DERBYSHIRE JOINT AREA PRESCRIBING COMMITTEE (JAPC)

DERBYSHIRE JOINT AREA PRESCRIBING COMMITTEE (JAPC) The prevention of stroke and systemic embolism in atrial fibrillation (AF) with warfarin and New Oral Anticoagulants Warfarin remains the first-line option for anticoagulation in patients with AF at high risk of a stroke. Warfarin is an extremely effective and cost-effective treatment for preventing stroke in AF patients. NOACs represent potentially useful additional treatment options in certain patients, but the paucity of long-term clinical and particularly long-term safety data is of significant concern. NOACs may be suitable for prescribing in primary care as an alternative treatment to warfarin only if a patient s INR cannot be stabilised adequately within the target range with a suitable trial of optimised warfarin treatment; or if a patient is intolerant of warfarin. The benefit of a new oral anticoagulant over warfarin declines as the time in therapeutic range (TTR) on warfarin increases. It may be that warfarin is clinically superior for those with very good control with no difference for those with reasonable control. JAPC and local specialist concerns with NOACs include: o As new agents there is lack of long term safety data. o There is no reversal antidote unlike vitamin K for warfarin. o Lack of monitoring may reduce compliance. is the preferred NOAC formulary choice: o There is no adjustment of dose for age. o may be used with caution in egfr 15 29, whereas is contraindicated in egfr <30. o is once daily whereas is twice daily. o may be put into Monitored Dosage Systems whereas must be left in its original blister. o is licensed for treatment of DVT, and secondary prevention of DVT/PE after DVT whereas is not. The decision about whether to start treatment with rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of rivaroxaban compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to rivaroxaban should be considered in light of their level of international normalised ratio (INR) control. JAPC Derbyshire Guideline The prevention of stroke and systemic embolism in atrial fibrillation with warfarin and New Oral Anticoagulants Page 1 of 12

Abbreviations apcc aptt AF ALT CrCl D110 D150 egfr GFR INR LMWH MI NOAC PCC SNRI SSRI TTR ULN VKA Activated prothrombin complex concentrate activated partial thromboplastin time Atrial fibrillation Alanine transaminase Creatinine Clearance 110mg 150mg Estimated glomerular filtration rate Glomerular filtration rate International normalised ratio Low molecular weight heparin Myocardial infarction New oral anticoagulants Prothombin complex concentrate Selective serotonin norepinephrine re-uptake inhibitors Selective serotonin re-uptake inhibitors Time in therapeutic range Upper limit of normal Vitamin K antagonist Content Page Background...3 Aim and objective....3 Recommendations..3 Contraindications....4 Contraindications specific to NOAC...4 Recommended dose schedule o....4 o. 4 Drug interactions o...5 o....5 HASBLED Conversion guidelines for oral anticoagulants.. 6 How to manage bleeding complications.. 7 Discontinuation before surgery..8 References: Appendix 1: GRASP AF and CHADS 2.9 Appendix 2: Summary of NICE TAGs.11 Appendix 3: Summary of Product Characteristics 12 Appendix 4: Summary of NOAC 12 Background Page 2 of 12

Atrial fibrillation affects about 1.2% of the population in the United Kingdom and accounts for about a sixth of all strokes 1, 2. Its prevalence increases steeply with age, from 0.5% of those aged 50-59 years to 10% of those over 80 1. Strokes are more disabling in patients with atrial fibrillation and have higher 30 day mortality than those of arterial origin. 3,4 Because of the ageing population, the burden of stroke caused by atrial fibrillation is expected to rise sharply over the next few decades unless more effective thromboprophylaxis can be given to the population at risk. 3 When compared with placebo or no antithrombotic treatment, warfarin reduces the risk of stroke by about two thirds in patients with atrial fibrillation. 5 Antiplatelet treatment with aspirin is much less effective than warfarin it reduces the risk of stroke by about a fifth compared with placebo. 5 Guidelines currently recommend warfarin for patients with atrial fibrillation at high risk of stroke (previous stroke or embolism or more than one of the following risk factors: age 75 years, hypertension, diabetes, or congestive cardiac failure), either aspirin or warfarin for those at moderate risk (only one stroke risk factor), and aspirin for patients at low risk for stroke (no stroke risk factors). 6 Stroke is a major cause of morbidity and mortality in the UK. Strokes are more common in individuals living in deprived communities and for those with co-morbidities. The estimated cost of strokes to the UK in 2005/06 was 4.5 billion 7. Aim and Objectives The aim of this policy is to support prescribers in identifying appropriate patients with atrial fibrillation for whom the newer oral anticoagulant drugs as an alternative to current treatment would be an effective and cost effective treatment to prevent embolic events, and to then guide prescribers to prescribe safely. Recommendations JAPC recommends that the NOAC can be considered for the prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation, in whom warfarin is indicated, and who meet the following criteria: A CHADS 2 score of 2 (see appendix1) AND meet NICE criteria (see appendix 2) plus one of the following: Poor control with Warfarin after a 6 month trial (provided compliance is good): o TTR < 50%; o more than 2 INRs >8.0 or more than 3 INR s > 5 in a given 6 month period. or Cannot tolerate warfarin. NOTE: Poor compliance with vitamin K antagonists is not an indication for changing to a NOAC. Intolerance to warfarin is uncommon and changing to another vitamin K antagonist is usually the solution. Contra-indications specific to NOACs Page 3 of 12

Hypersensitivity to the active substance or to any of the excipients Creatinine clearance <15 ml/min (egfr <15 ml/min/1.73 m2) Pregnancy and breast feeding Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C Active clinically significant bleeding Hypersensitivity to the active substance or any of the excipients Creatinine clearance <30 ml/min (egfr <30 ml/min/1.73 m2) Pregnancy and breast feeding Liver function tests elevated >2 x ULN Active clinically significant bleeding Organic lesion at risk of bleeding Spontaneous or pharmacological impairment of haemostasis Concomitant treatment with systemic ketoconazole, cyclosporine,dronedarone, itraconazole and tacrolimus is contraindicated in clinical conditions associated with a significant risk of bleeding, such as: current or recent gastrointestinal ulceration malignant neoplasms recent brain or spinal injury recent brain, spinal or ophthalmic surgery recent intracranial haemorrhage oesophageal varices arteriovenous malformations vascular aneurysms major intraspinal or intracerebral vascular abnormalities Recommended dosing schedule of NOACs (According to estimated GFR.) The recommended dose for prevention of stroke and systemic embolism in patients with non-valvular AF is 20mg once daily. Renal function Recommended dose Comments egfr <15 ml/min/1.73 m2 Do not use egfr 15 29 ml/min/1.73 m2 15 mg once daily Limited clinical data; use with caution. egfr 30 49 ml/min/1.73 m2 15 mg once daily * Age/ renal function/ concomitant medication Recommended dose Comments Adults aged <75 years 150 mg bd Consider 110 mg bd if high bleeding risk or GI irritation. Adults aged 75 80 years 150 mg bd If at low thromboembolic risk but high bleeding risk consider 110 mg bd. Adults aged >80 years 110 mg bd Page 4 of 12

egfr <30 ml/min/1.73 m2 Do not use egfr 30 50 ml/min/1.73 m2 150 mg bd Consider 110 mg bd if high bleeding risk or GI irritation. egfr 50 80 ml/min/1.73 m2 150 mg bd Consider 110 mg bd if high bleeding risk or GI irritation. + Verapamil 110 mg bd * While on treatment renal function should be assessed at baseline then at least once a year, or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate. Drug interactions Interacting drug Dronedarone Systemic azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir) Anticoagulants Antiplatelet drugs/ NSAIDs St John s wort/ rifampicin/ carbamazepine/ phenytoin/ phenobarbital Comments Limited data on combined use. Avoid concomitant use. May increase bleeding risk. Concomitant use with rivaroxaban is not recommended. Risk of bleeding increased. Use with caution. Detailed instructions for the transitions with warfarin are given below. May increase bleeding risk. Use with caution. May reduce rivaroxaban blood levels. Use with caution. Interacting drug St John s wort/ rifampicin/ carbamazepine/ phenytoin Systemic ketoconazole/ cyclosporine/ itraconazole/ tacrolimus Posaconazole Dronedarone Ritonavir Verapamil Amiodarone/ quinidine/ clarithromycin Selective serotonin re-uptake inhibitors (SSRIs) and selective serotonin norepinephrine re-uptake inhibitors (SNRIs) Anticoagulants Antiplatelet drugs/ NSAIDs Comments May reduce dabigatran blood levels. Avoid concomitant use. Use contraindicated with dabigatran. No data on combined use. Concomitant use not recommended. Use contraindicated with dabigatran. No data on combined use. Concomitant use not recommended. Reduce dabigatran to 110 mg bd. Use with caution. May increase dabigatran levels. Use with caution. Increased the risk of bleeding in RE-LY in all treatment groups. Risk of bleeding increased. Avoid concomitant use of other anticoagulants. Detailed instructions for the transitions with warfarin are given below. No parental anticoagulant should be given for 12 hours after last dose of dabigatran. Risk of bleeding increased. This bleeding risk increase is the same as with warfarin, so only use combination where you would with warfarin. Consider 110 mg bd. Page 5 of 12

Note Patients should seek urgent medical attention if they fall or injure themselves during treatment, especially if they hit their head, due to the increased risk of bleeding. 9 Those taking other anticoagulants must not take dabigatran/rivaroxaban except during a period where their treatment is being switched to or from the NOACs If compliance is the major factor for poor control this is not resolved with a change to a NOAC. Assessment of bleeding risk should be undertaken before initiating anticoagulant therapy. The simple HAS-BLED bleeding risk score has been developed to help guide choice of therapy. A score 3 indicates high-risk and hence action and regular review of these patients is required (this may include a referral to a haematology consultant led clinic. HAS-BLED bleeding risk score Hypertension >160mmHg 1 Abnormal renal and liver Creatinine >200 1 or 2 function ALT> 3x ULN Stroke/ TIA 1 Bleeding diathesis 1 Labile INR 1 Elderly (>65) 1 Drugs/alcohol 1 or 2 3 indicates high bleeding risk Conversion guidelines of oral anticoagulants (Adopted from Fife Area Drugs and Therapeutics committee) The newer oral anticoagulants should only be considered if there is poor INR control on warfarin as defined above. Conversion from Warfarin to: Warfarin should be stopped and treatment initiated when the INR is 3.0. When converting patients from warfarin, INR values will be falsely elevated after the intake of rivaroxaban. The INR is not valid to measure the anticoagulant activity of rivaroxaban, and therefore should not be used. Warfarin should be stopped and dabigatran started when INR is below 2.0 (usually 3-5 days after discontinuing warfarin for a patient with a stable INR 2.0-3.0) Conversion from NOAC to warfarin: It is important to ensure adequate anticoagulation while minimising the risk of bleeding during conversion of therapy. It should be noted that rivaroxaban can contribute to an elevated INR. Warfarin should be given concurrently until the INR is 2.0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by warfarin dosing guided by INR testing. When converting from dabigatran to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows: For CrCL>50mL/min, start warfarin 3 days before discontinuing dabigatran. For CrCL 31-50mL/min, start warfarin 2 days before discontinuing dabigatran. For CrCL 15-30mL/min, start warfarin 1 day before discontinuing dabigatran. Page 6 of 12

While on both rivaroxaban and warfarin the INR should NOT be tested earlier than 24 hours after the previous dose 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. Conversion from Parenteral Anticoagulants to: Rivaorixiban should be started 0 to 2 hours before the time of the next scheduled administration of the parenteral medicinal product (LMWH) or at the time of discontinuation of a continuously administered parenteral medicinal product ( e.g. IV unfractionated heparin) Conversion to Parenteral Anticoagulants from: Give the first dose of parenteral anticoagulant at the time the next rivaroxaban dose would be taken For CrCL <15 ml/min, start warfarin 2 days before discontinuing dabigatran. Because dabigatran can contribute to an elevated INR, the INR will better reflects warfarin s effect after dabigatran has been stopped for at least 2 days. should be started 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug ( e.g. IV unfractionated heparin) For patients taking dabigatran, wait 12 hours (CrCL>30mL/min) or 24 hours (CrCL<30mL/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant. How to manage bleeding complications Should bleeding complications arise in a patient receiving a NOAC the next administration dose should be delayed or treatment discontinued as appropriate Discuss with on-call haematology consultant. There is no reversal agent for rivaroxaban or dabigatran. Vitamin K and protamine sulphate do not reverse the effect of rivaroxaban or dabigatran. is not dialyzable. 10 Check the PT and, if available, anti Xa Check the APTT and, if available, the assay (with rivaroxaban standard). Haemoclot thrombin time. has a half-life of Discontinue treatment with dabigatran (half-life approximately 5-13 hours. Delay/omit the 13 hours with normal renal function) next dose of rivaroxaban. If taken within 2 Manage bleeding as per rivaroxaban. There is hours consider activated charcoal. some experimental evidence to support the Management should be individualised role of activated prothombin complex according to the severity and location of the concentrates (FEIBA), PCC or Novoseven. bleed. However, their usefulness in clinical settings Mild bleeding: has not been evaluated and therefore these Local haemostatic measures. alternatives cannot be relied upon. Consider tranexamic acid orally (15 mg/kg QDS) and/or topically (e.g. mouthwash, nasal drops, Around 85% of dabigtran clearance is renal: applied directly to a bleeding point). therefore, maintain adequate diuresis. Moderate severe bleeding: can be dialysed (protein binding is Local haemostatic measures. low), and it may take 6-8 hours to clear Give tranexamic acid IV (15 mg/kg) and/or topically dabigatran this way; however, data supporting (mouthwash, nasal drops, applied directly to this approach is limited. bleeding point). The duration of dialysis may be best guided by Give fluid replacement. Consider FFP (20ml/kg). normalisation of the aptt. Give blood product support as indicated by Hb, other coagulopathy, platelets (if count< 75 x 10 9 /L or antiplatelet agents). Consider use of Prothrombin Complex Concentrate Life threatening bleeding: As for moderate-severe bleeding. Give PCC. Page 7 of 12

If the above measures fail to work consider activated prothombin complex concentrate (apcc i.e. FEIBA)) or recombinant factor VIIa (Novoseven). There is currently very limited clinical experience with the use of PCC, apcc and Novoseven in individuals receiving rivaroxaban. The recommendation is based on limited non-clinical data. SURGERY: For emergency surgery consider measures recommended for moderate-severe bleeding. For planned surgery see below. Discontinuation before surgery If an invasive procedure or surgical intervention is required, rivaroxaban should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the physician. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. should be re-started after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. Renal function (Crcl ml/min) Half-life (hours) (see b) Timing of discontinuation after last dose of dabigatran before surgery Standard High risk of risk of bleeding (see c) bleeding >80 13 (11-24 hours 2-4 days 22) >50 to <80 15 (12-24-48 hours 2-4 days 34) >30 to <50 18 (13-48-72 hours 4 days 23) <30 (see 27 (22-2-5 days >5 days a) 35) Crcl- creatinine clearance a) Contraindicated for use in these patients b) Half-life data from renal impairment study in healthy volunteers 8 c) Types of surgery associated with a high risk of bleeding (or in major surgery where complete haemostasis may be required) include but is not limited to cardiac surgery neurosurgery, abdominal surgery or those involving a major organ. Other procedures such as spinal anaesthesia may also require complete haemostatic function. Other important determinants of bleeding risk include advancing age, co-morbidities (e.g. major cardiac, respiratory or liver disease), low body weight (<50kg) and concomitant use of antiplatelet therapy. Page 8 of 12

References 1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke 1991;2:983-8. 2. DeWilde S, Carey IM, Emmas C, Richards N, Cook DG. Trends in the prevalence of diagnosed atrial fibrillation, its treatment with anticoagulation and predictors of such treatment in UK primary care. Heart 2006;92;1064-70 3. Lin HJ, Wolk PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27:1760-4. 4. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke. Results from the national registry of atrial fibrillation. JAMA 2001;285:2864-70. 5. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients whohave nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857 6. Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidenced-Based Clinical Practice Guidelines (8th edition). Chest 2008;1333:546S. 7. Scarbrough et al. Stroke Stats. 2009 8. Strainger J, Rathgen K, Stahle H, et al. Influenceof renal impairment on the pharmacokinetics and pharmacodynamics of ral dabigatran etexilate. Clin Pharmacokinet 2010;49:259-268. 9. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=wc0b01ac05 8004d5c1 (accessed 01/06/2012). 10. Noakes T. : a guide to new indications. MIMS. April 2012. Appendix 1 GRASP AF Query and risk stratification tool is FREE and available for use with all GP clinical systems in England GRASP AF provides a set of MIQUEST queries to identify, for your practice, patients with a diagnosis of AF who are not on warfarin. It calculates their risk of stroke using the validated CHADS 2 scoring system and highlights patients with a CHADS 2 score of 2 or more who are not on warfarin and would benefit from a review to assess the issue of anticoagulation. To find out more about this new tool and to sign up to run the search simply go to www.improvement.nhs.uk/graspaf CHADS 2 scoring Congestive Cardiac Failure 1 point Hypertension 1 point Age >75 years 1 point Diabetes 1 point Stroke or TIA before 2 points CHADS 2 scores are 0-6; with 0 indicating a low risk of stroke and 6 indicating a very high risk; the scoring and concomitant medication recommended is shown below. These recommendations are used in the GRASP-AF tool and are based on the NICE recommendations for different absolute levels of risk associated with strata of the CHADS 2 scores. (NICE Guideline CG36 Atrial Fibrillation). Page 9 of 12

Risk Category CHADS Recommended stroke prevention Score High 2 Oral anticoagulation (OAC) Moderate particularly if age >65 & evidence of vascular 1 Either OAC or Aspirin 75-325 mg daily Preferred: OAC rather than Aspirin disease No risk factors and age < 65 0 Either Aspirin or no antithrombotic therapy Preferred: no antithrombotic therapy *Target INR 2-3 with time in therapeutic range > 50% CHADS 2 Score Adjusted Annual Stroke Rate (95% confidence interval) Risk rating (low, medium, high) Recommended Treatment 0 1.9 (1.2-3.0) Low Aspirin 1 2.8 (2.0-3.8) Medium Aspirin or Warfarin 2 4.0 (3.1-5.1) Medium Aspirin or Warfarin 3 5.9 (4.6-7.3) High Warfarin 4 8.5 (6.3-11.1) High Warfarin 5 12.5 (8.2-17.5) High Warfarin 6 18.2 (10.5-27.4) High Warfarin Page 10 of 12

Appendix 2 Summary of NICE TAGs NICE issued a Technology Appraisal (TA 249) etexilate for the prevention of stroke and systemic embolism in atrial fibrillation in March 2012. http://guidance.nice.org.uk/ta249 1.1 etexilate is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more of the following risk factors: previous stroke, transient ischaemic attack or systemic embolism left ventricular ejection fraction below 40% symptomatic heart failure of New York Heart Association (NYHA) class 2 or above age 75 years or older age 65 years or older with one of the following: diabetes mellitus, coronary artery disease or hypertension. 1.2 The decision about whether to start treatment with dabigatran etexilate should be made after an informed discussion between the clinician and the person about the risks and benefits of dabigatran etexilate compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to dabigatran etexilate should be considered in light of their level of international normalised ratio (INR) control. NICE issued a Technology Appraisal (TA 256) for the prevention of stroke and systemic embolism in atrial fibrillation in May 2012. http://guidance.nice.org.uk/ta256 1.1 is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more risk factors such as: congestive heart failure hypertension age 75 years or older diabetes mellitus, prior stroke or transient ischaemic attack. 1.2 The decision about whether to start treatment with rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of rivaroxaban compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to rivaroxaban should be considered in light of their level of international normalised ratio (INR) control. Page 11 of 12

Appendix 3: summary of product characteristics These can be found at the following link: http://www.medicines.org.uk/emc/ Appendix 4 Summary of NOAC (Note that the trials compared different levels of INR rates TTR was 64% in RE-LY and 55% in ROCKET AF) Efficacy in stroke prevention compared to warfarin Reduced risk of bleeding compared to warfarin Overall no difference Superior (150mg bd dose) Non-inferior (110mg bd dose) Evidence for reduced bleeding risk at lower dose. NB Increased risk of GI bleed than warfarin at higher dose which is the usual dose. Overall reduced intra cranial haemorrhage (ICH) Overall no difference Non inferior (ITT analysis) Equivalent to warfarin (except reduced ICH) Reversibility Uncertain. Uncertain (possible data supports use PCC) Dialysable Yes No Dosing bd od Drug interactions P- glycoprotein substrates Simultaneous PGP & CYP-3A4 Use in patients with swallowing difficulties Cannot be crushed Suitability for MDS Not suitable Suitable Cost / year (Costs may vary in different settings because of negotiated procurement discounts) 803 767 May be crushed and put through NG tube Possibility of using in other conditions NICE approved for orthopaedic prophylaxis. Phase III data shows efficacy in DVT but no NICE appraisal currently planned NICE approved for orthopaedic prophylaxis. Phase III data shows efficacy in DVT and NICE appraisal ongoing. Page 12 of 12