Reversal Agents For Direct Oral Anticoagulants Research Articles

A small-molecule hemostatic agent for the reversal of direct oral anticoagulant–induced bleeding

BackgroundThe bleeding risk associated with direct oral anticoagulants (DOACs) remains a major concern, and rapid reversal of anticoagulant activity may be required. Although specific and nonspecific hemostatic biotherapies are available, there is a need for small-molecule DOAC reversal agents that are simple and cost-effective to produce, store, and administer. ObjectivesTo identify and characterize a small molecule with procoagulant activity as a DOAC reversal agent. MethodsWe sought to identify a small procoagulant molecule by screening a chemical library with a plasma clotting assay. The selected molecule was assessed for its procoagulant properties and its ability to reverse the effects of the DOACs in a thrombin generation assay. Its activity as a DOAC reversal agent was also evaluated in a tail-clip bleeding assay in mice. ResultsThe hemostatic molecule (HeMo) dose-dependently promoted thrombin generation in plasma, with dose values effective in producing half-maximum response ranging between 3 and 5 μM, depending on the thrombin generation assay parameter considered. HeMo also restored impaired thrombin generation in DOAC-spiked plasma and reversed DOAC activity in the mouse bleeding model. HeMo significantly reduced apixaban-induced bleeding from 709 to 65 μL (vs 43 μL in controls; P < .01) and dabigatran-induced bleeding from 989 to 155 μL (vs 126 μL in controls; P < .01). ConclusionHeMo is a small-molecule procoagulant that can counterbalance hemostatic disruption by a thrombin inhibitor (dabigatran) or factor Xa inhibitors (apixaban and rivaroxaban). The compound’s effective clot formation and versatility make it a possible option for managing the inherent hemorrhagic risk during DOAC therapy.

Optimal management of cardiac surgery patients using direct oral anticoagulants: recommendations for clinical practice.

Literature is scarce on the management of patients using direct oral anticoagulants (DOACs) undergoing elective, urgent and emergency surgery. Therefore, we summarize the current evidence and provide literature-based recommendations for the management of patients on DOACs in the perioperative phase. A general literature review was conducted on the pharmacology of DOACs and for recommendations on the management of cardiac surgical patients on DOACs. Additionally, we performed a systematic review for studies on the use of direct DOAC reversal agents in the emergency cardiac surgical setting. When surgery is elective, the DOAC cessation strategy is relatively straightforward and should be adapted to the renal function. The same approach applies to urgent cases, but additional DOAC activity drug level monitoring tests may be useful. In emergency cases, idarucizumab can be safely administered to patients on dabigatran in any of the perioperative phases. However, andexanet alfa, which is not registered for perioperative use, should not be administered in the preoperative phase to reverse the effect of factor Xa inhibitors, as it may induce temporary heparin resistance. Finally, the administration of (activated) prothrombin complex concentrate may be considered in all patients on DOACs, and such concentrates are generally readily available. DOACs offer several advantages over vitamin K antagonists, but care must be taken in patients undergoing cardiac surgery. Although elective and urgent cases can be managed relatively straightforwardly, the management of emergency cases requires particular attention.

Practical Guide for Anticoagulant and Antiplatelet Reversal in Clinical Practice

In recent years, anticoagulant and antiplatelet use have increased over the past years for the prevention and treatment of several cardiovascular conditions. Due to the rising use of antithrombotic medications and the complexity of specific clinical cases requiring such therapies, bleeding remains the primary concern among patients using antithrombotics. Direct oral anticoagulants (DOACs) include rivaroxaban, apixaban, edoxaban, and betrixaban. Direct thrombin inhibitors (DTIs) include argatroban, bivalirudin, and dabigatran. DOACs are associated with lower rates of fatal, life-threatening, and significant bleeding risks compared to those of warfarin. The immediate reversal of these agents can be indicated in an emergency setting. Antithrombotic reversal recommendations are still in development. Vitamin K and prothrombin complex concentrate (PCCs) can be used for warfarin reversal. Andexanet alfa and idarucizumab are specific reversal agents for DOACs and DTIs, respectively. Protamine sulfate is the solely approved reversal agent for unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH). However, there are no specific reversal agents for antiplatelets. This article aims to provide a practical guide for clinicians regarding the reversal of anticoagulants and antiplatelets in clinical practice based on the most recent studies.

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants.

In 2018, the International Council for Standardization in Haematology (ICSH) published a consensus document providing guidance for laboratories on measuring direct oral anticoagulants (DOACs). Since that publication, several significant changes related to DOACs have occurred, including the approval of a new DOAC by the Food and Drug Administration, betrixaban, and a specific DOAC reversal agent intended for use when the reversal of anticoagulation with apixaban or rivaroxaban is needed due to life-threatening or uncontrolled bleeding, andexanet alfa. In addition, this ICSH Working Party recognized areas where additional information was warranted, including patient population considerations and updates in point-of-care testing. The information in this manuscript supplements our previous ICSH DOAC laboratory guidance document. The recommendations provided are based on (1) information from peer-reviewed publications about laboratory measurement of DOACs, (2) contributing author's personal experience/expert opinion and (3) good laboratory practice.

Act quickly to manage bleeding in patients taking direct oral anticoagulants

Direct oral anticoagulants (DOACs) are increasingly preferred anticoagulation options, with a lower risk of intracranial haemorrhage versus warfarin. Bleeding is, however, a predictable adverse event requiring urgent management. Specific DOAC reversal agents may be available, such as idarucizumab for the thrombin inhibitor dabigatran, and andexanet alfa for the factor Xa inhibitors apixaban, edoxaban (off-label) and rivaroxaban; but prothrombin complex concentrates are still often used in addition to supportive measures and haemostatic support.

Abstract MP38: Intracerebral Hemorrhage Across the United States: Incidence and Mortality Trends From 1990 to 2017

Background: Intracerebral Hemorrhage (ICH) accounts for 10% of strokes annually in the United States (US). Up-to-date trends in disease burden and regional variation remain unknown; especially after a dramatic increase in the use of direct oral anticoagulants (DOACs) since 2010. Our study reports updated incidence, mortality and mortality to incidence ratio (MIR) data related to ICH across the US. Methods: This observational study utilized the Global Burden of Disease database to determine age-standardized incidence (ASIR), death (ASDR) and MIR rates for ICH overall and for each state in the US from 1990-2017. All analyses were stratified by sex. Trends were analyzed using Joinpoint regression analysis, with presentation of estimated annual percentage changes (EAPCs) in ASIRs, ASDRs and MIRs over the observation period. Results: We observed an overall decrease in ASIRs, ASDRs and MIRs in both genders from 1990-2017, apart from female ASIRs and ASDRs in West Virginia and Kentucky. In 2017, the mean ASIR per 100,000 population for men was 25.67 and 19.17 for women. The 2017 mean ASDRs per 100,000 population for men and women were 13.96 and 11.35, respectively. The District of Columbia had the greatest decreases in ASIR EAPCs for males at -41.25% and females at -40.58%, and the greatest decreases in ASDR EAPCs for both males and females at -55.38% and -48.51%, respectively. The overall MIR during the study period decreased in males by -12.12% and females by -7.43%. However, MIR increased in males from 2014-2017 (EAPC +2.2% [95% CI +0.9%-+3.5%]) and in females from 2011-2017 (EAPC +1.0% [CI +0.7%-+1.4%]). Conclusion: This report reveals overall decreasing trends in incidence, mortality and MIR from 1990-2017. Notably, no significant change in mortality was found in the last 6 years of the study period, and MIR worsened in males from 2014-2017 and in females from 2011-2017, suggesting decreased ICH related survival lately. The substitution of vitamin K antagonists with DOACs is one possible explanation for a downtrend in incidence despite an aging population and increased use of anticoagulants. Limited access to reversal agents for DOACs is a potential reason for increase in MIR, however concrete deductions cannot be made owing to the observational nature of the study.

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.

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.

A Review on the Use of Reversal Agents of Direct Oral Anticogulant Drugs in Case of Gastrointestinal Bleeding.

Major bleeding is a life-threatening condition and a medical emergency with high mortality risk. It is often the complication of anticoagulant's intake. Anticoagulants are commonly used for the prevention and treatment of thrombotic events. The standard therapy with vitamin K antagonist (warfarin) has been frequently replaced by direct oral anticoagulants (DOACs). The latter agents (rivaroxaban, apixaban, edoxaban, dabigatran, and betrixaban) showed better efficacy and safety compared to standard warfarin treatment and they are recommended for the reduction of ischemic stroke. Literature data reported a high risk of gastrointestinal bleeding with DOACs, in particular with dabigatran and rivaroxaban. In case of life-threatening gastrointestinal bleeding, these patients could benefit from the use of reversal agents. We performed an electronic search on PUBMED of the literature concerning reversal agents for DOACs and gastrointestinal bleeding in the Emergency Department from 2004 to 2020. This review summarizes the current evidence about three reversal agents idarucizumab, andexanet alfa and ciraparantag, and the use of the first two in the emergency setting in patients with active major bleeding or who need urgent surgery which physicians indicate for a better management approach in order to increase patient's safety. Although these agents have been marketed for five years (idarucizumab) and two years (andexanet alfa) respectively, and despite guidelines considering antidotes as first-line agents in treating life-threatening hemorrhage when available, these antidotes seem to gain access very slowly in the clinical practice. Cost, logistical aspects and need for plasma level determination of DOAC for an accurate therapeutic use probably have an impact on this phenomenon.. An expert multidisciplinary bleeding team should be established so as to implement international guidelines based on local resources and organization.

The Potential of Andexanet Alfa as a Reversal Agent for Direct Oral Anticoagulants

Purpose: The purpose of this article is to describe the role of andexanet alfa as a reversal agent in the management of bleeding complications associated with direct oral anticoagulants (DOACs). Summary: Over the past several years, DOACs are increasingly being used in the management of patients with non-valvular atrial fibrillation or stroke prevention. Management of major bleeding in DOAC therapy includes supportive therapy and addressing any factors that are contributing to blood loss. Additionally, there may a need to expedite the removal of any anticoagulation effects by removing or neutralizing the anticoagulant. Until recently, there was no specific reversal agent for DOACs; management approaches were limited to util ©Wizing concentrated clotestern University oft Health Sciencesing factors or fresh frozen plasma. The FDA granted expedited approval of andexanet alfa as a specific reversal agent for the DOACs to meet this unmet need. Conclusion: In clinical trials, andexanet alfa demonstrated a significant reduction in anti-Xa activity in patients with a major bleeding event on apixaban or rivaroxaban. The clinical benefit of this anti-Xa activity reduction has yet to be demonstrated in a randomized controlled trial. The current lack of randomized controlled trials demonstrating clinical benefit and the high cost of the drug has limited the widespread use of this antidote.

The Peri-Operative Management of Anticoagulants: Systemic Review of Guidelines

Introduction Venous thromboembolism (VTE) and atrial fibrillation are thrombotic disorders resulting in significant morbidity and mortality, if left untreated. In Canada, 45,000 people, or 1-2 cases per 1000 people, per year will experience an acute VTE, and it is estimated that 200,000 Canadians have atrial fibrillation. The treatment of VTE and atrial fibrillation often includes the use of anticoagulants. Patients on anticoagulation may need interruption of treatment for surgeries and procedures. To evaluate differences in perioperative anticoagulation management strategies we conducted a systematic review of the peri-operative clinical practice guidelines for anticoagulants. Methods A protocol using the Preferred Reporting Items for Systematic review and Meta-analysis Protocols (PRISMA-P) was developed. Relevant primary clinical practice guidelines were identified using MEDLINE, EMBASE, and guideline-specific databases. All guidelines from the preceding 20 years up to January 11, 2019 were screened. Eligible manuscripts were reviewed by two independent reviewers. Data abstraction was independently completed in duplicate for included guidances and categorized according to thrombotic risks and bleeding risks. Guidances on emergency surgeries were not included for the purposes of this review. Information on anticoagulation interruption, bridging regimens, laboratory testing, and reversal strategies were collected. Results Eight guidelines met inclusion criteria and 6 contained sufficient information for peri-operative management of anticoagulants. One guideline focused on patients presenting with bleeding events and restated the same peri-operative guidelines as had been published a year prior by the same group, and was excluded. Another guideline only addressed emergency surgeries and was also excluded from this review. The majority of the guidelines had similar definitions of risk factors for venous and arterial thrombotic events (see table 1). There were no conflicting guidance recommendations identified, but there were differences in the component of peri-operative management addressed by each guideline, ie bridging, reversal agents, laboratory tests. The levels of evidence used to develop recommendations varied between guidelines. All guidelines provided recommendations on warfarin and low molecular weight heparins (LMWH) management and only one guideline provided suggestions for direct oral anticoagulants (DOACs). The findings for perioperative anticoagulation management for patients with atrial fibrillation and VTE are presented in Tables 2 and 3, respectively. For high bleeding risk surgeries, most guidelines cited similar studies resulting in similar recommendations for interruption of warfarin and bridging in high venous and arterial thrombotic risk patients. In high bleeding risk procedures and low thrombotic risk patients, no bridging is recommended. For low bleed risk procedures, regardless of thrombotic risk, guidelines recommended for continuation of anticoagulant therapy. Discussion This systematic review identified 6 guidelines of non-urgent peri-operative management recommendations of primarily warfarin and LMWH in patients with VTE and atrial fibrillation. While no major discrepancies in the guideline suggestions were noted, the scope of data examined (medication management, bridging, blood tests, reversal of agents) differed amongst the various agencies. The guidelines that were most consistent for recommendations of anticoagulant management and bridging tended to be from hematologic societies. The only guideline that addressed perioperative management of DOACs was the 2018 ASH guideline on management of VTE which was against measurement of DOAC levels prior to procedures. The lack of thorough guidance for DOACs is likely due to the year of publication of the guidelines examined and paucity of contributing studies. In terms of reversal agents, all clinical practice guidelines except for the ASH guidelines were prior to specific DOAC reversal agents such as idaracizumab. Future Directions We anticipate that there will be other guidelines developed that address specifically the use of DOACs in the perioperative setting, as well as their reversal agents. Disclosures Shivji: BMS-Pfizer Thrombosis Canada: Other: Fellowship award. Castellucci:BMS: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Sanofi: Honoraria; Aspen: Honoraria; Servier: Honoraria.

Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum.

Two specific reversal agents for direct oral anticoagulants (DOACs) have been approved in the United States: idarucizumab for dabigatran reversal and andexanet alfa for apixaban and rivaroxaban reversal. Non-specific prohemostatic agents such as prothrombin complex concentrate (PCC) and activated PCC have also been used for DOAC reversal. The goal of this document is to provide comprehensive guidance from the Anticoagulation Forum, a North American organization of anticoagulation providers, regarding use of DOAC reversal agents. We discuss indications for reversal, provide guidance on how the individual reversal agents should be administered, and offer suggestions for stewardship at the health system level.

Reversal of direct oral anticoagulants.

Reversal agents for direct oral anticoagulants (DOACs), including factor X inhibitors and direct thrombin inhibitors, are a major concern in clinical practice. After DOACs were introduced and became widely used as an alternative for vitamin K antagonists in the management of venous thromboembolism and nonvalvular atrial fibrillation, the need for effective reversal agents has increased, particularly for life-threatening bleeding episodes related to DOACs or to reverse medication effects during urgent interventions. In the absence of specific reversal agents, prothrombin complex concentrate (PCC) and activated PCC are reasonable options to reverse bleeding associated with DOACs. However, high-quality clinical evidence is lacking. Idarucizumab is the only agent approved by the US Food and Drug Administration to reverse the effects of dabigatran; andexanet alfa and ciraparantag are also under evaluation as reversal agents for DOACs. This review summarizes the current evidence for nonspecific and specific reversal of DOACs.

Clinical implications of reversal agents for direct oral anticoagulants.

Direct oral anticoagulants (DOACs) are effective in preventing and treating venous thromboembolism, and preventing stroke in atrial fibrillation. Until recently, there has been no specific reversal agent for DOACs. Now, a specific antidote for the direct thrombin inhibitor, dabigatran has been approved for use, and antidotes for factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) are being developed. We review the evidence for currently used and emerging reversal strategies, and discuss possible clinical implications, including increased prescription of DOACs, use of DOACs in clinical situations previously felt to pose too great a risk of bleeding, and use of reversal agents beyond currently approved indications.