title: Reduced anticoagulation variability in patients on warfarin monitored with Fiix-prothrombin time associates with reduced thromboembolism: The Fiix-trial.
abstract: 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 B10.17; 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.
authors.affiliation: Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.
authors.forename: Alma Rut
authors.initials: AR
authors.lastname: Oskarsdóttir
authors.affiliation: Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.
authors.forename: Brynja R
authors.initials: BR
authors.lastname: Gudmundsdottir
authors.affiliation: Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.
authors.forename: Olafur S
authors.initials: OS
authors.lastname: Indridason
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Sigrun H
authors.initials: SH
authors.lastname: Lund
authors.affiliation: Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.
authors.forename: David O
authors.initials: DO
authors.lastname: Arnar
authors.affiliation: Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Einar S
authors.initials: ES
authors.lastname: Bjornsson
authors.affiliation: Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Magnus K
authors.initials: MK
authors.lastname: Magnusson
authors.affiliation: Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.
authors.forename: Hulda M
authors.initials: HM
authors.lastname: Jensdottir
authors.affiliation: Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.
authors.forename: Brynjar
authors.initials: B
authors.lastname: Vidarsson
authors.affiliation: University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Francis
authors.affiliation: Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland. pallt@landspitali.is.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland. pallt@landspitali.is.
authors.forename: Pall T
authors.identifier: http://orcid.org/0000-0002-5342-9148
authors.initials: PT
authors.lastname: Onundarson
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage*; D016903:Drug Monitoring / Q000379:methods*; D005170:Factor X / Q000494:pharmacology; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D011516:Prothrombin / Q000494:pharmacology; D011517:Prothrombin Time; D013923:Thromboembolism / Q000188:drug therapy* / Q000517:prevention & control; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D011516:Prothrombin; D005170:Factor X
keywords: Fiix; INR; Monitoring; Oral anticoagulants; Prothrombin time; Warfarin