Open Access Open Badges Research article

Comparing marginal structural models to standard methods for estimating treatment effects of antihypertensive combination therapy

Tobias Gerhard12*, Joseph AC Delaney345, Rhonda M Cooper-DeHoff67, Jonathan Shuster8, Babette A Brumback45, Julie A Johnson67, Carl J Pepine7 and Almut G Winterstein345

Author Affiliations

1 Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, NJ, USA

2 Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA

3 Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA

4 Department of Epidemiology, University of Florida, Gainesville, FL, USA

5 Department of Biostatistics, University of Florida, Gainesville, FL, USA

6 Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA

7 Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, FL, USA

8 Department of Health Outcomes and Policy, College of Medicine, University of Florida, Gainesville, FL, USA

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BMC Medical Research Methodology 2012, 12:119  doi:10.1186/1471-2288-12-119

Published: 6 August 2012



Due to time-dependent confounding by blood pressure and differential loss to follow-up, it is difficult to estimate the effectiveness of aggressive versus conventional antihypertensive combination therapies in non-randomized comparisons.


We utilized data from 22,576 hypertensive coronary artery disease patients, prospectively enrolled in the INternational VErapamil-Trandolapril STudy (INVEST). Our post-hoc analyses did not consider the randomized treatment strategies, but instead defined exposure time-dependently as aggressive treatment (≥3 concomitantly used antihypertensive medications) versus conventional treatment (≤2 concomitantly used antihypertensive medications). Study outcome was defined as time to first serious cardiovascular event (non-fatal myocardial infarction, non-fatal stroke, or all-cause death). We compared hazard ratio (HR) estimates for aggressive vs. conventional treatment from a Marginal Structural Cox Model (MSCM) to estimates from a standard Cox model. Both models included exposure to antihypertensive treatment at each follow-up visit, demographics, and baseline cardiovascular risk factors, including blood pressure. The MSCM further adjusted for systolic blood pressure at each follow-up visit, through inverse probability of treatment weights.


2,269 (10.1%) patients experienced a cardiovascular event over a total follow-up of 60,939 person-years. The HR for aggressive treatment estimated by the standard Cox model was 0.96 (95% confidence interval 0.87-1.07). The equivalent MSCM, which was able to account for changes in systolic blood pressure during follow-up, estimated a HR of 0.81 (95% CI 0.71-0.92).


Using a MSCM, aggressive treatment was associated with a lower risk for serious cardiovascular outcomes compared to conventional treatment. In contrast, a standard Cox model estimated similar risks for aggressive and conventional treatments.

Trial registration Identifier: NCT00133692

Blood pressure; Hypertension; Time-dependent confounding; Marginal structural models