Pharmacogenetics, Biomarkers, and Antithrombotic Therapy

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DESCRIPTION (provided by applicant): The overall objective is to improve the safety and the effectiveness of anticoagulant therapy. The proposed project will be an ancillary study of 2 trials, the NHLBI-funded PREVENT trial and the VA-funded THINRS trialx PREVENT (Prevention of Recurrent Venous Thromboembolism) is a randomized comparison of low-intensity warfarin vs. placebo in subjects with a history of spontaneous venous thromboembolism who previously completed a standard course of warfarin therapy. The investigators have archived DNA from 508 PREVENT participants. THINRS (The Home INR Study) is a randomized comparison of warfarin management by an anticoagulation clinic versus patient self-testing of their International Normalized Ratio (INR). THINRS will enroll about 3200 participants with atrial fibrillation or a prosthetic heart valve from 32 VA Medical Centers and prospectively will obtain DNA and plasma. Despite improvements in dosing and monitoring over the past 50 years, warfarin therapy is still accompanied by a high rate of bleeding, especially during the first weeks to months of therapy. A major reason why the INR often is supratherapeutic during induction is that the therapeutic warfarin dose is widely variable and cannot be predicted based on clinical factors alone. In Aim 1, the investigators will use pharmacogenetics to predict the maintenance warfarin dose. They also will examine the relationship between polymorphisms that affect warfarin dose, hemorrhage, and INR values. In Aim 2 they will validate additional genetic and non-genetic biomarkers that identify patients at high risk of suffering ischemic or hemorrhagic adverse events. By using a nested, case-control design for Aim 2, they will correlate biomarkers with incident adverse events in patients taking warfarin. In Aim 3, they will determine whether self-testing will be especially beneficial in patients who have biomarkers presaging an adverse event. They anticipate that the weekly INR testing facilitated by self-testing will ameliorate the vulnerability to adverse events conferred by the laboratory markers in Aims 1 and 2. By elucidating the determinants of warfarin toxicity and effectiveness, the proposed study will help clinicians tailor the aggressiveness of antithrombotic therapy to patient's underlying risk of adverse events.