From the Guidelines
Anticoagulants carry a significant risk of bleeding, with the annual risk of major bleeding being around 2-3% for warfarin and slightly lower for direct oral anticoagulants (DOACs), as evidenced by a meta-analysis of VKA-associated bleeding which reported a rate of major hemorrhage of 2.06% during the initial 3 months of therapy 1. The risk of bleeding associated with anticoagulants is a critical consideration in their use, and it is influenced by several factors including the type of anticoagulant, patient characteristics, and the presence of comorbidities. Key factors that increase the risk of bleeding include:
- Advanced age, particularly over 70 years
- Previous bleeding episodes
- Increased or variable intensity of anticoagulation
- Comorbidities such as renal or hepatic impairment
- Concomitant use of drugs that affect hemostasis, such as aspirin, clopidogrel, or NSAIDs
- Duration of therapy, with longer durations increasing the risk of bleeding
According to a study published in the Journal of Thrombosis and Haemostasis, the risk of oral anticoagulant-associated bleeding is likely to be low in patients with a target INR of 2.5, younger patients, those who do not require long-term treatment with drugs that affect hemostasis, and patients who have not had episodes of overanticoagulation or suffered bleeding during the initial 3 to 6 months of therapy 1. In contrast, another study published in the Journal of the American College of Cardiology reported that the risk of major bleeding during oral anticoagulant therapy is 3% per year with an annual case fatality rate of 0.6% 1. The decision to use anticoagulants should be based on a careful assessment of the individual patient's risk of bleeding versus their risk of thrombotic events, with consideration of the potential benefits and harms of anticoagulant therapy 1. Regular monitoring of anticoagulation therapy, particularly for warfarin, is essential to minimize the risk of bleeding, and patients should be educated to recognize signs of bleeding and seek medical attention promptly if they occur. In case of serious bleeding, specific reversal agents are available, such as vitamin K and prothrombin complex concentrate for warfarin, idarucizumab for dabigatran, and andexanet alfa for factor Xa inhibitors. Ultimately, the goal of anticoagulant therapy is to balance the risk of bleeding against the risk of thrombotic events, with individualized assessment and management for each patient.
From the FDA Drug Label
The concomitant use of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on apixaban from 1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7% per year to 4.6% per year. Use of anticoagulants, including apixaban, may increase the risk of bleeding in the fetus and neonate. Use of anticoagulants, including dabigatran etexilate capsules, may increase the risk of bleeding in the fetus and neonate.
The risk of bleeding associated with the use of anticoagulants is increased, especially when combined with other medications such as antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use.
- The rate of major bleeding with apixaban was 2.8% per year with single antiplatelet therapy and 5.9% per year with dual antiplatelet therapy in the APPRAISE-2 trial.
- Concomitant use of aspirin increased the bleeding risk on apixaban from 1.8% per year to 3.4% per year in the ARISTOTLE trial.
- The use of anticoagulants, including apixaban and dabigatran, may increase the risk of bleeding in the fetus and neonate 2, 3. Key points:
- Increased risk of bleeding with anticoagulant use
- Higher risk of bleeding with concomitant use of other medications
- Risk of bleeding in fetus and neonate with anticoagulant use
From the Research
Risk of Bleeding Associated with Anticoagulants
- The risk of bleeding complications in patients on novel oral anticoagulants (NOACs) who underwent joint injections and arthrocentesis is relatively low, with only one patient experiencing a bleeding complication out of 668 patients 4.
- The incidence of hospitalization for upper gastrointestinal tract bleeding is higher in patients prescribed rivaroxaban compared to those prescribed apixaban, dabigatran, or warfarin 5.
- The risk of gastrointestinal bleeding associated with dabigatran and rivaroxaban is similar to that of warfarin in patients with and without atrial fibrillation 6.
- The risk of nonmajor bleeding is lowest for apixaban, followed by low-molecular weight heparin, dabigatran, edoxaban, and rivaroxaban for preventing venous thromboembolism (VTE) 7.
- The use of proton pump inhibitor (PPI) cotherapy with anticoagulants can lower the risk of upper gastrointestinal tract bleeding hospitalizations 5.
Comparison of Bleeding Risks Among Anticoagulants
- Apixaban has a lower risk of nonmajor bleeding compared to other anticoagulants, including dabigatran, edoxaban, and rivaroxaban 7.
- Rivaroxaban has a higher incidence of hospitalization for upper gastrointestinal tract bleeding compared to apixaban, dabigatran, and warfarin 5.
- Dabigatran and rivaroxaban have a similar risk of gastrointestinal bleeding as warfarin in patients with and without atrial fibrillation 6.