International normalized ratio control and subsequent clinical outcomes in patients with atrial fibrillation using warfarin
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We explored associations between INR measures and clinical outcomes in patients with AF using warfarin, and whether INR history predicted future INR measurements. We included patients in ARISTOTLE who were randomized to and received warfarin. Among patients who had events, we included those with ≥ 3 INR values in the 180 days prior to the event, with the most recent ≤ 60 days prior to the event, who were on warfarin at the time of event (n = 545). Non-event patients were included in the control group if they had ≥ 180 days of warfarin exposure with ≥ 3 INR measurements (n = 7259). The median (25th, 75th) number of INR values per patient was 29 (21, 38) over a median follow-up of 1.8 years. A total of 87% had at least one INR value < 1.5; 49% had at least one value > 4.0. The last INRs before events (median 14 [24, 7] days) were < 3.0 for at least 75% of patients with major bleeding and > 2.0 for half of patients with ischemic stroke. Historic time in therapeutic range (TTR) was weakly associated with future TTR (R2 = 0.212). Historic TTR ≥ 80% had limited predictive ability to discriminate future TTR ≥ 80% (C index 0.61). In patients with AF receiving warfarin, most bleeding events may not have been preventable despite careful INR control. Our findings suggest that INRs collected through routine management are not sufficiently predictive to provide reassurance about future time in therapeutic range or to prevent subsequent outcomes, and might be over-interpreted in clinical practice.
KeywordsInternational normalized ratio Clinical outcomes Warfarin Atrial fibrillation
This work and the ARISTOTLE study were funded by Bristol-Myers Squib (Princeton, NJ) and Pfizer, Inc. (New York, NY). All analyses were conducted at the Duke Clinical Research Institute (DCRI, Durham, NC) and all authors had full access to all data. The DCRI coordinate the trial and managed the database. An academic steering committee designed the trial and was responsible for oversight of study conduct, reporting of all results, and takes responsibility for the accuracy and completeness of the data analyses. The authors are fully responsible for the study design, data collection, analysis and interpretation of the data, and writing of the manuscript. All authors agreed to submit the manuscript for publication. The sponsor played no role in the decision to submit the manuscript for publication.
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Conflict of interest
Lopes: Research grant: Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer; Consultant/Advisory Board: Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Merck, Portola, GlaxoSmithKline, Pfizer. Alexander: Research grant: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, Sanofi, Tenax Therapeutics; Consultant/Advisory Board: Cempra, CryoLife, CSL Behring, Pfizer, Portola Pharmaceuticals, VasoPrep Surgical. Hijazi: Honoraria: Boehringer Ingelheim, Roche Diagnostics, Pfizer and Bristol-Myers Squibb; Consultant/Advisory board: Pfizer, Bristol-Myers Squibb, Roche Diagnostics, and Merck, Sharp & Dohme. Hylek: Consultant: Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, Johnson & Johnson; Research grant: Bristol Myers Squibb/Pfizer, Johnson & Johnson. Gersh: Consulting fees/Honoraria: Xenon Pharmaceuticals; Data monitoring board: Armetheon Inc, Baxter Helathcare Corporation, CardioVascular Research Foundation, Janssen Research & Development, MEDTRONIC, Mount Sinai St. Lukes, Teva Pharmaceuticals, Thrombosis Research Institute; Other: Boston Scientific, Cipla Limited, Janssen Scientific Affairs LLC, St. Jude Medical, Inc. Garcia: Consultant/Advisory Board: BMS/Pfizer, Genzyme, Boehringer Ingelheim, Incyte, Alexion. Research Support: Daiichi Sankyo, Janssen, Incyte. Verheugt: Honoraia/Consultant: Bayer Healthcare, Boehringer-Ingelheim, BMS/Pfizer, and Daiichi-Sankyo. Hanna: An employee of the sponsor (BMS), received salary and stock as part of his employment compensation. Vinereanu: Research grant: GlaxoSmithKline, Pfizer, Bristol-Myers Squibb. Granger: Research Grant: Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GlaxoSmithKline, Janssen, Medtronic Foundation, Novartis, Pfizer, The Medicines Company; Consultant/Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead Sciences, Inc, GlaxoSmithKline, Hoffman LaRoche, Janssen, Medtronic, Novartis, Pfizer, The Medicines Company, Verseon. Guimarães, Thomas, Hellkamp, and Flaker authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all participants included in the study.
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