NHS Lanarkshire Guidance on Anticoagulant treatment for patients with non-valvular atrial fibrillation

Transcription

1 1 NHS Lanarkshire Guidance on Anticoagulant treatment for patients with non-valvular atrial fibrillation Atrial fibrillation (AF) affects about 1.2% of the population in the United Kingdom and accounts for 20% of all strokes. AF is the most common sustained cardiac arrhythmia and if left untreated AF is a significant risk for stroke and other morbidities. For detailed guidance on management of atrial fibrillation please refer to NHS Lanarkshire Guideline on Management of Atrial Fibrillation 1. Aim The aim of this document is to support prescribers in identifying and managing appropriate patients with AF for whom anticoagulation with warfarin or Direct acting Oral Anticoagulant (DOAC) would be a beneficial and cost effective treatment for reducing stroke and systemic embolism risk in nonvalvular AF (NVAF). The recommendations are based on NICE CG180, July NVAF includes all cases of AF in which the patients do not have a prosthetic metallic valve that normally requires anticoagulation or mitral stenosis. Risk assessment for patients with atrial fibrillation Stroke and bleeding risk should be assessed in all patients with AF. Use CHA 2 DS 2 -VASc score to assess stroke risk and HAS-BLED to assess the risk of bleeding in patients who are going to be started on an anticoagulant. General key points about anticoagulants For most patients the benefit of anticoagulation outweighs the bleeding risk. For people with an increased risk of bleeding, the benefit of anticoagulation may not always outweigh the bleeding risk and careful monitoring of bleeding risk is important. Do not withhold anticoagulation solely because the person is at risk of having a fall. Do not offer aspirin (or clopidogrel) monotherapy solely for stroke prevention to people with AF. Anticoagulation If considering anticoagulation, the options include Warfarin or DOACs. Discussion of anticoagulation treatment options with the patient will help them make an informed decision.

2 2 Following a diagnosis of AF, the patient will need to make an informed decision regarding whether to commence anticoagulation or not. In most cases the decision to start immediate anticoagulation is not necessary. The patient should be given a few days to reflect and to talk over with family, friends or other healthcare professionals before making their decision. Choice of anticoagulant Warfarin is the first choice anticoagulant in NHSL. However, DOACs offer an alternative choice and the decision regarding the choice of anticoagulant in AF should be made with the patient and is also dependent upon patients clinical features and preferences. The risks and benefits of treatment options should be presented to the patient in an easily understandable and unbiased manner. The DOACs dabigatran 3, rivaroxaban 4, apixaban 5 and edoxaban 6 have not been directly compared in the same clinical trials, so it is not possible to say which one is better based on a head to head analysis. They share some of the same advantages and disadvantages compared to warfarin but because they work slightly differently, they also have some unique characteristics that make them better suited for different types of patients. Although the different DOACs have not been directly compared in the same clinical setting and potentially all the four DOACs which have SMC approval could be used as an alternative to warfarin, it was felt that making all of them available at the same time would cause confusion with regards to the choice of DOAC and it would be best to have preferred DOACs. The decision making committee developing this guidance decided to recommend apixaban and edoxaban for inclusion in NHSL formulary based on their overall efficacy, cost effectiveness and risk profile. The clinical benefits of DOACs compared to warfarin diminish with improving INR control. In existing patients, where warfarin treatment is well controlled (TTR >65%) the use of DOACs may be less favourable and there is no need to consider a change. Clinicians will need to take the level of INR control into consideration when assessing the benefits of a potential change to DOAC. Key points relating to apixaban and edoxaban Apixaban 5mg twice daily and edoxaban 60mg once daily (standard doses) have similar efficacy in preventing stroke and systemic embolism The incidence of intracranial haemorrhage is similar for standard dose apixaban and edoxaban Apixaban and edoxaban in standard dose are associated with reduced risk of major bleeding compared to warfarin In analysis of absolute rather than relative risk, the absolute risk of major bleeding for NVAF patients treated with standard dose DOAC was lowest in patients receiving apixaban 5mg twice daily

3 3 Edoxaban 30mg once daily was associated with more strokes and systemic embolism than standard dose edoxaban and apixaban Patients for consideration of DOAC: New patients Patients already on warfarin who have poor INR control (poor control is defined as TTR<65%) Warfarin allergy or intolerance (eg.alopecia) Significant problems with INR monitoring and/or accessing anticoagulant clinics Frequent medication changes or need for medication that interact with warfarin eg. Antibiotics Requirement for compliance aid such as blister pack or dosette box Unable to regularly attend anticoagulant clinic Antiplatelets and anticoagulation Antiplatelets may be indicated in combination with the anticoagulants, for other conditions associated with AF such as acute cardiac ischaemic events or PCI/stenting. The co-prescription of an antiplatelet with an anticoagulant confers an additional bleeding risk. The combination of dual antiplatelet therapy plus anticoagulant (referred to as triple therapy ) increases the risk of bleeding events by about 2-4 times compared to anticoagulant or aspirin alone. If a patient is on an antiplatelet because of pre-existing ischaemic heart disease (or cerebrovascular disease), the antiplatelet agent should be reviewed with a view to discontinuation. Patients with stable coronary artery disease (no acute ischaemic event or PCI/stent in preceding 12 months) and concurrent AF can be managed with anticoagulation alone. The period of dual antiplatelet therapy plus anticoagulant should be as short as possible after PCI/stenting (e.g. not exceeding 6 months for patients at low risk of bleeding or 4 weeks for patients at high risk of bleeding). This can be followed by single antiplatelet therapy plus anticoagulant for up to 12 months and then lifelong anticoagulant. The decision regarding length of combined antiplatelet and anticoagulant therapy should be clearly documented by treating Cardiologist in each case.

4 4 The use of P2Y12 inhibitors (ticagrelor or prasagrel) in combination with anticoagulants is not recommended due to increased risk of major bleeding. Key points: Warfarin Warfarin has been prescribed for more than 50 years. Warfarin remains an established and cost effective treatment option for anticoagulation in patients. Patients with prosthetic valves requiring anticoagulation (normally metallic valves) and mitral stenosis should be treated only with warfarin and not a DOAC. Unlike DOACs, Warfarin may be considered in patients with prosthetic heart valves requiring anticoagulation, mitral stenosis and/or hepatic impairment. The benefits of DOACs over Warfarin decline as the TTR for Warfarin increases. INR gives clinicians a guide to patient compliance. Effective and familiar use of antidote with Vitamin K should a severe bleed occur whilst being treated. Clearance of warfarin is not affected by renal function. Clinicians may choose to use warfarin in patients for whom the ability to readily or objectively monitor the extent of anticoagulation is paramount. For patients who may miss an occasional dose of warfarin, the long time to onset and offset of action, maybe advantageous as the anticoagulant effect of warfarin will persist for a few days after the last dose. In Warfarin, time to peak effect ranges from 3-5 days and life averaging 40 hours. Warfarin is known to interact with certain foods e.g. cranberries, alcohol and other food containing high amounts of Vitamin K. Patients may have difficulty around complying with or accessing INR monitoring. Key points: DOACs No requirement for INR monitoring. DOACs provide immediate anticoagulant effect (time to peak effect ranges from 1-4 hours).

5 5 DOACs currently have no known food interactions. The sole responsibility of anticoagulation remains with the prescriber without the support of anticoagulant clinic services. DOACs have shorter half life and missed doses may result in more time without any anticoagulation and greater risk of thromboembolic complications. Adherence can be a challenge for patients managing anticoagulants. Each DOAC has considerably higher acquisition cost than Warfarin (Warfarin cost per year 50, average NOAC cost per year ). Renal function should be assessed and monitored using Cockcroft and Gault formula to calculate the creatinine clearance, especially in patients with extreme BMI. DOAC s do also require baseline tests and ongoing monitoring intermittently. Cockcroft and Gault formula Estimated Creatinine Clearance (ml/min)= (140-age) X Ideal body weight X constant Serum Creatinine Age (years) Weight (Kg) Constant o 1.23 men o 1.04 women In patients with average body weight and height laboratory estimated egfr can be similar to calculated creatinine clearance values according to Cockcroft and Gault formula However a calculation of creatinine clearance is recommended according to SPC of DOACs

6 6 Appendix I Anticoagulation in NVAF The following algorithm is intended as a guide to support clinicians and should not replace individual clinical decisions. Is the patient: 1. Poorly controlled by warfarin (TTR <65%)? 2. Predicted to have a lot of interacting medicines (e.g. COPD patients requiring frequent courses of antibiotics)? 3. Unable or unwilling to take warfarin for other reasons (e.g. difficulty with monitoring requirements or unable to cope with variable dosing)? Yes No Warfarin Yes Is patient s creatinine clearance <30ml/min No Consider a DOAC Weight >60Kg and Creatinine clearance >59ml/min HAS BLED 3 or previous GI bleed + / - upper GI symptoms Yes No Yes Edoxaban 60mg once daily* Apixaban 5mg twice daily* 2.5mg twice daily if two or more of 80 years, 60kg, serum creatinine >133 µmol/l * for full prescribing details please refer to SPC or BNF

7 7 Appendix II Choice of Anticoagulant in AF based on Patient Characteristics Patient Characteristics Preferred Drug Choice Rationale Mechanical Heart Valve Warfarin DOACs not studied in this patient population or inferior to warfarin (Dabigatran) Valvular Disease (mitral stenosis or metallic valves) Moderate hepatic impairment (Child-Pugh B) Severe hepatic impairment (Child- Pugh C) Stable on warfarin (TTR>65%, no allergy or alopecia) CrCl <30 ml/min Warfarin Warfarin Warfarin Warfarin Warfarin preferred If using Apixaban, dose should be reduced to 2.5 mg twice daily DOACs not studied in this patient population Apixaban or Edoxaban should be used with caution DOACs either contraindicated or not studied in this patient population A switch not required unless change in patient characteristics (concomitant new drug having significant interaction with warfarin, unable to attend anticoagulant clinic) Very few patients with CrCl<30 ml/min included in DOAC trials. ESC guidelines recommend against use of DOAC in this population Recent gastrointestinal bleed Warfarin or apixaban Less bleeding risk with apixaban but warfarin can be reversed easily if further bleeding Extremes of weight (<50kg or >120kg) Frequent illness or health status change without significant deterioration in renal function Warfarin Apixaban or Edoxaban Limited trial data for DOACs Increased risk of under or over anticoagulation with warfarin

8 8 Frequent medication changes or need for medication that interact with warfarin such as antibiotics Previous intracranial bleed (decision to anticoagulate as per specialist advice) Requirement for compliance aid such as blister pack/dosette box Unable to regularly attend anticoagulant clinic Apixaban or Edoxaban Apixaban or Edoxaban Apixaban or Edoxaban Apixaban or Edoxaban Increased risk of under or over anticoagulation Risk of intracranial bleeding less with DOACs than warfarin. Patients with previous intracranial bleed generally excluded from trials Warfarin not normally dispensed in sealed compliance box (due to variable dosing) Additional resource required for home visits

9 9 Appendix III The following information is a summary guide for prescribers- for additional information consult individual SPCs. Licensed indications Doses Interactions (list not exhaustive refer to current SPC) Warfarin Apixaban Edoxaban Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) (with at least one additional risk factor) As per INR Multiple interactions requiring increased INR monitoring Cranberry juice, alcohol, foods with high amount of vitamin K e.g. leafy green veg such as cabbage, spinach, Brussel sprouts and broccoli Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) (with at least one additional risk factor) 5mg twice daily (CrCL 15-29ml/min 2.5mg twice daily) Patients with 2 or more of the following give 2.5mg twice daily: -age >80 years -body weight <60kg -serum Cr>133micromole/l Avoid concomitant use with strong inhibitors of both CYP3A4 and P-gp e.g. ketoconazole, intraconazole, voriconazole or HIV protease inhibitors. Caution with strong CYP3A4 inducers e.g. rifampicin, phenytoin, carbamazepine, Phenobarbital or St. John s Wort as they may lead to reduced apixaban concentrations There are no known food interactions Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (with one or more risk factors) 60mg once daily (For CrCl ml/min) For patients with one or more of the following clinical factors give 30mg once daily CrCl 15-50ml/min Body weight <60kg Concomitant P- glycoprotein inhibitorsciclosporin, dronedarone, erythromycin, ketoconazole Concomitant use with P-gp inhibitor (e.g. ketoconazole, ciclosporin, dronedarone or erythromycin) requires dose reduction to 30mg once daily Use with caution when coadministered with P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John s Wort)

10 10 Contraindications (List not exhaustive, refer to current SPC) Warfarin Apixaban Edoxaban Hypersensitivity A lesion or condition, if considered a significant risk factor for major bleeding Hepatic disease associated with coagulopathy and clinically relevant bleeding risk Anticoagulant in use (except during switching see below) CrCL<15ml/min Hypersensitivity Clinically significant active bleeding Hepatic disease associated with coagulopathy and clinically relevant bleeding risk Lesion or condition, if considered a significant risk factor for major bleeding Uncontrolled severe hypertension Anticoagulant in use (except during switching see below) End stage renal failure, patients undergoing dialysis Efficacy for stroke prevention Poor adherence Can monitor adherence by checking INR Superior to warfarin (ARISTOTLE) Non-inferior to warfarin (ENGAGE AF-TIMI 48) Not recommended Not recommended Dosing intervals Once daily Twice a day dosing Once daily Missed dose Missed dose should be taken immediately and then continue once daily with dose adjustment depending on INR Missed dose should be taken immediately and then continued with twice a day as before Do not double dose within the same day to make up for missed dose Missed dose should be taken immediately and then continued the following day with once daily intake as before Do not double dose within the same day to make up for missed dose

11 11 Compliance aid Not suitable for compliance aids due variable dosing Extremes of BMI Dose adjustment according to INR Renal impairment Can be used with caution in renal impairment (not excreted by kidneys) Warfarin Apixaban Edoxaban Shelf life of 3 years and no special storage requirementcan be used with compliance aids Exposure of DOAC may vary by 20-30% at extremes of bodyweight (<50kg or >120 Kg). This may be problematic given the difficulties in monitoring therapeutic effects. Patients must have a baseline renal function test before initiating DOAC. Renal function can decline while on treatment hence monitor annually or more often in high risk patients. egfr and CrCL are not interchangeable but in practice egfr can be used as a guide in most patients (>18years) with average height and weight. The SPC of each DOAC recommends that Cockcroft and Gault formula is used for dosing and monitoring Shelf life of 3 years and no special storage requirement-can be used with compliance aids Exposure of DOAC may vary by 20-30% at extremes of bodyweight (<50kg or >120 Kg). This may be problematic given the difficulties in monitoring therapeutic Patients must have a baseline renal function test before initiating DOAC. Renal function can decline while on treatment hence monitor annually or more often in high risk patients. egfr and CrCL are not interchangeable but in practice egfr can be used as a guide in most patients (>18years) with average height and weight. The SPC of each DOAC recommends that Cockcroft and Gault formula is used for dosing and monitoring

12 12 Hepatic impairment Warfarin Apixaban Edoxaban Should be used with caution Avoided in severe hepatic impairment (especially is prothrombin time is prolonged) Age No dose adjustment specified pregnancy Not recommended Major bleed risk compared to warfarin Not recommended in patients with elevated liver enzymes >twice upper limit of normal Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk Consider dose reduction in >80yrs- 2.5mg twice daily Not recommended in severe hepatic impairment Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk No dose reduction is required Not recommended Not recommended Reduced risk compared to warfarin Reduced risk compared to warfarin Intracranial bleed risk Small risk Reduced risk compared to warfarin Reduced risk compared to warfarin GI bleeding risk compared to warfarin Similar risk to warfarin Increased risk with high dose (60mg daily) Risk of dyspepsia/upper GI side effects Non reported Non reported Non reported Reversibility Can be reversed There is currently no antidote Conversion from warfarin to DOAC Conversion from DOAC to warfarin Discontinue warfarin and start apixaban when INR <2 Continue with apixaban for at least 2 days after starting warfarin therapy Check INR and continue coadministration until INR >2.0 There is currently no antidote Discontinue warfarin and start edoxaban when INR 2.5 For patients on edoxaban 60mg, reduce dose to 30 mg daily (reduce to 15mg for patients on 30mg) Co-administer appropriate dose warfarin until INR

13 13 Before surgery If the procedure can not be delayed the increased risk of bleeding should be assessed against urgency of intervention Discontinue at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding Discontinue at least 24 hours prior to elective surgery or invasive procedures with low risk of bleeding 2 If the procedure can not be delayed the increased risk of bleeding should be assessed against urgency of intervention Edoxaban should be stopped at least 24 hours before elective procedure

14 14 Appendix IV Check list for patients starting on a DOAC Tick when completed Explain the purpose of anticoagulation in AF Explain how the drug works i.e. blood takes longer to clot, not thinner Explain the intended duration of therapy Explain the pros and cons of warfarin versus DOAC including dosing regimen Explain the risk of bleeding/bruising and what action to take in the event of bleeding, fall or head injury (currently no antidote for apixaban) Explain follow up arrangements to assess compliance, side-effects, bleeding and monitoring (frequency of follow up blood tests depends on creatinine clearance or illness affecting LFTs) Explain the risk of potential drug interactions Explain to the patient how to take medication The frequency of administration Importance of compliance and to take regularly What to do if a dose is missed To seek help if extra dose is taken accidentally Not to stop taking medication Advise patient to always inform any healthcare professionals, including doctors, nurses, pharmacists and dentists that they are taking an anticoagulant Ensure patients carry a patient alert card and provide other available information to support DOAC use i.e. locally produced patient information leaflets

15 15 References: 1. Fibrillation Guideline.pdf Connolly et al., Dabigatran versus warfarin in in patients with atrial fibrillation, N Engl J Med 2009; 361: Manesh et al, Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation, N Engl J Med 2011; 365: Granger et al., Apixaban versus Warfarin in Patients with Atrial Fibrillation, N Engl J Med 2011; 365: Giugliano et al., Edoxaban versus Warfarin in Patients with Atrial Fibrillation, N Engl J Med 2013; 369: