Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial

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, ROCKET AF Investigators, 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, ROCKET AF Investigators

Abstract

Background: Vitamin 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 results: TTR (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.

Conclusions: Independent 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 registration: URL: ClinicalTrials.gov. Unique identifier: NCT00403767.

Figures

Figure 1.
Figure 1.
A, Overall distribution of mean i‐TTR (%) by country (gray bars), grouped by region (black bars). B, Distribution of mean i‐TTR (%) by country (gray bars), grouped by region (black bars), for patients naïve to vitamin K antagonist therapy at baseline. C, Distribution of mean i‐TTR (%) by country (gray bars), grouped by region (black bars), for patients experienced with vitamin K antagonist therapy but naïve to warfarin treatment at baseline. D, Distribution of mean i‐TTR (%) by country (gray bars), grouped by region (black bars), for warfarin‐experienced patients at baseline. E, Distribution of overall mean i‐TTR (%) by country (gray bars), grouped by region (black bars), excluding the first 90 days in the trial. TTR indicates time in therapeutic range at individual patient level; East Asia: CN, China; HK, Hong Kong; KR, Korea; MY, Malaysia; PH, Philippines; SG, Singapore; TH, Thailand; TW, Taiwan; Eastern Europe: BG, Bulgaria; CZ, Czech Republic; GR, Greece; HU, Hungary; LT, Lithuania; PL, Poland; RO, Romania; RU, Russia; TR, Turkey; UA, Ukraine; Western Europe/similar: AT, Austria; AU, Australia; BE, Belgium; CH, Switzerland; DE, Germany; DK, Denmark; ES, Spain; FI, Finland; FR, France; GB, Great Britain; IL, Israel; IT, Italy; NL, Netherlands; NO, Norway; NZ, New Zealand; SE, Sweden; Latin America: AR, Argentina; BR, Brazil; CL, Chile; CO, Colombia; MX, Mexico; PE, Peru; VE, Venezuela.
Figure 2.
Figure 2.
Distribution of times in therapeutic (INR 2.0 to 3.0), low, and high INR range by geographic region. INR indicates international normalized ratio.
Figure 3.
Figure 3.
Inter‐INR test interval by value of first INR, stratified by geographic region. INR indicates international normalized ratio; TTR, time in therapeutic range.

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