Clinical Outcome During Warfarin Anticoagulation Monitored With "Fiix-INR" Compared to Standard Monitoring With INR.A Prospective Randomized Double-blinded Trial.

Clinical outcome during warfarin anticoagulation to prevent thromboembolism monitored with "Fiix-INR" compared to standard monitoring with INR.

A prospective randomized double-blinded trial. Study protocol Abbreviated Version Jan 25 2012 Corresponding author: Pall T. Onundarson, M.D., Department of Laboratory Hematology and Hemostasis Center, K-building, Landspitali Hringbraut, 101 Reykjavik, Iceland, Phone: +354 543 1000/5010, Fax +354 543 5539, email: pallt@landspitali.is.

1. STUDY SYNOPSIS Experiments suggest that during treatment with vitamin K antagonists (VKA) the activity of coagulation factors (F) II and X better reflect anticoagulation than does FVII. Based on this a new monitoring prothrombin time base test (Fiix-PT) has been invented which is only sensitive to FII and FX. The Fiix-PT can be converted to INR ("Fiix-INR").We hypothesize that the Fiix-PT may reflect anticoagulation and the antithrombotic effect of VKA as accurately or better than the current PT based tests do (INR based on PT or P&P). The protocol describes a prospective randomized double-blind trial that will be conducted at the Landspitali Anticoagulation Management Center (AMC). The objective of the protocol is to evaluate the efficacy and safety of Fiix-INR as a monitoring test compared to the current PT based assays (INR) used to monitor patients treated with VKA in order to prevent thromboembolism. We will randomize 1200 clients of the AMC into two identically sized monitoring groups, Fiix-INR (test group) and INR (control group). Each individual will be assessed monthly for up to 24 months (an expected average of 18 months) until a total of 600 patients years of observation has been reached in each group. The clinical endpoints to be studied include efficacy (arterial and venous thromboembolic event rate) and safety (bleeding events). Also, surrogate convenience endpoints will be studied such as test frequency and time within target range.
2. INTRODUCTION AND RATIONALE 2.1 Background Vitamin K antagonists (VKA, coumarins) are orally active anticoagulants that prevent normal gamma carboxylation of the vitamin K dependent coagulation factors (FII, FVII, FIX, FX). The consequence is a reduction in the clotability of the blood, ie an anticoagulant effect that can be used therapeutically for the purpose of preventing thromboembolism. In order to assure efficacy and safety, the dose of VKA needs to be adjusted to maintain the normalized prothrombin time ratio (international normalized ratio, INR) within a safe therapeutic range (most often with INR target 2.5, range 2.0-3.0). The clotting times obtained with PT based tests have in practice for over 50 years been presumed to directly reflect the antithrombotic effect of VKA in patients (Loeliger 1984). The PT (or P&P-test) are used all over the world for the purpose of monitoring anticoagulation and to make dose-adjustments in patients taking VKA. Their results have been standardized by calculating the International Normalized Ratio (INR) which takes into account the sensitivity (strength) of the thromboplastin used by different reagents.

However, inherent problems exist with the PT. Due to the VKD factors´ significantly different half-lifes (above), the PT clotting time obtained early after initiation or dose change may mainly reflect the concentration of factor VII since FVII has the notably shortest half-life (about 4-8 hours). If the concentration of factor VII has little influence on the antithrombotic effect of VKA (see below), it is possible that unnecessary and too frequent dose adjustments are made based on the use of the PT. This, could potentially be harmful to the patient.

Prior studies by others have indicated that the thrombin generation(Xi, Beguin et al. 1989; Brummel, Paradis et al. 2001) and antithrombotic influence of factor VII in rabbits (Zivelin, Rao et al. 1993) may be less important than that of prothrombin or factor X. Based on those observations, it is possible that monitoring VKA and their safety could be improved by measuring either coagulation factor II or coagulation factor X. Measuring and monitoring coagulation factor II alone (native prothrombin antigen) has been shown to be very successful and more accurate than PT in clinical studies (Furie, Liebman et al. 1984; Xi, Beguin et al. 1989; Furie, Diuguid et al. 1990; Kornberg, Francis et al. 1993). The native prothrombin antigen assay, however, is not as convenient for laboratories as the PT or P&P. Monitoring coagulation factor X alone has not been tested in patients to our knowledge.