How to use marginal structural models in randomized trials to estimate the natural direct and indirect effects of

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Koji Oba1, Tosiya Sato, Toshio Ogihara

  • 1Translational Research and Clinical Trial Center, Hokkaido University Hospital, Hokkaido University, Japan. k.oba@huhp.hokudai.ac.jp

Clinical Trials (London, England)
|July 7, 2011
PubMed
Abstract

Insights

Marginal structural models helped estimate direct and indirect effects of antihypertensives in the CASE-J trial. A small systolic blood pressure reduction significantly suppressed cardiovascular events, with differing effects between drug classes.

Area of Science:

  • Cardiovascular Medicine
  • Clinical Trials
  • Epidemiology

Background:

  • Standard intention-to-treat analysis may not fully capture intervention-outcome relationships.
  • Evaluating mediation by intermediate variables is crucial for understanding treatment effects.
  • This study addresses the need to assess if an intervention's effect on an outcome is mediated by a specific intermediate variable.

Purpose of the Study:

  • To apply marginal structural models for estimating average natural direct and indirect effects.
  • To evaluate the direct effect's contribution within the total effect of interventions.
  • To utilize these methods in a large-scale randomized controlled trial (RCT) for in-depth analysis.

Main Methods:

  • Employed two marginal structural models to estimate average natural direct and indirect effects.
  • Defined average natural direct effect as the counterfactual outcome difference with intermediate set to control treatment.
  • Applied models to the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial data.

Main Results:

  • A systolic blood pressure reduction of approximately 1.9 mmHg was associated with event suppression.
  • Angiotensin receptor blockers showed positive contributions to cardiovascular/cardiac events and negative to cerebrovascular events.
  • Calcium channel blockers' blood pressure-independent effects were also analyzed for comparison.

Conclusions:

  • Successfully estimated average natural direct and indirect effects via systolic blood pressure in the CASE-J trial.
  • This novel application in an RCT provides deeper insights into treatment effects.
  • Findings can inform the development of similar interventions and refine understanding of antihypertensive mechanisms.

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