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

Abstract

During warfarin management, prothrombin time (PT) based PT-INR variability is partly due to clinically inconsequential fluctuations of factor (F) VII. The new Fiix-PT and Fiix-normalized ratio (Fiix-NR), unlike PT-INR, is only affected by reduced FII and FX. Starting July 1st 2016 we replaced PT-INR monitoring of warfarin with Fiix-NR in our patients. Using interrupted time series methods, we retrospectively assessed if this affected thromboembolism (TE) and major bleeding (MB) incidence during 12 months prior to and 18 months after the replacement, months 13-18 being predefined as transitional months. The dynamic cohort comprised all our service´s 2,667 maintenance phase warfarin patients managed at any time during the 30 months. Using two-segmented regression, a breakpoint in total TE monthly incidence became evident six months after laboratory monitoring test replacement, followed by 56% reduction in TE incidence (from 2.82% to 1.23% per patient year, P=0.019 by ANOVA). Three-segmented regression found no significant TE incidence trend (slope +0.03) prior to test replacement but during months 13-18 and 19-30 the TE incidence gradually decreased (slope -0.12; R2=0.20;P=0.007). Based on segmented regressions, MB incidence (2.79% ppy) did not differ pre- or post-intervention. Incidence comparison during the 12 month Fiix- and PT-periods confirmed a statistically significant 55-62% reduction 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 major reduction in thromboembolism without increasing bleeding.

Getting smart with coagulation

“…For example, one assay called the PT-FiiX, a new modified PT that is only sensitive to reductions in factor II or factor X, is reported to provide a better alternative to INR for monitoring of VKA therapy. 11,12 However, that assay is not yet widely available.…”

Replacement of traditional prothrombin time monitoring with the new Fiix prothrombin time increases the efficacy of warfarin without increasing bleeding. A review article

“…Although a target range is a different concept from a therapeutic range, calculating the time that the PT-INR stays within specified target ranges (TTR) has turned out to be a useful surrogate measure of likely efficacy and safety during VKA therapy [ 19 , 21 ]. Other informative variability measures include variance growth rate (VGR) [ 34 – 36 ], monitoring testing frequency, and dose change frequency [ 36 , 37 ].…”

“…All were then transitioned to Fiix-NR monitoring beginning on July 1st 2016. The effect of the transition was then retrospectively assessed [ 36 ]. This real-world single-cohort interrupted time series study assessed the incidence of TE and MB in 2667 patients and compared Fiix-NR to Owren’s PT-INR.…”

“…5 Relative risk plots showing major vascular event rates and relative risk plots comparing clinical outcome during Fiix-NR or traditional PT-INR. Reproduced with permission from Blood 2021;137 [ 20 ]:2745–55 [ 36 ]. …”

“…Therefore, a modified initiation algorithm must be used (Table 1 ) that prevents early over-anticoagulation during Fiix-warfarin initiation [ 44 ]. However, during maintenance Fiix-warfarin treatment, the dosing algorithm designed for PT-warfarin patients is appropriate as this did associate with favorable outcomes in our studies [ 35 , 36 ].…”