Confirmation of the Safety and Efficacy of the Kovacs 10 mg Warfarin Initiation Nomogram for Venous Thromboembolism and Derivation of a Rule To Predict the Weekly Maintenance Dose.
Authors: Monkman Katherine J. , Lazo-Langner Alejandro , Kovacs Michael J. 
Published: April 2020

Background: Initiation of oral anticoagulant therapy for acute venous thromboembolism requires balancing the need for rapid anticoagulation with the risk of major bleeding. The optimal means of initiating warfarin therapy in the outpatient setting remains controversial. We have previously demonstrated the efficacy of a 10 mg initiation nomogram in comparison to a 5 mg nomogram in a published RCT (Kovacs et al. 2003). Although this nomogram is used in many centres, some are still reluctant to use it due to a fear of potential increased bleeding.

Objective: To validate the safety and efficacy of the Kovacs 10 mg warfarin initiation nomogram and to identify patient-specific factors predictive of a maintenance warfarin dose.

Methods: We performed a retrospective chart review of 430 consecutive patients who were treated prospectively according to the Kovacs nomogram in the outpatient thromboembolism clinic of a tertiary care hospital. Data were analyzed for 90 days following the initiation of anticoagulation. All patients were treated with standard subcutaneous LMWH for 5 to 7 days and warfarin for a minimum of 3 months. Major bleeding and recurrent venous thromboembolism were defined according to standard criteria.

Results: 408 of 430 patients were followed for at least 90 days. Six patients (1.5%) experienced recurrent thrombosis, 3 (1%) suffered a major bleeding event, and 3 (1%) suffered a minor bleeding event requiring treatment with vitamin K. There were no deaths related to thrombosis or bleeding. Three patients died from unrelated causes. Ninety percent of the 297 patients who adhered to the nomogram achieved a therapeutic INR by day 5. Only 8 (2.7%) of patients who adhered to the nomogram had an INR measurement of ≥ 5.0 in the first 8 days of therapy. None of these suffered a major or minor bleed. The most common reason for non-adherence to the nomogram was failure to get an INR test on the days specified, due to the unavailability of testing on weekends and holidays or to patient non-compliance. On univariate analysis, six factors were found to be significantly associated (p &lt; 0.05) with the weekly maintenance warfarin dose: Day 3 INR, weight, age, creatinine, gender, and presence of malignancy. The day 3 INR was inversely related to the maintenance dose and was the most predictive factor (R2 = 0.397). Multivariate regression was performed using the above six variables. Gender and presence of malignancy were removed from the model because they did not meet the criteria for significance (p &lt; 0.10). Regression using the remaining variables generated the following model: Weekly maintenance dose = 63.835/(Day 3 INR) − 0.265(Age) + 0.115(Weight) − 0.061(Creatinine) + 8.126. R2 = 0.515.

Conclusions: The Kovacs 10 mg nomogram results in the rapid achievement of a therapeutic INR without a high incidence of bleeding events. The day 3 INR is strongly predictive of the required maintenance dose. If prospectively validated, our maintenance dose model would provide a simple means of estimating the appropriate maintenance dose using readily available information and without a need for genetic testing.