Reversal agents for oral anticoagulants

There is an increased use of oral anticoagulants for the prevention of venous and arterial thrombosis. Vitamin-K antagonists have been used for decades as the main oral anticoagulants but they have the draback a complex therapeutic management, slow onset of action and by a different oral intake caused by dietary vitamin K intake. New non-vitamin K antagonist oral anticoagulants (NOACs) have been developed to overcome the limitations of warfarin. Their management is easier as it requires a fixed daily dose without coagulation monitoring. Although their therapeutic profile is safe, proper attention should be paid in case of unexpected need for the reversal of their coagulation effect and in case a patient needs to have a scheduled surgery. For non-acute cardiac surgery, discontinuation of NOACs should start at least 48 hours prior surgery. Intracranial bleedings associated with NOACs are less dangerous comparing to those warfarin-induced. NOACs need to be stopped ≥24 hours in case of elective surgery for low bleeding-risk procedures and ≥48 hours for high bleeding-risk surgery in patients with normal renal function and 72 hours in case of reduced CrCl < 80. The therapy with NOACs should be resumed from 48 to 72 hours after the procedure depending on the perceived bleeding, type of surgery and thrombotic risks. There are some available NOAC reversal agents acting within 5 to 20 minutes. In case of lack of reversal agent, adequate diuresis, renal replacement therapy and activated charcoal in case of recent ingestion should be considered.

Download Full-text

A Review on the Use of Reversal Agents of Direct Oral Anticogulant Drugs in Case of Gastrointestinal Bleeding

Reviews on Recent Clinical Trials ◽

10.2174/1574887115666200624193938 ◽

2020 ◽

Vol 15 ◽

Author(s):

Veronica Ojetti ◽

Angela Saviano ◽

Mattia Brigida ◽

Luisa Saviano ◽

Alessio Migneco ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Medical Emergency ◽

Management Approach ◽

Emergency Setting ◽

Reversal Agents ◽

Life Threatening ◽

Andexanet Alfa

Background : Major bleeding is a life-threatening condition and a medical emergency with high mortality risk. It is often the complication of anticoagulant’s intake. Anticoagulants are commonly used for the prevention and the treatment of thrombotic events. The standard therapy with vitamin K antagonist (warfarin) has been frequently replaced by direct oral anticoagulants (DOACs). The latter agents (rivaroxaban, apixaban, edoxaban, dabigatran, betrixaban) showed a better efficacy and safety compared to standard warfarin treatment and they are recommended for the reduction of ischemic stroke. Literature data reported a high risk of gastrointestinal bleeding with DOACs, in particular with dabigatran and rivaroxaban. In case of life-threatening gastrointestinal bleeding, these patients could benefit from the use of reversal agents. Methods: We performed an electronic search on PUBMED of the literature concerning reversal agents for DOACs and gastrointestinal bleeding in the Emergency Department from 2004 to 2020. AIM: This review summarizes the current evidences about three reversal agents idarucizumab, andexanet alfa and ciraparantag, and the use of the first two in the emergency setting in patients with an active major bleeding or who need urgent surgery to offer physicians indications for a better management approach in order to increase patient’s safety. Conclusion: Although these agents have been marketed for five years (idarucizumab) and two years (andexanet alfa) respectively, and despite guidelines considering antidotes as first-line agents in treating life-threatening hemorrhage when available, these antidotes seem to gain access very slowly in the clinical practice. Cost, logistical aspects and need for plasma level determination of DOAC for an accurate therapeutic use probably have an impact on this phenomenon.. An expert multidisciplinary bleeding team should be established so as to implement international guidelines based on local resources and organization.

Download Full-text

Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications

Critical Care Research and Practice ◽

10.1155/2018/4907164 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 7

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.

Download Full-text

Emergency Cardiac Surgery in Patients on Oral Anticoagulants

10.22541/au.161383485.52601975/v1 ◽

2021 ◽

Author(s):

Rami Akhrass ◽

A. Marc Gillinov ◽

Faisal Bakaeen ◽

Scott Cameron ◽

Jay Bishop ◽

...

Keyword(s):

Circulatory Arrest ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Difficult Patient ◽

Disseminated Intravascular Coagulopathy ◽

Reversal Agents ◽

Coagulation Profile ◽

Intravascular Coagulopathy ◽

Time To Onset ◽

Case Basis

Emergency surgery, blood transfusion, and reoperation for bleeding have been associated with increased morbidity and mortality. Every effort is made to optimize patients preoperatively including cessation of oral anticoagulants in an attempt to normalize the coagulation profile. The recent explosive use of direct oral anticoagulants (DOACs) and antiplatelet medications has made the above more difficult. Cardiopulmonary bypass (CPB), with its associated fibrinolysis and platelet consumption, may exacerbate a pre-existing coagulopathy. In addition, the underlying surgical pathology, such as endocarditis accompanied by sepsis and disseminated intravascular coagulopathy (DIC) or aortic dissection requiring hypothermia and circulatory arrest, can aggravate an already challenged hematological profile. Ensuring a dry operative field upon entry by correcting the coagulopathy is offset by the concern of potentially hindering efforts to anticoagulate the patient in preparation for CPB, in addition to possibly creating a hypercoagulable state that could increase the risk of thromboembolic events. Management is challenging and decisions are typically made on a case-by-case basis. Surgery is delayed when possible and less invasive percutaneous options should be considered if feasible. If surgery is unavoidable, attention is paid to exercising meticulous techniques, avoiding excessive hypothermia, treating coexisting issues such as sepsis and correcting the coagulopathy with antidotes, reversal agents and blood products, with the understanding that a normal coagulation profile does not necessarily translate into hemostasis or the absence of thrombosis. Proper knowledge of the mechanism of action of the oral anticoagulants, available antidotes and their time to onset are essential in properly treating this difficult patient population.

Download Full-text

Assessing and Reversing the Effect of Direct Oral Anticoagulants on Coagulation

Anesthesiology ◽

10.1097/aln.0000000000003268 ◽

2020 ◽

Vol 133 (1) ◽

pp. 223-232

Author(s):

Arielle Langer ◽

Jean M. Connors

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Reversal Agents

This article presents a focused review of the available tests to assess the effect of direct oral anticoagulants on coagulation and the use of reversal agents in the perioperative setting for practicing anesthesiologists.

Download Full-text

Novel oral anticoagulants and reversal agents: Considerations for clinical development

American Heart Journal ◽

10.1016/j.ahj.2015.03.010 ◽

2015 ◽

Vol 169 (6) ◽

pp. 751-757 ◽

Cited By ~ 51

Author(s):

Troy C. Sarich ◽

Jonathan H. Seltzer ◽

Scott D. Berkowitz ◽

James Costin' ◽

John T. Curnutte ◽

...

Keyword(s):

Oral Anticoagulants ◽

Clinical Development ◽

Novel Oral Anticoagulants ◽

Reversal Agents

Download Full-text

Major bleeding with old and novel oral anticoagulants: How to manage it. Focus on reversal agents

International Journal of Cardiology ◽

10.1016/j.ijcard.2018.05.060 ◽

2018 ◽

Vol 268 ◽

pp. 75-79 ◽

Cited By ~ 2

Author(s):

Stefania Angela Di Fusco ◽

Fabiana Lucà ◽

Manuela Benvenuto ◽

Annamaria Iorio ◽

Damiana Fiscella ◽

...

Keyword(s):

Major Bleeding ◽

Oral Anticoagulants ◽

Novel Oral Anticoagulants ◽

Reversal Agents

Download Full-text

Abstract 17152: Frequency and Management of Major Bleeding in Atrial Fibrillation Patients Treated With Warfarin and Non-vitamin K Oral Anticoagulants in Community Practice: Results From the ORBIT-AF II Registry

Circulation ◽

10.1161/circ.132.suppl_3.17152 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Benjamin A Steinberg ◽

DaJuanicia N Simon ◽

Laine Thomas ◽

Jack Ansell ◽

Gregg C Fonarow ◽

...

Keyword(s):

Atrial Fibrillation ◽

Clinical Practice ◽

Vitamin K ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Recurrent Bleeding ◽

Bleeding Events ◽

Reversal Agents ◽

Major Bleeding Events

Background: Non-vitamin K oral anticoagulants (NOACs) are effective at preventing stroke in patients with atrial fibrillation (AF). However, little is known about the frequency of major bleeds on NOACs and how these events are managed in clinical practice. Methods: We assessed the rates, management, and outcomes of ISTH major bleeding events among AF patients in the ORBIT-AF II registry (mean follow-up 213 days). Results: Overall, 103 patients experienced 110 major bleeding events during follow-up n=90/4986 (1.8%) on NOAC, and n=20/1320 (1.5%) on warfarin. Patients with bleeding events on NOAC were slightly younger than those on warfarin (median age 76 vs. 80; p=0.2). Among mutually-exclusive bleeding types, intracranial bleeding was more common in warfarin treated patients than NOAC-treated (15% vs 6.7%), whereas GI bleeding was more common on NOACs (56% vs. 40%, overall p=0.1 for bleeding type). Management of bleeding differed by anticoagulation type: blood products and reversal agents were more commonly used in patients on warfarin (Table). No patient received prothrombin complexes, recombinant factor VIIa, aminocaproic acid, tranexamic acid, aprotinin, or desmopressin. Out of 90 major bleeding events in NOAC patients, only 1 was fatal (1%). Within 30 days following bleeding, there were no strokes and 1 TIA (NOAC). Following a major bleed, the recurrent bleeding rate in NOAC patients in the next 30-days was 4% and the death rate was 4%. Conclusions: Rates of major bleeding with NOACs in clinical practice are comparable to those reported in clinical trials. Compared with warfarin, bleeding among NOAC users was less likely intracranial and more likely to be GI. Management of bleeding in the setting of NOAC rarely includes reversal agents.

Download Full-text

HEMATURIA AND OTHER KINDS OF BLEEDINGS ON NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION: AN UPDATED OVERVIEW ON OCCURRENCE, PATHOMECHANISMS AND MANAGEMENT

Wiadomości Lekarskie ◽

10.36740/wlek202011135 ◽

2020 ◽

Vol 73 (11) ◽

pp. 2528-2534

Author(s):

Dagmara Wojtowicz ◽

Anna Tomaszuk-Kazberuk ◽

Jolanta Małyszko ◽

Marek Koziński

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Anticoagulant Activity ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Bleeding Complications ◽

Reversal Agents ◽

Limited Availability ◽

Increased Risk

Non-vitamin K antagonist oral anticoagulants (NOACs) are currently recommended for oral anticoagulation in patients with non-valvular atrial fibrillation. In the setting, NOACs effectively prevent from stroke and systemic embolic events. In spite of the favorable safety profile of NOACs when compared with vitamin K antagonists, the use of any kind of anticoagulation is associated with an increased risk of bleeding. However, there is still a lack of direct comparisons of effectiveness and safety among NOACs. The results of indirect comparisons and meta-analyses suggest that the risk of various types of hemorrhagic complications differ among the particular NOACs. Management of bleeding in patients under NOAC therapy can be challenging because of limited availability of antidotes and the lack of routine laboratory test monitoring the NOAC anticoagulant effect. In case of life-threatening or critical site bleeding, reversal of NOAC anticoagulant activity is essential together with immediate implementation of causative treatment. Moreover, some patients on chronic NOAC therapy may require urgent surgery or invasive procedures. Specific reversal agents for NOACs have been developed, i.e. more widely available idarucizumab for the factor IIa inhibitor (dabigatran) and andexanet alfa for the factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) with limited availability. This review summarizes the occurrence and management of NOAC-related bleeding complications with a particular emphasis on hematuria.

Download Full-text

Abstract MP38: Intracerebral Hemorrhage Across the United States: Incidence and Mortality Trends From 1990 to 2017

Stroke ◽

10.1161/str.52.suppl_1.mp38 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Augustin DeLago ◽

Harpreet Singh ◽

Arashdeep Rupal ◽

Chinmay Jani ◽

Arshi Parvez ◽

...

Keyword(s):

United States ◽

Intracerebral Hemorrhage ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

The United States ◽

Mortality Trends ◽

Reversal Agents ◽

Incidence And Mortality ◽

The Us

Background: Intracerebral Hemorrhage (ICH) accounts for 10% of strokes annually in the United States (US). Up-to-date trends in disease burden and regional variation remain unknown; especially after a dramatic increase in the use of direct oral anticoagulants (DOACs) since 2010. Our study reports updated incidence, mortality and mortality to incidence ratio (MIR) data related to ICH across the US. Methods: This observational study utilized the Global Burden of Disease database to determine age-standardized incidence (ASIR), death (ASDR) and MIR rates for ICH overall and for each state in the US from 1990-2017. All analyses were stratified by sex. Trends were analyzed using Joinpoint regression analysis, with presentation of estimated annual percentage changes (EAPCs) in ASIRs, ASDRs and MIRs over the observation period. Results: We observed an overall decrease in ASIRs, ASDRs and MIRs in both genders from 1990-2017, apart from female ASIRs and ASDRs in West Virginia and Kentucky. In 2017, the mean ASIR per 100,000 population for men was 25.67 and 19.17 for women. The 2017 mean ASDRs per 100,000 population for men and women were 13.96 and 11.35, respectively. The District of Columbia had the greatest decreases in ASIR EAPCs for males at -41.25% and females at -40.58%, and the greatest decreases in ASDR EAPCs for both males and females at -55.38% and -48.51%, respectively. The overall MIR during the study period decreased in males by -12.12% and females by -7.43%. However, MIR increased in males from 2014-2017 (EAPC +2.2% [95% CI +0.9%-+3.5%]) and in females from 2011-2017 (EAPC +1.0% [CI +0.7%-+1.4%]). Conclusion: This report reveals overall decreasing trends in incidence, mortality and MIR from 1990-2017. Notably, no significant change in mortality was found in the last 6 years of the study period, and MIR worsened in males from 2014-2017 and in females from 2011-2017, suggesting decreased ICH related survival lately. The substitution of vitamin K antagonists with DOACs is one possible explanation for a downtrend in incidence despite an aging population and increased use of anticoagulants. Limited access to reversal agents for DOACs is a potential reason for increase in MIR, however concrete deductions cannot be made owing to the observational nature of the study.

Download Full-text