What are the risks of bleeding associated with Direct Oral Anticoagulants (DOACs)?

From the Guidelines

Direct oral anticoagulants (DOACs) like apixaban, rivaroxaban, edoxaban, and dabigatran carry a significant risk of bleeding, though generally lower than warfarin, with major bleeding occurring in approximately 2-3% of patients annually, as reported in the 2024 ESC guidelines for the management of atrial fibrillation 1. The risk of bleeding on DOACs can be minimized by proper dosing based on age, weight, and kidney function, as well as regular monitoring of kidney function and avoiding unnecessary concomitant antiplatelet therapy.

• Temporarily stopping DOACs before surgical procedures can also reduce risks, with the timing of interruption depending on the type of procedure and the patient's renal function, as outlined in the 2024 AHA/ACC/ACS/ASNC/HRS/SCA/SCCT/SCMR/SVM guideline for perioperative cardiovascular management for noncardiac surgery 1.
• Unlike warfarin, most DOACs have shorter half-lives (8-14 hours), which can be advantageous if bleeding occurs.
• For severe bleeding on DOACs, specific reversal agents exist: idarucizumab for dabigatran and andexanet alfa for factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), though these may not be available at all facilities. The bleeding risk associated with DOACs is influenced by various factors, including:
• Patient characteristics, such as age, renal function, and history of bleeding
• Type of DOAC used, with some studies suggesting differences in bleeding risk between agents, as reported in the British Thoracic Society guideline for the initial outpatient management of pulmonary embolism 1
• Concomitant use of other medications that may interact with DOACs, such as antifungals, antibiotics, and antiplatelet drugs. To minimize bleeding complications, a team-based approach to perioperative management is recommended, taking into account the individual patient's risk factors and the type of procedure being performed, as emphasized in the 2024 AHA/ACC/ACS/ASNC/HRS/SCA/SCCT/SCMR/SVM guideline 1.

From the FDA Drug Label

The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleeding rate (percentage of subjects with at least one bleeding event per 100 patient-years) in ARISTOTLE and AVERROES Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE* Apixaban N=9088 n(per 100 pt-year) Warfarin N=9052 n(per 100 pt-year) Major † 327(2.13) 462(3.09) The most serious adverse reactions reported with dabigatran etexilate capsules were related to bleeding [see Warnings and Precautions (5.2)]. Table 3 shows the number of adjudicated major bleeding events during the treatment period in the RE-LY study, with the bleeding rate per 100 subject-years (%).

Risks of bleeding on DOACs include:

• Major bleeding events, such as intracranial hemorrhage, gastrointestinal bleeding, and fatal bleeding
• Increased risk of bleeding with concomitant use of medicinal products affecting hemostasis
• Increased risk of bleeding with postoperative use of indwelling epidural catheters
• Bleeding rates per 100 patient-years, ranging from 2.13% for apixaban to 3.09% for warfarin in the ARISTOTLE study The use of DOACs, including apixaban and dabigatran, is associated with a risk of bleeding, which can be major and potentially life-threatening 2, 2, 3.

From the Research

Risks of Bleeding on DOACs

• The risk of bleeding complications is associated with direct oral anticoagulants (DOACs) due to the DOAC itself, acute trauma, invasive procedures, or underlying comorbidities 4.
• DOACs are associated with similar or lower risk of bleeding compared with warfarin, but the need for reversal of their anticoagulant effect may occur in patients with life-threatening bleeding or those requiring urgent surgery 5.
• The use of DOACs is associated with the risk of bleeding events, and the rates of major bleeding were significantly lower for some DOACs and treatment doses than for warfarin 6.

Bleeding Risk Factors

• Add-on anti-platelet agents to DOACs in patients with nonvalvular atrial fibrillation may increase the bleeding risk 7.
• The postoperative bleeding risk of DOACs after oral surgery procedures is significantly greater than in healthy patients, especially for rivaroxaban 8.
• The risk of bleeding complications may be managed by withdrawing the DOAC, waiting and supporting the patient, or using specific reversal agents such as idarucizumab for dabigatran-treated patients 4.

Reversal Strategies

• Idarucizumab is a specific reversal agent for dabigatran, and andexanet alfa is a reversal agent for factor Xa inhibitors 5.
• Prothrombin complex concentrates may be used in patients with life-threatening bleeding in the absence of licensed reversal agents for oral factor Xa inhibitors 5.
• Vitamin K and fresh frozen plasma should not be used to reverse DOACs 5.