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Yorkshire & Humber Strategic Health Authority

Atrial Fibrillation / Stroke Prevention Guidelines

10th June 2011

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The following guidelines have been produced by a group of representatives covering the specialty subject from the three Cardiovascular Networks in the Yorkshire and Humber region; West Yorkshire, North Trent and North East Yorkshire and North Lincolnshire. Group membership:
Dr Campbell Cowan Consultant Cardiologist, Leeds Teaching Hospitals Trust National Clinical Lead for Atrial Fibrillation, NHS Improvement WYCN Clinical Lead for Chapter 8 Consultant Stroke Physician, Leeds Teaching Hospitals Trust WYCN Clinical Lead for Stroke GP Clinical Lead for NHS North Yorkshire and York Cardiac GPSI GP clinical Lead fro WYCN National Public Health Lead for AF, NHS Improvement GP/GPSI Clinical Lead for AF, NHS Bradford & Airedale National GP Lead for Stroke Prevention, NHS Improvement Advisor to WYCN Clinical lead, NEYNL Cardiac/Stroke Network/ York FT Clinical Lead, North Trent Stroke Network, Sheffield Teaching Hospitals Foundation Trust Consultant Cardiologist, Doncaster Foundation Trust Clinical Lead, North Trent Cardiac Network Consultant Haematologist, Sheffield teaching Hospitals Foundation Trust Public Health Consultant, NHS Bradford & Airedale Advisor to WYCN Network Director, WYCN Network Development Manager, WYCN Assistant Director Service Improvement, NHS Doncaster Public Health Lead, NHS Rotherham Commissioning Development Manager, NHS Hull Network Development Manager, WYCN Network Development Manager, NEYNL Service Improvement Facilitator, North Trent Cardiac Network Associate Director of Clinical Engagement, Chief Nurse, Y&H SHA Consultant Physician and Lead Clinician, Care Services Direct, Barnsley Consultant Stroke Physician, Mid Yorks Hospitals NHS Trust

Dr John Bamford Dr Kathryn Griffith

Dr Richard Healicon Dr Matthew Fay

Dr John Coyle Prof Graham Venables Dr Gillian Payne Dr Rhona MacLean Mr Greg Fell Alison Bagnall Adele Graham Martha Mayhew Jo Abbot Sam Barlow Chris Croden Carol Hargreaves Brian Nevin David Thompson Dr Pravin Jha Dr Michael Carpenter

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Contents
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Summary of Recommendations Foreword and Aims Introduction Commissioning the Prevention, Detection and Management of AF Improving Public Awareness of AF Strategies to Improve Detection of AF Guidance on Referral from Primary to Secondary Care The Efficacy of Anti-Coagulation in Stroke Prevention Assessment of Stroke Risk Assessment of Bleeding Risk Barriers of Anti-Coagulation How to Overcome the Barriers Promotion of the GRASP-AF Tool Secondary Prevention – Identification of AF after Stroke The Importance of Quality of Anti-Coagulation Promoting Quality Standards, Audit and Governance in Anti-coagulant Services New Drugs Left Atrial Appendage Occlusion Devices Patient Lifestyle Issues Appendices, Further Information and Useful Links References `

4 5 6 7 7 8 8 9 9 11 11 12 13 14 14

15 17 18 19 20 24

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Summary of Recommendations
• NHS commissioners should develop a clear commissioning strategy underpinned by comprehensive audit of current stroke prevention measures and services for AF patients. Commissioners should provide a clear assurance to the SHA they have afforded suitable priority to the implementation of this strategy. Read More • Commissioners should encourage practices to undertake targeted, opportunistic case finding (pulse taking) as the best approach to detecting patients with asymptomatic AF. Appropriate groups for targeting include patients over 65 and patients with known heart disease, peripheral vascular disease, hypertension, diabetes or previous stroke. Read More • Locally agreed guidelines/pathways are produced for the detection, treatment and management of AF including those patients for whom secondary care referral should be considered. Read More • In recognition of the fact that warfarin is much more effective than aspirin in preventing strokes associated with AF, commissioners should encourage the use of warfarin in AF patients at high risk of stroke. Read More • Risk scoring for stroke should be undertaken in all patients with AF and the result documented. CHADS is the easiest risk score to implement and on the basis we recommend its use. A CHADS score >1 provides a close approximation to high risk group as defined by NICE. Read More • All primary care teams should be educated on the benefits and risks of anti-coagulation. Individual practices should consider nominating an AF lead with focused training. Read More • There should be a focus on improved delivery of anti-coagulant services to minimise patient inconvenience and hence encourage anti-coagulant uptake. The concept of risk and relative risk should be explored with individual patients to encourage their fully informed participation in the decision whether or not to commence anti-coagulation. Read More • That all practices should run the GRASP-AF tool or it’s equivalent, and upload the data to CHART online. GP’s should use GRASP to identify high risk patients for review, and CHART online can be used by GP’s and commissioners to benchmark and audit the quality of local service delivery. Read More • The baseline medical assessment of stroke patients should include documentation of the cardiac rhythm and a standard 12 lead ECG. This should be the subject of regular audit. Measures should be undertaken to ensure the ECG recording and the detection of AF are an integral part on on-going, inpatient stroke care. Read More • Anti-coagulant clinics adhere to existing NPSA guidelines on audit and clinical governance, with particular emphasis on time in therapeutic range and that the audit data so generated is actively reviewed by commissioners. Read More • Individual patients on anti-coagulant therapy undergo an annual review which includes consideration of the continuing indication for anti-coagulation; the patient’s bleeding risk and the patient’s percentage of time in therapeutic range. Read More • New anti-coagulant agents are becoming available which will offer advantages to patients of greater convenience and may in some groups offer superior efficacy or safety, however, the use of these new agents requires careful economic appraisal prior to their introduction. Read More

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meaning 2. and to reduce the number of deaths by 600.Foreword and Aims The pressing need to reduce the number of strokes occurring in the Region is well documented. Dr Chris Welsh Medical Director Y+H SHA Dr Campbell Cowan National Clinical Lead for AF LTHT Dr Matt Fay National GP Clinical Lead Westcliffe Medical Centre Page 5 of 25 . This document however has been designed to take a few steps back to look at what primary and secondary healthcare professionals can do to detect. This will also allow for patient and public engagement in shaping services within the local statutory organisations. Much work has gone on in this region to develop acute stroke services. Provide guidance on referral from primary to secondary care. the financial and social impact on the individual and family due to disability and poor health. Promote. • • • • This document is not a commissioning guide nor will it detail out the costs of providing these recommended services. recommend how the quality of service provision can be audited and how changes in practice can be measured. • Improve secondary prevention by detecting AF in patients who already have had a TIA or stroke. It is expected that current and emerging commissioners within the current WYCOM. treat and manage AF which will help bring about the objectives described above. This Regional Prevention Guidance for Healthcare Professionals will help: • • • Raise professional awareness of AF and its role in stroke and scope how Social Marketing can improve the public’s awareness of symptoms of AF. via opportunistic pulse checks within other health initiatives. • • Identify how to risk stratify AF patients and treat those at risk via the use of oral anticoagulants. Address barriers to oral anti coagulation therapy and look at the use of other potential anti-coagulants on the market that may not already have a licence but will do so at some point in the near future. Through clinical audit. NORCOM and NEYHCOM undertake baseline assessments and gap analyses of AF services to arrive at a costed commissioning plan (as all are starting from differing baselines). This will lead to a corresponding reduction in emergency hospital admissions. the GRASP-AF tool to search Practice Registers and identify AF patients not on optimal management to support medication review. the quality of anti-coagulation and need for annual review. Look at anti-coagulant clinics and clinical management.000 fewer strokes. where applicable. Look at how the “Prevention and Lifestyle Behaviour Change Competency Framework” can enable healthcare professionals to support patients with known AF. Improve the detection of AF. The Y&H Corporate Strategy 2010-13 has set a health improvement target to reduce the number of stroke admissions by 33% by 2014/15. and the currently high regional avoidable mortality rate.

78% of the strokes were ischemic and atrial fibrillation was the most common cardiac source of thromboembolism.8% in those over 80. Using Network-wide clinical guidelines. we hope to enable healthcare professionals to support people with AF and offer them optimal therapy.000 cases of new stroke in 22 countries. The comparable risk reduction with aspirin was much less at only 22%. This occurs because a larger clot develops in the left atrium and atrial appendage when the atrial contraction is disorganised and stasis may occur. to increase the use of evidence based therapy and reduce stroke. rising to over 10% in people over 80. Atrial fibrillation is. strokes associated with atrial fibrillation tend to be bigger and associated with more severe residual disability than other thrombotic strokes. Page 6 of 25 . While many patients with AF present with their symptoms. particularly in the elderly. In the Euro Heart Survey. While any stroke is a disaster for an individual and their family. In the INTERSTROKE study of 3.Introduction Stroke is the second leading cause of death worldwide and the leading cause of acquired disability in adults. others remain asymptomatic. The particular importance of AF as a cause of stroke resides in the fact that the risk can be substantially reduced by anti-coagulation. in particular warfarin. may well be with a stroke. therefore: • • • • Very common. AF was asymptomatic in 40% of those over 80 [4] and first presentation of AF. A recent pooled analysis [5] showed a 64% reduction in annual rate of stroke with warfarin. Atrial fibrillation (AF) is the commonest sustained disorder of cardiac rhythm. prevalence was 13. Atrial fibrillation has been identified as an independent risk factor for stroke for over 20 years.3% in England and Wales [3]. Population data from the GP Quality and Outcome Framework suggests a prevalence of 1. Patients with AF have a five-fold increase in their risk of stroke [2] compared with people in sinus rhythm at the same age. particularly amongst older patients Frequently undetected A major cause of stroke and strokes which are larger than average A risk factor which is eminently treatable with anti-coagulation The purpose of this guide is to develop a multi-professional strategy to improve the detection and treatment of AF. [1]. There is clear evidence from numerous clinical trials that in many AF patients stroke can be prevented by using antithrombotic medication. AF prevalence is linked to age. In an audit of primary care patients in York in 2010.

Commissioners should provide a clear assurance to the SHA that they have afforded suitable priority to the implementation of this strategy. Based on these figures and the cost of one year’s anti-coagulant therapy.500 strokes in England that are attributable to AF to be £148 million. Recommendations: • NHS commissioners should develop a clear commissioning strategy underpinned by comprehensive audit of current stroke prevention measures and services for AF patients. Page 7 of 25 .8 billion more in lost productivity and disability. The voluntary sector is particularly active at present in promoting campaigns of public awareness of AF. This comprises: • • £103 million of direct hospital costs £45 million of additional costs for care requirements post-discharge. such as district nursing. the cost of preventing one stroke is of the order of £10.000 to £14. including monitoring. the annual informal care costs (costs of home nursing and care borne by patients’ families) are around £2.Commissioning the Prevention. These figures suggest that anti-coagulant treatment of AF is not only cost effective but that it will be associated with an overall cost saving when the costs of stroke care beyond the end of the first year are taken into account. With the advent of a number of new anti-coagulant drugs. Stroke prevention is a major priority area for the NHS in Yorkshire and the Humber. This is more than the cost of treating coronary heart disease and costs the wider economy some £1.8 billion a year in direct care costs.4 billion. it seems likely that the pharmaceutical industry will also participate in promoting public awareness. The number of patients needed to treat (NNT) for one year to prevent one stroke is approximately 37 for primary prevention and 12 for secondary prevention. Detection and Management of AF The National Audit Office reported in 2005 [6] that stroke care costs the NHS about £2. There are therefore enormous QIPP opportunities for Y&H organisations to effectively manage this problem. Through the voluntary sector and the pharmaceutical industry there is a wealth of educational material available to promote awareness of the significance and risks of AF. Improving Public Awareness of AF The knowledge that AF is a major cause of stroke and that it is a preventable cause is beginning to impact on public awareness. These campaigns are backed up by excellent patient information material explaining the significance of AF and the importance of anti-coagulation. NNT for one year for a mixed population comprising primary and secondary prevention patients is 25. encouraging patients to take their pulse and seek medical advice if the pulse is irregular.000 per annum [7]. Both the Atrial Fibrillation Association and the Stroke Association have pulse awareness campaigns. community based rehabilitation and pharmaceuticals prescribed in the community The estimated total cost of maintaining one patient on warfarin for one year. Avenues of co-operation amongst these various organisations are already in existence and are likely to become increasingly important. In addition. is £383. The Department of Health estimate the total costs in the first year of care for treating the 12.

Appropriate groups for onward referral might include: • • • • • Patients with newly identified atrial fibrillation who are haemodynamically unstable (acute assessment) Patients with newly identified atrial fibrillation and known valvular disease Patients with newly identified atrial fibrillation and a contributing metabolic co morbidity (sepsis. Strategies to Improve Detection of AF While many patients with AF present with symptoms related to a rapid or irregular pulse. The recently launched health check initiative does not necessarily include a pulse check. diabetes or previous stroke. Criteria for onward referral from primary to secondary care should be decided locally. opportunistic case finding (pulse taking) as the best approach to detecting patients with asymptomatic AF. hypertension. stroke risk will be lower. significant numbers of patients with atrial fibrillation can be identified. Recommendations: • Commissioners should encourage practices to undertake targeted. This study showed that opportunistic screening was as effective as systematic screening in detecting patients with AF. to be invited in they are not already included in a QoF population for vascular disease and do not already receive a statin therapy). However this can be included with local negotiation. in others the problem remains clinically silent.There is therefore a considerable opportunity for the medical sector to work directly with these organisations to support the use of their material and to foster public awareness. is to undertake screening of elderly patients attending flu vaccination clinics. peripheral vascular disease. stable cardiac condition unstable Patients with atrial fibrillation who remain symptomatic despite rate control Page 8 of 25 . Approaches to detection were considered in the SAFE study [8] undertaken in primary care in Birmingham. This has two consequences. simpler approach is to flag up the need for a pulse check amongst at risk groups such as the elderly when they attend their GP’s surgery for other reasons. This may increase the identification of atrial fibrillation. as long as a large population is screened. thyrotoxicosis etc) Patients with newly identified atrial fibrillation which has made a previously identified chronic. are not known to have cardiovascular disease (i. the routine management of AF can be appropriately undertaken in primary care. in the majority of patients.e. however. which has proved successful in Essex. The common factor for success is the level of population coverage. One approach. Another. The patients being invited for screening. This population will have a lower prevalence of AF and amongst patients in whom AF is identified. In NHS Bradford and Airedale a prescribing indicator has been devised to improve rate control in chronic heart disease (IHD and LVSD) and this will result in more pulses being assessed in this population. Guidance on Referral from Primary to Secondary Care We recommend that the mere diagnosis of atrial fibrillation does not in itself necessitate referral to secondary care and that. This holds the advantage that patients attending surgery for chronic disease monitoring are already carrying risks for stroke and hence targeting AF amongst this group is particularly appropriate. Appropriate groups for targeting include patients over 65 and patients with known heart disease. There are a number of approaches to opportunistic screening.

these figures indicate that anti-coagulation is highly effective treatment in stroke prevention. a low risk group not justifying warfarin but in whom aspirin is recommended and an intermediate risk group in whom the choice of warfarin or aspirin is deemed optional. In 2006 NICE proposed a risk stratification algorithm. By any standards. increased bleeding risk) in whom a further opinion is thought to be helpful Recommendations: • That locally agreed guidelines/pathways are produced for the detection. treatment and management of AF including for those patients for whom secondary care referral should be considered. A number of different risk stratification systems are available. For example. For a mixed population of patients comprising primary and secondary prevention the NNT is of the order of 25. The benefits of warfarin over aspirin were confirmed. is relatively ineffective. Amongst low risk patients the risks associated with anti-coagulation may outweigh the benefits. the NNT to prevent one stroke is 37. Most importantly. However. the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study. 2006 NICE Guidelines on AF recognised the superiority of warfarin to aspirin in stroke prevention and recommends the use of warfarin in preference to aspirin amongst high risk patients (see below). Concern has been expressed that the early clinical trials might not have adequately represented elderly patients. NICE. younger patients with no additional risk factors are found to be at low risk. A recent. CHADS and CHADSVASc. Page 9 of 25 .• • Patients with atrial flutter rather than AF on the basis that this group is readily amenable to radiofrequency ablation Patients posing particular issues with regard to anti-coagulation (e. there was no increased bleeding risk with warfarin in comparison with aspirin. For secondary prevention this falls to 12. pooled analysis of studies showed that warfarin reduced risk of stroke by 64% in comparison with placebo [5]. This concern was dispelled by a recent major trial from Birmingham [9]. in considering the cost efficacy of treatment. The Efficacy of Anti-coagulation in Stroke Prevention There is clear evidence from numerous clinical trails that in many AF patients stroke can be prevented by using antithrombotic medication in particular warfarin. the figures for absolute risk reduction and numbers needed to treat (NNT) are more relevant. in which patients over 75 with AF were randomised to treatment with warfarin or aspirin. commissioners should encourage the use of warfarin in AF patients at high risk of stroke. Stroke risk was halved in the warfarin group. Aspirin. In the case of primary prevention. Assessment of Stroke Risk Not all patients with AF are at the same high risk of stroke.g. Recommendations: • In recognition of the fact that warfarin is much more effective than aspirin in preventing strokes associated with AF. by contrast. Therefore national and international guidelines recommend a formal assessment of stroke risk in each individual AF patient. These are figures for relative risk reduction. reducing the risk of stroke by 22%. This defines patients into three risk groups: a high risk group in whom warfarin is indicated.

It can be used confidently by most healthcare professionals. diabetes and 2 points for stroke. Recent proposals from the European Society of Cardiology have favoured a more expansive approach to anti-coagulation. this strategy is yet to be endorsed by NICE. Choice of Stroke Risk Stratification Scheme There is no unique answer as to the choice of risk stratification scheme. As currently used. If the strategy is to treat only the higher risk patients. also be identified as high risk by the NICE system and CHADS successfully identifies a high risk group CHADS is less successful in stratifying risk amongst lower risk patients If a strategy of anti-coagulating all but the lowest risk patients is adopted. To address this. hypertension. However. giving a maximum score of 6. A score of 2 or greater is considered an indication for anticoagulant therapy. In its original iteration a score of 3 or greater was taken as indicative of a need for warfarin therapy. particularly for use in primary care Patients with a CHADS score of 2 or more would. • • Currently. virtually without exception. A number of generalisations are possible: • • • The NICE algorithm has not been greatly favoured by clinicians because of its relative complexity The CHADS system is easily memorable and has proved very popular. this will have different implications for choice of scoring system from a strategy to treat all but the lowest risk patients. most physicians regard a score of 2 or more as justifying warfarin.The risk stratification system in most common usage is the CHADS system [10]. This introduces a graded scoring system with respect to age and additionally takes account of gender and peripheral vascular disease. age >74. The most appropriate choice may vary both with the particular question being asked and with clinical circumstances. Patients score one point for each of the risk factors . underestimates the risk in some groups. CHADS is the easiest risk score to implement and on this basis we recommend its use. Page 10 of 25 . UK practice is guided by 2006 NICE guideline on anti-coagulation. Choice of scheme will also vary with anti-coagulation strategy. This approximates closely to the high risk group in the NICE scoring system. treating all but the lowest risk patients. then the CHADSVASC system offers advantages over CHADS. This is a quick and easy score to apply.cardiac failure. however. The CHADS scoring system. This gives a maximum score of 9. the CHADSVASC scoring system [11] has recently been introduced. Recommendations: • Risk scoring for stroke should be undertaken in all patients with AF and the result documented. A CHADS score >1 provides a close approximation to high risk group as defined by NICE.

use did not exceed 59%. although half of AF patients had a CHADS2 score which showed them to be at high risk of stroke. to identify patients with AF and at high risk of stroke. There is therefore a danger that it may deter anticoagulation on a basis of relatively modest risk in patients in whom there are clear-cut indications favouring anti-coagulation.Assessment of Bleeding Risk Assessment of bleeding risk is essential in any patient commencing warfarin. In the REACH registry [13] of an international cohort of stable outpatients at risk of cardiovascular disease. was pioneered in a study run in the York Health Group in 2009 which covered a PBC cluster of 232. if required. A study of the General Practice Research Database by Gallagher et al in 2008. abnormal liver function. 37% of those with a score of 0 were prescribed warfarin. In summary. giving an overall prevalence of 1. However. showed that in patients with chronic AF higher stroke risk assessed using CHADS2 was not associated with initiation with aspirin or warfarin according to guidelines. A score of greater than or equal to 3 indicates a high risk and caution and regular review of patients started on oral anticoagulants or antiplatelets are required. There were 3. bleeding / anaemia. 35%. only half of these were prescribed warfarin. Unfortunately there was no clear relationship between the score and use of warfarin. Even in those with very high CHADS2 scores. entitled GRASP-AF (Guidance on Risk Assessment and Stroke Prevention in Atrial Fibrillation). 56% with a score of 2 and 56% of those with a score of 5.883 patients in 24 practices. 54% with a score of 1. Many clinicians will be satisfied with a simple assessment of the patient’s clinical history. a more formal assessment of bleeding risk can be made using a scoring system called HAS-BLED [12] which is derived as follows: history of high blood pressure. This tool. In such cases it may be helpful to seek an opinion from secondary care before denying a patient a potentially important and valuable therapy. drug history and age. Page 11 of 25 . Are the York results representative? The York experience of under use of anticoagulation seems to be borne out in other parts of the country. systmone to replicate the function of GRASP-AF. Of those with a score of 2 or more only 54% were prescribed warfarin. but were more likely to persist with treatment than younger patients. most patients with AF received ant platelet treatment and only 53% were treated with oral anticoagulants. In the study only a minority. who are not receiving warfarin. from GP records throughout the UK. received warfarin for five years [14].g. Alternative systems can be used e. Prior to the study the practices had not been using any specific risk scoring system. Barriers to Anti-coagulation GRASP AF The West Yorkshire Cardiac and Stroke Network have developed a primary care database interrogation tool.699 AF patients. Elderly patients were much less likely to be initiated on warfarin despite being at highest risk. The disadvantage of a scoring system is that a number of the risk factors for bleeding are similar to the risk factors for stroke.58% and 54% were at high risk of stroke with a CHADS2 score of 2 or more.

Page 12 of 25 . despite the evidence that aspirin is relatively ineffective. 97. What are the misconceptions? • • • • • Warfarin is seen as an unsafe drug. with a proposal to introduce a scoring system based on CHADS and to reward practices for using the scoring system and for the proportion of high risk patients receiving anti-coagulation. That primary care should refer to secondary care in the decision to commence warfarin. Warfarin was seen as very inconvenient for patients. This stands in stark contrast to the fact that only 50% of high risk patients in York were receiving best treatment. • • • There were absolute contraindications to warfarin recorded in 24% and relative contraindications in 27%. There is poor awareness in general practice of the results of the BAFTA study demonstrating the safety of warfarin amongst an elderly population. In 36% the doctor made the decision with no further information recorded.What is the barrier to anti-coagulation? The project in York asked the practices to review all 767 patients who were inadequately treated but at high risk and consider anticoagulation. Practices are rewarded for maintaining a register of patients with AF. There is a view that only patients with persistent AF need warfarin. Aspirin is regarded as an efficacious and safer alternative. • How to Overcome the Barriers The role of QOF The Quality and Outcomes Framework was introduced in 2004 to improve the management of long term conditions in primary care. Warfarin is particularly seen as unsafe in the elderly with multiple medications and issues of poor memory and compliance/concordance. The York study therefore showed that there is reluctance amongst medical staff to prescribe warfarin.e. diagnosing AF using an ECG and for treating with antithrombotic therapy. In 2008/9. despite evidence that people with paroxysmal AF are at equivalent risk. In the interim. GPs were comfortable using aspirin rather than warfarin. In 12% the patient declined but in the majority this was not following a face to face discussion with the up to date review of the evidence i.8% of practices in the Yorkshire and Humber region earned full points for the AF domain. Equal importance is attached to the use of warfarin and aspirin. It is hoped that this proposed amendment to QOF will be formalised in the near future. Primary care physicians are in fact in a much better position to assess stroke risk because they will have a holistic view of the patient. of which over half were recorded as psychiatric reasons and 39% risk of falls (77 patients). Where this was not considered appropriate the practitioner was requested to record the reason. we would encourage local initiatives to similarly reward risk stratification and appropriate treatment. The current iteration of QOF in relation to AF is under review. Stroke risk was seen as a static rather than an evolving issue as people age and develop new risk factors. Any attempt to increase the uptake of warfarin therefore needs to be able to specifically address this barrier and misconceptions on the part of medical staff. not following the AFA advice ‘no decision about me without me’. Unfortunately this process did not result in a significant increase in prescribing and people with a score of 2 were more likely to be started on warfarin rather than those of 4 or more.

with no loss of quality of care. With regard to the poor image of warfarin. • Promotion of the GRASP-AF Tool The national implementation of the GRASP-AF tool is now being facilitated by NHS Improvement – Heart. A second is the image of warfarin as “rat poison”.The role of the patient in decision making It is an over-simplification to suggest that reluctance to commence warfarin is confined solely to medical staff. it may be necessary to ensure that domiciliary phlebotomy services are available. particularly the elderly and those with limited mobility. the perceived “faff” factor in warfarin. With these tools patients can be helped towards a better understanding of their current risk of stroke and how this might be reduced with anti-coagulation. It is possible that the new anti-coagulant drugs which will shortly become available (see later section) will also help to address the issue of inconvenience currently associated with anticoagulation. Tools are available to help explain to patients the concepts of risk and risk reduction. One is undoubtedly the very real inconvenience of needing to attend anti-coagulant clinics. In addition to use at individual practice level to identify patients at risk and currently untreated. Bleeding risk and balance of risk can also be addressed. including support from the national clinical leads A National GRASP workshop to educate PCT and practice staff on tool implementation Support for voluntary organisation and pharmaceutical educational events on AF. uploaded anonymised data can be viewed using Chart-on-Line to facilitate comparison of anti-coagulation between practices or indeed between the PCTs across a Page 13 of 25 . A number of factors contribute. Both these issues require addressing. Support for implementation of the tool is available in a number of ways: • • • • • Promotional materials from NHSI Direct support from NHSI service improvement personnel for tool implementation and problem solving Support for local training and educational events. For other patients. The concept of risk and relative risk should be explored with individual patients to encourage their fully informed participation in the decision whether or not to commence anti-coagulation. Recommendations: • All primary care teams should be educated on the benefits and risks of anticoagulation. There should be a focus on improved delivery of anti-coagulant services to minimise patient inconvenience and hence encourage anti-coagulant uptake. patients are often surprised to hear just how effective it is as a therapy. In some patients near patient testing will offer much greater convenience than attending an anti-coagulant clinic. to enable the patient to come to an informed judgement on their management. Anti-coagulant clinics need to be organised for maximal patient convenience and to minimise the faff factor. Individual practices should consider nominating an AF lead with focused training. Many patients are themselves reluctant.

who were participating in clinical trials which required. This should be the subject of regular audit. as part of the protocol. However. Approximately 7% were shown to have PAF with more than being identified >48 hours after the stroke [17]. offers an opportunity for enhanced detection of AF. More prolonged monitoring studies with event recorders have reported detection rates between 5. Recommendation: • The baseline medical assessments of a patient with stroke should include documentation of the cardiac rhythm and a standard 12 lead ECG. This would translate to between 50 – 100 patients per year in an average health district of 250. be used by a PCT or commissioning group as a quality marker for anti-coagulant services in their area and as a means of monitoring improvements in practice.7% in patients who initially had negative Holter monitoring. for example. particularly in older patients.region. it was also observed that the difference Page 14 of 25 . are associated with atrial fibrillation.3% and 7. either repeated standard ECGs or Holter monitoring. The tool could. the rhythm disturbance may not be identified on admission. Currently there is no consensus about the optimal strategy for more prolonged cardiac monitoring but. the AF is either known about before the stroke or identified at the time of first presentation with the stroke. clinicians should be alert to the fact that some patterns of stroke are more likely to be caused by cardiogenic embolism and target investigations appropriately. Secondary Prevention . The overall conclusion from the study was that the aspirin-clopidogrel combination was inferior to warfarin in stroke prevention. This is best illustrated from the Active-W study [18] which compared the efficacy of a combination of aspirin and clopidogrel in comparison with warfarin in stroke prevention in patients with AF. There has recently been a review of patients with ischemic stroke who did not have AF at the time of primary assessment after the stroke. Usually. The national recommendation that all patients with acute stroke are admitted to a Hyper Acute Stroke Unit (HASU) with more intensive physiological monitoring for two to three days.000. A systematic review of studies that have examined the utility of Holter monitoring for 24 – 72 hours post stroke reported an AF detection rate of 4. Measures should be undertaken to ensure that ECG recording and the detection of AF are an integral part of ongoing. However. Recommendations: • That all practices should run the GRASP-AF tool or its equivalent and upload the data to CHART online. inpatient care.6% [15]. This has major implications for secondary stroke prevention. The Importance of Quality of Anti-coagulation There is growing evidence that quality of anti-coagulation is an important factor in stoke prevention. GP’s should use GRASP to identify high risk patients for review and CHART online can be used by GP’s and commissioners to benchmark and audit the quality of local service delivery.Identification of AF after Stroke Approximately 30% of ischemic strokes are attributed to cardiogenic embolism and of these more than half. although these studies were relatively small [16].

and hybrid models. Time in therapeutic range varies considerably between anti-coagulant clinics in the UK. Some clinics have access to community phlebotomists who attend the patient’s home to perform the INR check (by NPT or blood sampling. In some services the patients have their blood sample taken at the GP surgery . • The second is that this variation has very important consequences for the therapeutic benefits of warfarin and that when TTR falls below 65% the benefits of warfarin are abolished or substantially reduced. With TTR values >65%. Patients attend the anticoagulation clinic to have their INR checked (by venous sampling. or by near patient testing (NPT)). There was no benefit of warfarin over aspirin-clopidogrel when TTR fell below 65%. Based on the Active-W study. with the INR result and warfarin dose recommendations sent by post to the patient). in primary care. Most primary care services are provided in GP practices. the RELY study (see below). There are two important conclusions from the Active W study: • The first is that different healthcare systems vary in the adequacy of anti-coagulant control as measured by TTR. Audit and Governance in Anti-coagulant Services There are a number of different models of anticoagulation provision within the region. Similar conclusions in respect of varying efficacy of warfarin in relation to TTR are deducible from a second study. warfarin was superior to aspirin-clopidogrel. Unpublished data from clinics using automated algorithms for anti-coagulant management shows that TTR for individual clinics varies between 60 and 80%. Most primary care anticoagulation services utilise INR near patient testing. Primary care anticoagulation services These do not usually start (induct) patients’ warfarin anticoagulation. but some are provided by pharmacists in commercial pharmacies. Some clinics will give the patient their warfarin dosing instruction when attending the clinic.this is then sent to the hospital laboratory and the INR result and dosage information sent to the patient from the hospital anticoagulation service. It is likely that a clinic offering a TTR of 60% is not providing its patients with an adequate therapeutic benefit from anti-coagulant therapy.between the aspirin-clopidogrel combination and warfarin varied substantially from country to country and that this variation was dependent on differences in the “quality” of anticoagulation in the different countries. it is possible to calculate the potential benefits that would be achieved with a small increase in TTR. analysed by the laboratory. These include services provided entirely in secondary care. Secondary care anticoagulation services Patients are referred to the clinic to start anticoagulant therapy by hospital consultants or GPs and start this using an approved induction regimen for the indication for anticoagulation. Patients will be given their INR result and warfarin dosing instruction at the time they have their INR check. A 5% improvement in TTR across anti-coagulant clinics in England would result in the prevention of an additional 400-500 strokes each year. whereas others function as a postal service (the patient returns home. Promoting Quality Standards. Page 15 of 25 . measured as the time in therapeutic range (TTR) in the warfarin group. with the INR result and dosing information subsequently sent to the patient by post). patients are transferred after their INRs have been stabilised by the secondary care service.

a proportion of GP practices offer anticoagulation monitoring services. In addition to recommending that staff involved with anticoagulation had the necessary competencies. then the benefits of anti-coagulation are substantially lost (see above). for example) b.Hybrid models In many regions. Has bleeding risk increased (see HASBLED score for guidance. and continuing to manage patients whose practice or pharmacist do not. Quality Standards. If the time in therapeutic range is lower than 65%. Page 16 of 25 . transferring stable patients to primary care if their practice or pharmacist provide this service. Consider patient’s preferences regarding anticoagulant therapy. A failure to make an appropriate referral at the point of discharge can lead to errors in anticoagulation therapy which can be life-threatening. Have other contraindications to anticoagulation developed/change in clinical circumstances? Review patient’s anticoagulation record (time in therapeutic range). Annual Review There is no ‘validated’ annual review of patients on anticoagulation therapy. It is well known that anticoagulation incidents are much more likely to happen when the patient is transferred between services (admitted to or discharged from hospital). where as others do not. The Safety Alert also included the requirement for all patients on oral anticoagulant therapy to have an annual review of their anticoagulation. Oral anticoagulant therapy is one of the highrisk medications most likely to cause preventable harm. The NPSA Safety Alert 18. with these results communicated to the appropriate clinical governance structures.g. the secondary care service will start the patient on warfarin. The aim of the review is to determine whether the patient is benefiting from the therapy and should include the following components: • • • Review indication for anticoagulation (e. In a hybrid model. revise CHADS2 score) Review target INR (has patient developed a new thrombosis on anticoagulation? Is target INR appropriate?) Review risks of anticoagulation therapy a. Audit and Governance Oral anticoagulation is effective in preventing stroke as a result of atrial fibrillation but only if the therapy is of sufficient quality (see above). Commissioners should ensure. admission to hospital and prolonged inpatient stay. In a hybrid model. confusion can arise at the point of discharge as to who provides the patient’s ‘usual’ anticoagulation care. when commissioning an anticoagulation service that it complies with these recommendations. made a series of recommendations to be implemented by all health sector organisations involved with medication safety. all services should undertake audit using the BSH/NPSA safety indicators. Actions that can make Anticoagulation Safer (2007) [19]. Outcomes: o Continue oral anticoagulation (no change required) o Stop anticoagulation if risks are now considered to outweigh benefits o Consider alternative anti-coagulants if the patient’s time in therapeutic range is low o Refer for further advice • • • Recommendations: • Anti-coagulant clinics adhere to existing NPSA guidelines on audit and clinical governance with particular emphasis on time in therapeutic range and that the audit data so generated is actively reviewed by commissioners.

By contrast in centres with a high time in therapeutic range. and the implications for local populations.003). 3. All had AF and at least one other risk factor. However. Three anticoagulation agents: apixaban. rivaroxaban and dabigatran etexilate are anticipated to be licensed for stroke prevention in atrial fibrillation shortly. dabigatran appeared to be equivalent but not superior to warfarin. Eight were achieving an average TTR of under 50%. Warfarin is currently the anticoagulant of choice for most patients with AF. The rate of major bleeding with Dabigatran Etexilate 110mg was 20% lower compared to warfarin (p=0. The UK centre had a TTR of 72%. The analyses commissioned by the West Yorkshire Cardiovascular Network (WYCN) showed that there is a strong effect of TTR on warfarin benefit and that there is a threshold below which the benefit of warfarin is limited. Both doses were shown to be non-inferior to warfarin on the primary endpoint of reducing the incidence of stroke (including Haemorrhagic) and system embolism (p <0. the principle that poor warfarin control is associated with more adverse clinical events is consistent with a post hoc analysis of the TTRs of patients on warfarin in a trial of warfarin versus clopidogrel plus aspirin ([ACTIVE-W – see above). The West Yorkshire Cardiovascular Network undertook economic modelling in 2010 to assist both commissioners and GPs in deciding (pre-NICE Guidance) whether to prescribe Dabigatran instead of Warfarin (appendix 1). indeed dabigatran etexilate was licensed for this indication in April 2011. These new drugs offer great practical advantages in avoiding the need for regular anti-coagulant checks and reducing the “faff” factor in anti-coagulation. These were calculated from the TTR values observed in that study. with another eight achieving an average TTR of higher than 70%.53-0.• Individual patients on anti-coagulant therapy undergo an annual review which includes consideration of: the continuing indication for anti-coagulation. This is driven by the quartiles used in the Wallentin et al study [21].113 participants. warfarin may be prescribed aspirin.11%/year. 95% I.001). Similar principles may in time be applied to the other new agents. The RE-LY study included 18. It is important that clinicians and commissioners have a very clear understanding of the strengths and weaknesses of study design. Two doses of dabigatran were assessed. The value itself has no clinical significance. Variation of time in therapeutic range appeared to influence the efficacy of dabigatran in comparison with warfarin.66. The efficacy of dabigatran in comparison with warfarin in patients with AF was considered in the RELY study [20]. or who cannot tolerate. Dabigatran 150mg was superior to warfarin in reducing the incidence of stroke and systemic embolism by 34% (RR 0. The first of the new agents likely to become clinically available is dabigatran and the possible implementation of this drug in clinical practice is discussed below. 0. the recommendations from the WYCN was that dabigatran should be considered in patients in whom warfarin was contra-indicated Page 17 of 25 .36%/year respectively p =0. the patient’s bleeding risk and the patient’s percentage of time in therapeutic range. New Drugs The current treatment for patients with moderate to severe disease is warfarin: patients who are contraindicated to. from 951 clinical centres in 44 countries. The countries varied widely in respect of the efficacious use of warfarin. The analysis based on quartiles of INR achieved by centres indicated a critical value for TTR of 65%. Based on this economic appraisal. Amongst centres with a low time in therapeutic range. P <0.31). There was no significant difference in the rate of major bleeding for Dabigatran compared to warfarin (3.82.001). dabigatran was superior to warfarin.

Left Atrial Appendage Occlusion Devices Anti-coagulation does. a detailed clinical consensus regarding the place of a treatment in the pathway of care. The work undertaken on Dabigatran has highlighted the need to think critically about new agents in general well before license or NICE Appraisal. the possibility that effectiveness varies within sub groups of the population and the potential impact of a switch on primary care prescribing budgets. which is considered the major thromboembolic source in patients with AF. in patients thought to be at a greater risk of bleeding Many clinicians believe that this will shift the paradigm of anti-coagulation towards anticoagulation of all but the lowest risk patients (see above). clinical and cost effectiveness and the place in the pathway needs to be fully considered. in whom there are clear-cut contra-indications to anti-coagulation [23]. In a relatively small number of patients. However. there are concerns that the trial demonstrated an increased incidence of adverse safety events in the device group and. use of these devices is currently best restricted to patients with a significant thrombo-embolic risk from their AF. As a generalisation it is likely that the advent of new anti-coagulants will have a major effect on anti coagulant practice in AF: • • • • The new anti-coagulants will offer much improved patient convenience with a major impact on the “faff” factor of warfarin This may help extend the use of anti-coagulants to the currently substantial population who are at risk and not receiving treatment Differential dosing (for example with the two doses of dabigatran) may provide the clinician with a choice of using a lower dose of the drug. Page 18 of 25 . of course.(other than for bleeding risk) and patients with poor therapeutic control on warfarin (defined as a TTR<65%). consideration of likely budget impact and what services need to be scaled back to make way for new treatments. Affordability. These devices are still relatively new and clinical trials relatively small. Recommendations: • That new anti-coagulant agents are becoming available which will offer advantages to patients of greater convenience and may in some groups offer superior efficacy or safety however. cost effectiveness analysis. An alternative approach in such patients is to consider the use of left atrial appendage (LAA) occlusion devices. Prescribing advice will need to be circulated widely. countering manufacturer marketing and strategies for switching patients onto new agents where indicated. bleeding risk is sufficiently great to mean that anticoagulation is contra-indicated. potential for destabilisation of existing anticoagulation services. service providers and the opportunity cost of poor investment decisions. have the drawback of an associated bleeding risk. The factors that should be considered for all new agents include a detailed and critical appraisal of the published evidence. if only for this reason. This is particularly acute given the relatively high cost of newer anticoagulants (compared to warfarin). These devices prevent the formation and subsequent dislodgement of thrombus in the LAA. The largest study using a device called the Watchman has been reported as demonstrating non-inferiority to warfarin in protection against stroke [22]. managing patient expectations. the use of these new agents requires careful economic appraisal prior to their introduction.

The publication of the Government’s public health white paper. Patient Lifestyle Issues Prevention remains a key national and regional priority for the future of our nation and for the NHS. Such interventions.no more than two . obesity and weight loss. will have a significant effect on population health and should lower the incidence of AF. The SHA has committed to supporting the NHS develop the concept of Making Every Contact Count – i. The Government has published evidence based messages for healthy eating. consistently applied to whole populations. This includes general guidance on behaviour change. evidence based interventions to promote healthy lifestyle choices need not be onerous and should be a part of routine clinical practice. Eat a balanced diet. in whom there are clear-cut contraindications to anti-coagulation. Exercise moderately for at least 30 minutes a day. that all interactions between NHS employees (clinical and non clinical) and patients/public are opportunities to promote healthy lifestyle choices. such as restriction of alcohol. In some cases. all will welcome referrals in from either general practice or cardiology re helping AF patients following a brief intervention and advice in primary or secondary care. Healthy People Healthy Lives has re emphasised the role that healthy lifestyle choices have in promoting good health. Page 19 of 25 .three units for women and three . alcohol use and the prevention of cardiovascular disease. which provide one-to-one support to enable individual behaviour change. smoking cessation. the benefit of improved lifestyle choices may be more general in preventing problems such as hypertension or coronary atherosclerosis which may predispose to AF in the long term. Try to maintain weight at a BMI of between 20 and 25. including five portions of fruit and vegetables per day. The core message which emerges is that systemic. lifestyle choice may have a direct benefit in preventing AF. Health Trainers.e.four units for men per day. Referral routes and exact model of service varies from place to place. physical activity. There are a range of “lifestyle support” services in place around the region to support individuals to change their lifestyle behaviours for example.Recommendation: • That the use of left atrial appendage occlusion devices is restricted to patients at significant thrombo-embolic risk. The key messages are relatively simple: • • • • Drink in moderation . In other areas. Recommendation: • NHS commissioners should ensure that services are supporting patients to adopt a healthy lifestyle and referring patients to community health improvement services as appropriate. NICE has published a range of advice on interventions to improve lifestyle choice.

html SPAF Academy – Stroke Prevention in Atrial Fibrillation www.yorksandhumberhearts.uk North Trent Stroke Strategy Project www. links to pathways/guidelines www.nice.gov.stroke.org.atrialfibrillation.uk North and East Yorkshire and North Lincolnshire Cardiac & Stroke Network www.nhs.nhs.nhs.org.Appendices.nice.uk http://www.uk http://guidance.uk/CG36 Guidelines for the management of AF.spafacademy.stroke.uk Department of Health www.php?o=4745 West Yorkshire Cardiovascular Network (Stroke and Cardiac) www.nhs.uk/usingguidance/commissioningguides/anticoagulationtherapyservice/c arepathway.nice.uk Page 20 of 25 .org/guidelines Atrial Fibrillation Association – professionals and patient information.yorksandhumberhearts.nice.uk/information/our_publications/leaflets/index.org.org.yorksandhumber. The task force for the management of AF of the European Society of cardiology www.org.uk/CG36 http://www.doh.jsp Stroke Association www.org. Further Information and Useful Links Y&H Corporate Strategy 2010-13 http://www.escardio.ntncc.uk http://guidance.org.uk/document.org.uk National Institution of Clinical Excellence – NICE www.

npsa.nlm.org.escardio.uk/Home/Home.com/journals/lancet/article/PIIS0140-6736(07)61233-1/abstract REACH Registry http://www.thelancet.medscape.ncbi.SPAF – Stroke Risk Resource http://www.spafacademy.gov/ct2/show/NCT00243178 RELY Study http://www.com/content/dam/internet/opu/com_EN/protected/document/01_news/02_Press_a nd_Informationpacks/3_AF_and_stroke_backgrounder.org/guidelines-surveys/ehs/atrial-fibrillation/Pages/ehs-on-af.com/journals/lancet/article/PIIS0140-6736(10)61194-4/abstract NPSA Safety Alert 18 http://www.com/journals/lancet/article/PIIS0140-6736(10)60975-0/fulltext Euro Heart Survey http://www.aspx?gclid=COymj6H4vqgCFQEY4QodPkKjow STUDIES INTERSTROKE STUDY http://www.nrls.nih.aspx SAFE Study http://www.gov/pubmed/16202350 BAFTA Study http://www.com/viewarticle/583610 Study of General Practice Research Databases –Gallagher et al 2008 http://www.uk/resources/?entryid45=59814 Page 21 of 25 .nhs.boehringeringelheim.pdf Active-W Study http://clinicaltrials.thelancet.thelancet.

AVVEROES Study http://www.nhs.gov.co.evidence.improvement.gpnotebook.nice.org.aspx ROCKET Study http://www.com/en/clinical-studies/stroke-prevention-in-atrialfibrillation/index.nhs.org/about/press/press-releases/esc10-stockholm/Pages/AVERROEStrial.org.nhs.cfm/NEWSID/252/CHADS2%20and%20HASBLED%20assess%20%20Coumadin%20bleeding%20risk%20in%20atrial%20fibrillation/warf arin%20anticoagulant HEALTHY LIVING SECTION http://www.uk Commissioning Guide for AF Services http://www.improvement.uk/PH25 .uk GRASP – AF Anticoagulation Commissioning Guide http://www.pdf CHADS2 http://www.nice.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidan ce/DH_121941 http://egap.uk/nicemedia/pdf/CG036niceguideline.nhs.dh.org/newsitem.cfm?ID=x20110126111352933383 CHADSVASc http://www.xarelto.improvement.uk/simplepage.php?user=HCP NHS Improvement Team – links and further information for Cardiac and Stroke Topics www.org/newsitem.stopafib.cfm/NEWSID/316/CHA2DS2VASc%20stroke%20risk%20tool%20better%20than%20CHADS2/atrial%20fibrillation%20pat ients HASBLED http://www.escardio.aspx Risk Assessment Tools Nice Algorithm (page 48) http://www.stopafib.uk/PH06/ Page 22 of 25 http://guidance.uk/heart/HeartImprovementHome/AtrialFibrillation/AtrialFibrillati onResources/tabid/136/Default.

jsp http://www.eatwell.uk/PH010 http://guidance.org.uk/PH24 http://www.org.dh.nice.nice.nice.nhs.http://guidance.org.yorksandhumber.nationalarchives.nice.co.gov.uk/Uploads/BetterForLess/08%20BETTER%20FOR%20LES S%20every%20contact%20counts.aspx http://www.htm http://www.uk/PHI002 http://egap.gov.gov.uk/newsroom/guidanceinfocus/obesity_and_maintaining_a_healthy_weig ht.org.uk/CG43/ http://webarchive.uk/en/Publichealth/Healthimprovem ent/Alcoholmisuse/index.org.nice.evidence.uk/ http://www.uk/PH2 http://guidance.org.healthyambitions.uk/PH1 http://www.nhs.uk/what_we_do/improving_the_health_of_the_population/m aking_every_contact_count/ http://www.nice.pdf Page 23 of 25 .uk/Livewell/Goodfood/Pages/eight-tips-healthy-eating.nhs.uk/+/www.

. et al. NHS. 2010. 361: 1139-1151 Wallentin et al. Chest 2010 Goto S. Atrial Fibrillation Cost benefit Analysis. 1500-6. 7. and Phillips KA. 2422-2434. Nieuwlaat R. Jones SC. New england J Med 2009. 6(9): p. Quality and Outcomes Framework Acheivement Data 2008/9. Johnston SC..References 1. Wright DG. Shuain A. Circulation 118. Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis? J Thormb Haemost. Nieuwlaat R et al.. health Technology assessment. 13. 12. Khalid Z. 18(6): 453-7 Connolly S et al on behalf of the ACTIVE W invetigatrs (2008) Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalised ratio control achieved by centres and countries as measured by time in therapeutic range. Delayed detection of Atrial Fibrillation after ischemic stroke. 137:263-272t Pisters R. 2009 Nov-Dec. Muriali S. o’Donnell M. Atrial fibrillation management: a prospective survey in ESC Member Countries. J Stroke Cerebrovasc Dis. JAMA 2001. Hobbs F. Singh D. Atrial Fibrillation detected by mobile cardiac outpatient telemetry in cryptogenic TIA or stroke. 2005. O'Donnell MJ. 9. 10. Waterman A. Fletcher K et al. 376: p. Editor. Tian M. 146: 857867. 6. Stroke. 4. Prevalence. Risk factors for ischemic and intracerebral haemorrhagic stroke in 22 countries ( the INTERSTROKE study): a case-control study. et al. Non invasive cardiac monitoring for detecting paroxysmal atrial fibrillation or flutter after acute ischemic stroke: a systematic review. Standards and Quality Analytical Team. 18. Morillo C. Gupta R. National Audit Office. Lees KR. 15. 26: p. 2008 Nov 18. Teal PA. Lyden PD. A novel user friendly score (HAS-BLED) to assess one year risk of major bleeding in atrial fibrillation patients: The Euro Heart Survey. 16 Nov 2005. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial Page 24 of 25 2. Lancet. Virtual International Stroke Trial Archive Investigation. 19.uk Hobbs. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor based approach. 20. DoH Marian Kerr. 2008. Ali M. Jarouse J. 2009. Reducing Brain Damage – Faster Access to Better Stroke Care. et al. 38(11): 2935-40 Tayal AH. Am Heart J. BAFTA) a randomised controlled trial. Lancet 2007. 112-23. 2029-2037 NPSA Alert 18. 855-863. Chest 2010. 8 9. Hart R. 370: 493-503 Gage B. Go AS. and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis. Brillam J. Validation of clinical classification schemes for predicting stroke: results from the national registry of atrial fibrillation. [93pp] Mant J. Action that can made anticoagulat therapy safer (2007) Connolly S et al. et al.. Land D.. Antonucci E. NHS Information Centre for health and social care. Pearce L. The SAFE Study. 285(18): p. NHS.improvement. 18:71(21): 1696-701 Kamel H. (40). Shannon W et al. 11. Dabigatran versus warfaring in patients with atrial fibrillation. Aguilar M. JAMA. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of AF and people aged 65 and over. European Heart Journal. the Euro heart survey on atrial fibrillation. Kelly KM. Neurology. Prevalence of Diagnosed Atrial Fibrillation in Adults. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study. 16 17. Hylek EM.21. Linkto access www. 156: p. 3.nhs. 2001. Grifonie E et al. 2008. . 5. Gallagher AM. clinical profile. Liao J. Scallan C. 2007 Nov. Meta analysis: antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. FDR et al (2005). 2370-2375. 285:2864-2870 Lip G. 14. Ann Intern Med 2007.

Reddy VY. Lancet 2009.22. Turi ZG. et al. Lancet 2009. 374:534-542. McCabe DJH. Dabigatran was considerably less effective (and thus less cost effective in those with good control) Holmes DR. 376: 975–83. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: A randomised non-inferiority trial. The Lancet 2010. Kinsella JA. Left atrial appendage occlusion in nonvalvular atrial fibrillation. 23. This study found a clear relationship between TTR and effectiveness of dabigatran. fibrillation: an analysis of the RE-LY trial. and Tobin WO. The clinical impact was considerably greater in those patients who were already treated with warfarin but unable to get good control. 374: 504-506 Page 25 of 25 .

. Vanbrugh Way. 4144762 Registered office as above. Heslington.co.ac.CONFIDENTIAL WEST YORKSHIRE CARDIAC NETWORK Economic Appraisal of Dabigatran Etexilate 150 mg Compared to Warfarin or Aspirin in Patients with Atrial Fibrillation Updated Report JOYCE CRAIG.yhec. York YO10 5NH Tel: 01904 433620 Fax: 01904 433628 Email: yhec@york. Market Square. Project Director NOVEMBER 2010 ©YHEC University of York.uk York Health Economics Consortium is a Limited Company Registered in England and Wales No.uk www.

4  Clinical Effectiveness Analysis: By CHADS2 Score For Patients in RE-LY 2.6  Limitations with the Data Section 3:  Health Benefits 3.Contents Page No. Licensed Indication and Comparators 1.5  The Dabigatran Etexilate 150 mg and Aspirin Model 2.1  Dabigatran Etexilate 150 mg Compared to Warfarin in RE-LY Study Group 5.2  Clinical Effectiveness Analysis: All Patients in RE-LY 2.2  Dabigatran etexilate 150 mg Compared to Aspirin in BAFTA Study Group 5.2  Cost of Disease States Section 5:  Results of Economic Model 5.1  Cost of Medication 4. Executive Summary Section 1:  Patient Group.3  Clinical Effectiveness Analysis: By TTR for Patients in RE-LY 2.1  Study Participants: RE-LY 1.5  Perspective Section 2:  Clinical Data 2.4  Comparators 1.2  Disease Related Utilities Section 4:  Costs 4.3  Sensitivity Analyses for Dabigatran Etexilate 150 mg and Warfarin 5.1  Life Expectancy 3.2  Study Participants: BAFTA 1.1  The Dabigatran Etexilate 150 mg and Warfarin Model 2.4  Sensitivity Analyses for Dabigatran Etexilate 150 mg and Aspirin Section 6:  References Discussion and Conclusions 1  1  2  2  2  2  3  3  3  3  5  6  7  8  8  8  10  10  10  12  12  12  12  14  15  Confidential to West Yorkshire Cardiac Network .3  Licensed Indication 1.

compared to aspirin. with the range being the international normalised range (INR) 2. By CHADS2 score. The clinical evidence on the efficacy and safety of dabigatran etexilate 150 mg. or cannot tolerate.Executive Summary 1. compared to warfarin. at high risk of stroke and unable to tolerate warfarin. The manufacturer of dabigatran etexilate declined to make a submission to WYCN. The UK centre in the study had an average TTR of 72%. The incremental cost per quality adjusted life year (QALY) was estimated at £12. it was not costeffective to treat patients with good INR control. The evidence for the efficacy and safety of warfarin. warfarin k. By different time in treatment ranges (TTR). utilities. The sensitivity analyses showed the results were robust to changes to the parameter values for all the main variables including efficacy. compared to aspirin. Confidential to West Yorkshire Cardiac Network . came from the Randomized Evaluation of Long-term anticoagulant therapy (RE-LY) study1. • A further analysis examined if dabigatran etexilate 150 mg was clinically and cost-effective. The appraisal was therefore conducted using published sources. This was in the patient group who were aged 75 years or over.0 to 3. However.000. defined as a TTR of greater than 65%. The base case results and sensitivity analyses suggest it was cost-effective to treat patients with AF with dabigatran etexilate 150 mg rather than warfarin. to manage elderly patients with a high stroke risk who are contraindicated to. rather. simple but transparent and robust models were developed using the clinical studies.640. INTRODUCTION The West Yorkshire Cardiac Network (WYCN) is reviewing the clinical and costeffectiveness of dabigatran etexilate 150 mg as first line treatment for patients with atrial fibrillation (AF) and at moderate or high risk of stroke. life expectancy and warfarin clinic costs. costs appropriate to WYCN and benefits from published sources. The comparison of dabigatran etexilate 150 mg compared to aspirin resulted in an incremental cost per QALY of under £5. The analyses compared the cost-effectiveness of dabigatran etexilate 150 mg to warfarin: • • In the AF population as defined in the RE-LY study.03. This note summarises the assumptions for each key aspect of the appraisal. Dabigatran etexilate was assumed to cost NHS primary care purchasers £900 a year. No complex economic modelling was used. came from the BAFTA study2.

9 37. and have a worse prognosis than strokes in patients without AF8. with another eight achieving an average TTR of higher than 70%. All had AF and at least one other risk factor. from 951 clinical centres in 44 countries.1 STUDY PARTICIPANTS: RE-LY The patient groups used in these analyses are those in the RE-LY1 and BAFTA2 studies. AF is estimated to cause up to 15% of all strokes. cautions and contraindications. The NICE Clinical Guideline on the ‘Management of Atrial Fibrillation’7 recommended that patients with AF be assessed for their risk of thromboembolism.2 32. Clinicians were advised to manage patients using an adjusted-dose approach.0 32.6%4 51. Warfarin has intensive monitoring requirements and many drug and disease interactions.6 63.5 63. Table 1.4%4 Characteristics Age years Male sex % CHADS2 score 0 or 1 2 3-6 Section 1 Confidential to West Yorkshire Cardiac Network 1 . The RE-LY study included 18. The absolute range was 41% to 77%. 1. slightly higher than the estimated prevalence of 1. cause greater disability.15 48. Eight were achieving an average TTR of under 50%. those who could not should receive aspirin (75 to 300 mg/day). The countries varied widely in respect of the efficacious use of warfarin. and given appropriate thromboprophylaxis.Section 1: Patient Group.3 30.2 35.113 participants.6 Warfarin 61. Licensed Indication and Comparators Atrial fibrillation (AF) is the most prevalent.0)7. Warfarin was recommended for patients at high risk of thromboembolism who could tolerate the drug. according to the ‘Stroke risk stratification algorithm’. AF-related strokes are more severe.5 (range 2. Table 1.24% in England and Wales6. The prevalence of AF rises sharply with age.2 32. being over 12% at age 757.1 summarises the baseline characteristics and compares these to the available information on the English population.58%5 of people in West Yorkshire.1 England 73. to achieve an INR of 2.0%4 40. sustained cardiac arrhythmia. This is important when interpreting the results. The risk of causing dangerous bleeding episodes and other issues mean that decisions regarding its use are complex9. The UK centre had a TTR of 72%3.1: Baseline characteristics of RE-LY Participants Dabigatran 150 mg 71. Patients at moderate risk should be considered for warfarin or aspirin.0 to 3. affecting about 1.8 5 8.

This study compared warfarin and aspirin 75 mg.4 COMPARATORS The comparators to dabigatran etexilate for the prevention of stroke and systemic embolism in patients with AF at moderate to high risk of these events are warfarin and aspirin4. the major difference is on the CHADS2 scores. the GRASP work5 estimated that fewer than 9% of patients treated for AF have a CHADS2 score of 0 or 1. 1. but fewer had CHADS2 scores higher than 2 compared to AF patients in WYCN. 1.2 summarises the baseline characteristics and compares these to the available information on the English AF population. Table 1. This probably reflects the exclusion criteria applied.5 PERSPECTIVE The perspective adopted in the model is NHS and personal social services costs.The study group was slightly younger and had fewer women than assumed by NICE. This is the same as the perspective used by NICE in technology appraisals10. all with AF or atrial flutter and aged 75 years or over. Section 1 Confidential to West Yorkshire Cardiac Network 2 . Moreover. One implication is that the event rate observed in the study may be lower than anticipated for patients in WYCN.5 54% 72% 28% England 73. 1.2: Baseline characteristics of RE-LY Participants Warfarin 81. dabigatran etexilate is not licensed for the prevention of stroke and systemic embolism in AF in the UK.15 49% 5 60%4 40%4 Characteristics Age years Male sex % CHADS2 score 1-2 3-6 The patients in BAFTA were thus significantly older. compared to over 30% in the RE-LY study. 1. These included those judged by their GP to be unsuitable for warfarin because of stroke or bleeding risk or with a history of haemorrhage. However. many of the CHADS2 patients with scores of 0 or 1 would not be prescribed warfarin under current practice.3 LICENSED INDICATION Currently. Table 1.2 STUDY PARTICIPANTS: BAFTA The BAFTA study recruited 973 patients from 260 general practices in England and Wales.5 55% 72% 28% Aspirin 81.

06% -0.17% 0.09% 2. 3 on the efficacy and safety of dabigatran etexilate 150 mg. For these centres.Section 2: Clinical Data 2. The parameter values are from the study report. giving an absolute risk reduction (ARR) of 1.9%.37% 90.1: Event Deaths Death – all causes Death from vascular cause Vascular outcomes All strokes including fatal Non-fatal strokes Myocardial Infarction Systemic embolisms Haemorrhage Major extracranial bleeds Minor bleeds Efficacy outcomes by treatment Dabigatran etexilate 150 mg Absolute Absolute risk Relative risk risk reduction 3.01% 0.1 THE DABIGATRAN ETEXILATE 150 MG AND WARFARIN MODEL Three clinical effectiveness analyses are presented.53% 0. The results inform the three cost-effectiveness analyses.41% 0.57% 1. for the patients in the RE-LY study.67% 16.21% -0.64% 2. Section 2 Confidential to West Yorkshire Cardiac Network 3 .49% 0.28% 1.62% 166.67% 106.33% 60.2 CLINICAL EFFECTIVENESS ANALYSIS: ALL PATIENTS IN RE-LY Table 2.56% 0.74% 0.2 summarises the results presented by Wallentin et al. For example. except the numbers of fatal strokes.68% 139. The first uses the clinical effectiveness data from the RE-LY Study1. are used in the model.14% 84. 25% of centres had a mean TTR of <56.71% 0.76% 64. by TTR in INR.65% Warfarin Absolute risk 4.8% for warfarin. The results were obtained by allocating each centre to a quartile based on the centre’s average TTR in the warfarin arm.69% 1.9% for dabigatran compared to 5. All the parameters.17% 1. 31 August 200911.67 with dabigatran etexilate 150 mg. 2.53% 88.37% 2.84% 0.15% 2. Table 2. These were obtained from slides presented by Lars Wallentin at an ESC Symposium. other than all cause death.9% and relative risk (RR) of 0. the second considers the clinical benefit by TTR and the third by CHADS2 score.84% 14.3 CLINICAL EFFECTIVENESS ANALYSIS: BY TTR FOR PATIENTS IN RE-LY Table 2. the absolute risk (AR) of total death was 3. compared to warfarin.1 gives the efficacy outcomes from the RE-LY study1.46% -0.13% 2.

70% 3. A small stroke benefit is still seen.27% 3.94% 1.40% -0.41% 7. To overcome this.67 0.05% 3.59% 6. the event risks from death.72% 2.69 1.04% 2.02% 0.Table 2.40% 7. The ratio of fatal to non-fatal strokes was Section 2 Confidential to West Yorkshire Cardiac Network 4 .09 1.4% or higher.13% for the warfarin arm from Table2.30% 0.26% -0.34% 0.54% 3.72% for warfarin for lowest quartile from Table 2.88 0.57 0.09% 8.2.04% 3.81 0. Death from vascular causes for each quartile These values were calculated by multiplying the study value of death from vascular causes (for example 2.13% 7.16 1.07% Total death Major bleeding All cardiovascular events Stroke or systemic embolism Total death Major bleeding All cardiovascular events Stroke or systemic embolism Total death Major bleeding All cardiovascular events Stroke or systemic embolism Total death Major bleeding All cardiovascular events Stroke or systemic embolism TTR <56.47% -0.06% -0. and may even increase. Stroke or systemic embolism risks for each quartile These were taken directly from Table 2. dabigatran etexilate 150 mg does not reduce.34% These data show that the benefits are all in the patient groups with poor warfarin control.65% 0. do not map directly to the parameters in the model.9% 3.11% 6.4% 3.4% 3.98 1. assumptions were made.03% 1.2) and dividing by the total death rate in the study for that intervention (4.04 0.30% 3.04% 1.2).4% 3. assumed to be same as in the study.67 0.42% 1.4 .06% TTR 65.65.92 0.82% 0.60% 7. major bleeds and cardiovascular events.87% 1.1) by the total death AR for the relevant quartile (5.85% 5.92% TTR 56.33% 4.64% 3.51% TTR >72.13% 1.50 0.9% . The parameters used by Wallentin et al.69% from warfarin – see Table 2.07% 1.10 0. With a TTR of 72.13% 1.95 ARR 1.71 0.09% 3.80% 3.28% 0.80% 0.75% 4.83% 10.72.49% -0.12 1.2: Outcomes by each quartile based on TTR from RE-LY DG 150mg AR Warfarin AR RR 0.10% 1.

00% Haemorrhage Major extracranial bleeds 2.66% 0.54% Minor bleeds 14.97% 2. For example.00% 1. defined as the expected stroke rate per 100 patient-years.Risk of myocardial infarction and minor bleeds In the absence of data on risk of myocardial infarction (MI) by quartile.29% 54. who had AF and were not prescribed warfarin at hospital discharge.42% 0.67 so the estimated MI risk for the warfarin arm was assumed to be 1.73% 57.3: Event Deaths Death from vascular cause Efficacy outcomes by treatment for lowest TTR quartile Dabigatran etexilate 150 mg AR ARR RR 1. CHADS2. For example.57%. Column 3 re-presents the CHADS2 stroke risks for the CHADS groups reported in RE-LY.36% 0.67).74%).05% 6. the dabigatran etexilate 150 mg arm.4 presents the NRAF adjusted stroke rate. compared to the study rate of 1.73% 1.41% Vascular outcomes All strokes including fatal 1.31% 0.4 CLINICAL EFFECTIVENESS ANALYSIS: BY CHADS2 SCORE FOR PATIENTS IN RE-LY This analysis took the clinical efficacy outcome for stroke from RE-LY and weighted it by CHADS2 score. Table 2.10% (0. The risk of minor bleeds in each quartile was assumed to have the same relative risk as major bleeds.43% 1. The Gage et al. consisting of 1. the absolute risk for each quartile was the dabigatran etexilate 150 mg risk (0. aged 65 to 95 years.75% Warfarin AR 3.74%/0.13% 64.2 shows the relative risk for cardiovascular events was 0. the sub-group with a CHADS2 score of 0-1 were estimated to have a stroke rate of 0.3 shows the risks for each parameter in the model for the lowest TTR quartile. Table 2.10% Non-fatal strokes 0. study combined two existing stroke classifications into a new stroke-risk index. The same approach was used for each quartile. The population used to form the data set was the National Register of AF (NRAF).10% 0.04% 67.733 Medicare patients. In the warfarin arm.75% 70.00% 70. Column 4 presents the estimated stroke risk by CHADS2 score from the RE-LY study. in the lowest quartile the risk of MI was assumed to be 0. Table 2. Column 2 of Table 2. and stratified the risk of a stroke by the value of the CHADS2 score.84% 2. was assumed to have the same absolute risk in each quartile as the study population (0.87%.59% 20. assuming each CHADS2 score had the same risk of stroke as that estimated by Gage et al12. Section 2 Confidential to West Yorkshire Cardiac Network 5 .77% MI 0.92% 1.82% 0.74% in the dabigatran etexilate 150 mg arm.74%) divided by the relative risk for all cardiovascular events in each quartile.00% 3.74% Systemic embolism (now combined with stroke) 0.

20% 1.06% 33.2 NRAF stroke risk by CHADS groups 2.80% 1.8 4.10% 1.9 8.Table 2.2 and >2) using the NRAF population in each CHADS2 group to weight the score (column 3).5 18.10% 0.52% The adjusted stroke risk from RE-LY was estimated by: a) Calculating the NRAF stroke risk for each of the three CHADS2 score groups in RELY (0-1. the other main event driving the model is stroke mortality.20% 1.61+X*7. b) c) Two scenarios were tested in the economic model. The value of X was 0.57% adjusted by CHADS score 0.33% 2.80% 1.9 2.87%.6% Section 2 Confidential to West Yorkshire Cardiac Network 6 . 2 and >2 groups and these were judged sufficiently similar to make the estimated weights valid.33% 91.0 5.20% 1.Table 2.4% ARR 0.67% 50. Solving the equation (X+X*4/2. Table 2.59/2. The NRAF study had 34/30/36 and RE-LY 31/37/32 in each of the 0-1. the second assumed all clinical outcomes had a similar risk stratification profile.20% 0. The first assumed only the stroke outcome was affected by CHADS2 score. 2.40% 3.60% 0. The latter seems the more clinically valid.5 12. All the data came from the study report.87% 1.5% Aspirin 75mg AR 4.5 sets out the observed clinical efficacy data for the same clinical end points.00% 87.5: Efficacy outcomes by treatment Warfarin AR Deaths Death from vascular cause Vascular outcomes All strokes Non-fatal strokes MI Systemic embolism Haemorrhage Major extracranial bleeds 4. no data were available for minor bleeds.40% 1.5 THE DABIGATRAN ETEXILATE 150 MG AND ASPIRIN MODEL The clinical effectiveness data for this model were developed from the BAFTA study3.57%) to give the value for each of the three stroke risks.4: CHADS2 score 0 1 2 3 4 5 6 CHADS2 risk adjusted stroke rate and estimated stroke risk from RE-LY NRAF adjusted stroke rate per 100 patient years 1.20% 0.10% 0.2% RR 95.61 4.59 RE-LY stroke risk of 1.61=1.45% 47. which is likely to be a continuum risk to non-fatal stroke.10% 0. Checking the population weights in each CHADS2 group in NRAF and RE-LY were reasonably similar.0 7.60% 1.

56% 1. assuming 2. using a lower event rate is conservative. Section 2 Confidential to West Yorkshire Cardiac Network 7 . The relative benefit of dabigatran etexilate 150 mg compared to aspirin in the WYCN patient group .54% 0. Table 2.34% 0. The importance of these factors can be addressed through sensitivity analyses.99% 83.37% 1.80% 1.6 LIMITATIONS WITH THE DATA The limitations with the data include uncertainty on: a) b) The baseline risk for the uncontrolled group on warfarin in WYCN.11% 80.27% 20.33% 93. Ideally we would have a breakdown between the groups. The event rate from the study was not altered because the study group was judged sufficiently representative of those in WYCN who are prescribed aspirin because they are unsuitable for warfarin.36% 1. However. The study reported that 72% had a CHADS2 score of 1-2. If dabigatran etexilate 150 mg is shown to be cost-effective against this AR of an event baseline.the assumed multiplicative nature of the relative risks is unlikely to be correct but may be the best assumption available.1). then it would also be cost-effective at a higher risk of baseline events. Table 2.49% 0.23% 127.The absolute event risk for dabigatran etexilate 150 mg was estimated by multiplying the absolute event rate in the aspirin arm (column 5 of Table 2.91% 30.20% 1.6 presents the estimated clinical efficacy of dabigatran etexilate 150 mg relative to aspirin and expresses the potential benefit.84% 2.44% -0. Thus the relative risks are assumed to be independent of the baseline risks and multiplicative.03% 0.40% 3.6% 2.5) by the RRR of warfarin (column 4 of Table 2.17% 1.07% Aspirin AR 4.000 patients are switched.20% 0.03% 0.5) and the RRR of dabigatran etexilate 150 mg to warfarin (column 4 of Table 2.40% 1.6: Estimated clinical events saved from using dabigatran etexilate 150 mg rather than aspirin Dabigatran etexilate 150 mg AR ARR RR Deaths Death from vascular cause Vascular outcomes All strokes Non-fatal strokes MI Systemic embolism Haemorrhage Major extracranial bleeds 3.

2 DISEASE RELATED UTILITIES Recently NICE considered the utilities applied in the manufacturer’s submission on dronedaraone13. The decrements thus adopted the manufacturer’s profile.gro-scotland.000 alive at the start of a year 120 are assumed to die in the year.8 years and a woman of the same age a further 11.000. 3. neither source had co-morbidity scores so only the baseline 0. The resulting values were compared to two external sources being: • • The Harvard University ‘Catalog of Prefernce Scores16.6 years. This benefit has been valued by assuming the additional survivors will have a utility value equivalent to a male aged 75 with AF and these survivors would die at a rate of 120/1000 a year. The economic models assume those who survive an event have a mortality rate of three times that rate.72 could be validated. Section 3 Confidential to West Yorkshire Cardiac Network 8 . The values used are set out in column 2 of Table 3. a man aged 75 years may expect to live a further 9.1 LIFE EXPECTANCY Life expectancy gained was measured using the interim life table which shows the mean length of remaining life assuming a person lives to a certain age.000.gov.10.Section 3: Health Benefits The two relevant health benefits are life expectancy and quality of life (QoL). However. For example. the dabigatran arm showed a 0. 3.1. The sensitivity of the results to these assumptions is tested by assuming a higher annual mortality rate of 200 per 1.41 reduced absolute risk of death from vascular causes compared to warfarin. these decrements were also supported by the NICE Review Group. ‘One Thousand Health related Quality of Life Estimates’ by Tengs and Wallace17. The annual mortality rate for men and women aged 75 years is stated to be about 40 per 1. a utility value for a 75 year old in good health was calculated by an independent source15 to be 0. To correct for this inappropriate base. in contrast the manufacturer used 0. In RE-LY.819.html For example.uk/statistics/publications-and-data/life-expectancy/lifeexpectancy-at-scotland-level/index.737. The main criticism from the Evidence Review Group was that the values were over-optimistic14. The table is constructed by the Office for National Statistics and available at: http://www. Thus for every 1. the values assumed in the model were those used by the manufacturer less 0.

Used in this model 0.1.773 STA Dronedarone Manufacturer submission adjusted down by 0. stroke.72 0.819 Disease AF male. with the remaining 70% having a utility value of 0.1. aged 70 with AF.67 0. aged 70 with stroke.52. STA Dronedarone Manufacturer submission adjusted down by 0. AF male. 0. (used for mild/moderate stroke) AF male. attracting a utility value of 0.204 STA Dronedarone Manufacturer submission Harvard University Catalog of Preference Scores Harvard University Catalog of Preference Scores Harvard University Catalog of Preference Scores Harvard University Catalog of Preference Scores 0.52 0.Severe strokes were assumed in 30% of all stokes.72 0.60 Section 3 Confidential to West Yorkshire Cardiac Network 9 . This is consistent with the morbidity rates among AF patient estimated by Kerr et al. aged 75 years.20 0. Table 3. aged 70 with Acute Coronary Syndrome (ACS) AF male.1. CHF and ACS (used for severe stroke) MI (MI with ACS assumed to be 0.20.623 0.60 0. assuming dependence is measured by a Barthel score of 6018.67 0.1: Utility values for relevant diseases Utility value from literature 0.67) Short-term morbidity from systemic haemorrhage Long-term morbidity from systemic haemorrhage Pulmonary embolism Sources of values STA Dronedarone Manufacturer submission adjusted down by 0.

This value was increased by 20% assuming those with poor control were required to attend services more frequently.17 4. the published cost of one surgery consultation lasting 11.1 Cost of the medicines. and management by two GP appointments annually. Outpatient costs were calculated from a weighted average of the costs to attend consultant led and non-consultant led anticoagulation services. associated administration and monitoring. DoH Reference Costs20.Section 4: Costs The relevant resources and costs comprise the: • • 4. updated for inflation of 3% a year for three years to £352. These were £417 and £258 respectively16. The cost of the clinical events avoided. in line with NICE assumptions. Each visit was costed at £35. The weighted cost for anticoagulation services assuming the 75%/25% split was £355. Note: NICE assumed 20 visits per patient a year in primary care and the NHS data showed that on average patients were attending consultant led clinics 16. Services were assumed to be conducted 75%/25% in primary care/outpatient settings (NICE Costing Report)5.2 COST OF DISEASE STATES The costs of diseases were obtained from various sources including: • • A review of the NICE website. The weighted average costs based on number of attendances was £354.9 times per year and non-consultant led clinics 14. at £35 each. from NICE Costing Report5. Two GP visits a year to administer the prescription. The cost of primary care was assumed to be £322 (NICE Costing Report).3 times per year. Section 4 Confidential to West Yorkshire Cardiac Network 10 .7 minutes19. COST OF MEDICATION The costs of administering dabigatran etexilate 150 mg were assumed to be: • • Drug costs of £900 a year. This value was increased by 3% for one year’s inflation to £364. This estimate was derived from assumptions in the NICE Costing Report5 updated to 2009 process and Department of Health (DoH) Reference Costs20. Annual administration and monitoring costs of £426 per patient. The costs of administering warfarin were assumed to be: • • Drug costs of £39 a year. The annual cost of aspirin was assumed to be £35.

1 summarises the values used in the models.462 £1. No systematic review was undertaken. These costs were used in the base case.1: Disease state Non-fatal stroke hospitalisation Annual costs of stroke MI Systemic embolism Major extracranial bleeds Minor bleeds Cost of disease states and sources (2009/10 prices) Cost £11.778 £5. AA10Z. indeed the wide variation in values indicates a high degree of uncertainty on the cost. The estimate was the annual cost for non-AF patients from the Kerr paper. having been admitted from their own home. The mean annual cost of AF stroke after discharge.573 £87 Source and description Kerr Kerr Manufacturer’s submission for dronedaraone. AA22Z and AA23Z). AA11Z.863.240 for a stroke was used for the in-hospital episode. Table 4. AA05Z. As a sensitivity analysis the Payment by Result tariff of £5. Table 4. updated for inflation NICE NICE Section 4 Confidential to West Yorkshire Cardiac Network 11 . AA16Z.141 £1. There are several potential sources of this cost.68 days in hospital.778.930 annually thereafter. This cost was calculated using 2010/11 NHS Payment by Results tariffs for stroke related codes (AA04Z.• A paper by M Kerr. Each patient was assumed to incur additional NHS and personal social services costs of £2. This cost includes the cost associated with residential stays in care homes for patients discharged to such homes. AA17Z. was estimated at £4. adjusted for pre-stroke residence. with a mean duration of 53. but used in HTA for NICE in 2004 DoH Reference Costs 2008/09 for Pulmonary Embolus. DoH. The Kerr paper quoted a Liverpool study that estimated the hospitalisation costs of AF patients admitted with strokes to be £11. The key cost is that of non-fatal stroke. on the cost of AF18.863 £4.

there is no health gain to offset the higher drug costs.9% TTR 56.1 Results of Economic Model DABIGATRAN ETEXILATE 150 MG COMPARED TO WARFARIN IN RE-LY STUDY GROUP The base case incremental QALY was £12.3.1 Table 2.Section 5: 5.000. 5.640. warfarin. The incremental cost per QALY for each quartile is shown in Table 5. had a similar effectiveness to that observed across all the 44 centres. Various sensitivity tests have been conducted to reflect the uncertainty around this result.4% Study Total The results showed if a patient and clinician were able to maintain a TTR of 72% or more then it was not cost-effective to switch to dabigatran etexilate 150 mg.820 suggesting dabigatran etexilate 150 mg is costeffective for this group of patients who were aged 75 years or over with AF.65. There is also Section 5 Confidential to West Yorkshire Cardiac Network 12 .365 is very close to the maximum of the NICE threshold of £30.2 DABIGATRAN ETEXILATE 150 MG COMPARED TO ASPIRIN IN BAFTA STUDY GROUP The base case cost per QALY was £4.4 -72.640 TTR quartiles TTR <56.1.365 Warfarin dominates lower cost and higher QALYs £12.1: ICER for each quartile in RE-LY study Incremental cost per QALY dabigatran etexilate 150 mg compared to warfarin £2.4% TTR 65.800 £5. or an age of 65 to 74 years plus diabetes mellitus if the comparator. The higher drug costs are offset by the cost of strokes avoided.3 SENSITIVITY ANALYSES FOR DABIGATRAN ETEXILATE 150 MG AND WARFARIN Clinical Efficacy: TTR 5. 5. At TTRs of between 65% and 75% the cost per QALY of £29.165 £29.2 set out the clinical efficacy of dabigatran etexilate 150 mg compared to warfarin. Table 5. This suggests dabigatran etexilate 150 mg is cost-effective in patients with AF and aged at least 75 years.4% TTR >72. by quartile of centres from their TTR.9% .

2 shows the incremental cost per QALY by CHADS score. 5.3.2: Incremental cost per QALY by CHADS2 score CHADS2 0-1 Stroke risk only adjusted £14. Using 200 deaths per year implies almost 50% still die within three years.910.65.000 increased the cost per QALY to £16. prior to a NICE recommendation. 5.3. borderline for those with a score of 2 and not cost-effective for those with scores of 1 or 0. Table 5.440. The analyses suggests it is cost effective to switch patients with poor control under a warfarin regimen (TTR < 65%) to dabigatran etexilate 150 mg.240 per inpatient stay and £2.130 CHADS2 >2 £1. The latter may not be unduly pessimistic in this patient group.6 Resource Use: Warfarin Clinics Section 5 Confidential to West Yorkshire Cardiac Network 13 . 5. This suggests that in the interim period.930 annually thereafter increased the cost per QALY to £15.370 CHADS2 = 2 £9.3.000 per annum.3. Increasing this to 200 per 1. then the cost per QALY could rise to almost £23. Using a value of 120 per 1.620. If for example the baseline utility was 0.640). This strategy avoids the risk that people are switched to dabigatran etexilate 150 mg only to revert back to warfarin post NICE advice.4 Mortality Rate The base case used a mortality rate of 120 per 1.3 Utility Rates There may be many patients with this disease and considerable co-morbidities. 5. The result is thus not that sensitive to stroke costs. 5. The results suggest it was cost-effective to treat patients with CHADS2 scores of more than two.2 Clinical Efficacy: CHADS2 Score Table 5.000 implies over half of the patients surviving with dabigatran etexilate 150 mg live for at least five more years.considerable uncertainty around the value.5 Resource Use: Stroke Costs Adopting the lower NHS reference cost of strokes of £5. it would not be appropriate to switch such patients to dabigatran etexilate 150 mg.3.730 The remaining sensitivity analysis using RE-LY study population as the base case (cost per QALY of £12.

000 a QALY.260 is obtained if one assumes clinic and primary care overheads of 30% do not change as a result of this decision.240.000 per annum was used. 5.7 Combined analysis Combining a cost of warfarin clinic of £300.765 benefit from dabigatran etexilate 150 mg (0. with annual costs thereafter £2.85) compared to aspirin). A similar incremental cost per QALY of £17. This seems plausible.4.840.820. Thus the annual savings were £300 for warfarin clinics.000 increased the cost per QALY to £7. the person attended on 20% fewer occasions than the average. Section 5 Confidential to West Yorkshire Cardiac Network 14 . not £426.The analysis assumed that people with poor control attended clinics 20% more often than the average person. This suggests the results of the appraisal have a reasonable likelihood of being under £30.3 Resource Use: Stroke Costs Adopting the lower inpatient stroke cost of £5.3. the cost the per QALY increased to £17.1 Clinical Efficacy The key uncertainty was the assumption that RRs were multiplicative (a 10% risk reduction of warfarin against aspirin and a 15% reduction from dabigatran etexilate 150 mg against warfarin was assumed to be give a 0.500.930 and mortality rate of 200 per 1000 per year gave a cost per QALY of £26. 5. base utility value 0.70. Increasing this to 200 per 1. If the clinical benefit in terms of strokes avoided were overstated by 30% the cost per QALY would be about £7.4.4 SENSITIVITY ANALYSES FOR DABIGATRAN ETEXILATE 150 MG AND ASPIRIN The base case cost per QALY was £4.000. 5. 5.240 and lower annual costs post discharge of £2. 5.930 increased the cost per QALY to £7.4.9 *0.900.2 Mortality Rate A mortality rate of 120 per 1. if however.100. inpatient hospital costs of £5.

or an age of 65 to 74 years plus diabetes mellitus. using point estimates for secondary endpoints. the clinical efficacy data from the RE-LY study. This is driven by the quartiles used in the Wallentin et al. compared to dabigatran etexilate 150 mg. as measured by QALYs. The analysis based on quartiles of INR achieved by centres indicated a critical value for TTR of 65%. in the patient group who are at high risk of stroke but who cannot tolerate or are contraindicated to warfarin. it may also reflect differences in overall care between centres. That study concluded that ‘For centers and countries. The impact of institutional factors has not been addressed but could be very important. together with one-way sensitivity analyses. The measure of warfarin control. the principle that poor warfarin control is associated with more adverse clinical events is consistent with a post hoc analysis of the TTRs of patients on warfarin in a trial of warfarin versus clopidogrel plus aspirin (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular 22 Events [ACTIVE W] ). These were calculated from the TTR values observed in that study. Section 6 Confidential to West Yorkshire Cardiac Network 15 .’ Patients with good control using warfarin (TTR above 72%) achieved slightly better health effects. TTR is taken as a measure of the clinical effectiveness of warfarin. The sensitivity analyses shows the results are robust for a range of parameter values. combined with relevant costs and utilities. The main limitation of this analysis is it is based on sub-group analyses. The base case results and sensitivity analyses suggests that dabigatran etexilate 150 mg is cost-effective. However. However. These were patients with AF and aged at least 75 years. Those with poor control on warfarin (TTR lower than 65%) should be switched to dabigatran etexilate 150 mg. Numerous assumptions have also been made to generalise the data from two clinical studies to the English AF population. This simple analysis cannot provide a clear recommendation on those patients managed on warfarin who achieve a level of control between these two values (65% to 72%).3 study. sub-group analyses suggest that it is not cost-effective to treat those with good warfarin control (defined as a TTR of 72% or greater). Warfarin is also considerably cheaper and dominates dabigatran etexilate 150 mg for this group. However.Section 6: Discussion and Conclusions The analyses showed that there is a strong effect of TTR on warfarin benefit and that there is a threshold below which the benefit of warfarin is limited. In conclusion. compared to aspirin. The value itself has no clinical significance. suggest it is cost-effective to use dabigatran etexilate 150 mg in a patient group similar to the study population. a target threshold TTR exists (estimated between 58% and 65%) below which there appears to be little benefit of OAC over antiplatelet therapy.

Journal of the American Medical Association.uk/nicemedia/live/11750/46784/46784. 118: 2029-2037. BAFTA): a randomised controlled trial. 5. York: Centre for Health Economics. Gage et al. Wallentin et al. Department of Health NHS Reference Costs 2008/09.rely-trial. (2007) Warfarin versus aspirin for stroke prevention in an elderly community population (the Birmingham Atrial Fibrillation Treatment of the Aged Study. Richards N. et al. July 2006. 6. 3. 9. et al. Slides presented by Lars Wallentin at an ESC Symposium. New Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation.uk/aboutnice/howwework/devnicetech/technologyappraisalproc essguides/guidetothemethodsoftechnologyappraisal. Personal Social Services Research.pdf 20. Hardman G.dh. (2009) Dabigatran versus warfarin in patients with atrial fibrillation. 2. (2001) Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. (2008) Benefit of oral anticoagulation therapy over antiplatelet therapy in atrial fibrillation depends on the quality of international normalised ratio control achieved by centers and countries as measured by time in therapeutic range.ac. Primary Care Lead WYCN. 376: 975–83 4. Atrial fibrillation-Cost Benefit Analysis.jsp 11. 370 (9586): 493-503. Carey IM.pssru. 8. 31 August 2009. http://www. Catalog of Preference Scores. Cook DG.gov. http://www. March 2010. Mant J. NICE Clinical Guideline No 36 The Management of Atrial Fibrillation. Manufacturer submission to NICE on Multaq® (Dronedarone). 285 (22): 2864-2870.pdf 15. Connolly SJ. http://www. provided by Dr C Cowan in confidence. Medical Care.uk/pdf/uc/uc2009/uc2009. 38 (6): 583-637. Canadian Agency for Drugs and Technologies in Health. Circulation. (2006) Trends in the prevalence of diagnosed atrial fibrillation. 7. (2000) One Thousand health-Related Quality of Life Estimates. Tengs TO & Wallace A. Slides by Dr Kathryn E Griffith. 92: 1064–1070. http://www. 19. Marion Kerr. Connolly et al. Atrial fibrillation: the management of atrial fibrillation.Confidential: for use by the Yorkshire Cardiac Network only References 1.nice. The Lancet. Emmas C. DeWilde S.org.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAn dGuidance/DH_111591 References 16 . 36. NICE Costing report. 361: 2671-2675. NICE Guide to the Methods of Technology Appraisal. July 2006.aspx?id=8beb47e5ffc3-4719-998b-6b3acbb4c2fa 12. & Macran. Unpublished paper. 18. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Adele Graham Network Development Manager and Dr C Cowan Leeds General Infirmary on ‘Chapter 8 and Stroke Prevention. Heart. University of York.nice. UK population norms for EQ-5D: Centre for Health Economics Paper 172.uk/nicemedia/live/11750/46777/46777. its treatment with anticoagulation and predictors of such treatment in UK primary care. The Lancet 2010. NICE Clinical Guideline No.org. ERG Report NICE Appraisal STA Dronedarone. 10.  http://www.org. Standards and Quality Analytical Team. Kind P. Harvard University. 13.pdf 14. https://www.nice. A Network Approach’.com/trial_results/monday_webcast/default. 1999. 16. New England Journal of Medicine. Unit Costs of Health and Social Care 2009. 17.

org. 22. 367 (9526): 1877.21. & Connolly S. National Institute for Health and Clinical Excellence. http://www. Verheuqt F.uk/media/E4A/79/SupplementaryAdviceTACEoL.nice. end of life treatments. References 17 . (2006) Lancet.pdf. Appraising life-extending.

Confidential: for use by the Yorkshire Cardiac Network only APPENDIX A Stroke Risk Stratification Algorithm7 .

Confidential: for use by the Yorkshire Cardiac Network only Stroke Risk Stratification Algorithm7 Appendix A i .