Non-vitamin K antagonist oral anticoagulants and atrial fibrillation guidelines in practice : barriers to and strategies for optimal implementation

REVIEW Non-vitamin K antagonist oral anticoagulants and atrial fibrillation guidelines in practice: barriers to and strategies for optimal implementation A. John Camm1*, Fausto J. Pinto2, Graeme J. Hankey3,4, Felicita Andreotti5, and F.D. Richard Hobbs6on behalf of the Writing Committee of the Action for Stroke Prevention alliance† 1 Department of Clinical Cardiology, St George’s University of London, London SW17 0RE, UK; 2 Lisbon University Medical School, Lisbon, Portugal; 3 School of Medicine and Pharmacology, The University of Western Australia, Nedlands, WA, Australia; 4 Department of Neurology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; 5 Department of Cardiovascular Science, Catholic University, Rome, Italy; and 6 Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK Received 16 January 2015; accepted after revision 27 February 2015 Stroke is a leading cause of morbidity and mortality worldwide. Atrial fibrillation (AF) is an independent risk factor for stroke, increasing the risk five-fold. Strokes in patients with AF are more likely than other embolic strokes to be fatal or cause severe disability and are associated with higher healthcare costs, but they are also preventable. Current guidelines recommend that all patients with AF who are at risk of stroke should receive anticoagulation. However, despite this guidance, registry data indicate that anticoagulation is still widely underused. With a focus on the 2012 update of the European Society of Cardiology (ESC) guidelines for the management of AF, the Action for Stroke Prevention alliance writing group have identified key reasons for the suboptimal implementation of the guidelines at a global, regional, and local level, with an emphasis on access restrictions to guideline-recommended therapies. Following identification of these barriers, the group has developed an expert consensus on strategies to augment the implementation of current guidelines, including practical, educational, and access-related measures. The potential impact of healthcare quality measures for stroke prevention on guideline implementation is also explored. By providing practical guidance on how to improve implementation of the ESC guidelines, or region-specific modifications of these guidelines, the aim is to reduce the potentially devastating impact that stroke can have on patients, their families and their carers. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords Atrial fibrillation †Guidelines †Oral anticoagulants †Stroke prevention Introduction In 2012, stroke was estimated to have contributed to the deaths of 6.7 million people worldwide, accounting for nearly 12% of all deaths. 1 Stroke causes permanent disability in nearly 5 million people each year. 2 Atrial fibrillation (AF) is a significant independent risk factor for stroke, associated with an approximately five-fold excess in risk, but is much less well recognized than, for example, hypertension, for which the excess stroke risk is three-fold. 3 In addition, unlike most other cardiovascular risk factors for stroke, the pivotal Framingham Study found an increase in attributable risk due to AF from 1.5% in individuals aged 50–59 years to 23.5% for those aged 80–89 years. 3 Atrial fibrillation is the most common sustained cardiac arrhythmia and represents a global problem (Figure 1). 4–8 Patients with AF are five times more likely to have a stroke than the general population. 3 Atrial fibrillation-related strokes are almost twice as likely to be fatal and, in survivors, cause severe disability, increasethelengthofhospitalstayanddecreasethelikelihoodofpatients returning to their own home, compared with non-AF-related strokes. 9,10 Atrial fibrillation-related strokes have also been associated with significantly higher mean direct costs per patient than non-AFrelated strokes. 11 However, AF-related strokes can be prevented and their impact minimized by effective management strategies including increased detection of AF, adherence to stroke prevention guidelines and anticoagulant use in at-risk patients. Left atrial appendage occlusion may also have a role in patients who are unable to receive long-term anticoagulant management, but it is not a recommended alternative to anticoagulation per se. 12 *Corresponding author. Tel: +44 20 8725 3414; fax: +44 20 8725 3416. E-mail address: [email protected] † See appendix for full list of authors. &The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology. Thisis an Open Access article distributed under the terms ofthe Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/),which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Europace (2015) 17, 1007–1017 doi:10.1093/europace/euv068 Downloaded from https://academic.oup.com/europace/article-abstract/17/7/1007/2398779 by Faculdade de Medicina de Lisboa user on 13 November 2018 Guidelines have an important role in optimizing evidence-based care, improving health outcomes for individuals and populations and decreasing costs to healthcare systems. Despite the risk of stroke in patients with AF, and the availability of clear global guidelines on the prevention of AF-related stroke since 1999, real-world data suggest that a large proportion of patients [38% of those with a CHADS 2 (Congestiveheartfailure,Hypertension,Age ≥75years,Diabetesmellitus, prior Stroke/transient ischaemic attack (doubled)) score of 2 in the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) Registry] are still not receiving stroke prophylaxis in line with guideline recommendations. 13 With the increased convenience and improved benefit–risk profile of the non-vitamin K antagonistoralanticoagulants(NOACs;rivaroxaban,dabigatran,apixaban,and edoxaban), this situation may improve. This consensus document aims to identify barriers to guideline implementation worldwide and to define clear strategies and practice models to help overcome these barriers, focusing on the European Society of Cardiology (ESC) guidelines for the management of AF published in EP Europace in 2012. 12 A Medline search was performed to identify guidelines for stroke prevention in patients with AF and barriers to guideline implementation, focusing on registry data but includingindividualstudieswhererelevant.TheActionfor Stroke Prevention alliance writing committee also provided their own country-specific experiences and, based on the collated information, identified key barriers to guideline implementation and developed consensus strategies to help overcome these barriers. Guidelines overview Afocusedupdateofthe2010ESCguidelinesforthemanagementofAF was issued in 2012. 12 This was partly in response to positive Phase III clinical trial data with the NOACs dabigatran, rivaroxaban, and apixaban, 14–16 and their subsequent approval for stroke prevention in at-risk patients with non-valvular AF. The NOACs have shown equivalentorimprovedefficacycomparedwithwarfarininrandomized controlledtrials,withareductionintheriskofseverebleedingevents,in particular intracranial haemorrhage (ICH). 14–17 In addition, they all offer fixed-dose regimens (with some dose reductions mandated in special populations, such as patients with renal impairment) that eliminate the need for the routine coagulation monitoring associated with vitamin K antagonists (VKAs). Edoxaban is currently the only one of these NOACs that is not yet widely approved in this indication. The ESC guidelines now recommend the use of the NOACs in most patientswitha CHA 2 DS 2 -VASc [Congestive heart failure/left ventricular dysfunction, Hypertension, Age ≥75 years (doubled) Diabetes, Stroke (doubled), Vascular disease, Age 65–74 years, Sex category (female)] score of ≥1 in preference to VKAs (Figure 2), although in certain patients, e.g. those with severe renal impairment or underlying disease on echocardiogram, VKAs remain preferred. Antithrombotic treatment is not recommended in low-risk patients with a CHA 2 DS 2 - VASc score of 0. 12 However, the latter group represented only 3–7% of patients in two large cohort studies, 13,18 indicating that the majority of patients with AF are candidates for oral anticoagulation. In large Phase III studies, the currently approved NOACs showed similar or improved efficacy compared with warfarin for the prevention of primary stroke or systemic embolism. 19–21 Several of the NOACs have also demonstrated benefits in the prevention of secondary strokes, with similar efficacy to warfarin, as well as reducing the incidence of ICH. 19–21 The risk of a stroke recurrence is 2.5-fold higher in patients with AF who have already had a stroke or transient ischaemic attack. 22 These patients may also be at increased risk of falls, have dementia or have limited access to international normalized ratio (INR) monitoring because of decreased mobility, making it problematic to ensure effective VKA therapy. United States: 2.3 million (2008) (estimated 5.6–>12 million by 2050) European Union: 10 million (2011) Japan: 0.8–2.0 million (2011) China: 8 million (2008) Australia: 0.9 million (2011) India: 1.2 million* (2011) Brazil: 4.8 million (2009) Figure 1 Estimates of the prevalence of AF. 4–8 *Based on data from a single community study. A.J. Camm et al.1008 Downloaded from https://academic.oup.com/europace/article-abstract/17/7/1007/2398779 by Faculdade de Medicina de Lisboa user on 13 November 2018 In addition to incorporation of the NOACs into the recommendations, another significant change to the ESC guidelines was a move away from the use of the CHADS 2 score to risk-stratify patients with AF, in favour of the CHA 2 DS 2 -VASc score. This was based on evidence that the CHA 2 DS 2 -VASc score could be used to more accurately identify truly ‘low-risk’ patients, who would not require antithrombotic therapy. 12 The 2012 guidelines also recommend the use of the HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (e.g. age .65 years, frailty, etc.), Drugs/alcohol use] score to assess bleeding risk, but highlight that it should focus efforts on improving the modifiable risk factors for bleeding and should not be used to exclude patients from oral anticoagulant therapy. 12 The simultaneous use of old and new guidelines, or of guidelines issued by different organizations, at either a global or regional level, can lead to a degree of confusion or contradictory guidance. In addition, recommendations may differ between guidelines because of variations inthepopulationsforwhichtheyareintended.However,recommendations for antithrombotic therapy are, for the most part, consistent between the major guidelines. In 2012, the American College of Chest Physicians (ACCP) issued guidelines on antithrombotic therapy for AF, which provide similar recommendations to the ESC guidelines (based onCHADS 2 scoring for risk assessment), including a preference for NOACsoveradjusted-doseVKAsinat-riskpatients. 23 Older guidelines, such as those jointly issued by theAmericanCollegeofCardiology (ACC), the American Heart Association (AHA), and the ESC in 2006, were developed long before the NOACs were available to clinicians and, in contrast with newer guidelines, recommend acetylsalicylic acid (ASA) as an alternative to warfarin in patients with one moderate risk factor for stroke. 24 Updated ACC/AHA guidance, issued in 2014, recommends oral anticoagulation for patients with prior stroke/transient ischaemic attack or CHA 2 DS 2 -VASc score ≥2, whereas patients with a score of 1 may be given oral anticoagulation, ASA, or no antithrombotic therapy. 25 In 2013, the European Heart Rhythm Association published a practical guide on the use of NOACs in patients with nonvalvular AF 26 based on the 2012 ESC recommendations. Country-specific guidelines, such as those from the National Institute for Health and Care Excellence (NICE) in the UK, recommend apixaban, dabigatran, and rivaroxaban as options for the prevention of stroke or systemic embolism in patients with AF. 27 A focused update of the Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines, published in 2012, recommends NOACs over other oral anticoagulants in eligible patients. 28 In the Asia-Pacific region, several countries have country-specific guidelines for the management of patients with AF but not all yet incorporate recommendations for the use of NOACs. However, the 2014 Japanese guidelines largely support the ESC 2012 guidelines, as does a consensus statement issued in 2013 by the Asia Pacific Heart Rhythm Society on antithrombotic therapy in patients with non-valvular AF. 29 Information provided by other organizations, such as the National Stroke Association in the UK or the Canadian Agency for Drugs and Technologies in Health, who issue therapeutic reviews, may also influence clinical practice at a national level. Guideline implementation and barriers to implementation Benefits of compliance with guidelines Acriticismofguidelinesisthattheysometimes relyon evidence thatis relatively weak and/or studies that have been conducted with Valvular AFa <65 years and lone AF (including females) Oral anticoagulant therapy NOAC VKA No antithrombotic therapy No No (i.e. non-valvular AF) 01≥2 Yes Yes Atrial fibrillation Assess bleeding risk (HAS-BLED score) Consider patient values and preferences Assess risk of stroke (CHA2DS2-VASc score) Figure 2 European Society of Cardiology (ESC) guideline recommendationsforthepreventionofstrokeinpatientswithAF. 12 Antiplatelet therapy with ASA plus clopidogrel, or—less effectively—ASA only, should be considered in patients who refuse any oral anticoagulant or cannot tolerate anticoagulants for reasons unrelated to bleeding.Iftherearecontraindicationstooralanticoagulationorantiplatelet therapy, left atrial appendage occlusion, closure, or excision may be considered. CHA 2 DS 2 -VASc score: turquoise, 0; yellow, 1; red, ≥2. Line:solid, best option; dashed, alternative option. a Includes rheumatic valvular disease and prosthetic valves. AF, atrial fibrillation; ASA, acetylsalicylic acid; CHA 2 DS 2 -VASc, ESC-recommended stroke risk score[Congestiveheartfailure/leftventriculardysfunction,Hypertension, Age ≥75 years (doubled) Diabetes, Stroke (doubled), Vascular disease, Age 65–74 years, Sex category (female)]; HAS-BLED, [ESC-recommended bleeding risk score, defined as Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (e.g. age .65 years, frailty, etc.), Drugs/ alcohol use]; NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist. From Camm et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. European Heart Journal Nov 2012, 33(21) 2719–2747. Reproduced with permission of Oxford University Press (UK) &European Society of Cardiology, www.escardio.org/guidelines Non-VKA oral anticoagulants: barriers and strategies 1009 Downloaded from https://academic.oup.com/europace/article-abstract/17/7/1007/2398779 by Faculdade de Medicina de Lisboa user on 13 November 2018 inconsistent methodologies. However, the evidence for the use of NOACs in patients with non-valvular AF comes from very large, multicentre, randomized controlled Phase III studies, 14–16 and the primary recommendations made by the ESC in 2012 on anticoagulation in patients with AF generally carried a high level (A or B) of evidence. 12 Nevertheless, prospective clinical data for the NOACs are lacking in some specific areas; e.g. a prospective randomized study of rivaroxaban for patients with AF undergoing cardioversion has been published recently, 30 but a similar trial for apixaban (NCT02100228) is only just getting underway, and there is no such prospective study planned for dabigatran. Studies to address other data gaps with the NOACs are ongoing. Published studies support the benefits of compliance with guideline recommendations for anticoagulation in patients with AF. A crosssectional study of patients admitted to the University of Maastricht Medical Centre between 2003 and 2006 found that 51% of those with known AF who were eligible for oral anticoagulation did not receive it, and that improved adherence to guidelines could potentially have prevented 22% of subsequent ischaemic strokes. 31 More recently, a real-world cohort-based study of almost 9000 patients recruited over 10 years found low annual rates of stroke or thromboembolism (0.64%), major bleeding (1.12%), and death (1.08%) among untreated patients classified as low risk according to the ESC 2012 guidelines (i.e. CHA 2 DS 2 -VASc score 0). 18 These data support the ESC recommendation that these patients should not receive antithrombotic therapy. Furthermore, simulations of patient outcomes from the RE-LY database using ESC-recommended dabigatran treatment protocols foundasignificantnetclinicalbenefitcomparedwithwarfarin,supporting the ESC recommendations. 32 Compliance with guidelines in practice Registry data offer valuable insights into patterns of drug use and can provide a means of tracking uptake of guideline recommendations. For example, global data from the GARFIELD-AF Registry, collected between 2009 and 2011, indicated that 27% of all patients with AF werestill receiving ASA therapy,compared with 60%whoreceived oral anticoagulation (Table 1). 13 However, observational data from the European PREFER AF (PREvention oF thromboembolic events—European Registry in Atrial Fibrillation) registry collected between 2012 and 2013 suggest that the introduction of the 2010 ESC guidelines was associated with a move away from the use of ASA to oral anticoagulation. 40 Other European registry data show variation in oral anticoagulation use depending on when the data were collected and from which country or countries (Table 1). 35–41 Outside of Europe, US registry data indicate a low use of oral anticoagulation across all stroke risk categories. 43 Data from the REACH registry (REduction of Atherothrombosis for Continued Health) demonstrated the lower use of oral anticoagulation in patients with AF recruited from Asia (excluding Japan) compared with those recruited from Japan and non-Asian regions. 45 These differences highlightthatoralanticoagulantuseisnotyetconsistentataglobal,country, or regional level and may be influenced by factors such asthe specialty ............................................................................................................................................................................... Table 1 Atrial fibrillation registries and surveys Registry or study Guidelines Patients with AF, n Country/region Data collection, year OAC use (%) GARFIELD-AF 13 Multiple 10 614 Global 2009–2011 60 RE-LY AF 33 Multiple 15 400 Global 2008–2011 30 GLORIA-AF 34 Multiple 56 000 Global 2011 onwards Awaiting data Euro Heart Survey on AF 35 ACC/AHA/ESC 2001 and ACCP 2004 5333 Europe 2003–2004 64 AFNET 36 ACC/AHA/ESC 2001 9582 Germany 2004–2006 71 ATRIUM 37 ACC/AHA/ESC 2001 and ACCP 2008 3667 Germany 2009 83 Prospective non-interventional study 38 Not specified 2753 Germany 2010 64–73 a ISAF 39 Not specified 6036 Italy 2011 46 PREFER AF 42 ESC 2010 7243 Europe 2012–2013 82 Retrospective, cohort study 43 ACC/AHA/ESC 2006 and ACCP 2008 171 393 USA 2003–2007 43 ORBIT-AF 44 ACC/AHA/ESC 2006 and ACCP 2008 10 098 USA 2010–2011 76 REACH 45 Not specified 300 Asia (ex. Japan) 2006–2011 36 REACH 45 Not specified 350 Japan 2006–2011 54 REACH 45 Not specified 6000 Global (ex. Asia) 2006–2011 55 ACC, American College of Cardiology; ACCP, American College of Chest Physicians; AF, atrial fibrillation; AFNET, Central Registry of the German Competence NETwork on Atrial Fibrillation; AHA, American Heart Association; ATRIUM, Outpatient Registry Upon Morbidity of Atrial Fibrillation; CHADS 2 , Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke/transient ischaemic attack (doubled); ESC, European Society of Cardiology; GARFIELD-AF, Global Anticoagulant Registry in the FIELD; GLORIA-AF, Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation; ISAF, Italian Network of Atrial Fibrillation Management survey; OAC, oral anticoagulant; ORBIT-AF, Outcomes Registry for Better Informed Treatment of Atrial Fibrillation; PREFER AF, PREvention oF thromboembolic events—European Registry in Atrial Fibrillation; REACH, REduction of Atherothrombosis for Continued Health; RE-LY AF, Randomized Evaluation of Long-term anticoagulant TherapY. a CHADS 2 score ≥2 (includes low molecular weight heparin). A.J. Camm et al.1010 Downloaded from https://academic.oup.com/europace/article-abstract/17/7/1007/2398779 by Faculdade de Medicina de Lisboa user on 13 November 2018 of the physicians enrolling patients into the registries and the degree of awareness of updated guidelines. Patient and physician-related barriers Registries can also provide useful information on the reasons for non-adherence to guidelines and identify barriers to their adoption. GARFIELD-AF highlighted that nearly half of patients with a CHADS 2 score ≥2 were not receiving VKA therapy because of physician choice, specifically because of concerns over bleeding risk, patient compliance, uncertainty regarding guideline recommendations, fall risk or low risk of stroke. 13 Patient factors, such as alcohol misuse, medication refusal, unsuitable co-medication use, or previous bleeding events, were the reasons for not initiating VKA therapy in ,16% of cases. 13 Similar reasons were given for warfarin discontinuation in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). 46 Similarly, in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) A trial, which enrolled patients who were considered unsuitable for VKA therapy, the primary reason for enrolment in the trial (accounting for 50% of patients) was physician judgement that a VKA was inappropriate. Patient preference accounted for 26% of patients enrolled, and specific risk of bleeding for 23% of patients. 47 In the Apixaban vs. Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) study, the most frequent reasons for not prescribing VKAs were physician judgement that INR monitoring could not be achieved at the requisite frequency (43%) and patient preference (37%). 48 The Stroke and Atrial Fibrillation Ensemble (SAFE) II study found that having a younger general practitioner and being followed up by a cardiologist were independently associated with the prescription of oral anticoagulants. 49 The presence of potential contraindications, lack of an indication, low compliance, and fear of bleeding were reasons given for non-prescription. 49 These findings highlight that the lack of physician awareness about oral anticoagulation and how to manage complications is a key barrier to adoption of guidelinerecommended therapies. A general survey of Dutch general practitioners also identified environmental factors such as organizational constraints, lack of time, and lack of resources as prominent barriers to guideline adherence. 50 Furthermore, uptake of NOACs may be limited by a physician preference for close INR monitoring, particularly in elderly or frail patients. Another barrier to the adoption of guidelines arises when theyare not considered applicable at a country level, possibly because of regional heterogeneity in patient baseline characteristics (e.g. a high proportion of patients not meeting the criteria for recommended treatments or a perception that the studies underpinningrecommendations are based on non-representative populations), differences in current standards of care or cultural perceptions of risk vs. benefit of the intervention. Forexample, in some Asian countries, such as Japan, the recommended target INR in patients with AF ≥70 years of age is lower (1.6–2.6) than the recommended target of 2.0–3.0, which is used more widely. 51 Similarly, a lower 15 mg once-daily dose of rivaroxaban (or 10 mg once-daily in patients with creatinine clearance 30–49 mL/min) was specifically tested in Japanese patients. 52 Access to guideline-recommended therapies In some countries, prescribing of the NOACs is restricted ata national, regional, or local level. For example, the National Health Service for Scotland limits the prescription of rivaroxaban to patients who appear compliant with coumarin therapy and yet still have poor INR control, as well as to those who are allergic to or are unable to tolerate coumarins. 53 In the UK, the Department of Health follows the NICE guidelines rather than the ESC guidelines. However, even though the NOACs are recommended as a therapeutic option by NICE, many clinical commissioning groups or regional prescribing groups in the UK interpret this ‘option’ as second line, with warfarin compulsory as first-line therapy. 54,55 In the UK and Ireland, patients who are closer to the hospital and can attend clinics regularly for coagulation monitoring and dose adjustments are also more likely to receive VKAs than those who live further away. In Eastern European countries (e.g. Hungary), the National Health Service limits the prescription of NOACs to patients who have had a previous stroke or patients with poor INR control on coumarin therapy. 56 This restriction is in place because the first-line use of the NOACs is considered financially prohibitive. Restricted access can also be a result of administrative barriers. For example, in Italy and Hungary, a limited number of specialists are allowed to prescribe the NOACs; to finalize the prescription, these specialists are required to fill out an electronic case report form, contributing to a compulsory national survey (www. agenziafarmaco.gov.it). This is a time-consuming process and, as such, the national Regulatory Authorities have indirectly discouraged routine implementation of the ESC guidelines for antithrombotic treatment. The bureaucratic situation in Italy is mirrored in other countries: in Ireland and some parts of England, justification forms must be completed to allow physicians to prescribe the NOACs and, in Spain, patients must have an INR that is recorded to be out of range three times in a row before a patient can be prescribed any of these drugs, and this may take weeks. Access issues can also arise when updates to guidelines are delayed. For example, the European Stroke Organisation (ESO) has not updated its guidelines on secondary stroke prevention since 2008, 57 and so the NOACs are not included. This influences the daily practice of stroke specialists: in some Eastern European countries, for instance, physicians face financial penalties or even imprisonment if they are not compliant with the guidelines recommended for their specialty, even if the guidelines are outdated and do not reflect the latest clinical advances in the field. In cases such as these, pre-existing guidelines, though relevant when they were published, are themselves a barrier to adopting new approaches or therapies. An update to the ESO guidelines is anticipated. Even if guidelines are up to date, it does not necessarily guarantee access to recommended therapies. For example, a group of Spanish medical experts developed a consensus document in line with the ESC guidelines that was approved by the Spanish Ministry of Health for national use. 58 However, access to NOACs is still often restricted by local authorities because warfarin is considered to be as effective as the NOACs and is a low-cost drug, albeit with high monitoring costs. Therefore, the newer drugs are often limited to patients Non-VKA oral anticoagulants: barriers and strategies 1011 Downloaded from https://academic.oup.com/europace/article-abstract/17/7/1007/2398779 by Faculdade de Medicina de Lisboa user on 13 November 2018 who are unstable on warfarin or who have had an ischaemic stroke and are at high risk of ICH. Financial barriers to guideline-recommended therapies One of the major reasons for restricted access to new guidelinerecommended therapies is perceived cost. Restrictions tend to be made based on a consideration of short-term budget impact, such as the lower acquisition costs of VKAs compared with the NOACs, rather than the potential longer term economic impact of events that might have been prevented. Non-vitamin K antagonist oral anticoagulants do not require routine coagulation monitoring, which, in one US study, was shown to cost between $291 and $943 annually per patient. 59 The National Institute for Health and Care Excellence has estimated the annual cost of INR monitoring, including transport costs,at£656inthefirstyearand£540thereafter. 60 Longerterm cost savings relate to the direct costs of managing the consequences of anticoagulation, which are summarized in Table 2. For example, considering that NOACs reduce the risk of ICH by at least half compared with warfarin, their use could contribute substantially to long-term cost savings (Table 3). A study in Denmark published in 1999 estimatedthat,afterICH, the mean total costof healthcareandsocialservices during the first year was 123 200 DKK or US$22 000. 63 More recently, a study in the USA analysing medicine and pharmacy claims for patients with AF estimated the mean unadjusted all-cause health costs in the year after a warfarin claim to be $41 903 for patients with at least one ICH. 64 Despite this, it is often difficult in practical termsto implement a scheme in which a more expensive therapy is paid for from one budget (in this case, drug costs) to provide cost savings that relate to a separate budget (blood tests and monitoring). The lack of monitoring of the NOACs may also represent a financial barrier to their implementation. In some countries, primary care practices and anticoagulation clinics receive a financial incentive for providing VKA monitoring services, which could be considered underthreat with the introductionof the NOACs.However, with appropriate training of personnel, these facilities could be repurposed to take on a role in the initiation and management of the NOACs and management of co-morbidities and to provide valuable guidance and reassurance to patients about their anticoagulation care. Indeed, overall risk factor control, not limited to the use of NOACs, is the most important therapeutic intervention for patients with AF. Financial barriers to appropriate VKA management specific to individual countries or regions also exist. In many Eastern and Central European countries, both INR monitoring and travel costs (for blood sampling) are covered by the healthcare system. However, blood sampling takes place in large centralized laboratories that are often a long distance from where the patient lives, meaning that substantial work time is lost through travelling to and from appointments; this can also have a negative impact on patient compliance. ............................................................................................................................................................................... Table 2 Overview of event costs. Adapted from Kleintjens et al. 61 Event a Acute (per event) (E) Rehabilitation (per event) b (E) Long-term follow-up (per 3 months) (E) Minor stroke 5946 3204 244 Major stroke 12 247 17 734 2216 Systemic embolism 5124 Not reported Not reported Clinically relevant non-major extracranial bleeding event 23 Not reported Not reported Major extracranial bleeding event 3510 Not reported Not reported Intracranial bleeding event c 7699 17 734 2216 Myocardial infarction 7891 Not reported Not reported a The range of event costs tested in sensitivity analyses was +25% of the mean. b Based on unpublished results (K. Putman, personal communication). c Based on market share and prices of locally available brands. ................................................................................................................... .............................................................................................................................................................................. Table 3 Absolute percentage annual risk of ICH stratified by stroke risk in patients with non-valvular AF receiving oral anticoagulation therapy for stroke prevention. Adapted from Rognoni et al. 62 Intracranial bleeding, absolute annual risk (%) CHADS 2 ≤ 1 CHADS 2 52 CHADS 2 ≥ 3 Warfarin 0.48 0.65 1.01 Rivaroxaban (20 mg od) Not investigated 0.44 0.68 Apixaban (5 mg bid) 0.2 0.27 0.42 Dabigatran (150 mg bid) 0.2 0.26 0.52 bid, twice daily; CHADS 2 , Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke/transient ischaemic attack (doubled); od, once daily; ICH, intracranial haemorrhage. A.J. Camm et al.1012 Downloaded from https://academic.oup.com/europace/article-abstract/17/7/1007/2398779 by Faculdade de Medicina de Lisboa user on 13 November 2018 In Brazil and many South East Asian countries, only 30% of patients have private health insurance and, therefore, have access to the newertherapiesfor stroke preventioninpatientswith AF.Incontrast, patientstreated in the public sector typically continue to receivewarfarin or another VKA because these drug costs are supported by the healthcare system. In Brazil and Mexico, the local authorities can subsidize more expensive medications, but it takes time to get new therapies included on these lists and, because it is not a national responsibility, differences in access exist between local authorities. In cost-effectiveness analyses, the NOACs have been shown to be cost-effective compared with warfarin. 61,65–74 Robust and welldesigned cost-effectiveness analyses can be important when arguing the case for consideration of new therapeutic options with policy makers. However, these analyses are not without limitations. Their general applicabilitycan be limited because of differencesin healthcare systems between countries. Furthermore, cost-effectiveness analyses may be inadequate because they do not take into consideration all factors, particularly indirect costs including loss of work for patients orcarersduetoINRclinicvisitsandassociatedtravelcosts. 75 Additionally, even demonstrating the cost-effectiveness of a drug within the parameters defined in the analysis may not provide a comparison of cost-effectiveness relative to other established treatments. In addition to their cost-effectiveness, the relative effectiveness and safety of the NOACs compared with the VKAs is an important benefit. The convenience to patients in terms of lack of monitoring and dietary restrictions, which is likelyto improve persistence and adherence and therefore clinical outcomes, should also not be underestimated. Best practice in European Society of Cardiology guideline implementation Registry data highlight that it can take several years for guideline recommendations to be implemented in clinical practice, and even then, recommendations may not be applied properly or consistently. It is also clear that there is wide variation between countries regarding which recommendations are implemented and how this is achieved. When the writing committee rated the importance of certain factors for guideline implementation, variation between countries did exist, but factors such as AF screening, diagnosis, and stroke risk assessment were rated of high importance across the group. The barriers to guideline implementation that the group identified (summarized in Table 4) fall into three main categories: practical, educational, and access related. Practical issues relate primarily not only to optimal diagnosis and risk stratification of patients with AF but also to the applicability of the ESC guidelines to non-European populations. Lack of awareness of the ESC guidelines and delays in updates to local or national guidelines are the key educational barriers that exist, despite the efforts of the ESC to promote its guidelines through various methods, including ‘train the teacher’ programmes, ESC guideline implementation toolkits, and mobile pocket guidelines. Another educational barrier stems from the variety of information available about the NOACs, which can lead to confusion over their specific properties and use protocols. Access-related issues are primarily due to cost and also include other factors that have been discussed above. In light of these barriers, the Action for Stroke Prevention alliance writing committee recommends several best-practice strategies (summarized in Table 5) to improve adherence to the ESC guidelines (or their region-specific modification) and access to guidelinerecommended therapies. Measuring healthcare quality for stroke prevention: potential role in guideline implementation Registries provide information on whether guidelines have been implemented. However, could healthcare quality measures be used to drive implementation of, and adherence to, guidelines as they are issued? Unfortunately, data on the use of healthcare quality measures to improve stroke prevention in patients with AF are generally limited, although national audit data are available in some countries, highlighting gaps in care for stroke prevention. 76,77 In the USA, there are several initiatives aimed at assessing the quality of stroke care, including the Stroke Practice Improvement Network, The Paul Coverdell National Acute Stroke Registry, ................................................................................ Table 4 Barriers to implementation of ESC 2012 guidelines Barrier Practical †Under-diagnosisof AFbecauseof lackofaccessto diagnostictools for AF (e.g. Holter monitoring) †Not screening using the most efficient technique, e.g. loop monitoring for paroxysmal AF †Underestimation of thromboembolic risk †Applicability of ESC guidelines to non-European populations Educational †Lack of widespread awareness of ESC 2012 Guidelines (coupled with use of other/pre-existing guidelines) †Delay in updates of local guidelines to reflect major environmental changes for practice †Fear of major bleeding/lack of validated scores to evaluate bleeding risk (HAS-BLED was developed based on VKA studies) †Lack of technical expertise †Development and availability of multiple NOACs in a relatively short timeframe has led to confusion about protocols for use and the specific properties of each drug – Exacerbated by manufacturers providing different information about the drugs in the prescribing information vs. the summary of product characteristics and using different marketing approaches – Influenced by media reports, e.g. reports of severe bleeding when dabigatran was first introduced Access †Budget restrictions and/or reimbursement issues with NOACs †Limitations/restrictions on patients considered eligible for NOACs that are inconsistent with broader guideline recommendations †Limitations of prescriber eligibility †Administrative hurdles associated with prescription of NOACs (e.g. completion of paperwork and justification of the clinical decision) AF, atrial fibrillation; HAS-BLED, Hypertension, Abnormal liver/renal function, Stroke history, Bleeding predisposition, Labile INR, Elderly (age .65 years), Drug/ alcohol use; NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist; INR, international normalized ratio. Non-VKA oral anticoagulants: barriers and strategies 1013 Downloaded from https://academic.oup.com/europace/article-abstract/17/7/1007/2398779 by Faculdade de Medicina de Lisboa user on 13 November 2018 and the ‘Get with the Guidelines’ programme. Likewise, in Australia, the national prescribing service MedicineWise is a programme that aims to improve cardiovascular management in primary care. However, although the use of healthcare quality measures has shown improvements in care and adherence to guidelines in some cases, methods for implementing these improvements have varied and the results have not been consistent. 78–80 In Japan, the Japanese Stroke Databank is a patient oriented, academically controlled database aimed at establishing rigorous evidence for the quality improvement of stroke care (http://cvddb.med.shimane-u. ac.jp). Physicians register data on their own academic incentive and the databank is endorsed by the representative of stroke patients, providing a successful collaboration between patients and physicians to overcome stroke. In the UK, the Quality and Outcomes Framework incentivizes providers for the provision of highquality care, against explicit clinical indicators and defined targets, and helps to standardize improvements in the delivery of primary medical services. This system is currently being used to improve records of patients with AF and their ongoing management and could be applied to improving the use of NOACs for stroke prevention in patients with AF. Until validated and standardized healthcare quality measures for stroke prevention in patients with AF are developed, the role of such measures in driving ESC guideline implementation is limited. However, measures developed at a local or hospital level could be of benefit and warrant further investigation. ............................................................................................................................................................................... Table 5 Best-practice strategies for implementation of the ESC 2012 guidelines and rationale for such strategies Strategy Rationale Practical Develop hospital and department protocols and checklists based on national/local guidelines and implement quality indicators Provides clinical practical guidance for day-to-day management of patients with AF and allows measurement of guideline adherence Regular multidisciplinary team meetings and local quality audits Allows assessment of individual patients and can act as an internal check to ensure they are being managed in line with guideline recommendations Enhances peer-to-peer learning experience Plan follow-up visits and laboratory check-ups Ensures patients are compliant with guideline-recommended therapy and reduces the risk of complications Provide clear practical guidance on the use of NOACs Provides reassurance for physicians not experienced in the use of these drugs Implement CHA 2 DS 2 -VASc and bleeding risk checklists before prescribing NOACs and at every follow-up visit Ensuresidentificationof patientssuitable forantithrombotictherapyand those at increased risk of bleeding Implement compliance checks, e.g. specific questions, pill ‘counting’, diary completion, SMS messages or alarm calls to take tablets Ensures patients are compliant with guideline-recommended therapy, improves adherence and reduces the risk of complications Educational Regularly disseminate ESC/national and local guideline information and updates Raises awareness of guidelines Develop timely country-specific/local guidelines based on the ESC recommendations Allows recognition of country-specific requirements, such as access, so that guidelines are compatible with local conditions Re-train/educate nurses currently involved in anticoagulation/warfarin clinics to take on a more general role in initiation and management of NOACs Can provide an established point of contact through which patients can receive advice on anticoagulation with the NOACs Develop simple algorithms for specific populations of patients with AF, as per Figure 2(e.g. post-ischaemic stroke, post-haemorrhagic stroke, geriatric patients) Provides guidance on when and how to start NOACsand for how long in these patients Inform physicians on how to educate patients on the importance of adherence to therapy Limits the likelihood of non-adherence to guideline-recommended protocols Access Approach the responsible person within your healthcare system to: Highlight to key target groups (e.g. budget holders, policy makers, formulary gate keepers, the media, patient groups) the potential impact of not providing access to guideline-recommended therapies, from both financial and clinical perspectives Raises awareness that AF is a significant risk factor for stroke and that AF-related stroke is preventable Perform country-specific cost-effectiveness analyses of the NOACs Educate payers/budget holders about better utilization of anticoagulants, including NOACs, highlighting potential long-term cost benefits Provides payers/budget holders with more robust evidence to consider the use of the NOACs as first-line therapy – Inform politicians, patient groups and the media about differences in access to AF stroke prevention treatment within regions or countries Lobby parliamentary and healthcare bodies for equality of access to guideline-recommended therapies globally or across regions Puts pressure on policy makers to provide equality of care for stroke prevention in patients with AF with regards to medication AF,atrialfibrillation; CHA 2 DS 2 -VASc, Congestive heart failure/leftventricular dysfunction, Hypertension, Age ≥75 years (doubled), Diabetes, Stroke (doubled), Vasculardisease, Age 65–74 years, Sex category (female); NOAC, non-vitamin K antagonist oral anticoagulant; SMS, short message service; ESC, European Society of Cardiology. A.J. Camm et al.1014 Downloaded from https://academic.oup.com/europace/article-abstract/17/7/1007/2398779 by Faculdade de Medicina de Lisboa user on 13 November 2018 Limitations of these recommendations It should be noted that, although the majority of the evidence cited in this document comes from published clinical studies or real-world investigations, some of the country-specific information, and the barriers identified as a result, are based on personal evidence provided by writing committee members. The recommendations provided represent the opinion of the group, and would require practical implementation to test their robustness and applicability to different healthcarescenarios. As noted above,the lackof certain standardized structures may prevent some recommendations from being implemented in practice at this time. Conclusions Atrial fibrillation-related stroke is potentially preventable and, through better implementation of the 2012 ESC guidelines, its impact on patients, their families, and carers, and healthcare systems can be reduced. However, this cannot be achieved without increased detection of patients with AF and the increased use of anticoagulation in those assessed to be at moderate or high stroke risk, using either well-controlled warfarin or, preferably, NOACs. Providing patients with a choice of therapy and allowing physicians to prescribe the most appropriate anticoagulant for their patients will only be possible if there is access to all guideline-recommended therapies. In outlining practical measures that physicians and medical health societies working in this fieldcan instigate to improve guideline implementation, we believe that substantial benefits, in terms of improved patient outcomes and reduced healthcare burden, can be achieved. Acknowledgements The authors would like to acknowledge Sarah Atkinson, who provided editorial support for this manuscript. Funding This work was supported by editorial support funded by Bayer HealthCare Pharmaceuticals and Janssen Scientific Affairs, LLC. The sponsors provided suggestions and comments, but the content of this document represents the work of the authors. Conflict of interest: A.J.C.: Speaker/consulting fees from Sanofi, Bayer, Daiichi Sankyo, Boehringer Ingelheim, Pfizer, and Bristol-Myers Squibb. F.J.P.: Speaker/consulting fees from AstraZeneca, Bayer, and Boehringer Ingelheim. G.J.H.: Speaker fees from Bayer. F.A.: Speaker/consulting fees from Amgen, Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, and Eli-Lilly. F.D.R.H.: Speaker/consulting fees from Bristol-Myers Squibb/Pfizer, Bayer, and Boehringer Ingelheim; grants/sponsorship from Bayer and Daiichi Sankyo. La ´szlo ´Csiba: Speaker/consulting fees from Bayer, Boehringer Ingelheim, MSD, sanofi-aventis, and Egis. Gabriel R. de Freitas: Speaker fees from Bayer and Boehringer Ingelheim. Shinya Goto: Honoraria from Eisai, sanofi-aventis, Otsuka, Bayer, Novartis, AstraZeneca, Astellas, Pfizer, Medtronics-Japan, Tanabe-Mitsubishi, Takeda, Daiichi Sankyo, Mochida, and MSD. Werner Hacke: Speaker/consulting fees from Bayer and Daiichi Sankyo. Lorenzo Mantovani: Consulting fees from Bayer; grants from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Daiichi Sankyo. ASP Writing Committee Members A. John Camm, Fausto J. Pinto, Graeme J. Hankey, Felicita Andreotti, F.D. Richard Hobbs, La ´szlo ´Csiba, Gabriel R. de Freitas, Shinya Goto, Carlos Cantu ´, Jorge Gonzalez-Zuelgaray, Werner Hacke, Han Hwa Hu, Lorenzo Mantovani, Byung-Woo Yoon, Dayi Hu, and Kui-Hian Sim. References 1. World Health Organization. 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