Reversal Of Anticoagulation In Patients Research Articles

Utility of thromboelastography to assess the effect of anticoagulation reversal in intracranial hemorrhage.

Intracranial hemorrhage (ICH) is a serious complication associated with oral anticoagulant use and is associated with significant morbidity and mortality. Although anticoagulation reversal agents are utilized as standard of care, practitioners are limited in their ability to assess degree of anticoagulation reversal for direct oral anticoagulants (DOACs). There is a clinical need identify biomarkers to assess anticoagulation status in patients with DOAC-associated ICH to ensure hemostatic efficacy of anticoagulation reversal agents in the acute setting. The purpose of this study was to assess the utility of thromboelastography (TEG) to assess the impact of anticoagulation reversal in patients presenting to the emergency department (ED) with DOAC-associated ICH. We conducted a prospective, observational cohort study in adult patients presenting to the ED with acute DOAC-associated ICH. Patients were excluded if last DOAC dose was >48 hours prior to hospital arrival, if they experienced polytrauma, were pregnant, incarcerated, had a history of hepatic failure or coagulopathy, or received anticoagulation reversal with products other than prothrombin complex concentrates (PCCs). We collected baseline TEG samples from participants prior to anticoagulation reversal, as well as 30-minutes, 12-hours, and 24-hours post-reversal. TEG samples were also collected from participants who transferred to our facility after reversal at ED presentation, as well as 12- and 24-hours post-reversal. Pre-reversal TEG was collected on 10 participants prior to DOAC reversal. A significant decrease in TEG R-time was observed at 30 minutes post-reversal. R-time increased at 12- and 24-hours to baseline levels. Significant changes were not observed in K-time, clot strength, maximum amplitude, or coagulation index. TEG R-time may be able to detect a change in anticoagulation activity of DOACs in ICH after anticoagulation reversal. R-time decreases acutely after anticoagulation reversal and rebounds at 12- and 24-hours post-reversal.

Cost-effectiveness of andexanet alfa versus four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-related intracranial hemorrhage in the US

Aim To conduct a cost-effectiveness analysis (CEA) on the use of andexanet alfa for the treatment of factor Xa inhibitor-related intracranial hemorrhage (ICH) from the US third-party payer and societal perspectives. Methods CEA compared andexanet alfa to prothrombin complex concentrate for the treatment of patients receiving factor Xa inhibitors admitted to hospital inpatient care with an ICH. The model comprised two linked phases. Phase 1 utilized a decision tree to model the acute treatment phase (admission of a patient with ICH into intensive care for the first 30 days). Phase 2 modeled long-term costs and outcomes using three linked Markov models comprising the six health states defined by the modified Rankin score. Results The analysis showed that the strategy of using andexanet alfa for the treatment of factor Xa inhibitor-related ICH is cost-effective, with incremental cost-effectiveness per quality-adjusted life-year gained of $35,872 from a third-party payer perspective and $40,997 from a societal perspective over 20 years. Limitations (1) Absence of head-to-head trials comparing therapies included in the economic model, (2) lack of comparative long-term data on treatment efficacy, and (3) bias resulting from the study designs of published literature. Conclusion Given these results, the use of andexanet alfa for the reversal of anticoagulation in patients with factor Xa inhibitor-related ICH may improve quality of life and is likely to be cost-effective in a US context.

Andexanet Alfa for Specific Anticoagulation Reversal in Patients with Acute Bleeding during Treatment with Edoxaban.

Background Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban. Methods Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients. Results Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population ( n = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3–202.4) ng/mL at baseline to 24.0 (IQR: 77.7–83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1–77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0–91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died. Conclusion In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.

Abstract P3: Andexanet Alfa for Acute Bleeding During Treatment With Edoxaban

Introduction: We previously reported results of a prospective cohort study evaluating andexanet alfa (andexanet) for anticoagulation reversal in patients with acute bleeding on a factor Xa inhibitor. Study enrollment continued to accumulate additional data on patients on edoxaban, which are presented here. Methods: Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a 400 or 800 mg bolus and a 480 or 960 mg 2-hour follow-on infusion of andexanet, depending on edoxaban dosage and time of last dose. The co-primary efficacy outcomes were change in anti-factor Xa activity and the rate of excellent or good hemostasis, 12 hours after andexanet treatment, as determined by an independent adjudication committee. Efficacy was analyzed in patients with confirmed major bleeding and baseline anti-factor Xa activity ≥75 ng/mL. Safety was analyzed in all patients. Results: A total of 36 patients (mean age 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 (80.6%) patients. In the efficacy population (n=20), median anti-factor Xa activity decreased from 160.5 (interquartile range [IQR] 106.2-222.2) ng/mL at baseline to 50.9 (IQR 19.9-119.4) ng/mL at the end of bolus (median decrease 69.2%, 95% confidence interval [CI] 25.5-80.2%). Excellent or good hemostasis at 12 hours was achieved in 75.0% (95% CI 50.9-91.3%) of patients overall and in 81.3% (95% CI 54.4-96.0%) of those with intracranial hemorrhage (ICH). Within 30 days, a total of 4 (11.1%) patients experienced at least one thrombotic event and 4 (11.1%) others died. Conclusions: In patients with acute bleeding on edoxaban, andexanet significantly decreased anti-factor Xa activity. Excellent or good hemostasis at 12 hours was observed in 75.0% of patients overall and 81.3% of those with ICH. Thrombotic events occurred at a rate expected in such patients.

Validation of a Modified Anti-FXa Assay on STA-Compact Analyzer for Measuring FXa Inhibitor Levels in the Presence of Andexanet Alfa

Introduction: The anticoagulants rivaroxaban and apixaban inhibit Factor Xa (FXa) activity and are effective therapeutic agents for the prevention and treatment of thromboembolism. Andexanet alfa (andexanet) is the only specific reversal agent approved for anticoagulation reversal in patients presenting with life-threatening bleeding treated with rivaroxaban or apixaban. Anti-FXa assays are functional assays used for measuring direct and indirect FXa inhibitor levels in plasma. Current commercially available anti-FXa assays are not suitable for accurately measuring anti-FXa activity in patient samples in the presence of andexanet due to the high sample dilutions (e.g.,1:44 with STA-Liquid Anti-Xa), which causes dissociation of the inhibitor from andexanet (due to reversible binding). This results in substantial underestimation of the reversal activity of andexanet, and in some cases with erroneously elevated anti-FXa levels in patient samples following andexanet treatment. Therefore, we modified the current anti-FXa assays to measure apixaban and rivaroxaban anti-FXa levels in the presence of andexanet. Methods: The modified anti-FXa assays were performed on STA®-Compact analyzer using reagents from STA-Liquid Anti-Xa assay kits (Stago). Andexanet was provided as a 10 mg/mL frozen stock. Plasma samples with FXa inhibitor in the presence or absence of andexanet were prepared using Stago Calibrator 1 and pooled normal human plasma (Precision Biologic). Previous anti-FXa assays (calibrator range: 0-500 ng/mL) employed 1:4 dilution of test plasma in Owren-Koller buffer followed by addition of FXa substrate and bovine FXa with an overall 1:44 sample dilution. In the modified assays, calibration curves for the anti-FXa assay were generated using apixaban or rivaroxaban calibrators in the range of 0 to 80 ng/mL; test samples were analyzed neat with an overall 1:2.6 sample dilution. Rivaroxaban and apixaban concentrations in the test samples were interpolated from the respective assay specific calibration curves. Validation of the modified anti-FXa assays was performed by assessing a) linearity and precision of the calibration curve and controls, b) lower limit of quantitation (LLOQ), c) inter-assay precision and d) sample stability. Results: The calibration curves for both apixaban and rivaroxaban assays demonstrated good correlation with a mean "r" value of 0.997 and 0.998, respectively (n=6). The percent recovery and precision of the modified anti-FXa assay are summarized in Table 1. The LLOQ for apixaban and rivaroxaban using the modified assays were <18.8 and <20.6 ng/mL, respectively, based on the preliminary results. Both apixaban and rivaroxaban assays demonstrated potent reversal of anti-FXa activity in presence of andexanet. Samples containing 232 ng/mL apixaban (0.5 µM) treated with equimolar andexanet (0.5 µM) resulted in 77.18 ng/mL of quantifiable apixaban (~66.7% reversal). Similarly, samples containing 242 ng/mL rivaroxaban (0.5 µM) treated with equimolar andexanet (0.5 µM) resulted in 29.44 ng/mL quantifiable rivaroxaban (~87.8% reversal). The short-term stability study with the modified anti-FXa assay included storage of plasma samples at 2-8oC up to 24 hours and under frozen conditions at -20oC up to 2 weeks. Conclusions: The modified anti-FXa assays intended for measuring FXa inhibitor levels in the presence of andexanet produced acceptable analytical performance characteristics. Application of the modified anti-FXa assays in plasma samples from andexanet-treated human subjects has yet to be studied. Table 1 Disclosures Cardenas: CirQuest Labs/MLM Medical Labs: Current Employment. Kotha:CirQuest Labs/MLM Medical Labs: Current Employment. Lu:Portola Pharmaceuticals, Inc.: Current Employment. Conley:Portola Pharmaceuticals, Inc.: Current Employment. Bourdin:Diagnostica Stago: Current Employment. Herve:Diagnostica Stago: Current Employment. Jennings:CirQuest Labs/MLM Medical Labs: Current Employment, Current equity holder in private company.

Andexanet versus prothrombin complex concentrates: Differences in reversal of factor Xa inhibitors in in vitro thrombin generation

BackgroundAndexanet alfa (andexanet) is a modified human factor Xa (FXa) approved for anticoagulation reversal in patients with life‐threatening bleeding treated with rivaroxaban or apixaban. Four‐factor prothrombin complex concentrates (4F‐PCCs) are approved for reversal of vitamin K antagonist–induced anticoagulation but not FXa inhibitors. The mechanism and effectiveness of 4F‐PCCs for FXa inhibitor reversal are unclear. ObjectiveTo investigate the mechanism and impact of 4F‐PCCs on reversal of rivaroxaban and apixaban in vitro compared to andexanet. MethodsThe effect of 4F‐PCCs (or individual factors) on tissue factor‐initiated thrombin generation (TF‐TG) was evaluated in human plasma, with or without rivaroxaban or apixaban, and compared with andexanet under the same conditions. ResultsIn the TF‐TG assay, 4F‐PCC completely reversed warfarin anticoagulation. Andexanet normalized TF‐TG over a wide range of apixaban and rivaroxaban concentrations tested (19‐2000 ng/mL). However, 4F‐PCC (or individual factors) was unable to normalize endogenous thrombin potential (ETP) or peak thrombin (Peak) in the presence of apixaban or rivaroxaban (75‐500 ng/mL). TF‐TG was only normalized by 4F‐PCC at inhibitor concentrations <75 ng/mL (ETP) or <37.5 ng/mL (Peak). These data can be explained by the estimated thresholds of FXa activity required to support normal TF‐TG based on the inhibitor:FXa ratios and levels of uninhibited FXa. The data are consistent with healthy volunteer studies where TF‐TG is not normalized until inhibitor levels are substantially decreased. ConclusionsBoth the theoretical calculations and experimental data demonstrated that 4F‐PCCs are only able to normalize TG over a low and narrow range of FXa inhibitor concentrations (<75 ng/mL).

Safety and efficacy of prothrombin complex concentrate (PCC) for anticoagulation reversal in patients undergoing urgent neurosurgical procedures: a systematic review and metaanalysis.

Anticoagulant therapy poses a significant risk for patients undergoing emergency neurosurgery procedures, necessitating reversal with prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP). Data on PCC efficacy lack consistency in this setting. This systematic review and metaanalysis aimed to evaluate efficacy and safety of PCC for anticoagulation reversal in the context of urgent neurosurgery. Articles from PubMed, Embase, and Cochrane databases were screened according to the PRISMA checklist. Adult patients receiving anticoagulation reversal with PCC for emergency neurosurgical procedures were included. When available, patients who received FFP were included as a comparison group. Pooled estimates of observational studies were calculated for efficacy and safety outcomes via random-effects modeling. Initial search returned 4505 articles, of which 15 studies met the inclusion criteria. Anticoagulants used included warfarin (83%), rivaroxaban (6.8%), phenprocoumon (6.1%), apixaban (2.2%), and dabigatran (1.5%). The mean International Normalized Ratio (INR) prePCC administration ranged from 2.3 to 11.7, while postPCC administration from 1.1 to 1.4. All-cause mortality at 30days was 27% (95%CI 21, 34%; I2 = 44.6%; p-heterogeneity = 0.03) and incidence of thromboembolic events was 6.00% among patients treated with PCC (95%CI 4.00, 10.0%; I2 = 0%; p-heterogeneity = 0.83). Results comparing PCC and FFP demonstrated no statistically significant differences in INR reversal, mortality, or incidence of thromboembolic events. This metaanalysis demonstrated adequate safety and efficacy for PCC in the reversal of anticoagulation for urgent neurosurgical procedures. There was no significant difference between PCC and FFP, though further trials would be useful in demonstrating the safety and efficacy of PCC in this setting.

A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers

AbstractAs with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor–induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

Association of Reversal of Anticoagulation Preoperatively on 30-Day Mortality and Outcomes for Hip Fracture Surgery

BackgroundHip fracture is common in the elderly, many of whom are on anticoagulation. However, data are limited on outcomes with anticoagulation reversal in patients undergoing hip fracture surgery. MethodsAdults ≥60 years old on oral anticoagulation who underwent hip fracture surgery at 21 hospitals in Northern California from 2006 to 2016 were identified through electronic databases. Outcomes were compared among patients treated and untreated with anticoagulation reversal preoperatively. ResultsOf 1984 patients on oral anticoagulation who underwent hip fracture surgery, 1943 (97.9%) were on warfarin and 41 (2.1%) were on direct oral anticoagulants. Reversal agents were administered to 1635 (82.4%). Compared to a watch-and-wait strategy, patients receiving reversal agents were more likely to be white, male, comorbid, and with higher admission and preoperative international normalized ratios (P <0.001 for all comparisons). No difference for 30-day mortality was detected between reversal vs non-reversal (7.8% vs 6.0%, respectively; hazard ratio [HR], 1.30 [95% confidence interval (CI), 0.82-2.07]). For secondary outcomes, reversal was associated with higher risk of delirium (8.6% vs 4.9%, risk ratio [RR], 1.77 [95% CI, 1.08-2.89]) and increased mean length of stay (6.4 vs 5.8 days, P <0.05). After adjustment, associations were no longer significant for delirium (RR 1.60, 95% CI, 0.97-2.65) or length of stay (mean difference 0.08, 95% CI, -0.55-0.71). No associations were detected between reversal and other secondary outcomes. ConclusionNo significant associations were found between reversal agents and 30-day mortality or other outcomes in patients on oral anticoagulation who underwent hip fracture surgery. Further investigation is needed.

Andexanet Alfa and its Clinical Application.

Factor Xa (FXa) inhibitors are widely used for stroke prevention in patients with nonvalvular atrial fibrillation, and for the treatment and prevention of deep venous thrombosis and pulmonary embolism. Compared with warfarin, individual FXa inhibitors are associated with a lower risk of major bleeding. Nevertheless, bleeding remains a feared complication of any anticoagulant therapy. Despite their demonstrated safety, implementation of FXa inhibitors in clinical practice may have been limited by the lack of a specific antidote. Recently, however, the United States Food and Drug Administration and the European Medicines Agency approved andexanet alfa for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who have life-threatening or uncontrolled bleeding. This review will discuss andexanet alfa's mode of action, indication for use and efficacy, with a focus on its appropriate use in clinical practice. Unnecessary usage should be prevented as this may compromise patient safety. Assessment of potentially suitable patients by a multidisciplinary team, use according to the institutional protocol and central storage, all contribute to proper use of andexanet alfa. A practical tool to direct appropriate use of andexanet alfa is proposed.

Reversing Direct Oral Anticoagulants in Acute Intracranial Hemorrhage.

Intracerebral hemorrhage is a major source of morbidity and mortality, accounting for 10% of all strokes. Oral anticoagulation therapy, while necessary to prevent thromboembolic complications, increases the risk of intracerebral hemorrhage and can potentially worsen bleeding in cases of acute hemorrhage. Before the introduction of direct oral anticoagulant agents in 2010, warfarin was the only option for oral anticoagulation. These new agents have an improved safety profile compared with warfarin but require different reversal strategies. Anticoagulation reversal in the setting of acute intracerebral hemorrhage is an evolving field. This article covers the most common direct oral anticoagulant medications, various available anticoagulant reversal strategies, and the latest guidelines for anticoagulation reversal in patients with acute intracranial hemorrhage.

Abstract 84: Idarucizumab in Patients Treated With Dabigatran Suffering Cerebral Ischemia or Intracranial Hemorrhage: A Retrospective Case Series From Germany

Reversal of anticoagulation in patients treated with NOACs is a rare but sometimes urgently needed therapeutic demand. Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. It is approved for patients on dabigatran with life-threatening or uncontrolled bleeding and those requiring emergency intervention. Case reports and smaller case series suggest a benefit for dabigatran-treated patients suffering ischemic stroke to regain eligibility for rt-PA thrombolysis. To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage in clinical routine, we asked all German Departments of Neurology and Neurosurgery to contribute their retrospective data on the use of idarucizumab collected following product launch in January 2016 to June 2018. In 64 responding stroke centers 112 patients presenting with signs of stroke received idarucizumab. 74 patients treated with dabigatran presented with ischemic stroke. In patients receiving rt-PA thrombolysis following idarucizumab, 87% had a benefit from i.v. thrombolysis with a median NIHSS improvement of 6 points. No symptomatic bleeding complications were observed. Nine patients did not improve functionally. Of those, 4 patients deceased during hospital stay (5.4%). Bolus administration of idarucizumab did not delay thrombolysis indicating its value in this emergency situation. A total of 38 patients had intracranial bleeding (SAH n=1, SDH n=12, ICH n=25). Out of 25 patients presenting with intracerebral hemorrhage and treated with idarucizumab, hematoma growth with clinical worsening was documented in three. Outcome was favorable with a median NIHSS improvement of 4 points in 35 patients. Overall mortality was 13%. In conclusion, idarucizumab is a beneficial therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage in daily German stroke center routine. A prospective registry with controls is ongoing in Germany.

Erratum to: Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study.

Oral factor Xa inhibitors are increasingly used for anticoagulation, but there is no approved reversal agent. Prothrombin complex concentrate (PCC) for the management of Xa-inhibitor–associated bleeding has been described in small case series and one cohort study. Patients on apixaban or rivaroxaban, suffering a major bleed, were treated at nine Canadian hospitals as per existing hospital protocol with a fixed dose of PCC 2,000 units and subsequently recruited for a 30-day follow-up. The treating physician evaluated the haemostatic effectiveness as observed during the first day as good, moderate or poor/none, using an assessment guide. Safety outcomes were thromboembolism or death. We recruited 66 patients with major bleeding who were treated with PCC and who were receiving rivaroxaban (56%) or apixaban (44%). The effectiveness was assessed as good in 65% (95% confidence interval [CI], 53–77), moderate in 20% (95% CI, 10–30) and poor/none in 15% (95% CI, 6–24). For the 36 patients with intracranial haemorrhage, the corresponding ratings were 67, 17 and 17%, and for 16 patients with gastrointestinal bleeding they were 69, 12 and 19%, respectively. There were nine deaths (14%) by 30 days, and five (8%) major thromboembolic events. In a post hoc analysis, according to International Society on Thrombosis and Haemostasis criteria, reversal was effective in 68% and ineffective in 32%. For major bleeding associated with oral Xa inhibitors, PCC may have a beneficial effect. The risk of thromboembolism after reversal of anticoagulation in patients with a prothrombotic background has to be taken into account.

Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study.

Oral factor Xa inhibitors are increasingly used for anticoagulation, but there is no approved reversal agent. Prothrombin complex concentrate (PCC) for the management of Xa-inhibitor-associated bleeding has been described in small case series and one cohort study. Patients on apixaban or rivaroxaban, suffering a major bleed, were treated at nine Canadian hospitals as per existing hospital protocol with a fixed dose of PCC 2,000 units and subsequently recruited for a 30-day follow-up. The treating physician evaluated the haemostatic effectiveness as observed during the first day as good, moderate or poor/none, using an assessment guide. Safety outcomes were thromboembolism or death. We recruited 66 patients with major bleeding who were treated with PCC and who were receiving rivaroxaban (56%) or apixaban (44%). The effectiveness was assessed as good in 65% (95% confidence interval [CI], 53-77), moderate in 20% (95% CI, 10-30) and poor/none in 15% (95% CI, 6-24). For the 36 patients with intracranial haemorrhage, the corresponding ratings were 67, 17 and 17%, and for 16 patients with gastrointestinal bleeding they were 69, 12 and 19%, respectively. There were nine deaths (14%) by 30 days, and five (8%) major thromboembolic events. In a post hoc analysis, according to International Society on Thrombosis and Haemostasis criteria, reversal was effective in 68% and ineffective in 32%. For major bleeding associated with oral Xa inhibitors, PCC may have a beneficial effect. The risk of thromboembolism after reversal of anticoagulation in patients with a prothrombotic background has to be taken into account.

Overview of direct oral anticoagulant therapy reversal.

Strategies for the management of bleeding complications and facilitation of an invasive procedure in patients receiving direct oral anticoagulants (DOACs) are reviewed. The DOACs provide clinical advantages versus vitamin K antagonists, including fixed dosing with no routine coagulation monitoring and evidence of a lower risk of bleeding. However, as with all anticoagulants, there is a risk of bleeding complications in patients receiving DOACs, so urgent reversal of their anticoagulant activity may be required for spontaneous or traumatic bleeding events and in patients undergoing emergency invasive procedures. Reversal strategies are dependent on the anticoagulant involved, the location and severity of the bleeding, and/or the urgency of the invasive procedure. The recently approved specific reversal agent for dabigatran, idarucizumab, together with other reversal agents in development will hopefully allow for the emergent reversal of DOACs, without increasing the underlying risk of thrombosis. However, research is required to determine the optimal use of these reversal agents, in terms of choice of agent, dosing, and concomitant management. A systematic approach to their implementation in hospitals is also required to ensure that physicians, nurses, and pharmacists receive appropriate education and have the necessary protocols and guidelines to manage these clinical situations. Reversal strategies in patients receiving a DOAC need to be tailored to the anticoagulant involved as well as the urgency and severity of the clinical situation. Reversal agents should help facilitate the urgent reversal of anticoagulation in patients with emergency bleeding or who require urgent surgery, though research and education are required to ensure the optimal use of these agents.

(327) - Anticoagulation Reversal With 4-Factor Prothrombin Complex Concentrate in Left Ventricular Assist Device Patients With Acute Hemorrhagic Stroke

Anticoagulation reversal in patients with left ventricular assist devices (LVAD) after acute hemorrhagic stroke must occur rapidly to prevent hemorrhage expansion and limit neurologic sequelae, keeping in mind the risk of thrombotic complications. The purpose of this study was to report a case series of our initial experience using a recently FDA approved (April 2013) 4-factor prothrombin complex concentrate (4F-PCC) for INR normalization after acute hemorrhagic stroke in LVAD patients, and compare the results with traditional INR reversal agents.

Massive Hemorrhage from Arterial Access during Intracranial Aneurysm Stent-Assisted Embolization: Endovascular Diagnosis and Therapy.

Massive hemorrhage from arterial access in patients receiving anticoagulation and antiplatelet therapy is a rare but potentially devastating complication. The authors present a patient who developed a large retroperitoneal and anterior abdominal wall hemorrhage following an unintentional and unrecognized arterial injury during an endovascular procedure. Reversal of anticoagulation in patients who have undergone stent-assisted coil embolization of intracranial aneurysms is an undesirable approach due to the risk of thromboembolism; rather, transcatheter embolization of the bleeding source should be considered.

Efficacy and safety of Prothrombin Complex Concentrates Weight-Based Dosing for Reversal of Warfarin Anticoagulation

▪Background: Prothrombin complex concentrates (PCCs) are widely used for correcting elevated international normalized ratio (INR) levels in patients anticoagulated with warfarin requiring an urgent reversal. However, the optimal dosing regimen has yet to be defined. In 2008, the Canadian National Advisory Committee (NAC) on blood product utilization recommended a single dose of 1000 IU for all adults over 18 years of age, irrespective of INR levels, and suggested further consultation with a Hematologist if extremes in weight or INR were observed. A revision in 2011, suggested dosing based on the INR elevation as an option and in 2014 the recommendation was updated to include a possible algorithm including both INR and weight. Currently there is insufficient evidence to suggest that one approach is more efficacious than another. Our institution has been using a novel weight-based dosing protocol for PCCs since 2009, which dispenses to a maximum of 3000 IU for adults weighing over 100kg. Herein, we sought to determine the efficacy of our weight-based dosing nomogram.Methods: We conducted a retrospective cohort study of all consecutive adult patients (age > 18 years) who received PCCs using our weight based dosing regimen between April 30, 2009 and December 31, 2010. All patients were anticoagulated with warfarin. Clinical and laboratory information was obtained through chart review. The weight based regimen consisted of 1000 IU for weight less than 40kg, 1500IU for 41 to 60kg, 2000 IU for 61 to 80kg, 2500 IU for 81 to 100kg, and 3000 IU for > 100kg. Doses of PCCs were based on the concentration of factor IX. PCCs utilized at this centre were Octaplex and Beriplex. The primary outcome was reversal of warfarin anticoagulation, as defined by an INR of 1.5 or less to achieve a clinical response within 6 hours. Statistical analysis was done using descriptive statistics and chi squared analysis.Results: A total of 227 charts were included in the study from April 30, 2009 to December 31, 2010. The median age was 74 years old (range 40-95), the median weight was 76kg (range 44-200), and 56% of patients were male. Medical indications for warfarin anticoagulation included atrial fibrillation (68%), DVT (32%) and stroke (21%). The most common indication for PCCs was active bleeding (44%: 13% intracranial, 12% gastrointestinal, 4% trauma, 15% other), reversal for a procedure (22%) and reversal for surgery (30%). Prior to receiving PCCs, 29% of patients were taking Aspirin and 4% were taking Clopidogrel. The percentages of patients treated with each dose were: 1000IU (1.3%), 1500IU (17.6%), 2000IU (41.0%), 2500IU (24.2%), 3000IU (15.9%). A second dose of PCC was given to 0.4% of patients. FFP was given to 7% of patients prior to PCCs administration and 14% of patients post PCCs administration. 63% of patients received vitamin K. Seventy-nine percent of patients achieved an INR of 1.5 or less within 6 hours of PCC administration. There was a statistically significant difference in response based on pre-PCC INRs (see table 1). The median baseline INR was 2.9 (range 1.5- >10) and decreased to a median of 1.3 (range 1.0-3.7) post-PCCs administration. Planned procedures were completed in 93% of 60 patients, and planned surgeries were completed in 94% of 70 patients within 24 hours of receiving PCCs. Four patients (2%) developed a deep vein thrombosis within 30 days of receiving PCCs.Conclusion: Our study demonstrates that weight based dosing is effective in reversal of anticoagulation in patients on warfarin. Laboratory response rates are similar to other studies (Wozniak et al). Although the majority of patients in our study (99%) received doses over 1000IU; rates of thrombosis are low. Future studies comparing different strategies are needed.Table 1INR rangePre-PCCProportion with Post-PCC INR of 1.5 or less (%)P-value1.5-3110/122 (90%)3.1-4.533/43 (77%)0.037*>4.535/62 (56%)<0.001***1.5-3 vs 3.1-4.5**1.5-3 vs >4.5 DisclosuresLazo-Langner:Pfizer Bayer LEO Pharma: Honoraria. Chin-Yee:Alexion Pharmaceuticals: Research Funding.

Assessing Thromboembolic Risk on Anticoagulation Reversal in Patients with Left-Ventricular Assist Devices

Assessing Thromboembolic Risk on Anticoagulation Reversal in Patients with Left-Ventricular Assist Devices

Safety of Anticoagulation Reversal in Patients Supported with Continuous-Flow Left Ventricular Assist Devices

The purpose of this study was to characterize the potential thromboembolic risk associated with the reversal of warfarin-based anticoagulation in patients with continuous-flow left ventricular assist devices (CF-LVADs). All patients implanted with a CF-LVAD between January 1, 2008, and August 1, 2012, at our institution were screened, and those who received anticoagulation reversal during an inpatient admission were enrolled. The primary outcome is the incidence of thrombotic events, including stroke, device thrombosis, or venous thromboembolism within 30 days of anticoagulation reversal. Of the 122 patients screened, 25 patients experienced 38 anticoagulation reversal events. All patients received vitamin K at a mean dose of 10 ± 8 mg, while 60% of patients received fresh frozen plasma. Only two patients received prothombin complex concentration and three patients received activated factor VII. The rate of thromboembolism within 30 days of attempted reversal was 2.6% (1/38). This patient developed an ischemic stroke after reversal with a high dose of activated factor VII for an acute intracranial bleed. The mortality rate within 30 days of reversal was 20% (5/25), with three of these deaths associated with acute intracranial hemorrhage. Anticoagulation reversal may be safely attempted in selected patients under CF-LVAD support.