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Anticoagulant Reversal Strategies
Anticoagulant Reversal Strategies: Considerations for Health System Pharmacists

Released: January 09, 2024

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Key Takeaways
  • In 2019, the Joint Commission issued the National Patient Safety Goal for anticoagulant therapy, requiring institutions to maintain evidence-based practice guidelines for anticoagulation reversal and the management of bleeding.
  • When designing an inpatient anticoagulation reversal protocol, health system pharmacists should consider the rise in anticoagulation prescribing in the U.S. and the need to develop institution specific protocols based on guidelines and emerging clinical evidence.

Key Considerations for a Health System Pharmacist Designing an Inpatient Anticoagulation Reversal Protocol
The first key item that health system pharmacists should consider is that over the last decade, the number of people prescribed oral anticoagulants, especially the direct oral anticoagulants (DOACs), has significantly increased. DOACs have increased our options to optimize treatment for patients, expanding access and use. However, as more patients were treated with anticoagulants, we saw an increase in the number of bleeding-related events. Data from phase III clinical trials shows that the incidence of bleeding with DOACs is no worse or possibly better when compared with warfarin, but the chance of experiencing a bleed is not zero. Thus, hospitals need to have protocols and evidence-based practice guidelines to manage bleeding situations, which can often constitute an emergency, when they occur.

The second key consideration is that having a protocol in place is now a regulatory requirement. In July of 2019 the Joint Commission issued the National Patient Safety Goal for anticoagulant therapy, stating that the hospital must “use approved protocols and evidence-based practice guidelines for reversal of anticoagulation and management of bleeding events related to each anticoagulant medication.” Therefore, an approved protocol must be in place to manage bleeding due to any anticoagulant. This is important because when patients come in with bleeding events, it is an urgent, if not an emergent situation, and having protocols in place that comply with current guidelines allows patients to be treated in a timely fashion.

The third key consideration is the use of guidelines that specifically addresses oral anticoagulant-related bleeding to construct your protocol, such as the 2020 American College of Cardiology (ACC) Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee. The ACC, American Heart Association, and the American College of Clinical Pharmacy guidelines for the management of atrial fibrillation also include recommendations for the management of warfarin or DOAC-related bleeding. With recommendations from several different guidelines available, it is important to remember that the guidelines are only as good as the literature that existed prior to their publication. Therefore, it is imperative for pharmacists to keep abreast of the most recent literature.

Selecting a Reversal or Replacement Agent for Management of Bleeding
Four-factor prothrombin complex concentrate (4F-PCC) contains concentrated amounts of Factor II (FII), Factor VII (FVII), Factor IX (FIX), and Factor X (FX) and is FDA-approved in United States for the reversal of vitamin K antagonists (VKA). With 4F-PCC you are restoring back to baseline the level of fully functional clotting factors that a patient does not have because they are on a VKA. Over the years, 4F-PCC has also been used in off-label situations such as a prohemostatic agent in trauma, in the operating room, or to correct coagulopathy due to DOACs.

Antidotes or reversal agents for DOACs were not available until many years after they were approved and used clinically in the United States. Apixaban was approved for use in patients with nonvalvular atrial fibrillation to reduce the risk of stroke and blood clots in 2012. Until 2018, when the reversal agent andexanet alfa was approved for use in patients with life-threatening or uncontrolled bleeding, clinicians had to figure out how to manage patients without having a specific reversal agent. Hemostasis and thrombosis are a balance of prothrombotic and antithrombotic factors. When managing a patient with active bleeding, additions should be made to the prothrombotic side to try and tip the balance in favor of minimizing or eliminating the bleeding. In the management of DOAC-related bleeding, using 4F-PCC provides a way to potentially tip the scale in favor of hemostasis by providing more clotting factors in hopes of overwhelming the anticoagulant concentrations in the patient. Several studies with small numbers of participants have been published using 4F-PCC in this way but the lack of comparator groups makes it difficult to attribute patient improvements to the use of 4F-PCC.  

A weight-based dosing strategy based on the pretreatment international normalized ratio was developed for 4F-PCC. This dosing strategy was designed to deliver the amount of clotting factors needed to restore clotting factor functionality back to normal.  The higher the INR, naturally the higher amount of clotting factors needed to restore baseline.  However, this is a cumbersome process; because the vials in a particular lot of 4F-PCC contain different amounts of factor, the calculation of the exact dose needed for a patient required some time. Therefore, as an alternative dosing strategy for emergencies, institutions started using a fixed-dose protocol where every vial of 4F-PCC is considered to have 500 units even though we know it may have more or less. For example, in a patient who presents with a gastrointestinal bleeding on warfarin, this would allow us to give them a fixed dose of 1500 units or 2000 units in a timelier matter. The fixed-dose approach has been adopted by most institutions including my own and is supported by the literature. However, if a patient has an intracranial hemorrhage, the providers have the option of using a weight-based dose.

The other option is to use a reversal agent or an antidote to eliminate the anticoagulant effect of an oral FXa agent such as andexanet alfa, which is a FXa molecule that has been modified to bind to either rivaroxaban or apixaban with a higher affinity than endogenous FXa. In this way, the FXa sequesters the DOAC allowing the natural hemostatic system to function normally. There are several clinical trials including a phase III study showing proof of concept that the drug works and works quickly to neutralize the DOAC.

There are some logistical challenges with andexanet alfa. It has to be given as a bolus followed by a 2-hour infusion. About 2 hours after the infusion is stopped, the effects of andexanet alfa wear off, and anticoagulation levels rise back to what they normally would have been based on an individual’s intrinsic clearance. In the phase III ANNEXA-4 trial which assessed the efficacy and safety of andexanet alfa in 352 patients with acute major bleeding and who were on a FXa inhibitor, andexanet alfa appeared to be effective at allowing hemostasis to take place. I think it is important to note that patients needing an urgent procedure within 12 hours after treatment with andexanet were excluded from this trial, but this is currently being investigated in ANNEXA-RS.

Considering Clinical Data and the Cost of Anticoagulant Reversal Strategies
When andexanet alfa first became available, it was more expensive than 4F-PCC. I suspect that because of the reasonable success with 4F-PCC, many thought it would be reasonable to continue with 4F-PCC because it was more cost effective. Until this year, we only had the results of indirect comparisons of these agents from nonrandomized trials to help us when making a decision regarding which agent to use. In 2023, Dobesh and colleagues published an observational cohort study using electronic health records of 4395 adults diagnosed with bleeding due to extrinsic coagulation. Their assessment demonstrated the odds of in-hospital mortality were 50% lower when using andexanet alfa vs 4F-PCC in individuals with a DOAC-related bleed. I think that this is by far the best and largest data set to use to make your clinical decisions. It is also important to note that the cost difference between these 2 agents is not as great as it once was with the price of andexanet alfa coming down and the price of 4F-PCC increasing. Therefore, it is important for pharmacists to consider the new and emerging data while balancing costs.

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