Final Study Report of Andexanet Alfa for Major Bleeding With Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented. METHODS: Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society on Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome. RESULTS: There were 479 patients enrolled (mean age, 78 years; 54% male; 86% White); 81% were anticoagulated for atrial fibrillation, and the median time was 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94-93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95-93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82-65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79-67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75-84]). In the safety population, thrombotic events occurred in 50 (10%) patients; in 16 patients, these occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54-0.70]) and correlated with lower mortality in patients <75 years of age (adjusted P=0.022; unadjusted P=0.003). Median endogenous thrombin potential was within the normal range by the end of andexanet alfa bolus through 24 hours for all FXa inhibitors. CONCLUSIONS: In patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02329327.

Prospective Observational Cohort Study of Tenecteplase Versus Alteplase in Routine Clinical Practice.

BACKGROUND: A 10-hospital regional network transitioned to tenecteplase as the standard of care stroke thrombolytic in September 2019 because of potential workflow advantages and reported noninferior clinical outcomes relative to alteplase in meta-analyses of randomized trials. We assessed whether tenecteplase use in routine clinical practice reduced thrombolytic workflow times with noninferior clinical outcomes. METHODS: We designed a prospective registry-based observational, sequential cohort comparison of tenecteplase- (n=234) to alteplase-treated (n=354) stroke patients. We hypothesized: (1) an increase in the proportion of patients meeting target times for target door-to-needle time and transfer door-in-door-out time, and (2) noninferior favorable (discharge to home with independent ambulation) and unfavorable (symptomatic intracranial hemorrhage, in-hospital mortality or discharge to hospice) in the tenecteplase group. Total hospital cost associated with each treatment was also compared. RESULTS: Target door-to-needle time within 45 minutes for all patients was superior for tenecteplase, 41% versus 29%; adjusted odds ratio, 1.85 (95% CI, 1.27-2.71); P=0.001; 58% versus 41% by Get With The Guidelines criteria. Target door-in-door-out time within 90 minutes was superior for tenecteplase 37% (15/43) versus 14% (9/65); adjusted odds ratio, 3.62 (95% CI, 1.30-10.74); P=0.02. Favorable outcome for tenecteplase fell within the 6.5% noninferiority margin; adjusted odds ratio, 1.26 (95% CI, 0.89-1.80). Unfavorable outcome was less for tenecteplase, 7.3% versus 11.9%, adjusted odds ratio, 0.77 (95% CI, 0.42-1.37) but did not fall within the prespecified 1% noninferior boundary. Net benefit (%favorable-%unfavorable) was greater for the tenecteplase sample: 37% versus 27%. P=0.02. Median cost per hospital encounter was less for tenecteplase cases ($13 382 versus $15 841; P<0.001). CONCLUSIONS: Switching to tenecteplase in routine clinical practice in a 10-hospital network was associated with shorter door-to-needle time and door-in-door-out times, noninferior favorable clinical outcomes at discharge, and reduced hospital costs. Evaluation in larger, multicenter cohorts is recommended to determine if these observations generalize.

Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. METHODS: We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin). RESULTS: Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage. CONCLUSIONS: In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).

Use of deep artificial neural networks to identify stroke during triage via subtle changes in circulating cell counts.

BACKGROUND: The development of tools that could help emergency department clinicians recognize stroke during triage could reduce treatment delays and improve patient outcomes. Growing evidence suggests that stroke is associated with several changes in circulating cell counts. The aim of this study was to determine whether machine-learning can be used to identify stroke in the emergency department using data available from a routine complete blood count with differential. METHODS: Red blood cell, platelet, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts were assessed in admission blood samples collected from 160 stroke patients and 116 stroke mimics recruited from three geographically distinct clinical sites, and an ensemble artificial neural network model was developed and tested for its ability to discriminate between groups. RESULTS: Several modest but statistically significant differences were observed in cell counts between stroke patients and stroke mimics. The counts of no single cell population alone were adequate to discriminate between groups with high levels of accuracy; however, combined classification using the neural network model resulted in a dramatic and statistically significant improvement in diagnostic performance according to receiver-operating characteristic analysis. Furthermore, the neural network model displayed superior performance as a triage decision making tool compared to symptom-based tools such as the Cincinnati Prehospital Stroke Scale (CPSS) and the National Institutes of Health Stroke Scale (NIHSS) when assessed using decision curve analysis. CONCLUSIONS: Our results suggest that algorithmic analysis of commonly collected hematology data using machine-learning could potentially be used to help emergency department clinicians make better-informed triage decisions in situations where advanced imaging techniques or neurological expertise are not immediately available, or even to electronically flag patients in which stroke should be considered as a diagnosis as part of an automated stroke alert system.

Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy.

Background and Purpose: Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH). Methods: ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days. Results: A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population). Conclusions: Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.

Anticoagulant Reversal in Gastrointestinal Bleeding: Review of Treatment Guidelines.

BACKGROUND: 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). AIM: 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. METHODS: This is a narrative review, based on PubMed and Internet searches reporting GI guidelines and supporting clinical data. RESULTS: 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. CONCLUSIONS: 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.

Tenecteplase Thrombolysis for Acute Ischemic Stroke.

Tenecteplase is a fibrinolytic drug with higher fibrin specificity and longer half-life than the standard stroke thrombolytic, alteplase, permitting the convenience of single bolus administration. Tenecteplase, at 0.5 mg/kg, has regulatory approval to treat ST-segment-elevation myocardial infarction, for which it has equivalent 30-day mortality and fewer systemic hemorrhages. Investigated as a thrombolytic for ischemic stroke over the past 15 years, tenecteplase is currently being studied in several phase 3 trials. Based on a systematic literature search, we provide a qualitative synthesis of published stroke clinical trials of tenecteplase that (1) performed randomized comparisons with alteplase, (2) compared different doses of tenecteplase, or (3) provided unique quantitative meta-analyses. Four phase 2 and one phase 3 study performed randomized comparisons with alteplase. These and other phase 2 studies compared different tenecteplase doses and effects on early outcomes of recanalization, reperfusion, and substantial neurological improvement, as well as symptomatic intracranial hemorrhage and 3-month disability on the modified Rankin Scale. Although no single trial prospectively demonstrated superiority or noninferiority of tenecteplase on clinical outcome, meta-analyses of these trials (1585 patients randomized) point to tenecteplase superiority in recanalization of large vessel occlusions and noninferiority in disability-free 3-month outcome, without increases in symptomatic intracranial hemorrhage or mortality. Doses of 0.25 and 0.4 mg/kg have been tested, but no advantage of the higher dose has been suggested by the results. Current clinical practice guidelines for stroke include intravenous tenecteplase at either dose as a second-tier option, with the 0.25 mg/kg dose recommended for large vessel occlusions, based on a phase 2 trial that demonstrated superior recanalization and improved 3-month outcome relative to alteplase. Ongoing randomized phase 3 trials may better define the comparative risks and benefits of tenecteplase and alteplase for stroke thrombolysis and answer questions of tenecteplase efficacy in the >4.5-hour time window, in wake-up stroke, and in combination with endovascular thrombectomy.

Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel.

Bleeding is the most common complication of anticoagulant use. The evaluation and management of the bleeding patient is a core competency of emergency medicine. As the prevalence of patients receiving anticoagulant agents and variety of anticoagulants with different mechanisms of action, pharmacokinetics, indications, and corresponding reversal agents increase, physicians and other clinicians working in the emergency department require a current and nuanced understanding of how best to assess, treat, and reverse anticoagulated patients. In this project, we convened an expert panel to create a consensus decision tree and framework for assessment of the bleeding patient receiving an anticoagulant, as well as use of anticoagulant reversal or coagulation factor replacement, and to address controversies and gaps relevant to this topic. To support decision tree interpretation, the panel also reached agreement on key definitions of life-threatening bleeding, bleeding at a critical site, and emergency surgery or urgent invasive procedure. To reach consensus recommendations, we used a structured literature review and a modified Delphi technique by an expert panel of academic and community physicians with training in emergency medicine, cardiology, hematology, internal medicine/thrombology, pharmacology, toxicology, transfusion medicine and hemostasis, neurology, and surgery, and by other key stakeholder groups.

A review of guidelines on anticoagulation reversal across different clinical scenarios - Is there a general consensus?

Anticoagulation is key to the treatment/prevention of thromboembolic events. The primary complication of anticoagulation is serious or life-threatening hemorrhage, which may necessitate prompt anticoagulation reversal; this could also be required for nonbleeding patients requiring urgent/emergent invasive procedures. The decision to reverse anticoagulation should weigh the benefit-risk ratio of supporting hemostasis versus post-reversal thrombosis. We appraise the available guidelines/recommendations for vitamin K antagonist (VKA) and direct oral anticoagulant (DOAC) reversal in the management of major bleeding, and also assess recent clinical data that may not yet be reflected in official guidance. In general, available guidelines are consistent in their recommendations, advocating administration of vitamin K and 4-factor prothrombin complex concentrates (4F-PCCs) rather than fresh frozen plasma to patients with VKA-associated intracranial hemorrhage and life-threatening bleeding, and specific reversal agents as essential therapy for DOAC reversal in those same severe conditions. However, guidelines also recommend off-label use of PCCs for DOAC reversal when specific reversal agents are unavailable. Limited recent evidence generally support the latter recommendation, but guidelines are likely to evolve as more data become available.

Intravenous Thrombolysis at 3.5 Hours From Onset of Pediatric Acute Ischemic Stroke.

Acute thrombolysis has a proven benefit for adults presenting with acute ischemic stroke, but data within the pediatric population are extremely limited. We report the case of a 14-year-old girl who presented with right-sided weakness and ataxia, loss of sensation, and altered mental status. Magnetic resonance imaging with diffusion-weighted imaging showed an acute lesion in the distribution of the left posterior cerebral artery, and magnetic resonance angiogram demonstrated occlusion of the third branch of the left posterior cerebral artery. With parental consent, clinicians decided to infuse an adult dose of weight-adjusted intravenous alteplase at 3.5 hours from onset of symptoms, with subsequent improvement in National Institutes of Health Stroke Scale score from 11 to 3. Computed tomography angiogram at 24 hours showed recanalization of the occluded vessel with no evidence of intracranial hemorrhage. Stroke Scale score at discharge was 3, with modified Rankin Scale scores at discharge of 1 and at 90 days of 0. This case highlights the importance of magnetic resonance imaging in diagnosing pediatric acute ischemic stroke and suggests consideration of thrombolysis in select confirmed pediatric stroke cases. However, a rigorous evidence base is lacking, and clinical trials have not been successful in recruiting patients.

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. METHODS: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication. RESULTS: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. CONCLUSIONS: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Prothrombin Complex Concentrates for Perioperative Vitamin K Antagonist and Non-vitamin K Anticoagulant Reversal.

Vitamin K antagonist therapy is associated with an increased bleeding risk, and clinicians often reverse anticoagulation in patients who require emergency surgical procedures. Current guidelines for rapid anticoagulation reversal for emergency surgery recommend four-factor prothrombin complex concentrate and vitamin K coadministration. The authors reviewed the current evidence on prothrombin complex concentrate treatment for vitamin K antagonist reversal in the perioperative setting, focusing on comparative studies and in the context of intracranial hemorrhage and cardiac surgery. The authors searched Cochrane Library and PubMed between January 2008 and December 2017 and retrieved 423 English-language papers, which they then screened for relevance to the perioperative setting; they identified 36 papers to include in this review. Prothrombin complex concentrate therapy was consistently shown to reduce international normalized ratio rapidly and control bleeding effectively. In comparative studies with plasma, prothrombin complex concentrate use was associated with a greater proportion of patients achieving target international normalized ratios rapidly, with improved hemostasis. No differences in thromboembolic event rates were seen between prothrombin complex concentrate and plasma, with prothrombin complex concentrate also demonstrating a lower risk of fluid overload events. Overall, the studies the authors reviewed support current recommendations favoring prothrombin complex concentrate therapy in patients requiring vitamin K antagonist reversal before emergency surgery.

Antifibrinolytic Therapy and Perioperative Considerations.

Fibrinolysis is a physiologic component of hemostasis that functions to limit clot formation. However, after trauma or surgery, excessive fibrinolysis may contribute to coagulopathy, bleeding, and inflammatory responses. Antifibrinolytic agents are increasingly used to reduce bleeding, allogeneic blood administration, and adverse clinical outcomes. Tranexamic acid is the agent most extensively studied and used in most countries. This review will explore the role of fibrinolysis as a pathologic mechanism, review the different pharmacologic agents used to inhibit fibrinolysis, and focus on the role of tranexamic acid as a therapeutic agent to reduce bleeding in patients after surgery and trauma.

Management of Factor Xa inhibitor-associated life-threatening major hemorrhage: A retrospective multi-center analysis.

BACKGROUND: Factor Xa (FXa) inhibitors, used for stroke prevention in atrial fibrillation and venous thromboembolism treatment and prevention, are the dominant non-Vitamin K oral anticoagulants on the market. While major bleeding may be less common with these agents compared to warfarin, it is always a risk, and little has been published on the most serious bleeding scenarios. This study describes a cohort of patients with FXa inhibitor-associated life-threatening bleeding events, their clinical characteristics, interventions and outcomes. METHODS: We performed a retrospective, 5-center review of FXa inhibitor-treated major bleeding patients. Investigators identified potential cases by cross-referencing ICD-9/10 codes for hemorrhage with medication lists. Investigators selected cases they deemed to require immediate reversal of coagulopathy, and reviewed charts for characteristics, reversal strategies and other interventions, and outcomes. RESULTS: A total of 56 charts met the inclusion criteria for the retrospective cohort, including 29 (52%) gastrointestinal bleeds (GIB), 19 (34%) intracranial hemorrhages (ICH) and 8 (14%) others. Twenty-four (43%) patients received various factor or plasma products, and the remainder received supportive care. Thirty-day mortality was 21% (n=12). Re-anticoagulation within 30-days occurred in 23 (41%) patients. Thromboembolic events (TEEs) occurred in 6 (11%) patients. No differences were observed in outcomes by treatment strategy. CONCLUSIONS: This cohort of FXa inhibitor-associated major bleeding scenarios deemed appropriate for acute anticoagulant reversal illustrates the variable approaches in the absence of a specific reversal agent.

Management of Major Bleeding Events in Patients Treated With Dabigatran for Nonvalvular Atrial Fibrillation: A Retrospective, Multicenter Review.

STUDY OBJECTIVE: There are limited data on the clinical presentations and management of dabigatran-associated major bleeding outside the clinical trial setting. The aim of this study is to describe clinical characteristics, interventions, and outcomes in patients with dabigatran-associated major bleeding who present to the emergency department (ED). METHODS: We performed a retrospective observational chart review study of dabigatran-treated patients with nonvalvular atrial fibrillation who presented with acute major bleeding to the ED. We searched electronic medical record databases cross-referencing medication lists and hemorrhage International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes. We studied the resulting charts to yield confirmed nonvalvular atrial fibrillation in patients with an index event of major bleeding and at least 1 dose of dabigatran in the 5 preceding days. RESULTS: The electronic search yielded 284 cases, and we assessed 93 as ineligible, leaving 191 in the final cohort. Of these, 118 patients (62%) had gastrointestinal hemorrhage; 36 (19%) had intracranial hemorrhage, 8 (4%) of which were nontraumatic cases and 28 (15%) traumatic. Thirty-six (19%) of the index events were in "other" locations and 1 (0.5%) "unknown." There were 12 deaths (6%): 8 from patients presenting with gastrointestinal bleeding events, 2 from intracranial hemorrhage (both nontraumatic), and 2 from other. Although RBC and plasma transfusions were common, only 11 patients (6%) received purified coagulation factors. CONCLUSION: Despite rare use of reversal strategies, mortality was low and outcomes were favorable, similar to reported outcomes from clinical trials, in this sample of patients with major bleeding while receiving dabigatran.

Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial.

BACKGROUND: Rapid reversal of vitamin K antagonist (VKA)-induced anticoagulation is often necessary for patients needing urgent surgical or invasive procedures. The optimum means of VKA reversal has not been established in comparative clinical trials. We compared the efficacy and safety of four-factor prothrombin complex concentrate (4F-PCC) with that of plasma in VKA-treated patients needing urgent surgical or invasive procedures. METHODS: In a multicentre, open-label, phase 3b randomised trial we enrolled patients aged 18 years or older needing rapid VKA reversal before an urgent surgical or invasive procedure. We randomly assigned patients in a 1:1 ratio to receive vitamin K concomitant with a single dose of either 4F-PCC (Beriplex/Kcentra/Confidex; CSL Behring, Marburg, Germany) or plasma, with dosing based on international normalised ratio (INR) and weight. The primary endpoint was effective haemostasis, and the co-primary endpoint was rapid INR reduction (≤1·3 at 0·5 h after infusion end). The analyses were intended to evaluate, in a hierarchical fashion, first non-inferiority (lower limit 95% CI greater than -10% for group difference) for both endpoints, then superiority (lower limit 95% CI >0%) if non-inferiority was achieved. Adverse events and serious adverse events were reported to days 10 and 45, respectively. This trial is registered at ClinicalTrials.gov, number NCT00803101. FINDINGS: 181 patients were randomised (4F-PCC n=90; plasma n=91). The intention-to-treat efficacy population comprised 168 patients (4F-PCC, n=87; plasma, n=81). Effective haemostasis was achieved in 78 (90%) patients in the 4F-PCC group compared with 61 (75%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 14·3%, 95% CI 2·8-25·8). Rapid INR reduction was achieved in 48 (55%) patients in the 4F-PCC group compared with eight (10%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 45·3%, 95% CI 31·9-56·4). The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving 4F-PCC had adverse events compared with 53 (60%) patients receiving plasma. Adverse events of interest were thromboembolic adverse events (six [7%] patients receiving 4F-PCC vs seven [8%] patients receiving plasma), fluid overload or similar cardiac events (three [3%] patients vs 11 [13%] patients), and late bleeding events (three [3%] patients vs four [5%] patients). INTERPRETATION: 4F-PCC is non-inferior and superior to plasma for rapid INR reversal and effective haemostasis in patients needing VKA reversal for urgent surgical or invasive procedures. FUNDING: CSL Behring.

Thromboembolic Events After Vitamin K Antagonist Reversal With 4-Factor Prothrombin Complex Concentrate: Exploratory Analyses of Two Randomized, Plasma-Controlled Studies.

STUDY OBJECTIVE: We evaluated thromboembolic events after vitamin K antagonist reversal in post hoc analyses of pooled data from 2 randomized trials comparing 4-factor prothrombin complex concentrate (4F-PCC) (Beriplex/Kcentra) with plasma. METHODS: Unblinded investigators identified thromboembolic events, using standardized terms (such as "myocardial infarction," "deep vein thrombosis," "pulmonary embolism," and "ischemic stroke"). A blinded safety adjudication board reviewed serious thromboembolic events, as well as those referred by an independent unblinded data and safety monitoring board. We descriptively compared thromboembolic event and patient characteristics between treatment groups and included detailed patient-level outcome descriptions. We did not power the trials to assess safety. RESULTS: We enrolled 388 patients (4F-PCC: n=191; plasma: n=197) in the trials. Thromboembolic events occurred in 14 of 191 patients (7.3%) in the 4F-PCC group and 14 of 197 (7.1%) in the plasma group (risk difference 0.2%; 95% confidence interval -5.5% to 6.0%). Investigators reported serious thromboembolic events in 16 patients (4F-PCC: n=8; plasma: n=8); the data and safety monitoring board referred 2 additional myocardial ischemia events (plasma group) to the safety adjudication board for review. The safety adjudication board judged serious thromboembolic events in 10 patients (4F-PCC: n=4; plasma: n=6) as possibly treatment related. There were 8 vascular thromboembolic events in the 4F-PCC group versus 4 in the plasma group, and 1 versus 6 cardiac events, respectively. Among patients with thromboembolic events, 3 deaths occurred in each treatment group. All-cause mortality for the pooled population was 13 per group. We observed no relationship between thromboembolic event occurrence and factor levels transiently above the upper limit of normal; there were no notable differences in median factor or proteins C and S levels up to 24 hours postinfusion start in patients with and without thromboembolic events. CONCLUSION: The incidence of thromboembolic events after vitamin K antagonist reversal with 4F-PCC or plasma was similar and independent of coagulation factor levels; small differences in the number of thromboembolic event subtypes were observed between treatment groups.

Re-initiation of dabigatran and direct factor Xa antagonists after a major bleed.

Direct oral anticoagulants (DOACs) are a relatively recent addition to the oral anticoagulant armamentarium, and provide an alternative to the use of vitamin K antagonists such as warfarin. Regardless of the type of agent used, bleeding is the major complication of anticoagulant therapy. The decision to restart oral anticoagulation following a major hemorrhage in a previously anticoagulated patient is supported largely by retrospective studies rather than randomized clinical trials (mostly with vitamin K antagonists), and remains an issue of individualized clinical assessment: the patient's risk of thromboembolism must be balanced with the risk of recurrent major bleeding. This review provides guidance for clinicians regarding if and when a patient should be re-initiated on DOAC therapy following a major hemorrhage, based on the existing evidence.