Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial

Abstract

BackgroundVitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial.Methods and ResultsTTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i‐TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i‐TTR was 55.2% (SD 21.3%) and the median i‐TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i‐TTR, dominant determinants were previous warfarin use (mean i‐TTR of 61.1% for warfarin‐experienced versus 47.4% in VKA‐naïve patients) and geographic region where patients were managed (mean i‐TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i‐TTRs had INR distributions shifted toward lower INR values and had longer inter‐INR test intervals.ConclusionsIndependent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i‐TTR in global studies of warfarin. Regional differences in mean i‐TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing.Clinical Trial RegistrationURL: ClinicalTrials.gov. Unique identifier: NCT00403767.

Effects of Regional Differences in Asia on Efficacy and Safety of Edoxaban Compared With Warfarin – Insights From the ENGAGE AF-TIMI 48 Trial –

“…3 Prior studies reported regional differences in terms of the safety and efficacy of NOACs, but similar data from ENGAGE AF-TIMI 48 have not been published. 7, 8 Regional variations in the genetic background of the population, socioeconomic and medical infrastructure, and unique regional patient characteristics may affect the relative efficacy and safety of the NOACs. However, it has been challenging to discern which factors explain regional differences, particularly when genetic factors are not controlled for.…”

Time in the Therapeutic Range (TTR): An Overly Simplified Conundrum

“…[8][9][10][11] Regardless of the method used, however, the question of whether we can truly compare TTRs across clinical trials still remains, especially given that the issues raised above (i.e., discrepancies in the frequency of measurements and/or in the handling of measurements at the initiation of therapy or during interruption) are handled differently, even when a single TTR calculation method such as the Rosendaal approach was used. 15 Interestingly, Singer et al suggested a modification of the Rosendaal approach that makes assumptions about alterations in INR that result from changes in warfarin doses between actual INR rechecks. 16 However, even this approach does not satisfy most of the concerns raised above.…”

Prediction of unstable anticoagulation with acenocoumarol versus warfarin in atrial fibrillation

“…It seems that the clinical factors predispose to unstable anticoagulation to a different extent during treatment with warfarin and acenocoumarol. It was found that COPD, reported to coexist in a considerable percentage of AF patients (10%) [19], strongly contributed to the prediction of the anticoagulation stability. A potential factor which might explain the association between COPD and stability of anticoagulation with acenocoumarol is drug-drug interaction.…”