Articles
Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial

https://doi.org/10.1016/S2213-2600(19)30271-1Get rights and content

Summary

Background

Despite the improvement in the prognosis of acute coronary syndrome (ACS), substantial morbidity and mortality remain. We aimed to evaluate the effect of obstructive sleep apnoea (OSA) and its treatment with continuous positive airway pressure (CPAP) on the clinical evolution of patients with ACS.

Methods

We designed a multicentre, open-label, parallel-group, randomised controlled trial of patients with ACS at 15 hospitals in Spain. Eligible non-sleepy patients were men and women aged 18 years and older, admitted to hospital for documented symptoms of ACS. All patients underwent respiratory polygraphy during the first 24–72 h after admission. OSA patients were randomly assigned (1:1) to CPAP treatment plus usual care (CPAP group) or usual care alone (UC group) by a computerised system available 24 h a day. A group of patients with ACS but without OSA was also included as a reference group. Because of the nature of the intervention, the trial intervention could not be masked to either investigators or patients. Patients were monitored and followed for a minimum of 1 year. Patients were examined at the time of inclusion; after 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months; and every 12 months thereafter, if applicable, during the follow-up period. The primary endpoint was the prevalence of a composite of cardiovascular events (cardiovascular death or non-fatal events [Acute myocardial infarction, non-fatal stroke, hospital admission for heart failure, and new hospitalisations for unstable angina or transient ischaemic attack]) in patients followed up for a minimum of 1 year. The primary analysis was done according to the intention-to-treat principle. This study is registered with Clinicaltrials.gov, NCT01335087 and is now closed.

Findings

Between April 25, 2011, and Feb 2, 2018, a total of 2834 patients with ACS had respiratory polygraphy, of whom 2551 (90·01%) were recruited. 1264 (49·55%) patients had OSA and were randomly assigned to the CPAP group (n=633) or the UC group (n=631). 1287 (50·45%) patients did not have OSA, of whom 603 (46·85%) were randomly assigned to the reference group. Patients were followed up for a median of 3·35 years (IQR 1·50–5·31). The prevalence of cardiovascular events was similar in the CPAP and UC groups (98 events [16%] vs 108 events [17%]; hazard ratio [HR] 0·89 [95% CI 0·68–1·17]; p=0·40) during follow-up. Mean time of adherence to CPAP treatment was 2·78 h/night (SD 2·73). The prevalence of cardiovascular events was similar between patients in the reference group (90 [15%] events) and those in the UC group (102 (17%) events) during follow-up (1·01 [0·76–1·35]; p=0·93). The prevalence of cardiovascular events seem not to be related to CPAP compliance or OSA severity. 464 (74%) of 629 patients in the CPAP group had 1538 serious adverse events and 406 (65%) of 626 patients in the UC group had 1764 serious adverse events.

Interpretation

Among non-sleepy patients with ACS, the presence of OSA was not associated with an increased prevalence of cardiovascular events and treatment with CPAP did not significantly reduce this prevalence.

Funding

ResMed (Australia), Fondo de Investigación Sanitaria (Fondo Europeo de Desarrollo Regional), the Spanish Respiratory Society, the Catalonian Cardiology Society, Esteve-Teijin, Oxigen Salud, and ALLER.

Introduction

Acute coronary syndrome (ACS) is a major health burden, with more than 1 million patients suffering from ACS annually in the USA.1 The short-term and long-term prognoses following diagnosis with ACS have improved (with acute revascularisation and treatment of known cardiovascular risk factors). However, substantial morbidity and mortality remain, including repeat cardiovascular events.

Obstructive sleep apnoea (OSA) is a common disease that affects 20–30% of the adult population2 and is caused by the collapse of the upper airway during sleep. OSA has been associated with an increase in oxidative stress, inflammation, hypercoagulability, and sympathetic activation that could induce cardiovascular disease.3, 4 Epidemiological studies have shown that a high proportion (40–60%) of patients with coronary artery disease have OSA.5, 6, 7 Previous randomised controlled trials have shown that the treatment of OSA with continuous positive airway pressure (CPAP) is associated with a reduction in blood pressure,8 left ventricular mechanical overload, and arrhythmia.9, 10, 11 These effects could improve the prognosis of patients with coronary artery disease.12 However, other studies have shown that the use of CPAP was not associated with reduced risk of cardiovascular outcomes or death for patients with sleep apnoea.13 Evidence suggests that in patients with chronic cardiovascular disease,14 CPAP treatment is not effective as secondary cardiovascular prevention. To gain insight in this area of research,15, 16, 17, 18 we designed a secondary prevention trial to evaluate the effect of OSA and the effectiveness of its treatment with CPAP on the clinical evolution and prognosis of patients with ACS.19

Research in context

Evidence before this study

Obstructive sleep apnoea (OSA) is a common condition among patients with cardiovascular disease, affecting 40–60% of such patients. Because the risk of recurrent cardiovascular events among these patients remains high despite contemporary therapies, CPAP could be a useful additional treatment for the prevention of these events. We searched PubMed with the terms “obstructive sleep apnea”, “acute coronary syndrome”, “CPAP treatment”, and “secondary prevention” for systemic reviews and randomised controlled trials published up to Jan 1, 2019. Previous randomised controlled trials have shown that the treatment of OSA with CPAP is associated with a reduction in blood pressure, left ventricular mechanical overload, and arrhythmia. In addition, observational clinical studies have shown that the use of CPAP is associated with lower prevalence of cardiovascular complications and of death from cardiovascular causes. Three previous randomised controlled trials have directly addressed cardiovascular clinical endpoints in patients who have suffered a major cardiovascular event and the authors observed a neutral effect of CPAP treatment for secondary cardiovascular prevention.

Added value of this study

Our findings indicate that the use of CPAP therapy, compared with usual care alone, had no positive effect on the prevention of recurrent major cardiovascular events in patients with OSA and acute coronary syndrome. Moreover, the presence of OSA was not associated with an increased prevalence of cardiovascular events.

Implications of all the available evidence

The results of this secondary prevention trial in adults with acute coronary syndrome and OSA, supported by further studies, contribute to understanding the observed neutral effect of CPAP treatment for secondary cardiovascular prevention.

Section snippets

Study design and patients

The ISAACC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome. Effect of intervention with CPAP) is a multicentre, open-label, parallel-group, randomised controlled trial of patients with ACS at 15 hospitals across Spain (appendix p 5) The detailed design of this study has been published previously.19

Eligible patients were aged ≥18 years, had been admitted to hospital for ACS with a hospital stay of 24–72 h at the time of sleep study, and had an Epworth Sleepiness

Results

Between April 25, 2011, and Feb 2, 2018, a total of 2834 patients with ACS had respiratory polygraphy, of whom 2551 were enrolled. 1264 (49·55%) patients had an AHI of more than 15/h and 1287 (50·45%) had an AHI of less than 15/h (figure 1). Patients with ACS and OSA were randomly assigned to either the CPAP group (n=633) or the UC group (n=631). Nine patients were excluded due to irregularities identified during monitoring, leaving 1255 patients for the primary analysis (n=629 in the CPAP

Discussion

The ISAACC study showed that among patients with ACS and OSA, CPAP treatment did not result in a significantly lower prevalence of cardiovascular events than did UC after a median follow-up of 3·35 years. CPAP adherence did not influence these results. Additionally, the presence of OSA was not associated with a worse prognosis in patients with ACS. In contrast, treatment with CPAP was associated with marginal improvement in ESS and blood pressure.

These results should contribute to understanding

Data sharing

All of the individual patient data collected during the trial will be shared. In addition, the study protocol and statistical analysis plan will be available as well. The data will be made available within 12 months of publication. All available data can be obtained by contacting the corresponding author ([email protected]). It will be necessary to provide a detailed protocol for the proposed study, to provide the approval of an ethics committee, to supply information about the

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  • Cited by (0)

    *

    Both authors contributed equally to this study

    A list of the Spanish Sleep Network investigators and collaborators is provided in the appendix

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