Gender Differences during Long-Term Warfarin Anticoagulation in Patients with Atrial Fibrillation Monitored with Fiix-Prothrombin Time or Prothrombin Time. the Fiix Trial

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 (VGR_B1 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 VGR_B1 of 0.18 vs 0.25, p=0.0372, and PT-warfarin men vs women had VGR_B1 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.