Relationship between time spent at extreme International Normalized Ratios and time in therapeutic range with bleeding and thrombosis in warfarin-treated patients.

PURPOSE: The relationship between the time spent at extreme International Normalized Ratios (INRs) and the time in the therapeutic range (TTR) with bleeding and thrombosis in warfarin-treated patients was examined. METHODS: Consecutive patients treated with warfarin for atrial fibrillation or for venous thrombosis who were managed by the anticoagulation management service or adult internal medicine clinic of a large, tertiary care, integrated health system between June 1, 2011, and October 9, 2012, were eligible for study inclusion. Data collected for the outcomes analysis included INRs and dates; current use of aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, or nonsteroidal antiinflammatory drugs; and any clinically significant bleeding or thrombosis events identified. RESULTS: In the 837 patients who met the inclusion criteria, 636.5 patient-years of therapy were provided, of which 14.4 patient-years (2.26% of time) were spent at INRs of <1.5; 2.9 patient-years of therapy (0.45% of time) were spent at INRs of >4.5. The patient population had a mean individual TTR of 65%. The percentage of time at an INR of >4.5 was positively associated with an increased risk of major bleeding (p = 0.0085). The percentage of time spent with an INR of <1.5 was not associated with a significant increase in the risk of thrombosis. CONCLUSION: The percentage of time spent with an INR of >4.5 was associated with an increased risk of major bleeding in patients receiving warfarin for atrial fibrillation or for venous thrombosis at two outpatient clinics. The relationships between thrombosis risk and the TTR or the time spent at an INR of <1.5 were not significant, but the thromboembolic event rate was unusually low, as was the time spent at an INR of <1.5.

Evaluation of warfarin management with international normalized ratio self-testing and online remote monitoring and management plus low-dose vitamin k with genomic considerations: a pilot study.

STUDY OBJECTIVES: As better international normalized ratio (INR) control and self-testing reduce events in warfarin-treated patients, and vitamin K supplementation may improve INR control, our primary objective was to evaluate the effect of a system combining frequent INR self-testing with online remote monitoring and management (STORM2) and low-dose vitamin K supplementation on INR control; our secondary objectives were to assess the impact of STORM2 on clinician time and to evaluate the influence of pharmacogenomics on INR stability and warfarin dose after vitamin K supplementation. DESIGN: Prospective pre- and postintervention study. SETTING: Freestanding clinical research center. PATIENTS: Fifty-five patients treated with long-term warfarin therapy who were referred from four anticoagulation clinics and seven medical practices. INTERVENTION: All patients performed weekly INR self-testing and received vitamin K 100 µg/day and online anticoagulation management for 1 year. MEASUREMENTS AND MAIN RESULTS: INR control and time required for anticoagulation management were assessed, and an analysis of warfarin dosing and INR stability by genetic polymorphism subgroup (vitamin K epoxide reductase complex 1 [VKORC1] and cytochrome P450 2C9 isoenzyme) was performed; vitamin K product content was also analyzed. The percentage of time that the INR is within the time in therapeutic range (TTR) improved from 56% before the intervention to 81% after the intervention (p<0.0001), and time spent at extreme INR values of lower than 1.5 or higher than 5 was reduced from 3.1% to 0.4% (p=0.01). Clinician time was less than 10 minutes per four patient visits per month. Genetic polymorphisms did not correlate with INR stability or the increase in warfarin dose after vitamin K supplementation. The content of the vitamin K product, however, was only 34-76% of the labeled amount. Patients with the GG VKORC1 genotype required a higher warfarin dose than predicted by the genomic-based dosing chart in the warfarin package insert. CONCLUSION: The 25% point improvement in TTR with STORM2 is a greater improvement than reported previously with other efforts to improve TTR. STORM2 required a minimum amount of clinician time. Pharmacogenomics were not predictive of improved INR control or the magnitude of the warfarin dose after vitamin K supplementation, although the content of the product was unreliable. Patients with the GG VKORC1 genotype required a higher warfarin dose than predicted by the product information. The potential clinical impact of improved INR control with this method warrants comparisons with conventionally managed warfarin and with the new oral anticoagulants.

Low-dose vitamin K to augment anticoagulation control.

STUDY OBJECTIVES: To determine the effect of daily low-dose oral vitamin K supplementation on reducing variations in the international normalized ratios (INRs) in patients taking warfarin. DESIGN: Retrospective analysis. SETTING: Anticoagulation clinic in a large, private-practice hematology group. PATIENTS: Eight motivated patients (three men, five women), aged 45-79 years, receiving anticoagulant therapy with warfarin, whose INRs had been fluctuating for reasons not associated with identifiable changes in diet, warfarin dosage, activity level, illness, or changes in drug therapy. INTERVENTION: Daily supplementation with oral vitamin K, starting with 100 microg/day MEASUREMENTS AND MAIN RESULTS: Anticoagulation providers monitored INR responses; all documented INR values were included in the analysis, even those intentionally allowed outside the therapeutic range when dosages were adjusted for procedures. After dietary vitamin K supplementation, INR fluctuations diminished in nearly all patients. Overall, a significant decrease was noted in the INR standard deviation (p<0.05), and more INRs were in the therapeutic range after the start of supplementation. Allowing for small fluctuations on either side of the target range, the number of INRs within 0.2 units of the target range increased from 32% to 57% (relative increase 76%). Time in range also increased by a similar degree. CONCLUSION: Supplementation with daily low-dose oral vitamin K significantly increased the number of INRs in range as well as the time in range, and decreased INR fluctuation in this small series of selected patients.