Lead Investigator: Issa Dahabreh, Harvard T.H. Chan School of Public Health
Title of Proposal Research: Development of statistical methods for comparison of the efficacy of anticoagulants in non-valvular atrial fibrillation
Vivli Data Request: 10138
Funding Source: PCORI (Patient-Centered Outcomes Research Institute) Project 8221240-01 Randomized Trials and Their Observational Emulations – Benchmarking and Joint Analysis (PI: Dr. Issa J. Dahabreh)
Potential Conflicts of Interest: None
Summary of the Proposed Research:
While clinical trials are considered the “gold standard” for evaluating the effect of treatments, they are not always possible to conduct, for instance due to logistical constraints, time, and cost. In the absence of head-to-head treatment comparisons, clinicians and public health researchers must find new ways to make use of available data to inform decision-making. In this research request, we propose the development and implementation of a suite of novel statistical methods combining trial data to facilitate head-to-head comparisons of treatments studied in separate clinical trials.
Atrial fibrillation (AF) is the medical term for an irregular heart rhythm. Non-valvular atrial fibrillation (NVAF) is a very common form of AF that is not associated with conditions that affect the valves in the heart. One particular complication of NVAF is the formation of blood clots, particularly in chambers of the heart (such as the left atrium) where blood flow is altered due to irregular heart rhythms. Once formed, such blood clots can dislodge and enter other parts of the body, including the brain (causing stroke), in internal organs and in limbs (the latter two complications are referred to as examples of “systemic embolism”). When blood clots dislodge and enter other parts of the body, it can cause death or severe disability.
One way to prevent blood clot formation is to apply preventive medications that thin the blood, including agents that block the formation or activation of “clotting factors” produced in the liver (proteins in the blood that are responsible for blood to clot). For many years, vitamin K antagonists such as warfarin have been the mainstay of clot prevention; such medications block the formation of clotting factors that need vitamin K. More recently, newer anticoagulants such as edoxaban and dabigatran have come onto the market and are now widely prescribed. These novel anticoagulants block other clotting factors involved in blood clot formation. Edoxaban and dabigatran have been individually compared to warfarin in large, randomized trials, but head-to-head comparisons of efficacy and safety between the novel anticoagulants remain lacking.
We are interested in combining two trials: the ENGAGE-AF-TIMI 48 trial, which randomized study participants to edoxaban or warfarin; and the RE-LY trial, which randomized study participants to dabigatran or warfarin. Specifically, we are interested in estimating the effect of initiating edoxaban and dabigatran on the risk of stroke and systemic embolism, as well as short to medium-term risk of major bleeding events. We are not aware of any trials that have been conducted or have been proposed to answer these questions.
Requested Studies:
A Phase 3, Randomized, Double-Blind, Double-Dummy, Parallel Group, Multi-Center, Multi-National Study for Evaluation of Efficacy and Safety of Edoxaban (DU-176b) Versus Warfarin In Subjects With Atrial Fibrillation – Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation (ENGAGE – AF TIMI – 48)
Data Contributor: Daiichi Sankyo, Inc.
Study ID: NCT00781391
Sponsor ID: DU176b-C-U301
Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) Comparing the Efficacy and Safety of Two Blinded Doses of Dabigatran Etexilate With Open Label Warfarin for the Prevention of Stroke and Systemic Embolism in Patients With Non-valvular Atrial Fibrillation: Prospective, Multi-centre, Parallel-group, Non-inferiority Trial (RE-LY Study)
Data Contributor: Boehringer Ingelheim
Study ID: NCT00262600
Sponsor ID: 1160.26