Ignoring instead of chasing after coagulation factor VII during warfarin management: an interrupted time series study.

During warfarin management, variability in prothrombin time-based international normalized ratio (PT-INR) is caused, in part, by clinically inconsequential fluctuations in factor VII (FVII). The new factor II and X (Fiix)-prothrombin time (Fiix-PT) and Fiix-normalized ratio (Fiix-NR), unlike PT-INR, are only affected by reduced FII and FX. We assessed the incidence of thromboembolism (TE) and major bleeding (MB) in all 2667 patients on maintenance-phase warfarin managed at our anticoagulation management service during 30 months; 12 months prior to and 18 months after replacing PT-INR monitoring with Fiix-NR monitoring. Months 13 to 18 were predefined as transitional months. Using 2-segmented regression, a breakpoint in the monthly incidence of TE became evident 6 months after test replacement, that was followed by a 56% reduction in incidence (from 2.82% to 1.23% per patient-year; P = .019). Three-segmented regression did not find any significant trend in TE incidence (slope, +0.03) prior to test replacement; however, during months 13 to 18 and 19 to 30, the incidence of TE decreased gradually (slope, -0.12; R2 = 0.20; P = .007). The incidence of MB (2.79% per patient-year) did not differ. Incidence comparison during the 12-month Fiix and PT periods confirmed a statistically significant reduction (55-62%) in TE. Fiix monitoring reduced testing, dose adjustments, and normalized ratio variability and prolonged testing intervals and time in range. We conclude that ignoring FVII during Fiix-NR monitoring in real-world practice stabilizes the anticoagulant effect of warfarin and associates with a major reduction in TEs without increasing bleeding.

Reduced anticoagulation variability in patients on warfarin monitored with Fiix-prothrombin time associates with reduced thromboembolism: The Fiix-trial.

Fiix-prothrombin time (Fiix-PT) differs from traditional PT in being affected by reduced factor (F) II or FX only. In the randomized controlled Fiix-trial, patients on warfarin monitored with Fiix-PT (Fiix-warfarin patients) had fewer thromboembolisms (TE), similar major bleeding (MB) and more stable anticoagulation than patients monitored with PT (PT-warfarin patients). In the current Fiix-trial report we analyzed how reduced anticoagulation variability during Fiix-PT monitoring was reflected in patients with TE or bleeding. Data from 1143 randomized patients was used. We analyzed the groups for anticoagulation intensity (time within target range; TTR), international normalized ratio (INR) variability (variance growth rate B1; VGR) and dose adjustment frequency. We assessed how these parameters associated with clinically relevant vascular events (CRVE), ie TE or MB or clinically relevant non-MB. TTR was highest in Fiix-warfarin patients without CRVE (median 82%;IQR 72-91) and lowest in PT-warfarin patients with TE (62%;56-81). VGR was lowest in Fiix-warfarin patients without CRVE (median VGR B1 0.17; 95% CI 0.08-0.38) and with TE (0.20;0.07-0.26) and highest in PT-warfarin patients with TE (0.50;0.27-0.90) or MB (0.59;0.07-1.36). The mean annual dose adjustment frequency was lowest in Fiix-warfarin patients with TE (mean 5.4;95% CI 3.9-7.3) and without CRVE (mean 6.0; 5.8-6.2) and highest in PT-warfarin patients with TE (14.2;12.2-16.3). Frequent dose changes predicted MB in both study arms. Compared to patients monitored with PT, high anticoagulation stability in Fiix-warfarin patients coincided with their low TE rate. Those with bleeding had high variability irrespective of monitoring method. Thus, although further improvements are needed to reduce bleeding, stabilization of anticoagulation by Fiix-PT monitoring associates with reduced TE.

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; pnon-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; pnon-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. FUNDING: Innovation Center Iceland, University of Iceland Science Fund, Landspitali Science Fund and Actavis.