Median International Normalized Ratio Research Articles

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.

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.

Scenario Decision-Making About Plasma and Platelet Transfusion for Intracranial Monitor Placement: Cross-Sectional Survey of Pediatric Intensivists and Neurosurgeons.

To report pediatric intensivists' and pediatric neurosurgeons' responses to case-based scenarios about plasma and platelet transfusions before intracranial pressure (ICP) monitor placement in children with severe traumatic brain injury (TBI). Cross-sectional, electronic survey to evaluate reported plasma and platelet transfusion decisions in eight scenarios of TBI in which ICP monitor placement was indicated. Survey administered through the Pediatric Acute Lung Injury and Sepsis Investigators and the American Association of Neurologic Surgeons. Pediatric intensivists and pediatric neurosurgeons. None. A total of 184 participants responded (85 identified as pediatric intensivists and 54 as pediatric neurosurgeons). In all eight scenarios, the majority of respondents reported that they would base their decision-making about plasma transfusion on international normalized ratio (INR) alone (60-69%), or platelet transfusion on platelet count alone (83-86%). Pediatric intensivists, as opposed to pediatric neurosurgeons, more frequently reported that they would have used viscoelastic testing in their consideration of plasma transfusion (32% vs. 7%, p < 0.001), as well as to guide platelet transfusions (29 vs. 8%, p < 0.001), for the case-based scenarios. For all relevant case-based scenarios, pediatric neurosurgeons in comparison with pediatric reported that they would use a lower median (interquartile range [IQR]) INR threshold for plasma transfusion (1.5 [IQR 1.4-1.7] vs. 2.0 [IQR 1.5-2.0], p < 0.001). Overall, in all respondents, the reported median platelet count threshold for platelet transfusion in the case-based scenario was 100 (IQR 50-100) ×10 9 /L, with no difference between specialties. Despite little evidence showing efficacy, when we tested specialists' decision-making, we found that they reported using INR and platelet count in pediatric case-based scenarios of TBI undergoing ICP monitor placement. We also found that pediatric intensivists and pediatric neurosurgeons had differences in decision-making about the scenarios.

Comparison of Coagulation Parameters between Severe and Non-severe COVID-19 Patients Treated in a Tertiary Hospital in Indonesia

Objective: To determine the differences in coagulation features in patients with severe versus non-severe COVID-19. Method: During the period of the study from July 2020 to June 2021, 371 COVID-19 patients were treated at Dr. Hasan Sadikin Hospital. These patients were divided into two groups based on the WHO critera into severe COVID-19 with clinical signs such as severe acute respiratory syndrome to respiratory failure and non-severe cases with no respiratory symptoms. Data analyzed were Prothrombin Time (PT), Activated Partial Thromboplastin Time (aPTT), International Normalized Ratio (INR), fibrinogen, D-dimer, and platelet count.Results: Median INR was significantly higher in patients with severe cases than in non-severe cases (1.04 vs. 0.94, p&lt;0.001), which was also true for median PT (12.3 vs. 12.0 sec, p=0.030) and median fibrinogen (522 vs. 428.5 mg/dl, p=0.004). Similarly, the median D-dimer was significantly higher in severe patients (1.91 vs. 0.75 mg/dl, p&lt;0.001). Median aPTT and platelet count were in normal limits for both severe and non-severe COVID-19 patients (28.6 vs. 29.15 sec, p&gt;0.652 and 246 vs. 242 x103/mm3, p&gt;0.924, respectively).Conclusions: The INR, PT, fibrinogen, and D-dimer can be considered as features that can be used to predict the severity of the disease and to choose the proper treatment for COVID-19 patients.

Vitamin K antagonist-associated microscopic hematuria.

Vitamin K antagonists (VKA) are the most widely used anticoagulants for the prevention of thrombotic events. Several renal adverse effects have been associated with the use of VKA. The main aim of our study was to explore the association between international normalized ratio (INR) levels and microscopic hematuria in patients with VKA. We performed a cross-sectional study of patients treated with VKA that attended the outpatient clinic for routine INR control. A simple urinalysis was performed on the day of the INR control and the precise number of red cells in the urine sediment was quantified. Demographic data, kidney function tests, comorbidities, anticoagulant dose and concomitant treatment were registered. A total of 337 patients were included with median INR levels of 2.6 (IQR 2.1-3.3). 11.9% of the patients presented microscopic hematuria (≥14 RBCs/µl). There was a significant correlation between INR levels and the number of red blood cells in the urine sediment (r=0.201, p=0.024). In the univariate analysis, microscopic hematuria was associated with having an INR >3.5 (19% vs. 10.2%, p=0.046), bacteriuria (15.2% vs. 3.6%, p=0.015), leukocyturia (14.8% vs. 6.6%, p= 0.026), hypertension (16.2% vs. 9.5%, p=0.053), and the use of renin-angiotensin system (RAS) blockers (6.9% vs. 17.2%, p=0.004). Multivariate logistic regression showed an association between microscopic hematuria and RAS blockade (OR 0.38, CI 95% 0.163-0.886, p=0.025), independent from INR levels, hypertension, leukocyturia or bacteriuria. INR overdose was significantly associated with the presence of microscopic hematuria. RAS blockade is an independent protective factor for the presence of microscopic hematuria in anticoagulated patients.

Prehospital Lyophilized Plasma Transfusion for Trauma-Induced Coagulopathy in Patients at Risk for Hemorrhagic Shock

Blood transfusion is a mainstay of therapy for trauma-induced coagulopathy, but the optimal modalities for plasma transfusion in the prehospital setting remain to be defined. To determine whether lyophilized plasma transfusion can reduce the incidence of trauma-induced coagulopathy compared with standard care consisting of normal saline infusion. This randomized clinical trial was performed at multiple centers in France involving prehospital medical teams. Participants included 150 adults with trauma who were at risk for hemorrhagic shock and associated coagulopathy between April 1, 2016, and September 30, 2019, with a 28-day follow-up. Data were analyzed from November 1, 2019, to July 1, 2020. Patients were randomized in a 1:1 ratio to receive either plasma or standard care with normal saline infusion (control). The primary outcome was the international normalized ratio (INR) on arrival at the hospital. Secondary outcomes included the need for massive transfusion and 30-day survival. As a safety outcome, prespecified adverse events included thrombosis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Among 150 randomized patients, 134 were included in the analysis (median age, 34 [IQR, 26-49] years; 110 men [82.1%]), with 68 in the plasma group and 66 in the control group. Median INR values were 1.21 (IQR, 1.12-1.49) in the plasma group and 1.20 (IQR, 1.10-1.39) in the control group (median difference, -0.01 [IQR, -0.09 to 0.08]; P = .88). The groups did not differ significantly in the need for massive transfusion (7 [10.3%] vs 4 [6.1%]; relative risk, 1.78 [95% CI, 0.42-8.68]; P = .37) or 30-day survival (hazard ratio for death, 1.07 [95% CI, 0.44-2.61]; P = .89). In the full intention-to-treat population (n = 150), the groups did not differ in the rates of any of the prespecified adverse events. In this randomized clinical trial including severely injured patients at risk for hemorrhagic shock and associated coagulopathy, prehospital transfusion of lyophilized plasma was not associated with significant differences in INR values vs standard care with normal saline infusion. Nevertheless, these findings show that lyophilized plasma transfusion is a feasible and safe procedure for this patient population. ClinicalTrials.gov Identifier: NCT02736812.

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.

COVID-19 in LVAD Patients Not Associated with Increased Risk of Thrombotic Complications: A Single-Center Experience

PurposeThe COVID-19 pandemic continues to afflict millions worldwide. Scientific knowledge about the virus is expanding including the thrombosis risk associated with COVID-19 infection. However, this data in end-stage heart failure patients requiring mechanical circulatory support is limited. Thus we examined the incidence of thrombotic complications in COVID-19 infected LVAD patients.MethodsWe identified durable LVAD patients infected with COVID-19 from January 2020 to July 2021. We examined anticoagulation regimens and laboratory monitoring parameters that were used. Evidence of thromboembolic phenomena including stroke, venous or arterial and pump thrombosis were evaluated by clinical, radiographic and laboratory assessment.ResultsOf the 146 LVAD patients followed at our institution, 21 (14%) were infected with COVID-19. Median age was 69 years (IQR 58-73), 18 (86%) were men and 12 (57%) had non-ischemic cardiomyopathy. In our cohort, 3 (14%) had HeartWare VAD, 9 (43%) HeartMate 2 LVAD and 9 (43%) HeartMate 3 LVAD. Eighteen (86%) were on warfarin with a median international normalized ratio (INR) of 2 (IQR 1.6-2.9) at the time of COVID-19 diagnosis. Reasons for holding antithrombotic therapy included a history of gastrointestinal and intracranial hemorrhage. Fourteen (66.7%) patients required admission for COVID-19 infection. Two (14%) were not on anticoagulation and had an INR of 1.1 and 1.6 on admission. Patients on anticoagulation had a median INR of 2.4 (IQR 1.9-2.7) during hospitalization. Notably, there was no clinical, radiographic or laboratory evidence of thrombotic complications, including stroke, pump thrombosis, DVT, or arterial thrombosis. Two (10%) patients died due to septic shock and hypoxic respiratory failure resulting in cardiopulmonary arrest.ConclusionAlthough COVID-19 is associated with increased thrombogenicity, there was no evidence of thrombosis in our 21 LVAD patients. Regardless of the patients’ anticoagulation status or INR, patients did not experience thrombotic events despite a theoretically heightened risk during acute COVID-19 infection.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Fixed-dose three-factor prothrombin complex concentrates is safe and effective in warfarin reversal.

Reversal of warfarin with prothrombin complex concentrates (PCC) is required in cases of significant bleeding or need for urgent surgery. A weight-based regimen is commonly, but a fixed-dose approach is also feasible with clinically equivalent outcomes. The purpose of this audit is to review the clinical and laboratory outcomes of patients treated in our centre where fixed-dose PCC is used for warfarin reversal. The primary objective was to evaluate the post-reversal international normalised ratio (INR). The secondary objectives were the proportion of patients requiring repeat PCC and 30-day complication rates (death, haemorrhage and thrombosis). A subgroup analysis was also performed to compare the outcomes of those who received a dose of ≤15 IU/kg (reduced dose) with those who received >15 IU/kg (standard dose). Patients who received three-factor PCC for warfarin reversal between 1 January and 31 December 2016 were identified and analysed. Clinical data and PCC dosages were extracted from electronic patient records. A total of 144 patients were analysed. The median INR pre-reversal was 3.25 (range 1.4-10), which reduced to 1.5 (0.9-3.0) post-reversal. Eighty-seven percent of patients achieved a post-reversal INR of less than 2 and 55% less than 1.5. Sixteen patients required a repeat dose. Complications occurred in 22 (15.3%) patients, which consisted of 15 deaths, 7 thrombosis and 2 haemorrhage. No statistically significant differences in the primary and secondary outcomes were noted between reduced-dose and standard-dose subgroups. Our results support the use of fixed-dose PCC for warfarin reversal in a day-to-day clinical practice in a hospital setting.

Time to Peak International Normalized Ratio Rise in Acute and Acute-on-Chronic Warfarin Overdoses.

Guidelines exist on the management of supratherapeutic/subtherapeutic international normalized ratio (INR) values for patients on warfarin. However, there is a paucity of the literature relating to an acute overdose of warfarin. This is a retrospective cohort study for all acute and acute-on-chronic (AOC) warfarin overdoses reported to the Maryland Poison Center in patients ≥12 years between January 1st, 2000, until October 31st, 2019, managed in a health care facility. The primary outcome was to determine the time after presentation to peak INR. Secondary outcomes included risk factors associated with INR >10 and describing patient characteristics. A total of 163 overdoses were included, 68 acute and 95 AOC. In patients who did not receive reversal therapies, INR peaked at a median value of 3.8 (interquartile range 2.6-5.5) between 24 and 36 hours. The median time to phytonadione was 22.0 hours. Most patients received phytonadione (62.0%), with fewer receiving blood products (16.6%). The median warfarin dose ingested was 75 mg. The AOC group had a greater mean age (56 vs. 43 years), median INR value (2.4 vs. 1.4), and men (62.1% vs. 41.2%). Factors associated with an INR > 10 included initial INR and reported quantity ingested. Peak INR was greater in the AOC than the acute overdose group (6.1 vs. 3.4), although the bleeding rate was similar. Peak INR values after warfarin overdose occur between 24 and 36 hours after presentation. Initial INRs and reported quantity ingested may be useful to predict those needing treatment.

INR Response to Low-Dose Vitamin K in Warfarin Patients.

Literature suggests that 2 mg of vitamin K intravenously (IV) provides a similar effect as 10 mg to reverse warfarin. Doses <5 mg haven't been studied in depth. The objective was to determine the international normalized ratio (INR) reduction effect of ultra low-dose (ULD) IV vitamin K. This retrospective, observational cohort study compared IV vitamin K doses of 0.25-0.5 mg (ULD) versus 1-2 mg (standard low dose [SLD]). The primary outcome assessed ΔINR at 36 hours; secondary outcomes assessed ΔINR at 12 hours and 30-day venous thromboembolism (VTE) and mortality rates. Of 88 patients identified (median baseline INR [IQR], 5.1 [3.1, 7.3] vs 4.5 [2.8, 8.2], ULD vs SLD, respectively), 59 had an INR at 12 hours. The ULD had fewer 12-hour INR values <2, with no statistical difference in the ΔINR at 12 hours between the ULD and SLD cohorts (median ΔINR, 2.2 [1.1, 3.4] vs 2.2 [1.1, 6.3]; P = 0.54; median INR, 2.3 vs 1.8). A total of 41 patients had both a 12- and 36-hour INR. No significant difference in the ΔINR between the 12- and 36-hour values occurred (median ΔINR, 0.52 [0.2, 0.91] vs ΔINR, 0.46 [0.18, 0.55]; P = 0.61), suggesting no rebound or excessive reversal and no difference in 30-day rates of VTE (P > 0.99) or death (P = 0.38). ULD IV vitamin K reversed INR similarly to doses of 1-2 mg without rebound. A ULD strategy may be considered in patients requiring more cautious reversal.

The outcome of three-factor Prothrombin Complex Concentrate (3F-PCC) in warfarin reversal: A single center retrospective cohort study

IntroductionThree-factor Prothrombin Complex Concentrate (3F-PCC) containing factors II, IX and X was introduced to Malaysian public hospitals for warfarin reversal since 2017. Local studies on the outcomes of 3F-PCC use are limited. ObjectiveThis study aimed to determine the extent of target international normalized ratio (INR) achievement and adverse drug reactions (ADRs) associated with 3F-PCC use in warfarin reversal. Materials and methodsThis retrospective cohort study analyzed data from adult patients on warfarin who received 3F-PCC for anticoagulation reversal between September 2017 to January 2020. Study endpoints included achievement of target INR, ADRs and in-hospital mortality. ResultsSeventy-seven patients with a median age of 65.0 (55.5–75.0) years comprising of 50.6% (n ​= ​39) men were included. Fifty-one patients required 3F-PCC for life-threatening (29.9%, n ​= ​23) and clinically significant (36.4%, n ​= ​28) bleeding. Initial INRs ranged from 1.69 to undetectable high (>24). All patients had INR reduction, of which 40.3% (n ​= ​31) achieved target INR whereas 6.5% (n ​= ​5) achieved INR below target range. Median INR reduced from 4.14 (2.89–8.13) to 1.57 (1.33–1.97). Race, gender, age, initial INR and concomitant use of adjuvant reversal therapy did not affect target INR achievement. Three (3.9%) out of four ADRs observed were associated with mortality including suspected acute coronary syndrome (n ​= ​2) and disseminated intravascular coagulopathy (n ​= ​1) among those with life-threatening bleeding. The incidence of in-hospital mortality was 19.5% (n ​= ​15). ConclusionThe use of 3F-PCC (Prothrombinex-VF®) produces variable reduction in INR in our population without apparent risk of thromboembolic events and in-hospital mortality.

Weight-Based Dosing Versus a Fixed-Dose Regimen of 4-Factor Prothrombin Complex Concentrate in Obese Patients Requiring Vitamin K Antagonist Reversal.

Despite an increase in the use of fixed-dose protocols of 4-factor prothrombin complex concentrate (4F-PCC) for the reversal of vitamin K antagonists (VKAs), there remains a paucity of data in obese patients. In this study, we aimed to compare the proportion of patients attaining international normalized ratio (INR) goals using a weight-based dosing strategy versus a fixed-dose regimen of 4F-PCC. This was a retrospective study conducted in patients 18years of age or older, weighing ≥ 100kg, who received either a weight-based dose or fixed dose of 4F-PCC (2000 units) for the reversal of VKA, and had a documented baseline and post-treatment INR. The primary outcome was the proportion of patients achieving an INR of < 2 for all indications of warfarin reversal, except in patients with intracranial hemorrhage, where the goal was an INR of < 1.5. A total of 44 patients met the inclusion criteria; 25 patients in the weight-based dosing group and 19 patients in the fixed-dose group. The median baseline INR was similar in both groups (weight-based dosing group 3.2 [interquartile range {IQR} 2.8-3.7] vs fixed-dose group 3.0 [IQR 2.7-4.9], p = 1). The median post-treatment INR was significantly lower in the weight-based dosing group compared to the fixed-dose group (1.3 [IQR 1.2-1.5] vs 1.6 [IQR 1.5-1.9], p < 0.01). However, there was no significant difference in the primary outcome between both groups (weight-based dosing strategy 84% vs fixed dose strategy 90%, p =0.68). Our findings suggest that a fixed-dose regimen of 2000 units in obese patients weighing ≥ 100kg is adequate to achieve these INR goals.

Prothrombin complex concentrate for vitamin K antagonist reversal in traumatic intracranial hemorrhage

ObjectiveAdministration of prothrombin complex concentrate (PCC) is recommended for vitamin K antagonist (VKA) reversal in patients with severe bleeding complications. However, there are only limited data available on its use for VKA reversal in patients with traumatic intracranial hemorrhage (ICH). MethodsData from all anticoagulated patients referred to our hospital for treatment of traumatic ICH and who received PCC for anticoagulation reversal were retrospectively analysed with specific focus on bleeding and thromboembolic complications during the further in-hospital course. ResultsA total of 142 patients were included in the present study. The median age was 78 years (Interquartile range [IQR]: 72–84) and the median Glasgow Coma Scale (GCS) score on admission was 12 (IQR: 7–14). Median International Normalized Ratio (INR) on admission was 2.5 [IQR: 2.0–3.3] and decreased to 1.2 [IQR: 1.1–1.3] following administration of a median dose of 2000 I.U. PCC [IQR: 1500–2625]. The in-hospital mortality rate was 13% and the median GCS of survivors at discharge was 14 [IQR: 12–15]. Thromboembolic events after PCC administration occurred in 4 patients (2.8%). The overall one-year mortality rate in this patient cohort was 49%. ConclusionsPCC administration rapidly normalises INR and facilitates urgent neurosurgical procedures in anticoagulated patients with traumatic ICH.

Outbreak of mass poisoning with anticoagulant rodenticides

Introduction. Rodenticides are pesticides used in the control of rodents. In Russia, only anticoagulant rodenticides are allowed to be used.Aim: describe a case of mass poisoning with anticoagulant rodenticides.Main findings. An observation is given of poisoning with anticoagulant rodenticides in 80 people due to the consumption of sunflower oil produced from seeds that have been treated with rodenticides. The victims had a pronounced hemorrhagic syndrome: all had ecchymosis, 79 % had macrohematuria, 1 had uterine bleeding, 3 had intra-abdominal hemorrhages, 16 had nosebleeds, 2 had gastrointestinal bleeding, and 2 had intracerebral hemorrhages. The international normalized ratio (INR) was not definable in 56 patients, while the remaining patients had a median INR of 3.9 (fluctuations from 1.29 to 16.2). Activated partial thromboplastin time (APTT) was not definable in 7 patients; the remaining patients had the median APTT of 65 seconds. Three of the victims died of hemorrhagic syndrome. This article analyzes the conducted therapy. In life-threatening hemorrhagic syndrome induced by rodenticide poisoning or warfarin overdose the drugs of choice are prothrombin complex concentrates and recombinant activated clotting factor VII, but not fresh frozen plasma and vicasol. For long-term therapy, vitamin K1 should be used.Conflict of interest: the authors declare no conflict of interest.

Quality of anticoagulation with warfarin in rural Chhattisgarh, India

Background & objectives:In most of rural India, warfarin is the only oral anticoagulant available. Among patients taking warfarin, there is a strong association between poor control of the international normalized ratio (INR) and adverse events. This study was aimed to quantify INR control in a secondary healthcare system in rural Chhattisgarh, India.Methods:The INR data were retrospectively obtained from all patients taking warfarin during 2014-2016 at a secondary healthcare system in rural Chhattisgarh, India. Patients attending the clinic had their INR checked at the hospital laboratory and their warfarin dose adjusted by a physician on the same day. The time in therapeutic range (TTR) was calculated for patients who had at least two INR visits.Results:The 249 patients had 2839 INR visits. Their median age was 46 yr, and the median body mass index was 17.7 kg/m2. They lived a median distance of 78 km (2-3 h of travel) from the hospital. The median INR was 1.7 for a target INR of 2.0-3.0 (n=221) and 2.1 for a target of 2.5-3.5 (n=28). The median TTR was 13.0 per cent, and INR was subtherapeutic 66.0 per cent of the time. Distance from the hospital was not correlated with TTR.Interpretation & conclusions:INR values were subtherapeutic two-thirds of the time, and TTR values were poor regardless of distance from the health centre. Future studies should be done to identify interventions to improve INR control.

Control of Anticoagulation Therapy in Patients with Atrial Fibrillation Treated with Warfarin: A Study from the Chinese Atrial Fibrillation Registry

BackgroundSeveral factors determine the efficacy of warfarin anticoagulation in patients with non-valvular atrial fibrillation (NVAF). This study aimed to use data from the Chinese Atrial Fibrillation Registry study to assess the control of anticoagulation therapy in Chinese patients with NVAF treated with warfarin.Material/MethodsFrom the Chinese Atrial Fibrillation Registry study the anticoagulant use and dosing, the time in therapeutic range (TTR) of the international normalized ratio (INR), and standard deviation of the observed INR values (SDINR), and their influencing factors were evaluated.ResultsThe median INR and SDINR were 2.04 (IQR 1.71–2.41) and 0.50 (IQR, 0.35–0.69), respectively. The median TTR was 51.7% (IQR, 30.6–70.1%) and only 25.1% had a TTR ≥70%. Age was ≥70 years (OR, 0.72; 95% CI, 0.55–0.94; P=0.015), bleeding history (OR 0.48; 95% CI, 0.23–0.89; P=0.029), the use of a single drug (OR, 0.62; 95% CI, 0.42–0.92; P=0.016), more than drug (OR, 0.60; 95% CI, 0.41–0.88; P=0.009), and lack of assessment of bleeding risk (OR, 0.72; 95% CI, 0.54–0.97; P=0.033) were associated with TTR <70% (INR 2.0–3.0). Coronary heart disease (CHD) and peripheral artery disease (PAD) (OR, 0.69; 95% CI, 0.52–0.90; P=0.007) and diabetes mellitus (OR, 0.79; 95% CI, 0.62–0.99; P=0.044) were associated with increased variability in INR (SDINR ≥0.5).ConclusionsIn Chinese patients with NVAF, warfarin anticoagulation was associated with lower TTR and less stable anticoagulation than in current guidelines, and risk factors for reduced safety and efficacy were identified.

High-Dose 4-Factor Prothrombin Complex Concentrate for Warfarin-Induced Intracranial Hemorrhage.

The ideal dosing regimen of 4-factor prothrombin complex concentrate (4FPCC) after warfarin-induced intracranial hemorrhage (WICH) remains unclear. We sought to compare the safety and efficacy of the 4FPCC package insert dosing strategy (standard dose [SD]) with our institutional guideline for high-dose (HD) 4FPCC for patients with WICH. We compared the percentage of SD and HD patients who achieved an international normalized ratio (INR) ≤1.3 at a single institution between January 2014 and July 2017. Additionally, we assessed hematoma expansion, recurrence of INR > 1.3, and occurrence of thrombotic events within 7 days of 4FPCC administration. Of 48 patients with WICH, 30 received SD and 18 received HD. The median baseline INR was 2.5 (2.0-3.8) for SD patients and 3.3 (2.5-5) for HD patients (P = .147). Successful achievement of an INR ≤ 1.3 after the initial 4FPCC dose was obtained in 70% of patients in the SD group and 94% of patients in the HD group (P = .124). A higher percentage of patients in the SD group had an INR > 1.3 at some point after admission (30% vs 6%; P = .053). There was a trend toward more hematoma expansion in the SD group, but this was not statistically significant (17% in the SD group vs 0% in HD group; P = .056). There were 2 thrombotic events: one deep vein thrombosis in each group (P = .243). High-dose 4FPCC appears to be more effective at lowering INR and preventing bleed expansion in patients with WICH, while maintaining a similar safety profile.