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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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).

CONCLUSIONS:

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:

Clinicaltrials.gov Identifier: NCT00133692.

• Authors: Tobias Gerhard, Joseph Ac Delaney, Rhonda M Cooper-Dehoff, Jonathan Shuster, Babette A Brumback, Julie A Johnson, Carl J Pepine, Almut G Winterstein
• Journal: BMC medical research methodology (BMC Med Res Methodol) Vol. 12 Pg. 119 (Aug 06 2012) ISSN: 1471-2288 [Electronic] England
• PMID: 22866767 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Antihypertensive Agents
• Indoles
• Hydrochlorothiazide
• trandolapril
• Verapamil

Topics

• Aged
• Antihypertensive Agents (therapeutic use)
• Blood Pressure (drug effects)
• Confounding Factors, Epidemiologic
• Coronary Artery Disease (drug therapy)
• Drug Therapy, Combination
• Female
• Follow-Up Studies
• Humans
• Hydrochlorothiazide (therapeutic use)
• Hypertension (drug therapy, prevention & control)
• Indoles (therapeutic use)
• Male
• Middle Aged
• Models, Structural
• Proportional Hazards Models
• Risk Factors
• Treatment Outcome
• Verapamil (therapeutic use)