Direct oral anticoagulants (DOACs) have provided a practical option for people requiring anticoagulation for several indications for over a decade now. Their advantages include a more predictable effect than vitamin K antagonists such as warfarin, with infrequent monitoring requirements, regular fixed doses, no food or drink interactions and few drug interactions (Baglin 2013). Four DOACs are currently licensed for use in the UK: dabigatran etexilate, rivaroxaban, apxixaban and edoxaban. National clinical guidelines now promote DOACs as first line treatment for venous thromboembolism (VTE) and prevention of stroke in non-valvular atrial fibrillation (AF).
The landmark phase III clinical trials of all four DOACs showed similar efficacy and safety to warfarin, with significantly reduced risk of intracranial haemorrhage (Raschi et al 2016). Real-world registry data has largely reflected these clinical trial findings, providing reassurance that these medicines offer a safe and practical option for patients requiring anticoagulation (Beyer-Westendorf et al 2013, Agnelli et al 2015, Camm et al 2016, Hecker et al 2016).
DOACs are high-risk medicines with the potential to cause harm, it is therefore important that clinicians initiating and managing these medications are trained and supported to provide safe and effective care to minimise risk to patients (National Patient Safety Alert 2007). This article aims to support practice nurses to do this by outlining the indications for use, properties, side effects and monitoring associated with DOACs.
What are DOACs used for?
Non-Valvular Atrial fibrillation
Atrial fibrillation (AF) is commonest reason for anticoagulation treatment to be indicated. It is a relatively common arrhythmia with approximately 25% of people over the age of 40 years developing AF in their lifetime (Staerk et al 2018). AF is associated with a prothrombotic state that increases risk of stroke in a multitude of ways. AF can lead to blood stasis within the atria, which increases the risk of thrombus formation, particularly within the atrial appendage. A thrombus can travel from the heart into the cerebral and peripheral circulation leading to thromboembolic complications including ischaemic stroke (Violi et al 2014). Additionally, changes in the atrial wall and to the coagulation and platelet pathways in AF contribute to the hypercoagulable state (Kahn & Yip 2019). AF related strokes make up 20-30% of all strokes and tend to cause more mortality, morbidity and disability than non-AF strokes (Jones et al 2018). Valvular AF is defined as involving either a mechanical heart valve or moderate to severe mitral stenosis. DOACs are not licensed in these situations at present (Kirchhof 2016).
Anticoagulation reduces the risk of stroke by approximately 65% (Kirchhof 2016). The decision to anticoagulate will involve careful consideration of individual risk factors for stroke against bleeding risk factors using risk stratification tools such as CHADs-VASc to calculate individual stroke risk and ORBIT for bleeding risk (NICE 2021).
Venous thromboembolism
DOACs are now the first line treatment for venous thromboembolism (VTE) in the UK (NICE 2020). VTE is the umbrella term used to describe deep vein thrombosis (DVT) and pulmonary embolism (PE). A DVT is a blood clot in any deep vein in the body, but commonly of the legs, pelvis and arms. The clot can partially or fully occlude the blood vessel and can lead to development of a PE if part of the clot breaks away, or if the whole clot moves from the vessel it originated from. When this occurs, the thrombus is termed an embolus. It may travel through the right side of the heart and lodge in the pulmonary arteries of the lungs, resulting in a PE. VTEs should be treated with at least three months of anticoagulation, although in some cases anticoagulation therapy will be lifelong, particularly if the VTE was unprovoked or if major VTE risk factors persist, such as cancer (NICE 2020).
NICE guidance suggests offering patients with newly diagnosed VTE either rivaroxaban or apixaban as first line treatment for VTE since these can be given with higher initial loading doses that negate the need for low molecular weight heparin (LMWH). If neither option is suitable, edoxaban or dabigatran can be considered after 5 days of LMWH. If DOACs are contraindicated, such as in severe renal impairment or liver failure, traditional therapy with vitamin K antagonists such as warfarin should be considered.
Cancer-associated thrombosis
When compared with LMWH, the previous standard of treatment for cancer associated thrombosis, edoxaban, rivaroxaban and apixaban had favourable outcomes in treating cancer associated thrombosis for selected patient groups (Raskob et al 2018, Young et al 2018, Agnelli et al 2020). International guidelines now reflect this (Khorana et al 2018, Key et al 2020), however, not all patients with cancer-associated thrombosis are suitable for a DOAC.
Consideration of individual bleeding risk, type of cancer and possible drug:drug interactions needs to be made. Risk factors for bleeding include previous history of bleeding, low platelet count and renal impairment (Carrier et al 2018). The clinical trials found DOACs to be associated with a higher risk of mucosal bleeding and should therefore be avoided in gastrointestinal or genitourinary cancers where LMWH should be used instead (Khorana et al 2018). Chemotherapy drugs and other cancer medications should be checked for interactions with the DOACs. Local guidelines and specialist advice should be sought when making clinical decisions about anticoagulation in cancer-associated thrombosis.
Other indications
DOACs were first licensed in the UK for thromboprophylaxis following orthopaedic surgery. The phase III clinical trials assessed the DOACs (dabigatran, rivaroxaban and apixaban) to be non-inferior to 40mg enoxaparin at preventing VTE after hip and knee arthroplasty, with similar bleeding rates (Eriksson et al 2007a, 2007b, 2008, Kakkar et al 2008, Lassen et al 2008, 2009, 2010a, 2010b, Turpie et al 2009). NICE (2019a) guidelines recommend offering patients with extended thromboprophylaxis following total hip replacement (28 days) and total knee replacement (14 days) with the choice of using LMWH, aspirin (after 10 days of LMWH in hip arthroplasty), rivaroxaban, apixaban or dabigatran.
Rivaroxaban is licensed for some additional indications such as acute coronary syndrome (ACS) (unstable angina and myocardial infarction). In patients with ACS, rivaroxaban can be used in combination with aspirin plus clopidogrel or aspirin alone for prevention of further atherothrombotic events (NICE 2015). Patients should be reassessed within a year to determine treatment duration due to the increased risk of bleeding associated with this treatment regime (Mega et al 2012), that is responsible for its limited uptake.
More recently, rivaroxaban has been approved for use in combination with aspirin in people with coronary or peripheral artery disease for prevention of atherothrombotic events (NICE 2019b). The clinical trial (Eikelboom et al 2017) found favourable outcomes for patients with coronary and peripheral artery disease when taking 2.5mg rivaroxaban twice daily and 100mg aspirin compared with those taking 100mg aspirin alone.
Table 1. Direct oral anticoagulants indications
| Dabigatran etexilate | Rivaroxaban | Apixaban | Edoxaban | |
|---|---|---|---|---|
| Thromboprophylaxis post hip and knee replacement | ✓ | ✓ | ✓ | X |
| Stroke prevention in non-valvular atrial fibrillation | ✓ | ✓ | ✓ | ✓ |
| Treatment of venous thromboembolism | ✓ | ✓ | ✓ | ✓ |
| Acute coronary syndrome | X | ✓ | X | X |
| Coronary artery disease and peripheral artery disease | X | ✓ | X | X |
Table 2. Doses and dosing adjustments for the direct oral anticoagulants (DOACs)
| DOAC | Dose in atrial fibrillation (AF) | Dose in acute venous thromboembolism (VTE) | Dose for secondary prevention VTE | Creatinine clearance cut-off before use contraindicated | Dose adjustments required | Administration considerations | Contraindicated with the following drugs |
|---|---|---|---|---|---|---|---|
| Apixaban | 5mg twice daily | 10mg twice daily for seven days then 5mg twice daily | 2.5mg twice daily | 15mL/min | AF: reduce the dose to 2.5 mg twice daily if two or more of the following apply:Age ≥80 years.Body weight ≤60kg Serum creatinine ≥133μmol | Can be crushed, suspended in water and administered orally or via nasogastric tube.Suitable for use in dosette boxes. | Ketoconazole Itraconazole Voriconazole HIV (human immunodeficiency virus) protease inhibitors, for example ritonavir Rifampicin Phenytoin Carbamazepine Phenobarbital St John's wort |
| Edoxaban | 60mg once daily | Five days of LMWH then 60mg once daily | 60mg once daily | 15mL/min | AF and VTE: reduce dose to 30mg once daily if one or more of the following apply:Renal impairment (creatinine clearance 15-50mL/min)Body weight <60kgConcomitant P-glycoprotein inhibitors | Can be administered without foodSuitable for patients with lactose intolerance.Suitable for use in dosette boxes. | Reduce dose to 30mg daily with concomitant:Ciclosporin Dronedarone Erythromycin Ketoconazole |
| Rivaroxaban | 20mg once daily | 15mg twice daily for 21 days then 20mg once daily | 10 mg once daily or 20 mg once daily | 15mL/min | AF: reduce dose to 15 once daily if renal impairment (15-49mL/min)VTE: reduce dose to 15 once daily if renal impairment (15-49mL/min) if bleeding risk outweighs risk of recurrence | Must be taken with food. Can be crushed, suspended in water and administered orally. Can also be administered via nasogastric tube followed immediately by enteral feed.Suitable for use in dosette boxes. | Ketoconazole Itraconazole Voriconazole HIV protease inhibitors, for example ritonavir Rifampicin PhenytoinCarbamazepine Phenobarbital St John's wort |
| Dabigatran etexilate | 150mg twice daily | Five days of LMWH then 150mg twice daily | 150mg twice daily | 30mL/min | AF and VTE: 110mg twice daily if moderate renal impairment or on concomitant verapamilAge ≥80 years | Capsules must not be opened.Capsules cannot be added to a dosette box | Ketoconazole Cyclosporine Itraconazole Dronedarone Tacrolimus Ritonavir Rifampicin St John's wort Carbamazepine Phenytoin |
When are DOACs not licensed?
At present, vitamin K antagonists such as warfarin remain the mainstay of treatment for patients with mechanical heart valves and antiphospholipid syndrome due to adverse outcomes with DOACs in clinical trials (Eikelboom et al 2013, Dufrost 2020). LMWH remains the drug of choice for patients requiring anticoagulation during pregnancy and LMWH or warfarin can be used during breastfeeding, although work is ongoing to assess the safety of DOACs in this setting (Cohen et al 2016).
Although not licensed, DOACs are increasingly being used to treat left ventricular thrombus with increasing evidence that they are non-inferior to VKAs for this indication (Chen et al 2022). This shift in practice is not yet reflected in national guidance, as such local protocols must be adhered to regarding off-label prescribing.
How do DOACs work?
All anticoagulants work by interrupting the clotting system within the body. The clotting cascade is a complex series of reactions whereby protein enzymes known as clotting factors become activated. Once activated, they trigger activation of other clotting factors in a sequential fashion, eventually resulting in the formation of fibrin. Fibrin strands form a net type of structure to secure and stabilise a blood clot (Palta et al 2014).
Unlike warfarin, which works on clotting factors II, VII, IX and X, the DOACs target a single clotting factor, making them much more predictable in their effects and enabling fixed dosing without regular monitoring. Rivaroxaban, edoxaban and apixaban all inhibit factor Xa, the activated version of factor X. All three drug names feature ‘xa’ which is helpful in remembering this. Factor Xa is the where the two clotting cascade pathways (intrinsic and extrinsic) meet and signals the start of the common pathway. Inhibiting the action of factor Xa results in reduced thrombin generation (Cabral and Ansell 2015). Thrombin is responsible for activating platelets and converting soluble fibrinogen to insoluble fibrin.
Dabigatran is a direct thrombin inhibitor, and therefore works a little further down the clotting cascade than the Factor Xa inhibitors. Like the Xa inhibitors, it's action ultimately results in less fibrin being formed.
The DOACs all have a standard treatment dose, suitable for most patients for VTE treatment and stroke prevention in AF, and a reduced dose, usually indicated for patients with renal impairment or frailty. Additionally, acute treatment for VTE with rivaroxaban and apixaban includes a higher initial loading dose. Lower prophylactic doses are indicated for thromboprophylaxis in the context of hip and knee arthroplasty. Table two summarises the DOAC doses in the UK as well as administration considerations and drug interactions.
Side effects and risks
Although the DOACs are generally well tolerated by patients, the most common side-effects observed with them include dizziness, headache, nausea, rash, pruritis, hypotension, increased liver function tests and dyspepsia with dabigatran (EMC 2019, 2020a, 2020b, 2020c). If tolerable in the short term, headaches and dizziness often resolve within the first few weeks. Where side effects are unable to be tolerated, switching to an alternative DOAC could be considered, failing that, the traditional regime of warfarin may be necessary (plus LMWH bridging if new VTE). Due to their mechanism of action, all anticoagulants carry an increased risk of bleeding and patients should be carefully assessed for their individual bleeding risks and counselled about measures to reduce their risk as well as clear guidance for what to do if they do experience any bleeding. Risk factors that increase the risk of bleeding include advanced age; history of bleeding or anaemia; active cancer; previous stroke; chronic renal or liver disease; hypertension; acute or chronic illness; excess alcohol intake; and certain concomitant medicines (Pisters 2010, Konstantinides et al 2020).
Bleeding rates in the landmark DOAC clinical trials for atrial fibrillation and VTE were similar to warfarin or LMWH and warfarin respectively (Connolly et al 2009, Patel et al 2011, Granger et al 2011, Giugliano et al 2013, Agnelli et al 2013, Bauersachs et al 2010, Buller et al 2014, Schulman et al 2009).
Bleeding occurs in around 20% of people on DOACs (Hellenbart et al 2017). This is often minor bleeding such as epistaxis or gingival bleeding, will usually be self-limiting and rarely serious. Major bleeding such as gastrointestinal, genitourinary and intracranial bleeding occurs in around 1-4% of people taking DOACs (Hellenbart et al 2017). Patients should be encouraged to report any unusual bleeding since DOACs do not cause spontaneous bleeding, rather they may unmask existing pathology such as occult malignancy (Ording et al 2021). When commencing a DOAC, patients should be counselled that in the event of any major bleeding, they should stop treatment immediately and attend the nearest emergency department for urgent treatment.
Patients should also be counselled to avoid using non-steroidal anti-inflammatory drugs (NSAIDs) whilst on a DOAC as persistent use can increase bleeding risk. Indication for concomitant antiplatelet therapy should be reviewed when initiating DOACs and where possible, stopped. If patients need to continue anti platelet therapy, they should be counselled regarding the associated increased risk of bleeding. Where dual antiplatelet therapy in AF is necessary, the lowest DOAC dose for stroke prevention should be applied if the patient is at increased risk of bleeding (European Society of Cardiology 2019).
Peri-operative planning
Management of DOACs around invasive procedures or surgery needs to be considered to optimally reduce the risk of both bleeding and thrombosis. Individual assessment of the bleeding and thrombosis risks of both the patient and the surgery or procedure is required. DOACs do not always need to be stopped for low bleeding risk procedures but it is sensible to perform them at trough drug concentration levels wherever possible. For interventions that carry a higher bleeding risk, DOACs may need to be paused for 24-48 hours beforehand (may be longer in renal impairment) (Sunkara et al 2016). National guidance exists to inform best practice (Keeling et al 2016), but local policies and procedures should always be followed, and specialist advice sought when necessary.
Drug Interactions
Far fewer drug interactions exist with the DOACs than with warfarin but there are some important ones to be aware of. DOAC drug interactions are linked to the action of cytochrome P450 3A4 (CYP3A4) enzymes, found in the liver and responsible for the metabolism of many drugs and p-glycoprotein (P-gp), transporter proteins that enable the uptake and removal of many drugs and are predominantly located in the intestines. Drugs that are inducers of CYP 3A4 and/or P-gp increase their activity and therefore may decrease the plasma levels of the DOAC. Examples of these drugs include phenytoin, carbamazepine, phenobarbital, St John's wort and rifampicin. Conversely, drugs that inhibit the actions of CYP 3A4 and/or P-gp may increase plasma levels of the DOAC, these include dronedarone, erythromycin, HIV protease inhibitors (such as ritonavir) and azole antimycotics (such as ketoconazole) (Wiggins et al 2020). The relevant DOAC summary of product characteristics should be checked for drug interactions before prescribing.
Monitoring in general practice
A major benefit of the DOACs is that they do not require regular laboratory coagulation monitoring, however, to optimise safety, it is recommended that patients be reviewed and assessed regularly (NICE 2023). Frequency of review will depend on the patient's individual circumstances but should be at least annually. This provides an opportunity to assess for adverse effects, check adherence, ensure the drug and dose are still appropriate, check that anticoagulation is still indicated and give relevant information and advice. Although routine drug level assay monitoring is not recommended, full blood count and renal and liver function tests should be performed annually, or more frequently in the context of renal or liver impairment or increased bleeding risk.
Conclusion
The DOACs are now commonplace in the treatment of VTE and for stroke prevention in AF. They are generally very well tolerated but the inherent risk of bleeding associated with all anticoagulants make DOACs high risk drugs. It is important that health care professionals caring for patients on DOAC therapy are proficient at assessing an individual's risk of bleeding and have a good understanding of the various nuances between the four DOACs. General practice is an ideal setting for initiation and management of DOACs, enabling a holistic and multi-disciplinary approach to be adopted for the benefit of the patient.
KEY POINTS
- Four DOACs are licensed in the UK for treatment of VTE and stroke prevention in AF, dabigatran, rivaroxaban, apixaban and edoxaban
- DOACs are contraindicated in patients with mechanical heart valves or with moderate to severe mitral stenosis
- Patients should be risk assessed and counselled regarding the risk of bleeding associated with DOACs
- Patients on DOACs should be reviewed at least once/year