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ACC recommends careful assessment of bleeding episodes with oral anticoagulants
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Assessment and treatment of a bleeding episode in patients on oral anticoagulants are essential for the proper care of these patients and the potential to reinitiate the therapy, according to an expert consensus decision pathway published in the Journal of the American College of Cardiology.
“What we tried to achieve as a writing committee was a pragmatic, clinically useful algorithm that would allow clinicians to do three things: to assess bleeding, provide recommendations to manage the bleeding and then give some guidance around reinitiation of anticoagulant therapy in patients who have had bleeding problems,” Kenneth W. Mahaffey, MD, FACC, director of the Stanford Center for Clinical Research, vice chair of clinical research in the department of medicine and professor of cardiovascular medicine at Stanford University and vice chair of the writing committee, told Cardiology Today.
Bleeding severity
When a patient who is on a direct oral anticoagulant has a bleeding episode, it is critical that a cardiologist determines the severity through patient history, physical examination, vital signs and laboratory evaluation. A bleeding event is considered major if it is linked to hemodynamic compromise that occurs in an anatomically critical site such as intracranial, leads to a decrease in hemoglobin greater than 2 g/dL or requires a transfusion of greater than 2 U of backed red blood cells. All bleeds that are not considered major are classified as nonmajor and may require hospitalization or intervention.
Laboratory measurements can help determine anticoagulant activity in patients. Ecarin clotting time, dilute thrombin time and ecarin chromogenic assay are recommended for those taking dabigatran (Pradaxa, Boehringer Ingelheim). Because they are not widely available on an emergent basis, the writing committee recommended thrombin time and activated partial thromboplastin time. A normal thrombin time may exclude clinically relevant levels of dabigatran, and a prolonged thrombin time does not distinguish between insignificant and clinically important drug concentrations.
Factor Xa inhibitors such as apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban (Xarelto, Janssen) can be measured using chromogenic anti-Xa assay. If that is not available, prothrombin time may be used to measure edoxaban and rivaroxaban, although normal prothrombin time does not exclude on-therapy levels. Normal prothrombin time and activated partial thromboplastin time do not exclude on-therapy or above on-therapy levels.
“Perhaps [the recommendation with the most impact] is the recommendations around the management of the anticoagulants, particularly for the direct oral anticoagulants dabigatran, rivaroxaban, edoxaban and apixaban; how to assess the current state of anticoagulation with those agents and what are some of the options for therapeutic interventions to try and mitigate the anticoagulant effect or reverse the anticoagulant effect,” Mahaffey said in an interview.
Physicians are recommended to use oral anticoagulant reversal agents if one is available for those with major bleeding, but only if it does not delay local hemostatic measures and resuscitation. Vitamin K can be used to reverse the effects of vitamin K antagonists, although it does not immediately correct coagulation. Patients with major bleeding should be administered a repletion strategy such as prothrombin complex concentrates in addition to vitamin K.
Patients with major bleeding while assigned dabigatran can be treated by stopping the medication and through measures such as stopping the oral anticoagulant. Idarucizumab (Praxbind, Boehringer Ingelheim) is a reversal strategy that targets dabigatran. If that is not available, prothrombin complex concentrates or activated prothrombin complex concentrates can be used.
Specific antidotes are not clinically available to reverse a direct factor Xa inhibitor anticoagulant effect. Prothrombin complex concentrates or activated prothrombin complex concentrates have previously been suggested, but they have not demonstrated safety or efficacy in previous studies. In patients that require emergency reversal, 4-factor prothrombin complex concentrate is a reasonable option. Few reversal agents for factor Xa inhibitors are under clinical development.
Therapy reinitiation
Oral anticoagulant therapy may be reinitiated after a bleeding event if there is net clinical benefit.
“I believe the most controversial part of the algorithm is likely the reinitiation guidance because there’s really a lack of empiric evidence from well-conducted studies to substantiate those recommendations that we provided,” Mahaffey said.
Before deciding on reinitiation, patients and care providers should participate in shared decision-making.
Patients who had gastrointestinal bleeding, which is a common hemorrhagic complication of chronic oral anticoagulant therapy, may reinitiate their therapy at least 7 days after a bleeding episode has been controlled. Those who had intracranial hemorrhage and do not have a high thrombotic risk may resume therapy at least 4 weeks after their bleeding has stopped.
“It is anticipated that as the population continues to age, more people will be treated with [oral anticoagulants],” Gordon F. Tomaselli, MD, FACC, chief of the division of cardiology and professor of medicine at Johns Hopkins School of Medicine, past president of the American Heart Association, and chair of the writing committee, and colleagues wrote. “As more evidence is generated from ongoing research and clinical practice, further refinement to this decision pathway will be needed. For now, the writing committee hopes that this decision pathway helps the multidisciplinary team of clinicians that care for patients treated with [oral anticoagulants] who have bleeding.” – by Darlene Dobkowski
For more information:
Kenneth W. Mahaffey, MD, FACC, can be reached at Department of Medicine, Stanford University, 300 Pasteur Drive, Grant S-102, Stanford, CA 94305; email: kenneth.mahaffey@stanford.edu.
Disclosures: Tomaselli reports no relevant financial disclosures. Mahaffey reports he has financial ties with numerous pharmaceutical and device companies. Please see the document for all other authors’ relevant financial disclosures.
Perspective
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Matthew S. McKillop, MD, FACC, FHRS
This consensus decision most importantly is a consolidation of the most up-to-date and evidence-based information available for physicians to use in triaging patients that develop bleeding on oral anticoagulation. These clinical pathways will give clinicians a stronger foothold on what to do with oral anticoagulants because there tends to be some practice variability. This document also offers a more systematic way to intervene on these patients standardizing definitions of what counts as major bleeding, when you should reverse anticoagulation and when you should consider restarting anticoagulation.
The main knowledge gap that still remains is how to reverse apixaban and rivaroxaban, the anti-Xa inhibitors. We currently do not have an available reversal agent. There are agents that are in the FDA approval process, but we do not really know what their safety and effectiveness are yet. The recommendation on prothrombin complex concentrate is controversial because the data are limited on whether this can effectively reverse anticoagulation in acute major bleeding. Most of the available data involve healthy subjects or minor bleeding. Nevertheless, the authors do try to provide a framework in which to approach patients with major bleeding on one of these target specific anticoagulants.
Another particularly helpful aspect of the consensus decision is that it directs physicians to assess for the presence of dual or triple therapy. If patients are on aspirin or on dual antiplatelet therapy, then we need to always evaluate for whether one or both of those agents can be stopped during a bleeding episode on oral anticoagulation. The concomitant use of these drugs tends to be overlooked sometimes, but is important as far as the clinical pathway is concerned in evaluating patients with acute bleeding.
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