Direct-acting oral anticoagulants (DOACs): reminder of bleeding risk, including availability of reversal agents
Remain vigilant for signs and symptoms of bleeding complications during treatment with DOACs (apixaban, dabigatran, edoxaban, rivaroxaban), especially in patients with increased bleeding risks. Specific reversal agents are available for dabigatran (Praxbind▼, idarucizumab), and apixaban and rivaroxaban (Ondexxya▼, andexanet alfa).
Post-publication note
Updates to advice regarding prescribing in patients with renal impairment, including a revised version of table 1, were published in Drug Safety Update, May 2023.
Advice for healthcare professionals:
-
use caution if prescribing direct-acting oral anticoagulants (DOACs) to patients at increased risk of bleeding (for example, older people or people with renal impairment)
-
remain vigilant for signs and symptoms of bleeding complications during treatment, especially patients with increased bleeding risk
-
remind patients of the signs and symptoms of bleeding and encourage them to always read the patient information leaflet that accompanies their medicines
-
ensure patients with renal impairment receive an appropriate dose (see advice below) and monitor renal function during treatment to ensure dose remains appropriate
-
specific DOAC reversal agents are available for dabigatran, apixaban, and rivaroxaban
-
monitor the reversal effects of andexanet alfa using clinical parameters; anti-FXa assays should not be used to measure the effectiveness of andexanet alfa as the results may not be reliable
-
report suspected adverse drug reactions associated with DOACs on a Yellow Card, including thromboembolic or haemorrhagic events
Risk of bleeding with DOACs
Direct-acting oral anticoagulants (DOACs) are approved for a variety of uses related to anticoagulation (see full indications in further information section). Available DOACs include the direct factor Xa inhibitors apixaban (Eliquis), edoxaban (Lixiana▼), and rivaroxaban (Xarelto▼) and the direct thrombin inhibitor dabigatran etexilate (Pradaxa).
Use of DOACs increases the risk of bleeding and can cause serious, potentially fatal, bleeds. We continue to receive reports of bleeds, often life-threatening or fatal, in association with DOACs in patients in the UK. In many reported cases, patients have underlying factors that suggest they are at increased risk of bleeding events.
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. 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. Of note, 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.
Dose of DOACs depends on renal function
Exposure to DOACs is increased in patients with renal impairment and it is therefore important that patients receive an appropriate dose depending on renal function. Calculate creatinine clearance (CrCl) in order to determine renal function for dosing of DOACs. Estimated glomerular filtration rate (eGFR) can overestimate renal function and increase the risk of bleeding events (see Drug Safety Update).
Dose adjustment may be necessary if renal function significantly changes during treatment. The product information for dabigatran and edoxaban advises to assess renal function if a decline in function is suspected during treatment (for example, due to hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).
DOACs can be used in patients with moderate renal impairment (creatinine clearance of 30mL/min or higher) but a reduced dose may be required depending on the indication. In patients with severe renal impairment (creatinine clearance of lower than 30mL/min) use of dabigatran is contraindicated, while other DOACs should be used with caution or at a reduced dose. Refer to table 1 and product information for specific dosing recommendations.
Table 1 - Recommendations for use of DOACs in patients with renal impairment
| Severity of renal impairment (creatinine clearance) | Dabigatran | Apixaban | Edoxaban | Rivaroxaban |
|---|---|---|---|---|
| End stage (<15 CrCl mL/Min) | Contraindicated | Not recommended | Not recommended | Not recommended |
| Severe (≤29 CrCl mL/Min) | Contraindicated | To be used with caution in some indications; dose reduction is required for other indications | Dose reduction required in all indications | Use with caution in all indications. Dose adjustment is required or should be considered in some indications |
| Moderate (30–50 CrCl mL/Min) | Dose adjustment required or should be considered in some indications | Dose reduction is required in some indications* | Dose reduction required in all indications | Dose adjustment required or should be considered in some indications |
| Mild (51–80 CrCl mL/Min) | No dose adjustment required | Dose reduction is required in some indications* | No dose adjustment required | No dose adjustment required |
| >80 CrCl mL/Min | No dose adjustment required | No dose adjustment required | Should only be used in some indications after a careful evaluation of the individual thromboembolic and bleeding risk | No dose adjustment required |
*In patients with serum creatinine ≥1.5mg/dL (133micromole/L) associated with age ≥80 years or body weight ≤60kg.
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 (Praxbind▼, idarucizumab) and apixaban and rivaroxaban (Ondexxya▼, andexanet alfa) but there is currently no specific authorised reversal agent available for edoxaban.
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).
Further information about DOACs
DOACs are oral anticoagulants that are increasingly used in UK clinical practice. DOACs are indicated for:
- prevention of atherothrombotic events in adult patients after an acute coronary syndrome with elevated cardiac biomarkers when co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine (2.5mg rivaroxaban only)
- prevention of atherothrombotic events in adult patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events when co-administered with ASA (2.5mg rivaroxaban only)
- prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery (dabigatran, apixaban and rivaroxaban)
- prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age of 75 years and older, diabetes mellitus, prior stroke or transient ischaemic attack (all DOACs)
- treatment of deep vein thrombosis and pulmonary embolism, and prevention of recurrent events in adults (all DOACs)
DOACs are not recommended in patients with antiphospholipid syndrome. Dabigatran is contraindicated and other DOACs are not recommended in patients with prosthetic heart valves.
Report adverse drug reactions on a Yellow Card
Rivaroxaban (Xarelto▼) and edoxaban (Lixiana ▼) are subject to additional monitoring, and so any suspected adverse drug reactions should be reported to the Yellow Card Scheme. For all DOACs, serious suspected adverse drug reactions, including thromboembolic or haemorrhagic events, should be reported on a Yellow Card.
Any suspected adverse drug reactions associated with any medicine used in patients with confirmed or suspected coronavirus (COVID-19), including medicines to manage long-term or pre-existing conditions such as DOACs, should be reported to the COVID-19 Yellow Card reporting site. By reporting suspected side effects of any medicines used in the context of COVID-19, healthcare professionals can provide valuable evidence to inform decisions on the safe and effective use of medicines as the pandemic evolves.
Article citation: Drug Safety Update volume 13, issue 11: June 2020: 2.