Estimating Oral Anticoagulant Comparative Effectiveness in the Setting of Effect Heterogeneity: Comparing Clinical Trial Transport and Non-experimental Epidemiologic Methods

Abstract

Oral anticoagulation is vital to the health of patients with atrial fibrillation at elevated risk of stroke. The first treatment for these patients, warfarin, was approved in the 1990s. Since 2010, dabigatran has been available for use after demonstrating non-inferiority to warfarin in a randomized controlled trial. Non-experimental studies comparing dabigatran to warfarin and censoring at treatment discontinuation have shown greater benefits than the original trial for all-cause mortality and attenuated harms for gastrointestinal bleeding. The goals of this dissertation, then, were to compute and compare 1) estimates of the absolute-scale effects of dabigatran vs warfarin initiation on ischemic stroke (IS), death, and gastrointestinal bleeding (GIB) in trial-eligible older adults using non-experimental Medicare data and 2) estimates of those effects in the same populations using inverse odds of sampling weights to transport results from the Randomized Evaluation of Long-Term Anticoagulation (RE-LY) trial. First, we conducted a propensity score weighted non-experimental study with the new user active comparator design in a 20% random sample of Medicare beneficiares. We estimated on-treatment two-year risk differences for IS (RD for dabigatran users, RDdabi: -0.67%, 95% CI -1.10%, -0.24%), mortality (RDdabi: -2.98%, 95% CI -3.97%, -1.95%) and GIB (RDdabi: 0.51%, 95% CI -0.30%, 1.31%). Intention-to-treat estimates showed attenuation for mortality (RDdabi: -1.65%, 95% CI -2.32%, -0.98%) and reversal for IS (RDdabi: 0.16%, 95% CI -0.20%, 0.52%). Next, we reweighted RE-LY to resemble the Medicare new users of warfarin or dabigatran (restricted to those with less than 15% predicted probability of frailty). After weighting, we estimated on-treatment two-year risk differences for IS (RDdabi: -0.77%, 95% CI -1.69%, 0.14%), death (RDdabi: -0.57%, 95% CI -1.83%, 0.68%) and GIB (RDdabi: 1.75%, 95% CI 0.76%, 2.74%). These twin studies show non-experimental and weighted trial analyses comparing dabigatran to warfarin agree much better for IS than they do for mortality or GIB. This could be due to confounding in the non-experimental estimates, missing treatment effect modifiers, or outcome misclassification. Researchers should be cautious about comparing studies without considering treatment effect heterogeneity and differences in adherence across study populations.Doctor of Philosoph