Emergent Warfarin Reversal Research Articles

744: FIXED-DOSE 4F-PCC IS SUPERIOR TO WEIGHT-BASED DOSING IN DELIVERY TIME AND COST WITH EQUAL REVERSAL

Introduction: Patients who suffer an intracranial hemorrhage (ICH) while on anticoagulation have higher mortality than those who are not. 4-factor prothrombin complex (4F-PCC) has become the standard therapy for emergent warfarin reversal and is traditionally dosed based on patient weight and INR. This strategy can lead to increased time before administration. A fixed-dose strategy has been found comparable in efficacy and may reduce the time to delivery. The goal of this study was to evaluate fixed-dose vs weight-based dosing strategies for 4F-PCC time to administration in patients with an ICH. Methods: A retrospective analysis was conducted at a single rural ACS verified Level 2 Trauma center in pts ≥18 y/o on warfarin with ICH who received 4F-PCC. Continuous variables were summarized using mean (±95% CI) and compared using two-tailed tests; p values ≤0.05 were considered statistically significant. Results: A total of 46 ICH pts were reversed by 4F-PCC (Fixed, n=27 and Weight, n=19). Baseline characteristics including admission GCS, ICH type on admit head CT, and baseline INR were statistically equivalent (p>0.05). Total units of 4F-PCC were reduced in the fixed-dose group (1623.3 (95% CI [1515.1, 1731.4]) vs. 2525.1 units, (95% CI [2091.7, 2895.4]); p=0.001) as was dose per kg (19.2 units/kg (95% CI [17.2, 21.2]) vs. 28.9 units/kg (95% CI [24.8, 33.0]); p < 0.001). This resulted in a mean cost saving of $1461 per patient. Eleven percent of patients required additional 4F-PCC (p=0.951). Total time from order to delivery was significantly reduced with the fixed-dose strategy, 28 (95% CI [25, 31]) vs. 43 (95% CI [33, 53]) minutes (p=0.015). Hospital length of stay (LOS), ICU LOS, and mortality were equivalent in groups with similar mechanism (traumatic vs non-traumatic; p>0.05). INR reversal success (INR ≤1.5 after 4F-PCC) was 84.2% vs. 85.2% (p=1.00) and total INR change was also comparable (2.1 vs. 2.4, p=0.68); with no difference in adverse thromboses between groups (p=1.00). Conclusions: A fixed-dosed strategy reduced time to administration of 4F-PCC for warfarin reversal in ICH as compared to a weight-based strategy. There was no increase in LOS, mortality, or need for additional 4F-PCC dosing. This also resulted in significant cost savings.

Comparison of 3-factor versus 4-factor prothrombin complex concentrate for emergent warfarin reversal: a systematic review and meta-analysis

BackgroundPatients requiring emergent warfarin reversal (EWR) have been prescribed three-factor prothrombin complex concentrate (PCC3) and four-factor prothrombin complex concentrate (PCC4) to reverse the anticoagulant effects of warfarin. There is no existing systematic review and meta-analysis of studies directly comparing PCC3 and PCC4.MethodsThe primary objective of this systematic review and meta-analysis was to determine the effectiveness of achieving study defined target INR goal after PCC3 or PCC4 administration. Secondary objectives were to determine the difference in safety endpoints, thromboembolic events (TE), and survival during the patients’ hospital stay. Random-effects meta-analysis models were used to estimate the odds ratios (OR), and heterogeneity associated with the outcomes. The Newcastle-Ottawa Scale was used to assess study quality, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.ResultsTen full-text manuscripts and five abstracts provided data for the primary and secondary outcomes. Patients requiring EWR had more than three times the odds of reversal to goal INR when they were given PCC4 compared to PCC3 (OR = 3.61, 95% CI: 1.97–6.60, p < 0.001). There was no meaningful clinical association or statistically significant result between PCC4 and PCC3 groups in TE (OR = 1.56, 95% CI: 0.83–2.91, p = 0.17), or survival during hospital stay (OR = 1.34, 95% CI: 0.81–2.23, p = 0.25).ConclusionPCC4 is more effective than PCC3 in meeting specific predefined INR goals and has similar safety profiles in patients requiring emergent reversal of the anticoagulant effects of warfarin.

Fixed-dose prothrombin complex concentrate for emergent warfarin reversal among patients with intracranial hemorrhage.

Four-factor prothrombin complex concentrate (4PCC) is the preferred reversal agent for warfarin reversal, although the ideal dose is unknown. Fixed-dose 4PCC offers simplified dosing compared to standard-dosing algorithms with potentially lower risks of thromboembolic complications given lower doses are typically utilized. Retrospective, observational, multicentered, pre- post- study of patients who received 4PCC for warfarin reversal among four hospitals within the same regional health system. Standard-dose patients received variable doses ranging from 25 to 50 units/kg based on total body weight and initial INR and fixed-dose patients received 2000 units. The primary outcome was achievement of a target INR ≤ 1.4 on the first post-4PCC INR result. After exclusions, 48 and 42 patients were analyzed in the standard-dose and fixed-dose groups, respectively. There was no difference in the ability to achieve a target INR of ≤1.4 (82.6% vs 81.5%, p = 0.14). Both groups received the same median dose of 2000 units, although fixed-dose patients actually received a higher weight-based dose than standard-dose patients (27 units/kg vs 24.5 units/kg). A fixed-dose 4PCC regimen of 2000 units among patients with ICH was as effective as standard-dose 4PCC for INR reversal among patients with ICH. However, fixed-doses of 2000 units at times exceeded standard 4PCC doses which may be contradictory to the goals of fixed-dose 4PCC for warfarin reversal.

Single Centre Retrospective Analysis of Patients Who Underwent Emergency Reversal of Warfarin Anticoagulation

IntroductionWarfarin is used in the treatment and prevention of thromboembolic disorders, with the risk of bleeding ranging from 1% to 3% per year resulting in hospitalisation or death. Emergency reversal of warfarin is indicated when warfarin therapy is complicated by bleeding, prior to emergency procedures / surgeries, and in patients who have supra-therapeutic INR with high risk of bleeding. Launceston General Hospital is a 330-bed hospital in regional Australia and we practise warfarin reversal in accordance with the national guidelines. Prothrombinex-VF (PTx-VF) is a 3-factor prothrombin complex concentrate (PCC) used in Australia, which contains factors II, IX, and X mainly. Due to low factor VII levels in PTx-VF, addition of 1 unit of FFP with PTx-VF is generally recommended, however there is lack of supportive evidence. There are a few reports of successful use of 3-factor PCC without the use of FFP. Hence in our hospital, the addition of FFP to PTx-VF for warfarin reversal is based on clinician's preference.Aim of studyTo study the clinical, laboratory, therapeutic and outcome data on patients who underwent emergency reversal of warfarin anticoagulation, and to compare the warfarin reversal (INR values) after administration of PTx-VF vs PTx-VF + FFP.MethodsWe performed a retrospective study of patients who underwent emergency reversal of warfarin in our hospital between January 2011 and December 2013. All the patients who underwent emergency reversal of warfarin with PTx-VF +/- FFP were captured from the blood bank database. Patients who received PTx-VF for indications other than emergency warfarin reversal and those with insufficient data were excluded from the study. The clinical, laboratory and transfusion data of these patients and the warfarin reversal strategies and clinical outcomes across different clinical settings were analysed. Non-parametric statistical analysis was used to compare the differences in post-treatment INR values in the PTx-VF vs PTx-VF + FFP groups and statistical significance was assumed at a P value of less than 0.05.ResultsA total number of 125 patients who underwent emergency warfarin reversal were included in the study. The median age was 77 years (range: 28 - 95) with 78 males (62%) and 48 females (38%). Table-1 presents clinical characteristics of the patients. Three clinical subgroups were identified - major bleeding in 61 patients (49%), emergency surgery in 54 patients (43%) and supra-therapeutic INR with high risk of bleeding in 10 patients (8%). Table-2 compares the clinical, laboratory, management and outcome characteristics in these subgroups. According to clinicians' preference, 56% of patients received PTx-VF alone, while 44% received PTx-VF + FFP. Statistically there were no differences in median INR values performed within 6 - 12 hours after administration of PTx-VF vs PTx-VF + FFP in all patients (P = 0.10), bleeding subgroup (P = 0.08) and emergency surgery subgroup (P = 0.24); and the number of patients in the supra-therapeutic INR subgroup was very small for evaluation. Overall 4 patients died due to warfarin-related complications, all of them in the bleeding subgroup.ConclusionIn our study majority (64%) of patients were above 75 years and the most common (69%) reason for warfarin anticoagulation was atrial fibrillation, which were similar in other studies. We observed that GI bleeding was the most common cause for warfarin reversal. Rapid INR correction with good clinical haemostasis occurred in most of the patients after administration of PTx-VF +/- FFP. The mortality rate in our cohort was 3% (4 of 125), and intracranial bleeding accounted for 75% (3 of 4) deaths. Among 14 patients who experienced intracranial bleeding, either spontaneous or induced by trauma, three (21%) died. There were no significant differences in the post-treatment INR values with PTx-VF alone when compared to PTx-VF + FFP, overall and also in the clinical subgroups. The major advantage of warfarin over DOACs is the rapid reversibility in emergency settings and we demonstrated that our 3-factor PCC (PTx-VF) was effective in emergency reversal of warfarin, without the need for FFP. There are a few limitations in this study since it is retrospective and observational. Hence prospective studies are required for better evaluation of the clinical characteristics, and the efficacy of 3-factor PCC without FFP in emergency reversal of warfarin anticoagulation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Emergent Warfarin Reversal With Fixed-Dose 4-Factor Prothrombin Complex Concentrate

Four-factor prothrombin complex concentrate (4FPCC) is used for emergent warfarin reversal, but dosing remains controversial. Following approval, further studies have evaluated a variety of fixed-dose regimens. The studies utilized lower doses as compared with package insert dosing and provided data in regard to efficacy, safety, and cost savings. Further data are needed, however, to determine which fixed-dose regimen provides optimal efficacy and safety for emergent warfarin reversal. The purpose of this study is to evaluate the efficacy, safety, and cost-savings of a fixed-dose 4FPCC protocol. This multicentered, retrospective chart review of adult patients requiring 4FPCC for emergent warfarin reversal utilized a fixed-dose regimen of 1500 units. The 2 primary outcomes were the proportion of patients who achieved a post-4FPCC international normalized ratio (INR) of ≤1.5 and ≤2. Secondary outcomes included thrombotic events within 7 days of 4FPCC administration and survival to discharge. A cost analysis was also performed to identify potential cost savings. Of the 64 patients included, 44 (68.8%) achieved a post-4FPCC INR ≤1.5, and 61 (95.3%) achieved a post-4FPCC INR ≤2.0. No thrombotic events were reported; 55 (85.9%) patients survived to hospital discharge. More than $1000 was saved per patient via utilization of the fixed-dose protocol. A fixed-dose of 1500 units of 4FPCC successfully achieved a target INR of ≤1.5 in the majority of patients and resulted in no thrombotic events. This study adds to the data evaluating alternative 4FPCC dosing regimens in comparison to package insert recommended dosing.

304 Comparative Thromboembolic Risk of 3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal

Prothrombin complex concentrates (PCCs) rapidly reverse anticoagulant-associated coagulopathy; however, thromboembolic complications (TECs) are a known risk. Studies designed to evaluate thromboembolic risk between 3-factor and 4-factor PCC have not been performed. The purpose of this study was to evaluate the risk of TEC between 3-factor and 4-factor PCC for warfarin reversal. This single center, multi-campus, retrospective cohort study included adult patients on warfarin who received at least one dose of 3-factor or 4-factor PCC for emergent warfarin reversal from December 1, 2011 to September 30, 2018. Hemophiliacs, pregnancy, incarcerated, and concomitant administration of recombinant FVIIa were excluded. The primary outcome was comparison of early TECs between 3-factor and 4-factor PCC for emergent warfarin reversal. Early TEC was defined as an acute deep venous thrombosis, pulmonary embolism, myocardial infarction, transient ischemic attack, or stroke within 14 days of PCC. Statistical analysis was performed with Fisher’s exact test and Student’s t-test as appropriate. Two-hundred and fifty patients were included with 125 patients in each group. Median age was 68 (IQR 59,80) years. Patients were most often anticoagulated for atrial fibrillation in both 4-factor and 3-factor PCC groups (70% vs 59%, p=0.11). The most common indication for reversal in both groups was intracerebral hemorrhage (50% vs 62%, p=0.098). TECs occurred in 26 patients (10.4%), with a median time to TEC of 6.5 (IQR 2,9.75) vs 4 (IQR 1.5,7.25) days (p=0.3). There was no difference in the rate of early TEC with 4-factor compared to 3-factor PCC (11.2% vs 9.6%, p=0.84). Arterial TECs trended towards being more common with 4-factor PCC (57.1% vs 16.7%, p=0.051). Risk factors for TECs present in >50% of the total TEC population included cardiovascular disease (88%) and concomitant administration of blood and/or reversal agents (81%). Of the 100 patients started on venous thromboembolism (VTE) prophylaxis, there was a trend towards delay of VTE prophylaxis initiation in patients who developed TECs (3.65 vs 2.70 days; 95% CI -0.39 to 2.29, p=0.16). In the 82 patients who had anticoagulation re-initiated, there was significant delay in time to re-initiation in patients experiencing TECs (9.07 vs 3.98 days; 95% CI 2.89 to 7.69, p<0.01). Patients had a lower median INR after receiving 4-factor PCC (1.4 vs 1.5 p<0.001) and greater frequency of achieving an INR <1.4 (45.2% vs 27.3%, p<0.01). Mean hospital length of stay trended towards being longer with 4-factor PCC (10.28 vs 8.96 days, p=0.23), while overall mortality was lower compared to 3-factor PCC (15.2% vs 26.4%, p=0.043). There was no difference in the early TEC rate between 3-factor and 4-factor PCC when administered for emergent warfarin reversal; however, this may be the first study to identify a trend towards greater risk of arterial thrombus with 4-factor PCC. It is prudent to assess patient-specific risk factors for development of TECs prior to warfarin reversal. Additionally, early re-initiation of anticoagulation may decrease the risk of TECs. The risk-benefit of anticoagulation re-initiation must be considered in all patients, especially those at risk for development of an arterial TEC.

Thromboembolic Risk of 4-Factor Prothrombin Complex Concentrate versus Fresh Frozen Plasma for Urgent Warfarin Reversal in the Emergency Department.

IntroductionWarfarin is a potent anticoagulant used for the prevention and treatment of venous and arterial thrombosis. Occasionally, patients require emergent warfarin reversal due to active bleeding, supratherapeutic international normalized ratio, or emergent diagnostic or therapeutic interventions. Various agents can be used for emergent warfarin reversal, including fresh frozen plasma (FFP) and 4-factor prothrombin complex concentrate (4F-PCC). Both FFP and 4F-PCC are generally considered safe; however, both agents contain coagulation factors and have the potential to provoke a thromboembolic event. Although clinical trials have compared the efficacy and safety of FFP and 4F-PCC, data are limited comparing the risk of thromboembolism between the two agents.MethodsA retrospective chart review was performed at a single, urban, academic medical center comparing the incidence of thromboembolism with FFP or 4F-PCC for warfarin reversal during a three-year period in the emergency department (ED) at Massachusetts General Hospital. Patients were included in the study if they were at least 18 years of age and were on warfarin per electronic health records. Patients were excluded if they had received both FFP and 4F-PCC during the same visit. The primary outcome was the frequency of thromboembolism within 30 days of 4F-PCC or FFP. Secondary outcomes included time to thromboembolic event and in-hospital mortality.ResultsThree hundred and thirty-six patients met the inclusion criteria. Thromboembolic events within 30 days of therapy occurred in seven patients (2.7%) in the FFP group and 14 patients (17.7%) in the 4F-PCC group (p=<0.001). Death occurred in 39 patients (15.2%) who received FFP and 18 patients (22.8%) who received 4F-PCC (p=0.115). Since the 4F-PCC group was treated disproportionately for central nervous system (CNS) bleeding, a subgroup analysis was performed including patients requiring reversal due to CNS bleeds that received vitamin K. The primary outcome remained statistically significant, occurring in four patients (4.1%) in the FFP group and nine patients (14.1%) in the 4F-PCC group (p=0.02).ConclusionOur study found a significantly higher risk of thromboembolic events in patients receiving 4F-PCC compared to FFP for urgent warfarin reversal. This difference remained statistically significant when controlled for CNS bleeds and administration of vitamin K.

Evaluation of Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal in Patients with Intracranial Hemorrhage

BackgroundDifferent strategies exist for dosing four-factor prothrombin complex concentrate (PCC4) for international normalized ratio (INR) reversal in the setting of life-threatening bleeding. Fixed doses ranging from 1000 IU to 1750 IU have demonstrated efficacy similar to weight-based dosing, however, few studies look exclusively at intracranial hemorrhage (ICH). ObjectiveOur aim was to evaluate whether a fixed dose of 1000 IU of PCC4 achieves INR reversal similar to weight-based dosing in patients with ICH who were anticoagulated with warfarin. MethodsWe compared a weight-based dose vs. 1000 IU PCC4 between January 2014 and January 2017. The primary end point was achieving an INR < 1.5. Secondary end points included in-hospital mortality, patient disposition, and reversal defined by INR < 1.6. ResultsA total of 31 patients were included in the weight-based group and 30 were included in the fixed-dose group, with baseline INRs of 2.98 and 2.84, respectively (p = 0.39). Twenty-two patients (71%) achieved an INR < 1.5 in the weight-based group vs. 16 (53%) in the fixed-dose group (p = 0.15), while 25 (81%) achieved an INR < 1.6 in the weight-based group vs. 22 (73%) in the fixed-dose group (p = 0.49). There was no difference in the number of patients discharged to home (19% vs. 20%; p = 0.95) or in-hospital mortality (26% vs. 27%; p = 0.93). ConclusionsWe found a non−statistically significant difference in warfarin reversal to an INR goal of < 1.5 when comparing a fixed dose of 1000 IU PCC4 and a weight-based dose for ICH. Further studies correlating clinical outcomes with INR reversal are needed.

Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis

Published literature suggests that a fixed-dose 4-factor prothrombin complex concentrate (4FPCC) may be efficacious in managing warfarin-associated hemorrhage, however the ideal dose is still unclear. The purpose of this evaluation was to determine the efficacy of fixed-dose 4FPCC in reducing the International Normalized Ratio (INR) to ≤ 1.5 among warfarin patients with need for urgent or emergent anticoagulation reversal. Starting October 2016, our institution changed from standard 4FPCC FDA-labeled dosing based on the patient's presenting INR and weight, to a fixed-dose of 1500 units for all patients requiring urgent or emergent warfarin reversal. We conducted a retrospective evaluation, after implementation, with the primary outcome being the proportion of patients who achieved an INR ≤ 1.5 with a single fixed-dose of 1500 units of 4FPCC. Secondary outcomes assessed included: medication turnaround times, attainment of target INR ≤ 2 or clinical hemostasis (as judged by the prescribing provider), use of rescue doses, thrombotic events, and cost savings. A total of 37 patients were included in the analysis. Almost 75% of patients achieved an INR ≤ 1.5 after a single fixed dose of 1500 units, and 100% of patients achieved an INR ≤ 2. The median pre- and post-dose INRs were 3.06 and 1.32 respectively. Based on this evaluation, the administration of a fixed dose of 1500 units 4FPCC, was shown to be effective in adequately reversing the INR in the majority of patients with minimal thrombotic risks.

Prothrombin complex concentrate for emergent reversal of warfarin: an international survey of hospital protocols.

For emergent warfarin reversal, four-factor prothrombin complex concentrates (4FPCCs) are recommended by many international guidelines. We surveyed international clinical sites including members of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Most sites have emergent warfarin reversal protocols (53% use PCC, 25% use PCC+ plasma and 2% use plasma alone); however, variation between adjusted dosing and fixed dosing was observed.

Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for emergent warfarin reversal

IntroductionThree- and 4-factor prothrombin complex concentrates (PCC) are routinely administered for emergent reversal of warfarin, but direct comparisons of clinical outcomes are lacking. The purpose of this study was to compare the safety and effectiveness of 3- and 4-PCC in patients requiring emergent warfarin reversal. Materials and MethodsThis was a single-center retrospective study in adult patients requiring administration of either 3-PCC or 4-PCC for emergent reversal of warfarin. ResultsOne hundred sixty-five patients were included (3-PCC, n=109; 4-PCC, n=56). The most frequent indications for PCC were intracranial and gastrointestinal bleeding. Baseline median INR was 2.5 (2.0-3.2) and 2.4 (2.0-4.2) in the 3-PCC and 4-PCC groups. Thirty minutes after PCC administration, median INR decreased to 1.3 in both groups (p<0.001), and 87 (80%) versus 47 (84%) of patients had INR values≤1.5 (p=0.52) in the 3-PCC group versus the 4-PCC group. Thromboembolic events occurred in 7 patients (4%) and were similar between the 3-PCC (n=3, 3%) and 4-PCC (n=4, 7%) groups (p=0.23). Thirty-four (31%) patients in the 3-PCC group died compared to 5 patients (9%) in the 4-PCC group (p=0.001). INR>1.5 thirty minutes after PCC was associated with increased mortality (OR 4.3; 95% CI 1.8-10.4, p=0.001), and administration of a 4-PCC was associated with decreased mortality (OR 0.19; 95% CI 0.06-0.54, p=0.002). ConclusionPatients who received 4-PCC, and those with INR≤1.5 regardless of type of PCC received were more likely to survive. Thromboembolic events were low in both groups and similar to previous studies.

Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal

ObjectivesFour-factor prothrombin complex concentrates (4FPCCs) are emerging as the standard of care for emergent warfarin reversal due to their ability to rapidly and effectively achieve hemostasis. The ideal dose of this medication is not known. Recently, our hospital instituted a protocol where all doses of 4FPCC were a fixed dose of 1500 IU. This protocol provides 4FPCC rapidly and precludes delay waiting for international normalized ratio (INR) values. The purpose of this study was to evaluate our experience with this fixed dose protocol. MethodsThis is a retrospective review of patients who received 1500 IU of 4FPCC for emergent warfarin reversal between March 2014 and January 2015. Demographic and clinical data regarding administration, efficacy, and safety were collected and analyzed. ResultsA total of 39 patients met inclusion criteria. The most common indication for treatment was intracranial hemorrhage (28, 71.8%). The median INR at presentation was 3.3, and the median INR after a single dose of 1500 IU was 1.4 (P < .001). A total of 36 patients (92.3%) achieved successful reversal with a target INR of less than 2.0, and 28 patients (71.8%) achieved successful reversal with a target INR of 1.5 or less. There were no thrombotic adverse events within 7 days. ConclusionsAdministration of a fixed dose of 1500 IU of 4FPCC leads to high rates of successful INR reversal and no related thrombotic adverse events within 7 days, and there was no need to wait for INR at presentation. These findings suggest good efficacy and safety when using 1500 IU of 4FPCC for emergent warfarin reversal.

Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal.

IntroductionProthrombin complex concentrate (PCC) and recombinant Factor VIIa (rFVIIa) have been used for emergent reversal of warfarin anticoagulation. Few clinical studies have compared these agents in warfarin reversal. We compared warfarin reversal in patients who received either 3 factor PCC (PCC3) or low-dose rFVIIa (LDrFVIIa) for reversal of warfarin anticoagulation.MethodsData were collected from medical charts of patients who received at least one dose of PCC3 (20 units/kg) or LDrFVIIa (1000 or 1200 mcg) for emergent warfarin reversal from August 2007 to October 2011. The primary end-points were achievement of an INR 1.5 or less for efficacy and thromboembolic events for safety.ResultsSeventy-four PCC3 and 32 LDrFVIIa patients were analyzed. Baseline demographics, reason for warfarin reversal, and initial INR were equivalent. There was no difference in the use of vitamin K or fresh frozen plasma. More LDrFVIIa patients achieved an INR of 1.5 or less (71.9% vs. 33.8%, p =0.001). The follow-up INR was lower after LDrFVIIa (1.25 vs. 1.75, p < 0.05) and the percent change in INR was larger after LDrFVIIa (54.1% vs. 38.8%, p = 0.002). There was no difference in the number of thromboembolic events (2 LDrFVIIa vs. 5 PCC3, p = 1.00), mortality, length of hospital stay, or cost.ConclusionsBased on achieving a goal INR of 1.5 or less, LDrFVIIa was more likely than PCC3 to reverse warfarin anticoagulation. Thromboembolic events were equivalent in patients receiving PCC3 and LDrFVIIa.

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Introduction: We studied the effectiveness of a standardized protocol for emergent warfarin reversal in intracranial hemorrhage using prothrombin complex concentrate (Profilnine SD®). Hypothesis: We hypothesized that Profilnine SD® would shorten time to achieve INR less than or equal to 1.4, limit hemorrhage growth and improve outcome at hospital discharge. Methods: Sixty three patients with INR greater than or equal to 1.2 from 2009-2011 (38 on protocol after 2010) were included in this retrospective analysis. Pre-protocol patients received Vitamin K and plasma; post-protocol patients with INR 1.6 – 4 and > 4 received in addition, 25 and 35-50 units/kg of Profilnine SD® respectively. Hemorrhage volumes were measured on consecutive CT scans using MIPAV semi-automated software. Modified Rankin Score (mRs) was calculated at hospital discharge. Results: Twenty three post protocol patients (61%) received Profilnine SD® (median dose 28 units, IQR 25-46). They had similar baseline median INR’s (2.7 Vs 2.3) and a trend towards larger baseline hemorrhage volumes (9.9 Vs 1.6 cc) compared to other post-protocol patients. Despite faster times to INR reversal in Profilnine SD® patients, (7 Vs 16 hrs, p = 0.008), absolute hemorrhage growth (1.6 Vs 3.1 cc) and median mRs at discharge (3 Vs 3) were similar. However, post-protocol patients had significantly lower hemorrhage growth (absolute: 1 Vs 6.3 cc, p=0.01 and relative: 29% Vs 95% p=0.02) and a higher proportion (66 Vs 52%) achieved good neurological outcome (mRs 0-3). Thirteen of 15 eligible post-protocol patients did not get Profilnine SD®. There were no thrombotic complications related to use of Profilnine SD®. Conclusions: Profilnine SD® significantly shortened time to INR reversal. We could not demonstrate improvement in terms of hemorrhage growth or neurological outcome from Profilnine SD® administration, probably due to small number of patients and imperfect protocol compliance. Despite these limitations, implementation of an emergency warfarin reversal protocol did result in less hemorrhage expansion and better outcomes at hospital discharge.

Real world usage of PCC to "rapidly" correct warfarin induced coagulopathy.

Life threatening bleeding and emergency procedures in patients on vitamin K antagonists are indications for urgent reversal with prothrombin complex concentrate and vitamin K. Rapid reversal in these situations is emphasized in the literature and guidelines, but only very limited information is available on its real life use, especially on the timing of treatment in relation to presentation. We retrospectively audited emergency warfarin reversal in 131 consecutive patients. We studied the indication, use of vitamin K, time between presentation and administration of vitamin K and PCC, effectiveness in INR reduction and clinical outcome. The median PCC dose was 26.8 IU/kg. The median INR was reduced from 3.1 to 1.2. Vitamin K (5 mg) was given in 91.6% of evaluable patients. We found significant delays in administration of PCC and vitamin K. The median time between presentation and administration of vitamin K/PCC was 3.6 and 5.2 hours respectively. The times in intracranial haemorrhage were 2.7 and 3.0 hours and in emergency procedures 17.4 and 15.9 hours respectively. Mortality related to bleeding was 7.6% overall but in patients with intracranial haemorrhage 22.8%. The thrombotic rate within 7 days of reversal was 1.5%. The local protocol for reversal with PCC and vitamin K was adhered to well but the delay in pre-procedural patients, suggests that intravenous vitamin K alone may be sufficient in many cases and PCC administration can be avoided by better planning. Intracranial haemorrhage in warfarinised patients carries a high mortality. Treatment delays should be avoided by making PCC stocks available within emergency departments, simple dosing structures independent of INR and administering PCC without waiting for INR and CT scan results in those with strong suspicion of intracranial haemorrhage and clear trauma. Future reports and studies should always include the time from presentation to PCC treatment.

Use of contrast-enhanced computed tomography for management of a late-onset spontaneous massive chest wall hematoma

This is a rare case of a 68-year-old woman who was rehospitalized after uneventful redo double-valve surgery. An 8.3 × 12.9 × 16.4 cm tense right chest wall hematoma was diagnosed. This was precipitated by a single cough. Contrast-enhanced computed tomography revealed a bleeding source. Hematoma evacuation and hemostasis following emergency warfarin reversal produced an excellent outcome.

Modeling the Cost-Effectiveness of Prothrombin Complex Concentrate Compared With Fresh Frozen Plasma in Emergency Warfarin Reversal in the United Kingdom

Background Warfarin is the most commonly used oral anticoagulant in the United Kingdom. Indications for its long-term use include recurrent venous throm-bosis, prosthetic heart valves, stroke prevention in atrial fibrillation, valvular heart disease, and prosthetic heart valve replacement. Objective The aim of this study was to estimate the cost-effectiveness of using prothrombin complex concentrate (PCC) compared with fresh frozen plasma (FFP) for emergency warfarin reversal in patients with a life-threatening intracranial, gastrointestinal, or retroperitoneal hemorrhage. Methods Mortality estimates associated with managing an intracranial, gastrointestinal, or retroperitoneal hemorrhage were obtained from published studies after a systematic literature search. Estimates of health care resource use pertaining to managing warfarin-treated patients after a life-threatening hemorrhage were provided by 11 consultant physicians with experience in warfarin reversal. These published clinical outcomes and clinician-derived health care resource use estimates were used to construct a decision model depicting the treatment patterns and associated resource use attributable to current management of a hypothetical cohort of adults undergoing emergency warfarin reversal as a result of an intracranial, gastrointestinal, or retroperitoneal hemorrhage in the United Kingdom. The model only considered direct health care costs borne by the secondary care sector of the National Health Service, and not those borne in the community (with the exception of the cost of stroke rehabilitation) and estimated the cost effectiveness of using PCC compared with FFP to reverse the anticoagulant effects of warfarin, from the perspective of the National Health Service, at 2007–2008 prices. Results The cost of warfarin reversal was estimated to be ≤15% of the total cost of managing a patient after a life-threatening intracranial, gastrointestinal, or retroperitoneal hemorrhage. The cost per life-year gained with PCC was estimated to range from £1000 to £2000, depending on hemorrhage type (ie, intracranial, gastrointestinal, or retroperitoneal). The cost per quality-adjusted life-year gained with PCC was estimated at £3000 or less depending on hemorrhage type. Conclusion PCC appeared to be a more cost-effective treatment than FFP for the emergency reversal of warfarin, from the perspective of the UK National Health Service, in this model analysis.

Emergency warfarin reversal with prothrombin complex concentrates: UK wide study

Emergency warfarin reversal with prothrombin complex concentrates: UK wide study

Warfarin Reversal in Anticoagulant-Associated Intracerebral Hemorrhage

Anticoagulant-associated intracerebral hemorrhage (ICH) is a devastating disease, causing death in half of patients and permanent disability in the majority of survivors. The finding that patients often continue bleeding after hospital presentation offers the possibility that emergency warfarin reversal may improve outcomes. As no clinical trials have demonstrated the superiority of any one treatment strategy, various treatment options are available. Intravenous vitamin K is the definitive therapy; however, as monotherapy it can require many hours to take effect. Therefore, it is often considered an adjunct agent. Coagulation factors can be repleted with fresh frozen plasma (FFP), which is widely available and relatively low cost, but can require substantial time to deliver in real-world settings. A number of coagulation factor products collectively termed prothrombin complex concentrates (PCCs) are widely available that can rapidly provide many or all the vitamin K-dependent coagulation factors. Recombinant activated factor VII is used in many centers for this purpose, as it is thought to provide a procoagulant effect that may compensate for the lack of the other critical factors. Until clinical trials demonstrate the superiority of any one means of warfarin reversal, a number of expert guidelines from national organizations are available to help local providers guide therapy. At our institution, we have focused on improving the rapid and reliable delivery of a combination of intravenous vitamin K and FFP, with continued re-dosing until the desired INR lowering is achieved.