Reversal Of Anticoagulation Research Articles

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.

Four-factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors versus Warfarin in Life-threatening Bleeding.

IntroductionFactor Xa (fXa) inhibitor reversal for life-threatening bleeding is controversial due to a lack of high-quality evidence. The purpose of this study was to determine the hemostatic efficacy of four-factor prothrombin complex concentrate (4F-PCC) for the reversal of fXa inhibitors compared to warfarin for life-threatening bleeding.MethodsThis was a multicenter, retrospective cohort study at two academic medical centers between January 1, 2014–December 31, 2019, which included patients who presented to the emergency department with a life-threatening bleed necessitating anticoagulation reversal with 4F-PCC. The primary endpoint was achievement of hemostatic efficacy after 4F-PCC administration.ResultsOf the 525 patients who had an order for 4F-PCC during the study period, 148 patients met the criteria for inclusion (n = 48 fXa inhibitor group; n = 100 warfarin group). Apixaban (52.1%) and rivaroxaban (45.8%) were the most commonly used fXa inhibitors. Effective hemostasis was similar between groups (79.2% fXa inhibitor group vs 85% warfarin group, p = 0.38). This was consistent across all types of bleeding. Thrombotic events were rare in both groups (2% vs 3%).ConclusionThis multicenter, retrospective cohort study demonstrated that using 4F-PCC for treatment of life-threatening bleeding produced effective hemostasis in patients on fXa inhibitors and warfarin.

Recommendations for Research Assessing Outcomes for Patients With Anticoagulant-Related Intracerebral Bleeds.

Intracerebral bleeds related to anticoagulant use have a poor prognosis and substantial risk of disability and death. Recent publications evaluating replacement or reversal therapies for anticoagulants lack consistency in controlling for key factors that significantly influence outcomes. In an effort to guide future research by providing a framework to improve consistency and reduce the potential for confounding in this dynamic and highly time-dependent brain insult, we provide here a brief overview of variables we consider critical in studies evaluating the risk and the reversal of anticoagulant therapies in anticoagulant-related intracerebral bleeds. Hematoma expansion stands out as one of the few potentially modifiable risk factors and its early control could mitigate secondary brain injury, and it, therefore, requires careful categorization. In addition to the baseline demographic, clinical, and radiological predictors of hematoma expansion, we specifically highlight time-dependent factors such as the time from the last dose, time from symptom onset and time to treatment, the computed tomography angiography spot sign, and the limitation of early care as especially critical predictors of outcomes in anticoagulant-related intracerebral bleeds. Intracerebral hemorrhage is a condition that requires fast diagnosis and treatment, especially when associated with anticoagulants. The advent of therapies with rapid reversal of anticoagulation open the opportunity to assess the scale to which faster reversal of anticoagulation modifies hematoma expansion and clinical outcomes. Thus, comprehensive assessment and reporting of these important potential confounding factors, particularly the critical time variables, is crucial to improving research and treatment of intracerebral hemorrhages.

From Natural Products to New Synthetic Small Molecules: A Journey through the World of Xanthones.

This work reviews the contributions of the corresponding author (M.M.M.P.) and her research group to Medicinal Chemistry concerning the isolation from plant and marine sources of xanthone derivatives as well as their synthesis, biological/pharmacological activities, formulation and analytical applications. Although her group activity has been spread over several chemical families with relevance in Medicinal Chemistry, the main focus of the investigation and research has been in the xanthone family. Xanthone derivatives have a variety of activities with great potential for therapeutic applications due to their versatile framework. The group has contributed with several libraries of xanthones derivatives, with a variety of activities such as antitumor, anticoagulant, antiplatelet, anti-inflammatory, antimalarial, antimicrobial, hepatoprotective, antioxidant, and multidrug resistance reversal effects. Besides therapeutic applications, our group has also developed xanthone derivatives with analytical applications as chiral selectors for liquid chromatography and for maritime application as antifouling agents for marine paints. Chemically, it has been challenging to afford green chemistry methods and achieve enantiomeric purity of chiral derivatives. In this review, the structures of the most significant compounds will be presented.

A DNA origami-based aptamer nanoarray for potent and reversible anticoagulation in hemodialysis

Effective and safe hemodialysis is essential for patients with acute kidney injury and chronic renal failures. However, the development of effective anticoagulant agents with safe antidotes for use during hemodialysis has proven challenging. Here, we describe DNA origami-based assemblies that enable the inhibition of thrombin activity and thrombus formation. Two different thrombin-binding aptamers decorated DNA origami initiates protein recognition and inhibition, exhibiting enhanced anticoagulation in human plasma, fresh whole blood and a murine model. In a dialyzer-containing extracorporeal circuit that mimicked clinical hemodialysis, the origami-based aptamer nanoarray effectively prevented thrombosis formation. Oligonucleotides containing sequences complementary to the thrombin-binding aptamers can efficiently neutralize the anticoagulant effects. The nanoarray is safe and immunologically inert in healthy mice, eliciting no detectable changes in liver and kidney functions or serum cytokine concentration. This DNA origami-based nanoagent represents a promising anticoagulant platform for the hemodialysis treatment of renal diseases.

Emergency medical services protocols for traumatic brain injury in the United States: A call for standardization.

Traumatic brain injury (TBI) with acute elevation in intracranial pressure (ICP) is a neurologic emergency associated with significant morbidity and mortality. In addition to indicated trauma resuscitation, emergency department (ED) management includes empiric administration of hyperosmolar agents, rapid diagnostic imaging, anticoagulation reversal, and early neurosurgical consultation. Despite optimization of in-hospital care, patient outcomes may be worsened by variation in prehospital management. In this study, we evaluate geographic variation between emergency medical services (EMS) protocols for patients with suspected TBI. We performed a cross-sectional analysis of statewide EMS protocols in the United States in December 2020 and included all complete protocols published on government websites. Outcome measures were defined to include protocols or orders for the following interventions, given TBI: (1) hyperventilation and end-tidal capnography (EtCO2) goals, (2) administration of hyperosmolar agents, (3) tranexamic acid (TXA) administration for isolated head injury, (4) non-invasive management including head-of-bed elevation, and (5) hemodynamic goals. We identified 32 statewide protocols including Washington, D.C., 4 of which did not include specific guidance for TBI. Of 28 states providing ventilatory guidance, 22/28 (78.6%) recommend hyperventilation, with 17/22 (77.3%) restricting hyperventilation to signs of acute herniation. The remaining 6 states prohibited hyperventilation. Regarding EtCO2 goals among states permitting hyperventilation, 17/22 (77.3%) targeted an EtCO2 of < 35 mmHg, while 5/22 (22.7%) provided no guide EtCO2 for hyperventilation. Rhode Island was the only state identified that included hypertonic saline (3%), and Delaware was the only state that allowed TXA in the setting of isolated TBI with GCS ≤ 12. Only 15/32 (46.9%) identified states recommend head-of-bed elevation. For blood pressure goals, 12/28 (42.9%) of states set minimum systolic blood pressure at 90 mmHg, while 10/28 (35.7%) set other SBP goals. The remaining 6/28 (21.4%) did not provide TBI-specific SBP goals. There is wide variation among civilian prehospital protocols for traumatic brain injury. Prehospital care within the first "golden hour" may dramatically affect patient outcomes. Neurocritical care providers should be mindful of geographic variation in local protocols when designing and evaluating quality improvement interventions and should aim to standardize prehospital care protocols.

Ciraparantag, an anticoagulant reversal drug: mechanism of action, pharmacokinetics, and reversal of anticoagulants

AbstractCiraparantag, an anticoagulant reversal agent, is a small molecule specifically designed to bind noncovalently by charge-charge interaction to unfractionated heparin and low-molecular-weight heparin. It shows binding characteristics that are similar to those of direct oral anticoagulants (DOACs). A dynamic light-scattering methodology was used to demonstrate ciraparantag's binding to the heparins and DOACs and its lack of binding to a variety of proteins including coagulation factors and commonly used drugs. Ciraparantag reaches maximum concentration within minutes after IV administration with a half-life of 12 to 19 minutes. It is primarily hydrolyzed by serum peptidases into 2 metabolites, neither of which has substantial activity. Ciraparantag and its metabolites are recovered almost entirely in the urine. In animal models of bleeding (rat tail transection and liver laceration), a single IV dose of ciraparantag given at peak concentrations of the anticoagulant, but before the bleeding injury, significantly reduced the blood loss. Ciraparantag, given after the bleeding injury, also significantly reduced blood loss. It appears to have substantial ability to reduce blood loss in animal models in which a variety of anticoagulants are used and has potential as a useful DOAC reversal agent.

The AAST prospective observational multicenter study of the initial experience with reversal of direct oral anticoagulants in trauma patients

BackgroundDrug-specific agents for the reversal of direct oral anticoagulants (DOACs) were recently approved. We hypothesized that the approval of these reversal agents would lead improved outcomes for trauma patients taking DOACs. MethodsA multicenter, prospective (2015–2018), observational study of all adult trauma patients taking DOACs who were admitted to one of fifteen participating trauma centers was performed. The primary outcome was mortality. ResultsFor 606 trauma patients on DOACs, those reversed were older (78 vs. 74, p = 0.007), more severely injured (ISS: 16 vs. 5, p < 0.0001), had more severe head injuries (Head AIS: 2.9 vs. 1.3, p < 0.0001), and higher mortality (11% vs. 3%, p = 0.001). Patients who received drug-specific agents (idarucizumab, andexanet alfa) had higher mortality (30% vs. 8%, p = 0.04) than those reversed with factor concentrates. However, the low usage of drug-specific reversal agents limits our ability to assess their efficacy and safety. ConclusionsDOAC reversal was not independently associated with mortality. At present, the overall usage of drug-specific reversal agents is too sparing to meaningfully assess outcomes in trauma.

Anticoagulant Reversal in Gastrointestinal Bleeding: Review of Treatment Guidelines.

Patients receiving anticoagulant therapies, such as vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), commonly experience gastrointestinal (GI) bleeding as a complication and may require anticoagulant reversal prior to endoscopic treatment. Anticoagulant reversal agents include prothrombin complex concentrates (PCCs; including 3 or 4 coagulation factors), plasma, vitamin K, and target-specific DOAC reversal agents (e.g., idarucizumab and andexanet alfa). To review current US, as well as international, guidelines for anticoagulant reversal agents in patients on VKAs or DOACs presenting with GI bleeding prior to endoscopy, guideline-based management of coagulation defects, timing of endoscopy, and recommendations for resumption of anticoagulant therapy following hemostasis. Supporting clinical data were also reviewed. This is a narrative review, based on PubMed and Internet searches reporting GI guidelines and supporting clinical data. GI-specific guidelines state that use of reversal agents should be considered in patients with life-threatening GI bleeding. For VKA patients presenting with an international normalized ratio > 2.5, guidelines recommend PCCs (specifically 4F-PCC), as they may exhibit greater efficacy/safety compared with fresh frozen plasma in reversal of VKA-associated GI bleeding. For DOAC patients, most guidelines recommend targeted specific reversal agents in the setting of GI bleeding; however, PCCs (primarily 4F-PCC) are often listed as another option. Resumption of anticoagulant therapy following cessation of GI bleeding is also recommended to reduce risks of future thromboembolic complications. The utility of anticoagulant reversal agents in GI bleeding is recognized in guidelines; however, such agents should be reserved for use in truly life-threatening scenarios.

Mortality in patients with intracerebral haemorrhage associated with oral anticoagulation. Efficacy of a reversal protocol and clinical follow-up (ICH-OAC project)

Spontaneous intracerebral haemorrhage associated with oral anticoagulants (ICH-OAC) has a high mortality rate. The emergence of new anticoagulant drugs and reversal protocols increases interest in this entity. The main objective is to determine the mortality rate in patients with ICH-OAC (early, in-hospital, global) in our health area and to analyse the main variables related to it. The secondary objective is to determine the efficacy of anticoagulation reversal therapies (ART) as reflected by radiological expansion of the haematoma and the functional prognosis. A prospective observational study that introduced a protocol aimed at the management of patients with ICH-OAC. It included general measures and neuromonitoring, individualised administration of ART, cranial tomography and a six-month follow-up. Data on the drugs prescribed in the area during this period, mortality and functional prognosis were collected. A bivariate and logistic regression study was designed to investigate mortality-related variables. Forty-nine patients were included over three years; of these, 71.4% received ART. Mortality was 16.3% (first 24 hours), 53.1% (admission) and 61.2% (180 days). Lower survival was observed among patients with higher baseline scores on the National Institutes of Health Stroke Scale (NIHSS) (p < 0.0001), creatinine value (p = 0.02), International Normalised Index (p = 0.048), bleeding volume (p = 0.008), hydrocephalus (p = 0.015) and acenocoumarol intake (p = 0.030). Patients who did not receive ART had a greater rate of early mortality (p = 0.003). The only variable independently related to overall mortality was the baseline NIHSS score (odds ratio = 1.282; 95% confidence interval: 1.023-1.608; p = 0.031). ICH-OAC has a high mortality rate, related to the use of acenocoumarol and regardless of the initial clinical situation. A lower rate of early mortality was found among patients who received ART.

Major publications in the critical care pharmacotherapy literature: 2019.

To summarize selected meta-analyses and trials related to critical care pharmacotherapy published in 2019. The Critical Care Pharmacotherapy Literature Update (CCPLU) Group screened 36 journals monthly for impactful articles and reviewed 113 articles during 2019 according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. Articles with a 1A grade, including three clinical practice guidelines, six meta-analyses, and five original research trials are reviewed here from those included in the monthly CCPLU. Clinical practice guidelines on the use of polymyxins and antiarrhythmic drugs in cardiac arrest as well as meta-analyses on antipsychotic use in delirium, stress ulcer prophylaxis (SUP), and vasoactive medications in septic shock and cardiac arrest were summarized. Original research trials evaluated delirium, sedation, neuromuscular blockade, SUP, anticoagulation reversal, and hemostasis. This clinical review and expert opinion provides summary and perspectives of clinical practice impact on influential critical care pharmacotherapy publications in 2019.

Hemopericardium with subsequent cardiac tamponade secondary to rivaroxaban treatment: a case report.

BackgroundThe use and utility of novel oral anticoagulants has been increasing in clinical practice due to their relatively lower incidence of side effects such as intracranial haemorrhage, particularly in the elderly, when compared with vitamin K antagonists. Rivaroxaban is a factor Xa and prothrombinase inhibitor indicated for stroke and venous thromboembolism prophylaxis in non-valvular atrial fibrillation as well as treatment of venous thromboembolism.Case summaryA patient with history of paroxysmal atrial fibrillation on Rivaroxaban presented with generalized malaise, lightheadedness, and dizziness. The patient was found to be in profound cardiogenic shock despite unremarkable cardiac enzymes. Electrocardiogram revealed rate controlled atrial fibrillation and T-wave inversions in the inferolateral leads without associated electrical alternans. Bedside echocardiogram revealed a large pericardial effusion consistent with cardiac tamponade physiology. Following anticoagulation reversal, the patient underwent urgent pericardiocentesis yielding haemorrhagic fluid, with subsequent improvement in haemodynamic status. Despite the presence of retroperitoneal lymphadenopathy on previous computed tomography of the abdomen and concern for underlying malignant effusion secondary to lymphoma, cytology of the fluid revealed no evidence of malignant cells and follow-up flow cytometry and bone marrow biopsy were unremarkable.DiscussionWhile hemopericardium is not listed as a known side effect of Rivaroxaban, previous cases of hemopericardium secondary to Rivaroxaban have been described in the literature secondary to pre-disposing risk factors including CYP450 drug interactions or cardiac device implantations. In this case, the patient experienced a spontaneous hemopericardium on Rivaroxaban without any previously elucidated risk factors or evidence of malignancy.

Reversal of warfarin and direct-acting oral anticoagulants in traumatic intracranial hemorrhage: Four factor prothrombin complex concentrates for all?

Background Patients receiving oral anticoagulation who experience a traumatic intracranial hemorrhage (ICH) should receive anticoagulation reversal. Four factor prothrombin complex concentrate (4FPCC) is indicated for reversal of warfarin, and is frequently used for reversal of direct-acting oral anticoagulants (DOACs). The purpose of this study is to compare the safety and efficacy of 4FPCC reversal for traumatic ICH in DOAC- and warfarin-anticoagulated patients. Methods This was a single-center, retrospective review of adult patients with traumatic ICH who received 4FPCC for reversal of anticoagulation between April 2013 and August 2018. The ICH volume on the pre- and post-reversal head CT scans was measured. The primary endpoint was the incidence of expansion of ICH volume of blood using pre-and post-4FPCC imaging. Results A total of 102 patients meeting inclusion criteria were identified with 75 patients in the warfarin group and 27 patients in the DOAC group. There were no significant differences in baseline characteristics between the groups except DOAC patients had larger ICH volumes at baseline as compared to warfarin patients (23.4 mm3 vs 3.7 mm3, p = 0.0001). There was neither a statistical difference in change in ICH volume pre-and post-4FPCC administration, nor in the rate of &gt;20% ICH expansion between the warfarin and DOAC groups. There was no difference in the rate of adverse events compared between groups. Conclusion There was no difference in the either the change in ICH volume or the rate of &gt;20% ICH expansion in patients receiving 4FPCC for reversal DOAC versus warfarin anticoagulation. Rates of complications were low in both groups.

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.

Conduta conservadora na perfuração coronária tipo III: quando o tratamento básico salva vidas

Coronary artery perforation is a rare but potentially lethal complication of percutaneous coronary intervention, mainly due to hemodynamic compromise secondary to cardiac tamponade development. All interventional cardiologists must thus be able to promptly recognize and solve coronary artery perforation. We describe a successfully and conservatively managed type III coronary artery perforation with prolonged balloon inflations, in the absence of covered stents and without compromising the percutaneous coronary intervention result by anticoagulation reversal.

Abstract 13722: There Will be Blood: A Cautionary Tale of Triple Therapy

A 54-year-old man with coronary artery disease, chronic kidney disease, atrial flutter, and chronic right internal carotid artery (ICA) occlusion was transferred to our institution for management of cardiogenic shock following an anterior ST-elevation myocardial infarction status post percutaneous coronary intervention of the left main coronary artery (LMCA). He was placed on short-term triple antithrombotic therapy. On the day before discharge, he acutely developed left sided neurological deficits and hypotension. Exam was concerning for a right hemispheric stroke. Labs revealed a creatinine of 2.8 mg/dL, INR of 3.7, and a hemoglobin of 6.6 g/dL (previously 10 g/dL). Prior to sending the patient for brain imaging, we performed a bedside echocardiogram to further evaluate his hypotension. This revealed a large pericardial effusion with tamponade physiology. We suspected hemorrhagic cardiac tamponade secondary to triple antithrombotic therapy. His hypotension initially responded to intravenous fluids and packed red blood cells, resulting in an improved neurologic exam and supporting our hypothesis that his deficits represented right cerebral hemispheric hypoperfusion in the setting of a known right ICA occlusion and tamponade. Pericardiocentesis was initially deferred, as the risk of bleeding appeared prohibitive without reversal of apixaban and his coagulopathy, and these measures would subject the patient to a significant risk of thrombosis (e.g. LMCA stent thrombosis). Unfortunately, the patient developed progressive shock. After careful informed consent, we proceeded with high-risk pericardiocentesis involving pre-procedural reversal of apixaban with andexanet alfa and successful evacuation of 300 ml of hemorrhagic fluid. The pericardial pressure improved from 24 mmHg to 4 mmHg with complete resolution of the patient’s shock and neurological deficits. Our case demonstrates the risks associated with triple antithrombotic therapy as well as the nuanced clinical decision-making and risk-benefit assessment required when considering the use of anticoagulant reversal agents to prevent bleeding complications in the context of recent ischemic events and the need for urgent invasive procedures.

Time to four‐factor prothrombin complex concentrate administration decreased by presence of a 24/7 pharmacist in the emergency department

AbstractStudy objectiveThe objective of this study was to determine the impact of a 24/7 pharmacist (RPh) on time from order to the administration of four‐factor prothrombin concentrate complex (4F‐PCC) in the emergency department (ED).MethodsThis is a retrospective study that included patients who received 4F‐PCC in the ED for acute reversal of oral anticoagulation before and after the implementation of a 24/7 RPh. Patients for whom 4F‐PCC was ordered between May 1, 2014 and June 30, 2015 were in the pre‐RPh group and those between November 1, 2018 and December 31, 2019 were in the post‐RPh group. The primary end point was time from order to administration of 4F‐PCC. Time from arrival to administration of 4F‐PCC was also evaluated.ResultsOf 168 patients evaluated, 100 were included in the study (n = 33 pre‐RPh; n = 67 post‐RPh). The majority of patients were on warfarin (97.0% pre‐RPh and 73.1% post‐RPh) for atrial fibrillation. Both groups included trauma and intracranial hemorrhage patients. The mean time from order to 4F‐PCC administration was significantly shorter in the post‐RPh group (71.2 vs 35.2 minutes, P &lt; .001, 95% confidence interval [CI] [27.013‐44.987]). In addition, the median time from arrival to 4F‐PCC administration was also shorter in the post‐RPh group (153 vs 106 minutes, P = .033).ConclusionsAt our institution, time from order, and from arrival, to administration of 4F‐PCC for reversal of oral anticoagulation in the setting of acute bleeding events in the ED was reduced by 36 minutes after the presence of a 24/7 pharmacist.

Reversal of Anticoagulation By Ciraparantag: Time to Onset and Duration of Effect

Introduction: There is an unmet need for safe and effective anticoagulant reversal agents, with rapid onset of effects, for use in cases such as serious or life-threating bleeding, prior to urgent or emergency surgery, after major trauma, or in cases of anticoagulant overdose. Ciraparantag, an anticoagulant reversal agent with broad activity, binds directly to anticoagulant molecules including direct oral anticoagulants (DOACs), enoxaparin, and unfractionated heparin, without binding to endogenous coagulation factors or other plasma proteins. Two Phase 2 studies evaluated the safety and efficacy of ciraparantag for reversal of anticoagulation induced by apixaban or rivaroxaban in healthy adults. Methods: Two randomized, placebo-controlled, dose-ranging studies were conducted in healthy subjects 50-75 years of age. Subjects received apixaban or rivaroxaban until steady state. Study 1 subjects received apixaban 10 mg orally twice daily for 3.5 days. Study 2 subjects received rivaroxaban 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous (IV) dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120 or 180 mg) or placebo. Efficacy was based on manual whole blood clotting time (WBCT) at multiple timepoints over 24 hours beginning at 15 minutes after dosing. Subjects and technicians performing the WBCT testing were blinded to treatment. WBCT measures were performed in triplicate (simultaneous testing by 3 different evaluators) at 3 separate timepoints to analyze inter-observer variability using an analysis of variance (ANOVA) model with effects for observer and subject. Results: In Study 1 (apixaban), 49 subjects were randomized to receive study drug (36 ciraparantag, 13 placebo) and completed the study as planned. In Study 2 (rivaroxaban), 64 subjects were randomized to receive study drug (48 ciraparantag, 16 placebo) and all but one subject completed the study as planned. Ciraparantag demonstrated a rapid and dose-dependent reversal of apixaban and rivaroxaban anticoagulation as measured by the proportion of subjects whose WBCT decreased to within 10% above baseline at 15 minutes after study drug infusion. A lower dose of ciraparantag was required to achieve reversal of apixaban in a large fraction of subjects compared to the dose required for reversal of rivaroxaban (Figure). Reversal of anticoagulation was sustained in these subjects throughout the 24-hour measurement period. In both studies, there was good agreement among the triplicate manual WBCT measurements; all inter-observer coefficient of variance values were &amp;lt;5%. Ciraparantag was well tolerated; the most frequent adverse events were mild, transient sensations of warmth during or soon after infusion. Conclusions: In healthy subjects at steady-state levels of anticoagulation, ciraparantag single IV doses were well tolerated and produced rapid reversal of anticoagulation in high proportions of subjects within 15 minutes of administration (the first timepoint assessed) at doses ≥60 mg for apixaban and at a dose of 180 mg for rivaroxaban which were maintained throughout the 24-hour measurement period. Figure. Proportion of subjects with WBCT reversed to within 10% above baseline at 15 minutes and 30 minutes after dosing Disclosures Ansell: Amag Pharmaceuticals, Inc.: Consultancy. Bakhru:Pherosphere Technologies, Inc.: Current Employment. Luo:Amag Pharmaceuticals, Inc.: Current Employment. Villano:Amag Pharmaceuticals, Inc.: Consultancy. OffLabel Disclosure: Ciraparantag is an investigational drug being evaluated for the reversal of anticoagulation induced by direct oral anticoagulant (DOAC) therapies.

Design of a Randomized, Controlled Study to Evaluate Reversal of Anticoagulation of Ciraparantag in Healthy Adults: Whole Blood Clotting Time Assessed By Automated and Manual Methods

There is a need for safe and effective reversal agents for patients on chronic anticoagulant therapy in cases such as serious or life-threatening bleeding, urgent or emergency surgery, after major trauma, or in cases of anticoagulant overdose. Ciraparantag, an anticoagulant reversal agent in clinical development, which is believed to bind directly to anticoagulant molecules through non-covalent bonds, with no binding to blood coagulation factors or proteins in the blood. Phase 2 clinical studies have shown that ciraparantag reverses anticoagulation in healthy volunteers treated with edoxaban, enoxaparin, apixaban, or rivaroxaban as assessed by manual whole blood clotting time (WBCT). WBCT is the key pharmacodynamic marker because ciraparantag is cationic and binds to the anionic substances in standard blood collection tubes, and to anionic, colloidal activators used in the traditional coagulation assays such as PT or aPTT. Therefore, such assays are not appropriate markers for measuring ciraparantag's effect. WBCT is a direct measure of the time required for blood clot formation ex vivo and uses blood drawn into reagent-free collection equipment, using only glass as the activating agent. A Phase 2b clinical study is planned to evaluate the efficacy and safety of ciraparantag for reversal of anticoagulation as measured by WBCT using an automated point-of-care (PoC) coagulometer (developed by Perosphere Technologies, Inc.) compared with a manual testing method. This is a randomized, double-blind, placebo-controlled study in healthy adults 18 to 75 years of age who are anticoagulated with apixaban (10 mg PO twice daily) or rivaroxaban (20 mg PO once daily). Subjects who reach steady-state anticoagulation will be stratified into 2 age groups and randomized 2:1 to receive a single IV dose of ciraparantag or placebo, followed by serial WBCT testing and standard safety assessments over 24 hours. The primary efficacy endpoint is based on the extent and timing of reversal of anticoagulation following ciraparantag administration as compared with placebo, based on WBCT measured using the PoC coagulometer. Manual WBCT testing also will be performed at selected timepoints in order to describe the correlation between results obtained with the two methods. The coagulometer is expected to provide greater sensitivity and precision compared to the manual method. Further details of the design of this study will be provided. The results of this study will inform dose selection for the future Phase 3 clinical trial and will provide data on the use of the PoC coagulometer for assessment of ciraparantag for reversal of anticoagulation. Disclosures Villano: Amag Pharmaceuticals, Inc.: Consultancy. Bakhru:Pherosphere Technologies, Inc.: Current Employment. Luo:Amag Pharmaceuticals, Inc.: Current Employment. Freedman:Amag Pharmaceuticals, Inc.: Current Employment. OffLabel Disclosure: Ciraparantag is an investigational drug being evaluated for the reversal of anticoagulation induced by direct oral anticoagulant (DOAC) therapies.

Surgical intervention for cardiac tamponade during atrial fibrillation ablation: who and when?-a single-center experience.

The critical decision between conservative therapy and surgical intervention to manage cardiac tamponade (CT) during atrial fibrillation (AF) ablation remains empirical. The aim of the study was to summarize the experience in management of CT during AF ablation to derive a proper management pathway. All patients with CT who underwent catheter ablation for AF in our center from 2013 to 2019 were included. In total of 4887 patients, 32 (0.65%) patients occurred CT and received pericardiocentesis and immediate reversal of anticoagulation. All the CT patients were classified into three groups: rapid and uncontrollable bleeding who needed urgent surgical intervention (4/32), continuous bleeding (14/32), once pericardiocentesis, and no further bleeding (14/32). In the continuous bleeding group, the drainage volume in the first hour after pericardiocentesis was statistically related to surgical repair (p = 0.04) with a cutoff point of 970 ml (AUC 0.84, sensitivity 71.4%, specificity 100%, p = 0.04). During surgical repair, most of perforation sites were detected at superior anterior wall of left atrium close to right or left superior pulmonary vein antrum. No patient died of CT in our cohort. Only a small proportion of patients with CT required surgical intervention during AF ablation. When pericardiocentesis was performed, if a drainage volume was more than 1000 ml in the first hour or bleeding was accelerated after an hour of observation, emergency surgical repair should be recommended.