Target Trial Emulation Applications in Hypertension Research: A Scoping Review

Objectives Target Trial Emulation (TTE) has emerged as a rigorous framework for causal inference using observational data, but its application in hypertension research remains underexplored. This scoping review aims to map current TTE applications, identify methodological strengths and weaknesses, and propose future directions for its use in hypertension research. Study Design and Setting We performed a scoping review following the Joanna Briggs Institute (JBI) guidance and the PRISMA extension for Scoping Reviews (PRISMA-ScR) checklist. We searched multiple databases, and three independent reviewers conducted screening and extraction using Covidence review management software. 14 out of 1,352 articles met the inclusion criteria.

Most studies used data from electronic health records, claims databases, and registries. All of the interventions were pharmacological except for one. Common confounding adjustment methods included inverse probability weighting (50%) and the g-formula (21.5%), complemented by regression-based models. However, time-varying confounders were inconsistently addressed, and loss to follow-up was often managed through simple censoring rather than statistical methods. Residual confounding remained a concern—although several studies acknowledged unobserved confounders, only five (36%) employed negative controls or e-values to assess their impact. While subgroup analyses were common, explicit heterogeneous treatment effect (HTE) estimation was limited. Advanced causal machine learning techniques for bias mitigation or HTE detection were not reported.

TTE shows strong potential to complement randomized controlled trials in hypertension research by providing more generalizable insights. While still in its early stages, current studies highlight its ability to address key challenges such as HTE, long-term outcomes, and dynamic treatment strategies. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study did not receive any funding Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes School of Public Health, University of Alberta, Edmonton, Alberta T6G 1C9, Canada, Email: hzuo3{at}ualberta.ca, Tel: +1 (587) 597-3110. Richelle J. Koopman, MD, MS, Professor, Department of Family and Community Medicine, University of Missouri-Columbia, Missouri, USA, Email: koopmanr{at}health.missouri.edu. Aditi Gupta, MD, MS, Professor, Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA, Email: agupta{at}kumc.edu. Diego Robles Mazzotti, Ph.D. Assistant Professor, Department of Internal Medicine, Division of Medical Informatics, Division of Pulmonary Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA, Email: droblesmazzotti{at}kumc.edu. Xing Song, PhD, Assistant Professor, Department of Biomedical Informatics, Biostatistics, and Medical Epidemiology (BBME), University of Missouri-Columbia, 1 Hospital Dr. | Columbia, MO 65212, Email: xsm7f{at}missouri.edu, Tel: +1 (573) 882-1352 There are some minor corrections. The co-authors have changed. Data Availability All data produced in the present study are available online in the cited papers online.