What are the risk factors for bleeding on Direct Oral Anticoagulants (DOACs)?

From the Guidelines

Risk factors for bleeding on direct oral anticoagulants (DOACs) include advanced age, low body weight, renal impairment, liver disease, history of prior bleeding events, and concomitant use of antiplatelet drugs or other medications that affect hemostasis, as highlighted in the 2024 AHA/ACC/ACS/ASNC/HRS/SCA/SCCT/SCMR/SVM guideline for perioperative cardiovascular management for noncardiac surgery 1. These risk factors are crucial in assessing the overall risk of bleeding in patients on DOACs.

• Advanced age, especially over 75, is a significant risk factor due to decreased renal function and increased susceptibility to bleeding.
• Low body weight, less than 60kg, can also increase the risk of bleeding due to higher drug concentrations.
• Renal impairment, with creatinine clearance less than 50 mL/min, affects the elimination of most DOACs, potentially leading to increased drug levels and bleeding risk.
• Liver disease can affect the metabolism of some DOACs, altering their blood levels and increasing the risk of bleeding.
• A history of prior bleeding events is a strong predictor of future bleeding risk.
• Concomitant use of antiplatelet drugs, NSAIDs, or other medications that affect hemostasis can significantly increase the risk of bleeding in patients on DOACs. Additional risk factors include uncontrolled hypertension, alcohol abuse, recent surgery, frequent falls, and certain genetic factors affecting drug metabolism. Specific DOACs (apixaban, rivaroxaban, edoxaban, dabigatran) may have different bleeding risk profiles, with intracranial hemorrhage generally lower compared to warfarin but gastrointestinal bleeding sometimes higher, particularly with rivaroxaban and dabigatran, as noted in various studies 1. Drug interactions are important to monitor, especially with P-glycoprotein inhibitors like amiodarone, verapamil, and certain antibiotics, which can increase DOAC blood levels. Patients with multiple risk factors require careful monitoring, possible dose adjustments, or consideration of alternative anticoagulation strategies. Regular assessment of renal function is essential as most DOACs are partially eliminated by the kidneys, with dabigatran having the highest renal clearance at approximately 80%.

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. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of apixaban tablets The next dose of apixaban tablets should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Direct-acting oral anticoagulants (DOACs), including Apixaban Tablets, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS) For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardioplipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy

Risk factors for bleeding on DOACs include:

• Concomitant use of medicinal products affecting hemostasis 2
• Postoperative use of indwelling epidural catheters 2
• Traumatic or repeated epidural or spinal puncture 2
• Triple-positive antiphospholipid syndrome (APS) 2 3 The use of DOACs, including apixaban and dabigatran, may increase the risk of bleeding in these patients.

From the Research

Risk Factors for Bleeding on DOACs

• Severe renal impairment: Patients with severe renal impairment are at a higher risk of bleeding when taking DOACs, as these drugs are renally eliminated and can accumulate to toxic levels in patients with decreased renal function 4, 5.
• Elderly patients: Elderly patients are also at a higher risk of bleeding when taking DOACs, due to age-related changes in renal function and drug metabolism 6, 7.
• Concomitant use of other medications: The use of other medications that interact with DOACs, such as antiplatelet agents or other anticoagulants, can increase the risk of bleeding 6, 7.
• History of bleeding: Patients with a history of bleeding are at a higher risk of recurrent bleeding when taking DOACs 8, 5.
• Laboratory monitoring: The lack of laboratory monitoring for DOACs can make it difficult to detect bleeding complications early, increasing the risk of severe bleeding 6, 8.

Patient Subgroups at High Risk of Bleeding

• Patients with end-stage renal disease (ESRD): Patients with ESRD are at a higher risk of bleeding when taking DOACs, due to the accumulation of these drugs in the body 4, 5.
• Patients with cancer: Patients with cancer are at a higher risk of bleeding when taking DOACs, due to the increased risk of thrombosis and bleeding associated with cancer 6.
• Patients with chronic thromboembolic pulmonary hypertension: Patients with chronic thromboembolic pulmonary hypertension are at a higher risk of bleeding when taking DOACs, due to the increased risk of thrombosis and bleeding associated with this condition 6.