David J Seiffge1, Georg Kägi2, Patrik Michel3, Urs Fischer4, Yannick Béjot5, Susanne Wegener6, Marialuisa Zedde7, Guillaume Turc8, Charlotte Cordonnier9, Peter S Sandor10, Gilles Rodier11, Andrea Zini12, Manuel Cappellari13, Sabine Schädelin14, Alexandros A Polymeris1, David Werring15, Sebastian Thilemann1, Ilaria Maestrini9, Eivind Berge16, Christopher Traenka1, Jochen Vehoff2, Gian Marco De Marchis1, Monika Kapauer2, Nils Peters1,17, Gaia Sirimarco3, Leo H Bonati1, Marcel Arnold4, Philippe A Lyrer1, Emmanuel De Maistre18, Andreas Luft6, Dimtrios A Tsakiris19, Stefan T Engelter1,17. 1. Stroke Center and Department of Neurology, Department of Clinical Research, University Hospital and University of Basel, Basel, Switzerland. 2. Department of Neurology, St Gallen Cantonal Hospital, St Gallen, Switzerland. 3. Department of Neurology, University Hospital, Lausanne, Switzerland. 4. Department of Neurology, Inselspital, Bern, Switzerland. 5. Department of Neurology, Dijon Stroke Registry, University Hospital, Dijon, France. 6. Department of Neurology, University Hospital Zurich, Zurich, Switzerland. 7. Neurology Unit-Stroke Unit, New Santa Maria Hospital, Institute of Hospitalization and Scientific Care, Reggio Emilia, Italy. 8. Department of Neurology, Saint Anne Hospital, National Institute of Health and Medical Research U894, Paris, France. 9. National Institute of Health and Medical Research U1171, Degenerative and Vascular Cognitive Disorders, Department of Neurology, Lille University Hospital Center, University of Lille, Lille, France. 10. Department of Neurology, Baden Cantonal Hospital, Baden, Switzerland. 11. Department of Neurology, Annecy Genevois Hospital Center, Épagny-Metz-Tessy, France. 12. Stroke Unit, Department of Neuroscience, S'Agostino-Estense Hospital, Modena University Hospital, Modena, Italy. 13. USD Stroke Unit, DAI of Neuroscience, Integrated University Hospital, Verona, Italy. 14. Clinical Trial Unit, University Hospital Basel, Basel, Switzerland. 15. Stroke Research Center, Department of Brain Repair and Rehabilitation, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom. 16. Departments of Internal Medicine and Cardiology, Oslo University Hospital, Oslo, Norway. 17. Neurorehabilitation Unit, University Center for Medicine of Aging and Rehabilitation Basel, Felix Platter Hospital, University of Basel, Basel, Switzerland. 18. Hematological Laboratory, University Hospital, Dijon, France. 19. Diagnostic Hematology, University Hospital Basel, Basel, Switzerland.
Abstract
OBJECTIVE: Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban. METHODS: In a multicenter registry-based study (Novel Oral Anticoagulants in Stroke Patients collaboration; ClinicalTrials.gov: NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS patients had RivLev ≤ 100ng/ml, indicating possible eligibility for thrombolysis, and how many ICH patients had RivLev ≥ 75ng/ml, making them possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation, regression models) and studied the sensitivity and specificity of international normalized ratio (INR) thresholds to substitute RivLev using cross tables and receiver operating characteristic curves. RESULTS: Among 241 patients (median age = 80 years, interquartile range [IQR] = 73-84; median time from onset to admission = 2 hours, IQR = 1-4.5 hours; median RivLev = 89ng/ml, IQR = 31-194), 190 had AIS and 51 had ICH. RivLev was similar in AIS patients (82ng/ml, IQR = 30-202) and ICH patients (102ng/ml, IQR = 51-165; p = 0.24). Trough RivLev(≤137ng/ml) occurred in 126/190 (66.3%) AIS and 34/51 (66.7%) ICH patients. Among AIS patients, 108/190 (56.8%) had RivLev ≤ 100ng/ml. In ICH patients, 33/51 (64.7%) had RivLev ≥ 75ng/ml. RivLev was associated with rivaroxaban dosage, and inversely with renal function and time since last intake (each p < 0.05). INR ≤ 1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev ≤ 100ng/ml. INR ≥ 1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev ≥ 75ng/ml. INTERPRETATION: RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under rivaroxaban had a RivLev low enough to consider thrombolysis. In ICH patients, two-thirds had a RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR thresholds perform poorly to inform treatment decisions in individual patients. Ann Neurol 2018;83:451-459.
OBJECTIVE: Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban. METHODS: In a multicenter registry-based study (Novel Oral Anticoagulants in StrokePatients collaboration; ClinicalTrials.gov: NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AISpatients had RivLev ≤ 100ng/ml, indicating possible eligibility for thrombolysis, and how many ICHpatients had RivLev ≥ 75ng/ml, making them possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation, regression models) and studied the sensitivity and specificity of international normalized ratio (INR) thresholds to substitute RivLev using cross tables and receiver operating characteristic curves. RESULTS: Among 241 patients (median age = 80 years, interquartile range [IQR] = 73-84; median time from onset to admission = 2 hours, IQR = 1-4.5 hours; median RivLev = 89ng/ml, IQR = 31-194), 190 had AIS and 51 had ICH. RivLev was similar in AISpatients (82ng/ml, IQR = 30-202) and ICHpatients (102ng/ml, IQR = 51-165; p = 0.24). Trough RivLev(≤137ng/ml) occurred in 126/190 (66.3%) AIS and 34/51 (66.7%) ICHpatients. Among AISpatients, 108/190 (56.8%) had RivLev ≤ 100ng/ml. In ICHpatients, 33/51 (64.7%) had RivLev ≥ 75ng/ml. RivLev was associated with rivaroxaban dosage, and inversely with renal function and time since last intake (each p < 0.05). INR ≤ 1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev ≤ 100ng/ml. INR ≥ 1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev ≥ 75ng/ml. INTERPRETATION: RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under rivaroxaban had a RivLev low enough to consider thrombolysis. In ICHpatients, two-thirds had a RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR thresholds perform poorly to inform treatment decisions in individual patients. Ann Neurol 2018;83:451-459.
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