Real-world utilization of andexanet alfa.

OBJECTIVE: In 2018, the FDA approved andexanet alfa for the reversal of life-threatening hemorrhages in patients anticoagulated with apixaban or rivaroxaban. Yet, cost-effective factor Xa inhibitor reversal remains controversial. The objective of this study was to describe real world utilization of andexanet alfa. METHODS: This was a retrospective case series of patients receiving andexanet alfa between July 28, 2018 and April 29, 2019 at a large academic health system. Baseline demographics, anticoagulant type and reversal, as well as brain imaging were collected. Primary endpoints were stability of hematoma for intracranial hemorrhage (ICH), and hemostatic effectiveness for patients undergoing surgical procedures. Secondary endpoints were thromboembolism and 30 day mortality. RESULTS: Of the 25 patients evaluated, 13 received andexanet alfa for ICH. Eleven of the 13 had follow-up imaging available and stability was observed in 90.9%. Three patients received andexanet alfa for reversal prior to surgical procedures, and 100% hemostatic effectiveness was achieved. Nine patients received andexanet alfa for reversal of extracranial bleeding, including gastrointestinal bleed (n=4). There were no thrombotic events in our cohort, and 30 day mortality was 24%. Sixty-four percent of patients would have met exclusion criteria for the ANNEXA-4 trial. CONCLUSION: This is the largest series to date describing real-world utilization of andexanet alfa. Our series showed hemostatic efficacy in 90.9% of patients with ICH, and 100% in patients undergoing surgical procedures. There were no thrombotic complications. Yet, larger and comparative studies are needed to clarify the optimal agent and patient selection for reversal of factor Xa inhibitors.

Reversal agents for oral anticoagulants.

For more than half a century, warfarin, a vitamin K antagonist, has been the anticoagulant of choice. However, direct oral anticoagulants are rapidly gaining in popularity, which poses the need for efficacious reversal agents. This review article summarizes the strategies and agents used to reverse oral anticoagulants.

[NOAC: Real-life data and the role of antidotes for the treatment of bleeding]. / NOAK: Real-life-Daten und Therapie von Blutungen mit Antidots.

The non-vitamin K antagonists (NOAC) are an integral component of our antithrombotic prevention and therapy. For four of the NOAC, their non-inferiority or even superiority versus vitamin K antagonists (VKA) has been proven. Thus, the management of special patient cohorts or the management of active bleeding complications is a focus of current discussion.In addition to prospective trials, numerous retrospective analyses of health insurers or public health provider data have been analyzed and published as "real life" or "real-world evidence" data. In almost all data sets the results of the NOAC approval trials were confirmed, demonstrating their non-inferiority or even superiority versus VKA. Attempts to compare the various NOAC with each other must be viewed critically since the real-world evidence (RWE) analysis provides very divergent results depending on the cohorts analyzed. Thus, a substantial prescriber-bias must be taken into account and never be excluded.In order to improve the management of bleeding complications, NOAC antidotes were developed. While the factors Xa antidote, andexanet alpha, a modified coagulation factor deleted of an intrinsic activity, will not be available before 2018, the dabigatran antidote idarucizumab is already in clinical use. Idarucizumab, a monoclonal antibody fragment directed against dabigatran, is able to completely antagonize the effect of dabigatran within minutes. Therefore, the drug has the potential to terminate life-threatening bleeding complications earlier and make emergency surgical or interventional procedures possible without an elevated bleeding risk.

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.

Reversal of Direct Oral Anticoagulants: Current Status and Future Directions.

Direct oral anticoagulants (DOACs) are increasingly used for prevention and treatment of venous thromboembolism and for prevention of stroke in patients with nonvalvular atrial fibrillation. In phase III clinical trials that included more than 100,000 patients, the DOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with less serious bleeding, particularly less intracranial bleeding. Real-world evidence supports these outcomes. Despite this, some physicians and patients are concerned about serious bleeding or emergencies unless specific reversal agents for the DOACs are available. However, in clinical trials performed without reversal agents, the outcome of major bleeds was similar or better in patients receiving DOACs than in those taking VKAs. Because of their short half-lives, supportive measures are sufficient to manage most bleeds in patients receiving DOACs. Anticoagulant reversal should only be considered with life-threatening bleeds, with bleeds that fail to respond to usual measures and in patients requiring urgent surgery. Idarucizumab is licensed for dabigatran reversal and andexanet alfa is likely to be soon licensed for reversal of rivaroxaban, apixaban, and edoxaban. To ensure responsible use of these agents, every hospital needs a bleeding management algorithm that identifies patients eligible for reversal and outlines appropriate dosing regimens.

Perspectivas clínicas del manejo de la hemorragia en el paciente tratado con anticoagulante oral: estudio DECOVER / Clinical perspectives on the management of bleeding in patients on oral anticoagulants: the DECOVER Study (DElphi Consensus on oral COagulation and therapy action reVERsal)

Objetivo: Evaluar el grado de acuerdo entre hematólogos y urgenciólogos respecto a las mejores prácticas para el manejo de hemorragias y la reversión de la anticoagulación oral. Método: Estudio Delphi multicéntrico español con médicos expertos en anticoagulación y manejo de hemorragias. Se realizaron dos rondas de preguntas entre abril y septiembre de 2015. Se obtenía consenso cuando el 75% o más de los panelistas puntuaban en el mismo tercil. Resultados: Se encuestó a 15 hematólogos y 17 urgenciólogos de 14 comunidades autónomas. La hemodiálisis y la administración de concentrados de complejo protrombínico (CCP) activado fueron tratamientos consensuados para antagonizar una hemorragia relevante/mayor en pacientes tratados con dabigatrán. Para rivaroxabán y apixabán solo se consideró el CCP. El panel no valoró ningún CCP como eficaz y seguro a la vez. Los tiempos de tromboplastina parcial activado, trombina, ecarina y de trombina diluido se indicaron para pacientes tratados con dabigatrán y la actividad anti-Xa específica para los tratados con rivaroxabán y apixabán cuando presentan una hemorragia. Disponer de un antídoto específico para el tratamiento de los anticoagulantes orales de acción directa (ACOD) sería útil en caso de hemorragia grave (97%) y supondría un cambio sustancial en el algoritmo de tratamiento actual (97%). Conclusiones: Los resultados estuvieron en general alineados con las guías de práctica clínica, pero mostraron que existen áreas de mejora en la unificación de criterios sobre el manejo de los pacientes con hemorragias, y destacan la necesidad de disponer de antídotos específicos para ACOD (AU)

Objective: To evaluate the level of agreement between hematologists and emergency medicine physicians regarding the best clinical practices for managing bleeding and anticoagulant reversal. Methods: Nationwide Spanish multicenter Delphi method study with a panel of experts on anticoagulation and the management of bleeding. Two survey rounds were carried out between April and September 2015. Consensus was reached when more than 75% of the panelists scored items in the same tertile. Results: Fifteen hematologists and 17 emergency medicine specialists from 14 Spanish autonomous communities participated. Consensus was reached on the use of both hemodialysis and an activated prothrombin complex concentrate (PCC) to antagonize significant/major bleeding in patients taking dabigatran. Use of an activated PCC was considered sufficient for patients on rivaroxaban or apixaban. The panel did not consider any PCC to be both effective and safe. Tests for activated partial thromboplastin, thrombin, diluted thrombin, and ecarin clotting times were considered useful in patients treated with dabigatran. A specific anti-Xa activity assay was suggested for patients who developed bleeds while treated with rivaroxaban or apixaban. Specific antidotes for direct-acting oral anticoagulants would be useful when severe bleeding occurs according to 97% of the panelists. Such antidotes would substantially change current treatment algorithms. Conclusion: The points of consensus were generally in line with clinical practice guidelines, but the Delphi process revealed that there are aspects of the clinical management of bleeding that require unified criteria. The need for specific antidotes for direct-acting oral anticoagulants was emphasized (AU)

Rivaroxaban significantly inhibits the stimulatory effects of bone-modulating hormones: In vitro study of primary female osteoblasts.

BACKGROUND: Anticoagulant therapy is a mainstay of treatment subsequent to major orthopedic surgeries. Evidence linking anticoagulant therapy, osteoporosis, and delayed fracture healing is not conclusive. We have previously reported that rivaroxaban significantly inhibited cell growth and energy metabolism in a human osteoblastic cell line. This study analyzed the response of primary female osteoblast cells to rivaroxaban in combination with various bone-modulating hormones. METHODS: Bone samples were taken from both premenopausal (pre-Ob) and postmenopausal (post-Ob) women. Cells were isolated from each sample and cultured to sub-confluence. Each sample was then treated with Rivaroxaban (10 µg/ml) in combination with the following hormones or with the hormones alone for 24 hours: 30nM estradiol-17ß (E2), 390nM estrogen receptor α (ERα) agonist PPT, 420nM estrogen receptor ß (ERß) agonist DPN, 50nM parathyroid hormone (PTH), and 1nM of vitamin D analog JKF. RESULTS: No effects were observed after exposure to rivaroxaban alone. When pre-Ob and post-Ob cells were exposed to the bone-modulating hormones as a control experiment, DNA synthesis and creatine kinase (CK)-specific activity was significantly stimulated with a greater response in the pre-Ob cells. When the cells were exposed to rivaroxaban in combination with bone-modulating hormones, the increased DNA synthesis and CK-specific activity previously observed were completely attenuated. CONCLUSIONS: Rivaroxaban significantly inhibited the stimulatory effects of bone-modulating hormones in both pre-Ob and post-Ob primary human cell lines. This finding may have clinical relevance for patients at high risk of osteoporosis managed with rivaroxaban or other factor Xa inhibitors.

Factor Eight Inhibitor Bypassing Agent (FEIBA) for Reversal of Target-Specific Oral Anticoagulants in Life-Threatening Intracranial Bleeding.

INTRODUCTION: As increasing number of patients present to emergency departments with life threatening hemorrhages, particularly intracranial hemorrhage on anticoagulation physicians must be cognizant of the limitations of the available reversal options. Based upon the available literature, our institution formulated a reversal algorithm for patients with life-threatening bleeding on factor Xa inhibitors by administering factor eight inhibitor bypassing agent (FEIBA) 20 units/kg. METHODS: A retrospective chart review was performed to include all patients who received FEIBA per institutional protocol. This case series excluded patients who received FEIBA for reversal of dabigatran. Pre and post FEIBA CT scans were compared for changes. Finally, patients were stratified by estimated mortality rates calculated based on pre-intervention characteristics via published risk models. RESULTS: Thirteen patients were initially included in this study yet two patients were excluded because they were on dabigatran. Fifty-five percent of patients demonstrated stable ICH on CT scan after FEIBA administration while thirty-six percent showed worsening scans. Two patients developed thrombotic events after FEIBA administration. DISCUSSION: FEIBA is a treatment option in patients on a TSOA with acute intracranial hemorrhage with evidence of at least partial pharmacologic reversal of their anticoagulation status. There does not appear to be any major risk of thromboembolic complications associated with FEIBA. Much larger study sizes will be necessary to establish statically significant clinical efficacy for FEIBA use in this patient population. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency medicine physicians are first-line caretakers for patients with life threatening intracranial hemorrhages whether spontaneous or traumatic. FEIBA is a potentially safe option to reverse TSOA in this patient population.

Reversal of direct oral anticoagulants: a practical approach.

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.

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.

Optimizing the safety of treatment for venous thromboembolism in the era of direct oral anticoagulants.

Direct oral anticoagulants (DOACs) are rapidly replacing vitamin K antagonists (VKAs) for treatment of venous thromboembolism (VTE). The DOACs include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. When compared with conventional VTE treatment consisting of a parenteral anticoagulant followed by a VKA, the DOACs were equally effective for prevention of recurrence, but were associated with less bleeding. With similar efficacy, better safety, and the convenience of fixed dosing without the need for routine coagulation monitoring, guidelines now recommend DOACs over VKAs for VTE treatment in patients without active cancer. Nonetheless, measures are needed to optimize the safety of DOACs. Focusing on these measures, this paper summarizes the results of phase III trials evaluating DOACs for VTE treatment; identifies which VTE patients are or are not candidates for DOACs; provides guidance on how to choose among DOACs; lists the licensed dosing information for DOACs; discusses the optimal treatment duration for VTE; describes periprocedural management of DOACs in patients requiring surgery or intervention; and finally, reviews the management of bleeding, including the role for specific reversal agents.

[Coagulation disorders in the intensive care unit - what is new?]. / Gerinnungsstörungen bei Intensivpatienten: Diagnostik und Therapie.

The phase III non-vitamin K dependent oral anticoagulants (NOAC) studies and recently published real world data on the use of dabigatran and rivaroxaban have shown that the bleeding profile in particular of intracranial and other life-threatening bleeding of NOAC is more favourable than that of warfarin. In case of a bleeding complication in a patient treated with a NOAC the recently updated EHRA practical guide offers management strategies. Idarucizumab, the specific antidot for dabigatran is approved to reverse the anticoagulant effect of dabigatran-treated patients who have serious bleeding and require an urgent procedure. Andexanet alfa, a specific antidot for direct and indirect factor Xa-inhibitors will be available in the future. The frequency of thrombocytopenia in ICU patients is high whereas the heparin induced thrombocytopenia (HIT) only counts for a small minority of patients with thrombocytopenia. To avoid an overdiagnosis of HIT a reliable and complete clinical and laboratory workup has to be performed. New immunoassays have been developed to provide results within a short period of time. These tests appear to have improved diagnostic accuracy compared with ELISAs in patients with suspected HIT and may reduce misdiagnosis and overtreatment. Acquired haemophilia (AH) is a rare and often life threatening bleeding disorder caused by autoantibodies against factor VIII. Susoctocog alfa is a B-domain deleted recombinant factor VIII porcine sequence that has recently been approved to treat severe bleeding in patients with AH. Susoctocog alfa offers the ability to effectively titrate and monitor dosing based on factor VIII activity levels.

Novel oral anticoagulants in plastic surgery.

Novel oral anticoagulants (NOACs) have emerged as a good alternative to warfarin in the prevention of stroke for patients with atrial fibrillation. NOAC use is increasing rapidly; therefore, greater understanding of their use in the perioperative period is important for optimal care. Studies and reviews that reported on the use of NOACs were identified, with particular focus on the perioperative period. PubMed was searched for relevant articles published between January 2000 and August 2015. The inevitable rise in the use of NOACs such as rivaroxaban (Xarelto™), apixaban (Eliquis™), edoxaban (Lixiana™) and dabigatran (Pradaxa™) may present a simplified approach to perioperative anticoagulant management due to fewer drug interactions, rapidity of onset of action and relatively short half-lives. Coagulation status, however, cannot reliably be monitored and no antidotes are currently available. When planning for discontinuation of NOACs, special consideration of renal function is required. Advice regarding the management of bleeding complications is provided for consideration in emergency surgery. In extreme circumstances, haemodialysis may be considered for bleeding with the use of dabigatran. NOACs will increasingly affect operative planning in plastic surgery. In order to reduce the incidence of complications associated with anticoagulation, the management of NOACs in the perioperative period requires knowledge of the time of last dose, renal function and the bleeding risk of the planned procedure. Consideration of these factors will allow appropriate interpretation of the current guidelines.

[Treatment with inhibitors of new oral direct anticoagulants in patients with severe bleedings or urgent surgical procedures. The new dabigatran antidote: the place of idarucizumab in clinical practice]. / Teendok súlyos vérzés vagy sürgos sebészeti beavatkozás esetén direkt orális antikoaguláns gyógyszerrel kezeltekben. Az új dabigatran-antidótum: idarucizumab helye a klinikai gyakorlatban.

Only vitamin K antagonists could be applied as oral anticoagulants over the past six decades. Coumarols have narrow therapeutic range, and unpredictable anticoagulant effects are resulted by multiple drug interactions. Therefore, regular routine monitoring of the international normalized ratio is necessary. There are two groups of factor-specific anticoagulants: molecules with anti-FIIa (dabigatran) and anti-FXa (rivaroxaban, apixaban and edoxaban) effect. Author summarizes the most important clinical features of the new oral anticoagulants, their indications and the possibilities of laboratory controls. Bleedings are the most important side effects of anticoagulants. This review summarizes the current published evidences for new oral anticoagulants reversal (non-specific and specific) agents, especially in cases with severe acute bleedings or urgent surgery procedures. It reports on how to use inhibitors, the recommended doses and the most important clinical results. The review focuses on idarucizumab - already approved by the U.S. Food and Drug Administration and the European Medicines Agency - which has a key role as the first specific inhibitor of dabigatran.

In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate.

Four-factor prothrombin complex concentrate (PCC) 50 iu/kg is able to swiftly restore haemostatic parameters in healthy subjects on rivaroxaban. We hypothesized that lower dosages of PCC may be sufficient to restore normal haemostasis. In this double-blind, crossover, placebo-controlled study, we compared the effects of PCC 37.5 iu/kg, PCC 25 iu/kg, and placebo on thrombin generation (endogenous thrombin potential, ETP) and prothrombin time in six healthy subjects receiving twice-daily rivaroxaban 15 mg for 2.5 days. Fifteen min after infusion of PCC 37.5 iu/kg, ETP increased from 47 ± 16% to 64 ± 22% (P = 0.03; pre-rivaroxaban ETP: 92 ± 14%) and remained higher than after placebo over 24 h (P = 0.001). PCC 25 iu/kg did not modify ETP within 15 min (53 ± 11% to 59 ± 12%; P = 0.14) and was not different from placebo over 24 h (P = 0.31). ETP reached pre-rivaroxaban levels within 6 h after PCC 37.5 iu/kg infusion and within 12-24 h after PCC 25 iu/kg infusion. Both dosages restored rivaroxaban-induced prothrombin time prolongation after 15 min (P < 0.001). Placebo did not have an effect on coagulation parameters. 37.5 iu/kg of PCC leads to partial restoration of thrombin generation, whereas 25 iu/kg does not. PCC 37.5 iu/kg may be insufficient for immediate full reversal of peak therapeutic rivaroxaban levels.