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

BMC Med Res Methodol. 2012 Aug 6;12:119. doi: 10.1186/1471-2288-12-119.

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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*
  • Hypertension / prevention & control
  • Indoles / therapeutic use
  • Male
  • Middle Aged
  • Models, Structural
  • Proportional Hazards Models*
  • Risk Factors
  • Treatment Outcome
  • Verapamil / therapeutic use

Substances

  • Antihypertensive Agents
  • Indoles
  • Hydrochlorothiazide
  • trandolapril
  • Verapamil

Associated data

  • ClinicalTrials.gov/NCT00133692