Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors. Proposals of the Working Group on Perioperative Haemostasis (GIHP) - March 2013

Vascular Medicine Department, University Hospital, UJF-Grenoble 1/CNRS TIMC-IMAG UMR 5525/Themas, Grenoble, France. Electronic address: .
Archives of cardiovascular diseases (Impact Factor: 1.84). 06/2013; 32(10). DOI: 10.1016/j.acvd.2013.04.009
Source: PubMed


New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30 ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50 U/kg, or non-activated 4-factors prothrombin concentrates 50 U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

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    • "However, in cases of life-threatening bleeding, or when urgent anticoagulation reversal is required (e.g. prior to emergency surgery), current guidelines suggest administering haemostatic agents, such as recombinant activated factor VII (rFVIIa) or activated/non-activated prothrombin complex concentrates (PCCs) [14] [15] [16] [17] [18] [19] [20] [21]. Owing to their potentially lower prothrombotic potential, non-activated PCCs may be preferable to rFVIIa and activated PCCs [21] [22]. "
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    ABSTRACT: Introduction: Rivaroxaban is an oral, selective direct factor Xa inhibitor approved for several indications in patients at risk of thrombotic events. One limitation of its clinical use is the lack of data pertaining to its reversal in situations where urgent response is critical (e.g. acute bleeding events or emergency surgery). Materials and methods: This study assessed the effectiveness of a four-factor prothrombin complex concentrate (4F-PCC; Beriplex(®)/Kcentra(®)) for the reversal of rivaroxaban-associated bleeding in an in vivo rabbit model, and evaluated the correlations between in vitro coagulation parameters and haemostasis in vivo. Results: Administration of single intravenous doses of rivaroxaban (150-450 μg/kg) resulted in increased and prolonged bleeding following standardised kidney incision. Pre-incision treatment with 4F-PCC (25-100 IU/kg) resulted in a dose-dependent reversal of rivaroxaban (150 and 300 μg/kg)-associated increases in time to haemostasis and blood loss; no reversal was seen at the highest rivaroxaban dose (450 μg/kg). Of the in vitro biomarkers tested, thrombin generation and whole-blood clotting time correlated well with in vivo measures of 4F-PCC-mediated effects. Thrombin generation was highly reagent-dependent, with the assay initiated using the phospholipid-only reagent being the most predictive of effective haemostasis in vivo. Conclusions: In summary, in a rabbit model of acute bleeding, treatment with 4F-PCC reduced bleeding to control levels following rivaroxaban 150 μg/kg and 300 μg/kg administration.
    Preview · Article · Jan 2015 · Thrombosis Research
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    • "Cette apparente facilité d'utilisation fait craindre une banalisation de la prescription et la multiplication des mésusages. L'Agence nationale de sécurité du médicament avec l'aide du GIHP (Groupe d'intérêt en hémostase péri-opératoire) exerce un suivi de pharmacovigilance et multiplie avec la Haute Autorité de santé (HAS) les communications à destination des professionnels de la santé sur les règles de bon usage des AOD qui ne sont qu'une alternative aux AVK [14]. Cependant, les données épidémiologiques et le recul sur l'usage des AOD demeurent faibles. "
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    ABSTRACT: Direct oral anticoagulants are a recent alternative to vitamin K antagonists but there is a lack of data regarding patients receiving these new types of treatment. The aim of the study was to identify and describe patients receiving direct oral anticoagulants admitted to an emergency unit. All the patients taking direct oral anticoagulants, admitted to the emergency room of the Clermont-Ferrand Hospital from January to August 2013, were included in this retrospective and descriptive study. Among the 73 patients included, 47.9 % were treated with dabigatran and 52.1 % with rivaroxaban. The indication was stroke prevention in 62 patients with atrial fibrillation whose average CHADS2 score was 2.6 [2.3-3](IC95 %). The average age was 76.4 years [73.7-79.1](IC95 %). Twenty-nine patients (39.7 %) had at least one drug association known for increasing the risk of bleeding. Average scores for bleeding risk were: HAS-BLED 3.1 [2.9-3.3](IC95 %) and Beyth 1.5 [1.3-1.6](IC95 %). Bleeding patients included a higher percentage of men (68.8 vs. 38.2 %, P=0.032). Creatinine clearance was lower in patients with major bleeding (45.2 % vs. 68.8mL/min, P=0.002). The Beyth score was highest in both sub-groups. In our study, we have found that the bleeding risk factors were: male gender, a high Beyth score, and a lowered creatinine clearance. Overall, patients treated with direct oral anticoagulants admitted to the emergency room were old with many co-morbidities, especially cardiovascular conditions; polymedication was frequent. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    Full-text · Article · Jan 2015 · Journal des Maladies Vasculaires
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    • "In addition, there are no evidence-based guidelines regarding the reversal of these anticoagulants. As such, the management of patients receiving NOACs who require surgery or experience emergent bleeding has been the focus of recent publications [6] [7] [8] [9] [10], including consensus statements from various working groups [11] [12] [13]. Prothrombin complex concentrates (PCC) and the recombinant active form of factor VII (rFVIIa) are hemostatic agents that could reverse the effects of direct factor inhibitors. "
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    ABSTRACT: Introduction Edoxaban is an oral, once-daily direct factor Xa (FXa) inhibitor that has been evaluated for stroke prevention in atrial fibrillation and for the treatment and secondary prevention of recurrent venous thromboembolism. Although rapidly cleared, strategies to reverse edoxaban-mediated effects on anticoagulation are needed in cases of excessive bleeding or emergency. This study evaluated the effect of two prohemostatic agents, recombinant factor VIIa (rFVIIa) and factor VIII inhibitor bypass activity (FEIBA), on the anticoagulatory effects of supratherapeutic concentrations of edoxaban in human whole blood ex vivo. Materials and Methods Blood samples were collected from six healthy volunteers. Edoxaban (500 or 1000 ng/mL), alone or followed by rFVIIa (0.8 or 1.8 μg/mL) or FEIBA (0.75 or 1.5 U/mL), was added to an aliquot of each sample. Biomarkers including prothrombin time (PT), activated partial thromboplastin time (aPTT), extrinsic FXa activity (anti-FXa), intrinsic factor X (FX) activity, and D-dimer were assessed at 0.25, 0.5, 1, 2, and 4 hours after adding rFVIIa or FEIBA. Results Decreases in measures of PT (p < 0.0001), aPTT (p < 0.0001), and anti-FXa (p < 0.0001) were observed when rFVIIa or FEIBA was added to edoxaban-containing blood samples. Intrinsic FX activity was increased up to 20% and 31% of normal in the presence of edoxaban by rFVIIa and FEIBA, respectively. The impact of these agents on the anticoagulant effects of edoxaban were observed within 15 minutes and remained relatively unchanged at each time point thereafter. Conclusions The findings of this ex vivo study suggest that rFVIIa and FEIBA rapidly reversed edoxaban-mediated anticoagulation effects.
    Full-text · Article · Oct 2014 · Thrombosis Research
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