Fiix-prothrombin time versus standard prothrombin time for monitoring of warfarin anticoagulation: a single centre, double-blind, randomised, non-inferiority trial

Background Rapid fluctuations in factor VII during warfarin anticoagulation change the international normalised ratio (INR) but contribute little to the antithrombotic effect. We aimed to assess non-inferiority of anticoagulation stabilisation with a warfarin monitoring method affected only by factors II and X (Fiix-prothrombin time [Fiix-PT]) compared with standard PT-INR monitoring that includes factor VII measurement as well. Methods The Fiix trial was a single centre, double-blind, prospective, non-inferiority, randomised controlled clinical trial. Ambulatory adults on warfarin with an INR target of 2-3 managed by an anticoagulation dosing service using software-assisted dosing at the National University Hospital of Iceland, Reykjavik, Iceland, were eligible for inclusion in this study. We excluded patients undergoing electroconversion and nursing home residents. Patients were randomly assigned (1: 1) to either the Fiix-PT monitoring group or the PT monitoring group by block randomisation. A blinded research INR (R-INR) based on results of the respective test was reported to the dosing staff. Participants were contacted by a study nurse at 4-week intervals to elicit information about thromboembolism or bleeding otherwise unknown to the anticoagulation management centre. The primary efficacy outcome was a composite of objectively diagnosed non-fatal and fatal arterial or venous thromboembolism, including myocardial infarction and transient ischaemic attacks, assessed in all eligible patients who were randomised (intention-to-monitor population). The safety endpoint was major bleeding or other clinically relevant bleeding, assessed in the per-protocol population. We assumed a 3% annual thromboembolism incidence and a non-inferiority margin of 2.5%. This trial is registered with ClinicalTrials.gov, number NCT01565239. Findings Between March 1, 2012, and Feb 28, 2014, we enrolled 1156 patients. 573 patients were assigned to Fiix-PT and 575 to PT-INR monitoring after exclusion of four patients from each group for various reasons. Median follow-up was 1.7 years (IQR 1.1-1.9). During days 1-720, ten (1.2% per patient year) thromboembolic events occurred in the Fiix-PT group versus 19 (2.3% per patient year) in the PT group (relative risk [RR] 0.52, 95% CI 0.25-1.13; p(non-inferiority) < 0.0001). Major bleeding occurred in 17 of 571 patients in the Fiix group (2.2% per patient year) versus 20 of 573 patients in the PT group (2.5% per patient year; RR 0.85, 0.45-1.61; p(non-inferiority) = 0.0034). Anticoagulation stability was improved with Fiix-PT monitoring as manifested by fewer tests, fewer dose adjustments, increased time in range and less INR variability than reported with standard PT monitoring. Interpretation Monitoring of warfarin with Fiix-PT improved anticoagulation and dosing stability and was clinically non-inferior to PT monitoring. Results from this trial suggest that during vitamin K antagonist treatment INR monitoring could be replaced by Fiix-PT and that this would lead to at least a non-inferior clinical outcome compared with monitoring with PT-INR.