NS: non-significant

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Full size table

Legend: Values are expressed as median over the first 3 months for T0 and over the 3 previous months for Y1 and Y2.

Amongst the 21 patients with CSR related to an underlying cardiovascular disease in first year of follow-up, seven patients experienced an additional significant cardiac event (SCE) during the second year of follow-up (two had already presented with an SCE during the first year), and all of them required hospitalisation in a cardiology unit. Conversely, no patient with CSR related to another aetiology experienced a SCE in the second year of follow-up.

Among the seven patients who experienced an SCE during the second year of follow-up, five had PAP data available for the last three months, enabling the evaluation of the number of nights with CSR and the percentage of CSR. Patients who experienced a SCE in year 2 had significantly more nights with CSR (median 48/90nights; IQR = 35) and a significantly greater mean percentage of CSR (median 13.8%; interquartile range (IQR) = 13.7) as compared with patients free of SCE (median 9.5/90 nights IQR = 27.8 (p = 0.012); 6.1% IQR = 4.5 (p = 0.008), respectively) (Fig.3). This was true whatever the underlying aetiology of the CSR (percentage of CSR (panel a, p = 0.005) and number of nights with CSR (panel b, p = 0.013) (Figure S1). Additionally, there was a significant relationship between the number of nights with CSR and the percentage of CSR (r = 0.5311, p < 0.001, Figure S2). The number of nights with CSR was associated with an increased risk of SCE (OR [IC95%] = 1.05 [1.01–1.09], p = 0.017).

Mean percentage of CSR (a) and number of nights with CSR (b) over three months in patients who experienced a significant cardiac event compared to those who did not. Legend: SCE: significant cardiac event. CSR: Cheyne stokes respiration. P value (Test Mann-Whitney U). The rectangular box contains 50% of the data and the lower and upper edges of the box indicate the first and third quartiles, the horizontal blue line denotes the median value, and the whiskers correspond to 1.5 times the interquartile range

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Discussion

Alertapnee 2 represents the first prospective study to assess the two-year follow-up of patients presenting with Cheyne-Stokes Respiration (CSR) occurring in CPAP-treated patients. Cheyne-Stokes respiration is recognized for its high prevalence among individuals with unstable cardiac failure and atrial fibrillation. An increased central apnea index and Cheyne-Stokes respiration have been identified as correlates with the progression of heart failure and acute heart failure exacerbations in a community-based cohort of older men [4]. Furthermore, numerous studies have consistently observed a high prevalence of central sleep apnea in individuals with acute [5, 6] and chronic heart failure [7]. Additionally, in a large prospective cohort, central sleep apnea (CSA) and Cheyne-Stokes respiration (CSR) were identified as predictors of incident atrial fibrillation, even after adjustment for other cardiovascular risk factors [8]. In our study, 9 out of 66 patients (13.6%) with a CSR episode during year 1 were hospitalized in a cardiology unit during the second year of follow-up, confirming the poor cardiovascular prognosis associated with Cheyne-Stokes respiration.

Previously, Ullah et al. demonstrated that a high percentage of periodic breathing, as detected by Positive Airway Pressure (PAP) device software, was a predictor of impending heart failure exacerbation and hospitalization. In our study, a greater number of nights with CSR, regardless of the percentage of CSR per night, was associated with unstable condition. Moreover, there was a significant increase in the number of nights with Cheyne-Stokes Respiration (CSR) over time that could reflect natural history of underlying cardiovascular disease. There is also a significant association between the number of nights with CSR and the occurrence of an SCE. Further studies with larger populations are needed to confirm these findings. A high loop gain (the ratio between the amplitude of the response to a disturbance over the disturbance itself) and a narrow CO2 reserve induce instability in respiratory control and underlie the development of CSR. Factors influencing loop gain [9] are chemosensitivity, the mean alveolar–inspired PCO2 gradient, mean lung gas volume buffering PACO2, and circulatory delay. Moreover, the association between leaks and central apnoea is complex and warrants a dedicated, specific study. To explain the association between the severity of cardiovascular condition and the burden of Cheyne-Stokes respiration, it is known that the severity of heart failure is associated with a progressive reduction in the threshold for triggering the onset of Cheyne-Stokes respiration.

Alertapnee is the first study to demonstrate that Cheyne-Stokes respiration has a significant prognostic value when associated with cardiovascular disease.

Conversely, our findings did not reveal any significant cardiovascular prognostic value for CSR when it was associated with clinical scenarios other than cardiovascular disease (a single hospitalization in the cardiology unit was evidenced during the second year in the 45 patients with CSR associated with a non-cardiovascular condition).

Several studies have shown that the cycle length of Cheyne-Stokes respiration correlates with cardiovascular deaths and hospitalizations in cardiology [10, 11]. Wedewardt and al. showed that the CSR cycle length, apnea duration, hyperpnea length, time to peak airflow, airflow to apnea duration ratio and lung to finger circulation times increase with the severity of heart failure [12]. Using raw airflow data from CPAP devices and clinical characteristics available for 23 OSA patients, A. Midelet and al proposed an identification of specific CSR patterns of heart failure: higher CSR duration, longer cycles, more nights with CSR over the 3 months preceding the alert, more repeatable cycles (lower variability), shorter breaths, lower expiratory-inspiratory ratio and a smaller big breath [13]. Measurements of these CSR characteristics might be integrated in CPAP software to separate the different causes of CSR and optimize the specificity of alerts when CSR is detected through CPAP telemonitoring.

Our study has several limitations. First, although 66 patients were included in the study, the number of patients allocated to the five underlying conditions associated with CSR was small, leading to a lack of statistical power. Second, the study lacked a control group comprising patients with cardiovascular pathology who were treated with CPAP but did not exhibit CSR. Moreover, medications and cardiovascular interventions (other than cardiovascular hospitalizations) were not documented during the second year of follow-up.

Perspectives

It is hypothesized that combining the automatic identification of CSR patterns with a composite indicator—including both the percentage of CSR time during the night and the number of nights with CSR—could enable early detection of cardiac instability in patients treated with CPAP and undergoing telemonitoring.

Conclusions

Our study shows that CSR occurrence depends on the underlying condition. CSR does not indicate a poor cardiovascular prognosis when it is associated with underlying conditions other than cardiovascular diseases. The number of nights with CSR and the identification of specific CSR patterns associated with heart failure could enable early detection of significant cardiac events through easy-to-implement telemonitoring in patients treated with CPAP.

Data availability

The data underlying this article (deidentified participant data, data analysis plan) will be shared (after publication) on reasonable request to the corresponding author, with a signed data access agreement.

Abbreviations

CPAP:

Continuous positive airway pressure

OSA:

Obstructive sleep apnea

rAHI:

Residual apnea-hypopnea index

CSR:

Cheyne-Stokes respiration

ASV:

Adaptative Servo-Ventilation

NIV:

Non-Invasive Ventilation

SCE:

Significant cardiac event

BMI:

Body Mass Index

CSA:

Central Sleep Apnea

IQR:

Interquartile range

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Acknowledgements

The authors would like to thank the Vitalaire team, as well as cardiology and pneumology teams for their help in conducting this study.

Funding

This work was supported by Vitalaire.

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Authors and Affiliations

  1. Groupe Medical de Pneumologie, Polyclinique Saint-Laurent, Rennes, France

    Arnaud Prigent&Régis Luraine

  2. Centre du sommeil, Polyclinique Saint-Laurent, Rennes, France

    Arnaud Prigent&Régis Luraine

  3. Cochin University Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France

    Joëlle Texereau

  4. Air Liquide HealthCare, Bagneux, France

    Joëlle Texereau

  5. HP2 Laboratory, Inserm Unit 1300, University Grenoble Alpes, Grenoble, France

    Sébastien Bailly&Jean Louis Pépin

  6. Service de cardiologie, Polyclinique Saint Laurent, Rennes, France

    Renaud Gervais

  7. SLB Pharma, Rennes, France

    Anne-Laure Serandour

  8. Groupe Médical de Pneumologie, Polyclinique Saint Laurent, 2 ter rue de Saint, Laurent, Rennes, 35000, France

    Arnaud Prigent

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  1. Arnaud Prigent

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Contributions

Conceptualization: AP, JT, JLP, ALS. Data curation: AP, JT, JLP, ALS. Formal analysis: ALS, AP Investigation: AP, RL, RG. Methodology: AP, JT, JLP, ALS. Visualization: AP, JT, JLP, ALS. Writing -original draft: AP. Writing-reviewing and editing: AP, JT, JLP, ALS, SB, RG, RL.

Corresponding author

Correspondence to Arnaud Prigent.

Ethics declarations

Ethics approval and consent to participate

The study complied with the Declaration of Helsinki and was approved by the French ethics committee ‘Ouest-VI’ (CPP 1083-HPS2). All patients provided written informed consent. Clinical trial registration: NCT03592108 at ClinicalTrials.gov.

Consent for publication

Not applicable.

Competing interests

Arnaud Prigent is a consultant for Resmed and reports personal fees from Elia Medical, AIR LIQUIDE SANTE, payment for presentations from RESMED Bastide, SOS oxygene, GSK and Isis medical, outside the submitted work. non-financial support from AIR LIQUIDE SANTE, ASTEN SANTE, SOS O2, Elia Medical, outside the submitted work.Joëlle Texereau, MD, PhD, is an employee of Air Liquide Healthcare.Sébastien Bailly, Dr Renaud Gervais, Anne-Laure Serandour, Dr Régis Luraine declare no conflict of interest.Jean Louis Pepin is supported by the French National Research Agency in the framework of the Investissements d’Avenir program [Grant ANR-15-IDEX-02] and the e-Health and Integrated Care chair of excellence from the Grenoble Alpes University Foundation and Sleep-AI chair in Artificial Intelligence MIAI cluster (ANR-19- P3IA-0003). He reports lecture fees or conference traveling grants from ResMed, Philips, Jazz Pharmaceuticals, Agiradom, Bastide, and Bioprojet.

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Incident Cheyne-Stokes respiration occurring in CPAP-treated patients and cardiovascular risk: a 2-years prospective follow-up (The Alertapnee study) (4)

Cite this article

Prigent, A., Texereau, J., Bailly, S. et al. Incident Cheyne-Stokes respiration occurring in CPAP-treated patients and cardiovascular risk: a 2-years prospective follow-up (The Alertapnee study). Respir Res 26, 31 (2025). https://doi.org/10.1186/s12931-025-03109-9

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Keywords

  • Cardiac event
  • Central sleep apnoea
  • Cheyne–stokes respiration
  • Chronic heart failure
  • Continuous positive airway pressure
  • CPAP
  • Telemonitoring
  • The AlertApnee study
Incident Cheyne-Stokes respiration occurring in CPAP-treated patients and cardiovascular risk: a 2-years prospective follow-up (The Alertapnee study) (2025)
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