The Sleep Apnea cardioVascular Endpoints (SAVE) Trial: Rationale, Ethics, Design, and Progress

Abstract

Abstract: The Sleep Apnea cardioVascular Endpoints (SAVE) study is an ongoing investigator-initiated and conducted, international, multicenter, open, blinded endpoint, randomized controlled trial that was designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the risk of serious cardiovascular (CV) events in patients with established CV disease (clinical trial registration NCT00738179). The results of this study will have important implications for the provision of health care to patients with sleep apnea around the world. The SAVE study has brought together respiratory, sleep, CV and stroke clinicians-scientists in an interdisciplinary collaboration with industry and government sponsorship to conduct an ambitious clinical trial. Following its launch in Australia and China in late 2008, the recruitment network expanded across 89 sites that included New Zealand, India, Spain, USA, and Brazil for a total of 2,717 patients randomized by December 2013. These patients are being followed until December 2015 so that the average length of follow-up of the cohort will be over 4 y. This article describes the rationale for the SAVE study, considerations given to the design including how various cultural and ethical challenges were addressed, and progress in establishing and maintaining the recruitment network, patient follow-up, and adherence to CPAP and procedures. The assumptions underlying the original trial sample size calculation and why this was revised downward in 2012 are also discussed.

Clinical trials registration number: NCT00738179.

Australia new zealand clinical trials registry number: ACTRN12608000409370.

Keywords: OSA; cardiovascular; clinical trial; outcomes.

© 2015 Associated Professional Sleep Societies, LLC.

Figures

Figure 1

SAVE design scheme. CPAP, continuous positive airway pressure; CV, cardiovascular; ODI, oxygen desaturation index.

Figure 2

Predicted odds ratio for cardiovascular events based on metaregression coefficients (n = 7 studies). Two researchers independently conducted literature searches for papers on the association of sleep apnea and cardiovascular disease/events. Studies needed to report adjusted odds or hazard ratios (OR, HR) stratified by groups with reports of mean apnea-hypopnea index (AHI) or range of AHI in the stratification. Twenty-four studies were identified, 17 were excluded (2 were cross sectional studies, 12 did not report on a composite cardiovascular outcome, e.g., only stroke, one was a subsequent publication of the same population included, one had no stratification or reports of AHI, one reported RDI only), and seven studies were included in the meta-regression. One researcher extracted data and conducted the meta-regression on the log OR/HR. Normal probability plot of shrunken residuals was conducted to confirm that there were no notable outliers as such a normal random effects model was sufficient. Sensitivity analyses were conducted removing the cross-sectional study. All analyses were conducted using STATA version 12. From the meta-regression coefficients it is possible to estimate the log OR of cardiovascular event (CVE) at a given AHI using the formula log OR = 0.1321137 + 0.0223362AHI. Based on the coefficients from the meta-regression we calculated that for a drop in AHI from 29 to 19 the resulting CVE risk reduction is 25%.

Figure 3

Cumulative recruitment of participants randomized into the SAVE trial.