Study Design and Oversight

The SAVE study was an international, multicenter, randomized, parallel-group, open-label trial, with blinded end-point assessment. Details of the design and analysis plan of the trial have been published previously.24,25 An executive committee (see the Supplementary Appendix, available with the full text of this article at NEJM.org) designed the study and supervised the conduct of the trial and the collection of the data. The Adelaide Institute for Sleep Health of Flinders University of South Australia was responsible for the overall management of the trial and provided the core sleep laboratory analysis and monitoring of the CPAP data and treatment at the sites. Investigators at the George Institute for Global Health coordinated the trial, managed the database, and performed the statistical analyses. All the authors vouch for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol, available at NEJM.org. An independent data and safety monitoring board monitored unblinded trial results and safety events. The trial protocol was approved by all appropriate regulatory authorities and ethics committees at the participating centers. All participants provided written informed consent.

The National Health and Medical Research Council of Australia and Philips Respironics provided the main funding for the trial. In-kind donations were provided by Respironics for the CPAP equipment and by ResMed for the sleep apnea diagnostic devices. None of the funding agencies contributed to the design of the trial, the collection or analysis of the data, the writing of the manuscript, or the decision to submit the manuscript for publication.

Patients and Procedures

Patients were recruited at 89 clinical centers in 7 countries; eligibility criteria included an age between 45 and 75 years, a diagnosis of coronary artery disease or cerebrovascular disease, and a diagnosis of moderate-to-severe obstructive sleep apnea. The diagnosis of moderate-to-severe obstructive sleep apnea, which was defined as an oxygen desaturation index (the number of times per hour during the oximetry recording that the blood oxygen saturation level drops by ≥4 percentage points from baseline) of at least 12, was established with the use of a home sleep-study screening device (ApneaLink, ResMed) and was confirmed by review of the data at a central core sleep laboratory. Patients were excluded from the study if they reported severe daytime sleepiness (Epworth Sleepiness Scale score >15; scores range from 0 to 24, with higher scores indicating greater severity) or were considered to have an increased risk of an accident from falling asleep, if they had very severe hypoxemia (oxygen saturation <80% for >10% of recording time), or if they had a pattern of Cheyne–Stokes respiration on the ApneaLink nasal pressure recording.

Potential participants were required to have a minimum level of adherence to CPAP therapy, which was defined as an average of 3 hours per night, during a 1-week run-in period in which sham CPAP was used (i.e., CPAP at subtherapeutic pressure). Further details of the inclusion and exclusion criteria and of the procedures performed at the core sleep laboratory are provided in the Supplementary Appendix.

Randomization and Interventions

After eligibility was confirmed, the patients were randomly assigned, at a central location, to receive either CPAP therapy plus usual care (CPAP group) or usual care alone (usual-care group). Randomization was performed with the use of a minimization procedure to balance the group assignments according to site, type of cardiovascular disease (cardiac, cerebrovascular, or both), and severity of daytime sleepiness (Epworth Sleepiness Scale score <11 vs. ≥11).

The patients who were assigned to receive mask-delivered CPAP treatment were provided with an automated positive airway pressure machine (REMstar Auto, M or PR series, Philips Respironics) that was initially set in automatic mode for 1 week and thereafter fixed to the 90th percentile of pressure that was calculated by the automated positive airway pressure device from the recorded data. The core sleep laboratory monitored trends in adherence to CPAP therapy and provided corrective advice to investigators (further details are provided in the Supplementary Appendix). Concomitant management of cardiovascular risk factors was performed in accordance with national guidelines. All participants were given advice on healthful sleep habits and lifestyle changes to minimize obstructive sleep apnea. Clinic visits were scheduled for all participants at 1, 3, 6, and 12 months and annually thereafter; the participants were contacted by telephone at 6 months between annual clinic visits.

Study Measurements

At randomization and at each follow-up visit, participants had resting blood pressure and heart rate measured at the clinic, and details of current medication use and health behaviors were documented through a structured interview. Among the participants in the CPAP group, data on adherence to the use of the CPAP device were recorded. At randomization, at 6 months, and at 2 and 4 years, anthropometric measurements were obtained in all participants, and all participants completed several questionnaires: questionnaires that assessed symptoms of obstructive sleep apnea (snoring, witnessed episodes of apnea, and degree of sleepiness according to the Epworth Sleepiness Scale score), the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36; scores range from 0 to 100, with higher scores indicating better quality of life) for assessment of health-related quality of life, and the Hospital Anxiety and Depression Scale (on which anxiety and depression scores range from 0 to 21, with higher scores indicating more symptoms) for assessment of mood. Electrocardiography was performed in all participants at the time of randomization and at 2 years. The European Quality of Life–5 Dimensions questionnaire (EQ-5D; scores range from 1 to 3, with higher scores indicating more problems across five categories of quality of life) was administered only at the end-of-study visit.

The end-of-study visits were conducted from September 2015 through January 2016 (except in India, where they were conducted from July through October 2013). In addition to performing a regular central review of data quality, research staff visited the participating sites to monitor and verify the completeness and authenticity of source documents and adverse-event reporting. Additional details on study measurements and monitoring procedures are provided in the Supplementary Appendix.

Study End Points

A committee whose members were unaware of the study-group assignments adjudicated the major cardiovascular outcomes specified in the protocol. The primary end point was a composite of death from any cardiovascular cause, myocardial infarction (including silent myocardial infarction), stroke, or hospitalization for heart failure, acute coronary syndrome (including unstable angina), or transient ischemic attack. Prespecified secondary cardiovascular end points included the individual components of the primary composite end point, other composites of cardiovascular events, revascularization procedures, new-onset atrial fibrillation, new-onset diabetes mellitus, and death from any cause. Other secondary end points included symptoms of obstructive sleep apnea, health-related quality of life, and mood.

Prespecified safety end points were assessed each time the participant was contacted; these end points included all serious adverse events, self-reported accidents causing personal injury that occurred while the participant was driving or while at work, and any accidents or near-miss accidents that occurred as a result of the participant falling asleep. Two safety end points that were not prespecified — the number of self-reported road-traffic accidents from any cause and the number of days off from work because of poor health — were also assessed. Descriptions of the study end points and of the procedures used by the data and safety monitoring board and end-point adjudicators are provided in the Supplementary Appendix.

Statistical Analysis

Our original plan was to recruit 5000 patients. In 2012, challenges in achieving recruitment targets prompted us to review the accumulated blinded study data and an updated meta-regression of studies of cardiovascular events and severity of obstructive sleep apnea. The meta-regression showed that cardiovascular risk increased by 25 to 32% for every increase of 10 events per hour in the apnea–hypopnea index (the number of occurrences of apnea or hypopnea per hour of sleep), which was a stronger relationship than we had originally assumed.24 In consideration of this information, together with interim blinded trial data showing an annual event rate of 6.86% and better-than-expected adherence to CPAP therapy, we revised our sample size to 2500 patients; we estimated that with this sample size, the study would have 90% statistical power (at an alpha level of 0.05) to detect a 25% lower incidence with CPAP plus usual care than with usual care alone of the primary composite cardiovascular end point, which was anticipated to occur in 533 patients overall over a mean follow-up of 4.5 years.

The primary analysis was an unadjusted survival analysis performed according to the intention-to-treat principle with the use of Cox proportional-hazards regression modeling that was based on positively adjudicated events. We performed a series of sensitivity analyses, including an analysis with adjustment for stratification variables, region, and severity of obstructive sleep apnea; an analysis with Poisson regression to account for participants with multiple events; and an analysis that included all events that were reported by the investigators and not just those that were positively adjudicated. To estimate the effect in patients who were adherent to CPAP therapy, which was defined as an average of 4 hours or more of treatment per night over the first 2 years, we used prespecified propensity-score matching to match adherent patients one-to-one with participants selected from the usual-care (control) group who never used CPAP. The change in clinical variables from baseline to 48 months or to the end-of-study visit (whichever came first) was assessed with the use of analysis of covariance with adjustment for baseline values. All P values are two-sided and were not adjusted for multiple testing. Statistical analyses were performed with the use of SAS software, version 9.3 (SAS Institute). (Additional details regarding the sample-size calculations and other aspects of the statistical analysis are provided in the Supplementary Appendix.)