Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants

Gómez-Outes, Antonio; Alcubilla, Pau; Calvo-Rojas, Gonzalo; Terleira-Fernández, Ana Isabel; Suárez-Gea, Ma Luisa; Lecumberri, Ramón; Castrillón, Emilio Vargas

doi:10.1016/j.jacc.2021.04.061

Cited by 101 publications

(90 citation statements)

References 73 publications

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“…6,7 The major bleeding rate in the standard monitoring group was higher than what was previously reported in hospitalized patients receiving an oral anticoagulant 20 and is concerning given the degree of morbidity and mortality associated with FxaI-related major bleeding. 21 There are several potential explanations for the high rate of bleeding observed. Patients in the anti-Xa monitoring group were more likely to be switched to a parenteral anticoagulant, which can be monitored and adjusted.…”

Section: Discussionmentioning

confidence: 99%

Apixaban and Rivaroxaban Anti-Xa Level Monitoring Versus Standard Monitoring in Hospitalized Patients With Acute Kidney Injury

et al. 2021

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Background: Oral direct factor Xa inhibitors (FxaIs) are renally eliminated; thus, acute kidney injury (AKI) may increase the risk for drug accumulation and bleeding. There is minimal data describing the effects of AKI on FxaI anti-Xa levels or clinical outcomes. Objective: To compare anti-Xa level monitoring with standard monitoring in patients who experience AKI on apixaban or rivaroxaban. Methods: This retrospective study included patients admitted within a large hospital system from May 2016 to October 2020. Patients were included if they received apixaban or rivaroxaban prior to AKI. Patients were stratified into 1 of 2 groups: those with anti-Xa level monitoring or those who received standard monitoring. The primary outcome was major bleeding as defined by the International Society of Thrombosis and Haemostasis. Results: A total of 196 patients were included in the final analysis. Major bleeding occurred in 2 patients who received anti-Xa level monitoring, compared with 14 patients who received standard monitoring (2.1% vs 14%; P < 0.01). Variables identified as predictors of major bleeding included a documented history of liver disease (adjusted odds ratio = 3.17; 95% CI = 1.04-9.67; P = 0.04) and antiplatelet use (adjusted odds ratio = 4.18; 95% CI = 1.28-13.7; P = 0.02). Conclusion and Relevance: This is the first study to demonstrate that anti-Xa level monitoring was associated with a significant reduction in major bleeding compared with standard monitoring in patients with AKI who received apixaban or rivaroxaban. The optimal management of antithrombotic medications in patients with AKI and recent exposure to an FxaI requires further investigation.

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Section: Discussionmentioning

confidence: 99%

Apixaban and Rivaroxaban Anti-Xa Level Monitoring Versus Standard Monitoring in Hospitalized Patients With Acute Kidney Injury

et al. 2021

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“…One could design specific neutralizing agents for FXIa active site inhibitors, as has been done for DOACs targeting factor Xa and thrombin. 5,6 Indeed, properties of an antibody-based reversal agent for milvexian were recently reported. 51 However, we feel that specific reversal agents are not necessary for drugs targeting FXI(a).…”

Section: Ta B L E 2 Drugs Targeting Fxi(a) Undergoing Testing In Clin...mentioning

confidence: 99%

“…The effects of inhibitors directed against the FXIa active site, including the antibody osocimab and the small molecule oral FXIa inhibitors milvexian (JNJ70033093/BMS‐986177) 48,49 and BAY‐243334, 50 may not be altered appreciably by FXI replacement, because functional FXI (as opposed to FXIa) is not low in patients on these drugs. One could design specific neutralizing agents for FXIa active site inhibitors, as has been done for DOACs targeting factor Xa and thrombin 5,6 . Indeed, properties of an antibody‐based reversal agent for milvexian were recently reported 51 .…”

Section: Preventing Bleeding In Patients On Therapeutic Fxi(a) Inhibi...mentioning

confidence: 99%

“…Because thrombin and factor Xa are central to the hemostatic response to injury, these drugs increase a patient's risk for severe bleeding, including life-threatening intracranial and gastrointestinal hemorrhage. [1][2][3][4] This reality has led to development of strategies for preventing or stopping anticoagulant-associated bleeding based on neutralizing or bypassing the anticoagulant 2,5,6 or, in the case of vitamin K antagonists, reconstituting normal levels of coagulation factors. 7,8 There has been substantial interest over the past 2 decades in identifying targets for antithrombotic drugs that play a smaller role in hemostasis than do thrombin and factor Xa.…”

Section: Introductionmentioning

confidence: 99%

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A proposal for managing bleeding in patients on therapeutic factor XI(a) inhibitors

Salomon

Gailani

2022

Journal of Thrombosis and Haemostasis

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Several drugs that reduce functional levels of the plasma protease zymogen factor XI (FXI), or that inhibit its activated form (FXIa), are being evaluated as treatments to prevent thrombosis. Based on the observation that individuals with inherited FXI deficiency have a relatively mild bleeding disorder, it is anticipated that therapeutic FXI(a) inhibitors will have a smaller impact on hemostasis than anticoagulants targeting thrombin or factor Xa. However, even if FXI(a) inhibitors are determined to be safer than currently used anticoagulants, some patients on these drugs will experience abnormal bleeding or require emergent surgery. Strategies for dealing with such situations are required. Treatment with antifibrinolytic agents and low doses of recombinant factor VIIa effectively prevent abnormal bleeding in FXI‐deficient patients with alloantibody inhibitors to FXI who undergo surgery. We propose that a similar strategy can be used for patients on therapeutic FXI(a) inhibitors who are bleeding or require invasive procedures.

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“…A recent multicentre clinical study in factor Xa inhibitor-related ICH patients demonstrated that PCC, achieved excellent haemostasis with very low thrombotic events (4%) 38 . Similarly, a recent meta-analysis in patients with DOAC-associated severe bleeding, reported that thromboembolism rates were higher in patients treated with andexanet (specific-Xa antidote) compared with those treated with PCC (10.7 vs. 4.3%) 10 . Nevertheless, PCC still lacks the clinical efficacy required to improve patients outcome, thus, further studies are needed to answer this clinical need 11 .…”

Section: Accepted Manuscriptmentioning

confidence: 94%

CM-352 Efficacy in a Mouse Model of Anticoagulant-Associated Intracranial Hemorrhage

et al. 2022

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Background: Intracranial haemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinases (MMPs) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives: We evaluated the effects of CM-352 (MMPs-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin concentrate complex (PCC). Methods: ICH was induced by collagenase injection into the striatum of WT (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24h later by diaminobenzidine staining and different behavioural test. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays. Results: Only PCC reduced haemorrhage volume and improved functional outcome in warfarin-ICH, but both, PCC and CM-352 treatments, diminished haemorrhage volume (46%, p<0.01 and 64%, p<0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC decreased neutrophil infiltration in the haemorrhage area at 24h. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10-/- mice showed lower haemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation. Conclusions: CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihaemorrhagic strategy for rivaroxaban-associated ICH.

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Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants

Cited by 101 publications

References 73 publications

Apixaban and Rivaroxaban Anti-Xa Level Monitoring Versus Standard Monitoring in Hospitalized Patients With Acute Kidney Injury

Apixaban and Rivaroxaban Anti-Xa Level Monitoring Versus Standard Monitoring in Hospitalized Patients With Acute Kidney Injury

A proposal for managing bleeding in patients on therapeutic factor XI(a) inhibitors

CM-352 Efficacy in a Mouse Model of Anticoagulant-Associated Intracranial Hemorrhage

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