Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data
Abstract Introduction: Increasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semagluti...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Cambridge University Press
2023-01-01
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| Series: | Journal of Clinical and Translational Science |
| Subjects: | |
| Online Access: | https://www.cambridge.org/core/product/identifier/S2059866123006568/type/journal_article |
| _version_ | 1797632522263199744 |
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| author | Lauren E. Dang Edwin Fong Jens Magelund Tarp Kim Katrine Bjerring Clemmensen Henrik Ravn Kajsa Kvist John B. Buse Mark van der Laan Maya Petersen |
| author_facet | Lauren E. Dang Edwin Fong Jens Magelund Tarp Kim Katrine Bjerring Clemmensen Henrik Ravn Kajsa Kvist John B. Buse Mark van der Laan Maya Petersen |
| author_sort | Lauren E. Dang |
| collection | DOAJ |
| description |
Abstract
Introduction:
Increasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semaglutide versus standard-of-care: (1) the actual sequence of non-inferiority and superiority randomized controlled trials (RCTs), (2) a single RCT, and (3) a hybrid randomized-external data study.
Methods:
The hybrid design considers integration of the PIONEER 6 RCT with RWD controls using the experiment-selector cross-validated targeted maximum likelihood estimator. We evaluate 95% confidence interval coverage, power, and average patient time during which participants would be precluded from receiving a glucagon-like peptide-1 receptor agonist (GLP1-RA) for each design using simulations. Finally, we estimate the effect of oral semaglutide on MACE for the hybrid PIONEER 6-RWD analysis.
Results:
In simulations, Designs 1 and 2 performed similarly. The tradeoff between decreased coverage and patient time without the possibility of a GLP1-RA for Designs 1 and 3 depended on the simulated bias. In real data analysis using Design 3, external controls were integrated in 84% of cross-validation folds, resulting in an estimated risk difference of –1.53%-points (95% CI –2.75%-points to –0.30%-points).
Conclusions:
The Causal Roadmap helps investigators to minimize potential bias in studies using RWD and to quantify tradeoffs between study designs. The simulation results help to interpret the level of evidence provided by the real data analysis in support of the superiority of oral semaglutide versus standard-of-care for cardiovascular risk reduction.
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| first_indexed | 2024-03-11T11:39:12Z |
| format | Article |
| id | doaj.art-064b65a77f6f41fc9bd8faca2850c2d2 |
| institution | Directory Open Access Journal |
| issn | 2059-8661 |
| language | English |
| last_indexed | 2024-03-11T11:39:12Z |
| publishDate | 2023-01-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | Journal of Clinical and Translational Science |
| spelling | doaj.art-064b65a77f6f41fc9bd8faca2850c2d22023-11-10T07:17:59ZengCambridge University PressJournal of Clinical and Translational Science2059-86612023-01-01710.1017/cts.2023.656Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world dataLauren E. Dang0https://orcid.org/0000-0002-2967-0855Edwin Fong1Jens Magelund Tarp2Kim Katrine Bjerring Clemmensen3Henrik Ravn4Kajsa Kvist5John B. Buse6https://orcid.org/0000-0002-9723-3876Mark van der Laan7Maya Petersen8Department of Biostatistics, University of California, Berkeley, CA, USANovo Nordisk, Søborg, DenmarkNovo Nordisk, Søborg, DenmarkNovo Nordisk, Søborg, DenmarkNovo Nordisk, Søborg, DenmarkNovo Nordisk, Søborg, DenmarkDivision of Endocrinology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USADepartment of Biostatistics, University of California, Berkeley, CA, USADepartment of Biostatistics, University of California, Berkeley, CA, USA Abstract Introduction: Increasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semaglutide versus standard-of-care: (1) the actual sequence of non-inferiority and superiority randomized controlled trials (RCTs), (2) a single RCT, and (3) a hybrid randomized-external data study. Methods: The hybrid design considers integration of the PIONEER 6 RCT with RWD controls using the experiment-selector cross-validated targeted maximum likelihood estimator. We evaluate 95% confidence interval coverage, power, and average patient time during which participants would be precluded from receiving a glucagon-like peptide-1 receptor agonist (GLP1-RA) for each design using simulations. Finally, we estimate the effect of oral semaglutide on MACE for the hybrid PIONEER 6-RWD analysis. Results: In simulations, Designs 1 and 2 performed similarly. The tradeoff between decreased coverage and patient time without the possibility of a GLP1-RA for Designs 1 and 3 depended on the simulated bias. In real data analysis using Design 3, external controls were integrated in 84% of cross-validation folds, resulting in an estimated risk difference of –1.53%-points (95% CI –2.75%-points to –0.30%-points). Conclusions: The Causal Roadmap helps investigators to minimize potential bias in studies using RWD and to quantify tradeoffs between study designs. The simulation results help to interpret the level of evidence provided by the real data analysis in support of the superiority of oral semaglutide versus standard-of-care for cardiovascular risk reduction. https://www.cambridge.org/core/product/identifier/S2059866123006568/type/journal_articleCausal inferencereal-world evidencehybrid study designsdiabetescardiovascular outcomes |
| spellingShingle | Lauren E. Dang Edwin Fong Jens Magelund Tarp Kim Katrine Bjerring Clemmensen Henrik Ravn Kajsa Kvist John B. Buse Mark van der Laan Maya Petersen Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data Journal of Clinical and Translational Science Causal inference real-world evidence hybrid study designs diabetes cardiovascular outcomes |
| title | Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data |
| title_full | Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data |
| title_fullStr | Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data |
| title_full_unstemmed | Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data |
| title_short | Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data |
| title_sort | case study of semaglutide and cardiovascular outcomes an application of the causal roadmap to a hybrid design for augmenting an rct control arm with real world data |
| topic | Causal inference real-world evidence hybrid study designs diabetes cardiovascular outcomes |
| url | https://www.cambridge.org/core/product/identifier/S2059866123006568/type/journal_article |
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