Evidence-based Management of Major Bleeding in Patients Receiving Direct Oral Anticoagulants: An Updated Narrative Review on the Role of Specific Reversal Agents

Abstract

The indications of direct oral anticoagulants (DOACs) have expanded over the past 15 years. DOACs are effective and safe oral anticoagulants associated with lower bleeding risks and mortality than vitamin K antagonists. However, DOAC users are prone to a considerable bleeding risk, which can occur at critical sites or lead to severe life-threatening conditions. Recent statistics indicated that major bleeding occurs in up to 6.62 DOAC users per 100 treatment years. With the increased use of DOACs in clinical practice, DOAC-associated major bleeding is expected to be encountered more frequently in the emergency department. The current international guidelines recommend specific reversal agents for the management of DOAC users with severe bleeding to reverse the anticoagulant effect and restore normal hemostasis. An individualized assessment was incorporated in specific clinical situations to guide the decision pathway of major bleeding management. However, specific reversal agents are unavailable or have limited availability in many countries, which is expected to negatively impact the clinical outcomes of DOAC-associated major bleeding. Limited real-world evidence is available from these countries regarding the clinical outcomes of patients with DOAC-associated major bleeding. This narrative review provided an updated assessment of the evidence-based approaches for the management of major bleeding in DOAC users. We also explored the clinical outcomes of patients with major bleeding from clinical settings where specific reversal agents are unavailable.

Keywords

direct oral anticoagulants major bleeding intracranial hemorrhage andexanet alfa idarucizumab

Introduction

The introduction of direct oral anticoagulants (DOACs) has significantly expanded the indications of oral anticoagulants (OACs) to a wider patient profile and shifted the management of patients requiring OACs to safer alternatives.¹ DOACs are noninferior alternatives to vitamin K antagonists (VKAs), which are associated with a lower risk of bleeding complications.² DOACs represent more convenient options for candidates for OACs due to the predictable pharmacokinetics and shorter half-life, fewer interactions with food or other drugs, and the lack of routine monitoring compared to VKAs.³ Recent statistics showed a 2-fold increase in the utilization rate of OACs worldwide in the past ten years, which was attributed to the increased use of DOACs.⁴

Despite their benefits, DOACs are risk-prone medications associated with a considerable bleeding risk, which can occur at critical sites or lead to severe life-threatening conditions.⁵ Real-world studies and national registries demonstrated that major bleeding—including intracranial hemorrhage (ICH) and gastrointestinal bleeding (GIB)—occurs in up to 6.62 DOAC users per 100 treatment years.^6,7 With the expanded use of DOACs in clinical practice, DOAC-associated major bleeding is expected to be encountered more frequently in the emergency department. The number of hospitalized patients in the United States due to DOAC-related bleeding grew from 90 000 in 2015 to nearly 190 000 in 2019.^8,9 Untreated major bleeding can significantly increase mortality risk, the need for intensive care, and long-term disabilities.^10,11 Additionally, major bleeding can exert a substantial burden on healthcare resources and lead to increased healthcare resource utilization.¹² Therefore, prompt diagnosis and proper management of major bleeding are critical to reduce the mortality risk and short- and long-term morbidities.⁶

Until recently, the management of major bleeding complications in DOAC users received little attention from international guidelines due to the lack of specific reversal agents. The introduction of reversal antidotes has significantly improved the outcomes of emergency bleeding among DOAC users.^13,14 The current international guidelines recommend specific reversal agents for the management of major bleeding in DOAC users to reverse the anticoagulant effect and restore normal hemostasis.¹⁵ An individualized assessment was also incorporated in specific clinical situations to guide the decision pathway of major bleeding management.¹⁵ However, specific reversal agents are unavailable or have limited availability in many countries, which is expected to negatively impact the clinical outcomes of DOAC-associated major bleeding. Limited real-world evidence is available from these countries regarding the clinical outcomes of patients with DOAC-associated major bleeding.

This narrative review provided an updated assessment of the evidence-based approaches for the management of major bleeding in DOAC users. We also explored the clinical outcomes of patients with major bleeding from clinical settings where specific reversal agents are unavailable.

Review Development

The present review was based on a narrative assessment of the recent studies that evaluated the management approaches and outcomes of major bleeding in DOAC users. An online bibliographic search was conducted on MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). The search was performed using a combination of Medical Subject Headings and free text terms related to “direct oral anticoagulants,” “major bleeding,” and “specific reversal agents.” Additional relevant articles were identified through manual scanning of reference lists of included studies and relevant publications from the major relevant societies, such as the American College of Cardiology (ACC) and the American Heart Association. The search was limited to articles published in English up to June 2023.

DOACs Indications and Rates of Major Bleeding

Five DOACs are currently approved for a wide range of clinical indications, including the direct thrombin inhibitor, dabigatran, and the direct factor X inhibitors, rivaroxaban, apixaban, edoxaban, and betrixaban (Table 1). Nonvalvular atrial fibrillation (NVAF) is the most common indication for DOACs in international guidelines.¹⁶ Several meta-analyses and clinical trials favored DOACs over VKAs for preventing systemic thromboembolic events or stroke in NVAF patients due to their more tolerable safety profile.^17,18 The international guidelines recommend DOACs over VKAs for a myriad of conditions, including NVAF, deep vein thrombosis and pulmonary embolism (PE), acute coronary syndrome, and patients undergoing hip or knee arthroplasty^3,19,20 (see Table 1).

Table 1.

Pharmacological Properties and Indications of DOACs.

Characteristics	Apixaban	Dabigatran etexilate	Rivaroxaban	Edoxaban	Betrixaban
Targeted factor	Direct FXa inhibitor	Direct thrombin inhibitor	Direct FXa inhibitor	Direct FXa inhibitor	Direct FXa inhibitor
Pro-drug	–	Dabigatran	–	–	–
Bioavailability %	50	7	66	62	34
Tmax (h)	1-3	2	2-4	1-2	3-4
Half-life	12	12-17	5-9	10-14	19-27
Drug interactions	CYP3A4 and P-gp	P-gp	CYP3A4 and P-gp	P-gp
Renal excretion (%)	25	85	66	35	17.8
FDA-approved indications	NVAF, DVT/PE treatment	NFAF, DVT/PE treatment, recurrent DVT/PE prevention, prophylaxis in patients undergoing hip surgery	NFAF, DVT/PE treatment, recurrent DVT/PE prevention, prophylaxis in patients undergoing hip surgery, hospitalized acutely ill medical patients, and patients with CAD	NFAF, DVT/PE treatment	DVT/PE prevention in hospitalized acutely ill medical patients

Abbreviations: P-gp, P-glycoprotein; FXa, factor Xa; NVAF, nonvalvular atrial fibrillation; DVT, deep venous thrombosis; PE, pulmonary embolism; CAD, coronary artery disease.

The ever-growing expansion in DOACs indications resulted in a significant increase in OACs over the past year. Recent analyses indicated that the use of OACs grew by more than 30% and that the interest in DOACs exponentially increased from 2004 to 2017.^21,22 Likewise, population-based studies from the US showed a constant increase in the DOACs’ prescriptions from 2011 to 2020, reaching 47.9% of the total OACs users.^23,24 The same findings were observed in a cohort study covering the period from 2008 to 2014,²⁵ and reports from Canada,²⁶ Europe,²⁷ Germany,²⁸ England,²⁹ and the Middle East.^30–32 To confirm these trends, a recent meta-analysis showed an increase in OAC use from 2010 to 2018 due to the increased use of DOACs.⁴

The incidence of major and life-threatening bleeding associated with DOACs varies depending on the specific DOAC and the studied population (Table 2). In general, the incidence of major bleeding is higher in older patients with a history of bleeding or other risk factors for bleeding. Two meta-analyses showed that the incidence of fatal bleeding and major bleeding associated with DOACs varies between 0.06% to 0.30% and 1.1% to 4%, respectively.^33,34 Additionally, the incidence of clinically relevant nonmajor bleeding varies from 6.6% to 10.24%, major GIB ranges from 0.35% to 2.09%, and the incidence of ICH ranges from 0.09% to 0.51%.^33,34 The incidence of life-threatening bleeding is lower than that of major bleeding, estimated to be around 0.5% to 1% per year with DOACs.³⁵

Table 2.

Rate of Major Bleeding in DOAC Users Enrolled in Clinical Trials and Real-World Studies.

Study	DOACs	Major bleeding	ICH	GIB
Rocket-af ³⁷	Rivaroxaban	3.60%	0.50%	3.20%
Dresden ³⁸	Rivaroxaban	3.40%	0.21%	1.49%
Aristotle ³⁶	Apixaban	2.13%	0.33%	0.76%
Averroes ³⁹	Apixaban	1.40%	0.40%	0.40%
OLDW ⁴⁰	Apixaban	2.33%	0.29%	1.78%
	Dabigatran	2.37%	0.28%	1.97%
	Rivaroxaban	4.04%	0.44%	3.26%
Gloria AF Registry ⁴¹	Dabigatran	0.68 per 100 patients/year	0.18 per 100 patients/year	0.35 per 100 patients/year
Gloria AF Registry ⁴¹	Apixaban	0.93 per 100 patients/year	0.24 per 100 patients/year	0.31 per 100 patients/year
Xantus ⁴²	Rivaroxaban	1.90%	0.40%	0.80%
ETNA-AF-Europe ⁴³	Edoxaban	1.05%	0.24%	0.40%

Abbreviations: ICH, intracranial hemorrhage; GIB, gastrointestinal bleeding; DOACs, direct oral anticoagulants.

Patients with major bleeding are at increased risk of mortality, with reports showing an overall mortality rate as high as 48%, especially in patients with ICH.⁵ Major bleeding can also lead to long-term debilitating conditions. Notably, previous reports showed that patients with major bleeding are at increased risk of subsequent thrombotic events within 30 days of the bleeding event.³⁶

Diagnosis and Classification of DOACs-Associated Bleeding

The diagnosis of DOAC-associated bleeding can be challenging due to the limited availability of reliable point-of-care tests measuring their anticoagulant effect.¹⁵ The first step in diagnosing DOAC-associated bleeding is obtaining a thorough history and physical examination. The patient should be asked about the onset and duration of bleeding, any associated symptoms, and any recent changes in medication use.^44,45 A physical examination should be performed to assess for signs of bleeding, such as ecchymoses, petechiae, hematomas, or melena. Laboratory tests can also be useful in diagnosing DOAC-associated bleeding.⁴⁵

The severity of bleeding can be assessed using various clinical and laboratory criteria. One commonly used clinical criterion for evaluating the severity of bleeding is the International Society on Thrombosis and Hemostasis (ISTH) definition of major bleeding.⁴⁶ According to this definition, major bleeding is defined as fatal bleeding, occurs in a critical area or organ (such as intramuscular, retroperitoneal, pericardial, intraocular, intraspinal, and intracranial), or leads to a decrease in hemoglobin of 2 g/dL or more, or requires transfusion of 2 or more units of red blood cells.⁴⁶ The ACC used the same definition of ISTH and added hemodynamic instability.⁴⁷

For the purpose of cardiovascular clinical studies and patients taking anticoagulant medication, the Bleeding Academic Research Consortium has recently created highly standardized bleeding severity criteria.⁴⁸ These criteria categorize the patients into 6 types, from type 0 (no bleeding) to type 5 (fatal bleeding). In addition to assessing the severity of bleeding, it is also important to evaluate the presence of any underlying comorbidities that may affect the patient's ability to tolerate bleeding. For example, patients with advanced age, renal impairment, or other underlying medical conditions may be at increased risk of bleeding complications and require more aggressive management.⁴⁷

Laboratory assessment plays an important role in the diagnosis and management of bleeding associated with the use of DOACs. Several laboratory tests can be used to assess the severity of bleeding and guide treatment decisions, including platelet count and clotting factors assays (FII, FV, FVII, FX, FXI, FXII).⁴⁹ Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are not specific for DOACs and can also be prolonged in patients taking VKAs.⁵⁰ However, according to the ACC, PT and/or aPTT should be done for all patients with suspected bleeding associated with DOAC use.⁴⁷

Dabigatran levels may be subjectively evaluated using the thrombin time (TT) and aPTT. Although a prolonged TT does not distinguish between clinically significant and insignificant drug concentrations, it is particularly sensitive to dabigatran.^51,52 A normal TT excludes clinically relevant dabigatran levels. A normal aPTT test result does not necessarily mean that there are no on-therapy levels of dabigatran present. However, if the aPTT is prolonged, it indicates that the patient is receiving or has received a high dose of dabigatran.⁴⁷

The assessment of DOACs level in blood can be done by specific assays such as anti-FXa assays for rivaroxaban, apixaban, and edoxaban, and anti-IIa assay for dabigatran.^53,54 These assays can confirm the presence of serum DOACs and assess the anticoagulation level. However, it is important to note that these assays are not widely available, results may take several hours to obtain, and the measurement of the DOAC level is complex.⁵⁵ If an anti-FXa assay is unavailable, the PT test may be useful for assessing betrixaban, edoxaban, and rivaroxaban, but it is not sensitive to apixaban.^56,57 Whole-blood viscoelastic assays such as thromboelastography and rotational thromboelastometry show changes in response to DOACs but do not have established thresholds for guiding decisions about using reversal agents.⁴⁷ If these assays are calibrated with low-molecular-weight heparin or unfractionated heparin, it can be useful for excluding clinically important levels of the drug but not for measuring it.^51,52

The fact that DOACs are excreted through the urine has raised interest in the “point of care” test concept, in which urine samples can be assessed for the presence of DOACs, with different colors and designate the presence or absence of DAOCs. Urine analysis of DOACs is an easy and rapid approach for assessing the presence of DOACs while avoiding the risks associated with blood sampling. In addition, the patient can perform this qualitative assay.⁵⁸ Recently, a study using DOAC Dipstick tests demonstrated feasibility and accuracy in detecting DOAC-associated major bleeding in the emergency department.⁵⁹ The test is rapid (results can be obtained in 15 min) and has 100% accuracy across all factor Xa inhibitors; there was no reported interaction between the test pads and heparin, nadroparin, fondaparinux, or coumadin. In addition, the DOAC Dipstick urine test can support the diagnosis of DOAC-associated major bleeding in the emergency department.

Management of Major Bleeding

The management of DOAC-associated bleeding is based primarily on the severity and location of the bleeding.⁶⁰ Minor bleeding that does not meet the definition criteria of ISTH/ACC is usually treated by skipping the DOAC for 1 dose or day.⁴⁷ However, patients with minor bleeding may need local measures to control bleeding and extended discontinuation of DOACs, according to the individualized assessment.⁴⁷

Conversely, major bleeding requiring hospitalization necessitates individualized assessment, discontinuation of the DOACs, restoration of hemodynamic stability, and reversal of DOAC activity to restore normal hemostasis. The first step in managing major bleeding in the emergency department is providing adequate supportive care and ensuring that the DOAC is stopped. The supportive care can include local measures to control bleeding, volume resuscitation, blood product transfusion, and correction of acidosis.⁵ Although the discontinuation of the DOACs is essential, there is a lack of consensus regarding the duration of withholding DOACs in patients with major bleeding. The 2020 ACC consensus suggested a withholding duration for each DOAC based on the half-lives in patients undergoing surgical procedures according to the expected bleeding risk.⁴⁷ However, a similar consensus for patients with DOAC-associated major bleeding has not been published yet. Alongside supportive care and DAOCs discontinuation, specific reversal antidotes are recommended by most international guidelines.^47,61–63

When specific antidotes are unavailable, the nonspecific procoagulant, prothrombin complex concentrate (PCC), can be used (Table 3). Patients on dabigatran with renal insufficiency may benefit from hemodialysis.⁴⁷ Other measures have been described, such as activated charcoal within 2 hours of DOACs and fresh frozen plasma (FFP), but the evidence shows the limited benefit of FFP.

Table 3.

Guidelines’ Recommendations for the Management of major or Life-Threatening Bleedings due to DOACs.

Guidelines	Condition	Recommendations
American College of Cardiology ⁴⁷	Major bleeding	- Approved specific reversal antidotes according to the type of DOAC (Andexanet alfa for FXa inhibitors, Idarucizumab for dabigatran) - If specific antidotes are not available, PCC for FXa inhibitors should be used - FFP is not recommended - No specific recommendation for rFVIIa
Anticoagulation Forum ⁶¹	Major bleeding	- Approved specific reversal antidotes according to the type of DOAC (andexanet alfa for FXa inhibitors, idarucizumab for dabigatran) - If specific antidotes are not available, 4-F PCC for FXa inhibitors should be used. - No specific recommendation for FFP or rFVIIa
American Society of Hematology ⁶²	Life-threatening bleeding	- Either 4-F PCC or approved specific reversal antidotes according to the type of DOAC (andexanet alfa for FXa inhibitors, idarucizumab for dabigatran)
British Society for Haematology ⁶³	Life-threatening bleeding or surgery	- Approved specific reversal antidotes according to the type of DOAC (andexanet alfa for FXa inhibitors, idarucizumab for dabigatran) - No specific recommendation for PCC, FFP, or rFVIIa
Canadian Cardiovascular Society ⁶⁴	Severe or life-threatening bleeding/ urgent surgery	- Approved specific reversal antidotes according to the type of DOAC (andexanet alfa for FXa inhibitors, idarucizumab for dabigatran) - No specific recommendation for PCC, FFP, or rFVIIa
CHEST expert panel	Severe or life-threatening bleeding	- Approved specific reversal antidotes according to the type of DOAC (andexanet alfa for FXa inhibitors, idarucizumab for dabigatran) - If specific antidotes are not available, PCC for FXa inhibitors should be used - No specific recommendation for FFP or rFVIIa
European Stroke Organization ⁶⁵	ICH	- Approved specific reversal antidotes according to the type of DOAC (andexanet alfa for FXa inhibitors, idarucizumab for dabigatran) - If specific antidotes are not available, 4-F PCC (37.5-50 IU/kg) for FXa inhibitors should be used - If PCC is not available, FFP can be used.
Neurocritical Care Society ⁶⁶	ICH	- Approved specific reversal antidotes according to the type of DOAC (andexanet alfa for FXa inhibitors, idarucizumab for dabigatran) - If specific antidotes are not available, 4-F PCC (for FXa inhibitors should be used - FFP or rFVIIa are not recommended.

Abbreviations: ICH, intracranial hemorrhage; DOACs, direct oral anticoagulants; 4F-PCC, 4-factor prothrombin complex concentrate; PCC, prothrombin complex concentrate; FXa, factor Xa; FFP, fresh frozen plasma.

Below, we discuss the evidence supporting reversal antidotes and nonspecific procoagulants (Table 4).

Table 4.

Clinical Evidence Supporting Reversal Antidotes and Procoagulants.

Trial	Antidote/procoagulants	DOAC	Design	Condition	Number of patients	Dosing	Outcomes
Re-verse ad ⁶⁷	Idarucizumab	Dabigatran	Single-arm, open-label, trial	Uncontrollable or life-threatening bleeding or urgent surgery	503	5 g IV (administered bolus infusions of 2.5 g)	- 100% achieved reversal of anticoagulant within four hours. - 6.3% and 7.4% experienced thromboembolic events in life-threatening bleeding and surgery group - 19% Mortality rate
ANNEXA-4 ⁶⁸	Andexanet alfa	Apixaban, enoxaparin, rivaroxaban or edoxaban	Single-arm, open-label, trial	Major bleeding within 18 h from FXa inhibitor administration	352	Low dose: 400 mg IV bolus over 15 min, then 480 mg IV infusion over 2 h, if apixaban or >7 h from rivaroxabanHigh dose: 800 mg IV bolus over 30 min, then 960 mg infusion over 2 h, if edoxaban, enoxaparin, or ≤7 h of rivaroxaban	- 82% of the patients had good-to-excellent hemostatic efficacy within 12 h. - 10% thromboembolic events within 30 days. - 14% 30-day mortality.
Uprate ⁶⁹	4F- PCC	Apixaban or rivaroxaban	Observational study	Major bleeding within 24 h from FXa inhibitor administration	84	∼ 25 IU/kg	- 69.1% of the patients had hemostatic efficacy. - 2.4% thromboembolic events within 30 days. - 32% 30-day mortality.
Schulman et al ⁷⁰	4F-PCC	Apixaban or rivaroxaban	Observational study	Major bleeding	66	2000 IU	- 68% of the patients had hemostatic efficacy. - 8% thromboembolic events within 30 days. - 14% 30-day mortality.

Abbreviations: 4F-PCC, 4-factor prothrombin complex concentrate; IV, intravenous; PCC, prothrombin complex concentrate; DOAC: Direct oral anticoagulant.

Specific Reversal Antidotes

Although the rate of major bleeding among DOAC users is relatively low, the lack of specific antidotes has been a concern for treating physicians and was reported as a cause of limited OAC use in eligible populations.⁷¹ In clinical practice, procoagulants and vitamin K have remained the mainstay options for patients presenting with major or life-threatening bleeding due to DOACs, despite their limited effectiveness.⁷² However, recent years have witnessed the approval of 2 specific reversal agents, idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban, which can optimize the management of DOAC-associated major bleeding and expand the utilization of DAOCs in eligible populations.^73,74 Additionally, a third specific antidote, ciraparantag, is under investigation.⁷²

Dabigatran Reversal Antidote

Idarucizumab is a monoclonal antibody fragment that rapidly and specifically binds to the dabigatran molecule without interactions with the intrinsic coagulation system.⁷⁵ Intravenous idarucizumab was reported to act within 10 to 30 min from administration and has a half-life of 45 min; previous pharmacokinetics studies demonstrated that idarucizumab had sustained binding activities towards the free and thrombin-bound dabigatran.^76,77 The recommended dosing regimen of idarucizumab is 5 g divided into 2 bolus infusions, 15 min apart; idarucizumab can be readministrated, if needed, after 12 to 24 h due to the short half-life.^77,78

In the full cohort analysis of the RE-VERSE AD trial, 503 patients on dabigatran with life-threatening, uncontrolled bleeding or needed urgent surgery received idarucizumab 5 g.¹⁴ The median maximum percentage of DOAC reversal was 100%, and 88%–98% of the patients restored normal hemostasis. Within 90 days of follow-up, 6.3% and 7.4% of the patients with severe bleeding or needed surgery, respectively, experienced thromboembolic events. The overall mortality rate was 19%. The most common adverse events were constipation (7%) and headache (5%), with no observation of serious adverse events,¹⁴ Table 4. Based on these findings, the FDA approved idarucizumab for dabigatran users with life-threatening bleeding or who need surgery.⁷⁹ The feasibility and efficacy of idarucizumab were also shown in the international real-world RE-VECTO study.⁸⁰

Factor Xa Inhibitor Reversal

Andexanet alfa is a recombinant modified factor Xa decoy protein that binds to the active site of factor Xa inhibitors in a high affinity and interferes with the factor Xa inhibitor without affecting the intrinsic coagulation system. Andexanet alfa has a rapid onset of action (2-5 min) with a half-life of 60 min.⁸¹ Two dosing regimens of intravenous andexanet alfa are recommended: A low-dose regimen consists of a bolus infusion of 400 mg at 30 mg per minute, followed by a continuous infusion of 4 mg per minute for 120 min, and a high-dose regimen consists of a bolus infusion of 800 mg at 30 mg per minute, followed by a continuous infusion of 8 mg per minute for 120 min.⁸²

Early phase I/IIa clinical trials confirmed the well-tolerated safety profile of andexanet alfa and the lack of serious adverse events or interactions.⁸² The ANNEXA-A and ANNEXA-R trials evaluated andexanet alfa in healthy older volunteers receiving apixaban or rivaroxaban. The results showed that when andexanet was administered as a bolus plus a 2-h infusion, it restored thrombin generation in 100% of the patients, and the median anti-FXa activity was reduced by 92% to 97%.⁸³ This was followed by the single-arm open-label ANNEXA-4 trial, which evaluated 352 DOAC users with major bleeding; nearly 85% were apixaban or rivaroxaban users. Overall, 82% of the patients had adequate restoration of homeostasis within 12 h, while the median reduction in the anti-factor Xa activity was 92% within 18 h. Within 30 days of follow-up, 10% of the patients had thromboembolic events. The overall mortality rate was 14%. The most common adverse events were urinary tract infection (5%) and infusion-related reactions (3%).⁶⁸ Based on these findings, andexanet alfa was approved in 2018 by the FDA for apixaban and rivaroxaban-treated patients.⁸⁴

The final study report of the ANNEXA-4 trial enrolled 479 patients who experienced acute major bleeding within 18 h of FXa inhibitor administration. The majority of the bleeding cases were intracranial (69%) or gastrointestinal (23%). The study found that in patients taking apixaban, rivaroxaban, edoxaban, and enoxaparin, the median anti-FXa activity decreased significantly. For patients taking apixaban and rivaroxaban, there was a 93% to 94% reduction in anti-FXa activity, while patients taking edoxaban and enoxaparin saw a 71% to 75% reduction. Among these patients, 80% had excellent or good hemostasis. Within 30 days of follow-up, 10.4% of the patients had thromboembolic events, and the overall mortality rate was 15.7%.⁸⁵ Real-world evidence from the US demonstrated the effectiveness of andexanet alfa in patients on DOACs with ICH or who need urgent surgery.⁸⁶

Although the population of the ANNEXA-4 trial was not limited to apixaban and rivaroxaban users, the study included only a small number of patients receiving edoxaban and enoxaparin. In small cohort studies, andexanet alfa was evaluated in healthy edoxaban and betrixaban users and showed promising results.⁴⁷ Ongoing trials are investigating andexanet alfa in DOAC users with major bleeding and ICH (NCT02329327 and NCT03661528).⁴⁷

Nonspecific Procoagulants

In case of specific reversal antidotes unavailability, PCC is recommended for DOAC users with major bleeding (see Table 3). The PCC is a nonspecific procoagulant that contains highly concentrated coagulation factors; in the 3-factor PCC, factors II, IX, and X are present, while factor VII is added in high concentration in the 4-factor PCC.⁸⁷ PCC can potentially reverse the action of DOACs by increasing the level of coagulation factors available for the intrinsic coagulation system. It is well-established that the 4-factor PPC is more effective than FFP, is nonspecific, needs thaw time, and can lead to volume overload or allergic reactions.⁸⁸ In 2 observational studies (Table 4), the 4-factor PCC restored the hemostatic efficacy in nearly two-thirds of the patients with major bleeding due to apixaban or rivaroxaban.^69,70 However, the mortality associated with 4-factor PCC is notably high; in the UPRATE study, which evaluated the 4-factor PCC in patients with major bleeding due to apixaban or rivaroxaban, the 30-day mortality rate was 32%, and nearly 2.4% of the patients had thromboembolic events within 30 days.⁶⁹ Likewise, in Schulman et al,⁷⁰ 30-day mortality and thromboembolic events rates were notably high (14% and 8%, respectively). The superior benefits of specific reversal agents over PCC were confirmed in recent real-world evidence. In this study, the risk of in-hospital mortality was significantly lower with andexanet alfa than with 4-factor PCC (4% vs 10%). The length of hospital stay and ICU stay was significantly shorter with andexanet alfa.⁸⁹

Continuing DOACs After Major Bleeding

Patients with nonmajor bleeding can safely continue DOACs after the restoration of hemostasis. However, the evidence is limited to guide the decision to continue DOACs in patients presenting with major bleeding. Previous reports showed that NVAF patients, who experienced ICH on DOACs, had an increased risk of ischemic events after the bleeding event due to the discontinuation of DOACs.⁹⁰ Despite this, resuming DOACs after ICH was found to be feasible and safe without increased risk of future major bleeding events.⁹¹ In a 1-year follow-up analysis, resuming DOACs in patients with ICH increased functional gain and reduced the severity of long-term disability.⁹²

The decision to continue DOACs should be individualized according to the risk of thromboembolic events and the location of major bleeding. Previous reports showed that lobar ICH is associated with a higher risk of recurrence than nonlobar ICH; thus, it was recommended that OACs should be avoided after lobar ICH.⁹³ However, it should be noted that the evidence is inconclusive, with other reports showing no difference in the risk of recurrent ICH between lobar and nonlobar ICH.⁹⁴ In the case of subarachnoid bleeding due to malformation or aneurysm and postepidural or subdural hematoma, DOACs can be resumed under the guidance of repeated brain imaging.⁹⁵ In other types of bleeding, such as GIB, the decision to continue DOAC should be guided by the presence of other risk factors, such as age, history of thromboembolic events, and the presence of multiple angiodysplasias.⁹⁶

Major Bleeding Where Specific Antidotes are Unavailable: An Expert Perspective

Several clinical guidelines have positioned specific reversal antidotes as the recommended options for major bleeding in DOAC users. However, these antidotes are not widely available yet in several healthcare settings due to their high cost. Specific antidotes are expensive, which poses a significant barrier to their routine use. Consequently, this leads to a situation where the availability of these antidotes is not consistent across all hospitals. In several settings, the use of antidotes is restricted to life-threatening complications.⁷⁴ Furthermore, the cost issue may not only restrict the availability of these antidotes but also potentially influence clinicians’ decisions regarding the selection of anticoagulant therapy.

Real-world studies from countries where antidotes have limited availability can provide valuable insights into the real-world implications of managing DOAC-associated major bleeding without reversal agents. These insights can be instrumental in informing healthcare policy, potentially advocating for the expedited approval and dissemination of such reversal agents at affordable prices. However, limited real-world evidence is available in this regard. In the START-Event registry, only 5.8% of dabigatran users with major bleeding received idarucizumab. The results showed an overall mortality rate of 15.5% and a long-term residual disability rate of 30%.⁹⁷ Such findings reflect the suboptimal clinical outcomes of DOAC-associated major bleeding in the case of limited use of specific reversal agents.

Conclusion

The introduction of reversal antidotes has improved the management landscape of DOAC-associated major bleeding management. Reversal antidotes exhibited a significant restoration of normal hemostasis in more than 90% of the patients with DAOC-associated major bleeding, with a well-tolerable safety profile and low mortality rate, opening the gate for wide use of DOACs in eligible populations. However, specific reversal antidotes have limited availability in several countries; real-world experience with specific antidotes is still limited. Despite the recommendations of off-label PCC use in the case of unavailable antidotes, the efficacy of PCC is modest, and the mortality rate is notably high. The lack of accessibility to specific antidotes may even limit the use of DOACs in eligible populations. Therefore, it is crucial to ensure the availability and accessibility of antidotes and develop local guidelines to direct their uses. Further studies assessing the use of specific antidotes in real-world practice are needed to inform emergency department physicians. There are no specific reversal agents for edoxaban, which warrants further investigation.

Footnotes

Acknowledgment

Medical writing and publication support were provided by CTI Clinical Trial and Consulting Services, which was funded by AstraZeneca, Saudi Arabia.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Zohair Al Aseri

References

Russell

. Warfarin and other VKAs: Dosing and adverse effects—UpToDate. Published 2020. Accessed December 4, 2022. https://www.uptodate.com/contents/warfarin-and-other-vkas-dosing-and-adverse-effects

Mekaj

Duci

Miftari

. New oral anticoagulants: Their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag. 2015;11:967-977. doi:10.2147/TCRM.S84210

Paul

Baby

Anthraper

Krishnakumar

. NOACs: An emerging class of oral anticoagulants—a review article. Futur J Pharm Sci. 2020;6(1):1-7. doi:10.1186/S43094-020-00114-1

Grymonprez

Simoens

Steurbaut

De Backer

Lahousse

. Worldwide trends in oral anticoagulant use in patients with atrial fibrillation from 2010 to 2018: A systematic review and meta-analysis. EP Eur. 2022;24(6):887-898. doi:10.1093/EUROPACE/EUAB303

Kaide

Gulseth

. Current strategies for the management of bleeding associated with direct oral anticoagulants and a review of investigational reversal agents. J Emerg Med. 2020;58(2):217-233. doi:10.1016/J.JEMERMED.2019.10.011

Ballestri

Romagnoli

Arioli

, et al. Risk and management of bleeding complications with direct oral anticoagulants in patients with atrial fibrillation and venous thromboembolism: A narrative review. Adv Ther. 2023;40:41-466. doi:10.1007/S12325-022-02333-9

Wallvik

Renlund

Själander

. Bleeding risk in patients with venous thromboembolic events treated with new oral anticoagulants. J Thromb Thrombolysis. 2021;52(1):315-323. doi:10.1007/S11239-020-02319-W

Anticoagulation reversal agent | ANDEXXA | For HCPs. Accessed January 22, 2023. https://www.andexxa.com/

Kessler

Goldstein

. A new strategy for uncontrollable bleeding after treatment with rivaroxaban or apixaban: Q&A. Clin Adv Hematol Oncol. 2019;17(9):16-17. https://www.hematologyandoncology.net/supplements/a-new-strategy-for-uncontrollable-bleeding-after-treatment-with-rivaroxaban-or-apixaban/. Accessed January 22, 2023.

10.

Bassand

Virdone

Badoz

, et al. Bleeding and related mortality with NOACs and VKAs in newly diagnosed atrial fibrillation: Results from the GARFIELD-AF registry. Blood Adv. 2021;5(4):1081-1091. doi:10.1182/BLOODADVANCES.2020003560

11.

van den Ham

Souverein

Klungel

, et al. Major bleeding in users of direct oral anticoagulants in atrial fibrillation: A pooled analysis of results from multiple population-based cohort studies. Pharmacoepidemiol Drug Saf. 2021;30(10):1339-1352. doi:10.1002/PDS.5317

12.

Deitelzweig

Lovelace

Christoph

Lingohr-Smith

Lin

Fermann

. Evaluation of the incremental healthcare economic burden of patients with atrial fibrillation treated with direct-acting oral anticoagulants and hospitalized for Major bleeds in the USA. Adv Ther. 2020;37(9):3942-3953. doi:10.1007/S12325-020-01440-9

13.

Beik

Reddy

Sylvester

, et al. Andexanet alfa (andexxa) formulary review. Crit Pathw Cardiol. 2019;18(2):66-71. doi:10.1097/HPC.0000000000000177

14.

Garrett

. Idarucizumab for dabigatran reversal. Drug Topics. 2015;159(8). doi:10.1056/NEJMOA1502000/SUPPL_FILE/NEJMOA1502000_DISCLOSURES.PDF

15.

Chen

Stecker

Warden

. Direct oral anticoagulant use: A practical guide to common clinical challenges. J Am Heart Assoc. 2020;9(13):17559. doi:10.1161/JAHA.120.017559

16.

Abdelnabi

Benjanuwattra

Okasha

Almaghraby

Saleh

Gerges

. Switching from warfarin to direct-acting oral anticoagulants: it is time to move forward! Egypt Hear J Off Bull Egypt Soc Cardiol. 2022;74(1). doi:10.1186/S43044-022-00259-9

17.

Costa

Beyer-Westendorf

Ashton

, et al. Effectiveness and safety of rivaroxaban versus warfarin in obese nonvalvular atrial fibrillation patients: Analysis of electronic health record data. Curr Med Res Opin. 2020;36(7):1081-1088. doi:10.1080/03007995.2020.1762554

18.

Gómez-Outes

Terleira-Fernández

Calvo-Rojas

Suárez-Gea

Vargas-Castrillón

. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: A systematic review and meta-analysis of subgroups. Thrombosis. 2013;2013:1-18. doi:10.1155/2013/640723

19.

Laslo

Bacalbasa

Stanescu

AMA

, et al. New oral anticoagulants—possible extension to other indications (review). Exp Ther Med. 2020;20(3):2401-2405. doi:10.3892/ETM.2020.8713

20.

Update on expanded indications for NOACs beyond stroke prevention. Accessed December 4, 2022. https://www.clinicaladvisor.com/home/topics/cardiovascular-disease-information-center/update-on-expanded-indications-for-noacs/

21.

Bezabhe

Bereznicki

Radford

, et al. Ten-Year trends in the use of oral anticoagulants in Australian general practice patients with atrial fibrillation. Front Pharmacol. 2021;12:441. doi:10.3389/FPHAR.2021.586370/BIBTEX

22.

Lippi

Mattiuzzi

Cervellin

Favaloro

. Direct oral anticoagulants: Analysis of worldwide use and popularity using google trends. Ann Transl Med. 2017;5(16):322-322. doi:10.21037/ATM.2017.06.65

23.

Wheelock

Ross

Murugiah

Lin

Krumholz

Khera

. Clinician trends in prescribing direct oral anticoagulants for US medicare beneficiaries. JAMA Netw Open. 2021;4(12):e2137288-e2137288. doi:10.1001/JAMANETWORKOPEN.2021.37288

24.

Navar

Kolkailah

Overton

, et al. Trends in oral anticoagulant use among 436 864 patients with atrial fibrillation in community practice, 2011 to 2020. J Am Heart Assoc. 2022;11:26723. doi:10.1161/jaha.122.026723

25.

Alalwan

Voils

Hartzema

. Trends in utilization of warfarin and direct oral anticoagulants in older adult patients with atrial fibrillation. Am J Heal Pharm. 2017;74(16):1237-1244. doi:10.2146/AJHP160756

26.

Lenglet

Qazi

Boivin Proulx

Legault

Dorais

Perreault

. Trends of use and factors that determine the choice of oral anticoagulants in women and men with atrial fibrillation. Pharmacol Res Perspect. 2022;10(6). doi:10.1002/PRP2.1012

27.

Vora

Morgan Stewart

Russell

Asiimwe

Brobert

. Time trends and treatment pathways in prescribing individual oral anticoagulants in patients with nonvalvular atrial fibrillation: An observational study of more than three million patients from Europe and the United States. Int J Clin Pract. 2022;2022:6707985. doi:10.1155/2022/6707985

28.

De Jong

Koops

Gout-Zwart

, et al. Trends in direct oral anticoagulant (DOAC) use: health benefits and patient preference. Published online 2012. Accessed December 4, 2022. www.ephor.nl

29.

Afzal

Zaidi

STR

Merchant

Babar

ZUD

Hasan

. Prescribing trends of oral anticoagulants in England over the last decade: A focus on new and old drugs and adverse events reporting. J Thromb Thrombolysis. 2021;52(2):646-653. doi:10.1007/S11239-021-02416-4

30.

Elewa

Alhaddad

Al-Rawi

Nounou

Mahmoud

Singh

. Trends in oral anticoagulant use in Qatar: A 5-year experience. J Thromb Thrombolysis. 2017;43(3):411-416. doi:10.1007/S11239-017-1474-4

31.

El Kadri

Bazargani

Farghaly

, et al. Profiling clinical characteristics and treatment patterns among non-valvular atrial fibrillation patients: A real-world analysis in Dubai, United Arab Emirates. Open Med J. 2019;6(1):33-41. doi:10.2174/1874220301906010033

32.

Alajami

Alshammari

Al-Dossari

, et al. Knowledge of anticoagulation among Saudi patients with atrial fibrillation: A cross-sectional study. Cureus. 2021;13(11). doi:10.7759/CUREUS.19237

33.

van der Hulle

Kooiman

den Exter

Dekkers

Klok

Huisman

. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: A systematic review and meta-analysis. J Thromb Haemost. 2014;12(3):320-328. doi:10.1111/jth.12485

34.

Chai-Adisaksopha

Crowther

Isayama

Lim

. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: A systematic review and meta-analysis. Blood. 2014;124(15):2450-2458. doi:10.1182/BLOOD-2014-07-590323

35.

Rubboli

Becattini

Verheugt

. Incidence, clinical impact and risk of bleeding during oral anticoagulation therapy. World J Cardiol. 2011;3(11):351. doi:10.4330/WJC.V3.I11.351

36.

Held

Hylek

Alexander

, et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: Insights from the ARISTOTLE trial. Eur Heart J. 2015;36(20):1264-1272. doi:10.1093/EURHEARTJ/EHU463

37.

Patel

Mahaffey

Garg

, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMOA1009638/SUPPL_FILE/NEJMOA1009638_DISCLOSURES.PDF

38.

Tittl

Marten

Naue

Beyer-Westendorf

. 5-year Outcomes from rivaroxaban therapy in atrial fibrillation: Results from the Dresden NOAC Registry. Thromb Res. 2021;202:24-30. doi:10.1016/J.THROMRES.2021.03.004

39.

Connolly

Eikelboom

Joyner

, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817. doi:10.1056/NEJMOA1007432/SUPPL_FILE/NEJMOA1007432_DISCLOSURES.PDF

40.

Yao

Abraham

Sangaralingham

, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc. 2016;5(6):1-18. doi:10.1161/JAHA.116.003725

41.

Lip

GYH

Kotalczyk

Teutsch

, et al. Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry. Clin Res Cardiol. 2022;111(5):560-573. doi:10.1007/s00392-022-01996-2

42.

Martínez

CAA

Lanas

Radaideh

, et al. XANTUS-EL: A real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation in Eastern Europe, Middle East, Africa and Latin America. Egypt Hear J. 2018;70(4):307-313. doi:10.1016/J.EHJ.2018.09.002

43.

De Groot

Weiss

Kelly

, et al. Edoxaban for stroke prevention in atrial fibrillation in routine clinical care: 1-year follow-up of the prospective observational ETNA-AF-Europe study. Eur Hear J—Cardiovasc Pharmacother. 2021;7(FI1):F30-F39. doi:10.1093/ehjcvp/pvaa079

44.

Briete

Towers

Bone

, et al. Perioperative anticoagulation management. Crit Care Nurs Q. 2022;45(2):119-131. doi:10.1097/CNQ.0000000000000395

45.

Bashawri

LAM

Ahmed

. The approach to a patient with a bleeding disorder: For the primary care physician. J Family Community Med. 2007;14(2):53-58.

46.

Schulman

Kearon

. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694. doi:10.1111/J.1538-7836.2005.01204.X

47.

Tomaselli

Mahaffey

Cuker

, et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants. J Am Coll Cardiol. 2020;76(5):594-622. doi:10.1016/j.jacc.2020.04.053

48.

Mehran

Rao

Bhatt

, et al. Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736-2747. doi:10.1161/CIRCULATIONAHA.110.009449

49.

Sang

Roest

de Laat

de Groot

Huskens

. Interplay between platelets and coagulation. Blood Rev. 2021;46:100733. doi:10.1016/j.blre.2020.100733

50.

Yang

Moosavi

. Prothrombin time; 2022.

51.

Samuelson

Cuker

Siegal

Crowther

Garcia

. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: A systematic review. Chest. 2017;151(1):127-138.

52.

Cuker

Siegal

Crowther

Garcia

. Laboratory measurement of the anticoagulant activity of the non–vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64(11):1128-1139.

53.

Dunois

. Laboratory monitoring of Direct Oral Anticoagulants (DOACs). Biomedicines. 2021;9(5):445. doi:10.3390/biomedicines9050445

54.

Samuelson

Cuker

. Measurement and reversal of the direct oral anticoagulants. Blood Rev. 2017;31(1):77-84. doi:10.1016/j.blre.2016.08.006

55.

van Gorp

Schurgers

. New insights into the pros and cons of the clinical use of Vitamin K Antagonists (VKAs) versus Direct Oral Anticoagulants (DOACs). Nutrients. 2015;7(11):9538-9557. doi:10.3390/nu7115479

56.

Siriez

Evrard

Dogné

, et al. Betrixaban: Impact on routine and specific coagulation assays—a practical laboratory guide. Thromb Haemost. 2018;118(7):1203-1214.

57.

Cuker

Husseinzadeh

. Laboratory measurement of the anticoagulant activity of edoxaban: A systematic review. J Thromb Thrombolysis. 2015;39(3):288-294.

58.

Harenberg

Krämer

Weiss

Krämer

. Concept of a point of care test to detect new oral anticoagulants in urine samples. Thromb J. 2013;11(1):15. doi:10.1186/1477-9560-11-15

59.

Harenberg

Martini

Krämer

Weiss

Hetjens

. Performance characteristics of DOAC dipstick in determining direct oral anticoagulants in urine. Clin Appl Thromb. 2021;27:107602962199355. doi:10.1177/1076029621993550

60.

Von Heymann

Rosenthal

Kaufner

Sander

. Management of direct oral anticoagulants-associated bleeding in the trauma patient. Curr Opin Anaesthesiol. 2016;29(2):220-228. doi:10.1097/ACO.0000000000000294

61.

Cuker

Burnett

Triller

, et al. Reversal of direct oral anticoagulants: Guidance from the anticoagulation forum. Am J Hematol. 2019;94(6):697-709. doi:10.1002/AJH.25475

62.

Witt

Nieuwlaat

Clark

, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-3291. doi:10.1182/BLOODADVANCES.2018024893

63.

Keeling

Tait

Watson

. British Committee of Standards for Haematology. Peri-operative management of anticoagulation and antiplatelet therapy. Br J Haematol. 2016;175(4):602-613. doi:10.1111/BJH.14344

64.

Andrade

Verma

Mitchell

, et al. 2018 Focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation. Can J Cardiol. 2018;34(11):1371-1392. doi:10.1016/J.CJCA.2018.08.026

65.

Christensen

Cordonnier

Kõrv

, et al. European stroke organisation guideline on reversal of oral anticoagulants in acute intracerebral haemorrhage. Eur Stroke J. 2019;4(4):294-306. doi:10.1177/2396987319849763

66.

Frontera

Lewin

Rabinstein

, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: A statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. doi:10.1007/S12028-015-0222-X

67.

Pollack

Reilly

van Ryn

, et al. Idarucizumab for dabigatran reversal — full cohort analysis. N Engl J Med. 2017;377(5):431-441. doi:10.1056/NEJMOA1707278/SUPPL_FILE/NEJMOA1707278_DISCLOSURES.PDF

68.

Connolly

Crowther

Eikelboom

, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326-1335. doi:10.1056/nejmoa1814051

69.

Majeed

Ågren

Holmström

, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: A cohort study. Blood. 2017;130(15):1706-1712. doi:10.1182/BLOOD-2017-05-782060

70.

Schulman

Gross

Ritchie

, et al. Prothrombin Complex concentrate for Major bleeding on factor Xa inhibitors: A prospective cohort study. Thromb Haemost. 2018;118(5):842-851. doi:10.1055/S-0038-1636541

71.

El-Bardissy

Elewa

Khalil

, et al. Assessing pharmacists knowledge and attitude toward the direct oral anticoagulants in Qatar. Clin Appl Thromb. 2020;26. doi:10.1177/1076029620933946/ASSET/IMAGES/10.1177_1076029620933946-FIG1.PNG

72.

Almegren

. Reversal of direct oral anticoagulants. Vasc Health Risk Manag. 2017;13:287-292. doi:10.2147/VHRM.S138890

73.

Backus

Beyer-Westendorf

Body

, et al. Management of major bleeding for anticoagulated patients in the Emergency Department: An European experts consensus statement. Eur J Emerg Med. 2023;30(5):315-323. doi:10.1097/MEJ.0000000000001049

74.

Foletti

Schmutz

Fleury

Magnin

Le Terrier

Guechi

. Bleeding on oral anticoagulants: Overview of reversal strategies. Swiss Med Wkly. 2023;153(2):40036. doi:10.57187/SMW.2023.40036

75.

Sié

. Spotlight on idarucizumab and its potential for the reversal of anticoagulant effects of dabigatran. Drug Des Devel Ther. 2016;10:1683. doi:10.2147/DDDT.S94167

76.

Schiele

Van Ryn

Canada

, et al. A specific antidote for dabigatran: Functional and structural characterization. Blood. 2013;121(18):3554-3562. doi:10.1182/BLOOD-2012-11-468207

77.

Pollack

Reilly

Bernstein

, et al. Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015;114(1):198-205. doi:10.1160/TH15-03-0192

78.

Crawley

Anderson

. Prevention and treatment of bleeding with direct oral anticoagulants. Drugs. 2020;80(13):1293-1308. doi:10.1007/s40265-020-01345-5

79.

Idarucizumab receives full FDA approval | MDedge Hematology and Oncology. Accessed December 6, 2022. https://www.mdedge.com/hematology-oncology/article/185007/thrombosis/idarucizumab-receives-full-fda-approval

80.

Fanikos

Murwin

Gruenenfelder

, et al. Global use of idarucizumab in clinical practice: Outcomes of the RE-VECTO surveillance program. Thromb Haemost. 2020;120(1):27-35. doi:10.1055/S-0039-1695771

81.

Abuan

Wong

Bolinske

Hale

. Andexanet alfa: A recombinant modified human factor Xa protein for drug reversal of rivaroxaban and apixaban. J Pharm Technol. 2019;35(3):119-125. doi:10.1177/8755122519839437

82.

Kaatz

Bhansali

Gibbs

Lavender

Mahan

Paje

. Reversing factor Xa inhibitors – Clinical utility of andexanet alfa. J Blood Med. 2017;8:141-149. doi:10.2147/JBM.S121550

83.

Siegal

Curnutte

Connolly

, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413-2424. doi:10.1056/NEJMOA1510991/SUPPL_FILE/NEJMOA1510991_DISCLOSURES.PDF

84.

Andexanet becomes first FDA-approved antidote for factor Xa inhibitors. Published online 2021.

85.

Milling

Middeldorp

, et al. Final study report of andexanet alfa for Major bleeding with factor Xa inhibitors. Circulation. 2023;147(13):1026-1038. doi:10.1161/CIRCULATIONAHA.121.057844

86.

Brown

Scott

Sridharan

Rabinstein

. Real-world utilization of andexanet alfa. Am J Emerg Med. 2020;38(4):810-814. doi:10.1016/J.AJEM.2019.12.008

87.

Sarode

Milling

Refaai

, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: A randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234-1243. doi:10.1161/CIRCULATIONAHA.113.002283

88.

Milling

Refaai

Sarode

, et al. Safety of a four-factor prothrombin Complex concentrate versus plasma for vitamin K antagonist reversal: An integrated analysis of two phase IIIb clinical trials. Academic Emergency Medicine. 2016;23:466-475. doi:10.1111/acem.12911

89.

Coleman

Dobesh

Danese

Ulloa

Lovelace

. Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: A multicenter study. Future Cardiol. 2021;17(1):127-135. doi:10.2217/FCA-2020-0073

90.

Nielsen

Larsen

Gorst-Rasmussen

Skjøth

Rasmussen

Lip

GYH

. Intracranial hemorrhage and subsequent ischemic stroke in patients with atrial fibrillation: A nationwide cohort study. Chest. 2015;147(6):1651-1658. doi:10.1378/CHEST.14-2099

91.

Lip

GYH

. Anticoagulation resumption after intracerebral hemorrhage. Curr Atheroscler Rep. 2018;20(7). doi:10.1007/S11883-018-0733-Y

92.

Murphy

Kuramatsu

Leasure

, et al. Cardioembolic stroke risk and recovery after anticoagulation-related intracerebral hemorrhage. Stroke. 2018;49(11):2652. doi:10.1161/STROKEAHA.118.021799

93.

Hemphill

Greenberg

Anderson

, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032-2060. doi:10.1161/STR.0000000000000069

94.

Biffi

Kuramatsu

Leasure

, et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017;82(5):755-765. doi:10.1002/ANA.25079

95.

Mujer

MTP

Rai

Atti

, et al. An update on the reversal of non-vitamin K antagonist oral anticoagulants. Adv Hematol. 2020;2020:1-10. doi:10.1155/2020/7636104

96.

Steffel

Verhamme

Potpara

, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330-1393. doi:10.1093/EURHEARTJ/EHY136

97.

Testa

Ageno

Antonucci

, et al. Management of major bleeding and outcomes in patients treated with direct oral anticoagulants: Results from the START-event registry. Intern Emerg Med. 2018;13(7):1051-1058. doi:10.1007/S11739-018-1877-Z/TABLES/5