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

Tobias Gerhard,Babette A Brumback,Almut G Winterstein,Carl J Pepine,Rhonda M Cooper-Dehoff,Joseph Ac Delaney,Julie A Johnson,Jonathan Shuster

doi:10.1186/1471-2288-12-119

Abstract

BackgroundDue 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.MethodsWe 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.Results2,269 (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).ConclusionsUsing 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 registrationClinicaltrials.gov Identifier: NCT00133692

Highlights

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
This study aims to estimate the effect of aggressive (≥3 concomitant antihypertensive drugs) vs. conventional (≤2 concomitant antihypertensive drugs) antihypertensive therapy on serious adverse cardiovascular outcomes in the 22,576 patients enrolled in the INternational VErapamilTrandolapril STudy (INVEST) using a Marginal Structural Cox Model (MSCM) to account for time-dependent confounding by systolic blood pressure and differential loss to follow-up over the course of the study
The MSCM estimated a statistically significant 19% (HR 0.81, 95% CI 0.71-0.92) reduction in the hazard for the primary outcome for patients treated with aggressive antihypertensive therapy as compared with conventional therapy

Summary

Introduction

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. Antihypertensive therapy commonly involves multi-drug treatment strategies that are initiated and continuously adapted based on clinical characteristics, blood pressure response, and adverse drug reactions. There has been increasing interest in the question of whether combination antihypertensive therapies lead to improved clinical outcomes [1,2,3,4]. Because more aggressive combination treatments are more likely to be initiated in patients with uncontrolled blood pressure, it is likely that the beneficial treatment effects of such combination therapies will be underestimated. This potential underestimation occurs because uncontrolled blood pressure simultaneously increases the likelihood of treatment with aggressive antihypertensive therapy and risk for adverse clinical outcomes

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