Pharmacology Rounds: Andexanet Alfa and 4-Factor PCC
Sean Nordt and Megan Rech
- Factor Xa inhibitor (direct-acting oral anticoagulant) with critical bleeding and needs to be reversed
- 2 options: 4 factor prothrombin complex concentrate (PCC) or andexanet alfa
- DOACs
- DOACs inhibit factor Xa, which is toward the end of the cascade. It activates thrombin.
- The 2 most commonly used are apixaban and rivaroxaban.
- If it has an “XA” in the name, it is a Xa inhibitor
- If it has a “TR” in the name (eg, dabigatran), it is a direct thrombin inhibitor.
- A new factor 11a inhibitor is coming out, which will have “XIAN” in the name
- Are factor Xa inhibitors safe?
- Generally, yes, especially when compared to warfarin.
- Andexanet alfa acts as a decoy protein; it binds up the drug and removes it from circulation. It also has a pro-coagulant effect by increasing thrombin generation. This means it can be associated with thrombosis.
- It is important to know when the last dose was taken.
- If the patient has taken a dose within the last 24 hours, consider reversal in the setting of a life-threatening bleed.
- Patients with renal dysfunction may need reversal for up to 3 days.
- Can we test to see how anticoagulated they are? No. We can order the heparin-specific anti-Xa level, and some labs have this calibrated for these 2 drugs but most labs don’t. You could order it and get some information, but can’t get something like an international normalized ratio (INR).
- Efficacy: Andexanet alfa has an efficacy of about 80%; 4-factor PCC has about the same efficacy. The literature is weak.
- Both carry a thromboembolic risk. Andexanet alfa may be more pro-coagulant.
- Dosing regimens: Andexanet is given either as a high dose or low dose; PCC is given either as a weight-based dose or a fixed dose.
- Cost: Andexanet is about $12-15K a dose; 4-factor PCC is about $4-8K.
- Several professional organizations formally recommend giving andexanet alfa.
- The level of evidence is weak for both. Andexanet alfa has a slight edge on level of evidence.
References:
CorePendium: Anticoagulant Reversal
EMA 2017 January: Andexanet Alfa For Acute Major Bleeding Associated With Factor Xa Inhibitors
EMA 2022 September: Andexanet Alfa vs 4F-PCC in Intracranial Bleed While on an "Xaban"
EMA 2019 January: Andexxa – An Antidote For Apixaban And Rivaroxaban
EMA 2020 August: Factor Xa inhibitor-related intracranial hemorrhage and PCC
EMA 2022 May: Anti-Factor Xa Levels to Guide Reversal of Factor Xa Inhibitors
EMA 2022 November: A Qualitative Point-of-Care Strip Test to Detect DOAC Exposure
EMA 2022 August: Oral factor XIa inhibitor Asundexian in A-Fib (PACIFIC-AF)
Shawn V. - May 3, 2023 6:02 AM
Lots of rural EDs don't even carry PCC, would have liked a discussion on FFP as well.
Sean N. - May 4, 2023 8:49 AM
Hi Shawn,
Thank you for the comment!
Fresh frozen plasma was for years used, before 4 factor prothrombin complex concentrate, as one of the methods to reverse vitamin K antagonists (eg, warfarin) with vitamin K. The benefit of FFP for this indication is FFP contains all the inactive components of the coagulation cascade in physiologic concentrations. This is potentially useful in warfarin reversal as vitamin K antagonists inhibit the production of factors II, VII, IX, and X, and thus are repleted.
Fresh frozen plasma is not recommended for the reversal of direct oral anticoagulants, including the factor Xa inhibitors. This is because direct oral anticoagulants bind to specific factors. The volume needed to have a potential beneficial effect is probably over 2 L of FFP. This is a large volume and would take a long time to thaw and infuse and has a risk of adverse effects.
Other therapies that can be considered in addition to the 4 factor prothrombin complex concentrate or andexanet alfa are tranexamic acid and desmopressin, although these would be adjunctive.
One possibility for rural hospitals is to do what we do for expensive antidotes (eg, antivenom, digoxin-specific Fab fragments) and have your pharmacy develop a mechanism to share cost (ie, each regional hospital has a few vials) with a protocol to distribute within the state when needed.
If you do not have 4 factor prothrombin complex concentrate at your institution, maybe discuss with hematology and develop a protocol for how to treat and reverse direct oral anticoagulants to have in place for how to reverse.
If reversal at your institution is not possible, transferring the patient to an institution where reversal can be done is recommended.
Thanks for what you do!
Sean