Baseline International Normalized Ratio Research Articles

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.

Safety and Effectiveness of Four-Factor Prothrombin Complex Concentrate in Special Populations with INR Below 2: A Post-Marketing Surveillance Study.

We previously conducted a prospective, observational post-marketing surveillance study to assess the safety and effectiveness of four-factor prothrombin complex concentrate (4F-PCC) for rapid vitaminK antagonist (VKA) reversal in Japanese patients. This subgroup analysis compared the safety, especially thromboembolic events (TEEs), and effectiveness of 4F-PCC by stratifying patients into two subgroups according to baseline international normalized ratio (INR) levels with < 2.0 and ≥ 2.0. Of 1271 eligible patients, 215 (17.9%) had INR < 2.0 and 987 (82.1%) had INR ≥ 2.0. Overall baseline characteristics were similar between groups; age (74.0years vs 74.0years), body mass index (22.1kg/m2 vs 21.9kg/m2), ratio of inpatients (90.2% vs 88.7%), manifested atrial fibrillation (46.0% vs 48.8%). Median INRs at baseline were 1.72 (minimum 0.92, maximum 1.99) in the INR < 2.0 group and 2.95 (2.00, 27.11) in the INR ≥ 2.0 group. The most common reason for 4F-PCC administration was intracranial hemorrhage (67.0% vs 59.5%), and lesser gastrointestinal bleeding (0.9% vs 7.5%). After 4F-PCC administration (average doses 24.5IU/kg [INR < 2.0 group] and 29.2IU/kg [INR ≥ 2.0 group]), INRs were significantly reduced to 1.21 (- 28%) and 1.31 (- 68%), respectively, and resulted in hemostasis in a similarly rapid manner. The incidences of adverse drug reactions were 3.7% in each group. TEEs occurred in 4 (1.9%) patients in the INR < 2.0 group and 11 (1.1%) patients in the INR ≥ 2.0 group and were predominantly composed of stroke, while similar rates (67.0% vs 62.9%) of bleeding events post-anticoagulant resumption were observed between groups. This study supports the favorable tolerability and efficacy of 4F-PCC regardless of baseline INR (< 2.0 or ≥ 2.0), with a prompt reduction of INR and substantial hemostatic effectiveness in the real-world setting for patients requiring urgent VKA reversal, although no indicated 4F-PCC dose for VKA reversal exists for INR < 2.0 to date.

Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates

Millions of people take vitamin K antagonists (VKAs). Some people who need urgent surgical procedures require rapid VKA reversal to prevent excessive intraoperative bleeding. To evaluate the hemostatic noninferiority of an investigational 4-factor prothrombin complex concentrate (4F-PCC) to a control 4F-PCC for rapid VKA reversal before urgent surgery. This phase 3, double-blind, noninferiority randomized clinical trial (LEX-209) was conducted in 24 hospitals in the US, Russia, Georgia, Belarus, Ukraine, and Romania from June 7, 2017, through November 8, 2021; the study was stopped in February 2022. Participants were adult patients taking VKA who had an international normalized ratio (INR) of 2 or higher and needed urgent surgery with a substantial bleeding risk (≥50 mL). Patients were randomized 1:1 to a single infusion of either the investigational 4F-PCC or the control 4F-PCC. Data analysis followed intention-to-treat and per-protocol approaches. Single intravenous infusion was dosed by body weight and baseline INR. A dose of 25, 35, or 50 IU/kg of investigational 4F-PCC or control 4F-PCC was administered for baseline INR of 2 to less than 4, 4 to 6, or over 6, respectively. The primary end point was hemostatic efficacy at surgery end. An independent adjudication board, blinded to the 4F-PCC treatment allocation, assessed hemostatic efficacy using an objective 4-point scale. A total of 208 patients (median [range] age, 67.5 [31-92] years; 118 males [56.7%]) received the investigational (n = 105) or the control (n = 103) 4F-PCC. The median (range) dose was 25 (16-50) IU/kg in the investigational group and 25 (15-50) IU/kg in the control group, with a median (range) infusion time of 12 (8-50) minutes and 13 (7-30) minutes and a median (range) time from infusion to surgery start of 1.42 (0.25-15.25) hours and 1.50 (0.42-18.50) hours, respectively. Baseline median (range) INR was 3.05 (1.97-21.10) in the investigational group and 3.00 (2.00-11.30) in the control group. In the intention-to-treat analysis, the investigational 4F-PCC was noninferior to the control 4F-PCC, resulting in effective hemostasis in 94.3% of patients vs 94.2% of patients (proportion difference, 0.001; 95% CI, -0.080 to 0.082; P < .001), meeting the prespecified noninferiority margin of 0.15. An INR of 1.5 or lower at 30 minutes after infusion occurred in 78.1% of patients in the investigational group vs 71.8% of patients in the control group (proportion difference, 0.063; 95% CI, -0.056 to 0.181). Thrombotic events (2.9% vs 0%, respectively) and mortality (4.8% vs 1.0%, respectively) were no different than expected for 4F-PCC use. One patient in each treatment group discontinued due to adverse events (cardiac disorders unrelated to 4F-PCC). This randomized clinical trial found that the investigational 4F-PCC was hemostatically noninferior to the control 4F-PCC for rapid VKA reversal in patients needing urgent surgery with considerable bleeding risk; the safety profile of these two 4F-PCCs was similar. These results support the investigational 4F-PCC as a therapeutic option for surgical patients requiring rapid VKA reversal. ClinicalTrials.gov Identifier: NCT02740335.

Outcomes of patients with acute severe autoimmune hepatitis: Predictors of non-response to corticosteroids and need for liver transplantation.

Acute severe autoimmune hepatitis (AS-AIH) is an evolving concept and the outcomes and optimal treatment have been less studied. In this study, we aimed to investigate the outcomes of patients with AS-AIH and predictors of non-response to corticosteroid therapy and need for liver transplantation. In a retrospective cohort, we included patients with AS-AIH admitted to our liver center. We defined AS-AIH based on the international autoimmune hepatitis group score as acute presentation of AIH with an international normalized ratio (INR)≥1.5 and without liver cirrhosis and hepatic encephalopathy. All patients received high dose corticosteroid therapy. Treatment response was defined as liver transplant free survival at 4months after presentation. Factors associated with response to corticosteroids and survival of patients were studied. In total, 61 patients with AS-AIH were included. Forty-seven patients responded to corticosteroid therapy. In the multivariate regression model, baseline INR (odds ratio [OR]: 0.184; 95% confidence interval [CI]: 0.048-0.699; p=0.013) and delayed versus early initiation of corticosteroid (after vs. before 5days of presentation) (OR: 0.189; 95% CI: 0.039-0.919; p=0.039) were independent predictors of clinical non-response to corticosteroid therapy. In the multivariable Cox regression model, baseline INR level (hazard ratio [HR]: 2.542; 95% CI: 1.188-5.440; p=0.016) and delayed initiation of corticosteroids (HR: 3.578; 95% CI: 1.084-11.812; p=0.036) were independent predictors of liver transplant free survival at 6months after diagnosis. Delayed initiation of corticosteroid therapy might be predictive of clinical non-response to medical therapy and need for liver transplantation in patients with AS-AIH.

Radiomic Features of Acute Cerebral Hemorrhage on Non-Contrast CT Associated with Patient Survival.

The mortality rate of acute intracerebral hemorrhage (ICH) can reach up to 40%. Although the radiomics of ICH have been linked to hematoma expansion and outcomes, no research to date has explored their correlation with mortality. In this study, we determined the admission non-contrast head CT radiomic correlates of survival in supratentorial ICH, using the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) trial dataset. We extracted 107 original radiomic features from n = 871 admission non-contrast head CT scans. The Cox Proportional Hazards model, Kaplan-Meier Analysis, and logistic regression were used to analyze survival. In our analysis, the "first-order energy" radiomics feature, a metric that quantifies the sum of squared voxel intensities within a region of interest in medical images, emerged as an independent predictor of higher mortality risk (Hazard Ratio of 1.64, p < 0.0001), alongside age, National Institutes of Health Stroke Scale (NIHSS), and baseline International Normalized Ratio (INR). Using a Receiver Operating Characteristic (ROC) analysis, "the first-order energy" was a predictor of mortality at 1-week, 1-month, and 3-month post-ICH (all p < 0.0001), with Area Under the Curves (AUC) of >0.67. Our findings highlight the potential role of admission CT radiomics in predicting ICH survival, specifically, a higher "first-order energy" or very bright hematomas are associated with worse survival outcomes.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study*

Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

Futility of fresh frozen plasma in the correction of coagulopathy prior to image-guided drainage of infected collections: Results from a prospective case–control study

Abstract BACKGROUND: Fresh frozen plasma (FFP) is frequently used as prophylactic hemostatic therapy for correction of periprocedural coagulopathy. This practice is frequently based on the assumption that deranged international normalized ratio (INR) predicts the risk of periprocedural bleeding and that FFP transfusion is effective in mitigating the procedure-associated bleeding risks. There is limited evidence to support both these assumptions in the context of image-guided drainage of infected collections. AIMS: The study aimed to analyze the efficacy of weight-based standard FFP dose for correction of infection-associated coagulopathy in patients with clinicoradiologically diagnosed infected collections planned for image-guided drainage. MATERIALS AND METHODS: In this prospective case–control study, 229 patients with clinicoradiologically diagnosed infected abdominal collection(s) planned to undergo image-guided drainage were included. Cases and controls were defined as patients with baseline INR &gt;1.2–3 (in the absence of any other bleeding diathesis) and INR ≤1.2, respectively. Cases received 10–15 mL/kg of FFP before drainage. Costs and time delays in drainage among the two groups, efficacy of plasma transfusion in the correction of coagulopathy, incidence of transfusion reactions, bleeding complications, and inhospital mortality were analyzed. RESULTS: There were 117 cases and 112 controls. A total of 445 FFP units were utilized. The median (interquartile range) time required from diagnosis of collection to the procedure was 25.3 (20.8–40.3) hours among cases and 16.4 (8.7–20.1) hours among controls (P &lt; 0.001). FFP transfusion resulted in INR normalization (≤1.2) only in 7.9% of cases (n = 9). Among the 81 cases who had pretransfusion INR ≥1.5, INR improved to ≤1.5 in 49 (60.4%) patients. There was an average of 2.9% decrease in INR per unit of FFP transfused. No bleeding complications were noted in patients undergoing drainage despite a persistent deranged INR (&gt;1.5) postplasma transfusion. Transfusion reactions occurred in 17/117 (14.5%) patients. There were no deaths among the controls while five patients died among the cases. CONCLUSION: Prophylactic FFP transfusion for infection-associated coagulopathy leads to a significant delay in lifesaving drainage procedures. Minority of patients attain normalization of INR with FFP transfusion.

Effect of Phytonadione on Correction of Coagulopathy in Pediatric Patients With Septic Shock.

The purpose of this study was to evaluate phytonadione in children with septic shock with disseminated intravascular coagulopathy (DIC). The primary objective was to identify the number of patients with an international normalized ratio (INR), defined as ≤1.2, following phytonadione. Secondary objectives were to compare patients who achieved a normalized INR versus those with INR >1.2 and to determine factors associated with a normalized INR. A retrospective study of children <18 years of age receiving phytonadione from October 1, 2013, to August 31, 2020, with a diagnosis of septic shock, were included. Data collection included demographics, phytonadione regimen, INR values, Pediatric Index of Mortality 2 (PIM2) and Pediatric Risk of Mortality III (PRISM III) scores, fresh frozen plasma (FFP) and cryoprecipitate use. A logistic regression model and generalized linear model were used to explore factors associated with a normalized INR and evaluate phytonadione dosing. Data for initial phytonadione course for 156 patients were evaluated. Sixty-six (42.3%) patients had a normalized INR. Most patients (n = 145; 92.9%) received ≤3 phytonadione doses, with the largest reduction in INR occurring after the second dose. In the logistic regression model, baseline INR, FFP, cryoprecipitate, vasopressors, PIM2, PRISM III, or cumulative phytonadione dose were not associated with achieving a normalized INR. Less than half of patients achieved a normalized INR. The median cumulative dose of phytonadione and receipt of FFP or cryoprecipitate was not associated with an increased odds of a normalized INR. Future studies are needed to further explore phytonadione use in children with sepsis-induced coagulopathy.

Clinically relevant increases in the international normalized ratio and model of end-stage liver disease score by therapeutic doses of direct oral anticoagulants in patients with cirrhosis

BackgroundPatients with cirrhosis are increasingly using direct oral anticoagulants (DOACs) in therapeutic doses for the treatment of portal vein thrombosis or for concomitant atrial fibrillation. DOACs may affect routine diagnostic tests of coagulation including the international normalized ratio (INR). The INR is a part of the model of end-stage liver disease (MELD) score, a validated score that predicts the mortality risk in patients with cirrhosis and is used to prioritize patients for liver transplantation. DOAC–induced increases in the INR may thus lead to artificial inflation of the MELD score. ObjectiveWe studied the effect of DOACs on INR prolongation in patients with cirrhosis. MethodsWe spiked plasma from 20 healthy individuals and 20 patients at the start of liver transplantation with DOACs in concentrations representing peak therapeutic levels. In addition, we studied INR increases in healthy controls and patients with mild cirrhosis who received the DOAC edoxaban for 1 week for study purposes. ResultsIn controls and patients, the INR increased by an ex vivo addition of a DOAC, and the INR increase in patients was proportional to the baseline INR values. The increase in INR translated to a median increase of between 3 and 10 MELD points, depending on the DOAC used. In controls and patients alike, the INR increased on the ingestion of edoxaban, which translated to an increase in 5 MELD points. ConclusionsTaken together, DOACs result in an INR increase that translates to clinically meaningful increases in MELD points in patients with cirrhosis, and precautions to avoid artificial inflation of the MELD score in these patients are warranted.

A Phase 3, Prospective, Randomized, Double-Blind, Multicenter, Non-Inferiority Study Comparing Two Four-Factor Prothrombin Complex Concentrates for Reversal of Vitamin K Antagonist-Induced Anticoagulation in Patients Needing Urgent Surgery with Significant Bleeding Risk

Introduction: The 4-factor prothrombin complex concentrates (4F-PCCs) are very effective in urgent reversal of vitamin K antagonist (VKA) anticoagulant therapy, including correction of the International Normalized Ratio (INR). This study (LEX-209) compared the hemostatic efficacy of an investigational 4F-PCC (Octaplex®; Octapharma) with a control 4F-PCC (Beriplex® P/N, also known as Kcentra®; CSL Behring). Methods: Patients included were ≥18 years old, on VKA therapy, hospitalized for urgent surgery with a significant bleeding risk (≥50 mL) for which VKA withdrawal and intravenous vitamin K were considered to be insufficient, and had an INR ≥2.0. Patients received a single intravenous 4F-PCC dose of 25, 35, or 50 international units (IU)/kg body weight per baseline INR (2-<4, 4-6, >6, respectively); infusion rate was 0.12 mL/kg/min (~3 IU/kg/min) up to 8.4 mL/min (~210 IU/min). The primary endpoint was hemostatic efficacy rating at surgery end assessed by a blinded Independent Endpoint Adjudication Board using establised objective criteria. Secondary efficacy endpoints were the proportion of patients with INR ≤1.5, and changes in coagulation factor levels (FII, FVII, FIX, FX), at 30 (±15) minutes post-infusion. Safety endpoints included treatment-emergent adverse events (TEAEs), and thromboembolic events (TEEs) and mortality at 3, 21, and 45 days post-surgery. The Farrington-Manning test was used to assess the primary hypothesis that investigational 4F-PCC was non-inferior to control 4F-PCC (80% power, 15% non-inferiority margin). A pre-planned interim analysis was performed on the first 50% of randomized patients (≥185 patients). Results: This Phase 3 study was performed at 24 sites in the USA and Europe from June 2017-November 2021 and randomized 208 patients to investigational 4F-PCC (N=105) or control 4F-PCC (N=103). Baseline characteristics with respect to age, sex, and baseline INR for patients included in the two groups were similar, and the most common location of the planned surgery was gastrointestinal. The pre-procedural estimated maximum blood loss ≥200 mL was also similar in both groups (67.6% vs. 67.0% patients, respectively). Median dose was 25 IU/kg in both groups (range: 16-50 IU/kg investigational 4F-PCC, 15-50 IU/kg control 4F-PCC). Median (range) duration of infusion was 12 (8-50) minutes and 13 (7-30) minutes, respectively. The primary objective was met at the interim analysis and the study was stopped for non-inferiority. In the final analysis, investigational 4F-PCC was non-inferior to the control 4F-PCC, with effective hemostasis at surgery end achieved in 94.3% vs. 94.2% patients (Table 1). The proportion of patients achieving INR ≤1.5 was 78.1% with investigational 4F-PCC vs. 71.8% with control 4F-PCC (proportion difference 0.063; 95% confidence interval [CI] −0.056, 0.181; Figure 1). No patient had surgery cancelled for inadequate INR correction. Mean activities of coagulation factors (FII, FVII, FIX, FX) similarly increased in both groups. Similar proportions of patients in the investigational and control 4F-PCC groups experienced TEAEs (81.9% vs. 77.7%) and drug-related TEAEs (both 1.0%). The most common adverse reactions observed in patients who received investigational 4F-PCC were asthenia, anemia, and catheter site related reaction. One death occurred <21 days post-surgery, in the control 4F-PCC group, which was considered unrelated to the product by the investigator. Two TEEs occurred <21 days post-surgery in the investigational 4F-PCC group (unstable angina on day 5, reported as possibly related). Conclusions: The investigational 4F-PCC was non-inferior to control 4F-PCC for reversal of VKA in patients undergoing urgent surgery with significant bleeding risk. INR reductions and coagulation factor increases supported the primary endpoint. The safety profile was similar between treatment arms and consistent with previous studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

215 Fixed-dose vs. Weight-Based 4-Factor Prothrombin Complex Concentrate Dosing for Reversal of Warfarin-induced Intracranial Hemorrhage

215 Fixed-dose vs. Weight-Based 4-Factor Prothrombin Complex Concentrate Dosing for Reversal of Warfarin-induced Intracranial Hemorrhage

Assessment of Stability of Prothrombin Time, International Normalized Ratio, and Activated Partial Thromboplastin Time Under Different Storage Conditions in Human Plasma.

BackgroundIn this study, we aimed to determine the effects of storage time and temperature on commonly performed coagulation tests such as prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (APTT) in human plasma.MethodologyWhole blood samples from 100 patients were collected in a 3.2% sodium citrate vacutainer. The blood was centrifuged within two hours of collection at 2,000 g for 10 minutes, and the platelet-poor plasma (PPP) obtained was analyzed for PT, INR, and APTT tests at zero hours (baseline) and repeated at 12 hours, 24 hours, and 36 hours on a fully automated coagulation analyzer at various storage conditions (room temperature, refrigerator, and freezer). The results were categorized into two groups: group 1 comprised results with normal coagulation profile and group 2 comprised results with abnormal coagulation profile. The percentage change of the results from baseline (zero hours) for PT, INR, and APTT tests was also studied. A percentage change of more than ±10% from baseline was considered as a clinically significant change.ResultsIn this study, a total of 95 PPP samples were evaluated. The median age of all patients was 44 years (range: 19-65 years). The male-to-female ratio was 0.9:1. The baseline PT, INR, and APTT values were 12.1 seconds, 1.06, and 26.5 seconds, respectively, in group 1, whereas the baseline PT, INR, and APTT values were 19.1 seconds, 1.80, and 36.0 seconds, respectively, in group 2. In the freezer, the samples were stable for PT, INR, and APTT tests at 12 hours, 24 hours, and 36 hours showing a change of <10% from baseline at all three time-points. In the refrigerator, the samples were stable for PT and INR tests for up to 24 hours showing a change of <10% from baseline. In comparison, the samples for the APTT test were not stable at 12 hours, 24 hours, and 36 hours showing a change of 12.1%, 15.5%, and 17.9%, respectively, from the baseline (zero hours). Finally, at room temperature, the samples deteriorated at 12 hours for all coagulation parameters (PT, INR, and APTT).ConclusionsThe patient plasma samples for PT, INR, and APTT tests could be safely stored for up to 36 hours in the freezer. In the refrigerator, samples for PT and INR tests could be safely stored for up to 24 hours while the samples for APTT deteriorated at 12 hours. All patient samples for PT, INR, and APTT tests deteriorated at 12 hours at room temperature.

Elevated international normalized ratio is correlated with large volume transfusion in pediatric trauma patients

BackgroundPediatric trauma patients may benefit from a balanced transfusion strategy, however, determining when to activate massive transfusion protocols remains uncertain. The purpose of this study was to explore whether certain scoring systems can predict the need for large volume transfusion. MethodsWe conducted a retrospective review of pediatric trauma patients who presented to our center and required a transfusion of packed red blood cells. Baseline laboratory and clinical data were used to calculate Trauma Associated Severe Hemorrhage (TASH) score and a previously reported composite of acidosis and coagulopathy. ResultsWe identified 518 pediatric trauma patients who presented to our center between January 1, 2013 and December 31, 2018. These patients were less than 18 years of age (mean 9.6 years) and had an injury severity score ranging from 1 to 50 (mean 11.3). Forty-three patients (8.3%) received a transfusion within 24 hours of presentation, ranging from 4 to 139 mL/kg of packed red blood cells (mean 23.1 mL/kg). Transfusion volume was associated with acidosis and coagulopathy scores (r = 0.37, p = 0.033) and international normalized ratio (INR) (r = 0.34, p = 0.03) but not TASH (p = 0.72). Patients with INR≥1.3 received a higher mean volume of packed red cells compared to those with normal values (34 versus 18 mL/kg, p = 0.046). ConclusionPediatric trauma patients who undergo transfusion of packed red blood cells are likely to require large volume transfusion if their baseline INR is ≥1.3. These patients may benefit from a balanced transfusion strategy, such as utilization of massive transfusion protocols or whole blood.

Abstract 13467: Using Data Analytics Toward Precision Warfarin Dosing in Children With Heart Disease

Introduction: Warfarin is the most common anticoagulant used in children with heart disease. Multiple factors make initial warfarin dose selection and management subjective and variable in children. This variability increases hospital length of stay and impacts efficacy and safety. We sought to develop a data-driven tool to optimize time to warfarin goal dose in children with heart disease. Methods: We collected all demographic and clinical data for all patients &lt;18 years who received warfarin at our institution. We developed a warfarin sensitivity metric (Δ International Normalized Ratio (INR)/mg warfarin) to assess individual medication processing and characterize influential factors. Each inpatient interaction with warfarin was analyzed to assess the impact of concomitant medications, hepatic impairment, and procedure type on dosing, sensitivity, and resultant INR. A linear regression model was formulated to predict ending warfarin dose based on these influential factors. Results: A total of 714 patients were identified; 334 patients met inclusion criteria, and 447 unique encounters with warfarin were analyzed. Warfarin sensitivity was 94.3% higher in patients receiving major anticoagulation enhancing drugs and 13.6% higher in patients with minor liver injury. Patients undergoing a Fontan procedure had increased warfarin sensitivity compared to other procedures; 60% and 66% increase from ventricular assist device and valve replacement, respectively. A linear regression model was used to predict a patient’s warfarin ed dose based on age, baseline INR, other medications, liver injury, and Fontan procedure status. The Fontan binary indicator and age were the most impactful in predicting end dose with an adjusted R 2 of 0.1792. Conclusions: We have identified multiple factors that could affect individualized warfarin. Further analysis will refine our warfarin sensitivity metric and finalize and validate our tool to allow accurate and efficient warfarin dose prediction.

Factors associated with bleeding complications in hernia repair of warfarin users.

In this retrospective study, we aimed to determine factors associated with bleeding complications in patients on long-term warfarin, undergoing inguinal hernia repair using low-molecular-weight heparin (LMWH) bridging. Two-year hospital records yielded 44 inguinal hernia repair patients on long-term warfarin (26 men, 4 women, aged 57.4 [38-72] years). All patients were managed with LMWH bridging. Patient and operative characteristics, LMWH bridging characteristics, and international normalized ratio (INR) values were compared between patients with and without postoperative bleeding complications. Indication for warfarin use was heart valve disease (n=15), atrial fibrillation (n=7), deep venous thrombosis (n=3), cerebrovascular event (n=3), and pulmonary embolism (n=2). Four of the operations were urgent, while the remaining were elective. There were four ecchymosis cases and three hematoma cases in a total of seven patients. Baseline (2.94±0.26 versus 2.16±0.38, p<0.001) and preoperative INR values (1.69±0.67 versus 1.31±0.35, p=0.027) were significantly higher, while postoperative INR values (1.04±0.09 versus 1.2±0.13, p=0.004) were significantly lower in patients having bleeding complications. Baseline, preoperative INR, and postoperative INR were the only variables associated with postoperative bleeding complications in patients undergoing LMWH-bridged inguinal hernia repair. We suggest close monitoring of INR levels in long-term warfarin users, even for relatively low-bleeding risk operations such as inguinal hernia repair.

Comparison between 5 mg and 10 mg warfarin loading doses therapy in cardiac care unit patients at Elobied Hospital, Elobied City- Sudan

Background and objectives: Warfarin sodium therapy is usually initiated with a loading dose to reduce the time needed to reach the target international normalized ratio (INR). The right initial dose of warfarin is controversial. This study aimed to determine the best initial dose of warfarin in terms of safety and efficacy. Patients and methods: This is a prospective hospital-based study. Fifty-nine patients who were admitted to the coronary care unit with clinical indication for warfarin were assigned to use the initial dose of warfarin 5 mg or 10 mg with the target INR of 2-3. An ethical clearance was obtained from the state ministry of health. A written consent was taken from each patient. An INR was measured at baseline and then after 72 hours. The data were then collected using a data sheet including age, gender, baseline INR, initial dose of warfarin, INR after 72 hours and whether the patient developed bleeding or not. Patients on Aspirin and other non-steroidal anti-inflammatory drugs were excluded. The data were analyzed using SPSS version 18. Results: A total number of 59 patients were enrolled in the study. In this series, 59% of patients were females. The mean age of patients was 56 years. Five mg loading dose was used in 35 of patients (59%) while 10 mg was used in 24 patients (41%). The mean INR after 72 hours was 2.8 for those with the initial dose of 5 mg. For those with the initial loading dose of 10 mg the mean INR after 72 hours was 3.2. Minor bleeding occurred in three patients, two of them used the initial loading dose of 5mg and only one patient from the group of 10mg. Conclusion: From this study, it seems that 5 mg loading dose of warfarin is reasonable and cost effective; nevertheless, 10mg initial loading dose is not associated with increased risk of bleeding.

Novel predictors for liver transplantation or death in drug-induced acute liver failure.

Drug-induced liver injury (DILI) is a leading cause of acute liver failure (ALF). Predictors for orthotopic liver transplantation (OLT) or death in drug-induced ALF (DI-ALF) are scarce. In total 33 of 346 patients recruited for our prospective study on potentially hepatotoxic drugs had ALF. DILI diagnosis was based on Roussel Uclaf Causality Assessment Method (RUCAM) score and expert opinion. Area under the receiver operating characteristic (AUROC) curve, Youden's index and positive and negative likelihood ratios were calculated to identify the best performing predictive markers and scores for OLT or death. Poor outcome was associated with lower baseline platelet counts and cholinesterase (CHE) levels, higher International Normalized Ratio (INR) levels and Model for End-Stage Liver Disease (MELD) scores. Yet, AUROC reached a maximum of only 0.71-0.75 for either of those laboratory markers or the MELD score. Notably however, combinations of those scores were highly discriminatory, in particular INR/(CHE*platelet count) and MELD/(CHE*platelet count), showing an AUROC of 0.91, a positive likelihood ratios of 13.78 and a negative likelihood ratios of 0.08. While baseline MELD score, INR, CHE, and platelet counts had limited potential to discriminate between DI-ALF with survival or poor outcome, their combinations were highly associated with OLT or death in patients with DI-ALF.

Warfarin-fenofibrate-interaction-hospital-kuala-lumpur-experience

Case reports in western populations reported that fenofibrate enhances the anticoagulatory effect of warfarin. We are reporting ten cases of warfarin-fenofibrate interaction among Malaysian patients’ cases that were managed at the anticoagulation clinic of Hospital Kuala Lumpur. Patients taking warfarin and micronized fenofibrate 145mg daily concurrently between the year 2014 to 2018 were identified in May 2018. Ten active patients were included, and the relevant data were retrieved retrospectively. All patients received warfarin for stroke prevention in atrial fibrillation (AF), with a target international normalised ratio (INR) of 2 to 3. No dose adjustment was done upon initiation of fenofibrate. Warfarin doses were adjusted to achieve the targeted range but fenofibrate was not discontinued. Eight patients had INR levels above the target range when INR being reassessed between 20 to 62 days after initiation of fenofibrate. Their weekly warfarin doses were between 17.5mg-46.5mg. Baseline INR ranged between 1.6 -3.1. Percentage of dose reduction ranged between 5%-60%. Four of the patients were on other concurrent interacting medications such as statin and levothyroxine. Only one patient, whose case was with an INR 3.1 before initiation of fenofibrate, required admission for hematoma (INR 12). Two patients had INR within the target range, and INR were assessed at 14 and 21 days after fenofibrate initiation. Their weekly warfarin doses were between 24.5mg and 26.5mg while baseline INR was 2.8 and 1.9 respectively. Interaction between fenofibrate and warfarin may increase INR among Malaysian patients, thus close monitoring of INR is warranted. Empirical warfarin dose reduction may be considered upon initiation of this drug combination for patients with AF. The next INR reassessment date should be arranged not later than three weeks after initiation of fenofibrate.

28-Year-Old Man With Recurrent Vertigo, Syncope, and Progressive Memory Impairment

28-Year-Old Man With Recurrent Vertigo, Syncope, and Progressive Memory Impairment

Unfractionated and Low-Molecular-Weight Heparin for Bridging Patients with Left Ventricular Assist Device: An Event-Based Analysis.

The relative efficacy of bridging with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in left ventricular assist device (LVAD) patients has not been established. We performed a retrospective, longitudinal cohort study to evaluate safety and efficacy of bridging strategies including all adult LVAD patients implanted at the Medical University of South Carolina from August 2014 to July 2017. In addition to LMWH and UFH exposure, we recorded any time period a patient did not receive a bridging agent for a subtherapeutic international normalized ratio (INR) value as a control group; these events were defined as nonbridging (NB) events. Multivariable Cox regression survival models were utilized for analysis. There were 563 episodes evaluated in 50 patients. Compared with NB events, UFH (adjusted hazard ratio [aHR], 3.75; 95% CI, 1.45-9.73; p = 0.007) and LMWH (aHR, 2.25; 95% CI, 1.03-4.94; p = 0.043) were both associated with an increased risk of bleeding. Compared with NB events, LMWH was not associated with a decreased risk of clotting events (aHR, 1.56; 95% CI, 0.28-8.73; p = 0.616). In the 381 NB events, a nonsignificant signal was noted toward increased risk of thrombotic events in those with an INR ≤ 1.5 (aHR, 2.99; 95% CI, 0.57-15.8; p = 0.2). Among all 563 episodes, those with a baseline INR ≥ 2.0 demonstrated an increased risk of bleeding events (aHR, 2.35; 95% CI, 1.18-5.69; p = 0.016). Our data suggest that the efficacy of LMWH bridging in LVAD patients warrants further investigation.