Background: Traditional prothrombin time (PT) based international normalized ratio (INR) is often highly variable. Often this is caused by rapid factor VII reductions due to its short (4 hour) ...half-life. Thus, factor VII variation is an important confounder during vitamin K antagonist (VKA) dosing. Furthermore, prior studies have demonstrated that factor VII reductions only minimally influence the antithrombotic effect and bleeding risk of VKA, the clinical effect depending mainly on controlled reduction of factors II and X. Therefore, ignoring the influence of FVII during VKA monitoring has the potential to simplify management and outcome.
The Fiix prothrombin time (Fiix-PT) is a new modified PT that is only affected by reduced factors II and X. The Fiix-PT is not affected by variations in factor VII. Hence, the Fiix normalized ratio (Fiix-NR) fluctuates less than the standard standard PT-INR. In the double-blind randomized clinical Fiix-trial, published in 2015, monitoring of warfarin with with Fiix-PT (Fiix-NR) was compared to standard high time-in-range PT-INR monitoring. Fiix-NR monitoring led to improved time-in-range, reduced testing frequency, reduced dose-adjustment need and a 50% reduction in thromboembolism (TE). Bleeding did not increase and it occurred at a low rate in both trial arms. Subsequently starting on July 1st 2015 we replaced the PT-INR with Fiix-NR in our anticoagulation monitoring practice.
Aim: We compared anticoagulation outcome and dosing frequency during 12 months prior to switching from PT-INR based management (Pre-Fiix monitoring period) and during 12 months following switch to Fiix-NR monitoring (Fiix monitoring period).
Methods: This is a retrospective before and after study involving unselected patients managed at a single anticoagulation management service at the Landspitali University Hospital in Reykjavik, Iceland. All patients on warfarin during two consecutive twelve month periods were analysed irrespective of indication or anticoagulation target range. Pre-Fiix patients analysis was based on events occuring during months -12 to -1 before replacing the PT with Fiix PT and the Fiix patients´outcome was analysed during months +4 to +15. Three transitional months were excluded. All patients were dosed by specialized staff using the DAWN anticoagulation software®. Hospital chart diagnostic codes were reviewed for occurrence of TE or major bleeding (MB) during the two separate monitoring periods.Surrogate assessments included the number of tests, testing intervals and dose adjustment frequencies and will be analyzed later.
Results: During the Pre-Fiix period 2,345 patients were managed with PT-INR for 1,984 patient years (0.85 years/patient) and during the Fiix period 1,909 patients were managed with Fiix-NR for 1,643 patient years (0.86 y/pt). Indications for warfarin were identical during both periods (atrial fibrillation 57%, venous thromboembolism 26%, prosthetic heart valves 5% and other 12%). The INR target range during both periods was 2.0-3.0 in 92% and 2.5-3.5 in 6%. Clinical outcome with respect to TE and MB is shown in the figure. Overall the point estimates were suggestive of a 34-52% reduction of TE with Fiix-NR monitoring whereas major bleeding was similar. The reduction in untoward events in the Fiix group was statistically significant for composite new TE (OR 0.63;0.41-0.97) and total stroke (ischemic and hemorrhagic, OR 0.57;CI 0.33-0.98), mainly driven by reduced cerebral infarction. Intracranial bleeding occurred in 0.76% in the Pre-Fiix group and in 0.37% in the Fiix montoring group (n.s., OR 0.51;0.19-1.32). The median time-within-Target-range (TTR, Rosendaal method) was similar in both groups (75 vs 76%, respectively), despite dose adjustment frequency being reduced by 18% in the Fiix monitoring group (OR 0.82;CI 0.79-0.85, p <0.0001).
Conclusions: These results are in agreement with the results of the Fiix-trial and show that ignoring factor VII during VKA monitoring is safe and leads to reduction in thromboembolism without increasing bleeding. Although TTR was identical in both groups, the dose adjustment need was reduced possibly indicating that less anticoagulation variability in the Fiix-NR group explains reduced thromboembolism.
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Gudmundsdottir:Hart Biologicals Ltd: Consultancy, Patents & Royalties: Hart Biologicals Ltd is commercializing the Fiix-PT which will be ready for marketing in Europe in the beginning of year 2019 and possibly later that year in the USA. Patent fees will be paid to Fiix Diagnostics Ltd once the test is commercialized.; Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: The Fiix prothrombin time (Fiix-PT) is a patented invention of P. T. Onundarson and B.R. Gudmundsdottir that is owned by Fiix Diagnostics Ltd, a start-up company founded by the inventors. . Onundarson:Hart Biologicals Ltd: Consultancy, Other: Hart Biologicals Ltd is commercializing the Fiix-PT which will be ready for marketing in Europe in the beginning of year 2019 and possibly later that year in the USA. Patent fees will be paid to Fiix Diagnostics Ltd once the test is commercialized.; Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: The Fiix prothrombin time (Fiix-PT) is a patented invention of P. T. Onundarson and B.R. Gudmundsdottir that is owned by Fiix Diagnostics Ltd, a start-up company founded by the inventors. .
Background: During warfarin treatment rapid fluctuations occur in the traditional prothrombin time (PT) as a result of the short half-life of factor (F) VII which has little effect on the ...antithrombotic activity of warfarin, contrary to FII and FX. Such confounding INR fluctuations influence dosing and, hence also the variability of FII and FX. The new Fiix-PT measures only the activity of the longer half-life FII and FX leading to less variability of anticoagulation as shown in the Fiix-trial.
Objectives: To assess if stability of warfarin anticoagulation monitored by PT and Fiix-PT was affected differently by gender.
Methods: This study is a subgroup analysis of the prospective, randomized, double-blind Fiix-trial. A subgroup of 815 atrial fibrillation patients on long-term warfarin monitored with Fiix-PT (Fiix-warfarin patients) or PT (PT-warfarin patients) were assessed in an intention-to-monitor manner by comparing surrogate anticoagulation indicators such as dose and dose frequency, time in therapeutic range (TTR, Rosendaal method) and variance growth rate of the INR (VGR; an indicator of INR fluctuation size).
Results: Baseline parameters between the 396 Fiix-warfarin and 419 PT-warfarin patients did not differ. The median observation time was 1.4 years. Fiix-warfarin patients had more tests within therapeutic range (66% vs 63%, p=0.0019) and fewer tests below range (19% vs 21%, p=0.0061) than PT-warfarin patients. The test-in-range improvement observed with Fiix-warfarin over that with PT-warfarin was mainly explained by an improvement observed in women, i.e. the fraction of monitoring tests within range was higher (64% vs 59%, p=0.0001) and the fraction below range was lower (20% vs 24%, p=0.0002) in women on Fiix-warfarin. Likewise, with Fiix-warfarin TTR was higher (81% compared with 79%) and this was mainly explained by higher TTR in women on Fiix-warfarin (80%) than in women on PT-warfarin (75%; p=0.0401). Little difference was observed in TTR in men. The INR varied less with Fiix-warfarin than with PT-warfarin (VGRB1 0.20 vs 0.24, p=0.0810). There was significantly more variation in VGR in women than in men. Thus, Fiix-warfarin men vs women had a VGRB1 of 0.18 vs 0.25, p=0.0372, and PT-warfarin men vs women had VGRB1 0.21 vs 0.30, p=0.0056. A trend for fewer annual dose changes with Fiix-warfarin than with PT-warfarin was observed (5.6 vs 6.2 annually, p=0.0822) and this was mainly explained by 20% fewer annual dose changes with Fiix-warfarin than with PT-warfarin in women (6.0 vs 7.4, p=0.0342). Also, there were fewer dose changes per monitoring test in Fiix warfarin women (0.27 vs 0.32, p=0.0292). Finally, women treated with Fiix-warfarin used a lower median daily warfarin dose than women treated with PT-warfarin (3.4 vs 4.2 mg, p=0.0029).
Conclusions: Monitoring warfarin with the Fiix-PT improved the stability of warfarin anticoagulation and reduced the daily dose significantly in women. A non-significant but consistent smaller effect in the same direction was seen in men.
Gudmundsdottir:Fiix Diagnostics Ltd.: Equity Ownership, Patents & Royalties: Patent pending for Fiix prothrombin time. Onundarson:Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: Patent pending status for Fiix prothrombin time.
Introduction: Anticoagulation with vitamin K antagonists (VKA) requires monitoring of their effect, traditionally with the prothrombin time (PT) that is affected by VKA influence on coagulation ...factors (F) II, VII and X. Rapid fluctuations in factor VII, which has a short half-life, contribute to the PT (INR) variation but not to the antithrombotic effect that depends mainly on reductions of FII and FX. This was lately confirmed by the Fiix-trial that showed that monitoring warfarin with Fiix-PT (affected only by FII and FX) improved anticoagulation stability. Here, we assessed anticoagulation variability in relation to the occurrence of thromboembolism and bleeding in patients monitored with Fiix-PT or PT.
Methods and materials: This is a subgroup analysis of the Fiix-trial, a single-center, double blind, prospective, randomized controlled clinical trial, comparing outcomes in patients in whom warfarin was monitored with either Fiix-PT/Fiix-INR (Fiix-warfarin patients) or PT/INR (PT-warfarin patients). Patients on warfarin, 18 years and older, with target INR range of 2.0 - 3.0, were randomized and assessed for occurrence of clinically relevant vascular events (CRVE), i.e. thromboembolism (TE), major bleedings (MB) and other non-major clinically relevant bleedings. Using an intention-to-monitor method, we assessed test parameters, dosing, time in range (TTR) and the variance growth rate (VGR) of the INR (an INR fluctuation index) in relation to occurrence of CRVE.
Results: The median observation time was 1.4 years in 572 patients managed with Fiix-warfarin and 571 with PT-warfarin. CRVE occurred in 115 Fiix-warfarin patients and 132 PT-warfarin patients (PNI=0.0066). MB and TE occurred in 19 vs. 21 (PNI=0.0142) and 10 vs. 19 (PNI=0.0002) patients, respectively. There were 11,026 monitoring tests in the Fiix-arm and 11,499 in the PT-arm. Patients suffering CRVE had significantly more frequent monitoring tests and shorter intervals between tests than those without. Patients with CRVE also had significantly greater dose changes (p<0.0001 in both arms). The median TTR was lower with PT-warfarin than with Fiix-warfarin and patients with CRVE had lower TTR than those without in both study arms (Fiix-warfarin 79% vs. 82%, p=0.0441 vs. PT-warfarin 75% vs. 80%, p=0.0004). The lowest median TTR was observed in PT-warfarin patients suffering from MB (73%) or TE (62%). There was consistently more INR-fluctuation (higher VGR, here shown by B1 method measuring INR jumps from one test to the next) with PT-warfarin than with Fiix-warfarin. Also, patients with CRVE had VGR of 0.35 vs. 0.21 (p=0.0643) and without CRVE 0.21 vs. 0.17 (p=0.0146), respectively. The fluctuation was particularly high in both PT-warfarin and Fiix-warfarin patients suffering from MB (0.59 and 0.31, n.s.). PT-warfarin patients with TE had VGR 0.50 vs. 0.20 with Fiix-warfarin (p=0.0051). Finally, the median INR observed at the time of major events corresponded to the risk of bleeding and TE in the Fiix arm, and with risk of TE in the PT arm.
Conclusions: Fiix-warfarin is a more stable anticoagulant than PT-warfarin. The significantly lower INR variation in Fiix-warfarin patients with TE is in agreement with the reduced long-term thromboembolism observed in the Fiix-trial. Monitoring warfarin with the Fiix-PT (Fiix-INR) instead of the PT (INR) and paying particular attention to patients demonstrating anticoagulation instability could improve the clinical outcome of patients on warfarin further.
Gudmundsdottir:Fiix Diagnostics Ltd.: Equity Ownership, Patents & Royalties: Patent pending for Fiix prothrombin time. Onundarson:Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: Patent pending status for Fiix prothrombin time.
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 B
1
; 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 B
1
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.
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