NORTH WEST LONDON GUIDANCE ANTITHROMBOTIC MANAGEMENT OF ATRIAL FIBRILLATION

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1 North West London CardioVascular & Stroke Network NORTH WEST LONDON GUIDANCE ON ANTITHROMBOTIC MANAGEMENT OF ATRIAL FIBRILLATION Key Messages 1. Efforts should be made to identify patients with Atrial Fibrillation (AF) 2. Patients with AF should have their risk assessed based on the CHA 2 DS 2 VASc score 3. Anti-platelet agents offer little benefit in terms of stroke reduction in AF 4. Patients with a CHA 2 DS 2 VASc score of 1 should be strongly considered for oral anticoagulation 5. Warfarin should remain the first line treatment for patients with AF requiring anticoagulation 6. Novel anticoagulants, including dabigatran, as per NICE guidelines, may be considered as an alternative, within their licensed indications, as an alternative to warfarin, especially in patients with a poor TTR or who are intolerant of, or allergic to, warfarin and other vitamin K antagonist anticoagulants. 1

2 1. Atrial Fibrillation and Stroke Atrial fibrillation (AF) occurs in 1 2% of the general population. The prevalence increases with age; from 0.7% in people aged years to 18% in those older than 85 years. AF increases the risk of stroke in patients 5-fold. AF related strokes are associated with a 50% one year mortality rate and survivors of such strokes are frequently left severely disabled. Under-diagnosis is a significant issue and as many as 50% of AF cases are undiagnosed. Key message 1 : Efforts should be made to identify patients with AF 2. Assessing the risk of stroke CHA 2 DS 2 VASc is a more comprehensive tool than CHADS 2 and improves the distinction between patients who are at very low risk and do not need anticoagulation (score 0) and those who would benefit from anticoagulation (score 1-2) A review of risk should be performed annually and following any changes in clinical condition Key message 2 : Patients with AF should have their risk assessed based on the CHA 2 DS 2 VASc risk stratification score (below) CHA 2 DS 2 -VASc acronym Score Congestive heart failure/lv dysfunction 1 Hypertension 1 Aged 75 years ( Major) 2 Diabetes mellitus 1 Prior Stroke/TIA ( Major) 2 Vascular disease (prior MI, PAD, or aortic plaque) 1 Aged years 1 Sex category (i.e. female gender) 1 MAXIMUM SCORE 9 2

3 European Society of Cardiology (ESC) GUIDANCE on antithrombotic therapy for AF Risk category CHA 2 DS 2 VASc score Recommended antithrombotic therapy One major risk factor or 2 clinically relevant non-major risk factors 2 Oral Anticoagulation (OAC) One clinically relevant 1 OAC or aspirin mg daily. Preferred: OAC non-major risk factor [1] No risk factors 0 Either aspirin mg daily or no antithrombotic therapy. Preferred: no antithrombotic therapy rather than aspirin. Note: Major risk factors are those associated with the highest risk for stroke in patients with AF: prior thrombo-embolism (stroke, TIA, or systemic embolism), age 75 years. Clinically relevant non-major risk factors: hypertension, heart failure, or moderate to severe LV dysfunction (ejection fraction 40% or less), diabetes mellitus, female sex, age years, and vascular disease (myocardial infarction, complex aortic plaque, carotid disease, peripheral artery disease). The CHA 2 DS 2 VASc score applies to patients with non-valvular AF. Additional significant risk factors for thromboembolism complicating atrial fibrillation and in particular, the presence of mitral stenosis should also be strongly considered HAS-BLED Score. A prediction of Bleeding Risk on anti-coagulant therapy in AF (Recommended by the ESC Guidelines) Feature Score Interpretation Hypertension (systolic 160 mmhg) 1 Abnormal renal /liver function 1 or 2 Previous Stroke 1 Bleeding History or predisposition 1 Labile INR 1 Elderly ( 65 years)or biological age 1 Other Drugs including aspirin, NSAIDS/ Concomitant Alcohol 1 or 2 Max =9 This simple tool can help assess risk of bleeding in patients with AF. Increasing scores are associated with a progressive increase in rate of major bleeding. A score of 3 indicates high-risk and justifies some caution, with regular patient review required when taking anti-thrombotic therapy. However, there is evidence of net clinical benefit with oral anticoagulants, even in patients with high HAS-BLED scores, and especially in those with a high CHA 2 DS 2 VASc score. Circulation. 2012;125:

4 3. Role of Antiplatelet agents in AF Aspirin has little or no benefit in reduction of stroke risk 1 It has been unequivocally demonstrated that warfarin and vitamin K antagonists(vka) are significantly superior to antiplatelet agents, with an additional risk reduction Dual antiplatelet therapy with aspirin in combination with clopidogrel has been compared to warfarin and whilst it is more effective than aspirin monotherapy it is less effective than warfarin with similar major bleed rates 2 Key message 3 : Anti-platelet agents offer little benefit in terms of stroke reduction in AF 4. Treatment Strategies The most recent European Society of Cardiology guidelines (see section 2) on management of AF recommend anticoagulation as first line antithrombotic treatment for AF patients with CHA 2 DS 2 VASc 1 and recommend a move away from routine use of aspirin. Key message 4 : Patients with a CHA 2 DS 2 VASc score of 1 should be strongly considered for oral anticoagulation 5. Warfarin It has been demonstrated that warfarin significantly reduces the risk of ischaemic stroke in patients with AF by approximately 67% compared with placebo. Warfarin requires INR monitoring and it is suggested that anticoagulation control measured by Rosendaal s Therapeutic Time in range of between 60-70% offers patients good protection against stroke. Warfarin has been the mainstay of oral anticoagulation management for nearly 60 years, as such its safety profile is well understood. Key message 5 : Warfarin should remain first line treatment for patients with AF requiring anticoagulation 1 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Yusuf S. Clopidogrel plus asprin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for prevention of vascular events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:

5 6. New oral anticoagulants Two new oral anticoagulants (NOACs) are licensed for stroke prevention in non-valvular atrial fibrillation (NVAF): dabigatran, a direct thrombin inhibitor and rivaroxaban, a direct factor Xa inhibitor. Dabigatran is largely (80%) excreted by the kidneys. Data suggests that in trial populations: Dabigatran 110mg bd is non-inferior to warfarin in terms of reduction in the primary composite end point of stroke (haemorrhagic and ischaemic) and systemic embolism (NNT=588), with less major bleeding. ( Note please bd dosage) Dabigatran 150mg bd demonstrates significant superiority over warfarin with an NNT of 167 for stroke (haemorrhagic and ischaemic) and systemic embolism. Rates of major bleeding with dabigatran 150mg are similar to rates observed with warfarin. However the overall bleeding profile of Dabigatran is different with significantly less intracranial haemorrhage (including haemorrhagic stroke) compared with warfarin, but a significantly higher rate of gastrointestinal bleeding (both doses). Note: dabigatran 150mg is licensed in patients <80 years only. Rivaroxaban Data suggests that in trial populations: Rivaroxaban 20 mg od demonstrated non-inferiority in the ITT analysis and superiority in the safety analyses of the trial data with an NNT of 333 for haemorrhagic and ischaemic stroke and systemic embolism (based on ITT analysis). Rivaroxaban demonstrated similar rates of major bleeding, but with an overall different bleeding profile, with significantly more major GI bleeding (NNH 101) and significantly less intracranial haemorrhage (including haemorrhagic stroke). The ITT data demonstrated that rivaroxaban was non-inferior to warfarin controlled to 58% TTR. Numbers needed to treat to prevent one stroke (ischaemic or haemorrhagic) or systemic embolism with rivaroxaban instead of warfarin are 200 (based on safety on treatment analysis) Data suggest a modest overall benefit in patients controlled to TTR of 58%; therefore it is reasonable to try warfarin prior to rivaroxaban. Important considerations related to the NOACs When assessing a patient for anti-coagulation we should actively consider risk of thrombosis against risk of haemorrhage, not only in deciding to start an OAC but also in choosing the agent and the dose. The benefit of the NOACs may be greater in patients with poor TTR but there is some controversy in this area. NOACs do not require routine monitoring which may be an advantage for some patients. However laboratory assessment of anticoagulant effect is not yet available, which may be a problem in an emergency or when assessing efficacy. 5

6 Currently no specific antidote to reverse over-anticoagulation and in the management of major haemorrhage Please see comments on reversal on p 8. Dose adjustments are required in renal impairment. Please ascertain CrCl prior to starting treatment. Dabigatran is not suitable for dispensing into a compliance aid as the capsules are moisture sensitive Rivaroxaban and Dabigatran both have increased rates of GI bleed relative to warfarin, but less intracranial haemorrhage. Drug Interactions with the NOACs This is not meant to be an exhaustive list of interactions. The reader is directed to view the latest version of the summary of product characteristics and the BNF for a comprehensive update of interactions Drug interactions with dabigatran The concomitant systemic use of the following is contra-indicated: Drugs that impair haemostasis including unfractionated heparin, low molecular weight heparins, heparin derivatives (e.g. fondaparinux), oral anticoagulants except under the circumstances of switching therapy to or from dabigatran. The strong Pgp inhibitors, ketoconazole, cyclosporin, itraconazole and tacrolimus The concomitant systemic use of the following is to be avoided: Drugs that impair haemostasis including aspirin, clopidogrel, dipyridamole, NSAIDs, SSRIs, SNRIs Rate-lowering and anti-arrhythmic drugs including dronedarone, amiodarone, quinidine, verapamil. Other P-gp inhibitors such as clarithromycin P-gp inducers such as rifampicin, carbamazepine, or phenytoin Protease inhibitors including ritonavir and its combinations with other protease inhibitors Other azole-antimycotics such as fluconazole or posoconazole Drug interactions with rivaroxaban. (There have been no contra-indications listed to date) The concomitant systemic use of the following is to be avoided: Drugs that impair haemostasis including aspirin, clopidogrel, dipyridamole, NSAIDs, SSRIs, SNRIs The cardiac drug dronedarone (no others listed at present) Drugs that impair haemostasis including unfractionated heparin, low molecular weight heparins, heparin derivatives (e.g. fondaparinux), oral anticoagulants except under the circumstances of switching therapy to or from rivaroxaban Azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole HIV protease inhibitors including ritonavir and its combinations with other protease inhibitors Strong CYP3A4 and P-gp inducers such as rifampicin, carbamazepine, or phenytoin 6

7 Dabigatran specific Recent reports have shown an increased risk of bleeding and bleeding-related fatalities in particular patient groups such as the elderly and those with poor renal function (note dabigatran is contraindicated in severe renal impairment). In October 2011 the European Medicines Agency s Committee for Medicinal Products for Human Use (CHMP) recommended changes to the product information following reports of fatal cases of bleeding. The recommended updated product information includes advice that renal function should be assessed in all patients before starting treatment; while on treatment, it should be assessed at least once a year in patients over 75 years of age and in those with renal impairment. Additionally it should be assessed in any patient whenever a decline in renal function is suspected. Use in patients with previous ACS Re-analysis of the RE-LY data on MI indicated that there was no significant increased risk of MI with dabigatran when compared with warfarin. However, data indicate that rivaroxaban may be a more suitable option for patients with previous ACS. Advice to prescribers As outlined in NICE guidance, prescribers are asked to note the following: The decision about whether to start treatment with dabigatran etexilate / rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of dabigatran etexilate / rivaroxaban compared with warfarin. All patients should be supplied with a patient alert card, available from the manufacturers. Please see contact addresses on page 9. Please check Creatinine Clearance, Cr Cl, before initiating therapy. For people who are taking warfarin, the potential risks and benefits of switching to dabigatran etexilate / rivaroxaban should be considered in light of their level of international normalised ratio (INR) control. NICE guidance allows doctors and patients to decide whether to use dabigatran / rivaroxaban on the basis of anticoagulation control (measured as TTR) if they wish to do so. For clinical queries / advice Contact local consultant haematologists or, Royal Brompton Hospital Anticoagulation Clinic Professor Mike Laffan, Professor of Haemostasis and Thrombosis; Hammersmith Hospital Dr Abdul Shlebak,Consultant Haematologist, St Mary s Hospital,

8 Reversal of anticoagulation Life-threatening bleed - refer to local guidelines and contact haematology VKA anticoagulants Stop VKA Major (limb / life-threatening): Give vitamin K 5 mg by slow intravenous infusion. Give prothrombin complex concentrate (PCC, Beriplex or Octaplex) by intravenous infusion as per local guidance. Reassess the INR immediately and after 4 hours. INR >8.0 with minor bleeding: Give vitamin K 1-3mg by slow intravenous infusion. If INR still too high after 24 hours repeat dose of vitamin K. INR >8.0 no bleeding or and high bleeding risk: Give vitamin K 1-5mg by mouth using the intravenous preparation orally (unlicensed use). If INR still too high after 24 hours repeat dose of vitamin K. INR , with minor bleeding: Give vitamin K 1-3mg by slow intravenous infusion, or by mouth according to urgency, monitor INR daily, restart when INR <5.0 INR , no bleeding: withhold one or two doses and reduce subsequent maintenance dose Unexpected bleeding at therapeutic levels always investigate possibility of underlying cause e.g. unsuspected renal or gastro-intestinal tract pathology. New oral anticoagulants The newer agents have no specific antidote therefore one cannot reverse the effect pharmacologically. Haemostatic agents may be useful (see below). Their shorter half -life is an advantage when haemostasis is required. Until formal guidance is released please refer to local policies and please contact haematology. Dabigatran Contact Haematology in all cases Stop dabigatran Give fluid replacement to maintain good urine output ( adequate renal diuresis important) In addition, as appropriate (based on severity of bleed and response to reversal measures) consider the following: Mechanical compression Surgical intervention Blood product or component transfusion support Oral liquid charcoal (if last dose within 2 hours) Prothrombin complex concentrate, activated PCC or recombinant Factor VIIa. There is currently very limited clinical experience with the use of these products in individuals receiving dabigatran but some evidence that it may be of benefit. Haemodialysis especially if renal failure Investigate cause of bleeding 8

9 Rivaroxaban Contact Haematology in all cases Stop rivaroxaban Give fluid replacement In addition, as appropriate (based on severity of bleed and response to reversal measures) consider the following: Mechanical compression Surgical intervention Blood product or component transfusion support Prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa). There is currently very limited clinical experience with the use of these products in individuals receiving rivaroxaban but some evidence that it may be of benefit Investigate cause of bleeding Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. Elective surgery Vitamin K antagonists Refer to local guidelines for peri-operative management of VKA anticoagulation / contact local haematology team for advice. New oral anticoagulants Dabigatran Stopping dabigatran before elective surgery Renal function (CrCl in ml/min) Estimated half-life (hours) High risk of bleeding in major surgery Standard risk of bleeding in major surgery 80 ~13 2 days before 24 hours before 50 - <80 ~ days before 1-2 days before 30 - <50 ~18 4 days before 2-3 days before (>48 hours) When to re-start dabigatran will depend predominantly on the patient s haemostatic status and relative bleeding risk, seek haematology advice as appropriate. NOTE: dabigatran is licensed for use in hip and knee replacement surgery, where it is started 1-4 hours after surgery (110mg (elderly over 75 years, 75mg) 1 4 hours after surgery, then 220mg (elderly over 75 years, 150mg) once daily for specified duration). 9

10 Rivaroxaban Rivaroxaban should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the physician. Rivaroxaban should be restarted as soon as possible after the invasive procedure or surgical intervention provided the clinical situation allows and adequate haemostasis has been established. NOTE: rivaroxaban is licensed for use in hip and knee replacement surgery, where it is started 6-10 hours after surgery (10mg once daily starting 6 10 hours after surgery, for specified duration). Emergency Surgery Contact Haematology for advice Switching between the new Oral Anticoagulants and other anticoagulants. In all cases discussion with Haematology is recommended. Switching from dabigatran to a parenteral anticoagulant A period of 12 hours should be left after the last dose of dabigatran before starting the parenteral anticoagulant. Switching from rivaroxaban to a parenteral anticoagulant The first dose of the parenteral anticoagulant should be given at the time the next rivaroxaban dose would have been taken. Switching from a parenteral anticoagulant to dabigatran Dabigatran should be given 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH) Switching from a parenteral anticoagulant to rivaroxaban Rivaroxaban should be given 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) Switching from dabigatran to warfarin. Recommend contact Haematology for advice. PT should be checked (take at dabigatran trough, pre next dose) BEFORE starting warfarin and the result taken into account to assess when warfarin anti-coagulation has been achieved and dabigatran can be stopped. When switching to warfarin, dabigatran and warfarin should overlap until the INR is 2.0. For the first two days of the conversion period, standard initial dosing of warfarin should be used followed by dosing adjusted as per INR results. The starting time of warfarin should be based on the patients CrCL as follows: CrCL 50 ml/min, start warfarin 3 days before discontinuing dabigatran CrCL 30-< 50 ml/min, start warfarin 2 days before discontinuing dabigatran. 10

11 Switching from rivaroxaban to warfarin. Recommend contact Haematology for advice. PT should be checked (take at rivaroxaban trough, pre next dose) BEFORE starting warfarin and the result taken into account to assess when warfarin anti-coagulation has been achieved and rivaroxaban can be stopped. When switching to warfarin, rivaroxaban and warfarin should overlap until the INR is 2.0. For the first two days of the conversion period, standard initial dosing of warfarin should be used followed by dosing adjusted as per INR results. Switching from warfarin to dabigatran. Warfarin should be stopped and dabigatran initiated when INR < 2.0. Switching from warfarin to rivaroxaban. Warfarin should be stopped and rivaroxaban initiated when INR 2.0 (local consensus) Key message 6 : Novel anticoagulants, including dabigatran, as per recent NICE guidelines, may be considered as an alternative, within their licensed indications, as an alternative to warfarin, especially in patients with poor TTR (( 65%) or who are intolerant of, or allergic to, warfarin and other vitamin K antagonist anticoagulants and also in patients whose medications are frequently changed. See also for manufacturer educational resources Please note: The NWL Guideline is not intended to remove the clinical responsibility of the prescriber to make prescribing decisions on a case by case basis and is not intended to contradict NICE TA249: Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation (Further advice for Rivaroxaban when available.) 11