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Randomized Controlled Trial
. 2023 Dec 7;62(6):2300828.
doi: 10.1183/13993003.00828-2023. Print 2023 Dec.

Hypoxic burden to guide CPAP treatment allocation in patients with obstructive sleep apnoea: a post hoc study of the ISAACC trial

Lucía Pinilla  1   2   3   4 , Neda Esmaeili  3   5   4 , Gonzalo Labarca  3 , Miguel Ángel Martinez-Garcia  2   6 , Gerard Torres  1   2 , Esther Gracia-Lavedan  2   7 , Olga Mínguez  7 , Dolores Martínez  7 , Jorge Abad  2   8 , Maria José Masdeu  2   9 , Olga Mediano  2   10 , Carmen Muñoz  11 , Valentín Cabriada  12 , Joaquín Duran-Cantolla  2   13 , Mercè Mayos  2   14 , Ramón Coloma  15 , Josep María Montserrat  2   16 , Mónica de la Peña  17 , Wen-Hsin Hu  3 , Ludovico Messineo  3 , Mohammadreza Sehhati  5 , Andrew Wellman  3 , Susan Redline  3 , Scott Sands  3 , Ferran Barbé  2   7 , Manuel Sánchez-de-la-Torre  18   2   19 , Ali Azarbarzin  3   19
Affiliations
Randomized Controlled Trial

Hypoxic burden to guide CPAP treatment allocation in patients with obstructive sleep apnoea: a post hoc study of the ISAACC trial

Lucía Pinilla et al. Eur Respir J. .

Abstract

Background: Hypoxic burden (HB) has emerged as a strong predictor of cardiovascular risk in obstructive sleep apnoea (OSA). We aimed to assess the potential of HB to predict the cardiovascular benefit of treating OSA with continuous positive airway pressure (CPAP).

Methods: This was a post hoc analysis of the ISAACC trial (ClinicalTrials.gov: NCT01335087) including non-sleepy patients with acute coronary syndrome (ACS) diagnosed with OSA (apnoea-hypopnoea index ≥15 events·h-1) by respiratory polygraphy. Patients were randomised to CPAP or usual care and followed for a minimum of 1 year. HB was calculated as the total area under all automatically identified desaturations divided by total sleep time. Patients were categorised as having high or low baseline HB according to the median value (73.1%min·h-1). Multivariable Cox regression models were used to assess whether the effect of CPAP on the incidence of cardiovascular outcomes was dependent on the baseline HB level.

Results: The population (362 patients assigned to CPAP and 365 patients assigned to usual care) was middle-aged (mean age 59.7 years), overweight/obese and mostly male (84.5%). A significant interaction was found between the treatment arm and the HB categories. In the high HB group, CPAP treatment was associated with a significant reduction in the incidence of cardiovascular events (HR 0.57, 95% CI 0.34-0.96). In the low HB group, CPAP-treated patients exhibited a trend toward a higher risk of cardiovascular outcomes than those receiving usual care (HR 1.33, 95% CI 0.79-2.25). The differential effect of the treatment depending on the baseline HB level followed a dose-response relationship.

Conclusion: In non-sleepy ACS patients with OSA, high HB levels were associated with a long-term protective effect of CPAP on cardiovascular prognosis.

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Conflict of interest statement

Conflict of interest: M.Á. Martinez-Garcia received grants from VitalAire and Philips, Spain, and serves as a consultant for ResMed Inc., Australia, companies that develop products related to sleep apnoea. L. Messineo received a consultancy fee from Apnimed. A. Wellman works as a consultant for Apnimed, SomniFix and Nox, and has received grants from SomniFix and Sanofi; A. Wellman has a financial interest in Apnimed, a company developing pharmacological therapies for sleep apnoea. His interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. S. Redline received grant support and consulting fees from Jazz Pharmaceuticals, and consulting fees from Apnimed and Lilly Pharma. S. Sands receives personal fees as a consultant for Nox Medical and Merck, outside the submitted work, and receives grant support from Apnimed and ProSomnus. F. Barbé received a research grant from ResMed Inc., Australia, a company that develops products related to sleep apnoea. A. Azarbarzin reports grant support from SomniFix and serves as a consultant for SomniFix, Respicardia, Eli Lilly and Apnimed. Apnimed is developing pharmacological treatments for obstructive sleep apnoea. A. Azarbarzin's interests were reviewed by Brigham and Women's Hospital and Mass General Brigham in accordance with their institutional policies. All other authors declare no competing interests.

Figures

FIGURE 1
FIGURE 1
Calculation of the oximetry-based hypoxic burden (HB). a) All automatically detected desaturations are synchronised at their minimum saturation levels (time 0) and ensemble averaged to obtain the search window (duration between two maximum peaks around time 0). b) HB is calculated as the normalised summation of the coloured arterial oxygen saturation (SaO2) areas within the search window for all desaturation episodes divided by total sleep time.
FIGURE 2
FIGURE 2
Study flowchart. Of the 1851 participants enrolled in the ISAACC trial, 1255 patients with obstructive sleep apnoea (OSA) were considered for the present post hoc analysis. Respiratory polygraphy (RP) data were available for a total of 793 patients, of whom 33 had irregularities in the sleep recording and 33 involved inadequate arterial oxygen saturation (SaO2) signal quality. The final study cohort comprised 727 OSA patients. AHI: apnoea–hypopnoea index; CPAP: continuous positive airway pressure.
FIGURE 3
FIGURE 3
Differential patterns of cardiovascular response to continuous positive airway pressure (CPAP) treatment according to the baseline hypoxic burden (HB) level. Unadjusted Kaplan‒Meier curves showing the cumulative incidence of cardiovascular events (CVEs) in the CPAP versus usual care groups for a) all participants (n=727), b) participants with low HB (n=364) and c) participants with high HB (n=363). The pre-intervention HB was categorised as “low” or “high” based on the median value (≤73.1%min·h−1 or >73.1%min·h−1, respectively).
FIGURE 4
FIGURE 4
Dose–response relationship between baseline hypoxic burden (HB) and predicted risk for cardiovascular events (CVEs) stratified by treatment arm. The curves illustrate the predicted hazard for the primary end-point in the continuous positive airway pressure (CPAP) and the usual care groups, according to the continuous HB level. The predicted hazard ratios were estimated using the average baseline characteristics: average age (59.7 years), male sex (majority), average body mass index (29.3 kg·m−2) and absence of previous cardiovascular disease (majority). The x-axis is log-scaled.
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