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      Effect of switching from acenocoumarol to phenprocoumon on time in therapeutic range and INR variability: A cohort study

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          Abstract

          Background

          Treatment with vitamin K antagonists (VKA) requires a high proportion of time in the therapeutic range (TTR) and a low international normalised ratio (INR) variability to be maximally safe and effective. Switching from short-acting acenocoumarol to long-acting phenprocoumon could improve VKA control.

          Aims

          We assessed whether switching from acenocoumarol to phenprocoumon improves the time in the therapeutic range (TTR) and INR variability.

          Methods and results

          In a retrospective cohort with data on 236,957 patients-years of VKA management from two first-line anticoagulation clinics in the Netherlands, we identified 124 patients in target range 2–3, 269 patients in target range 2–3.5 and 98 patients in target range 2.5–3.5 who switched from acenocoumarol to phenprocoumon. They were matched in a 1:2 ratio to non-switching controls using propensity score matching. Over the first 180 days after a switch, switchers’ TTR declined 5 (95% CI 1 to 10), 10 (95% CI 7 to 13) and 5 (95% CI 0 to 11) percentage points relative to non-switchers, in target ranges 2–3, 2–3.5 and 2.5–3.5. Anticoagulation was more often supra-therapeutic in switchers, and switchers had a higher INR variability. In the following 180 days, TTR in switchers became 1 (95% CI -4 to 6), 4 (95% CI 0 to 7) and 6 (95% CI 1 to 12) percentage points better than in non-switchers. Switchers’ INRs were much more stable than non-switchers’.

          Conclusion

          Eventually, a switch from acenocoumarol to phenprocoumon leads to a higher TTR and a lower INR variability. However, this is preceded by a transition period with opposite effects. An improved conversion algorithm could possibly shorten the transition period. Until then, physicians and patients should decide whether switching is worth the increased risk during the transition phase.

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          Most cited references26

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          MatchIt: Nonparametric Preprocessing for Parametric Causal Inference

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            Quality of Vitamin K Antagonist Control and 1-Year Outcomes in Patients with Atrial Fibrillation: A Global Perspective from the GARFIELD-AF Registry

            Aims Vitamin K antagonists (VKAs) need to be individually dosed. International guidelines recommend a target range of international normalised ratio (INR) of 2.0–3.0 for stroke prevention in atrial fibrillation (AF). We analysed the time in this therapeutic range (TTR) of VKA-treated patients with newly diagnosed AF in the ongoing, global, observational registry GARFIELD-AF. Taking TTR as a measure of the quality of patient management, we analysed its relationship with 1-year outcomes, including stroke/systemic embolism (SE), major bleeding, and all-cause mortality. Methods and Results TTR was calculated for 9934 patients using 136,082 INR measurements during 1-year follow-up. The mean TTR was 55.0%; values were similar for different VKAs. 5851 (58.9%) patients had TTR<65%; 4083 (41.1%) TTR≥65%. The proportion of patients with TTR≥65% varied from 16.7% in Asia to 49.4% in Europe. There was a 2.6-fold increase in the risk of stroke/SE, 1.5-fold increase in the risk of major bleeding, and 2.4-fold increase in the risk of all-cause mortality with TTR<65% versus ≥65% after adjusting for potential confounders. The population attributable fraction, i.e. the proportion of events attributable to suboptimal anticoagulation among VKA users, was 47.7% for stroke/SE, 16.7% for major bleeding, and 45.4% for all-cause mortality. In patients with TTR<65%, the risk of first stroke/SE was highest in the first 4 months and decreased thereafter (test for trend, p = 0.021). In these patients, the risk of first major bleed declined during follow-up (p = 0.005), whereas in patients with TTR≥65%, the risk increased over time (p = 0.027). Conclusion A large proportion of patients with AF had poor VKA control and these patients had higher risks of stroke/SE, major bleeding, and all-cause mortality. Our data suggest that there is room for improvement of VKA control in routine clinical practice and that this could substantially reduce adverse outcomes. Trial Registration ClinicalTrials.gov NCT01090362
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              Outcomes in a Warfarin-Treated Population With Atrial Fibrillation.

              Vitamin K antagonist (eg, warfarin) use is nowadays challenged by the non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). NOAC studies were based on comparisons with warfarin arms with times in therapeutic range (TTRs) of 55.2% to 64.9%, making the results less credible in health care systems with higher TTRs.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing – original draft
                Role: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 July 2020
                2020
                : 15
                : 7
                : e0235639
                Affiliations
                [1 ] Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
                [2 ] Certe Thrombosis Service Groningen, Groningen, the Netherlands
                [3 ] Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
                [4 ] Department of Vascular Medicine, Heart and Vascular Center, Maastricht University Medical Centre, Maastricht, the Netherlands
                [5 ] Laboratory for Thrombosis and Hemostasis, Cardiovascular Research Institute, Maastricht, the Netherlands
                Hospital Dr. Rafael A. Calderón Guardia, CCSS, COSTA RICA
                Author notes

                Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The authors report the following potential conflicts of interest: J.H.A. van Miert has nothing to disclose. N.J.G.M. Veeger has nothing to disclose. A.J. ten Cate-Hoek has nothing to disclose. M. Piersma-Wichers reports travel support from LEO pharma, travel and conference support from Pfizer, and a research grant from Federatie van Nederlandse Trombosediensten, outside the submitted work. K. Meijer reports travel support from Baxter; grants, travel support and speaker fees from Bayer; grants and speaker fees from Sanquin; grants from Pfizer; speaker fees from Boehringer Ingelheim; speaker fees from BMS; speaker fees from Aspen; consulting fees from Uniqure; grants from Federatie van Nederlandse Trombosediensten; all outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0002-5177-1660
                http://orcid.org/0000-0002-1492-7937
                Article
                PONE-D-20-07682
                10.1371/journal.pone.0235639
                7351201
                32649714
                5beb2c0c-514a-4461-bbe8-85ae0db79ab6
                © 2020 van Miert et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 March 2020
                : 19 June 2020
                Page count
                Figures: 8, Tables: 3, Pages: 17
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Hematology
                Blood Coagulation
                Coagulation Disorders
                Thrombosis
                Medicine and Health Sciences
                Cardiovascular Medicine
                Cardiovascular Diseases
                Coagulation Disorders
                Thrombosis
                Medicine and Health Sciences
                Vascular Medicine
                Thrombosis
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Physical sciences
                Chemistry
                Chemical compounds
                Organic compounds
                Vitamins
                B vitamins
                Vitamin K
                Physical sciences
                Chemistry
                Organic chemistry
                Organic compounds
                Vitamins
                B vitamins
                Vitamin K
                Medicine and Health Sciences
                Geriatrics
                People and Places
                Population Groupings
                Age Groups
                Elderly
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Vascular Medicine
                Hemorrhage
                People and Places
                Population Groupings
                Professions
                Medical Personnel
                Medical Doctors
                Physicians
                Medicine and Health Sciences
                Health Care
                Health Care Providers
                Medical Doctors
                Physicians
                People and places
                Geographical locations
                Europe
                European Union
                Netherlands
                Custom metadata
                Code for the analyses is available at https://doi.org/10.5281/zenodo.3831170 An anonymous dataset, containing only matched patients, is available at the same repository. Per Dutch regulations around re-use of anonymous patient data, we are only able to provide an aggregated, anonymous dataset. Karen Thedinga ( k.thedinga@ 123456umcg.nl ) will serve as an additional point contact for data access.

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