Reversal Agents for Anticoagulation Therapy

Educational Objectives

The goal of this program is to improve reversal of anticoagulation. After hearing and assimilating this program, the clinician will be better able to:

1. Manage anticoagulant therapy in patients undergoing scheduled surgical procedures.

2. Choose appropriate reversal agents for patients on anticoagulant therapy.

Summary

Direct oral anticoagulants (DOACs): currently in wide use; associated rates of major bleeding and mortality are lower, compared with vitamin K antagonists (VKAs), but remain significant; among the top 10 drugs whose side effects result in emergency department (ED) visits

Indications for reversal agents: significant blood loss resulting in hemodynamic instability, and decrease in hemoglobin level of ≥2 g/dL or requiring transfusion of ≥2 U of red blood cells; blood loss in a critical site or closed space (eg, intracranial hemorrhage, paraspinal hematoma with risk for compromise of the cord, pericardial hemorrhage, posterior epistaxis, hemothorax), even without significant blood loss

Minor hemorrhages: may be clinically significant, distressing to the patient, and necessitate a visit to the ED; often require temporary hold of the anticoagulant agent, site-directed management, and dose adjustment but not anticoagulant reversal

Risk stratification: determine the bleeding site, status of bleeding (ie, active vs inactive), and bleeding rate; determine the type of anticoagulant the patient receives and time of the last dose; evaluate comorbidities (eg, renal disease, hepatic disease, thrombocytopenia); consider discontinuation of other drugs affecting hemostasis; determine the reason anticoagulant therapy was initiated (eg, recent pulmonary embolus [filter placement may be considered]), possible consequences of discontinuation, and timing of re-initiation

Pharmacokinetics: warfarin — onset and offset are slow (ie, days for each), so reversal is necessary; restoration of coagulation requires resynthesis of factors II, VII, IX, and X as well as drug elimination; dabigatran, rivaroxaban, and apixaban — onset is rapid (within hours) and offset is fast, relative to warfarin; therefore, reliance on drug clearance may be possible; half-lives are ≈12 hr; elimination is variably renal dependent (80% for dabigatran, so drug accumulation can occur in patients with renal insufficiency or acute kidney injury [AKI]; least for apixaban [safe for patients on hemodialysis])

Hold times prior to surgery: allow 5 drug half-lives (with normal renal clearance, 3 days for dabigatran, 1-2 days for rivaroxaban, apixaban, and edoxaban); 5 days is required for warfarin

Nonurgent reversal or periprocedural management: warfarin — dose adjustment is possible for international normalized ratio (INR) <4.5; with INR of 4.5 to 10.0, omit and adjust dose; consider low-dose oral vitamin K for patients at high risk for bleeding; for INR >10, hold the dose and consider intravenous (IV) vitamin K (10 mg is effective in 6-8 hr, vs 24 hr for oral dosing); Xa inhibitors — low-risk procedures (eg, skin biopsy, cataract surgery, dental extraction) require hold for only 24 hr (≥48 hr with higher risk for bleeding); AKI or chronic renal insufficiency creates greater uncertainty and requires additional testing

Anticoagulation tests: VKAs — anticoagulation is assessed with prothrombin time (PT)/INR; INR >5 predicts high risk for bleeding; DOACs — specialized testing is not routinely indicated; INR and activated partial thromboplastin time (aPTT) are frequently abnormal; determine the time of the last dose and to consider renal and hepatic function that could modify the clearance of these drugs; if time allows, specialized testing is warranted for major bleeding, emergent or invasive procedures, or gastrointestinal (GI) absorption or renal clearance issues; PT/INR and aPTT reflect the activity of the clotting factors in the intrinsic, extrinsic, and common pathways; for dabigatran, diluted thrombin time (DTI) is preferred; the anti-Xa test is most sensitive for calculating levels of Xa inhibitors

Interpretation of results: dabigatran — a normal PTT excludes excess levels and reflects a low (but not necessarily clinically negligible) level; a normal thrombin time excludes clinically relevant levels; DTI correlates with plasma concentration; Xa inhibitors — a prolonged PT indicates the drug is present, but a normal PT or aPTT does not exclude a clinically relevant drug level, unless there is validation with anti-Xa testing; apixaban — the level can be correlated with an Xa level <0.3 IU/mL (the lower limit of expected values for low-molecular-weight heparin), assures that the drug level is low (also true for rivaroxaban); however, consultation with a hematologist is required

Hemostatic reversal agents: 4-factor prothrombin complex concentrate (4F-PCC) — contains concentrated levels of factor II, VII, IX and X, along with therapeutic doses of proteins C and S; used for patients on VKAs, along with IV vitamin K; idarucizumab — a monoclonal antibody that binds dabigatran and reverses its effect; andexanet alfa — an antigen that neutralizes Xa inhibitors; activated charcoal — recommended to prevent further absorption of drug in all cases

Supporting studies: 4F-PCC vs fresh frozen plasma (FFP) in major bleeding — a randomized controlled trial showed rapid reversal in 4 hr in 82% of cases with 4F-PCC and in 50% of cases with FFP; at 24 hr, rates of reversal were similar; RE-VERSE AD trial — assessed idarucizumab for reversal of dabigatran; reported cessation of bleeding within 2.5 hr in patients with intracranial or GI bleeding; in all patients, PTT was elevated but reverted to normal; PTT was determined to be a useful measure for activity of dabigatran (reversed rapidly in the idarucizumab arm); ANNEXA-4 trial — rapid restoration of hemostasis was achieved with andexanet alfa for patients taking Xa inhibitors; hemostasis was considered excellent or good in ≈80%

Summary of options: warfarin — use 4F-PCC or FFP; dabigatran — use idarucizumab; direct anti-Xa activity — first-line therapy is andexanet alfa, 4F-PCC is second line (also for dabigatran); for major hemorrhage, discontinue the anticoagulant, assess anticoagulant effects, consider using a specific reversal agent for life-threatening hemorrhage; after bleeding is controlled, determine appropriate timing for restarting anticoagulation

Readings

Becattini C et al. Major bleeding with vitamin K antagonists or direct oral anticoagulants in real‐life. Int J Cardiol. 2017;227:261‐266; Božič-Mijovski M et al. Diluted thrombin time reliably measures low to intermediate plasma dabigatran concentrations. Ann Clin Biochem. 2016;53(Pt 4):446-451. doi:10.1177/0004563215599795; Burnett AE et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41:206‐232; Connolly SJ et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326-1335. doi:10.1056/NEJMoa1814051; Cuker A et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol. 2019;94:697‐709; doi:10.1002/ajh.25475; Holzmacher JL, Sarani B. Indications and methods of anticoagulation reversal. Surgical Clinics. 2017;97:1291‐1305; Müller M et al. Application of prothrombin complex concentrate for reversal of direct oral anticoagulants in clinical practice: indications, patient characteristics and clinical outcomes compared to reversal of vitamin K antagonists. Scand J Trauma Resusc Emerg Med. 2019:27; doi:10.1186s13049‐019‐0625‐3; Siontis KC et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States [published correction appears in Circulation. 2018 Oct 9;138(15):e425]. Circulation. 2018;138(15):1519-1529. doi:10.1161/CIRCULATIONAHA.118.035418.

Disclosures

Dr. Kiss is a consultant for Sanofi Genzyme. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Kiss was recorded virtually at Advances Changing Practice, held October 22-23, 2020, and presented by the University of Pittsburgh, Department of Medicine. For information on future CME activities from this presenter, please visit DOM.pitt.edu. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

IM682302

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.