Change In International Normalized Ratio Research Articles

AI‐assisted warfarin dose optimisation with CURATE.AI for clinical impact: Retrospective data analysis

AbstractBackgroundStandard‐of‐care for warfarin dose titration is conventionally based on physician‐guided drug dosing. This may lead to frequent deviations from target international normalized ratio (INR) due to inter‐ and intra‐patient variability and may potentially result in adverse events including recurrent thromboembolism and life‐threatening hemorrhage.ObjectivesWe aim to employ CURATE.AI, a small‐data, artificial intelligence‐derived platform that has been clinically validated in a range of indications, to optimize and guide warfarin dosing.Patients/methodsA personalized CURATE.AI response profile was generated using warfarin dose (inputs) and corresponding change in INR between two consecutive days (phenotypic outputs) and used to identify and recommend an optimal dose to achieve target treatment outcomes. CURATE.AI's predictive performance was then evaluated with a set of metrics that assessed both technical performance and clinical relevance.Results and conclusionsIn this retrospective study of 127 patients, CURATE.AI fared better in terms of Percentage Absolute Prediction Error and Percentage Prediction Error of 20% compared to other models in the literature. It also had negligible underprediction bias, potentially translating into lower bleeding risk. Modeled potential time in therapeutic range with CURATE.AI was not significantly different from physician‐guided dosing, so it is on‐par yet provides a systematic approach to warfarin dosing, easing the mental‐burden on guesswork by physicians.This study lays the groundwork for the prospective study of CURATE.AI as a clinical decision support system. CURATE.AI may facilitate the effective use of affordable warfarin with a well‐established safety profile, without the need for costly, new oral anticoagulants. This can have significant impact both on the individual and public health.

Phytonadione Utilization and the Risk of Bleeding in Chronic Liver Disease.

Purpose: To determine the safety and efficacy of phytonadione in patients with an elevated international normalized ratio (INR) secondary to chronic liver disease without active bleeding. Methods: This retrospective chart review compared hospitalized patients from 2015 to 2022 with a diagnosis of chronic liver disease, a baseline INR of 1.2 to 1.9, and without active bleeding who did or did not receive phytonadione. The primary outcome was the incidence of new bleeding. The incidence of thrombosis and change in INR were also evaluated. Results: A total of 133 patients were included, of which 46 received phytonadione (mean 2.46 doses and mean dose 7.95 mg, 72.74% intravenously). Child-Pugh scores were higher in phytonadione patients (8.7 vs 9.93, P = .0003). There was no difference in the incidences of new bleeding (9.20 vs 13.04%, P = .492) or thrombosis (3.45 vs 0%, P = .203) between the control and phytonadione groups. After phytonadione administration, there was no change in INR, while INR increased by 0.24 in the control group (P = .025). Conclusion: In chronic liver disease patients who were not bleeding, phytonadione did not reduce INR or the incidence of new bleeding.

Evaluation of Clotting Parameters in Pregnant Women with Placental Blood Clots: Impact of Patient Characteristics and Assessment of Clexane Efficacy

Background: Clexane is used in pregnant women (PW) to minimize placental blood clotting (PBC) and fetal danger. Standard coagulation tests such as prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) are critical for anticoagulant medication optimization. As a result, the study's goal was to evaluate the efficacy of clexane as well as adherence to the American Heart Association's recommended limits for routine coagulation tests. Methods: The study included forty normal PW as controls and forty PW with PBC as patients from Al-Mafraq Hospital in Jordan. Patients were administered daily subcutaneous injections of 40 mg of clexane as an anticoagulant, in conjunction with a daily 75 mg aspirin regimen. During the first trimester, 5 ml of venous blood were drawn from each participant. The PT, INR and APTT were measured. This assessment also considered variables including plasma fibrinogen concentration (PFC), age, body mass index (BMI), blood type, and fetal gender. Results: The mean age \(\pm\) SD were 29.6 \(\pm\) 6.2 for the patient group and 28.3 \(\pm\) 5.9 years for the control group. The changes in PT, INR, APTT and PFC between the control and patient groups were statistically significant independent of mother's age, BMI, baby gender, or blood type. Patients displayed inadequate anticoagulation with an INR of 0.8, falling below the recommended therapeutic range of 2-3 for anticoagulant treatment. Surprisingly, by the end of the clinical study, all patients under investigation had safely delivered their babies without difficulties. Conclusion: The observed rise in fibrinogen levels among patients may contribute to PBC formation, necessitating further investigation. Evaluation of the safety and efficacy of a combined 40 mg Clexane and 75 mg aspirin regimen in PW from the Al-Mafraq region, Jordan, is warranted.

Effect of chamomile intake on blood coagulation tests in healthy volunteers: a randomized, placebo-controlled, crossover trial

BackgroundChamomile is consumed worldwide for enjoyment and its potentially desirable properties. Widespread patient resource websites, however, discourage preoperative chamomile intake, lest bleeding could worsen. This precaution, though, stems largely from indirect evidence in one case report. To evaluate if chamomile ingestion impacts coagulation assays via coumarin-like substances, we designed a randomized, placebo-controlled, crossover study.Materials and methodsHealthy volunteers were randomized to three interventions in a cross-over-design spanning 5 weeks per subject. Interventions included 7-day consumption of chamomile tea (3 tea bags × 3 times daily = 9 tea bags daily), a chamomile extract capsule (3 times daily), or a placebo capsule (3 times daily). A 7-day washout period elapsed between intervention periods. The primary outcome was the change in prothrombin time (PT) before vs. after each intervention. Secondary outcomes included changes in the international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time (TT), reptilase time (RT), and fibrinogen (FG) surrounding each intervention.ResultsAll 12 enrolled subjects were randomized and completed the study. The primary outcome of PT change (mean ± SD) was similar across interventions (chamomile tea = − 0.2 ± 0.4 s, extract capsule = − 0.2 ± 0.4 s, and placebo capsule = 0.1 ± 0.5 s; p = 0.34). INR change was 0 s (p = 0.07) for each intervention. The aPTT, TT, RT, and FG, did not change significantly across interventions (p = 0.8, p = 0.08, p = 0.8, and p = 0.2 respectively).ConclusionsChamomile intake by tea or capsule does not prolong PT. These findings challenge the notion to avoid perioperative chamomile intake in patients not taking warfarin.Trial registrationClinicalTrials.gov, NCT05006378; Principal Investigator: Jonathon Schwartz, M.D.; Registered August 16, 2021.

Effect of INR on Outcomes of Endovascular Treatment for Acute Vertebrobasilar Artery Occlusion.

Endovascular treatment (EVT) has been proven to be the standard treatment for acute vertebrobasilar artery occlusion (VBAO). This study aimed to analyze the effects of international normalized ratio (INR) indicators on outcomes in patients with acute VBAO treated with EVT. Dynamic data on INR in patients with VBAO who received endovascular treatment (EVT) at 65 stroke centers in China were retrospectively enrolled. Outcome measures included the modified Rankin Scale (mRS) score at 90days and 1year and symptomatic intracranial hemorrhage (sICH). The associations between elevated INR (INR > 1.1), INR variability (time-weighted variance of INR changes), and various clinical outcomes were analyzed in all patients and subgroups stratified by oral anticoagulation (OAC) by mixed logistic regression analysis. A total of 1825 patients met the study criteria, of which 1384 had normal INR and 441 had elevated INR. Multivariate analysis showed that elevated INR was significantly associated with poor functional outcomes (mRS 4-6) at 90days (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.08-1.72) and 1year (OR 1.32, 95% CI 1.05-1.66), but was not associated with an increased risk of sICH (OR 1.00, 95% CI 0.83-1.20). Similar associations exist between INR variability and poor functional outcomes at 90days (OR 2.17, 95% CI 1.09-4.30), 1year (OR 2.28, 95% CI 1.16-4.46), and sICH (OR 1.11, 95% CI 0.93-1.33). Subgroup analyses further revealed that elevated INR and INR variability remained associated with poor functional outcomes in patients not receiving oral anticoagulation (OAC) therapy, while no significant associations were observed in OAC-treated patients, regardless of whether they were on warfarin or direct oral anticoagulants. Elevated INR and INR variability in VBAO patients treated with EVT were associated with poor functional outcomes. The mechanism underlying the association between elevated INR and poor functional outcomes might be attributed to the fact that elevated INR indirectly reflects the burden of comorbidities, which could independently worsen outcomes. These findings underscore the importance of a comprehensive and dynamic evaluation of INR levels in the management of VBAO patients receiving EVT, providing valuable insights for optimizing patient outcomes.

Impact of Vitamin K Administration on Elevated International Normalized Ratio in Chronic Liver Disease.

Limited studies assess the efficacy of vitamin K administration in patients with chronic liver disease (CLD). However, vitamin K is commonly used to treat elevations in international normalized ratio (INR) in these patients with the intended benefit of reducing bleeding risk. This retrospective, single-center cohort study aimed to evaluate the impact of vitamin K administration on INR in patients with CLD. Hospitalized patients ≥ 18 years of age with a diagnosis of CLD or cirrhosis and received vitamin K were included. The primary outcome was the absolute change in INR from baseline to 24 to 48 h after vitamin K administration. Secondary endpoints included subgroup analyses of the primary outcome by route of administration and single versus multidose administration, and incidence of in-hospital venous thromboembolism (VTE) or major bleeding. A total of eighty-five patients, primarily with Child-Pugh class C (76.5%), were included. Route of vitamin K administration included oral (PO) (72%) and intravenous (IV) (26%) with a mean daily dose of 8.5 ± 2.3 mg. The absolute change in INR was -0.07 ± -0.35 following vitamin K administration. There was no difference in absolute INR change between single versus multiple dose administration (-0.16 ± -0.35 and -0.03 ± -0.35; P= .13) or between PO versus IV administration (-0.06 ± -0.23 and -0.18 ± -0.48; P = .11). The incidences of in-hospital VTE and major bleeding were 2.4% and 3.5%, respectively. The administration of vitamin K in hospitalized patients with CLD resulted in minimal INR change, suggesting this intervention may not have the intended benefit of reducing bleeding risk.

752: EVALUATION OF RESPONSE TO HIGH-DOSE VITAMIN K ADMINISTRATION

Introduction: Essential to the coagulation pathway, vitamin K is used to correct clotting factor deficiencies and for reversal of warfarin-induced bleeding. In practice, and particularly for cirrhosis-associated coagulopathy, high-dose IV vitamin K is often given on consecutive days despite limited evidence to support repeated dosing and potential risks with parenteral administration. This study sought to characterize differences in responders and non-responders to high-dose vitamin K to better guide dosing strategies in patients with coagulopathy. Methods: This was a case-control study of hospitalized adults (≥18 years) who received vitamin K 10 mg IV daily for three days for treatment of coagulopathy, defined as an international normalized ratio (INR) of greater than 1.5. Patients with an INR < 1.5 or ≥30% lower than baseline following the first dose of vitamin K were considered responders and compared to non-responders. The primary outcome was the change in INR over time with subsequent IV vitamin K doses. A linear mixed-effects model (LMM) compared the reduction of INR on follow-up time points between groups. Secondary outcomes included factors associated with response to IV vitamin K and the incidence of safety events. Results: There were 497 patients included in this study, and 182 patients responded to the first dose of IV vitamin K. Most patients were white males (73%) with a mean age of 54 ± 15 years. Most patients had underlying cirrhosis (91.5%), with a MELD score of 23.9 ± 10.6. The INR decreased from 1.87 (adjusted least square mean from LMM, 95% CI 1.73-2.03) to 1.61 (95% CI 1.49-1.74), which was a 16.5% reduction from baseline to day 3 (95% CI 12.6%-20.5%). In responders, the INR decreased from 1.89 at baseline (95% CI 1.74-2.04) to 1.40 (1.3-1.5) on day 3 (95% CI 1.30-1.50). In non-responders, the INR decreased from 1.97 at baseline (95% CI 1.83-2.13) to 1.85 on day 3 (95% CI 1.72-1.99). Predictors of response included lower weight, absence of cirrhosis, and lower bilirubin. There was a low incidence of safety events observed in this study. Conclusions: In this cohort of which the majority were patients with cirrhosis, the overall adjusted change in INR over 3 days was 0.3, which didn’t vary much clinically between responders and non-responders.

Abstract 12256: Symptomatic Supratherapeutic International Normalized Ratio on Rivaroxaban: A Case Report and a Systematic Review

Rivaroxaban is a direct oral anticoagulant that works by inhibiting factor Xa. Direct anticoagulants have largely replaced direct vitamin K inhibitors (VKAs) due to the increased risk of major hemorrhages and the need for regular monitoring and dose adjustments. However, there have been multiple reports of elevated international normalized ratio (INR) and incidents of bleeding in patients on rivaroxaban, which brings into question the potential need for monitoring. The purpose of this review is to differentiate the patients that may benefit from regular monitoring and to propose future directions for implementation of monitoring. Here we report a case of an INR of 4.8 in a patient who presented with a gastrointestinal bleed and a drop of five gm/dL in hemoglobin four days after starting rivaroxaban following right femoral popliteal bypass graft stenting. The patient had no liver or kidney abnormalities and was not taking any medication or consuming any foods that could introduce any significant drug interaction. Additionally, we conducted a systematic review of similar reports in the literature with the goal of identifying the factors that could influence rivaroxaban’s levels in the blood or its influence on the INR. We reviewed PubMed using keywords including; “rivaroxaban”, “anti-Xa”, “DOAC”, “elevated”, “INR”, “bleeding”, “hemorrhage”, “pharmacology”, and “pharmacokinetics”. The literature revealed reports of INRs up to 5.2. Reviewing the pharmacokinetics of rivaroxaban indicated possibly higher drug levels in Caucasians, patients with a low body mass index (BMI), and patients with polymorphisms in the genes coding for CYP3A4, CYP2J2, or p-glycoprotein, assuming no renal or liver disease and no significant drug-drug or drug-food interactions. INR can be falsely normal if the thromboplastin reagent used to monitor the INR on warfarin is not sensitive to the changes in INR due to rivaroxaban. We suggest finding a thromboplastin reagent that is sensitive to INR changes with rivaroxaban, which could yield clinically relevant INRs on rivaroxaban allowing for accurate monitoring. We then suggest conducting studies to evaluate the cost effectiveness of regular monitoring in at-risk patients.

Covid-19: Consumption coagulopathy with increased severity and mortality - A retrospective study

To compare quantitative values of parameters of coagulation pathway like Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), International Normalized Ratio (INR) and D-Dimer (DD) on date of admission versus date of patient's mortality. A total of 50 patients who were tested positive for COVID-19 in our hospital between April 21, 2021 and May 30, 2021, were taken into this study. The changes in PT, APTT, INR and DD were compared at day of admission and day of patient's mortality. The study involved 50 patients (36 male and 14 female). D-dimer at the day of admission (mean 1540.79 ng/ml; IQR 231-8776) was found with an elevation of 250% at the day of mortality (mean 5379.04ng/ml; IQR 434-10000). PT at the day of admission (mean 13.602; IQR 11.6-14.8) was found elevated (Normal range-10.5-13.5sec) in 19/50 patients which increased to 43/50 patients at the day of mortality, an increase of 126%. According to the study done, the number of patients with increased levels of PT, APTT, INR and DD were substantially greater at the time of mortality compared to the same patients at their time of admission, suggesting a dynamic coagulation process in COVID-19 patients. This likely suggested that the patients were in progression from a hypercoagulating state that transforms into a fibrinolytic state as a result of the extensive use of coagulation factors.

A Case Report of International Normalized Ratio Changes in Patients Taking Warfarin with Regorafenib

A Case Report of International Normalized Ratio Changes in Patients Taking Warfarin with Regorafenib

Analysis of the Dose-Response Relationship Between the International Normalized Ratio and Hepatic Encephalopathy in Patients With Liver Cirrhosis Using Restricted Cubic Spline Functions.

BackgroundThe International Normalized Ratio (INR) is significantly associated with Hepatic Encephalopathy (HE) in patients with liver cirrhosis. However, the dose-response relationship between continuous INR changes and HE risk has not been clearly defined. Thus, our goal was to explore the continuous relationship between HE and INR among patients hospitalized with liver cirrhosis and to evaluate the role of the INR as a risk factor for HE in these patients.MethodsA total of 6,266 people were extracted from the Big Data Platform of the Medical Data Research Institute of Chongqing Medical University. In this study, unconditional logistic regression and restricted cubic spline (RCS) model were used to analyze the dose-response association of INR with HE. Alcoholic liver disease, smoking status, and drinking status were classified for subgroup analysis.ResultsThe prevalence of HE in the study population was 8.36%. The median INR was 1.4. After adjusting for alcoholic liver disease, age, smoking status, drinking status, total bilirubin, neutrophil percentage, total hemoglobin, aspartate aminotransferase, serum sodium, albumin, lymphocyte percentage, serum creatinine, red blood cell, and white blood cell, multivariate logistic regression analysis revealed that INR ≥ 1.5 (OR = 2.606, 95% CI: 2.072–3.278) was significantly related to HE risk. The RCS model showed a non-linear relationship between the INR and HE (non-linear test, χ2 = 30.940, P < 0.001), and an increased INR was an independent and adjusted dose-dependent risk factor for HE among patients with liver cirrhosis.ConclusionThis finding could guide clinicians to develop individualized counseling programs and treatments for patients with HE based on the INR risk stratification.

Post-thrombolytic coagulopathy and complications in patients with pulmonary embolism treated with fixed-dose systemic alteplase

Alteplase treatment can cause a systemic coagulopathy although the incidence and contributory factors are unknown in pulmonary embolism (PE). Fixed-dosing of alteplase for PE may lead to interpatient variability in drug exposure and influence post-thrombolytic coagulopathy (PTC). While changes in fibrinogen and INR have been used to describe PTC, no universal PTC definition is available. Evaluate the incidence of PTC after alteplase treatment for PE, the effect of patient weight and blood/plasma volume and the association with bleeding complications. We conducted a retrospective cohort study of patients treated with alteplase for massive or high-risk submassive PE. Demographics, alteplase dosing, laboratory assessment of coagulopathy, and bleeding events were collected. The primary endpoint was incidence of PTC defined as an international normalized ratio (INR) > 1.5 or fibrinogen < 170mg/dL. Secondary outcomes included correlation between coagulopathies and alteplase dose normalized to actual body weight (ABW), ideal body weight (IBW), plasma volume (PV), and estimated blood volume (EBV). Bleeding events in patients with and without PTC were compared. 125 patients met criteria for inclusion in the study. PTC occurred in 35.3% of patients, with INR >1.5 in 21.8% and fibrinogen <170mg/dL in 26%. Alteplase dose >50mg was associated with increased odds of PTC (OR 6.5, CI 2.1-19.9). Dose normalized to ABW and EBV correlated weakly with absolute increase in post-alteplase INR (r =0.20, p =0.06 and r =0.21, p =0.057 respectively) and to percent change in INR (r =0.20, p = 0.058 and r =0.21, p =0.048 respectively). Dose/ABW, dose/PV, and dose/EBV each correlated moderately with absolute decrease in fibrinogen (r =-0.53, -0.49, and -0.47 respectively, p <0.001 for each) and percent change in fibrinogen (r = -0.55, -0.49, and -0.49 respectively, p < 0.001 for each). Dose/IBW correlated weakly with absolute and percent decrease in fibrinogen (r = -0.32, p =0.013 and r =-0.33, p =0.011). Patients with bleeding were more likely to have PTC (58.3% vs. 28.6%, p= 0.05) and a bleeding event was predictive of PTC (OR 5.33, 1.32-23.99). PTC is prevalent in patients with PE. PTC is influenced by alteplase dose and exposure parameters (ABW, IBW, PV, EBV) and may contribute to the bleeding risk.

Effect of the reaction temperature on the prothrombin time and the apparent International Normalized Ratio determined with International Standards for thromboplastins.

IntroductionThe definition of the International Normalized Ratio (INR) depends on a reference measurement procedure for the prothrombin time (PT) determined with international standards for thromboplastins. The agreed water bath temperature for PT determination in the reference measurement procedure is 37°C. The aim of the study was to assess the influence of small deviations of the agreed reaction temperature on PT and INR determined with World Health Organization international standards for thromboplastins rTF/16 (recombinant human) and RBT/16 (rabbit brain).MethodsProthrombin time was determined, with a manual hook technique, in glass test tubes in a water bath at a controlled temperature. The PT reaction temperatures were varied between 28 and 40°C. Pooled normal plasma and pooled coumarin plasma (INR ≈ 2.8) were used as test plasmas. The data were fitted to a quadratic relationship between PT and temperature.ResultsProthrombin times with rTF/16 were shortened by increasing the reaction temperature up to approximately 39‐40°C. PTs with RBT/16 were shortened by increasing the reaction temperature up to approximately 34‐37°C, but were prolonged at higher temperatures. The apparent INR change of the coumarin plasma at 37.0°C was 0.06/°C and 0.11/°C for rTF/16 and RBT/16, respectively.ConclusionsReaction temperature had a significant effect on PT and the apparent INR with the International Standards. At 37.0°C, the apparent INR of coumarin plasma determined with RBT/16 was more responsive to temperature change than the apparent INR determined with rTF/16. The required accuracy of the water bath temperature should be 37.0 ± 0.1°C.

Blasting the myth of predictive INR changes related to plasma transfusion: an academic institution's experience

IntroductionPlasma transfusion is a common therapeutic strategy used to lower international normalized ratio (INR) values in the non-emergent setting. However, due to lack of evidence of its efficacy, standardized guidelines for this practice have not been well established. MethodsThis retrospective observational cohort study analyzed 276 inpatient encounters that involved plasma transfusions focusing on change in INR values from pre- to post-transfusion, with respect to the following predictor variables: vitamin K co-administration, number of plasma units transfused, order indication and body mass index (BMI). ResultsThe overall average change in the INR was 1.35. Patients who received vitamin K showed an average change of 2.51, while patients that did not receive vitamin K demonstrated an average change of 0.70. Increased numbers of plasma units transfused showed benefit up to three-unit orders. Greater decreases in the INR were observed for patients requiring plasma for anticoagulation reversal or active bleeding. There was no significant difference in the change in INR based on the BMI. By multivariate and regression analyses, the stepwise addition of each successive predictor variable demonstrated an increase in the shared variance in the outcome of the post-transfusion INR: the pre-transfusion INR and vitamin K co-administration alone was not significant (p = 0.45); the additional number of plasma units transfused was significant (R² = 0.13, p < 0.001), and; the subsequent additional plasma order indications (R² = 0.19, p < 0.001) and BMI (R² = 0.18, p < 0.001) were increasingly significant. ConclusionTaking into consideration the combination of multiple predictive factors may aid in a more efficient use of plasma products.

Comparison of 3 Different Prothrombin Complex Concentrate Regimens for Emergent Warfarin Reversal: PCCWaR Study.

The ideal dose and specific prothrombin complex concentrate (PCC) for warfarin reversal is unknown. To evaluate the reduction in international normalized ratio (INR) of 3 different PCC dosing regimens: fixed-dose activated 4-factor PCC (aPCC), fixed-dose 4-factor PCC (4PCC), and standard-dose 4PCC. This was a multicenter retrospective cohort review. Patients >18 years of age who received PCC for warfarin reversal between January 1, 2017, and December 31, 2017, were screened for inclusion. Patients were excluded if they did not receive the correct PCC dosing regimen, received PCC for nonwarfarin bleeding, had a baseline INR less than 2, or received a massive transfusion protocol. Two institutions utilized aPCC dosed at 500 IU for INR <5 and 1000 IU for INR ≥5. Two institutions utilized fixed-dose 4PCC at 1500 to 2000 units depending on patient factors. Two institutions utilized 4PCC package insert dosing. The primary outcome was achievement of post-PCC target INR ≤1.4. Secondary outcomes included percentage change in INR, lowest 24-hour INR, and mortality. A total of 154 patients were included (fixed-dose aPCC: n = 29; fixed-dose 4PCC: n = 53; standard-dose 4PCC: n = 72). There was no statistical difference between groups in achieving the primary outcome (58.6% vs 69.8% vs 79.2%, respectively; P = 0.103) or any secondary outcomes. There was no difference in the ability to achieve a post-PCC INR of ≤1.4 between 3 different PCC regimens for warfarin reversal. Additional research is warranted to determine the ideal dose and PCC agent for warfarin reversal.

Propensity score adjusted comparison of three-factor versus four-factor prothrombin complex concentrate for emergent warfarin reversal: a retrospective cohort study

BackgroundProthrombin Complex Concentrates (PCC) are prescribed for emergent warfarin reversal (EWR). The comparative effectiveness and safety among PCC products are not fully understood.MethodsPatients in an academic level one trauma center who received PCC3 or PCC4 for EWR were identified. Patient characteristics, PCC dose and time of dose, pre- and post-INR and time of measurement, fresh frozen plasma and vitamin K doses, and patient outcomes were collected. Patients whose pre-PCC International Normalized Ratio (INR) was > 6 h before PCC dose or the pre-post PCC INR was > 12 h were excluded. The primary outcome was achieving an INR ≤ 1.5 post PCC. Secondary outcomes were the change in INR over time, post PCC INR, thromboembolic events (TE), and death during hospital stay. Logistic regression modelled the primary outcome with and without a propensity score adjustment accounting for age, sex, actual body weight, dose, initial INR value, and time between INR measurements. Data are reported as median (IQR) or n (%) with p < 0.05 considered significant.ResultsEighty patients were included (PCC3 = 57, PCC4 = 23). More PCC4 patients achieved goal INR (87.0% vs. 31.6%, odds ratio (OR) = 14.4, 95% CI: 3.80–54.93, p < 0.001). This result remained true after adjusting for possible confounders (AOR = 10.7, 95% CI: 2.17–51.24, p < 0.001). The post-PCC INR was lower in the PCC4 group (1.3 (1.3–1.5) vs. 1.7 (1.5–2.0)). The INR change was greater for PCC4 (2.3 (1.3–3.3) vs. 1.1 (0.6–2.0), p = 0.003). Death during hospital stay (p = 0.52) and TE (p = 1.00) were not significantly different.ConclusionsPCC4 was associated with a higher achievement of goal INR than PCC3. This relationship was observed in the unadjusted and propensity score adjusted results.

Antimycotic Treatment of Oral Candidiasis in Warfarin Users

PurposeAzole antimycotics and nystatin oral solution are used to treat oral candidiasis. Azoles inhibit cytochrome (CYP) P450-dependent metabolism of warfarin, which could increase the anticoagulant effect of warfarin. Nystatin is not expected to interfere with warfarin metabolism, but current data are conflicting. With this study, we aimed to explore the potential drug-drug interactions between warfarin and azole antimycotics used in the treatment of oral candidiasis, that is, systemic fluconazole, miconazole oral gel, and nystatin oral solution. MethodsBy linking clinical data on international normalized ratio (INR) measurements with administrative data on filled prescriptions of warfarin and antimycotics during 2000-2015, we explored INR changes in warfarin users relative to initiation of systemic fluconazole (n = 413), miconazole oral gel (n = 330), and nystatin oral solution (n = 399). ResultsWe found a significant increase in mean INR of 0.83 (95% confidence interval [CI] 0.61-1.04) and 1.27 (95% CI 0.94-1.59) following initiation of systemic fluconazole and miconazole oral gel, respectively. Also, the proportion of patients experiencing an INR-value above 5 was increased after initiation of fluconazole (from 4.3% to 15.3%) and miconazole (from 5.5% to 30.1%). INR was unaffected by initiation of nystatin oral solution (mean change 0.08; 95% CI -0.10 to 0.25). ConclusionInitiation of systemic fluconazole and miconazole oral gel was associated with increased INR in warfarin users. A similar association was not found for nystatin oral solution, which thus appears to be the safest alternative when treating oral candidiasis in warfarin users.

P0642EFFECTIVENESS OF HEMADSORPTION IN REDUCING FREE LIGHT CHAINS IN PATIENTS WITH MULTIPLE MYELOMA A.M.FOMIN, A.V.VATAZIN MOSCOW REGIONAL RESEARCH AND CLINICAL INSTITUTE. MOSCOW, RUSSIAN FEDERATION

Abstract Background and Aims Acute kidney injury is a frequent complication of multiple myeloma with unfavorable prognostic significance. The aim of the present study is to evaluate the effectiveness of hemadsorption to reducing free light chains (FLCs) in patients with multiple myeloma without replacement kidney therapy. Method The research was conducted for 6 patients ages 65- 74 with multiple myeloma. All patients were already suffering from a mild degree of renal insufficiency and elevated free light chains (4 kappa, 2 lambda). All patients didn’t have renal replacement therapy. Patients received VMP induction chemotherapy after two sessions of hemadsorption. The level of creatinine was from 198 µmol/l to 289 µmol/l. The glomerular filtration rate (eGFR) was from 34,8 to 21,3 mL/min/1,73 m2. The level of kappa FLC was 1714 – 5600 mg/L. The level of lambda FLC was 1575 – 3220 mg/L. In CytoSorb therapy, the blood is purified by adsorption in a procedure similar to hemoperfusion. The hemadsorption procedures were carried out on the AK10 device (Gambro, Sweden) with use of CytoSorb adsorbent cartridge. The content of the CytoSorb cartridge consists of a highly porous high-tech polymer. The patients were treated with 2 CytoSorb hemoadsorption treatments for 10 hours each separated and from one another by a pause interval of 12-14 hours. The blood flow rate was 130-160 ml/min. Anticoagulation was ensured by washing the bloodlines and a cartridge with a sorbent with normal saline with heparin – 4,000 units of activity per 1 L. 5,000 units of activity of heparin were injected intravenously at the beginning of the procedure. The FLCs, the level of creatinine and coagulogram test results of patients were studied prior to procedure and upon termination of procedure. Results An extracorporeal blood purification methods reduce elevated levels of FLCs. The cartridge with a total surface of&amp;gt;40,000 square meters, an adsorber is able to effectively and over time lower hydrophobic (water-insoluble) molecules that can be removed up to a size of 55kDa. FLC have high molecular weight (monomeric kappa of 22.5 kDa, dimeric lambda of 45 kDa). FLC removal, combined with chemotherapy may be associated with renal function recovery. As a result of hemadsorption after carrying out two procedures, there was a significant decrease in level kappa FLCs by 78.3 %, lambda FLCs by 64,0 %. All patients were dialysis independent. The level of creatinine decreased and the glomerular filtration rate increased. Other blood chemistry parameters did not show any changes. Throughout the treatment, the study did not show a decrease in dynamics of hemoglobin or platelets. There were not negative dynamics in change of INR (international normalized ratio), APTT (activated partial thromboplastin time), level of fibrinogen, prothrombin, or anti-thrombin III. No bleeding complication occurred in any patient during the procedure of hemadsorption. Other biochemical values did not change significantly. Conclusion The research showed that an extracorporeal blood purification method by CytoSorb therapy reduce elevated levels of FLCs in patients with multiple myeloma. The benefits of this modality need confirmation with a randomized controlled trial.

A Novel LC-MS/MS Assay for Quantification of Des-carboxy Prothrombin and Characterization of Warfarin-Induced Changes.

Warfarin is a narrow therapeutic index anticoagulant drug and its use is associated with infrequent but significant adverse bleeding events. The international normalized ratio (INR) is the most commonly used biomarker to monitor and titrate warfarin therapy. However, INR is derived from a functional assay, which determines clotting efficiency at the time of measurement and is susceptible to technical variability. Protein induced by vitamin K antagonist‐II (PIVKA‐II) has been suggested as a biomarker of long‐term vitamin K status, providing mechanistic insights about variation in the functional assay. However, the currently available antibody‐based PIVKA‐II assay does not inform on the position and number of des‐carboxylation sites in prothrombin. The assay presented in this paper provides simultaneous quantification of carboxy and des‐carboxy prothrombin that are essential for monitoring early changes in INR and, thus, serves as the superior tool for managing warfarin therapy. Additionally, this assay permits the quantification of total prothrombin level, which is affected by warfarin treatment. Prothrombin recovery from plasma was 95% and the liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assay was linear (r 2 = 0.98) with a dynamic range of 1–100 µg/mL. The assay interday precision was within 20%. A des‐carboxy peptide of prothrombin (GNLER) was negatively correlated with active prothrombin (Pearson r = 0.99, P < 0.0001), whereas its association was positively linked with INR values (Pearson r = 0.75, P < 0.015). This novel LC‐MS/MS assay for active and inactive prothrombin quantification can be applied to titrate anticoagulant therapy and to monitor the impact of diseases, such as hepatocellular carcinoma on clotting physiology.

Impact of prophylactic oseltamivir on INR in patients on stable warfarin therapy.

Influenza prophylaxis with oseltamivir is recommended for exposed high-risk patients. Patients with many comorbidities have an increased likelihood of co-administration of oseltamivir and warfarin. Evidence of a drug interaction is conflicting in the literature and is limited to a 5-day treatment course. This study evaluates the impact of prophylactic oseltamivir on international normalized ratio (INR) in patients taking warfarin. This retrospective cohort study conducted within the Veterans Health Administration included patients on warfarin who received oseltamivir for influenza prophylaxis. The primary endpoint was change in INR from baseline to day 10 of oseltamivir treatment. Secondary endpoints included change in INR based on renal function and duration of oseltamivir prophylaxis, trend in INR, and frequency of bleeding and thrombosis events. A total of 1041 patients were included and received oseltamivir for a mean of 12.9days. The mean post-oseltamivir INR was significantly increased compared to the pre-oseltamivir INR (2.39 to 2.52; p < 0.001). Patients with a creatinine clearance of 31-60mL/min had a significant increase in INR (2.40 to 2.59; p < 0.01). There was an increase in INR when oseltamivir was used for 7 or 8-10days. Of included patients, 5.1% and 1.8% had a recorded thrombosis or bleeding event, respectively. There was a significant increase in INR in patients on chronic warfarin therapy and concomitant prophylactic oseltamivir, but this change may only be clinically significant for certain patient populations. The most impact on INR was within 7-10days of oseltamivir initiation and in patients with impaired renal function.