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INTRODUCTION

The clinical use of direct oral anticoagulants (DOACs) has dramatically increased over the last decade, especially the oral factor Xa agents apixaban and rivaroxaban. Among all oral anticoagulants prescribed for the prevention of thromboembolic events such as stroke and myocardial infarction, apixaban accounts for 25%, followed by rivaroxaban at 21%.¹ In 2019, the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) updated its atrial fibrillation (AF) guidelines to preferentially recommend use of DOACs rather than warfarin for patients with AF.² Bleeding still occurs with DOACs, and phase 3 clinical trials demonstrate a similar or lower risk of major bleeding compared to warfarin depending on the specific trial and DOAC.³ Importantly major bleeding events such as intracranial hemorrhage (ICH) still occur with the DOACs (Table 1).⁴ Because of the significant morbidity and mortality associated with ICH and other major bleeding events, the ability to promptly reverse oral anticoagulation is essential. This monograph will review the most recent data on the reversal of DOACs.

Bleeding Risks Associated with Oral Anticoagulation

For over 50 years, the vitamin K antagonist warfarin was the sole oral anticoagulant available. S previously mentioned, the risk of major bleeding can be similar or lower than warfarin depending on the trial and toe DOAC. However, an important consideration is that the risk of ICH is approximately 50% lower when a DOAC is used than when a patient is on warfarin.⁴ Regardless of which agent is used or how well it is managed, there is a risk of bleeding events with any oral anticoagulant. Anticoagulation is not the direct cause—bleeding is caused by damage or rupture to blood vessels, often due to diseases of the large vessels such as atherosclerosis, or vascular malformation of the small vessels. If an oral anticoagulant is present in the bloodstream, it can make the bleeding more severe by inhibiting clotting. Most cases of bleeding are minor and easily treated, such as superficial gastrointestinal (GI) bleeding, but ICH is a serious and potentially catastrophic bleeding event.⁵

Managing bleeding may include surgical intervention, compression, supportive care, and reversal of anticoagulation. The ability to reverse anticoagulation at the site of bleeding is critical, and the sooner reversal of anticoagulation can be implemented, the better.² Failure to lower the international normalized ratio (INR) in the setting of ICH rapidly increases the volume of blood in the brain, prolongs bleeding and increases the risk of poor outcomes including severe neurological deficits. The goal is to preserve brain tissue before significant damage takes place. If neurological deficits have already occurred when a patient presents to the emergency department, efforts to manage the bleed (including reversal of anticoagulation) will be less effective than when neurological function is still relatively intact. There are some predictors of poor outcomes from ICH, whether the patient is on warfarin or a DOAC. These include:^{6, 7}

• Failure to lower INR rapidly
• Large volume of blood
• Intraventricular extension
• Midline shift
• Severe neurologic deficits

Bleeding Risks: Warfarin vs DOAC

Management of anticoagulation with warfarin requires attention to multiple clinical factors to ensure that the patient receives the appropriate level of anticoagulation while staying within the targeted therapeutic range. It is not uncommon for patients on warfarin to be under- or over-anticoagulated. Although bleeding can occur when the degree of anticoagulation is within the desired range, it more often occurs when the level of anticoagulation is too high.⁸ In contrast, with DOACs there are generally fewer clinical factors that can impact the degree of anticoagulation, although attention to these factors is critical to optimizing anticoagulant therapy with DOACs. The more consistent dose response with DOACs is likely reflected in the data showing significantly lower rates of ICH in DOAC-treated patients versus those treated with warfarin.^{9, 10} Trends reported in the literature suggest that warfarin-associated ICH has been on the rise, potentially due to treatment in an older patient population, as well as to improved clinician awareness, diagnosis, and reporting of these events.¹¹

No matter how well patients are managed on any oral anticoagulant, there is always a risk of bleeding. An estimated 200,000 hospitalizations and 30,000 deaths occur each year due to Factor Xa inhibitor–associated bleeding.¹² While this may be a small percentage relative to the total number of patients who take these agents, bleeding is a serious issue that warrants improved vigilance, appropriate interventions, and effective use of reversal agents to optimize outcomes.

Reversal of Warfarin

Although the clinical use of DOACs has increased significantly, there are still some patients for whom warfarin may be the preferred oral anticoagulant. Scenarios in which warfarin might be the anticoagulant of choice include the presence of a critical drug–drug interaction with a DOAC, severe renal dysfunction, or a patient with a mechanical heart valve. To manage bleeding events in a patient taking warfarin, prothrombin complex concentrates (PCCs) are the preferred reversal strategy.¹³ Warfarin inhibits recycling of vitamin K in the body, preventing its participation in the synthesis of fully functional clotting factors. Thus, the clotting factors are less capable of producing a clot when the coagulation cascade is activated. PCCs act to replace fully functional clotting factors. This results in immediate reversal of warfarin’s effects, but not in sustained reversal over a period of days. For this reason, PCCs are often augmented by administration of exogenous vitamin K, either orally or intravenously.¹⁴

Historically, other methods have been used to give back clotting factors, such as fresh frozen plasma, but this is not as efficient or effective as PCC. Pro-hemostatic agents such as recombinant factor VII act to turn on the coagulation cascade, but this approach is neither preferred nor guideline-recommended because of the risk of thromboembolic events.² The pros and cons of PCCs and other methods are outlined in Figure 1.¹³

DOAC Reversal

Unlike warfarin, which impacts the synthesis of fully functional clotting factors, DOACs directly bind to a particular clotting factor and turn it off, preventing its participation in the coagulation cascade. A different approach for reversal is required. Replacing or augmenting the level of clotting factors would not be expected to be effective in reversing the anticoagulant effect of DOAC because the DOAC present in the bloodstream will simply bind to those clotting factors and turn them off. Indications and dosage of the FDA-approved DOACs are summarize in Table 2.^15-18

Rivaroxaban and apixaban are the most widely used DOACs in the U.S. Each of these agents is approved for multiple indications: venous thromboembolism (VTE) treatment and prevention, stroke prevention, and AF. Andexanet alfa is the DOAC-specific agent approved for reversing the oral factor Xa inhibitors rivaroxaban and apixaban.¹⁹ Andexanet alfa is a recombinant modified human factor Xa which acts as a decoy molecule. It combines to the factor Xa inhibitor and prevents it from participating in the coagulation cascade. No interaction occurs with other coagulation factors beyond factor Xa. Andexanet alfa was approved in 2018 based on the results of two Phase 3 clinical trials in healthy volunteers: ANNEXA-A studied subjects receiving therapeutic levels of apixaban, while ANNEXA-R looked at subjects on therapeutic anticoagulation with rivaroxaban.^{20, 21} Both trials demonstrated an effective reversal of anticoagulation effect based on anti-factor Xa assays. In ANNEXA-R, the primary endpoint of mean percent change in anti-Factor Xa activity was 97 ± 2% for andexanet vs 45 ± 12% placebo (P<0.001).²¹

ANNEXA-4 was a study of andexanet alfa in patients who presented with bleeding complications from a DOAC.²⁰ This prospective multicenter open-label study analyzed outcomes from 352 patients with acute major bleeding who were taking an oral factor Xa inhibitor. Most subjects were on a fixed dose of rivaroxaban or apixaban, although the trial included a small number of patients on edoxaban or enoxaparin, a low-molecular-weight heparin. Eligible patients had received their last dose of oral anticoagulant within 18 hours and had a potentially life-threatening bleed, defined as hemodynamic compromise; major bleeding in a critical area or organ such as GI or ICH; or bleeding associated with a decrease in hemoglobin levels of ≥2 g/dL. Anti-factor Xa activity was decreased approximately 92% with the antidote, while excellent or good hemostasis occurred in about 82% of patients.²⁰

Safety

Reversal of anticoagulation exposes the existing risk of thromboembolism. In addition, the antidote or reversal strategy may initiate a thromboembolic event by turning on the coagulation cascade. In the two healthy volunteer studies, andexanet alfa showed a good safety profile with no thromboembolic events and few infusion-related reactions, none of them severe.^{14, 21} In the ANNEXA-4 trial, most thromboembolic events occurred remotely from the administration of the antidote and primarily in patients whose anticoagulation had not yet been restarted.²⁰ This suggests that andexanet alfa is not pro-thrombotic and that patients had an underlying risk of thrombosis that was unmasked with the removal of the anticoagulant. Clinicians must be aware of guidelines directing when to restart anticoagulation after a patient is stabilized.

Andexanet Alfa Dosage

Andexanet alfa is given via a bolus dose to immediately reverse the anticoagulant effect, followed by an infusion over 2 hours to maintain reversal of anticoagulation.¹⁹ The reversal occurs only while the antidote is being administered. After the infusion of the reversal agent is stopped, the patient will return to whatever baseline level or endogenous level of anticoagulation is still present. The dosage strategy of andexanet alfa should be based on which DOAC was taken and the timing of when the patient took the last dose (Table 3).^{19, 20} The low dose is a 400 mg bolus with a 4 mg/minute infusion for 2 hours. The high dose is an 800 mg bolus with an 8 mg/minute infusion for up to 2 hours.¹⁹ Rivaroxaban has a higher volume of distribution relative to apixaban, therefore patients taking rivaroxaban are more likely to need the higher dose, especially if they present within a short time frame of taking the drug. To reverse apixaban, a lower dose is more often used. The majority of patients are treated with the low dose approach because they have already cleared much of the drug from their body by the time they present for treatment of the bleeding event.

PCC and Other Antidotes for Factor Xa Inhibitors

Many recent guidelines that discuss the reversal of anticoagulation with oral agents do not list PCCs as preferred reversal agents for Factor Xa inhibitors.^{14, 22} Most studies of PCC in DOAC-associated bleeding have been retrospective and observational in nature. Three main PCC studies together evaluated approximately 300 patients, and a more recent study at 26 stroke centers evaluated 633 patients with apixaban- or rivaroxaban-associated bleeding who received a PCC.^23-25 All of these studies showed good or excellent hemostasis but lacked a control group and excluded people with more severe ICH. Another limitation of these studies was that they did not clearly document whether patients had clinically relevant plasma concentrations of the DOAC when they presented for treatment. This is an important distinction, because if there is minimal or no anticoagulant in the body, the bleeding event will need to be treated with supportive care, surgical measures, or transfusion—but anticoagulant reversal is not needed. Giving a PCC might help to promote coagulation, but it is not necessarily reversing the activity of the anticoagulant.

Among investigational agents for reversal of DOACs, ciraparantag is a small molecule agent that binds noncovalently to heparin, low-molecular weight heparin, and DOACs, allowing a broad range of reversal.²⁶ A study in healthy human volunteers treated with edoxaban showed that IV ciraparantag rapidly corrected prolonged whole blood clotting time over a 24-hour period.²⁷ Adverse events were mild with no evidence of procoagulant activity. A Phase 2 trial of ciraparantag for reversing apixaban and rivaroxaban is under way.²⁸

Reversal of Dabigatran

The direct thrombin inhibitor dabigatran was the first DOAC approved in the U.S. and is still used in a significant number of patients.²⁹ Idarucizumab is the antidote specifically designed for dabigatran reversal. Idarucizumab is a humanized recombinant antibody that binds directly to free and thrombin-bound dabigatran, remaining bound so that dabigatran cannot inhibit thrombin in the coagulation cascade.³⁰ Unlike andexanet alfa, which is approved only for the management of bleeding, idarucizumab is approved to manage bleeding in patients taking dabigatran, but also to reverse the anticoagulant effect of dabigatran in patients who require urgent procedures. Idarucizumab is given as an IV bolus of two 2.5-gram doses, given about 10 minutes apart for a total of 5 grams. It has an immediate onset of action and there is no need for a continuous infusion because it binds to and turns off dabigatran permanently.³⁰

Reverse AD was a Phase 3 open-label study of idarucizumab in dabigatran-treated patients.³¹ This trial included patients with uncontrolled bleeding in addition to patients who required an urgent surgical procedure. The dose of 5 grams given as two boluses effectively and immediately reversed the anticoagulant effect and maintained that reversal for 24 hours. Because idarucizumab has a very short plasma half-life, dabigatran can be restarted within 24 to 36 hours if necessary. Thrombotic events during the Reverse AD trial occurred remotely from the administration of the antidote (mean 6.5 days), suggesting that idarucizumab does not promote thrombosis. In addition, thrombotic events occurred almost exclusively in patients who had not restarted anticoagulation, indicating that clinicians must be vigilant about when it is appropriate to restart anticoagulation.³¹

In a small number of patients, the 5-gram dose of idarucizumab did not reverse all of the anticoagulant that was present. This may have been due to reduced elimination of dabigatran because of renal failure. In rare cases, a supplemental dose of idarucizumab may be needed for re-elevation of anticoagulation, based on coagulation assay results.³⁰

Pharmacokinetic and pharmacodynamic properties of the available DOACs are summarized in Table 4.³²

Practice Guidelines for Oral Anticoagulation that Discuss Reversal

The 2020 American College of Cardiology (ACC) Consensus Decision Pathway on the management of bleeding and patients on oral anticoagulants is a robust and reliable decision pathway based on what is currently known in the scientific literature.¹⁰ This document contains information on the reversal of oral anticoagulation, including DOACs and warfarin. Important components include criteria for determining:

• whether the bleed is considered a major bleed or non-major bleeding
• when and how to administer the appropriate reversal agent
• when to implement supportive measures to treat the bleed, such as surgical measures or procedural measures or even just transfusion
• if and when to resume oral anticoagulation.

If the bleeding is non-major, in many cases patients could be continued on oral anticoagulation and have appropriate measures to control the bleeding at the site. For major bleeding, stopping anticoagulation and potentially reversal of the anticoagulant effect has a dramatic effect to appropriately treat the patient. If restarting of anticoagulation is delayed, there is a higher risk of recurrent thromboembolic events. Thus the ACC consensus pathway places emphasis on the timing of restarting anticoagulation with a DOAC or warfarin.¹⁰

Other Guidelines

Other practice guidelines on anticoagulation cover important points not specifically related to reversal but discuss management of thromboembolic risk. These include the 2018 Chest Guidelines on Antithrombotic Therapy for Atrial Fibrillation, and the American Society of Hematology Guidelines on Venous Thromboembolic Disease (Table 5).^{8, 33}

Need for Institutional Protocols on Oral Anticoagulant Reversal

Because a broad range of healthcare professionals are involved in the care of patients experiencing bleeding from oral anticoagulation, every healthcare institution should implement a systematic process for the management of these patients. Bleeding events from oral anticoagulation can occur anywhere—in the emergency department, surgical unit, elsewhere in the hospital, or in the outpatient setting. In addition to the significant clinical need, these protocols are part of the National Patient Safety Goals quality metrics required by the Joint Commission.³⁴ The ACC decision pathway’s recommendations should form the basis for this protocol (Figure 2).¹⁰

The protocol should establish criteria for when patients need reversal agents, when they can be managed without reversal, formulary selection, use of coagulation assays such as prothrombin time, determination of major and life-threatening bleeding, and steps for managing bleeding events prior to and during any procedures the patient is undergoing. Once the patient is stabilized, attention should focus on how to prevent recurrent bleeding and when to restart anticoagulation (Figure 3).¹⁰

Formulary management considerations may include:

• Performance of current reversal strategies (some organizations prefer to stay with existing blood factor product strategy)
• Frequency of patients presenting with life-threatening bleeding
• Types of patients presenting with bleeding (trauma, neurosurgery, GI bleeding)
• Ability to control and monitor use (will providers attempt to use high-cost specific reversal agents for indications other than life-threatening bleeding?)

When developing institutional guidelines and stewardship, the team should address the following questions:

• Which patients should receive these reversal agents?
• Which agents does the institution carry on formulary?
• Is reversal limited to life-threatening bleeding? How is that defined?
  • Should we treat abnormal coagulation tests?
• What about urgent surgery? Elective surgery?
• When should labs be drawn to assess effect?
• When should anticoagulation be restarted?

Pharmacists serve a number of roles as part of the multidisciplinary team that develops and implements institutional protocols for reversal of anticoagulation, as well as dissemination and education about how to execute, oversee, and update the protocol (Table 6). Pharmacists who may be involved in the care of patients experiencing bleeding must be knowledgeable about the various pharmacologic agents, procedures, and protocols, and be able to educate other healthcare providers if needed, especially during an urgent situation. Pharmacists may be involved with the selection of reversal agents and gatekeepers for reversal agents, many of which are costly. When patients are stabilized, the pharmacist may serve as a point person to raise awareness about when it may be appropriate to restart anticoagulation in order to minimize the risk of thromboembolic events.

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