Title: What is/are the best oral anticoagulant/s for primary prevention treatment and secondary prevention of venous thromboembolic disease and for prevention of stroke in atrial fibrillation?
Funder: Department of Health (England)

Abstract: Approximately 950000 people at risk of thrombosis (2% of the GP population) in the UK are prescribed warfarin; increasing by about 10% per year. Warfarin-related bleeding is one of the top 5 reasons for hospitalisation for adverse drug effects in England because of the narrow therapeutic index and numerous drug/dietary interactions. Unlike warfarin new oral anticoagulants dabigatran rivaroxaban apixaban edoxaban otamixaban and betrixaban have rapid action and predictable dosing requirements negating the need for therapeutic drug monitoring. However their annual acquisition cost per patient will remain substantially higher than that of warfarin until patent expiry. These costs may be offset by the reduced need for therapeutic monitoring through anticoagulation services by increased effectiveness or by improved safety.We will conduct systematic reviews network meta-analyses and health economic analyses to (1) identify the most effective safe and cost-effective oral anticoagulant for primary prevention and treatment of venous thromboembolic disease (VTE) (2) identify the most effective safe and cost-effective anticoagulant for stroke prevention in atrial fibrillation (AF) (3) identify optimal anticoagulation strategies for use by Trust Drugs and Therapeutics Committees based on the best drug(s) for each of the main therapeutic indications and (4) estimate the value of conducting further research on the cost-effectiveness of these drugs for example by conducting a head-to-head trial of two or more new anticoagulants. The health technologies being assessed are the oral-anticoagulants warfarin dabigatran rivaroxaban apixaban edoxaban and betrixaban and newer agents from the same drug class. We will conduct detailed searches for published and unpublished literature and for previous economic evaluations. Detailed review protocols will be developed. Primary outcomes for VTE are incident VTE (primary prevention) and recurrent VTE (treatment). The primary outcome for AF is stroke. The primary safety outcomes is major bleeding.For each outcome and research question we will construct a network meta-analysis (NMA): this is a method of synthesising information from a collection of trials by simultaneously combining all the direct (head to head) and indirect evidence. It enables estimation of relative intervention effect estimates for every pairwise contrast and the ranking of treatments according to the probability that each is the best or worst for a given outcome. Separate decision analytic models will be developed to estimate the cost-effectiveness of anticoagulants for each of the three populations: results will be used to make recommendations for optimal use of anticoagulants based on current evidence. Expected value of information analysis will be used to estimate the expected benefit of future research.Total project time is 15 months. We estimated the time and resources required by conducting scoping searches designed by an experienced information specialist. Total time to conduct the reviews will be 9 months. Data extraction for the first review will be complete after 6 months following which statistical analyses will start. The final 6 months will be for health economic analyses completion of analyses and for writing the project report. We will also disseminate research results through peer reviewed journals and through methodological and clinical conferences. We will liaise with commissioners and with drugs and therapeutics committees to help translate the results of this project into practice. Our patient representatives will help to ensure that the results of the study are communicated in an accessible way - in particular via charity websites and publicity materials.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: STROKE;BLOOD;CARDIOVASCULAR