title: 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.
  
  
  BACKGROUND
  Clinicaltrials.gov Identifier: NCT00133692.
authors.affiliation: Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, NJ, USA. tgerhard@rci.rutgers.edu
authors.forename: Tobias
authors.initials: T
authors.lastname: Gerhard
authors.forename: Joseph Ac
authors.initials: JA
authors.lastname: Delaney
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-Dehoff
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shuster
authors.forename: Babette A
authors.initials: BA
authors.lastname: Brumback
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: Almut G
authors.initials: AG
authors.lastname: Winterstein
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D015986:Confounding Factors, Epidemiologic; D003324:Coronary Artery Disease / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy* / Q000517:prevention & control; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008961:Models, Structural; D016016:Proportional Hazards Models; D012307:Risk Factors; D016896:Treatment Outcome; D014700:Verapamil / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D007211:Indoles; D006852:Hydrochlorothiazide; C052035:trandolapril; D014700:Verapamil