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
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; 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
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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.
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.
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.
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.
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.
Innovation Center Iceland, University of Iceland Science Fund, Landspitali Science Fund and Actavis.
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.
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Introduction: Experiments suggest that the anticoagulation effect of warfarin is mainly influenced by a reduction in coagulation factor (F) II and X activity and that FVII may have relatively ...little effect. Due to the short half-life of FVII but its strong influence on the prothrombin time (PT), monitoring warfarin using PT may therefore confound warfarin dosing. The Fiix-prothrombin time is specially designed to circumvent measuring FVII activity and is only sensitive to the activity of FII and FX in the sample. The Fiix-trial was a single center randomized prospective and blinded non-inferiority clinical trial that examined monitoring warfarin with the Fiix-PT compared to the PT.
Methods: All community dwelling patients 18 years and older with an INR target of 2-3 managed by our center´s anticoagulation management service were eligible for participation. A PT ratio adapted for thromboplastin sensitivity (INR) was calculated for both tests and results were reported by the laboratory as R-INR (“research INR”) to the dosing staff that was blinded to each patient´s test method. Warfarin dosing was software assisted using the DAWN anticoagulation software. Protocols designed for monitoring with PT were used, including a recommended maximum six week interval between tests. The major efficacy endpoint was fatal and non-fatal thromboembolism (TE) rate and the major safety endpoint was major bleeding per patient year (ppy). Surrogate efficacy parameters included number of tests, tests in range, time within target range 2-3 (TTR), monitoring test interval and dose adjustment rate.
Results: After exclusion of 4 patients in each group, 573 patients were evaluable in the Fiix-PT arm and 575 in the control arm. About 69% had atrial fibrillation (AF) and 21% had venous thromboembolism (TE). The median monitoring time was 1.7 (IQR 1.1-1.9) years per patient in both study arms. The TE rate was similar in the first six months but thereafter the event curves diverged (Figure 1) and therefore we specially examined events occuring after six months in a secondary analysis. In the primary analysis of events during days 1-720, the TE rate ppy was 1.2% in the Fiix-arm vs 2.3% in controls (-48%, p = 0.09) demonstrating at least non-inferiority of Fiix-PT monitoring compared to the PT in reducing TE. The major bleeding rate did not differ; 2.2% and 2.5%, respectively (p = n.s., non-inferior). In the secondary analysis, after excluding the first six observation months, the Fiix-PT lead to a superior long-term reduction in TE (1.1% vs 2.2% annual rate, -50%, p = 0.03) with major bleeding rate of 1.5% vs 2.3% respectively (p = 0.8). A subanalysis of patients with AF yielded similar results. The intracranial hemorrhage (ICH)/intracerebral hemorrhage rate was 0.26%/0.13% ppy in the Fiix-arm and 0.64%/0.38% ppy in the PT-arm. In the first six months the test volume was the same in both arms but therafter a 5.8% reduction occurred in the Fiix-arm. The dose adjustment rate was reduced 12% overall and 18% during long term monitoring (4.1 vs 5.0 ppy, p = 0.01). At six month intervals, the median percent TTR was 84.9 (79.9-86.7) in the Fiix-arm vs 80.3 (78.5-81.3%) in the PT-arm.
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Conclusion: Monitoring warfarin with Fiix-PT is non-inferior and possibly superior to the PT in reducing long-term recurrent TE. Bleeding is not increased despite omitting FVII activity in the monitoring test. With the Fiix-PT, the warfarin effect fluctuates less than with standard PT as manifested by a higher TTR and reduced dose-adjustment need. Overall, the results suggest that the fluctuation typically observed during warfarin treatment is partly caused by the traditional prothrombin time itself.
Onundarson:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties. Gudmundsdottir:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties.
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