Notes From Rounds: Anticoagulation Reversal Strategies for ICUs

February 24, 2020
Adam Sturts, MSIV

A fourth-year medical student discusses strategies for anticoagulation reversal in intensive care units from a presentation during the 49th Annual Critical Care Congress in Orlando.

Anticoagulation Reversal Strategies in ICUs

In an effort to diversify on-site coverage at meetings and conferences throughout the year, HCPLive® created Notes from Rounds—a program where we enlist the aid of aspiring medical students, fellows, and early career providers to document key takeaways from the sessions they attend.Adam Sturts, MSIV, a fourth-year medical student at Rowan University School of Osteopathic Medicine, volunteered to contribute to HCPLive's Notes from Rounds while attending the Society of Critical Care Medicine (SCCM) 49th Annual Critical Care Congress (CCC 49) in Orlando, FL. Below is Sturts' journal of notes on the sessions he attended at CCC 49 throughout the conference. Medical students, care providers, and experts interested in contributing to HCPLive coverage can contact us here.Jorge Gutierrez, an interventional cardiologist from Duke University, began a session on anticoagulation reversal for life-threatening bleeding with a presentation with an assessment of the risk factors for anticoagulant associated bleeding. The HAS-BLED score estimates the risk of major bleeding for patients on anticoagulation, which is particularly useful among those with atrial fibrillation, and designates patients with a score of greater than 3 are high risk.

Gutierrez also highlighted risk factors for DOAC associated bleeding including advanced age, renal dysfunction and concurrent use of antiplatelet drugs—going on to explain the physiologic mechanisms by which drug metabolism changes as we age: decreased hepatic first-pass metabolism, impaired CYP mediated phase 1 reactions, decreased renal excretion and changes in body composition with age increase the risk of bleeding. DOAC bioavailability increases with age.

“Remember the magic number of 75,” Gutierrez iterated during his presentation—this is the threshold after which the risk ratio of major bleeding on DOACs rises to 2.37 (95% CI, 1.03-5.44) (Geldhof V, et al. Thromb J. 2014). However, pharmaceutical companies have their own age-specific dose reductions.

Patients with at least moderate renal dysfunction (less than or equal to 50 CrCl) have increased bleeding risk on DOACs (RR 3.64 [95% CI, 0.96-13.77]) (Geldhof V, et al. Thromb J. 2014). The DOACs have varying degrees of renal clearance: dabigatran (80%), edoxaban (50%), rivaroxaban (36%), and apixaban (27%). Apixaban is generally the best option for patients with renal dysfunction. Rivaroxaban and edoxaban are considered better options for medication non-compliant patients as they are taken once daily.

Gutierrez simplified coagulation testing in the setting of DOAC.

“There are 3 clinical pearls that I want you to walk away with here,” Gutierrez said. “Thrombin time can be checked to assess the presence of dabigatran. Anti-Xa levels will detect the presence of direct FXa inhibitors. However, neither will quantify the degree of the anticoagulation effect. All they will tell you is that the drug is on board and is doing something.”

During the portion of the session he led, Gregory Piazza, MD, assistant professor of medicine at Harvard Medical School and faculty in the Cardiovascular Division at Brigham and Women’s Hospital, discussed takeaways from recent guidelines and the clinical roles of emerging reversal agents.

The “2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants” provides guidelines for bleeding management. In the event of major bleeding (defined as more than 1 of the following: critical site, hemodynamic instability, bleeding with hemoglobin decrease greater or equal to 2 g/dL or requirement of 2U PRBC) stop the anticoagulant, initiate measures to control bleeding and administer suggested reversal agent. FDA approved DOAC reversal agents include idarucizumab and andexanet alfa.

“A consistent message from the guidelines about anticoagulation reversal is that you are not supposed to wait for anti-Xa levels or dilute thrombin times to make a decision about whether you are going to give a reversal agent or not,” Piazza said.

Idarucizumab (monoclonal Fab) targets free and thrombin-bound dabigatran—this was studied in the REVERSE-AD trial. Results of REVERSE-AD demonstrated a median maximum reversal within 4 hours of 100%, with a high level of hemostasis reported in both intracranial hemorrhage and non-intracranial hemorrhage groups.

“Although we can dialyze, now with the availability of idarucizumab we are going to usually use that acute reversal agent,” said Dr. Piazza. Activated charcoal can also be used if ingestion was within 2-4 hours prior.

Andexanet alfa acts as a decoy protein targeting the factor Xa inhibitors—this was studied in ANNEXA-4. In this study, 79% of patients with acute major bleeding achieved effective hemostasis. The “2017 ACC Expert Consensus” guidelines recommend 4F-PCC for FXa Inhibitor reversal.

“They looked at whether reversal of the anti-Xa level correlated with control of the bleed. It’s interesting to note that for all patients, reversing the anti-Xa level did not necessarily strongly correlate with how good control you have of the clinical bleed with the exception of ICH where achieving a reduction in anti-Xa level portended a very good prognosis for getting control of the clinical bleed.”

The dosing of andexanet alfa differs for reversal of apixaban- versus rivaroxaban-associated bleeding.

“This is one of the nuances that makes andexenet alfa challenging to use,” Piazza added.

The “2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation” recommends NOAC over warfarin except in patients with moderate to severe mitral stenosis or prosthetic heart valve (Class of Recommendation [COR] I, Level of Evidence [LOE] A). Idarucizumab is recommended for the reversal of dabigatran in the event of a life-threatening bleed or urgent procedure (COR I, LOE B-NR). Andexanet alfa is also included in the guidelines for the reversal of rivaroxaban and apixaban in the event of life-threatening bleeding (COR IIa, LOE B-NR).

Piazza mentioned the 2018 American Society of Hematology contained valuable information on the topic. They include 2 main approaches for handling bleeding on Xa inhibitors. Either 4-factor PCC or andexanet alfa are recommended for managing bleeding on Xa inhibitors.

However, the 2 treatments have never been compared and the individual studies lack a comparator group. These guidelines also recommend that in patients who receive anticoagulation therapy for VTE and survive a major bleeding episode that oral anticoagulation should be resumed within 90 days.

“There was a strong recommendation from the ASH panel that we need to make every effort possible to resume oral anticoagulation within 90 days,” Piazza remarked.