Review of Recently Approved Alternatives to Anticoagulation With Warfarin for Emergency Clinicians

Elizabeth Brem, MD; Alex Koyfman, MD; Mark Foran, MD, MPH

Disclosures

J Emerg Med. 2013;45(1):143-149. 

In This Article

Abstract and Introduction

Abstract

Background: Dabigatran and rivaroxaban are novel anticoagulants that have been approved for the prevention of thromboembolic events in atrial fibrillation. These medications are attractive to both patients and clinicians, as, unlike warfarin, they do not require laboratory monitoring or dietary restrictions. However, they carry bleeding risks similar to that of warfarin and are without a reliable reversal agent.

Objectives: The objectives of this article are to 1) summarize the pivotal trials leading to the U.S. Food and Drug Administration approvals of dabigatran (Pradaxa; Boehringer Ingelheim, Ridgefield, CT) and rivaroxaban (Xarelto; Janssen Pharmaceuticals, Inc., Titusville, NJ); 2) present the limited data available regarding the management of bleeding patients on these agents; and 3) provide suggestions to guide emergency providers given the limited data.

Discussion: Dabigatran and rivaroxaban were approved based on large, non-inferiority trials comparing the new agents to warfarin with stroke or systemic embolism as the primary outcome. Traditional coagulation studies cannot be used to determine the degree of anti-coagulation produced by these agents. Fresh frozen plasma is unlikely to be effective in patients on these drugs who are acutely bleeding. Prothrombin complex concentrate can be considered in patients on rivaroxaban. Dabigatran is renally cleared, so dabigatran could be removed by hemodialysis. Theoretically, DDAVP (Sanofi-Aventis U.S. LLC, Bridgewater, NJ), aminocaproic acid, tranexamic acid, or recombinant activated factor VII could also be used in an attempt to control bleeding.

Conclusion: There is a need for assays for the degree of anticoagulation produced by drugs such as dabigatran and rivaroxaban. Additionally, studies are needed to evaluate reversal agents that could be effective in the setting of acute bleeding.

Introduction

Anticoagulation with warfarin carries a significant risk of bleeding, that emergency physicians, internists, and cardiologists have learned to minimize with careful monitoring and manage with reversal. Recently, Budnitz et al. reported that 42.3% (n = 99,628) of emergency hospitalizations of older patients (age 65 years or older) for adverse drug events were related to hematologic agents.[1] These hematologic adverse drug events included gastrointestinal (GI) hemorrhage (40.8%, 95% confidence interval [CI] 29.9–51.7%), elevated international normalized ratio (INR) or other lab abnormality (23.7%, 95% CI 16.8–30.6%), and intracranial hemorrhage (5.6%, 95% CI 2.1–9.1%). Of the medications evaluated in the study, warfarin was the most common cause of an Emergency Department (ED) visit (33.3%), leading to inpatient admission 46% of the time.[1] The overwhelming majority of these admissions (95.1%, 95% CI 91.7–98.4%) were the result of unintentional overdoses.[1]

The major advantages of the recently approved alternatives to anticoagulation with warfarin include their oral route of administration, lack of dietary restrictions, and no requirement for routine laboratory monitoring (e.g., INR). Many physicians have adopted these new drugs quickly, leading to a rapidly growing number of patients taking them for indications such as atrial fibrillation (AF). According to the Food and Drug Administration (FDA), from its approval in October 2010 through August 2011, a total of approximately 1.1 million prescriptions for dabigatran were dispensed.[2]

Dabigatran as an alternative to warfarin is now a class IB recommendation in the revised American College of Cardiology Foundation/American Heart Association Task Force guidelines for the management of AF.[3] Recent guidelines from the American College of Chest Physicians mention dabigatran, rivaroxaban, and apixaban as options for short term (10–14 days) use for prevention of venous thromboembolism (VTE) for patients undergoing total knee or hip replacement or hip fracture surgery. This is grade 1B evidence, the same grade given to the use of low-molecular-weight heparins, fondaparinux, and low-dose unfractionated heparin for this indication.[4] A significant percentage of these patients will develop bleeding complications and be seen in EDs; 14–16% of patients in large clinical trials experienced clinically significant bleeding.[5,6] Given limited clinical experience with management of bleeding caused by these agents and a lack of effective reversal agents, there is a growing need for improved understanding and increased familiarity among emergency providers.

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