scholarly journals The Reversal of Bleeding Caused by New Oral Anticoagulants (NOACs): A Systematic Review and Meta-Analysis

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 117S-126S ◽  
Author(s):  
Sariya Udayachalerm ◽  
Sasivimol Rattanasiri ◽  
Teeranan Angkananard ◽  
John Attia ◽  
Nakarin Sansanayudh ◽  
...  
Keyword(s):  
Case Reports ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
New Oral Anticoagulants ◽  
Thrombin Inhibitor ◽  
Aggregated Data ◽  
Reversal Agents ◽  
Death Studies ◽  
Risk Of Death

New oral anticoagulants (NOACs; ie, direct thrombin inhibitor [DTI] and factor Xa [FXa] inhibitors) were used as alternatives to warfarin. Specific antidotes (idarucizumab for dabigatran and andexanet alfa for FXa inhibitors) and hemostatic reversal agents were used for lowering bleeding, but their efficacies were still uncertain. The objectives of this study were to estimate and compare the efficacy of NOAC antidotes on bleeding reversal and death. Studies were identified from MEDLINE and Scopus databases until May 2018. Case reports/series and cohorts were selected if they assessed reversal or death rates. Data were independently extracted by 2 reviewers. Individual patient data and aggregated data of outcomes were extracted from case reports/series and cohorts. Binary regression was used to estimate outcome rates, risk ratio (RR) along with 95% confidence interval (CI). Interventions were NOACs and reversal agents (ie, DTI-specific, DTI-standard, FXa-specific, and FXa-standard). Among 220 patients of 93 case reports/series, reversal rates were 95.9%, 77.6%, and 71.5% for DTI-specific, FXa-standard, and DTI-standard. Pooled RRs for DTI-specific and FXa-standard versus DTI-standard, respectively, were 1.34 (CI: 1.13-1.60) and 1.09 (CI: 0.84-1.40). Death rate was 0.18 (CI: 0.06-0.57) times lower in DTI-specific versus DTI-standard. For pooling 10 subcohorts, pooled RRs were 1.08 (CI: 1.00-1.16), 1.29 (CI: 1.20-1.39), and 1.13 (CI: 1.01-1.25) for DTI-specific, FXa-specific, and FXa-standard versus DTI-standard. In conclusion, specific reversal agents might be useful for reversal of bleeding and lowering the risk of death than standard reversal agents. Our findings were based on case reports/series and selected cohorts, further comparative studies are thus needed.

scholarly journals Perioperative management of patients receiving non-vitamin K antagonist oral anticoagulants: up-to-date recommendations

2020 ◽  
Vol 15 (2) ◽  
pp. 133-142
Author(s):  
Kwang-Sub Kim ◽  
Jong Wook Song ◽  
Sarah Soh ◽  
Young-Lan Kwak ◽  
Jae-Kwang Shim
Keyword(s):  
Vitamin K ◽  
Clinical Evidence ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Bleeding Risk ◽  
Vitamin K Antagonist ◽  
Thrombin Inhibitor ◽  
Reversal Agents ◽  
Perioperative Bleeding ◽  
Number Of Patients

Indications of non-vitamin K antagonist oral anticoagulants (NOACs), consisting of two types: direct thrombin inhibitor (dabigatran) and direct factor Xa inhibitor (rivaroxaban, apixaban, and edoxaban), have expanded over the last few years. Accordingly, increasing number of patients presenting for surgery are being exposed to NOACs, despite the fact that NOACs are inevitably related to increased perioperative bleeding risk. This review article contains recent clinical evidence-based up-to-date recommendations to help set up a multidisciplinary management strategy to provide a safe perioperative milieu for patients receiving NOACs. In brief, despite the paucity of related clinical evidence, several key recommendations can be drawn based on the emerging clinical evidence, expert consensus, and predictable pharmacological properties of NOACs. In elective surgeries, it seems safe to perform high-bleeding risk surgeries 2 days after cessation of NOAC, regardless of the type of NOAC. Neuraxial anesthesia should be performed 3 days after cessation of NOACs. In both instances, dabigatran needs to be discontinued for an additional 1 or 2 days, depending on the decrease in renal function. NOACs do not require a preoperative heparin bridge therapy. Emergent or urgent surgeries should preferably be delayed for at least 12 h from the last NOAC intake (better if > 24 h). If surgery cannot be delayed, consider using specific reversal agents, which are idarucizumab for dabigatran and andexanet alfa for rivaroxaban, apixaban, and edoxaban. If these specific reversal agents are not available, consider using prothrombin complex concentrates.

scholarly journals Direct-Acting Oral Anticoagulants and Their Reversal Agents—An Update

Medicines ◽  
2019 ◽  
Vol 6 (4) ◽  
pp. 103 ◽  
Author(s):  
Stephanie Kustos ◽  
Pius Fasinu
Keyword(s):  
Oral Anticoagulants ◽  
Anticoagulation Therapy ◽  
Factor Xa ◽  
Rapid Onset ◽  
Thrombin Inhibitor ◽  
Reversal Agent ◽  
Onset Of Action ◽  
Reversal Agents ◽  
Direct Acting ◽  
Direct Acting Oral Anticoagulants

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.

Direct Oral Anticoagulants

2017 ◽  
Author(s):  
Panna A. Codner ◽  
Michael G Mount
Keyword(s):  
Perioperative Management ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Vitamin K Antagonist ◽  
Direct Thrombin Inhibitor ◽  
Thrombin Inhibitor ◽  
Clinical Use ◽  
Nonvalvular Atrial Fibrillation ◽  
Reversal Agents

Non–vitamin K antagonist oral anticoagulants, also known as direct oral anticoagulants, are a relatively recent class of medications introduced into clinical practice. Due to their safety profiles, fixed dosing, and lack of need for frequent laboratory monitoring, they are becoming preferred to traditional anticoagulation with warfarin in many cases of nonvalvular atrial fibrillation and venous thromboembolism. Currently, four drugs are available: dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban, and edoxaban, factor Xa inhibitors. This review covers the pharmacology, monitoring, and reversal agents currently available for these medications. The indications for their use are covered through a review of the major clinical trials that led to their US and European approvals for clinical use. Perioperative management of these medications is discussed. Tables list indications, dosing, and monitoring, as well as bleeding risks and efficacy compared with warfarin.  This review contains 1 figure, 11 tables, and 70 references. Key words: apixaban, dabigatran, direct oral anticoagulant, edoxaban, rivaroxaban

Treatment and secondary prevention of venous thromboembolism in cancer patients

2012 ◽  
Vol 03 (03) ◽  
pp. 121-125
Author(s):  
I. Pabinger ◽  
C. Ay
Keyword(s):  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Cancer Patients ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
New Oral Anticoagulants ◽  
Phase Iii ◽  
Patients With Cancer ◽  
Potential Use

SummaryCancer is a major and independent risk factor of venous thromboembolism (VTE). In clinical practice, a high number of VTE events occurs in patients with cancer, and treatment of cancerassociated VTE differs in several aspects from treatment of VTE in the general population. However, treatment in cancer patients remains a major challenge, as the risk of recurrence of VTE as well as the risk of major bleeding during anticoagulation is substantially higher in patients with cancer than in those without cancer. In several clinical trials, different anticoagulants and regimens have been investigated for treatment of acute VTE and secondary prophylaxis in cancer patients to prevent recurrence. Based on the results of these trials, anticoagulant therapy with low-molecular-weight heparins (LMWH) has become the treatment of choice in cancer patients with acute VTE in the initial period and for extended and long-term anticoagulation for 3-6 months. New oral anticoagulants directly inhibiting thrombin or factor Xa, have been developed in the past decade and studied in large phase III clinical trials. Results from currently completed trials are promising and indicate their potential use for treatment of VTE. However, the role of the new oral thrombin and factor Xa inhibitors for VTE treatment in cancer patients still has to be clarified in further studies specifically focusing on cancer-associated VTE. This brief review will summarize the current strategies of initial and long-term VTE treatment in patients with cancer and discuss the potential use of the new oral anticoagulants.

Direct (new) oral anticoagulants (DOACs): Drawbacks, bleeding and reversal

2021 ◽  
Vol 19 ◽  
Author(s):  
Ozgur Karcioglu ◽  
Sehmus Zengin ◽  
Bilgen Ozkaya ◽  
Eylem Ersan ◽  
Sarper Yilmaz ◽  
...  
Keyword(s):  
Oral Anticoagulants ◽  
Fresh Frozen Plasma ◽  
New Oral Anticoagulants ◽  
Coagulation Cascade ◽  
Thrombin Inhibitor ◽  
Severe Bleeding ◽  
Prothrombin Complex Concentrates ◽  
Clinical Scenarios ◽  
Fresh Frozen ◽  
Frozen Plasma

Background and Objective: Direct (new) Oral Anticoagulants (DOACs) have emerged as a contemporary and promising option in the treatment of thromboses and VTE, while protecting the coagulation cascade against untoward bleeding events. They are used in the management and prophylaxis of Venous Thromboembolism (VTE) and other thrombotic diseases. The most prominent complication of these agents is bleeding. These agents have similar or lower rates of major intracranial hemorrhages, while they had a higher risk of major gastrointestinal bleeding when compared to warfarin. This manuscript is aimed to revise and update the literature findings to outline the side effects of DOACs in various clinical scenarios. Methods: A narrative review of currently published studies was performed. Online database searches were performed for clinical trials published before July 2021, on the efficacy and adverse effects attributed to the anticoagulant treatment, especially DOACs. A literature search via electronic databases was carried out, beginning with the usage of the agents in the Western Languages papers. The search terms initially included direct (new) oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, idarucizumab, andexanet, prothrombin complex concentrates, and fresh frozen plasma. Papers were examined for methodological soundness before being included. Results: Severe bleeding episodes require aggressive interventions for successful management. Therefore, bleeding should be evaluated in special regard to the location and rate of hemorrhage, and total volume of blood loss. Patient's age, weight and organ dysfunctions (e.g., kidney/liver failure or chronic respiratory diseases) directly affect the clinical course of overdose. Conclusion: Management recommendations for hemorrhage associated with DOAC use vary, depending on the class of the culprit agent (direct thrombin inhibitor vs. FXa inhibitor), the clinical status of the patient (mild/ moderate vs. severe/life-threatening), and capabilities of the institution. Specific reversal agents (i.e., idarucizumab and andexanet alfa) can be used if available, while prothrombin complex concentrates, fresh frozen plasma and/ or tranexamic acid can also be employed as nonspecific replacement agents in the management of DOAC-related bleeding diathesis.

scholarly journals Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Alok Dabi ◽  
Aristides P. Koutrouvelis
Keyword(s):  
Side Effects ◽  
Intracranial Hemorrhage ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Reversal Agents ◽  
United States Food ◽  
Life Threatening

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-α 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.

scholarly journals The Severity of Intracranial Hemorrhages Measured by Free Hemoglobin in the Brain Depends on the Anticoagulant Class: Experimental Data

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Kyle M. Ware ◽  
Douglas L. Feinstein ◽  
Israel Rubinstein ◽  
Prudhvi Battula ◽  
Jose Otero ◽  
...  
Keyword(s):  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Hemoglobin Concentration ◽  
Thrombin Inhibitor ◽  
Free Hemoglobin ◽  
Intracranial Hemorrhages ◽  
The Brain

Background and Purpose. Anticoagulant therapy is broadly used to prevent thromboembolic events. Intracranial hemorrhages are serious complications of anticoagulation, especially with warfarin. Direct oral anticoagulants reduce but do not eliminate the risk of intracranial hemorrhages. The aim of this study is to determine the degree of intracranial hemorrhage after application of anticoagulants without additional triggers. Methods. Rats were treated with different anticoagulant classes (vitamin K antagonists, heparin, direct thrombin inhibitor, and factor Xa inhibitor). Brain hemorrhages were assessed by the free hemoglobin concentration in the brain parenchyma. Results. Vitamin K antagonists (warfarin and brodifacoum) significantly increased free hemoglobin in the brain. Among direct oral anticoagulants, thrombin inhibitor dabigatran also significantly increased free hemoglobin in the brain, whereas treatment with factor Xa inhibitor rivaroxaban did not have significant effect on the free hemoglobin concentration. Conclusions. Our data indicates that the severity of brain hemorrhages depends on the anticoagulant class and it is more pronounced with vitamin K antagonists.

scholarly journals Bleeding Risk in Non-Valvular Atrial Fibrillation Patients Receiving Direct Oral Anticoagulants and Warfarin: A Systematic Review and Meta-Analysis of Observational Studies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3672-3672 ◽  
Author(s):  
Yimin Pearl Wang ◽  
Rohan Kehar ◽  
Alla Iansavitchene ◽  
Alejandro Lazo-Langner
Keyword(s):  
Major Bleeding ◽  
Lower Risk ◽  
Observational Studies ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Bleeding Risk ◽  
Risk Of Bleeding ◽  
Significant Difference

Introduction: The standard oral anticoagulant therapy administered to non-valvular AF patients has typically been Vitamin K Antagonists (VKA) particularly warfarin. In recent years, Direct Oral Anticoagulants (DOACs) including Direct Thrombin Inhibitors (DTI) and Direct Factor Xa inhibitors (FXa inhibitors) have become an alternative to warfarin. Randomized trials comparing warfarin and DOACs showed comparable effectiveness without significant additional major bleeding risk. However, bleeding events in RCTs may differ from those in daily use due to the routine exclusion of patients with a higher risk of bleeding from many studies. We aimed to assess bleeding risk between DOACs and warfarin in AF patients in observational studies and we also sought to determine differences between patients that were experienced or naïve to oral anticoagulants. Methods: A systematic literature search was conducted in the OVID MEDLINE® and EMBASE® electronic databases. Observational studies and randomized control trials (RCT) from 1990 to January 2019 were retrieved and examined by two independent reviewers. A pooled effect hazard ratio (HR) was calculated using a random effects model using the generic inverse variance method. Subgroup analyses according to previous exposure to anticoagulants, study type, funding type and DOAC type were conducted. The primary outcome was major bleeding risk. The secondary outcome was clinically relevant non-major bleeding. All studies must have used an established or validated definition of major bleeding. Results: The initial literature search identified 3359 potentially eligible citations. After primary screening, 150 articles were eligible for full text review and there were 35 studies including 2,356,201 patients that met the inclusion criteria. Overall, patients on DOACs were less likely to experience a bleeding event compared to warfarin (HR 0.78, 95%CI 0.71, 0.85, P<0.001). The results were consistent when analyzing patients receiving DTIs or FXa inhibitors (DTI: HR 0.76, 95% CI 0.67,0.87; FXa inhibitors: HR 0.79, 95% CI 0.69,0.89). However, among patients receiving factor Xa inhibitors, there was a significant difference in the risk of bleeding according to individual drug. Among patients receiving rivaroxaban the risk of bleeding was similar to warfarin (HR 0.98, 95%CI 0.91,1.06, p=0.60) whereas in those receiving apixaban there was a 40% reduction in the risk of bleeding compared to warfarin (HR 0.60, 95%CI 0.50,0.71, p<0.001) (Figure 1). Three studies reported information according to previous anticoagulant exposure. The overall pooled hazard ratio was 0.68 (95% CI 0.55, 0.82 p<0.001) in favor of patients on DOACs. In the subgroup analysis of previous anticoagulant use, the risk of bleeding was lower for DOACs compared to warfarin in both the experienced population (HR 0.70, 95%CI 0.51, 0.96) and the naïve population (HR 0.64, 95% CI 0.47,0.87). However, heterogeneity was moderate to high among both subgroups. Conclusion: This review and meta-analysis of observational studies including over 2.3 million patients showed that overall DOACs have a lower risk of major bleeding and clinically relevant non-major bleeding compared to warfarin. Most importantly, although the pooled effect estimate did not differ between DTIs and FXa inhibitors, among patients receiving FXa inhibitors there was a significant difference between individual agents. Patients on apixaban had a significantly lower risk of bleeding compared to warfarin in contrast to patients on rivaroxaban who had a similar risk. Disclosures No relevant conflicts of interest to declare.

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