How to use marginal structural models in randomized trials to estimate the natural direct and indirect effects of therapies mediated by causal intermediates.

Abstract

BACKGROUND:

Although intention-to-treat analysis is a standard approach, additional supplemental analyses are often required to evaluate the biological relationship among interventions, intermediates, and outcomes. Therefore, we need to evaluate whether the effect of an intervention on a particular outcome is mediated by a hypothesized intermediate variable.

PURPOSE:

To evaluate the size of the direct effect in the total effect, we applied the marginal structural model to estimate the average natural direct and indirect effects in a large-scale randomized controlled trial (RCT). Method The average natural direct effect is defined as the difference in the probability of a counterfactual outcome between the experimental and control arms, with the intermediate set to what it would have been, had the intervention been a control treatment. We considered two marginal structural models to estimate the average natural direct and indirect effects introduced by VanderWeele (Epidemiology 2009) and applied them in a large-scale RCT - the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J trial) - that compared angiotensin receptor blockers and calcium-channel blockers in high-risk hypertensive patients.

RESULTS:

There were no strong blood pressure-independent or dependent effects; however, a systolic blood pressure reduction of about 1.9  mmHg suppressed all events. Compared to the blood pressure-independent effects of calcium channel blockers, those of angiotensin receptor blockers contributed positively to cardiovascular and cardiac events, but negatively to cerebrovascular events.

LIMITATIONS:

There is a particular condition for estimating the average natural direct effect. It is impossible to check whether this condition is satisfied with the available data.

CONCLUSION:

We estimated the average natural direct and indirect effects through the achieved systolic blood pressure in the CASE-J trial. This first application of estimating the average natural effects in an RCT can be useful for obtaining an in-depth understanding of the results and further development of similar interventions.

• Authors: Koji Oba, Tosiya Sato, Toshio Ogihara, Takao Saruta, Kazuwa Nakao
• Journal: Clinical trials (London, England) (Clin Trials) Vol. 8 Issue 3 Pg. 277-87 (Jun 2011) ISSN: 1740-7753 [Electronic] England
• PMID: 21730076 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Calcium Channel Blockers

Topics

• Aged
• Angiotensin Receptor Antagonists (administration & dosage, therapeutic use)
• Calcium Channel Blockers (administration & dosage, therapeutic use)
• Female
• Humans
• Hypertension (drug therapy)
• Intention to Treat Analysis (statistics & numerical data)
• Japan
• Male
• Middle Aged
• Models, Statistical
• Outcome Assessment, Health Care (statistics & numerical data)
• Prospective Studies