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Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies.

ABSTRACT: This study evaluated the influence of rivaroxaban 20?mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin.We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6?h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR.The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0-3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5-1.2, decreasing to 0.3-0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38??g l(-1) ).The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24?h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR.

SUBMITTER: Siegmund HU

PROVIDER: S-EPMC4456128 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies.

Siegmund Hans-Ulrich HU Burghaus Rolf R Kubitza Dagmar D Coboeken Katrin K

British journal of clinical pharmacology 20150601 6

<h4>Aim</h4>This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin.<h4>Methods</h4>We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warf ...[more]

PMID: 25510952

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Project description:BackgroundAnticoagulation management is difficult in chronic kidney disease, with frequent supratherapeutic international normalized ratios (INRs ≥ 4) increasing hemorrhagic risk. We evaluated whether the interaction of INR and lower estimated glomerular filtration rate (eGFR) increases hemorrhage risk and whether patients with lower eGFRs experience slower anticoagulation reversal.Study designProspective cohort study.Setting & participantsWarfarin pharmacogenetics cohort (1,273 long-term warfarin users); warfarin reversal cohort (74 warfarin users admitted with INRs ≥ 4).PredictoreGFR, INR as time-dependent covariate, and their interaction in the pharmacogenetics cohort; eGFR in the reversal cohort.Outcomes & measurementsIn the pharmacogenetics cohort, hemorrhagic (serious, life-threatening, and fatal bleeding) risk was assessed using proportional hazards regression. In the reversal cohort, anticoagulation reversal was assessed from changes in INR, warfarin and metabolite concentrations, clotting factors (II, VII, IX, and X), and PIVKA-II (protein induced by vitamin K absence or antagonist II) levels at presentation and after reversal, using linear regression and path analysis.ResultsIn the pharmacogenetics cohort, 454 (35.7%) had eGFRs < 60 mL/min/1.73 m(2). There were 137 hemorrhages in 119 patients over 1,802 person-years of follow-up (incidence rate, 7.6 [95% CI, 6.4-8.9]/100 person-years). Patients with lower eGFRs had a higher frequency of INR ≥ 4 (P<0.001). Risk of hemorrhage was affected significantly by eGFR-INR interaction. At INR<4, there was no difference in hemorrhage risk by eGFR (all P ≥ 0.4). At INR≥4, patients with eGFRs of 30 to 44 and < 30 mL/min/1.73 m(2) had 2.2-fold (95% CI, 0.8-6.1; P=0.1) and 5.8-fold (95% CI, 2.9-11.4; P<0.001) higher hemorrhage risks, respectively, versus those with eGFRs ≥ 60 mL/min/1.73 m(2). In the reversal cohort, 35 (47%) had eGFRs < 45 mL/min/1.73 m(2). Patients with eGFRs < 45 mL/min/1.73 m(2) experienced slower anticoagulation reversal as assessed by INR (P=0.04) and PIVKA-II level (P=0.008) than those with eGFRs ≥ 45 mL/min/1.73 m(2).LimitationsLimited sample size in the reversal cohort, unavailability of antibiotic use and urine albumin data.ConclusionsPatients with lower eGFRs have differentially higher hemorrhage risk at INR ≥ 4. Moreover, because the INR reversal rate is slower, hemorrhage risk is prolonged.

Project description:BackgroundCurrently, there is a lack of sepsis screening tools that can be widely used worldwide. Pulmonary sepsis can be of sufficient concern to physicians due to their noticeable symptoms, which usually rely less on screening tools.AimTo investigate the efficiency of the international normalized ratio (INR) for the early rapid recognition of adult nonpulmonary infectious sepsis.MethodsThis is a prospective observational study. A total of 108 sepsis patients and 106 nonsepsis patients were enrolled according to relevant inclusion and exclusion criteria. Commonly used clinical indicators, such as white blood cell, neutrophil count, lymphocyte count, neutrophil-lymphocyte count ratio (NLCR), platelets (PLT), prothrombin time, INR, activated partial thromboplastin time, and quick Sequential "Sepsis-related" Organ Failure Assessment (qSOFA) scores were recorded within 24 h after admission. The diagnostic performances of these clinical indicators were analyzed and compared through multivariate logistic regression analysis, Spearman correlation, and receiver operating characteristic curve analysis.ResultsThe INR value of the sepsis group was significantly higher than that of the nonsepsis group. INR has superior diagnostic efficacy for sepsis, with an area under the curve value of 0.918, when those preexisting diseases which significantly affect coagulation function were excluded. The diagnostic efficacy of the INR was more significant than that of NLCR, PLT, and qSOFA (P < 0.05). Moreover, INR levels of 1.17, 1.20, and 1.22 could be used to categorize the relative risk of nonpulmonary infections sepsis into three categories: low, medium and high risk, respectively.ConclusionThe INR is a promising and easily available biomarker for diagnosis, and it can be used as one of the indicators for early screening of adult nonpulmonary infectious sepsis. When its value is higher than the optimal cutoff value (1.22), high vigilance is required for adult nonpulmonary infectious sepsis.

Dataset Information

Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies.

Publications

Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies.

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