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Is 4-factor Prothrombin Complex Concentrate (4F-PCC) or Andexxa® Better to Reverse Xa Inhibitor Bleeding?

Posted by gulseth.michael on August 6, 2019 at 1:05 PM

By Jenna Cariddi, Pharm D Student Pharmacist

Edited by Michael P Gulseth, Pharm. D., BCPS, FASHP


A current controversial topic amongst anticoagulation management providers is what is the best agent to use for the reversal of bleeding from oral Xa inhibitors. This is a debatable topic because many anticoagulation reversal guidelines were published prior to the approval of andexanet alfa and because there have been no studies comparing andexanet alfa to other therapies such as 4-factor prothrombin complex concentrate (4F-PCC).


Andexanet alfa was approvedby the FDA in May 2018 as a reversal agent for bleeding in patients on apixaban or rivaroxaban(1). This was exciting news to the anticoagulation world but concerns regarding thrombosis rates, lacking data in specific treatment areas, and price ultimately resulted in many hospitals not placing the drug on formulary.


Prior to the approval of andexanet alfa, 4F-PCC has been the off-label treatment of choice for the reversal of factor Xa inhibitor associated bleeding. Due this, experience was gained in use 4F-PCC for direct oral anticoagulant (DOAC) reversal.


Dosing 4F-PCC for factor Xa inhibitor bleeding reversal using weight-based (50 units/kg) or fixed dosing (2000 units) has also been debated as to which is best. The recent consensus statement of the Anticoagulation Forum (AC Forum) states they prefer fixed dosing due to it having been studied in patients with bleeding from factor Xa inhibitors, simpler for the pharmacy and provider ordering it, and the lower cost (1).


This lack of definitive data on optimal DOAC reversal has led to controversy within guidelines.


Examples:

2017 ACC Management of Bleeding in patients on anticoagulants guidelines state:


- 4F-PCC is a reasonable option for emergency bleeding reversal in patients using oral direct factor Xa inhibitors(2).


2018 ACC Guidance for anticoagulation reversal update from 2017 states:


- First line for edoxaban reversal is 4F-PCC


- First line for apixaban and rivaroxaban reversal is andexanet alfa dose dependent on apixaban/rivaroxaban dose and time since last dose (3).


2019 AHA/ACC/HRS update of Afib management guidelines states:


- Andexanet alfa can be useful to reverse life threatening bleeding of rivaroxaban and apixaban (4).


2018 American Society of Hematology (ASH) guidelines for management of VTE state:


- They SUGGEST using either 4F-PCC in addition to stopping the Xa inhibitor or just stopping the Xa inhibitor alone (for life threatening bleeding during treatment with Xa inhibitor for VTE treatment) – also SUGGEST using andexanet alfa in addition to stopping the Xa inhibitor rather than no andexanet alfa – They state they have no recommendation for one approach over the other (5).


2019 AC Forum comprehensive guidance statement on DOAC reversal:


- For patients with apixaban or rivaroxaban associated major bleeding they suggest using andexanet alfa – if andexanet alfa not available then they suggest using 4F-PCC (1).


Considering the variability of these statements, we’d encourage health-systems to evaluated the pros and cons of each agent prior to making a decision on formulary status/use.


Andexanet alfa pros:


-FDA approved for the reversal of apixaban and rivaroxaban


-Logical mechanism of action for reversal of factor Xa bleeding


-Proven anti-factor Xa activity reduction by more than 90%


-Rapid onset/offset; within 2-5 minutes of IV bolus dose the generation of thrombin was fully restored


-Sustained results when given IV infusion after bolus (but only when infusion is running) (6)


Andexanet alfa cons:


-Relatively short duration of action necessitating bolus followed by IV infusion


-Optimal length of infusion is largely unknown, particularly in the surgical population


-Lack of surgical data; not tested for the reversal of surgical bleeding; unknown if 2-hour infusion is enough for long surgeries


-High cost


-Higher than expected thromboembolism rate in patients within 30 days (1)


-Complex dosing depending on DOAC dose and time since last dose


-Potential prothrombic effect from inhibiting activity of Tissue Factor Pathway Inhibitor (TFPI), increasing tissue factor-initiated thrombin generation


-Time consuming preparation; requires many vials and preparation time is not ideal when emergent use is needed


-Unable to use heparin during surgical procedure following administration of andexanet alfa due to it neutralizing heparin’s effect (7)


4F-PCC pros:


-Has been available longer with more experience


-Greater availability


-Reduced cost


-Easier preparation


-Recommended dosing does not depend on DOAC dose and time since last dose


-Theoretical longer duration of action (7)


4F-PCC cons:


-Not FDA approved for reversal of anticoagulation with DOACs


-No safety or efficacy data on using 4F-PCC for factor Xa bleeding reversal


-Unable to be used in HIT patients due to presence of heparin in small variable amounts


-Does not reliability lower Xa activity in trials


-In theory, drug that is attempting to be reversed would inhibit the factor Xa generated from the 4F-PCC


-Thrombotic risk (unknown if better or worse than the alternative)


In conclusion, at this time there is no definitive answer on which is the better agent to use. Not all hospitals have added andexanet alfa to their formulary and this is due to the current lack of definitive data and high cost. There may be situations when one is preferred over the other.


There is a Phase IV clinical trial currently in progress that will evaluate the use of andexanet alfa vs standard of care in ICH patients taking a DOAC. Although this is not a direct comparison to treatment with 4F-PCC specifically, it will hopefully give us more conclusive data.


Below is a link to this clinical trial:


clinicaltrials.gov/ct2/show/NCT03661528?term=andexanet+alfa&phase=23&rank=3



References:



1. Cuker A, Burnett A, Triller D, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol. 2019; 94: 697-709.



2. Tomaselli GF, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants. Journal of the American College of Cardiology. 2017;70(24)3042-3067.



3. Tomaselli GF, et al. 2018 Update on 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants. Journal of the American College of Cardiology. 2017 [2018 July update Guidance for Anticoagulation Reversal];70(24)3042-3067



4. January CT, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. Circulation. 2019;140:125-151



5. Witt DM, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Advances. 2018;2:3257-3291.



6. Siegal DM, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015; 373:2413-2424.



7. Dager WE, Gulseth MP, Nutescu EA. Anticoagulation Therapy: A Clinical Practice Guide. 2nd edition. Bethesda: American Society of Health-System Pharmacists; 2018.



8. Shaw JR, Siegal DM. Pharmacological reversal of the direct oral anticoagulants-A comprehensive review of the literature. Res Pract Thromb Haemost. 2018 Apr; 2(2):251-265.


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