Preventing AF related stroke. Clinical guidance.

Transcription

1 V2.0: (06/02/15) Preventing AF related stroke Clinical guidance Declaration; The Programme is funded through a joint working project between Bayer Healthcare and West of England AHSN This document was funded with an unrestricted educational grant from Boehringer-Ingelheim

2 What is this toolkit for? It is intended to support clinicians in making decisions about AF-related stroke prevention and anticoagulation for people with AF. It has been produced as part of the Don t Wait to Anticoagulate project.

3 ...don t wait to anticoagulate...labile INR....are on aspirin or are not on anticoagulation at all....they do not have an AF diagnosis. more effective at preventing AF related stroke than aspirin Nearly 50% of people with AF are not effectively protected against stroke because 230,000 people with AF still at risk of stroke because treated with aspirin monotherapy instead of anticoagulants 3 times Anticoagulation is 800,000 people are currently diagnosed with AF 9% 1 in 5 aged % aged in 4 250,000 people are believed to be undiagnosed with AF currently in the UK in UK population 1.6% Prevalence of AF increases with age... From the age of 55 the likelyhood of developing AF is... with atrial fibrillation (AF) will suffer a stroke in the UK will end up needing residential care for the rest of their lives will go home 3 5 In the next 4 hours 10 people 2 will die Every year 7,000 strokes x5 2,000 premature deaths People with AF have a five-fold higher stroke risk than those without could be avoided through effective detection and protection with anticoagulant drugs Each year approximately 1 in 20 people with AF will have a stroke because they are not anticoagulated Mortality rate from stroke for people with AF is double that of people with normal heart rhythm Each AF related stroke cost the NHS 12,000 in the first year alone 15% of all strokes are caused by AF An estimated 3 people from each GP practice in the West of England AHSN will suffer an AF related stroke per year

4 Contents Section One Clinical Overview: The Case for Change 1 Section Two AF-related Stroke Prevention: Guides to Clinical Practice 9 1. West of England AF related stroke prevention guidance 2. Key factors influencing anticoagulant choice in Non-Valvular AF 3. Oral anticoagulants: Frequently Asked Questions 4. Identifying stroke & bleed risk 5. Managing & predicting bleeding & switching between anticoagulants 6. Anticoagulating the frail and elderly 7. Managing patients with a labile INR 8. Shared decision making with patients 9. Local formulary guidance References 38

5 Section One: Clinical Overview: The Case for Change Foreword Dr Jim Moore, Stoke Road Surgery, Gloucestershire, Cardiology GPwSI and Clinical Lead for AF Stroke Prevention Atrial fibrillation (AF) is a major cause of stroke. The 2014 National Institute for Health and Clinical Excellence (NICE) publication, Atrial Fibrillation: The Management of Atrial Fibrillation, resulted in a welcome focus on the risks of stroke associated with AF. Thousands of strokes in the UK are avoidable with both the timely identification of patients with AF and the appropriate management of their thromboembolic risk with anticoagulation. The risk of stroke is five times greater in a patient with AF and the associated disability and mortality are also significantly increased when compared to strokes in patients with a normal cardiac rhythm. It is no coincidence that the guidelines published both nationally and internationally in the last few years emphasise the importance of addressing stroke risk early in the assessment and management of patients with newly diagnosed AF. Those same guidelines have additionally stressed that Aspirin should no longer be seen as a safe and effective drug for stroke prevention in AF patients, and most importantly should not be considered as an alternative to anticoagulation. In recent years we have seen the introduction of several new oral anticoagulants (NOACs) available with NICE approval for use in AF patients. NOACs have been shown in clinical trials to be non inferior to warfarin in their ability to reduce stroke, and in addition to warfarin, they provide increased anticoagulant choice and flexibility in the management of stroke risk. Lastly and most importantly, progress in this area will best be achieved through a balanced and honest dialogue with patients about the risks of stroke and the potential benefits of treatment. The recent NICE guidance supports this, highlighting the need for a personalised package of care and information as a key recommendation. 1

6 Foreword Jo Jerrome Deputy CEO AF Association Atrial fibrillation (AF) is a common heart arrhythmia. The number of patients with AF is rising and we expect this to continue, with GRASP- AF data for England showing a prevalence rate of 1.8%. Symptoms of AF can include breathlessness, palpitations, dizziness and chest discomfort. However, the condition can also remain silent and asymptomatic. Either way, AF is the single most powerful independent risk factor for stroke. As well as being more deadly and disabling, AF-related strokes are also more expensive. Every AF-related stroke costs the NHS almost 12,000 pounds in the first year - putting a disproportionately high burden both on healthcare budgets and on those providing care, either formally or informally. Early diagnosis and appropriate management with an anticoagulant can prevent at least two thirds of AF-related strokes suffered annually. Consequently there is urgent need for the improved diagnosis and management of AF to prevent thousands suffering avoidable strokes, disability and premature death. In order to improve health outcomes for people with AF and to achieve significant financial savings in the NHS, it is imperative that more AF patients in need of anticoagulation are identified. The tools included within this package provide extensive and significant support to facilitate accurate assessment and appropriate management of AF for patients and clinicians. The Don t Wait to Anticoagulate resources reflect national guideline recommendations in practical, manageable and supportive tools. Life with AF can be long and healthy when patients are able to appropriately manage and control this potentially devastating and debilitating condition. The power to do so is in a well-informed partnership between patient and clinician. This toolkit provides the inspiration and know-how to initiate and make a real difference to the lives of AF patients and those close to them. 2

7 Introduction Dr Matthew Fay, GPwSI in Cardiology, Westcliffe Medical Practice, Bradford, and member of the NICE Guideline Development Group We often hear that there is an epidemic of AF coming with the ageing population. The truth is that it is already upon us. In the UK there are a million or more patients suffering from the dysrhythmia, and as a result, shouldering the risk of stroke. With the development of better risk assessment tools and alternative anticoagulants emerging since the 2006 NICE Clinical Guideline, it has become clear that further guidance is needed to ensure that patients receive the best and most appropriate treatment. The CG180 shows a simplified assessment of stroke, working from the view that all patients require intervention to minimise their risk of AF-related stroke apart from the small minority without risk features; that the risk factors for bleeding complications should be identified and where possible minimised and that the patient should choose the intervention best suited to their personal situation. With only 1 in 2 of those at risk protected against stroke, the guideline is a call to arms for every clinician to support our patients with AF to prevent at least 7,000 strokes per year which are devastating the lives of patients and their carers. The assessment of stroke risk should be undertaken using the CHA2DS2-VASc risk score. Calculations using this assessment tool use a greater number of risk factors than the more commonly used CHADS tool, giving additional emphasis to the importance of older age, female gender and pre-existing vascular disease as risk factors for stroke. CHA2DS2-VASc identifies those at truly low risk who do not require treatment for their stroke risk. Changing the paradigm for seeking those at risk of AF related stroke to an attitude of wishing to treat all but those at very low risk of AF stroke In those at high risk of stroke and eligible for anticoagulation we should routinely assess their bleeding risk using the HAS-BLED risk calculator identifying those risk factors which we can address and modify thereby reducing the risks of anticoagulation. Rarely will the bleeding risk be such that anticoagulation is not offered to a patient at high risk of stroke. 3

8 A stroke physician s perspective Dr Louise Shaw, Consultant Physician MB, ChB, FRCP, Royal United Hospital, Bath I have seen a dramatic increase in the prevalence of AF and its consequences on the Acute Stroke Unit at the RUH in the past five years. Firstly, the incidence of AF rises rapidly with age and our population is living longer than ever before. Secondly, a person is 5 times more likely to have a stroke if they are in AF than if they are in sinus rhythm. It is predicted that the prevalence of AF will double over the next 30 years, although already in 2014 I find that almost half of the patients on my stroke unit have AF as a cause of their stroke. Having a stroke in itself is devastating; however strokes caused by AF tend to be more severe than strokes from other causes. AF stroke patients are: Twice as likely to die as a patient in sinus rhythm. More likely to become seriously disabled. More likely to end up bedridden and in a nursing home. It is important to be aware that the risk posed by AF is the same whether the AF is asymptomatic, paroxysmal or persistent. Patients with CHA2DS2-VASc 1 or higher should be anticoagulated. The default position should be Opt Out, not Opt In. Aspirin is ineffective at preventing AF strokes and is not an acceptable substitute. A lot of stroke deaths and disability can be prevented by simple stroke prevention at all opportunities in all health settings. The most important aspect is a manual pulse check. If there is an irregular pulse, an ECG is needed. If AF is confirmed, always consider anticoagulation. This simple check can have a profound impact. Key messages for GPs The case for change needs to be actioned by us all. Everyone who is involved in the AF pathway needs to think anticoagulation and ask Why should we not anticoagulate this patient? We therefore need to embed a culture in our practice where: We use every opportunity to look for AF. CHA2DS2-VASc 1 or more means that anticoagulation is necessary. Antiplatelets are no longer an acceptable or appropriate treatment for AF. 4

9 Summary of NICE Clinical Guideline 180 on the management of AF Dr Matthew Fay CG180 Background Atrial fibrillation (AF) is the most common sustained arrhythmia, with a prevalence of 1.7% in the general practice population and over 10% in the practice population >65 years of age. It is associated with significant morbidity and mortality both as a result of symptoms caused by rhythm disturbance, and from increased stroke risk. Although some patients present with cardiovascular symptoms of palpitations, and breathlessness/dyspnoea, AF may often be asymptomatic. It is commonly associated with other cardiovascular risk factors such as hypertension, diabetes, structural heart issues, occlusive vascular disease, and advancing age ( 75 years). CG180 Patient-centred care summary Support for people with AF should be centred on their needs and personal choices. With rhythm management in AF failing to reduce mortality or stroke risk, the need to intervene is based purely on the patient s dysrhythmia symptoms, which can vary greatly between individuals. The benefits and risks of anticoagulants should be outlined to the patient. Clinician concerns regarding haemorrhagic risk are misaligned with patient concerns as to the risk of stroke, often making it difficult to support clinical decision making. For this reason, an updated Patient Decision Aid was produced by NICE at the same time as Clinical Guideline (CG) After initial management, on-going review of the patient is needed to: assess symptoms associated with AF progression, the risk/benefit of intervention with anticoagulants, and the quality of anticoagulation if a vitamin K antagonist (VKA) is used to ensure time in therapeutic range. CG 180 Stroke risk reduction summary Stroke related to AF is largely avoidable with appropriate assessment and intervention. There has been a paradigm shift in the attitude to stroke risk assessment meaning that all but those with no risk factors should be considered for intervention. The CHA2DS2-VASc is recommended for assessment of risk in AF. Anticoagulation should be offered to those with a score of 2 or above, taking bleeding risk into account, and should be considered for those with a score of 1 (except if they are aged <65 years and the point is due to gender alone). The HAS-BLED tool should be used to assess bleeding risk in patients starting anticoagulation, to demonstrate how bleeding risk can be reduced by risk factor modification. The type of anticoagulant, VKA or non-vka oral anticoagulant, should be agreed with the patient, taking into account their clinical circumstances and personal preferences. Individuals with no risk factors (or only gender as a risk factor) do not require anti-thrombotic intervention. Antiplatelet monotherapy with aspirin should not be offered to patients with AF solely for stroke prevention. If an anticoagulant is contraindicated or not tolerated should a left atrial appendage occlusion be considered. The risks and benefits should be discussed with the patient. The first consideration for symptom management should be rate control except in situations where: AF has a reversible cause. AF is thought to have caused heart failure. The patient has new onset AF. 5

10 Atrial flutter is diagnosed and the patient s condition is suitable for ablation therapy. Clinical judgement suggests a rhythm control strategy could be more suitable. If rate control with beta-blockers, diltiazem, or digoxin, individually or any two in combination, is unsuccessful in symptom management then a rhythm control strategy should be considered. The guideline recommends that patients should be referred promptly (within 4 weeks) for specialised management if symptoms remain uncontrolled, despite treatment. In patients with symptomatic paroxysms of AF we should initially consider pharmacological interventions; however, if this strategy fails to control the AF then ablation therapy should be considered. Stroke prevention of people with non-valvular AF Assess stroke risk stratification using CHA 2 DS 2 -VASc Assess bleeding risk stratification using HAS-BLED Discuss risks and benefits of anticoagulation People who choose not to have treatment Identify low risk patients i.e. CHA 2 DS 2 -VASc = 0 (men) or 1 (women) Low risk No antithrombotic therapy CHA 2 DS 2 -VASc = 1 (in men) Consider oral anticoagulant CHA 2 DS 2 -VASc 2 Offer oral anticoagulant Discuss the options for anticoagulation with the person and base the choice on their clinical features and preferences Vitamin K antagonists (VKA) Non-VKA oral anticoagulant [See TA numbers 249, 256, 275] Assess anticoagulation control Poor control Anticoagulation contraindicated Non-VKA oral anticoagulant Non-VKA contraindicated or not tolerated Left atrial appendage occlusion Annual review for all patients Algorithm reproduced with permission from: National Clinical Guideline Centre. Atrial Fibrillation. Clinical Guideline 180, Methods, evidence and recommendations. National Clinical Guideline Centre, Available at: Non-VKA oral anticoagulants are rivaroxaban, dabigatran, and apixaban References 1. NICE. Atrial fibrillation: the management of atrial fibrillation. Clinical Guideline 180. NICE, Available at: CG Cowan C, Healicon R, Robson I et al. Heart 2013; 99 (16): National Clinical Guideline Centre. Atrial fibrillation: the management of atrial fibrillation. Clinical Guideline. 2014, NICE. 4. NICE. Atrial fibrillation: medicines to help reduce your risk of a stroke what are the options? Patient decision aid. NICE, Available at: guidance.nice.org.uk/cg180/ PatientDecisionAid/pdf/English 6

11 Antiplatelet therapy Does it still have a place in AF Stroke prevention? Dr Jim Moore For too long the use of aspirin has been considered as a reasonable alternative to anticoagulation in protecting AF patients. The evidence supporting the use of aspirin is unconvincing. A meta-analysis comparing the use of aspirin with placebo or no treatment in patients with AF showed a non-significant 19% reduction in the incidence of stroke in the aspirin treated group. This compares unfavourably with similar studies looking at dose adjusted warfarin that showed a highly significant 64% reduction in stroke incidence. The risk reduction achieved by aspirin is very similar to that achieved when it is used as prophylaxis in patients with established vascular disease. Vascular disease is a common finding in patients with atrial fibrillation and the limited benefit of aspirin in this group of patients is likely to be due to its effect on vascular disease. Guidelines for using aspirin Recommendations in recent guidelines written both in the UK and abroad 1 clearly state that aspirin monotherapy should not be used as thromboprophylaxis for patients with AF as the modest benefit derived from taking aspirin is offset by the risk of major bleeding or intracranial haemorrhage. Dual antiplatelet therapy in the form of aspirin combined with clopidogrel may provide better protection against stroke but at the expense of increased bleeding. As a consequence some guidelines recommend that dual therapy should not be offered as thromboprophylaxis. Recent NICE guidance does suggest that this combination may be considered in exceptional circumstances for patients who are intolerant of all forms of anticoagulant therapy or where anticoagulants are contraindicated. It is worth noting that the majority of patients unsuitable for anticoagulant therapy are so because they are at increased risk of major bleeding and, as dual antiplatelet therapy increases the risk of serious bleeding, it should not be considered in this group. The use of aspirin with warfarin therapy in patients who have either chronic AF alone 1. NICE CG 180, Royal College of Physicians of Edinburgh UK Consensus Conference 2012; European Society of Cardiology Focussed update on management of AF

12 or the combination of chronic AF and stable vascular disease does not further reduce the risk of arterial thromboembolism when compared to those on oral anticoagulant therapy alone. Antiplatelet drugs (aspirin or clopidogrel) may be used in the short term with anticoagulant therapy for AF patients with concomitant coronary artery disease (CAD) following ACS or PCI. Such combination therapy is associated with an increased risk of bleeding and it is therefore recommended that warfarin should be used alone in patients with AF and stable vascular disease. In summary, NICE guidance recommends oral anticoagulants as first-line therapy for AF patients at increased stroke risk. Anticoagulation should be offered to people with a CHA2DS2VASc score of 2 or more, and considered for men with a CHA2DS2VASc score of 1, taking bleeding risk into account. Aspirin monotherapy should not be offered solely for protection against stroke and should be used in combination with clopidogrel only in exceptional circumstances. Aspirin for elderly patients Elderly patients are commonly denied anticoagulation and prescribed aspirin in preference to warfarin because of concerns over their risk of haemorrhage associated with falling. Research suggests that an anticoagulated patient would have to fall 295 times for the risks associated with falling to outweigh the benefits in stroke reduction. Reassuringly, the Birmingham Atrial Fibrillation Treatment of the Aged study (BAFTA) also showed that AF patients aged 75 years had no significant difference in the risk of major bleeding (or intracranial bleeding) when those taking warfarin were compared to patients given aspirin. 8

13 Section Two: Af Related Stroke Prevention: Guides to Clinical Practice Overview of AF-related stroke prevention guides The following guides are intended to assist clinicians in managing the anticoagulation of people with AF. Guidance is designed to support primary care clinicians in the anticoagulation of AF patients. The decision to initiate anticoagulation and by what therapy remains a clinical decision, and should be made following discussions with patients. Working in tandem with the 2014 update to the NICE AF (CG180), this toolkit provides a wealth of resources to aid the decision making process for GPs and to promote shared decision making in AF thromboprophylaxis. It also aims to address myths surrounding the anticoagulation of patients through the presentation of the best available evidence including input from haematology. Most importantly, this toolkit includes the West of England; Optimising Anticoagulation to Prevent AF-Related Stroke Protocol. This document should provide a platform when clinical consideration is being given to the decision to initiate a patient on anticoagulation. In line with NICE updates, the toolkit also provides information on the use of antiplatelet monotherapy in AF thromboprophylaxis. Contents 1. West of England AF related stroke prevention guidance 2. Key factors influencing anticoagulant choice in Non-Valvular AF 3. Oral anticoagulants: Frequently Asked Questions 4. Identifying stroke & bleed risk 5. Managing & predicting bleeding & switching between anticoagulants 6. Anticoagulating the frail and elderly 7. Managing patients with a labile INR 8. Shared decision making with patients 9. Local formulary guidance 9

14 AF-related stroke prevention guide 1: West of England AF-related stroke prevention guidance West of England Anticoagulation for AF Related Stroke Prevention Guidance V1: Draft Jan 2015 All AF Patients with non-valvular (paroxysmal, persistent or permanent) Discuss risks and benefits of anticoagulation Assess stroke risk stratification using CHA2DS2-VASc Low risk: CHA2DS2-VASc score = 0 (men) or 1 (women) Increased risk: CHA2DS2- VASc score = 2 (consider men 1) & Assess bleeding risk stratification using HAS-BLED NOTE: BENEFITS OF STROKE PREVENTION OUTWEIGH RISK OF BLEED AT ALMOST ANY HAS-BLED LEVEL (for guidance) No anticoagulation at current point No anticoagulation at current point Low risk or patient declines treatment (review as per review criteria) ANTICOAGULATE Unmodifi ably high bleed risk or patient declines treatment (review as per review criteria) Discuss options for anticoagulation with patient and base choice on clinical features and preferences WARFARIN Consider for patients who: when reviewed are currently well controlled on warfarin are at risk of drug interactions with a NOAC have CrCL (egfr)< 30 ml/min Note: consider bridging with heparin or LWMH for acute onset AF or for patients at a high risk of stroke consider self-monitoring where appropriate calculate TTR at each patient contact review warfarin use if Iabile INR DABIGATRAN, RIVAROXABAN, APIXABAN Consider for patients who: are not taking warfarin because of allergy or intolerance or where INR monitoring is impractical (access to Renal & LFTs monitoring necessary) have labile INR despite evidence of adherence or practical difficulties with treatment have drug interactions with warfarin ask to start a NOAC ASPIRIN IS NOT EFFECTIVE IN PREVENTING AF RELATED STROKE AND SHOULD NOT BE INITIATED IN AF PATIENTS IN PLACE OF ANTICOAGULATION Review criteria for anticoagulation for AF stroke prevention a) All patients with a new diagnosis of AF b) Patients with existing diagnosis of AF e.g identifi ed through audit c) All AF patients when turning 65 and over d) Patients with labile INRs (discount initial 6 weeks): 2 INR values > 5 or 1 INR value > 8 within past 6 months 2 INR values < 1.5 within less than 6 months TTR less than 65%. e) Annually from decision to not anticoagulate f) For all AF patients on development of: Diabetes Heart failure Peripheral arterial disease Coronary heart disease Stroke, transient ischaemic attack Systemic thromboembolism. Hypertension Declaration; The Programme is funded through a joint working project between Bayer Healthcare...don t wait to anticoagulate 10

15 AF-related stroke prevention guide 2: Key factors influencing anticoagulant choice in Non-Valvular AF Licensing All novel OACS (NOACs) are licensed for prevention of stroke in non valvular AF plus at least one additional risk factor. Warfarin is licensed for use without additional risk factors present. NICE Guidance and patient choice The decision about whether to start treatment with any anticoagulant in AF should be made after an informed discussion between the clinician and the patient about the risks and benefits of individual agents. Compliance NOACs are not a safe option in patients who are not suitable for warfarin for reasons of poor compliance or in those deemed to have too high a risk of bleeding for warfarin. Patients prescribed NOACs should have an on-going review of treatment, preferably after one month and then on a 3-monthly basis 1. Risk of haemorrhage NOACs have been demonstrated to have a lower risk of catastrophic intracerebral haemorrhage but some (Rivaroxaban and Dabigatran 150mg) have a slightly higher risk of gastrointestinal haemorrhage. Reversal The major concern with the new anticoagulants is the lack of an effective antidote. This is counterbalanced to some degree by the lower risk of severe haemorrhage reported within clinical trials when compared to warfarin. NOACs however have a relatively short half-life compared to warfarin and protocols for managing bleeding events in NOAC treated patients are available. Acute bleeding In the event of acute bleeding patients receiving a NOAC may require surgical haemostasis, fluid replacement or blood products. These may also be appropriate for those receiving warfarin in addition to vitamin K. Suggested approaches to the management of bleeding complications are outlined in the EHRA practical guide on the use of NOACs1 Renal function Dose reduction (or cessation) of the newer drugs is required with reduced renal function Frequency of dosing Dabigatran and Apixaban require twice daily dosing, compared to once daily for Rivaroxaban and warfarin. Extremes of BMI The relative dose of NOACs may vary by 20-30% at extremes of bodyweight (<50 kg or > kg). This may be problematic given the difficulties in monitoring the therapeutic effects. Specific indications E.g. need for elective cardioversion, plans for ablation etc. Where continuation of anticoagulation therapy, up to and during the procedure, would be considered advantageous, the use of a NOAC could be appropriate where patient compliance can be 11

16 reliably confirmed. Warfarin may however be preferred given the possibility of reversal in the case of major bleeding. Monitored Dosage Systems Neither warfarin nor Dabigatran is suitable for use in a compliance aid. Comparative costs Each of the newer drugs has a considerably higher acquisition cost than warfarin. When the cost of INR monitoring is taken into account, warfarin is likely to remain the least expensive option up-front. Comparative cost-effectiveness is not clear. If a NOAC is preferred and where all other factors are equal the NOAC with the lowest acquisition cost should be chosen Time in therapeutic range The newer drugs are likely to be more beneficial in patients whose INR is regularly outside the therapeutic range despite good medication adherence. INR testing INR testing with warfarin is time consuming, but provides an opportunity to monitor adherence and effectiveness. Experience Compared to warfarin, there is less clinician experience of long term use of the NOACs. Identifying patients taking anticoagulants Patients anticoagulated with either warfarin or newer agents should carry a card identifying their medication and who to contact in case of emergency related to their anticoagulation. When might warfarin be the preferred option? In patients with a history of GI problems warfarin may be the preferred option as it has a more favourable GI side effect profile, and was associated with a lower rate of GI haemorrhage compared with Rivaroxaban and Dabigatran (at the 150 mg twice daily dose). Compared with warfarin, Apixaban does not significantly alter the risk of major GI bleeding. Warfarin has the additional advantage of being reversible. Patients on co-administered medication Some co-administered medications may inhibit metabolism and potentiate bleeding risk with novel agents (e.g. azole anti fungals, ritonavir) are probably safer managed on warfarin as the INR may be adjusted accordingly. Patients will still need appropriate dose adjustment of warfarin on commencement or withdrawal of such therapy. Active swapping from warfarin to novel agents Where patients are established on warfarin with a stable INR there is little or no reason to actively swap over to novel agents. Inadequate control of INR may be a reason to consider a NOAC as are warfarin-specific side effects e.g. alopecia. There is a potential for inadequate anticoagulation during the transition between OACs. 12

17 AF-related stroke prevention guide 3: Frequently Asked Questions 1. How do oral anticoagulants work? Warfarin 2 Dabigatran 3 Rivaroxaban 4 Apixaban 5 Inhibits the production of vitamin K dependent clotting factors II, VII, IX and X Acts as a direct thrombin (factor IIa) inhibitor. It is formulated as Dabigatran etexilate; a prodrug converted to Dabigatran after administration. Acts as a selective direct factor Xa inhibitor. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban prevents thrombin generation and thrombus development. No direct effects on platelet aggregation, but indirectly inhibits aggregation induced by thrombin. 13

18 2. What are their main contraindications? Warfarin Dabigatran Rivaroxaban Apixaban Known hypersensitivity to warfarin or any excipients Hypersensitivity to the active substance or any excipients. Hypersensitivity to the active substance or any excipients. Hypersensitivity to the active substance or any excipients. Haemorrhagic stroke Clinically significant bleeding Within 72 hours of major surgery with risk of severe bleeding Within 48 hours postpartum Pregnancy (first and third trimesters) Drugs where interactions may lead to a significantly increased risk of bleeding Severe renal impairment (CrCL < 30 ml/min) Active clinically significant bleeding. Any lesion or condition considered a significant risk factor for bleeding. Concomitant treatment with any other anticoagulant Hepatic impairment or liver disease expected to have any impact on survival. Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole, tacrolimus, dronedarone. Active clinically significant bleeding. Concomitant treatment with any other anticoagulant Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C Pregnancy and breast feeding. Prosthetic heart valves requiring anticoagulation treatment Severe renal impairment (CrCL <15ml/min) Dronaderone and other drug interactions Active clinically significant bleeding. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Any lesion or condition considered a significant risk factor for bleeding. Concomitant treatment with any other anticoagulant Prosthetic heart valves requiring anticoagulation treatment Severe renal impairment (CrCL <15ml/min) Dronaderone and other drug interactions Prosthetic heart valves requiring anticoagulant treatment. 14

19 3. Do the preparations contain wheat and lactose? Warfarin Dabigatran Rivaroxaban Apixaban Yes - Lactose No - lactose Yes- Lactose Yes -Lactose Yes - Maize starch (Marevan) No - wheat No - wheat No - wheat 4. When should specific OACs be avoided? Warfarin Dabigatran, Rivaroxaban, Apixaban Intolerance to warfarin including allergy and rash. Demonstrated impossibility of monitoring arrangements Warfarin is teratogenic and should not be given in the first trimester of pregnancy AVOID in patients with a history of poor medication adherence (unless poor adherence relates to e.g. difficulty managing flexible warfarin dosage that may be addressed through a fixed dose regime) The NOACs are not a suitable alternative to warfarin in patients with bleeding complications associated with warfarin treatment, contraindications to warfarin therapy due to a high bleeding risk, alcohol abuse, drug overdose or trivial side effects related to warfarin. Dabigatran is not stable in compliance aids such as dosette boxes. Manufacturers advise to avoid use in pregnancy. 15

20 5. What pre-testing and monitoring are necessary? Warfarin Dabigatran Rivaroxaban Apixaban Tests prior to starting treatment Clotting screen, U& E s, LFTs, FBC, BP, CrCl, Thyroid status Ongoing monitoring requires adjustment to the individual needs of the patient and therefore requires regular monitoring using blood tests. Tests prior to starting treatment Clotting screen, U& E s, LFTs, FBC, BP, CrCl Monitoring until patient is stabilised Ideally assess every 3 months to: Assess compliance and reinforce advice regarding regular dosing schedule. Enquire about adverse effects such as bleeding. Assess for the presence of thromboembolic events Enquire about other medicines, including OTC medicines. Ongoing monitoring U& E s, LFTs, FBC at least once a year especially in elderly and patients with renal impairment. Repeat U&E s every 6 months if CrCl ml/min, patient > 75 years or fragile. Repeat U&E s every 3 months if CrCl ml/min. More frequent U&E s/ LFTs advised where intercurrent illness may impact on renal or hepatic function. Tests prior to starting treatment Clotting screen, U& E s, LFTs, FBC, BP, CrCl Monitoring until patient is stabilised Ideally assess every 3 months to: Assess compliance and reinforce advice regarding regular dosing schedule. Enquire about adverse effects such as bleeding. Assess for the presence of thromboembolic events Enquire about other medicines, including OTC medicines. Ongoing Monitoring U& E s, LFTs, FBC at least once a year. Repeat U&E s every 6 months if CrCl ml/min or every 3 months if CrCl ml/min. More frequent U&E s/ LFTs advised where intercurrent illness may impact on renal or hepatic function. Tests prior to starting treatment Clotting screen, U& E s, LFTs, FBC, BP, CrCl, body weight Monitoring until patient is stabilised Ideally assess patient every 3 months to: Assess compliance and reinforce advice regarding regular dosing schedule. Enquire about adverse effects such as bleeding. Assess for the presence of thromboembolic events Enquire about other medicines, including OTC medicines Ongoing monitoring U& E s, LFTs, FBC at least once a year. Repeat U&E s every 6 months if CrCl ml/min or every 3 months if CrCl ml/min. More frequent U&E s/ LFTs advised where intercurrent illness may impact on renal or hepatic function. 16

21 6. What doses should be given and what adjustments as necessary for renal impairment? Warfarin For patients who require rapid anticoagulation the usual adult induction dose of warfarin is 5 10 mg on the first day (elderly patients should receive a lower induction dose). For patients who do not require rapid anticoagulation, a lower loading dose can be used over 3 4 weeks. In both cases subsequent doses depend upon the prothrombin time, reported as INR (international normalised ratio). Consider Apixaban in preference to warfarin with egfr of ml/min/1.73 m2. Dabigatran Rivaroxaban Apixaban (CrCl above 50ml/min) Patients under 80 years: 150 mg twice daily Patients >80 years: 110 mg twice daily (due to the increased risk of bleeding in this population) Reduce to 110 mg twice daily in patients who are taking verapamil Consider 110 mg twice daily when the thromboembolic risk is low and the bleeding risk is high (e.g. CrCL ml/min) or patients weigh <50kg. 20 mg once daily with food 5 mg twice daily Reduce to 2.5 mg twice daily in patients with two or more of the following characteristics: Age 80 years Body weight 60kg Serum creatinine 1.5mg/dL (133 micromoles/l) CrCl 30-49ml/min mg twice daily Reduce dose to 15mg daily Use normal dose CrCl 15-29ml/min Do not use Reduce dose to 15mg daily Reduce dose to 2.5mg twice daily CrCl < 15ml/min Do not use Do not use Do not use 17

22 7. How safe are oral anticoagulants? Warfarin Dabigatran, Rivaroxaban, Apixaban Long-term safety based on 50 years use in clinical practice No information available on long-term safety. Reduce dose in renal impairment (based on Cockcroft Gault calculation of CrCl) 8. What are the main drug interactions? Warfarin Dabigatran Rivaroxaban, Apixaban Drug-food interactions Cranberry juice and alcohol interact with warfarin. Some foods interact with warfarin (e.g. foods containing high amounts of Vitamin K). Drug-drug interactions Many interactions requiring additional INR monitoring. Drug-food interactions There are no known food interactions. Drug-drug interactions Contraindicated with the strong P-gp inhibitors ketoconazole, cyclosporine, itraconazole, tacrolimus and dronedarone. Use with caution if co-administered with mild to moderate P-gp inhibitors such as amiodarone, quinidine, verapamil, & ticagrelor. Co-administration with P-gp inducers such as rifampicin, St John s Wort, carbamazepine or phenytoin) should be avoided. SSRIs and SNRIs increased the risk of bleeding in RE-LY in all treatment groups. Drug-food interactions There are no known food interactions. Drug-drug interactions Not recommended with concomitant systemic administration of strong inhibitors of both CYP3A4 and P-gp, such as ketoconazole, itraconazole, voriconazole, posaconazole or HIV protease inhibitors. Strong inducers of both CYP3A4 and P-gp (such as rifampicin, phenytoin, carbamazepine, phenobarbital or St John s Wort) should be coadministered with caution because of the risk of a loss of effectiveness. Concomitant administration with any other anticoagulants is contraindicated (some overlap may be necessary whilst transferring between anticoagulants). Consult the SPC for full details of interactions. 18

23 9. What are the common side effects? Warfarin Dabigatran Rivaroxaban Apixaban Nausea, vomiting, diarrhoea, jaundice, alopecia, rash, hepatic dysfunction, pyrexia Dyspepsia more frequent with both doses of Dabigatran than warfarin. GI adverse events frequently led to drug discontinuation (7%, 6.5% and 3.9% in the Dabigatran 150 mg, 110 mg and warfarin groups respectively) 4. The rate of myocardial infarction (MI) was numerically, but not statistically significantly, higher with Dabigatran in the pivotal trial (0.82% for 110 mg and 0.81% for 150 mg vs. 0.64% p=0.12). 7-9 There were no significant differences in the incidence of any adverse event other than bleeding in the pivotal Rivaroxaban trial. 11 The rate of MI was numerically, but not statistically significantly lower, in the Rivaroxaban arm compared with warfarin. There were no significant differences between warfarin and Apixaban in the incidence of any adverse events in the pivotal Apixaban trial. 12 A meta-analysis combining 7 studies showed Dabigatran was associated with a significantly higher risk of MI or ACS. The control group varied and included enoxaparin, warfarin and placebo

24 AF-related stroke prevention guide 4: Identifying stroke & bleed risk CHA2DS2-VASc and HASBLED Dr Dipankar Dutta, Consultant Physician, Gloucestershire Royal Hospital Using CHA2DS2-VASc to assess stroke risk The CHA2DS2-VASc stroke risk score should be used in people with paroxysmal, persistent, or permanent AF (regardless of symptoms), atrial flutter, and people with continuing risk of AF recurrence after cardioversion. CHA2DS2-VASc The GRASP-AF toolkit includes options to risk stratifies patients using CHA2DS2-VASc scores. The tool also highlights those who would benefit from review to assess their appropriateness for anticoagulation. HAS-BLED Item Score Item Score C Congestive heart failure 1 H Hypertension (uncontrolled BP) 1 H Hypertension 1 A Abnormal renal/ liver function 1 or 2 A 2 Age 75 years 2 S Stroke history 1 D Diabetes mellitus 1 B Bleeding tendency or predisposition 1 S 2 V Previous stroke, TIA or thromboembolism Vascular disease (MI, PVD, aortic plaque) 2 L Labile INR 1 1 E Elderly (Age 65 years) 1 A Age years 1 D Sc Sex category (female gender) 1 Drugs (concurrent aspirin or NSAIDs ) or alcohol 1 or 2 Maximum total 9 Maximum total 9 Anticoagulation with warfarin or NOACs should be considered in men with a CHA2DS2-VASc score of 1. Men or women with a CHA2DS2-VASc score of 2 or above should definitely be offered anticoagulants. Assessment of bleeding risk using HAS-BLED Use of the score prompts users to identify bleeding risk factors which, in some instances, may be modifiable. It must be emphasised it is not primarily intended to deny people anticoagulants but to identify modifiable risk factors, such as hypertension, high alcohol intake, and the use of concurrent aspirin and NSAIDs, that could be addressed. In most instances, preventing strokes will take priority over avoidance of a bleed. 20

25 AF-related stroke prevention guide 5: Managing & predicting bleeding & switching between anticoagulants When a patient is anticoagulated they can encounter bleeding either spontaneously or as a result of trauma. In primary care, your role is to reassure patients that regardless of the anticoagulant agent used; there are procedures to deal with bleeding effectively. Practices should consider the key actions to be taken for the management of anticoagulation associated bleeding in primary care, including the development of an emergency policy. The management of patients post-bleed should also be considered in planning the practice stroke prevention action plan. For anticoagulated patients in primary care, the key to good management is to ensure that they are sent to an accident and emergency department immediately if they are actively bleeding or bleeding from a significant site e.g. the eye. This is a situation where calling an ambulance for the patient should be employed. Once the patient is in hospital the level of bleeding will be assessed. This assessment will direct care for bleeding associated with both warfarin and novel oral anticoagulants (NOACs), as seen in table 1. If a patient has a major bleed, they will be kept in hospital where their anticoagulation and drug therapies will be reviewed. All changes should be recorded in the discharge letter to the GP surgery. It is important that as the practice nurse managing a patient s anticoagulation, you are aware of these events and changes, and arrange to review their care. Management of bleeding associated with anticoagulation The approach taken to the management of bleeding will depend on the type of anticoagulant used. It is therefore important to ensure that staff managing the bleeding are aware of the anticoagulant that has been prescribed. Warfarin Over anticoagulation and bleeding can occur as a result of noncompliance, drug interactions, liver failure, variations in diet, misuse of alcohol and underlying conditions e.g. gastric ulcer. Management is dependent on the international normalised ratio (INR) and the presence of active bleeding. Treatments include stopping warfarin for a short time, the use of the antidote Vitamin K and in more severe bleeding, the Prothrombin Complex Compound (PCC). 21

26 primary care your role is to ensure that the patient is referred to secondary care in a timely manner, which we will be discussing further during this webinar. 3 Table 1: Management of warfarin associated bleeding (adapted from BCSH 2011) Identify warfarin indication and therapeutic INR range, as well as the patient s weight Urgent blood tests to be taken: full blood count, clotting screen, INR, urea and electrolytes, liver function test INR < 5.0 No evidence of bleeding Reduce warfarin dose INR > 5.0 plus bleeding Start resuscitation measures Monitor blood pressure and urine output Mild or no bleeding If other risk factors for bleeding reversal is required in 48 hours Give Vitamin K orally 1-2mg Restart warfarin when INR < 5.0 at reduced dose Moderate bleeding ** Local first aid measures including surgery Give Vitamin K 5-10mg IV Contact Haematologist Consider PCC Life threatening bleeding ** And /or emergency surgery As for moderate bleeding plus give Vitamin K 10mg IV Contact Haematologist for PCC ** Hemoglobin drop > 2.0g/l and/or bleeding in a critical site o Administer PCC as soon as available from laboratory o Re-check INR within min after administration o Contact Haematologist if INR not reversed or ongoing bleeding is taking place NOACs Studies have shown that the bleeding profile of NOACs especially with regard to life-threatening bleeding, is more favourable than warfarin. However, as more people start taking NOACs the number of bleeds is expected to rise. 22

27 1. Does the risk of a bleed vary between OACs? Warfarin Dabigatran Rivaroxaban Apixaban See respective agent for comparison Major bleeding: No difference between Dabigatran 150 mg BD and warfarin. Less common with Dabigatran 110 mg BD than warfarin GI bleeding: More common with Dabigatran 150 mg BD than warfarin (p=0.0008). No difference between Dabigatran 110 mg BD and warfarin. Major bleeding: No difference between Rivaroxaban and warfarin. GI bleeding: More common with Rivaroxaban than warfarin (p<0.001) Intracranial bleeding: less common with Rivaroxaban than warfarin (p=0.02) Major bleeding: Less common with Apixaban than warfarin (p<0.001) GI bleeding: No difference between Apixaban and warfarin Intracranial bleeding: Less common with Apixaban than warfarin (p<0.001) Intracranial bleeding: Less common with both doses of Dabigatran than with warfarin (p<0.001). Bleeding risk high in the frail and elderly, particularly with renal impairment and low body weight. 23

28 2. Can bleeding be reversed? Warfarin Dabigatran Rivaroxaban Apixaban Effective and well known antidote, should a severe bleed occur whilst being treated No antidote currently known. Patients with bleeding risk factors excluded from pivotal trial. Clearance can be increased with haemodialysis. Prolonged bleeding has increased morbidity and possibly contributed to deaths 13. No antidote currently known although prothrombin complex concentrate has been successful in showing normalisation of laboratory clotting parameters (prothrombin time and endogenous thrombin potential) in a small preliminary trial. 14 No antidote currently known 3. What are the half-lives of the OACs? Warfarin Dabigatran Rivaroxaban Apixaban About 40 hours GFR [ml/min] half-life (range) hours] 5 to 9 hours in young individuals, 12 hours ( ) 50-< ( ) 11 to 13 hours in the elderly. 30-< ( ) < ( ) 24

29 4. How should the dose of OACs be adjusted when patients are having dental treatment or surgery? Warfarin OAC use with no clinically important bleeding risk OAC use and undergoing surgery with a low bleeding risk OAC use and undergoing surgery with a high bleeding risk Dental procedures outpatient dental surgery (including extractions) can usually be undertaken without temporarily stopping or reducing the dose of warfarin. It is recommended that the INR is checked 72 hours before dental surgery. The risk of significant bleeding in people with a stable INR within the range of 2 to 4 is very small, but the risk of thrombosis may be increased if oral anticoagulants are temporarily discontinued Surgery in general, warfarin is usually stopped 5 days before planned surgery, and once the person s international normalised ratio (INR) is less than 1.5 surgery can go ahead. warfarin is usually resumed at the normal dose on the evening of surgery or the next day if haemostasis is adequate. Restarting OACs after surgery See local guidelines. Treatment should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician. Onset of action of NOACs is much faster than that of warfarin. 25

30 Dabigatran Rivaroxaban Apixaban OAC use with no clinically important bleeding risk The procedure can be performed just before the next dose of Dabigatran, Rivaroxaban or Apixaban is due, or approximately hours after the last dose was taken (treatment should be restarted 6 hours later). For dental procedures, consider prescribing tranexamic acid 5% mouth wash; instruct the person to use 10 ml as a mouth wash four times a day for 5 days. OAC use and undergoing surgery with a low bleeding risk Dabigatran should be stopped 24 hours before the procedure. If the person has creatinine clearance ml/min Dabigatran should be stopped 36 hours before the intervention. If the person has creatinine clearance ml/min Dabigatran should be stopped 48 hours before the intervention. Rivaroxaban should be stopped 24 hours before the procedure. If the person has a creatinine clearance between ml/ min Rivaroxaban should be stopped 36 hours before the procedure. Apixaban should be stopped 24 hours before the procedure. If the person has a creatinine clearance between ml/min, Apixaban should be stopped 36 hours before the procedure. OAC use and undergoing surgery with a high bleeding risk Dabigatran should be stopped 48 hours before the procedure. If the person has creatinine clearance ml/min Dabigatran should be stopped 72 hours before the intervention. If the person has creatinine clearance ml/min Dabigatran should be stopped 96 hours before the intervention. Rivaroxaban should be stopped 48 hours before the procedure. If the person has a creatinine clearance between ml/ min Rivaroxaban should be stopped 96 hours before the procedure. Apixaban should be stopped 48 hours before the procedure. If the person has a creatinine clearance between ml/min Apixaban should be stopped 96 hours before the procedure. Restarting OACs after surgery See local guidelines. Treatment should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician. Onset of action of NOACs is much faster than that of warfarin. 26