DOAC - risk of bleeding

Risk of bleeding with DOACs

Direct-acting oral anticoagulants (DOACs) are approved for a variety of uses related to anticoagulation. Available DOACs include the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban and the direct thrombin inhibitor dabigatran etexilate.

Use of DOACs increases the risk of bleeding and can cause serious, potentially fatal, bleed

For this reason, DOACs should be used with caution in patients at increased risk of bleeding such as older people and patients with low body weight or renal impairment

• although routine anticoagulant monitoring is not required for DOACs as it is for vitamin K antagonists, patients (particularly those with an increased bleeding risk) should be made aware of the risk of bleeding and be routinely examined clinically for signs of bleeding or anaemia
• bleeding can occur at any site during treatment with DOACs
• increased risk of gastrointestinal bleeding with DOACs when used concomitantly with oral glucocorticoids; compared to use of DOACs alone
• treatment with DOACs should be discontinued if severe bleeding occurs

DOACs interact with a number of medicines, some of which increase bleeding risk. Refer to product information (Summaries of Product Characteristics linked to above) for advice on use of DOACs with other medicines

• DOACs should not be taken with other anticoagulants
• strong inhibitors of P- glycoprotein or CYP3A4 (or both) increase circulating levels of DOACs therefore may be not recommended or may require DOAC dose reduction

Management of bleeding and availability of reversal agents

• the product information for DOACs includes guidance on the management of bleeds and bleeding complications
• specific reversal agents are available for dabigatran ( idarucizumab) and apixaban and rivaroxaban (andexanet alfa) but there is currently no specific authorised reversal agent available for edoxaban (1)

A calibrated quantitative anti-Factor Xa (anti-FXa) assay may help to inform clinical decisions in exceptional situations about use of apixaban, edoxaban, or rivaroxaban, for example in overdose and emergency surgery

• however, use of anti-FXa assays should not be used to measure the effectiveness of andexanet alfa as the results may not be reliable

Treatment monitoring should be based mainly on clinical parameters indicative of appropriate response (achievement of haemostasis), lack of efficacy (re-bleeding), and adverse events (thromboembolic events).

Comparison of bleeding risk between DOACs (2):

• network meta-analysis of patients using DOACs or conventional therapy showed that apixaban reduced the risk for major GI bleeding compared to warfarin
  
  
  • compared with warfarin, apixaban showed a decreased the risk of major GI bleeding (relative risk [RR] 0.54, 95% confidence interval [CI] 0.25-.76), and rivaroxaban tended to increase this risk (RR 1.40, 95% CI 1.06-1.85)
  • dabigatran (RR 1.25, 95% CI 0.98-1.60), edoxaban (RR 1.07, 95% CI 0.69-1.65), and enoxaparin (RR 1.24, 95% CI 0.63-2.43) did not significantly increase the risk of GI bleeding than did warfarin
  • in the subgroup analysis, according to indications, apixaban showed a decreased risk of major GI bleeding (RR 0.50, 95% CI 0.34-0.74) than did warfarin in AF studies
  • dabigatran (RR 2.36, 95% CI 1.55-3.60, and rivaroxaban (RR 1.75, 95% CI 1.10-6.41) increased the risk of major GI bleeding than did apixaban
  • analysis of studies on venous thromboembolism or pulmonary embolism showed that no individual NOAC or enoxaparin was associated with an increased risk of major GI bleeding compared to warfarin
    
    
  • in conclusion:
    • in contrast, rivaroxaban increased the risk for major GI bleeding compared to warfarin
      
      
    • no association with increased GI bleeding was found with dabigatran, edoxaban, or enoxaparin compared to warfarin
      
      
    • in the subgroup analysis of patients with AF, apixaban significantly decreased the risk of major GI bleeding compared to warfarin. Similar GI bleeding rates were observed among the other individual NOACs

Use of non-steroidal anti-inflammatory drugs (NSAIDS) with anticoagulants after venous thromboembolism (4)

• study evidence showed that patients treated with oral anticoagulants for VTE had a more than two-fold increased bleeding rate when using NSAIDs. This increased bleeding rate was not restricted to the gastrointestinal tract

Reference:

1. MHRA (June 2020). Direct-acting oral anticoagulants (DOACs): reminder of bleeding risk, including availability of reversal agents.
2. Oh HJ, Ryu KH, Park BJ, Yoon BH.The risk of gastrointestinal hemorrhage with non-vitamin K antagonist oral anticoagulants: A network meta-analysis Medicine. 2021;100(11):e25216. doi: 10.1097/MD.0000000000025216
3. Holt A, Blanche P, Zareini B, et al.Gastrointestinal bleeding risk following concomitant treatment with oral glucocorticoids in patients on non-vitamin K oral anticoagulants.Heart Published Online First: 13 August 2021. doi: 10.1136/heartjnl-2021-319503.
4. Peterson SR et al. Bleeding risk using non-steroidal anti-inflammatory drugs with anticoagulants after venous thromboembolism: a nationwide Danish study, European Heart Journal, 2024; ehae736