Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation

Transcription

1 Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Contents Authors... 2 Updates... 2 Glossary... 3 Background... 4 Algorithm 1 Initiating Direct Oral Anticoagulants (DOACs) for Prevention of Stroke and Systemic Embolism in Adult Patients with Non Valvular Atrial Fibrillation and CHA 2 DS 2- VASc score Algorithm 2 Anticoagulant naïve patient... 6 Algorithm 3 Patients on warfarin... 7 Prescriber Checklist for Initiation of DOACs for the Prevention of Stroke and Systemic Embolism in Adult Patients with Non-Valvular Atrial Fibrillation & CHA 2 DS 2 -VASc score Decision aids and prescriber information for DOACs... 9 Appendix 1: Patient decision aid for Oral Anticoagulant Treatment in Atrial Fibrillation & CHA 2 DS 2 - VASc score Appendix 2: Apixaban Prescriber Information Appendix 3: Dabigatran Prescriber Information Appendix 4: Edoxaban Prescriber Information Appendix 5: Rivaroxaban Prescriber Information Appendix 6: Bleeding Risk Assessment tools for prescribers Patient Information Appendix 7: DOAC patient booklets Appendix 8: LMSG Medicine Leaflets for DOACs Apixaban in adult patients Dabigatran in adult patients Edoxaban in adult patients Rivaroxaban in adult patients Monitoring Compliance Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version 1.5 1

2 Authors Dr.Patrick Mensah: Consultant Haematologist. Gill Stead. Principal Pharmacist Medicines Information LMSG Task and Finish Group Original version written , on behalf of LMSG Major update Dr Amit Mistri, for the LLR Anticoagulation Interface Group & UHL Anticoagulation Task & Finish Group Next review date Updates Date New version Reason Updated Version 1.1 Apixaban traffic light green. Prescribing information included for apixaban initiation and dabigatran maintenance. Patient information leaflet added for apixaban Updated K Carter 1.2 Dabigatran traffic light green. Flow charts and algorithms updated. Patient info leaflet for dabigatran added Updated Link to GP notebook removed (P6 step1) K Carter Updated NOAC changed to DOAC K Carter Updated A Mistri Edoxaban added 1.5 Scheduled update, for the Anticoagulation Interface Group Added contents & glossary; updated algorithms, checklist and prescriber information Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version 1.5 2

3 Glossary AF CHA 2 DS 2 -VASc DOAC egfr HAS-BLED HCP INR CrCl LMSG NICE NOAC NPSA TIA UFH U&E Atrial Fibrillation Scoring system to quantify annual embolic stroke risk (in AF) Direct Oral Anti-Coagulant estimated Glomerular Filtration Rate (MDRD equation, as reported with U&Es) Scoring system to quantify annual major bleeding risk (in AF, on anticoagulation) Health Care Practitioner International Normalised Ratio Creatinine Clearance (Cockroft-Gault calculation) Leicestershire Medicines Strategy Group National Institute of Health & Clinical Excellence Novel Oral Anti-Coagulant (now defunct, use DOAC instead) National Patient Safety Alert Transient Ischaemic Attack Un-Fractionated Heparin Urea & Electrolytes Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version 1.5 3

4 Background The Direct Oral Anti-Coagulants (DOACs), including direct factor Xa and Factor II (thrombin) inhibitors represent a paradigm shift in anticoagulation management. The NICE Technology Appraisals for apixaban, dabigatran, edoxaban and rivaroxaban state that they should be offered to patients as an alternative to warfarin. The decision about whether to start treatment should be made after an informed discussion between the clinician and the patient about the risks and benefits of all available oral anticoagulants. For people who are taking warfarin, the potential risks and benefits of switching to a DOAC should be considered. For the purposes of this guidance and in line with licensing of the DOAC, non-valvular atrial fibrillation refers to atrial fibrillation in the absence of moderate or severe mitral stenosis. An Echocardiogram is not mandated, can be considered if there is clinical suspicion of mitral disease, but should not delay initiation of anticoagulation. The major advantage of the DOACs is that frequent coagulation monitoring is not necessary. However, monitoring is required at intervals guided by the renal function (Cockroft-Gault Creatinine Clearance CrCl) see Algorithm 1 and Prescriber Checklist (Page 6). Education about anticoagulation has been shown to improve outcomes by reducing thrombotic and haemorrhagic adverse events. Outcomes improve when patients take responsibility for, understand and adhere to an anticoagulation care plan. There are many educational materials for warfarin, low molecular weight heparin for the direct oral anticoagulants, with key emphasis on stressing adherence to prescribed regimes. Special attention should be directed at recognizing the signs of bleeding and stressing that major bleeding requires urgent medical attention. (4) The NPSA Anticoagulation Alert (NPSA/2007/18) was published in 2007 before DOACs were available. (6) Subsequently, an implementation resource document was updated on 1 st May 2018 to support NHS organisations in implementing medication-related requirements as highlighted in the NPSA alert. (7) Compliance with relevant standards is listed in Table 1 below. NPSA alert standard Compliant 1. Review and, where necessary, update written procedures and clinical protocols for anticoagulant services to ensure they reflect safe practice, and that staff are trained in these procedures. a. How to safely initiate anticoagulant therapy. b. Effective communication systems when clinical responsibility for anticoagulant treatment is being transferred eg discharge from hospital. c. The healthcare practitioner who provides this information must record in the patient s healthcare record that this information has been supplied. d. An annual clinical review 2. Ensure patients prescribed anticoagulants receive appropriate verbal and written information. a. Information should be provided before the first dose of anticoagulant is administered, and reinforced at hospital discharge, at the first anticoagulant clinic appointment and throughout the course of their treatment when necessary. b. An anticoagulation alert card should be provided and is designed to be carried by patients at all times. It informs health professionals that the patient is taking oral anticoagulants and provides a contact telephone number. c. General information about the safe use of oral anticoagulants which reinforces the information that the prescribers and other Health Care Practitioners give to the patient before the first dose of A/C was administered, at the first A/C clinic appointment and when necessary throughout the course of the treatment. It is a concise guide on practical issues to consider when taking oral anticoagulants. It is intended to remain with the patient and be readily available for reference but not carried by the patient at all times. Table 1. Compliance with NPSA Alert Standards References 1. NICE TA 275 Stroke and systemic embolism (prevention, non-valvular atrial fibrillation) apixaban. Feb NICE TA 249 Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. March NICE TA 256 Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation May NICE TA 355 Edoxaban for the prevention of stroke and systemic embolism in atrial fibrillation Sept Smythe M et al. Rivaroxaban: Practical Considerations for Ensuring Safety and Efficacy. Pharmacotherapy 2013; 33(11): NPSA Actions that can make Anticoagulants Safer. Patient Safety Alert. Accessed on line at 7. Implementing Patient Safety Alert 18: Anticoagulant Therapy Resource [UPDATE] - Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version 1.5 4

5 Algorithm 1 Initiating Direct Oral Anticoagulants (DOACs) for Prevention of Stroke and Systemic Embolism in Adult Patients with Non Valvular Atrial Fibrillation and CHA2DS2-VASc score 2 Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version 1.5 5

6 Algorithm 2 Anticoagulant naïve patient Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version 1.5 6

7 Algorithm 3 Patients on warfarin Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version 1.5 7

8 Prescriber Checklist for Initiation of DOACs for the Prevention of Stroke and Systemic Embolism in Adult Patients with Non-Valvular Atrial Fibrillation & CHA2DS2-VASc score 2 Step 1 Step 2 Step 3 Step 4 Step 5 Confirm LMSG criteria met Algorithms 1, 2 and 3 Confirm patient (/representative) understanding of the following: Clinical need for anticoagulation How anticoagulants work Risks and benefits of anticoagulant options Check suitability Check for contraindications Check dose adjustment if renal impairment Interactions with other drugs Correct modifiable bleeding risk factors Safe use of DOACs Ensure the patient understands: Possible side effects Importance of compliance When to seek help urgently What to do in an emergency How to obtain supplies Emphasise compliance at all visits. Minimum standard frequency of monitoring is recommended as follows: CrCl Minimum monitoring frequency >=60 Annual 45 - <60 6 monthly 30 - <45 OR HAS- BLED>= <30 {Haematology approval needed} <=15 3 monthly 3 monthly (or more frequent) DOACs contraindicated Amend frequency in light of individual patient circumstances (e.g. HAS- BLED score, bleeding, labile renal function, other drugs) which may increase risk of bleeding or worsening renal function. Patient decision aid for Oral Anticoagulant Treatment in Atrial Fibrillation (to be discussed face to face with the patient). See Appendix 1 Drug Specific Prescriber Information for initiation in AF See Appendices 2, 3, 4, 5 for drug specific prescriber information New oral anticoagulant booklet containing general information to keep at home for reference. Add contact numbers. An Anticoagulant Alert card to keep on their person in the event of an emergency. Drug specific patient information LMSG Medicine Leaflet. Supply 28 days therapy Review at 1 month from initiation and regularly after Consider blood test a week before in anticipation of monitoring visit. Re-assessment of suitability of a DOAC as outlined by the LMSG Criteria. Review to include structured approach e.g. ABCDEF A Adherence assessment B Bleeding risk assessment C Creatinine clearance (blood results: FBC, U&E, LFT) D Drug list for interactions see appendices below and refer to BNF, if needed E Examination (BP, mobility ~ falls risk) F Final Decision / Follow up appointments CONTINUE CHANGE DOSE (reduce if dose reduction criteria met; or increase if inappropriately low dose) CHANGE DRUG STOP anticoagulation & review in.. Patient education & counselling rationale, compliance, OTC drugs (asp; NSAIDs), peri-procedural management (Adapted from: Thrombosis Canada Ann Intern Med 2015; 163: ) Consider the use of DOACs (for licensed indications) in housebound patients if compliance can be assured, due to relative practical ease of use. Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version 1.5 8

9 Decision aids and prescriber information for DOACs Appendix 1: Patient decision aid for Oral Anticoagulant Treatment in Atrial Fibrillation & CHA2DS2-VASc score 2 Anticoagulants are medicines that make it harder for the blood to clot and reduce the chance of a stroke in patients with atrial fibrillation (AF). In AF, a blood clot can form in the heart and migrate to different arteries (embolism). If it migrates to the brain, an embolic stroke is sustained. Without any medicine to reduce the risk, about 40 in every 1,000 people who have AF will have a stroke in the course of a year. The individual risk for each person will also depend on other factors including age, whether you have already had a stroke or heart failure, diabetes or high blood pressure. Each of these will further increase your risk of a stroke if you have AF. Objective risk assessment using the CHA 2 DS 2 VASc score is mandatory. Available oral anticoagulants include: Apixaban, Dabigatran, Edoxaban, Rivaroxaban and Warfarin. The table below lists some of the differences between the newer anticoagulants and warfarin to help you and your healthcare professional decide the best option for you, if you wish to have treatment. Does this medicine reduce the risk of stroke? Risk of bleeding? Can the effects of the medicine be reversed? Do I need regular blood tests to monitor the dose? What are the risks if I forget to take medication? Food, alcohol and other medicines. WARFARIN Warfarin reduces the risk of stroke to 14 people in every 1,000. The risk of stroke is 40 people in every 1000 not taking any anticoagulant to prevent a stroke. The most common side effect of all anticoagulants is bleeding which can occur inside or outside the body. Bleeding into the brain (haemorrhagic stroke) is the most serious side effect and occurs in 5-7 people in every 1000 taking warfarin over a year. Bleeding in the stomach or bowel occurs in 9-22 people in every 1000 over a year. Yes, using Vitamin K and clotting factors. Warfarin is taken once daily. You will need blood tests regularly to monitor its effect on the blood, usually at your GP practice. The dose may need to be adjusted. If you forget to take your medication, you significantly reduce the stroke prevention benefit of the treatment. Warfarin is affected by some foods, alcohol and many other medicines. You will be provided advice on dietary restrictions. DIRECT ORAL ANTICOAGULANT The direct oral anticoagulants are more effective than warfarin in reducing the overall risk of stroke. There are no clinical trials that directly compare the newer agents with each other in AF. Your prescriber will recommend the most appropriate medicine with you. Haemorrhagic stroke with the direct anticoagulants occurs in about 1-5 people in every 1000 over a year. The risk of gastrointestinal bleeding is between 8-32 people in every 1000 over a year. There are small differences in bleeding risks between the direct anticoagulants compared to warfarin and your prescriber will recommend the most appropriate medicine with you. The DOAC stays for a shorter duration in the body and stopping them is often all that is required in the case of significant bleeding. Currently, there is a specific antidote for Dabigatran (Idarucizumab), but not the other DOACs. Supportive treatment with clotting factors is also used. The direct anticoagulants are taken once or twice a day. They have a predictable effect on the body and so you will not need to have frequent blood tests. However you will need to have a blood test initially and at regular intervals to check your kidney and liver function. If you forget to take your medication, you significantly reduce the stroke prevention benefit of the treatment. The direct anticoagulants are not generally affected by food and alcohol. There are limited interactions with other drugs. NB. Rivaroxaban must be taken with a meal. Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version 1.5 9

10 Appendix 2: Apixaban Prescriber Information Apixaban in AF for the Prevention of Stroke and Systemic Embolism in Adult Patients with Non-Valvular Atrial Fibrillation & CHA 2 DS 2 VASc score 2 Section A: Contraindications to apixaban. Section B: Dosing in renal impairment Hypersensitivity to the active substance or to any of the excipients. Active clinically significant bleeding Hepatic disease associated with coagulopathy and clinically relevant bleeding risk Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulant except under specific circumstances of switching therapy to or from apixaban or when UFH is given at doses necessary to maintain an open central venous or arterial catheter Pregnancy and breast feeding Use the Cockcroft-Gault equation to estimate creatinine clearance (use a current actual weight) (egfr should NOT be used to estimate the dose as it will result in many patients being under or over dosed) CrCl <15mL/min: Contraindicated CrCl ml/min: Apixaban is not recommended unless under specialist supervision. Drug levels may need to be monitored and a lower dose used-discuss with Haematology. This is local guidance. CrCl 30 ml/min Apixaban 5mg twice daily (unless dose reduction criteria below are met) Age/ weight Patients with any two of the following three criteria should receive the lower dose of apixaban 2.5 mg twice daily (serum creatinine 1.5 mg/dl (133 micromoles/l); age 80 years; body weight 60 kg. Section C: Drug interactions Section D: Switching from warfarin to apixaban. Switching apixaban to and from LMWH. Switching from apixaban to warfarin. Patients with exclusive criteria of severe renal impairment (creatinine clearance ml/min) should be referred to haematology, if being considered for Apixaban. Not recommended in patients < 18 years. Not recommended in patients receiving strong inhibitor of P-gp and CYP-3A4 eg tacrolimus, azoles (ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors eg ritonavir Caution in strong inducers of P-gp and CYP-3A4 eg phenytoin, carbamazepine, phenobarbitone, St John's Wort and rifampicin. Caution with concomitant administration of antiplatelet agents, NSAIDs. Discontinue warfarin. Initiate apixaban when INR 2. Switching treatment from parenteral anticoagulants to apixaban (and vice versa) can be done at the next scheduled dose. Continue the administration of apixaban for at least 2 days after beginning warfarin until the INR is 2.0. After 2 days of co-administration, obtain an INR prior to the next scheduled dose of apixaban. SPC Eliquis 5 mg film-coated tablets. Date of revision of the text 19 October 2017.See here for further information Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

11 Appendix 3: Dabigatran Prescriber Information Dabigatran in AF for the Prevention of Stroke and Systemic Embolism in Adult Patients with Non-Valvular Atrial Fibrillation & CHA 2 DS 2 -VASc score 2 Section A: Contraindications to dabigatran. Section B: Dosing in renal impairment Dose reductions Based on age, weight and other risk factors. Hypersensitivity to the active substance or to any of the excipients. Active clinically significant bleeding Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and dronedarone. Patients with elevated liver enzymes > 2 upper limit of normal (ULN) or where hepatic impairment or liver disease expected to have any impact on survival. Concomitant treatment with any other anticoagulant except under the circumstances of switching therapy to or from apixaban or when UFH is given at doses necessary to maintain an open central venous or arterial catheter. Pregnancy and breast feeding Use the Cockcroft-Gault equation to estimate creatinine clearance. (egfr should NOT be used to estimate the dose as it will result in many patients being under or over dosed.) CrCl <30mL/min: Contraindicated CrCl ml/min: Dabigatran 150 mg twice daily. Consider reducing the dose to 110mg twice daily for patients with a high risk of bleeding. Close clinical surveillance is recommended in patients with renal impairment. CrCL ml/min: Dabigatran 150mg twice daily. Reduce the dose to 110mg bd in the following patients: Patients aged 80 years or above Patients who receive concomitant verapamil The daily dose of dabigatran of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding in the following groups of patients: Patients between years Patients with moderate renal impairment (CrCl ml/min) Patients with gastritis, oesophagitis or gastroesophageal reflux Other patients at increased risk of bleeding Given the available clinical and kinetic data, no dose adjustment is necessary but close clinical surveillance is recommended in patients with a body weight < 50 kg Dabigatran is not recommended in patients < 18 years. Section C: Drug interactions Contraindicated in patients receiving strong inhibitors of P-gp and CYP-3A4 eg. systemic ketoconazole, dronedarone, itraconazole and cyclosporine Concomitant treatment with tacrolimus is not recommended. Caution in moderate inducers of P-gp. amiodarone, posaconazole, quinidine, verapamil and ticagrelor and CYP-3A4 eg phenytoin, carbamazepine, phenobarbitone, St John's Wort, rifampicin and clarithromycin. SSRIs and SRNIs increased the risk or bleeding in the RELY study in all groups. Pantoprazole but not other PPIs significantly lower dabigatran plasma levels. Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

12 Section D: Switching from warfarin to dabigatran Switching from dabigatran to warfarin Warfarin should be stopped and dabigatran can be given as soon as the INR is < 2.0. Adjust the starting time of the warfarin based on CrCL as follows: CrCL 50 ml/min, start warfarin 3 days before discontinuing dabigatran etexilate CrCL ml/min, start warfarin 2 days before discontinuing dabigatran etexilate Because dabigatran can contribute to an elevated INR, INR testing should not be performed until dabigatran has been stopped for at least 2 days. Switching from dabigatran to LMWH How to switch to LMWH from dabigatran It is recommended to wait 12 hours after the last dose before switching from dabigatran etexilate to a parenteral anticoagulant. Dabigatran should be given 0-2 hours prior to the time that the next dose of LMWH would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous unfractionated Heparin (UFH)). SPC Pradaxa 150 mg hard capsules. Date of revision of the text 8 th January See here for further information Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

13 Appendix 4: Edoxaban Prescriber Information Initiating Edoxaban in AF for the Prevention of Stroke and Systemic Embolism in Adult Patients with Non- Valvular Atrial Fibrillation & CHA 2 DS 2 -VASc score 2 Section A: Contraindications to edoxaban Hypersensitivity to the active substance or to any of the excipients. Active clinically significant bleeding Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk Concomitant treatment with any other anticoagulant except under the circumstances of switching therapy to or from rivaroxaban or when UFH is given at doses necessary to maintain an open central venous or arterial catheter Pregnancy and breast feeding Section B: Dosing in renal impairment Uncontrolled severe hypertension Use the Cockcroft-Gault equation to estimate creatinine clearance. (egfr should NOT be used to estimate the dose as it will result in many patients being under or over dosed) CrCl <15ml/min: Not recommended CrCl ml/min: Edoxaban is not recommended unless under specialist supervision. Drug levels may need to be monitored-discuss with Haematology. This is local guidance. CrCl ml/min: Edoxaban 30mg once daily Age Weight Section C: Drug interactions Section D: Switching from warfarin to edoxaban Switching from edoxaban to warfarin Switching edoxaban to and from LMWH CrCl 50ml/min: Edoxaban 60mg once daily No adjustments based on age alone are required. Not recommended in patients < 18 years. Reduce dose to 30mg in patients 60kg Dose reduction required with concomitant use of the following P-glycoprotein (P-gp) inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole. See Lixiana - Summary of Product Characteristics (SPC) - (emc) Discontinue warfarin. Initiate edoxaban when INR 2.5. See Lixiana - Summary of Product Characteristics (SPC) - (emc) See Lixiana - Summary of Product Characteristics (SPC) - (emc) SPC Lixiana 60mg film-coated tablets. Date of revision of text 17 th July See here for further information Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

14 Appendix 5: Rivaroxaban Prescriber Information Initiating Rivaroxaban in AF for the Prevention of Stroke and Systemic Embolism in Adult Patients with Non-Valvular Atrial Fibrillation & CHA 2 DS 2 -VASc score 2 Section A: Contraindications to rivaroxaban. Section B: Dosing in renal impairment Age Weight Section C: Drug interactions Section D: Switching from warfarin to rivaroxaban Switching from rivaroxaban to warfarin Switching rivaroxaban to and from LMWH Hypersensitivity to the active substance or to any of the excipients. Active clinically significant bleeding Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C Concomitant treatment with any other anticoagulant except under the circumstances of switching therapy to or from rivaroxaban or when UFH is given at doses necessary to maintain an open central venous or arterial catheter Pregnancy and breast feeding Use the Cockcroft-Gault equation to estimate creatinine clearance. egfr should NOT be used to estimate the dose as it will result in many patients being under or over dosed. CrCl <15ml/min: Contraindicated CrCl ml/min: Rivaroxaban is not recommended unless under specialist supervision. Drug levels may need to be monitored-discuss with Haematology. This is local guidance. CrCl ml/min: Rivaroxaban 15mg once daily CrCl 50ml/min: Rivaroxaban 20mg once daily No adjustments based on age alone are required. Not recommended in patients < 18 years. No dose adjustment required for extreme body weight alone Not recommended in patients receiving strong inhibitor of P-gp and CYP-3A4 eg tacrolimus, azoles (ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors eg ritonavir. Macrolide antibiotics clarithromycin and telithromycin can affect levels to a lesser extent additive to the effect if renal impairment. Caution in strong inducers of P-gp and CYP-3A4 eg phenytoin, carbamazepine, phenobarbitone, St John's Wort and rifampicin. Caution with concomitant administration of antiplatelet agents, NSAIDs. Avoid dronedarone Discontinue warfarin. Initiate rivaroxaban when INR 3 for AF patients. Start warfarin alongside rivaroxaban until the INR is 2.0. For the first two days of the conversion period, standard initial dosing of warfarin should be used and then adjust the dose as guided by INR testing. Whilst patients are on both rivaroxaban and warfarin the INR should not be tested earlier than 24 hours after the previous dose of rivaroxaban but prior to the next dose of rivaroxaban. Once rivaroxaban is discontinued INR testing may be done reliably at least 24 hours after the last dose Note: Rivaroxaban can affect prothrombin levels although INR is not an appropriate reflection of the anticoagulant activity of rivaroxaban. Switching treatment from parenteral anticoagulants to rivaroxaban (and vice versa) can be done at the next scheduled dose. SPC Xarelto 20mg film-coated tablets. Date of revision of text November See here for further information Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

15 Appendix 6: Bleeding Risk Assessment tools for prescribers Risk benefit assessment within this context involves making a clinical assessment in respect of the safety or otherwise of continuing anticoagulation. Relevant indicators to look out for include: Major spontaneous bleeding complications including gastrointestinal, intracranial bleeding etc. Deterioration in cognitive function, onset of dementia etc. (e.g. patient unable to remember whether has taken medication or not). Recurrent accidental falls with significant head injury or likely to lead to significant head injury. Requirement for new medication likely to potentiate risk of bleeding e.g. NSAIDs. Significant deterioration in renal or hepatic function (both likely to increase bleeding risk). Warfarin: Stability of anticoagulation (widely fluctuating INRs with no obvious cause may indicate a higher risk of bleeding, stable INR control is associated with a more favourable bleeding risk profile. The HAS-BLED tool can be used to assess bleeding risk but should not be used on its own to exclude patients from oral anticoagulant therapy. Instead, it enables the clinician to identify bleeding risk factors, with a view to correcting those that are modifiable e.g. controlling blood pressure, discontinuing concomitant antiplatelet or NSAID therapy and counselling patient about reducing alcohol intake where appropriate. Thus, the HAS-BLED score SHOULD NOT be used as an excuse to not prescribe oral anticoagulants as this will almost invariably exclude those patients most at risk of stroke from AF from receiving much needed anticoagulation 1. This is because patients with the highest HAS-BLED scores also tend to have corresponding high CHA 2 DS 2 VASc score. The real value of the HAS-BLED score is to identify and address bleeding risk factors and to highlight those patients in whom caution with oral anticoagulation and more frequent review is warranted. 1. Lane DA, Lip GYH. Circulation 2012;126: HAS-BLED Major Bleeding Risk Score 1 Clinical Characteristic Points HAS-BLED Major Bleed score* Risk % pa 1 H Hypertension A Abnormal renal &/or liver function 1 or S Stroke B Bleeding diatheses L Labile INR E Elderly 1 Insufficient 5 to 9 D Drugs / Alcohol 1 or 2 data Add points to get score * HAS-BLED Notes Hypertension: systolic blood pressure >160 mm Hg. Renal function: creatinine >200 or dialysis. Liver function: chronic liver disease (eg. cirrhosis) or bilirubin >2x ULN +AST /ALP >3x upper limit normal). Bleeding: previous bleeding, bleeding diathesis or unexplained anaemia. Labile INRs: Time in Treatment Range <60%. Drugs: concomitant use of drugs, e.g. antiplatelet agents and non-steroidal anti-inflammatory drugs. Alcohol: excess alcohol A score of 0-2 indicates low risk A score of 3 indicates high risk. This suggests caution and more frequent reviews are recommended 1. Pisters R, Lane DA, Nieuwlaat R et al. A novel user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: The Euro Heart Survey. Chest 2010 Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

16 Patient Information Leicestershire Medicines Strategy Group Appendix 7: DOAC patient booklets THE DOAC BOOKLET provides the patient with important information about DOAC treatment. The booklet should be used by the prescriber to record contact details and patient specific information upon initiation, and whenever renal and hepatic function tests have been undertaken. Patients should keep the book at home for easy reference but take it to show the pharmacist when they collect their prescription. This is akin to the yellow booklet for patients on warfarin. ANTICOAGULANT ALERT CARD Rivaroxaban in adult patients should be given to the patient at initiation (and if a replacement is needed). The card should be filled in and carried by/with the patient at all times in the event of an emergency. What is it used for? Locally produced orange DOAC booklets can be obtained either via the local CCG Medicines Optimisation Teams or from cubiquity media ( admin.print@cubiquitymedia.com Telephone: ) Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

17 Appendix 8: LMSG Medicine Leaflets for DOACs Please click on the chosen DOAC below to jump to the relevant patient information leaflet, and you can print the current page to give to your patient. Apixaban page 18 Dabigatran page 19 Edoxaban page 20 Rivaroxaban page 21 Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

18 Apixaban in adult patients What is it used for? Apixaban is used to prevent blood clots in the brain (stroke) in adults who have an abnormal heart beat called non-valvular atrial fibrillation and are considered to be at risk of stroke. How the medicine works Apixaban is an anticoagulant medicine that helps to prevent blood from clotting. It does this by interfering with a substance in the body called Factor Xa which is involved in the development of blood clots. How and when you should take your medicine Apixaban should be swallowed whole with water twice a day with or without food. It is best taken at the same times each day. There are no specific foods or drinks that you need to avoid. If you forget to take your tablet, take it as soon as you remember and then take the next one at the normal time. Possible side effects The most common side effect of apixaban is bleeding. This can occur inside or outside the body, and may cause symptoms such as extreme tiredness, pale skin, headache, dizziness, breathlessness or chest pain depending on the severity. Consult your doctor if any of these become troublesome. If you experience any of the following, seek medical attention: Prolonged nose bleeds (more than 10 minutes) Blood in vomit, sputum, urine or stools or pass black stools. Severe or spontaneous bruising or unusual headaches. For women, heavy or increased bleeding during your period or any other vaginal bleeding. If you cut yourself, apply firm pressure for at least 5 minutes with a clean dry dressing. Seek immediate attention if you are involved in a major physical trauma; suffer a significant blow to the head or are unable to stop bleeding. Other information You should not take other anticoagulants with apixaban except if your treatment is being switched to or from apixaban. Always discuss with your healthcare provider whether you need to withhold apixaban before a surgical or invasive procedure and check before you take other medicines including over the counter complementary remedies. Carry your patient alert card with you at all times. Talk to your doctor if you are planning to become pregnant or breast feed. General Information about your medicines This leaflet outlines essential information that you need if you have been prescribed this medicine. It outlines common side effects and also symptoms of serious side effects that require urgent medical attention. It does not list all side effects reported for this medicine and we recommend that you also read the package insert that is supplied with your medicine for a full list of side effects and drug interactions. The following websites are also useful: and Review date Version 1.5 Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

19 Dabigatran in adult patients What is it used for? Dabigatran is used to prevent blood clots in the brain (stroke) in adults who have an abnormal heart beat called non-valvular atrial fibrillation and are considered to be at risk of stroke. It is also used to prevent and treat blood clots which cause deep vein thrombosis (DVT) or pulmonary embolism (PE). How the medicine works Dabigatran is an anticoagulant medicine that helps to prevent blood from clotting. It does this by blocking a substance in the body which is involved in the development of blood clots. How and when you should take your medicine Dabigatran should be swallowed whole with water twice a day either with or without food. There are no specific foods or drinks that you need to avoid. The dose and the length of treatment will depend on the reason you are taking dabigatran and also your own individual factors. Your doctor or nurse will advise you. If you take dabigatran TWICE daily and you miss a dose you can take it up to 6 hours prior to the next due dose. A missed dose should be omitted if the remaining time is below 6 hours prior to the next due dose. Do not take a double dose to make up for missed doses. Continue the next day taking it twice a day. Possible side effects The most common side effect of dabigatran is bleeding. This can occur inside or outside the body, and may cause symptoms such as extreme tiredness, pale skin, headache, dizziness, breathlessness or chest pain depending on the severity. Other common side effects include indigestion, nausea and stomach pain. Consult your doctor if any of these become troublesome. If you experience any of the following, seek medical attention: Prolonged nose bleeds (more than 10 minutes) Blood in vomit, sputum, urine or stools or pass black stools. Severe or spontaneous bruising or unusual headaches. For women, heavy or increased bleeding during your period or any other vaginal bleeding. If you cut yourself, apply firm pressure for at least 5 minutes with a clean dry dressing. Seek immediate attention if you are involved in a major physical trauma; suffer a significant blow to the head or are unable to stop bleeding. Other information You should not take other anticoagulants with dabigatran except if your treatment is being switched to or from dabigatran. Always discuss with your healthcare provider whether you need to withhold dabigatran before a surgical or invasive procedure and check before you take other medicines including over the counter complementary remedies. Carry your patient alert card with you at all times. Talk to your doctor if you are planning to become pregnant or breast feed. Further information is available in the leaflet supplied with your medicine. General Information about your medicines This leaflet outlines essential information that you need if you have been prescribed this medicine. It outlines common side effects and also symptoms of serious side effects that require urgent medical attention. It does not list all side effects reported for this medicine and we recommend that you also read the package insert that is supplied with your medicine for a full list of side effects and drug interactions. The following websites are also useful: and Review date Version 1.5 Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

20 Edoxaban in adult patients What is it used for? Edoxaban is used to prevent blood clots in the brain (stroke) in adults who have an abnormal heart beat called non-valvular atrial fibrillation and are considered to be at risk of stroke. It is also used to prevent and treat blood clots which cause deep vein thrombosis (DVT) or pulmonary embolism (PE). How the medicine works Edoxaban is an anticoagulant medicine that helps to prevent blood from clotting. It does this by blocking a substance in the body which is involved in the development of blood clots. How and when you should take your medicine Edoxaban should be swallowed whole with water once a day either with or without food. There are no specific foods or drinks that you need to avoid. The dose and the length of treatment will depend on the reason you are taking edoxaban and also your own individual factors. Your doctor or nurse will advise you. If you miss a dose, take it as soon as you remember and then continue as normal the next day. Never take a double dose on the same day to make up for a missed dose. Possible side effects The most common side effect of edoxaban is bleeding. This can occur inside or outside the body, and may cause symptoms such as extreme tiredness, pale skin, headache, dizziness, breathlessness or chest pain depending on the severity. Other common side effects include indigestion, nausea and stomach pain. Consult your doctor if any of these become troublesome. If you experience any of the following, seek medical attention: Prolonged nose bleeds (more than 10 minutes) Blood in vomit, sputum, urine or stools or pass black stools. Severe or spontaneous bruising or unusual headaches. For women, heavy or increased bleeding during your period or any other vaginal bleeding. If you cut yourself, apply firm pressure for at least 5 minutes with a clean dry dressing. Seek immediate attention if you are involved in a major physical trauma; suffer a significant blow to the head or are unable to stop bleeding. Other information You should not take other anticoagulants with edoxaban except if your treatment is being switched to or from edoxaban. Always discuss with your healthcare provider whether you need to withhold edoxaban before a surgical or invasive procedure and check before you take other medicines including over the counter complementary remedies. Carry your patient alert card with you at all times. Talk to your doctor if you are planning to become pregnant or breast feed. Further information is available in the leaflet supplied with your medicine. General Information about your medicines This leaflet outlines essential information that you need if you have been prescribed this medicine. It outlines common side effects and also symptoms of serious side effects that require urgent medical attention. It does not list all side effects reported for this medicine and we recommend that you also read the package insert that is supplied with your medicine for a full list of side effects and drug interactions. The following websites are also useful: and Review date Version 1.5 Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

21 Rivaroxaban in adult patients What is it used for? Rivaroxaban is used to prevent blood clots in the brain (stroke) in adults who have an abnormal heart beat called non-valvular atrial fibrillation and are considered to be at risk of stroke. It is also used to prevent and treat blood clots which cause deep vein thrombosis (DVT) or pulmonary embolism (PE). How the medicine works Rivaroxaban is an anticoagulant medicine that helps to prevent blood from clotting. It does this by interfering with a substance in the body called Factor Xa which is involved in the development of blood clots. How and when you should take your medicine Rivaroxaban should be swallowed whole with water at the same time of day with food. There are no specific foods or drinks that you need to avoid. The dose and the length of treatment will depend on the reason you are taking rivaroxaban and also your own individual factors. Your doctor or nurse will advise you. If you take rivaroxaban ONCE daily and you miss a dose, take it as soon as you remember and then continue as normal the next day. Never take a double dose on the same day to make up for a missed dose. If you take rivaroxaban TWICE daily and you miss a dose, take it as soon as you remember but you may take both tablets together if necessary. Continue the next day taking it twice a day. Possible side effects The most common side effect of rivaroxaban is bleeding. This can occur inside or outside the body, and may cause symptoms such as extreme tiredness, pale skin, headache, dizziness, breathlessness or chest pain depending on the severity. Other common side effects include indigestion, nausea and stomach pain. Consult your doctor if any of these become troublesome. If you experience any of the following, seek medical attention: Prolonged nose bleeds (more than 10 minutes) Blood in vomit, sputum, urine or stools or pass black stools. Severe or spontaneous bruising or unusual headaches. For women, heavy or increased bleeding during your period or any other vaginal bleeding. If you cut yourself, apply firm pressure for at least 5 minutes with a clean dry dressing. Seek immediate attention if you are involved in a major physical trauma; suffer a significant blow to the head or are unable to stop bleeding. Other information You should not take other anticoagulants with rivaroxaban except if your treatment is being switched to or from rivaroxaban. Always discuss with your healthcare provider whether you need to withhold rivaroxaban before a surgical or invasive procedure and check before you take other medicines including over the counter complementary remedies. Carry your patient alert card with you at all times. Talk to your doctor if you are planning to become pregnant or breast feed. Further information is available in the leaflet supplied with your medicine. General Information about your medicines This leaflet outlines essential information that you need if you have been prescribed this medicine. It outlines common side effects and also symptoms of serious side effects that require urgent medical attention. It does not list all side effects reported for this medicine and we recommend that you also read the package insert that is supplied with your medicine for a full list of side effects and drug interactions. The following websites are also useful: and Review date Version 1.5 Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version

22 Monitoring Compliance What will be measured to monitor compliance DATIX incidents related to use of DOAC for AF (e.g. incorrect dose or bleeding complications) GP complaints / concerns related to DOAC use in AF How will compliance be monitored Medication Safety Pharmacist to report quarterly to UHL Anti- Coagulation Committee (ACC) Review of GP complaints / concerns & summary report to UHL ACC Monitoring Lead Elizabeth McKechnie Medication Safety Pharmacist Elizabeth.McKechnie@uhltr.nhs.uk Catherine Headley (GP Engagement Lead) Catherine.Headley@uhltr.nhs.uk Frequency Quarterly Quarterly Reporting arrangements UHL ACC UHL ACC Direct Oral Anti-Coagulants for Non-Valvular Atrial Fibrillation Version