C100-01 Determining the Effect of PAP on Cardiovascular Risk in the Real World: A Target Trial Emulation of the Save Trial Using State-wide Medicare Claims

Abstract Introduction Positive Airway Pressure (PAP) is the treatment of choice for severe or symptomatic obstructive sleep apnea (OSA). However, a meta-analysis of randomized controlled trials (RCTs) failed to demonstrate that PAP prevents major adverse cardiovascular events (MACE). Conversely, observational studies showed significant effects towards preventing MACE. It is unclear whether these differences are due to observational study design considerations, or patient selection. To address this gap, we proposed a target trial emulation (TTE) of the Sleep Apnea Cardiovascular Endpoints (SAVE) study, the largest RCT assessing the effect of PAP on MACE risk. We hypothesize that an emulation of the SAVE trial using observational data would result in a non-significant effect of PAP on MACE risk. Methods We used the TTE framework to formalize the analysis of state-wide Medicare claims across nine states in the Central U.S. from 2011-2020 towards addressing the question proposed by the SAVE trial (our target trial). We explicitly described all components of our target trial (eligibility, treatment strategies, assignment, follow-up, causal contrasts, analysis plan) and operationalized them using observational claims data, making any necessary adjustments. Evidence of PAP initiation was based on claims and MACE was defined as a composite of myocardial infarction, heart failure, stroke, or coronary revascularization. We used prescription time distribution matching to assign index dates and propensity score matching to control for confounding using baseline covariates when assessing causal contrasts. Cox proportional hazards models estimated treatment effect sizes. Results After applying the SAVE eligibility criteria, 168,415 Medicare beneficiaries were included in the analysis (mean SD age 75.1 6.3 years; 40% women), and 22,372 (13.3%) had evidence of initiating PAP. Our estimated intention-to-treat effect (hazard ratio HR) of PAP on MACE risk using TTE was 1.21 (95%CI: 0.70-2.09), suggesting that in this emulated trial, PAP was not associated with lower MACE risk, consistent with our initial hypothesis and with the intention-to-treat estimates reported by SAVE (HR 95%CI 1.10 0.91-0.32). Conclusion Emulation of the SAVE trial using Medicare claims data did not show an association between PAP and lower MACE risk, consistent with the trial results. These results suggest that differences between RCTs and observational studies are likely to reflect patient selection (e.g., non-sleepy, secondary prevention, age) rather than biases usually attributed to observational studies (e.g., healthy adherer bias). This study reinforces the use of TTE to guide the design of robust observational studies assessing the effect of OSA therapies on cardiovascular risk. This abstract is funded by: American Heart Association (20CDA35310360); Patient-Centered Outcomes Research Institute (RI-CRN-2020-003-IC); National Institutes of Health Clinical and Translational Science Awards National Center for Advancing Translational Sciences Frontiers; University of Kansas Clinical and Translational Science Institute (UL1TR002366)