English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Tools annual

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Presents the access of premium content as premium feature

Premium Content

Global: Zendy Plus annual

Global: Zendy Free Plan

Introduction: Increasing interest in real-world evidence has fueled thedevelopment of study designs incorporating real-world data (RWD). Using theCausal Roadmap, we specify three designs to evaluate the difference in risk ofmajor adverse cardiovascular events (MACE) with oral semaglutide versusstandard-of-care: 1) the actual sequence of non-inferiority and superiorityrandomized controlled trials (RCTs), 2) a single RCT, and 3) a hybridrandomized-external data study. Methods: The hybrid design considersintegration of the PIONEER 6 RCT with RWD controls using theexperiment-selector cross-validated targeted maximum likelihood estimator. Weevaluate 95% confidence interval coverage, power, and average patient-timeduring which participants would be precluded from receiving a glucagon-likepeptide-1 receptor agonist (GLP1-RA) for each design using simulations.Finally, we estimate the effect of oral semaglutide on MACE for the hybridPIONEER 6-RWD analysis. Results: In simulations, Designs 1 and 2 performedsimilarly. The tradeoff between decreased coverage and patient-time without thepossibility of a GLP1-RA for Designs 1 and 3 depended on the simulated bias. Inreal data analysis using Design 3, external controls were integrated in 84% ofcross-validation folds, resulting in an estimated risk difference of-1.53%-points (95% CI -2.75%-points to -0.30%-points). Conclusions: The CausalRoadmap helps investigators to minimize potential bias in studies using RWD andto quantify tradeoffs between study designs. The simulation results help tointerpret the level of evidence provided by the real data analysis in supportof the superiority of oral semaglutide versus standard-of-care forcardiovascular risk reduction.

A Causal Roadmap for Hybrid Randomized and Real-World Data Designs: Case Study of Semaglutide and Cardiovascular Outcomes