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.

Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding: A Systematic Review and Meta-Analysis.

OBJECTIVES: To combine evidence on andexanet alfa and prothrombin complex concentrates for factor Xa inhibitor-associated bleeding to guide clinicians on reversal strategies. DATA SOURCES: Embase, Pubmed, Web of Science, and the Cochrane Library. STUDY SELECTION: Observational studies and randomized clinical trials studying hemostatic effectiveness of andexanet alfa or prothrombin complex concentrate for acute reversal of factor Xa inhibitor-associated hemorrhage. DATA EXTRACTION: Two independent reviewers extracted the data from the studies. Visualization and comparison of hemostatic effectiveness using Sarode et al or International Society of Thrombosis and Hemostasis Scientific and Standardization Committee criteria at 12 and 24 hours, (venous) thrombotic event rates, and inhospital mortality were performed by constructing Forest plots. Exploratory analysis using a logistic mixed model analysis was performed to identify factors associated with effectiveness and venous thromboembolic event. DATA SYNTHESIS: A total of 21 studies were included (andexanet: 438 patients; prothrombin complex concentrate: 1,278 patients). The (weighted) mean effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours. The (weighted) mean effectiveness for prothrombin complex concentrate was 88% at 12 hours and 76% at 24 hours. The mean 30-day symptomatic venous thromboembolic event rates were 5.0% for andexanet alfa and 1.9% for prothrombin complex concentrate. The mean 30-day total thrombotic event rates for andexanet alfa and prothrombin complex concentrate were 10.7% and 3.1%, respectively. Mean inhospital mortality was 23.3% for andexanet versus 15.8% for prothrombin complex concentrate. Exploratory analysis controlling for potential confounders did not demonstrate significant differences between both reversal agents. CONCLUSIONS: Currently, available evidence does not unequivocally support the clinical effectiveness of andexanet alfa or prothrombin complex concentrate to reverse factor Xa inhibitor-associated acute major bleeding, nor does it permit conventional meta-analysis of potential superiority. Neither reversal agent was significantly associated with increased effectiveness or a higher rate of venous thromboembolic event. These results underscore the importance of randomized controlled trials comparing the two reversal agents and may provide guidance in designing institutional guidelines.

Andexanet Alfa, the Possible Alternative to Protamine for Reversal of Unfractionated Heparin.

The recent shortage of protamine prompted an investigation of alternatives for reversal of unfractionated heparin. Heparin is an anticoagulant utilized in the hospital setting. Available options for anticoagulation include direct oral anticoagulants, vitamin K antagonists, thrombin inhibitors, low-molecular-weight heparins, and heparin. Protamine is the approved reversal agent for heparin with few alternatives under investigation. Although andexanet was designed as an antidote for apixaban and rivaroxaban, in vitro studies show that in a dose-dependent technique, andexanet had near full reversal of heparin, reversed anti-factor Xa activity, and neutralized anticoagulant effects of activated partial thromboplastin time and thrombin time induced by heparin.

What is the role of andexanet alfa in the reversal of anticoagulant effects?

ABSTRACT: Although using direct oral anticoagulants increases patient risk for hemorrhagic events, FDA-approved options for reversing anticoagulant effects are limited. This article discusses one of the more recent FDA-approved antidotes, andexanet alfa, and provides guidelines for its safe and effective use.

Direct oral anticoagulants: a review on the current role and scope of reversal agents.

New guideline recommendations prefer direct oral anticoagulants (DOACs) over warfarin in DOAC-eligible patients with atrial fibrillation and patients with venous thromboembolism. As expected with all antithrombotic agents, there is an associated increased risk of bleeding complications in patients receiving DOACs that can be attributed to the DOAC itself, or other issues such as acute trauma, invasive procedures, or underlying comorbidities. For the majority of severe bleeding events, the widespread approach is to withdraw the DOAC, then provide supportive measures and "watchful waiting" with the expectation that the bleeding event will resolve with time. However, urgent reversal of anticoagulation may be advantageous in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Until recently, the lack of specific reversal agents, has affected the uptake of these agents in clinical practice despite a safer profile compared to warfarin in clinical trials. In cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, idarucizumab has been recently approved for reversal of anticoagulation in dabigatran-treated patients and andexanet alfa for factor Xa inhibitor-treated treated patients. The current review summarizes the current clinical evidence and scope of these agents with the potential impact on DOAC use in clinical practice.

Cost comparison of andexanet versus prothrombin complex concentrates for direct factor Xa inhibitor reversal after hemorrhage.

Andexanet-alpha is a specific reversal agent for direct factor Xa inhibitors (dFXaI). We aimed to project utilization rates and cost of andexanet for reversal of dFXaI-related major hemorrhage compared to 4-factor prothrombin complex concentrates (4F-PCC). A retrospective, multicenter review was conducted between 1/1/2014 and 7/15/2018 of patients who received 4F-PCC for reversal of dFXaI-related life-threatening hemorrhages. Total hospital reimbursements/patient were calculated based on national average MS-DRG payments adjusting for Medicare discounts. The projected cost for andexanet (based on dose and insurance) and % reimbursement/patient was compared to the actual cost of 4F-PCC. Hemostasis at 24 h (excellent/good vs. poor) and 30-day thrombotic complications were assessed. Of 126 patients who received 4F-PCC to reverse dFXaI, 46 (~ 10 per-year) met inclusion criteria. The median projected cost of andexanet was $22,120/patient, compared to $5670/patient for 4F-PCC (P < 0.001). The median hospital reimbursement was $11,492/hospitalization. The projected cost of andexanet alone would exceed the entire hospital reimbursement in 74% of patients by a median of $7604, while 4F-PCC cost exceeded the total hospital payments in 7% of patients in the same cohort (P < 0.001). Hemostasis was excellent/good in 72% of patients post-4F-PCC, compared to 82% in andexanet trials. Thromboembolic events occurred in 4% of patients following 4F-PCC versus 10% in andexanet trials. The projected cost of andexanet would exceed the national average hospital reimbursement/patient in nearly 75% of patients by over $7500/hospitalization. 4F-PCC was significantly less expensive, had lower rates of thrombosis, but also lower rates of good/excellent hemostasis compared to published data for andexanet.

Non-Vitamin K Oral Anticoagulants (NOACs) and Their Reversal.

PURPOSE OF REVIEW: An 80-year-old man presents with an acute right hemiparesis and National Institutes of Health Stroke Scale (NIHSS) of 25, 14 h after taking dabigatran. Activated partial thromboplastin time (aPTT) is 42.8 s. Arteriogram demonstrates left internal carotid artery thrombosis. What is the appropriate management of this patient with acute ischemic stroke while on a NOAC? RECENT FINDINGS: Idarucizumab is a reversal agent approved for dabigatran, and two more reversal agents, andexanet alfa and aripazine, are currently in development for NOACs. In this article, we review currently available NOACs, their laboratory monitoring, and reversal agents.

Efficacy and safety of bovine activated factors IIa/VIIa/IXa/Xa in patients with active gastrointestinal bleeding: a proof of concept study.

BACKGROUND AND STUDY AIMS: Endoscopic treatment of active gastrointestinal bleeding often remains difficult, and considerable technical expertise is required. Our aim was to assess the efficacy and safety of endoscopic hemostasis with a liquid combination of bovine activated factors IIa/VIIa/IXa/Xa (SeraSeal). METHODS: Patients with active gastrointestinal bleeding were prospectively included. In group A, 5 mL of bovine activated factors IIa/VIIa/IXa/Xa was topically applied via catheters to the bleeding site as initial hemostasis; group B received a similar application but as rescue therapy after failure of conventional endoscopic hemostasis. RESULTS: In group A, bleeding was stopped by the agent in 15 /22 patients (68 %) and by conventional endoscopic hemostasis in 5 of the other 7, with coiling and surgery required for definitive hemostasis in 2. In group B, the addition of the agent definitively stopped bleeding in 13 /15 patients (87 %), with hemostasis in the remaining 2 achieved with fibrin glue. Rebleeding was observed in 1 patient. CONCLUSIONS: Our proof of concept study suggests that the use of bovine activated factors IIa/VIIa/IXa/Xa might be a safe and effective addition to current endoscopic hemostatic strategies, but further studies are necessary.ClinicalTrials.gov identifier: NCT02349490.

Idarucizumab and factor Xa reversal agents: role in hospital guidelines and protocols.

As expected with all antithrombotic agents, there is a risk of bleeding complications in patients receiving direct oral anticoagulants (DOACs) because of the DOAC itself, acute trauma, invasive procedures, or underlying comorbidities. For many bleeding events, a prudent course of action will be to withdraw the DOAC, then "wait and support" the patient, with the expectation that the bleeding event should resolve with time. Likewise, DOAC therapy may be interrupted ahead of a planned procedure, the stopping time being dependent on the agent involved and the patient's renal function. However, urgent reversal of anticoagulation is required in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Novel specific reversal agents, either under development or recently approved, will need to be incorporated into local anticoagulation reversal protocols. For dabigatran-treated patients, idarucizumab recently has been approved for clinical use in cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, both associated with a high risk of bleeding. As clinical experience with individual specific reversal agents grows, their roles in managing major bleeding events in DOAC-treated patients will become better defined. Future research, as well as ongoing use of idarucizumab, should help establish when it is appropriate to re-dose with idarucizumab, coadminister with prothrombin complex concentrates, or re-initiate DOAC after idarucizumab use. Ongoing trials should help identify the appropriate doses and expected durations of effect for andexanet alfa and ciraparantag, which are likely to vary depending on the individual oral anticoagulants.

Role of hepsin in factor VII activation in zebrafish.

Factor VII, the initiator of the extrinsic coagulation cascade, circulates in human plasma mainly in its zymogen form, factor VII and in small amounts in its activated form, factor VIIa. However, the mechanism of initial generation of factor VIIa is not known despite intensive research using currently available model systems. Earlier findings suggested serine proteases factor VII activating protease and hepsin play a role in activating factor VII, however, it has remained controversial. In this paper we estimated the levels of factor VIIa and factor VII for the first time in zebrafish adult population and also reevaluated the role of the above two serine proteases in activating factor VII in vivo using zebrafish as a model system. Knockdown of factor VII activating protease and hepsin was performed followed by assaying for their effect on factor VIIa concentration and extrinsic coagulation as measured by the kinetic prothrombin time. Factor VII activating protease knockdown showed no change in kinetic prothrombin time and no effect on factor VIIa levels while hepsin knockdown increased the kinetic prothrombin time and significantly reduced the factor VIIa plasma levels. Our results thus indicate that hepsin plays a physiologically important role in factor VII activation and hemostasis in zebrafish.

Management of venous thromboembolism--controversies and the future.

Despite the availability of comprehensive evidence-based guidelines there are difficult and controversial areas in the management of venous thromboembolism. Institutions and even countries disagree on the importance of calf vein thrombosis, with some rigorously detecting and treating it and others deliberately not looking for it. The need to treat proximal deep vein thrombosis and pulmonary embolism is accepted but which patients with an unprovoked first event should have long-term anticoagulation has become a difficult clinical decision. We are uncertain how to reduce the incidence of post-thrombotic syndrome seen in a substantial number of patients. How hard to look for an undiagnosed underlying cancer has become a contentious issue particularly in the United Kingdom following the recent publication of a guideline from the National Institute for Health and Clinical Excellence. Whilst we are wrestling with these dilemmas we are entering an era of new anticoagulants and have to solve the logistical problems of introducing them into clinical practice despite cost pressures. These issues will be explored in this review.

Clinical judgment when using coagulation tests during direct oral anticoagulant treatment: a concise review.

Because their anticoagulant effect is dose predictable, steady, and little influenced by diet and drugs, laboratory monitoring was deemed unnecessary in trials on venous and arterial thromboprophylaxis with the direct oral anticoagulant drugs (DOACs) rivaroxaban, apixaban, edoxaban, or dabigatran. However, there are special clinical settings in which measurement of their anticoagulant effect may be clinically desired. Because of lack of standardization between reagents employed and their global nature, the activated partial thromboplastin time (APTT) and the prothrombin time (PT) are not generally suitable for accurately assessing the anticoagulant effect of DOACs. The modified (diluted) PT reliably quantifies the anticoagulant effect of rivaroxaban or of apixaban. However, a higher intraindividual variability from one PT reagent to another is found when the data are compared with those obtained with standard PT. The HEMOCLOT (HYPHEN BioMed, France) assay is a modified (diluted) thrombin time (TT) provided with dabigatran calibrators. However, it is performed only in few specialized centers. Anti-factor Xa (anti-FXa) chromogenic assays employ routine automated coagulometers or manual spectrometers, and kits for anti-FIIa assays that measure dabigatran levels and kits for anti-Xa with rivaroxaban calibrators are commercially available. However, no correlation has been identified between any of these tests and clinical outcomes in patients taking any of the DOACs. Thus, currently, there are evidence gaps regarding the role of laboratory testing for surveillance and management of adverse events associated with DOACs. In view of this, in addition to standardization, validation of such assays is mandatory before they can be used to make clinical decisions.

[Andexanet alfa (ONDEXXYA® for Intravenous Injection 200†mg), a reversal agent for direct factor Xa inhibitors: pharmacological characteristics and clinical evidence].

Andexanet alfa is a modified recombinant human factor Xa (FXa) that was designed to serve as a binding target for FXa inhibitors as decoy protein. It sequesters FXa inhibitors from binding to endogenous FXa, thereby reversing anticoagulant effect of FXa inhibitors. Andexanet alfa has been approved in March 2022 in Japan for patients with life-threatening or uncontrolled bleeding while on treatment with a FXa inhibitor, apixaban, rivaroxaban, or edoxaban tosilate hydrate. It is administered via two dosing regimens, based on the type of FXa inhibitor, dose, and time since the last dose. In nonclinical studies, andexanet alfa significantly inhibited bleeding induced by FXa inhibitors in animal bleeding models. In the development for Japanese patients, the following two clinical studies have been conducted to confirm the efficacy and safety. First, safety and the reversal effect of andexanet alfa on the FXa inhibitor-mediated anticoagulant activity in healthy adults were confirmed in the overseas phase 2 study including Japanese subjects. Next, the reversal effect of andexanet alfa on the anticoagulation activity and the hemostasis were demonstrated in patients with acute major bleeding while on FXa inhibitor treatment in the global phase 3b/4 study (ANNEXA-4 study). The subgroup analysis of Japanese population showed that the efficacy and safety results were consistent with those of overall population. Andexanet alfa is the first approved reversal agent for FXa inhibitors in Japan and is expected to contribute to the improvement of prognosis in patients with fatal and/or uncontrolled bleeding by timely reversing anticoagulant effect of FXa inhibitors.

Outcomes Associated With 4-Factor Prothrombin Complex Concentrate Administration to Reverse Oral Factor Xa Inhibitors in Bleeding Patients.

Compared with vitamin K antagonists (VKAs), oral factor Xa inhibitors are associated with at least equivalent efficacy and a lower incidence of major bleeding. Despite this benefit, bleeding remains the most common adverse event. Prior to the approval of andexanet alfa, alternative agents such as 4-factor prothrombin complex concentrate (4F-PCC) were utilized for reversal. This was a retrospective, descriptive study conducted on patients 18 years of age or older who received 4F-PCC for reversal of oral factor Xa inhibitors-associated bleeding. Patients were excluded if they received a VKA or dabigatran in the previous 48 hours. A subgroup analysis comparing 4F-PCC with andexanet alfa was conducted on patients who met the inclusion and exclusion criteria of the ANNEXA-4 trial. The primary end point of this study was to evaluate the incidence of hemostasis and associated dosing strategies in patients receiving 4F-PCC for reversal of oral factor Xa inhibitors-associated bleeding. Thirty-eight patients were included, and 28 patients (74%) achieved hemostasis. The median dose of 4F-PCC was 50 units/kg. In patients who achieved hemostasis, the median dose was 50 units/kg, and in those who failed to reach hemostasis, a median dose of 30 units/kg was seen. Within the subgroup analysis, there was no difference in overall rates of hemostasis between the 4F-PCC and andexanet alfa groups. Remaining a reasonable option to utilize for reversal of oral factor Xa inhibitors is 4F-PCC, especially when andexanet alfa is unavailable, with 50 units/kg appearing to be the most effective dose to achieve hemostasis. Further studies are needed to determine a preferential agent.

Restart of Anticoagulant Therapy and Risk of Thrombosis, Rebleeding, and Death after Factor Xa Inhibitor Reversal in Major Bleeding Patients.

BACKGROUND: Lack of data on balancing bleeding and thrombosis risk causes uncertainty about restarting anticoagulants after major bleeding. Anticoagulant reversal trials offer prospectively gathered data after major bleeding with well-documented safety events and restarting behavior. OBJECTIVES: To examine the relationship of restarting anticoagulation with thrombosis, rebleeding, and death. METHODS: This is a posthoc analysis of a prospective factor Xa inhibitor reversal study at 63 centers in North America and Europe. We compared outcomes of restarted patients with those not restarted using landmark and time-dependent Cox proportional hazards models. Outcomes included thrombotic and bleeding events and death and a composite of all three. RESULTS: Of 352 patients enrolled, oral anticoagulation was restarted in 100 (28%) during 30-day follow-up. Thirty-four (9.7%) had thrombotic events, 15 (4.3%) had bleeding events (after day 3), and 49 (14%) died. In the landmark analysis comparing patients restarted within 14 days to those not, restarting was associated with decreased thrombotic events (hazard ratio [HR] = 0.112; 95% confidence interval [CI]: 0.001-0.944; p = 0.043) and increased rebleeding (HR = 8.39; 95% CI: 1.13-62.29; p = 0.037). The time-dependent Cox model showed evidence for a reduction in a composite (thrombotic events, bleeding, and death) attempting to capture net benefit (HR = 0.384; 95% CI: 0.161-0.915; p = 0.031). CONCLUSION: This analysis provides modest evidence that restarting anticoagulation in factor Xa inhibitor-associated major bleeding patients is correlated with reduced risk of thrombotic events and increased risk of rebleeding. There is low-level evidence of net benefit for restarting. A randomized trial of restarting would be appropriate.

Massive Gastrointestinal Hemorrhage.

Massive gastrointestinal hemorrhage is a life-threatening condition that can result from numerous causes and requires skilled resuscitation to decrease patient morbidity and mortality. Successful resuscitation begins with placement of large-bore intravenous or intraosseous access; early blood product administration; and early consultation with a gastroenterologist, interventional radiologist, and/or surgeon. Activate a massive transfusion protocol when initial red blood cell transfusion does not restore effective perfusion or the patient's shock index is greater than 1.0. Promptly reverse coagulopathies secondary to oral anticoagulant or antiplatelet use. Use thromboelastography or rotational thromboelastometry to guide further transfusions. Secure a definitive airway and minimize aspiration.

Prevention and Treatment of Bleeding with Direct Oral Anticoagulants.

Anticoagulant-related bleeding carries considerable morbidity and mortality. Major or life-threatening bleeding is among the most severe of these complications. As the number of patients treated with direct oral anticoagulants (DOACs) continues to increase, so does the number of DOAC-related bleeding events. The incidence of CRNM bleeding related to DOAC therapy ranges from 15 to 18% per 100-year patients, while the incidence of major bleeding ranges from 2.71 to 3.6%. Many of these bleeding events can be prevented with tailored dosing regimens or proper peri-procedural management. When unable to be prevented, DOAC-related bleeding can lead to significant long-term disability or death. Management with newer reversal agents such as andexanet alfa and idarucizumab, as well as prothrombin complex concentrates, may improve outcomes for patients with DOAC-related bleeding. The purpose of this review is to explore strategies for preventing and treating bleeding in patients receiving DOACs for anticoagulant therapy.