title: Comparing Inverse Probability of Treatment Weighting and Instrumental Variable Methods for the Evaluation of Adenosine Diphosphate Receptor Inhibitors After Percutaneous Coronary Intervention.
abstract: There is increasing interest in performing comparative effectiveness analyses in large observational databases, yet these analyses must adjust for treatment selection issues.
  
  
  
  To conduct comparative safety and efficacy analyses of prasugrel vs clopidogrel bisulfate after percutaneous coronary intervention and to evaluate inverse probability of treatment weighting (a propensity score method) and instrumental variable methods.
  
  
  
  This study used data from the Treatment With Adenosine Diphosphate Receptor Inhibitors-Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study. Included in the study were patients undergoing percutaneous coronary intervention for myocardial infarction, 26.0% of whom received prasugrel. The study dates were April 4, 2010, to October 31, 2012.
  
  
  
  Choice of initial antiplatelet agent (prasugrel or clopidogrel).
  
  
  
  Safety and efficacy outcomes included 1-year composite major adverse cardiovascular events, moderate to severe bleeding, and stent thrombosis. Hospitalizations for pneumonia, bone fractures, and planned percutaneous coronary intervention were used as the falsification end points.
  
  
  
  The study cohort comprised 11 784 participants (mean [SD] age, 60.0 [11.6] years, and 28.0% were female). Using inverse probability of treatment weighting adjustment, prasugrel and clopidogrel had similar major adverse cardiovascular events (hazard ratio [HR], 0.98; 95% CI, 0.83-1.16) and bleeding outcomes (1.18; 0.77-1.80), but prasugrel had a lower rate of stent thrombosis (0.51; 0.31-0.85). Using instrumental variable methods, prasugrel use was associated with a lower rate of the major adverse cardiovascular event end point (HR, 0.68; 95% CI, 0.47-1.00) but nonsignificant differences in the rates of bleeding (0.95; 0.41-2.08) and stent thrombosis (0.67; 0.16-2.00). There was no significant treatment difference noted in any of the falsification end-point rates when analyses were performed using inverse probability of treatment weighting, although the bone fracture end point approached statistical significance. Nevertheless, a lower rate of pneumonia-related hospitalizations was noted in the prasugrel-treated patients when analyses were performed using instrumental variable methods.
  
  
  
  Conclusions regarding the safety and efficacy of antiplatelet therapy varied depending on analytic technique, and none were concordant with the results from randomized trials. In addition, both statistical strategies demonstrated concerning associations when tested in the falsification analyses. A high level of scrutiny and careful attention to assumptions and validity are required when interpreting complex analyses of observational data.
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina2Department of Gynecology and Obstetrics, The Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Jerome J
authors.initials: JJ
authors.lastname: Federspiel
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina3Department of Biostatistics, Duke University, Durham, North Carolina.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Anstrom
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xian
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: McCoy
authors.affiliation: Lilly USA, LLC, Indianapolis, Indiana.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Effron
authors.affiliation: Lilly USA, LLC, Indianapolis, Indiana.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Faries
authors.affiliation: Lilly USA, LLC, Indianapolis, Indiana.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Zettler
authors.affiliation: Harvard Clinical Research Institute, Boston, Massachusetts6Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Laura
authors.initials: L
authors.lastname: Mauri
authors.affiliation: Harvard Clinical Research Institute, Boston, Massachusetts7Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Yeh
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina8Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Peterson
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina8Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Tracy Y
authors.initials: TY
authors.lastname: Wang
mesh_terms: D000244:Adenosine Diphosphate; D000368:Aged; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects*; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine