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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

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. 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

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

Abstract

Keywords

Introduction

Review Development

DOACs Indications and Rates of Major Bleeding

Diagnosis and Classification of DOACs-Associated Bleeding

Management of Major Bleeding

Specific Reversal Antidotes

Dabigatran Reversal Antidote

Factor Xa Inhibitor Reversal

Nonspecific Procoagulants

Continuing DOACs After Major Bleeding

Major Bleeding Where Specific Antidotes are Unavailable: An Expert Perspective

Conclusion

Footnotes

Acknowledgment

Declaration of Conflicting Interests

Funding

ORCID iD

References