• Daniel E Singer, Anne S Hellkamp, Jonathan P Piccini, Kenneth W Mahaffey, Yuliya Lokhnygina, Guohua Pan, Jonathan L Halperin, Richard C Becker, Günter Breithardt, Graeme J Hankey, Werner Hacke, Christopher C Nessel, Manesh R Patel, Robert M Califf, Keith A A Fox, and ROCKET AF Investigators.
• Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. dsinger@partners.org
• J Am Heart Assoc. 2013 Feb 1;2(1):e000067.

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.

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