Project description:Bleeding is the main complication of oral anticoagulant (OAC) therapy, with major bleeds occurring in about 2% to 4% of OAC-treated patients per year. Although direct oral anticoagulants (DOACs) reduce the risk of major, fatal, and intracranial hemorrhage, major DOAC-related bleeding is associated with substantial morbidity and mortality, with case-fatality rates of 8% to 15% reported. Specific reversal agents for dabigatran (idarucizumab) and factor Xa inhibitors (andexanet) correct laboratory indices of anticoagulant effect. Clinical studies suggest that the majority of patients receiving these agents for DOAC-associated major bleeds experience clinical hemostasis. However, uncertainty remains regarding the incremental benefit of these agents and prothrombin complex concentrates over supportive measures alone, based on cohort studies that lacked control groups. Similar methodologic limitations preclude firm conclusions regarding the harms associated with use of these agents. Importantly, patients with DOAC-related major bleeding have substantial short-term risks of thrombosis and mortality, emphasizing the need for individualized patient assessment and protocolized bleed management strategies that include assessment of candidacy for safe resumption of OACs. With expanding indications and increasing prevalence of DOAC-eligible patients, bleeding complications and their management represent an ever-greater major health problem.
Project description:Direct oral anticoagulants (DOACs) are a new class of anticoagulants that directly inhibit either thrombin or factor Xa in the coagulation cascade. They are being increasingly used instead of warfarin or other vitamin K antagonists (VKAs). Adverse side effects of DOACs may result in hemorrhagic complications, including life-threatening intracranial hemorrhage (ICH), though to a much lesser degree than VKAs. Currently there are relatively limited indications for DOACS but their usage is certain to expand with the availability of their respective specific reversal agents. Currently, only idarucizumab (antidote for dabigatran) has been United States Food and Drug Administration- (FDA-) approved, but others (andexanet-? and ciraparantag) may be approved in near future, and the development and availability of such reversal agents have the potential to dramatically change the current anticoagulant use by providing reversal of multiple oral anticoagulants. Until all the DOACs have FDA-approved reversal agents, the treatment of the dreaded side effects of bleeding is challenging. This article is an attempt to provide an overview of the management of hemorrhage, especially ICH, related to DOAC use.
Project description:Background: Over the last ten years, a new class of drugs, known as the direct-acting oral anticoagulants (DOACs), have emerged at the forefront of anticoagulation therapy. Like the older generation anticoagulants, DOACs require specific reversal agents in cases of life-threatening bleeding or the need for high-risk surgery. Methods: Published literature was searched, and information extracted to provide an update on DOACS and their reversal agents. Results: The DOACs include the direct thrombin inhibitor-dabigatran, and the factor Xa inhibitors-rivaroxaban, apixaban, edoxaban, and betrixaban. These DOACs all have a rapid onset of action and each has a predictable therapeutic response requiring no monitoring, unlike the older anticoagulants, such as warfarin. Two reversal agents have been approved within the last five years: idarucizumab for the reversal of dabigatran, and andexanet alfa for the reversal of rivaroxaban and apixaban. Additionally, ciraparantag, a potential "universal" reversal agent, is currently under clinical development. Conclusions: A new generation of anticoagulants, the DOACs, and their reversal agents, are gaining prominence in clinical practice, having demonstrated superior efficacy and safety profiles. They are poised to replace traditional anticoagulants including warfarin.
Project description:Novel oral anticoagulants (NOACs) are no longer "novel" but their reversal agents definitely are. Although NOACs enjoy high clinical efficacy, monitoring and reversal of their effect is a challenge which this review attempts to surmount. Ideally, for NOAC activity measurement, specific anti-Factor IIa levels and anti -Factor Xa levels should be monitored (chromogenic assays), but such tests are not readily available. Modifications of the existing coagulation tests catering to this unmet need for quantification of DOAC activity have been reviewed. The available United States Food and Drug Administration (FDA) approved reversal agents, idarucizumab for dabigatrin and andexanet alfa for anti-Xa direct acting oral anticoagulants have given promising results but are prohibitively priced. Medline, Embase, and Scopus databases were thoroughly searched for clinical trials on laboratory investigations and specific as well as non-specific reversal-agents for DOACs.
Project description: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.
Project description:Four nonvitamin K antagonist oral anticoagulants (NOACs) are approved for the prevention of stroke in patients with nonvalvular atrial fibrillation and for the treatment of venous thromboembolism. These include the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. Bleeding is a complication for all anticoagulants and concerns regarding bleeding risk and the suitability of effective reversal strategies may be a barrier to their prescription. Despite the reduced risk of bleeding compared with vitamin K antagonists, questions persist regarding the management of bleeding related to NOAC use.To date, although a number of assays are responsive to NOACs, no single routine laboratory test has been identified to accurately measure the clinical anticoagulation state of patients on NOACs or established as a reliable predictor of bleeding risk. In addition, the establishment of a reliable human bleeding model to test novel inhibitors of the coagulation cascade has proved challenging. Although routine monitoring of anticoagulant levels is not necessary in patients taking NOACs, anticoagulant reversal and a means of measuring reversal may be required for patients who present with bleeding or require urgent surgery. Prothrombin complex concentrates are pooled plasma products containing varying amounts of inactive vitamin K-dependent clotting factors in addition to vitamin K-dependent proteins and can replenish factors in the intrinsic and extrinsic coagulation cascade, reversing an anticoagulant effect. Only one agent, idarucizumab, has been approved for rapid reversal of dabigatran-induced anticoagulation and one more agent, andexanet alfa, has been submitted for approval to reverse the anticoagulatory effects of direct and indirect factor Xa inhibitors.This review discusses the laboratory tests available for assessing anticoagulation, human models of bleeding, and the use of current strategies-including prothrombin complex concentrates for reversal of anticoagulation by NOACs-to manage bleeding in patients.
Project description:After a gap of almost 60 years following the development of warfarin, 2 new categories of oral anticoagulant agents have been approved for clinical use - the direct thrombin inhibitors and factor Xa inhibitors. These agents promise to be more convenient to administer with fixed dosing but still have equivalent efficacy and improved bleeding risk compared to warfarin. The clinical community is looking forward to the widespread usage of these agents but there is also some apprehension regarding bleeding risks, non-availability of specific reversal strategies and lack of specific monitoring parameters. This review article will attempt to educate the reader about three representative drugs from these classes: Dabigatran, Rivaroxaban and Apixaban. We will discuss the historical perspective to the development of these drugs, available research data and pharmacology of these agents. The best strategies for monitoring and reversal of these drugs in special situations will also be touched upon.
Project description:Background:Direct oral anticoagulants (DOACs) are indicated for prevention of stroke and embolism in patients with nonvalvular atrial fibrillation (NVAF). These agents have been shown to be non-inferior to warfarin in terms of efficacy and safety. However, their uptake in practice has been variable, and prescribed dosages may be inconsistent with manufacturer recommendations. Objectives:To evaluate patterns of oral anticoagulant use in patients with NVAF, including determination of patient characteristics associated with the prescribing of warfarin or DOACs and whether prescribed dosages of DOACs were concordant with manufacturer recommendations. Methods:This retrospective chart review was conducted from April to September 2017 at Abbotsford Regional Hospital, Abbotsford, British Columbia. Patients at least 18 years of age with NVAF and CHADS-65 score of 1 or higher were included. Patients with contraindications to oral anticoagulants, those with reversible atrial fibrillation, and those undergoing renal dialysis were excluded. The dosage of DOACs was categorized as too low, too high, or correct in relation to manufacturer recommendations for the Canadian product. Results:A total of 120 patients were included. At discharge, 83 (69%) of the patients had a prescription for DOAC, 25 (21%) had a prescription for warfarin, and 12 (10%) had no prescription for an oral anticoagulant. There were no statistically significant differences between the warfarin and DOAC groups with respect to patient characteristics. Among the 56 patients for whom a full DOAC dose was indicated, 7 (13%) received a dose that was too low. Among the 23 patients for whom a full DOAC dose was not indicated, 4 (17%) received a dose that was too high. Conclusions:At the study hospital, most patients with NVAF and CHADS-65 score of at least 1 had a discharge prescription for DOAC. Patient characteristics appeared to be similar between the warfarin and DOAC groups. For a notable proportion of patients who received a DOAC, the dosage was incorrect. Appropriate prescribing of oral anticoagulants could be further improved by education for prescribers and involvement of hospital pharmacists.
Project description:Direct oral anticoagulants (DOACs) offer noninferior efficacy and improved safety compared to vitamin K antagonists (VKAs) for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Unlike VKAs, DOACs do not require routine laboratory monitoring of anticoagulant effect and dose adjustment. In certain situations, however, laboratory assessment of anticoagulant effect may be desirable. Here we review the utility of currently available assays for assessment of DOAC effect and recommend an optimal assessment strategy for each drug, including calibrated dilute thrombin time or ecarin-based assays for dabigatran and calibrated anti-Xa activity assays for the factor Xa inhibitors. We also discuss reversal strategies, both specific and nonspecific, for each drug, including the preferential use of idarucizumab for the reversal of dabigatran and two agents, andexanet and ciraparantag, currently under development for the reversal of rivaroxaban, apixaban, and edoxaban.
Project description:Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.