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

REVIEW Non- i amin K an agonis o al an icoagulan s and a ial ib illa ion guidelines in p ac ice: ba ie s o and s a egies o op imal implemen a ion A. John Camm1*, Faus o J. Pin o2, G aeme J. Hankey3,4, Felici a And eo i5, and F.D. Richa d Hobbs6on behal o he W i ing Commi ee o he Ac ion o S oke P e en ion alliance† 1 Depa men o Clinical Ca diology, S Geo ge’s Uni e si y o London, London SW17 0RE, UK; 2 Lisbon Uni e si y Medical School, Lisbon, Po ugal; 3 School o Medicine and Pha macology, The Uni e si y o Wes e n Aus alia, Nedlands, WA, Aus alia; 4 Depa men o Neu ology, Si Cha les Gai dne Hospi al, Nedlands, WA, Aus alia; 5 Depa men o Ca dio ascula Science, Ca holic Uni e si y, Rome, I aly; and 6 Nu ield Depa men o P ima y Ca e Heal h Sciences, Uni e si y o Ox o d, Ox o d, UK Recei ed 16 Janua y 2015; accep ed a e e ision 27 Feb ua y 2015 S oke is a leading cause o mo bidi y and mo ali y wo ldwide. A ial ib illa ion (AF) is an independen isk ac o o s oke, inc easing he isk i e- old. S okes in pa ien s wi h AF a e mo e likely han o he embolic s okes o be a al o cause se e e disabili y and a e associa ed wi h highe heal hca e cos s, bu hey a e also p e en able. Cu en guidelines ecommend ha all pa ien s wi h AF who a e a isk o s oke should ecei e an icoagula ion. Howe e , despi e his guidance, egis y da a indica e ha an icoagula ion is s ill widely unde used. Wi h a ocus on he 2012 upda e o he Eu opean Socie y o Ca diology (ESC) guidelines o he managemen o AF, he Ac ion o S oke P e en ion alliance w i ing g oup ha e iden i ied key easons o he subop imal implemen a ion o he guidelines a a global, egional, and local le el, wi h an emphasis on access es ic ions o guideline- ecommended he apies. Following iden i ica ion o hese ba ie s, he g oup has de eloped an expe con- sensus on s a egies o augmen he implemen a ion o cu en guidelines, including p ac ical, educa ional, and access- ela ed measu es. The po- en ial impac o heal hca e quali y measu es o s oke p e en ion on guideline implemen a ion is also explo ed. By p o iding p ac ical guidance on how o imp o e implemen a ion o he ESC guidelines, o egion-speci ic modi ica ions o hese guidelines, he aim is o educe he po en ially de as a ing impac ha s oke can ha e on pa ien s, hei amilies and hei ca e s. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywo ds A ial ib illa ion †Guidelines †O al an icoagulan s †S oke p e en ion In oduc ion In 2012, s oke was es ima ed o ha e con ibu ed o he dea hs o 6.7 million people wo ldwide, accoun ing o nea ly 12% o all dea hs. 1 S oke causes pe manen disabili y in nea ly 5 million people each yea . 2 A ial ib illa ion (AF) is a signi ican independen isk ac o o s oke, associa ed wi h an app oxima ely i e- old excess in isk, bu is much less well ecognized han, o example, hype ension, o which he excess s oke isk is h ee- old. 3 In add- i ion, unlike mos o he ca dio ascula isk ac o s o s oke, he pi o al F amingham S udy ound an inc ease in a ibu able isk due o AF om 1.5% in indi iduals aged 50–59 yea s o 23.5% o hose aged 80–89 yea s. 3 A ial ib illa ion is he mos common sus ained ca diac a hy hmia and ep esen s a global p oblem (Figu e 1). 4–8 Pa ien s wi h AF a e i e imes mo e likely o ha e a s oke han he gene al popula ion. 3 A ial ib illa ion- ela ed s okes a e almos wice as likely o be a al and, in su i o s, cause se e e disabili y, in- c ease heleng ho hospi als ayanddec ease helikelihoodo pa ien s e u ning o hei own home, compa ed wi h non-AF- ela ed s okes. 9,10 A ial ib illa ion- ela ed s okes ha e also been associa ed wi h signi ican ly highe mean di ec cos s pe pa ien han non-AF- ela ed s okes. 11 Howe e , AF- ela ed s okes can be p e en ed and hei impac minimized by e ec i e managemen s a egies includ- ing inc eased de ec ion o AF, adhe ence o s oke p e en ion guide- lines and an icoagulan use in a - isk pa ien s. Le a ial appendage occlusion may also ha e a ole in pa ien s who a e unable o ecei e long- e m an icoagulan managemen , bu i is no a ecommended al e na i e o an icoagula ion pe se. 12 *Co esponding au ho . Tel: +44 20 8725 3414; ax: +44 20 8725 3416. E-mail add ess: [email p o ec ed] † See appendix o ull lis o au ho s. &The Au ho 2015. Published by Ox o d Uni e si y P ess on behal o he Eu opean Socie y o Ca diology. Thisis an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License (h p://c ea i ecommons.o g/licenses/by-nc/4.0/),which pe mi s non-comme cial e-use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Fo comme cial e-use, please con ac jou nals.pe [email protected] Eu opace (2015) 17, 1007–1017 doi:10.1093/eu opace/eu 068 Downloaded om h ps://academic.oup.com/eu opace/a icle-abs ac /17/7/1007/2398779 by Faculdade de Medicina de Lisboa use on 13 No embe 2018 Guidelines ha e an impo an ole in op imizing e idence-based ca e, imp o ing heal h ou comes o indi iduals and popula ions and dec easing cos s o heal hca e sys ems. Despi e he isk o s oke in pa ien s wi h AF, and he a ailabili y o clea global guidelines on he p e en ion o AF- ela ed s oke since 1999, eal-wo ld da a sugges ha a la ge p opo ion o pa ien s [38% o hose wi h a CHADS 2 (Conges i ehea ailu e,Hype ension,Age ≥75yea s,Diabe esmel- li us, p io S oke/ ansien ischaemic a ack (doubled)) sco e o 2 in he Global An icoagulan Regis y in he FIELD-A ial Fib illa ion (GARFIELD-AF) Regis y] a e s ill no ecei ing s oke p ophylaxis in line wi h guideline ecommenda ions. 13 Wi h he inc eased con eni- ence and imp o ed bene i – isk p o ile o he non- i amin K an agon- is o alan icoagulan s(NOACs; i a oxaban,dabiga an,apixaban,and edoxaban), his si ua ion may imp o e. This consensus documen aims o iden i y ba ie s o guideline im- plemen a ion wo ldwide and o de ine clea s a egies and p ac ice models o help o e come hese ba ie s, ocusing on he Eu opean Socie y o Ca diology (ESC) guidelines o he managemen o AF pub- lished in EP Eu opace in 2012. 12 A Medline sea ch was pe o med o iden i y guidelines o s oke p e en ion in pa ien s wi h AF and ba - ie s o guideline implemen a ion, ocusing on egis y da a bu includ- ingindi iduals udieswhe e ele an .TheAc ion o S oke P e en ion alliance w i ing commi ee also p o ided hei own coun y-speci ic expe iences and, based on he colla ed in o ma ion, iden i ied key ba - ie s o guideline implemen a ion and de eloped consensus s a egies o help o e come hese ba ie s. Guidelines o e iew A ocusedupda eo he2010ESCguidelines o hemanagemen o AF was issued in 2012. 12 This was pa ly in esponse o posi i e Phase III clinical ial da a wi h he NOACs dabiga an, i a oxaban, and apixaban, 14–16 and hei subsequen app o al o s oke p e en ion in a - isk pa ien s wi h non- al ula AF. The NOACs ha e shown equi alen o imp o ede icacycompa edwi hwa a inin andomized con olled ials,wi ha educ ionin he isko se e ebleedinge en s,in pa icula in ac anial haemo hage (ICH). 14–17 In addi ion, hey all o e ixed-dose egimens (wi h some dose educ ions manda ed in special popula ions, such as pa ien s wi h enal impai men ) ha elim- ina e he need o he ou ine coagula ion moni o ing associa ed wi h i amin K an agonis s (VKAs). Edoxaban is cu en ly he only one o hese NOACs ha is no ye widely app o ed in his indica ion. The ESC guidelines now ecommend he use o he NOACs in mos pa ien swi ha CHA 2 DS 2 -VASc [Conges i e hea ailu e/le en icu- la dys unc ion, Hype ension, Age ≥75 yea s (doubled) Diabe es, S oke (doubled), Vascula disease, Age 65–74 yea s, Sex ca ego y ( emale)] sco e o ≥1 in p e e ence o VKAs (Figu e 2), al hough in ce ain pa ien s, e.g. hose wi h se e e enal impai men o unde lying disease on echoca diog am, VKAs emain p e e ed. An i h ombo ic ea men is no ecommended in low- isk pa ien s wi h a CHA 2 DS 2 - VASc sco e o 0. 12 Howe e , he la e g oup ep esen ed only 3–7% o pa ien s in wo la ge coho s udies, 13,18 indica ing ha he majo i y o pa ien s wi h AF a e candida es o o al an icoagula ion. In la ge Phase III s udies, he cu en ly app o ed NOACs showed simila o imp o ed e icacy compa ed wi h wa a in o he p e en- ion o p ima y s oke o sys emic embolism. 19–21 Se e al o he NOACs ha e also demons a ed bene i s in he p e en ion o second- a y s okes, wi h simila e icacy o wa a in, as well as educing he in- cidence o ICH. 19–21 The isk o a s oke ecu ence is 2.5- old highe in pa ien s wi h AF who ha e al eady had a s oke o ansien ischae- mic a ack. 22 These pa ien s may also be a inc eased isk o alls, ha e demen ia o ha e limi ed access o in e na ional no malized a io (INR) moni o ing because o dec eased mobili y, making i p oblema - ic o ensu e e ec i e VKA he apy. Uni ed S a es: 2.3 million (2008) (es ima ed 5.6–>12 million by 2050) Eu opean Union: 10 million (2011) Japan: 0.8–2.0 million (2011) China: 8 million (2008) Aus alia: 0.9 million (2011) India: 1.2 million* (2011) B azil: 4.8 million (2009) Figu e 1 Es ima es o he p e alence o AF. 4–8 *Based on da a om a single communi y s udy. A.J. Camm e al.1008 Downloaded om h ps://academic.oup.com/eu opace/a icle-abs ac /17/7/1007/2398779 by Faculdade de Medicina de Lisboa use on 13 No embe 2018 In addi ion o inco po a ion o he NOACs in o he ecommenda- ions, ano he signi ican change o he ESC guidelines was a mo e away om he use o he CHADS 2 sco e o isk-s a i y pa ien s wi h AF, in a ou o he CHA 2 DS 2 -VASc sco e. This was based on e idence ha he CHA 2 DS 2 -VASc sco e could be used o mo e accu a ely iden i y uly ‘low- isk’ pa ien s, who would no equi e an i h ombo ic he apy. 12 The 2012 guidelines also ecommend he use o he HAS-BLED [Hype ension, Abno mal enal/li e unc ion, S oke, Bleeding his o y o p edisposi ion, Labile INR, Elde ly (e.g. age .65 yea s, ail y, e c.), D ugs/alcohol use] sco e o assess bleeding isk, bu highligh ha i should ocus e o s on imp o ing he modi iable isk ac o s o bleeding and should no be used o exclude pa ien s om o al an icoagulan he apy. 12 The simul aneous use o old and new guidelines, o o guidelines issued by di e en o ganiza ions, a ei he a global o egional le el, can lead o a deg ee o con usion o con adic o y guidance. In addi ion, ecommenda ions may di e be ween guidelines because o a ia ions in hepopula ions o which heya ein ended.Howe e , ecommenda- ions o an i h ombo ic he apy a e, o he mos pa , consis en be ween he majo guidelines. In 2012, he Ame ican College o Ches Physicians (ACCP) issued guidelines on an i h ombo ic he apy o AF, which p o ide simila ecommenda ions o he ESC guidelines (based onCHADS 2 sco ing o isk assessmen ), including a p e e ence o NOACso e adjus ed-doseVKAsina - iskpa ien s. 23 Olde guide- lines, such as hose join ly issued by heAme icanCollegeo Ca diology (ACC), he Ame ican Hea Associa ion (AHA), and he ESC in 2006, we e de eloped long be o e he NOACs we e a ailable o clinicians and, in con as wi h newe guidelines, ecommend ace ylsalicylic acid (ASA) as an al e na i e o wa a in in pa ien s wi h one mode a e isk ac o o s oke. 24 Upda ed ACC/AHA guidance, issued in 2014, ecommends o al an icoagula ion o pa ien s wi h p io s oke/ ansi- en ischaemic a ack o CHA 2 DS 2 -VASc sco e ≥2, whe eas pa ien s wi h a sco e o 1 may be gi en o al an icoagula ion, ASA, o no an i h- ombo ic he apy. 25 In 2013, he Eu opean Hea Rhy hm Associa ion published a p ac ical guide on he use o NOACs in pa ien s wi h non- al ula AF 26 based on he 2012 ESC ecommenda ions. Coun y-speci ic guidelines, such as hose om he Na ional Ins i- u e o Heal h and Ca e Excellence (NICE) in he UK, ecommend apixaban, dabiga an, and i a oxaban as op ions o he p e en ion o s oke o sys emic embolism in pa ien s wi h AF. 27 A ocused upda e o he Canadian Ca dio ascula Socie y (CCS) A ial Fib illa- ion Guidelines, published in 2012, ecommends NOACs o e o he o al an icoagulan s in eligible pa ien s. 28 In he Asia-Paci ic egion, se e al coun ies ha e coun y-speci ic guidelines o he manage- men o pa ien s wi h AF bu no all ye inco po a e ecommenda- ions o he use o NOACs. Howe e , he 2014 Japanese guidelines la gely suppo he ESC 2012 guidelines, as does a consen- sus s a emen issued in 2013 by he Asia Paci ic Hea Rhy hm Socie y on an i h ombo ic he apy in pa ien s wi h non- al ula AF. 29 In o ma ion p o ided by o he o ganiza ions, such as he Na ional S oke Associa ion in he UK o he Canadian Agency o D ugs and Technologies in Heal h, who issue he apeu ic e iews, may also in luence clinical p ac ice a a na ional le el. Guideline implemen a ion and ba ie s o implemen a ion Bene i s o compliance wi h guidelines Ac i icismo guidelinesis ha heysome imes elyon e idence ha is ela i ely weak and/o s udies ha ha e been conduc ed wi h Val ula AFa <65 yea s and lone AF (including emales) O al an icoagulan he apy NOAC VKA No an i h ombo ic he apy No No (i.e. non- al ula AF) 01≥2 Yes Yes A ial ib illa ion Assess bleeding isk (HAS-BLED sco e) Conside pa ien alues and p e e ences Assess isk o s oke (CHA2DS2-VASc sco e) Figu e 2 Eu opean Socie y o Ca diology (ESC) guideline ecom- menda ions o hep e en iono s okeinpa ien swi hAF. 12 An ipla- ele he apy wi h ASA plus clopidog el, o —less e ec i ely—ASA only, should be conside ed in pa ien s who e use any o al an icoagu- lan o canno ole a e an icoagulan s o easons un ela ed o bleed- ing.I he ea econ aindica ions oo alan icoagula iono an ipla ele he apy, le a ial appendage occlusion, closu e, o excision may be conside ed. CHA 2 DS 2 -VASc sco e: u quoise, 0; yellow, 1; ed, ≥2. Line:solid, bes op ion; dashed, al e na i e op ion. a Includes heuma - ic al ula disease and p os he ic al es. AF, a ial ib illa ion; ASA, ace ylsalicylic acid; CHA 2 DS 2 -VASc, ESC- ecommended s oke isk sco e[Conges i ehea ailu e/le en icula dys unc ion,Hype en- sion, Age ≥75 yea s (doubled) Diabe es, S oke (doubled), Vascula disease, Age 65–74 yea s, Sex ca ego y ( emale)]; HAS-BLED, [ESC- ecommended bleeding isk sco e, de ined as Hype ension, Abno mal enal/li e unc ion, S oke, Bleeding his o y o p edispos- i ion, Labile INR, Elde ly (e.g. age .65 yea s, ail y, e c.), D ugs/ alcohol use]; NOAC, non- i amin K an agonis o al an icoagulan ; VKA, i amin K an agonis . F om Camm e al. 2012 ocused upda e o he ESC Guidelines o he managemen o a ial ib illa ion. Eu opean Hea Jou nal No 2012, 33(21) 2719–2747. Rep oduced wi h pe mission o Ox o d Uni e si y P ess (UK) &Eu opean Socie y o Ca diology, www.esca dio.o g/guidelines Non-VKA o al an icoagulan s: ba ie s and s a egies 1009 Downloaded om h ps://academic.oup.com/eu opace/a icle-abs ac /17/7/1007/2398779 by Faculdade de Medicina de Lisboa use on 13 No embe 2018 inconsis en me hodologies. Howe e , he e idence o he use o NOACs in pa ien s wi h non- al ula AF comes om e y la ge, mul- icen e, andomized con olled Phase III s udies, 14–16 and he p ima y ecommenda ions made by he ESC in 2012 on an icoagula- ion in pa ien s wi h AF gene ally ca ied a high le el (A o B) o e i- dence. 12 Ne e heless, p ospec i e clinical da a o he NOACs a e lacking in some speci ic a eas; e.g. a p ospec i e andomized s udy o i a oxaban o pa ien s wi h AF unde going ca dio e sion has been published ecen ly, 30 bu a simila ial o apixaban (NCT02100228) is only jus ge ing unde way, and he e is no such p ospec i e s udy planned o dabiga an. S udies o add ess o he da a gaps wi h he NOACs a e ongoing. Published s udies suppo he bene i s o compliance wi h guideline ecommenda ions o an icoagula ion in pa ien s wi h AF. A c oss- sec ional s udy o pa ien s admi ed o he Uni e si y o Maas ich Medical Cen e be ween 2003 and 2006 ound ha 51% o hose wi h known AF who we e eligible o o al an icoagula ion did no ecei e i , and ha imp o ed adhe ence o guidelines could po en ially ha e p e en ed 22% o subsequen ischaemic s okes. 31 Mo e ecen - ly, a eal-wo ld coho -based s udy o almos 9000 pa ien s ec ui ed o e 10 yea s ound low annual a es o s oke o h omboembolism (0.64%), majo bleeding (1.12%), and dea h (1.08%) among un ea ed pa ien s classi ied as low isk acco ding o he ESC 2012 guidelines (i.e. CHA 2 DS 2 -VASc sco e 0). 18 These da a suppo he ESC ecommen- da ion ha hese pa ien s should no ecei e an i h ombo ic he apy. Fu he mo e, simula ions o pa ien ou comes om he RE-LY da abase using ESC- ecommended dabiga an ea men p o ocols oundasigni ican ne clinicalbene i compa edwi hwa a in,suppo - ing he ESC ecommenda ions. 32 Compliance wi h guidelines in p ac ice Regis y da a o e aluable insigh s in o pa e ns o d ug use and can p o ide a means o acking up ake o guideline ecommenda ions. Fo example, global da a om he GARFIELD-AF Regis y, collec ed be ween 2009 and 2011, indica ed ha 27% o all pa ien s wi h AF we es ill ecei ing ASA he apy,compa ed wi h 60%who ecei ed o al an icoagula ion (Table 1). 13 Howe e , obse a ional da a om he Eu opean PREFER AF (PRE en ion oF h omboembolic e en s—Eu opean Regis y in A ial Fib illa ion) egis y collec ed be ween 2012 and 2013 sugges ha he in oduc ion o he 2010 ESC guidelines was associa ed wi h a mo e away om he use o ASA o o al an icoagula ion. 40 O he Eu opean egis y da a show a ia ion in o al an icoagula ion use depending on when he da a we e collec ed and om which coun y o coun ies (Table 1). 35–41 Ou side o Eu ope, US egis y da a indica e a low use o o al an icoa- gula ion ac oss all s oke isk ca ego ies. 43 Da a om he REACH egis y (REduc ion o A he o h ombosis o Con inued Heal h) demons a ed he lowe use o o al an icoagula ion in pa ien s wi h AF ec ui ed om Asia (excluding Japan) compa ed wi h hose ec ui ed om Japan and non-Asian egions. 45 These di e ences high- ligh ha o alan icoagulan useisno ye consis en a aglobal,coun y, o egional le el and may be in luenced by ac o s such as he special y ............................................................................................................................................................................... Table 1 A ial ib illa ion egis ies and su eys Regis y o s udy Guidelines Pa ien s wi h AF, n Coun y/ egion Da a collec ion, yea OAC use (%) GARFIELD-AF 13 Mul iple 10 614 Global 2009–2011 60 RE-LY AF 33 Mul iple 15 400 Global 2008–2011 30 GLORIA-AF 34 Mul iple 56 000 Global 2011 onwa ds Awai ing da a Eu o Hea Su ey on AF 35 ACC/AHA/ESC 2001 and ACCP 2004 5333 Eu ope 2003–2004 64 AFNET 36 ACC/AHA/ESC 2001 9582 Ge many 2004–2006 71 ATRIUM 37 ACC/AHA/ESC 2001 and ACCP 2008 3667 Ge many 2009 83 P ospec i e non-in e en ional s udy 38 No speci ied 2753 Ge many 2010 64–73 a ISAF 39 No speci ied 6036 I aly 2011 46 PREFER AF 42 ESC 2010 7243 Eu ope 2012–2013 82 Re ospec i e, coho s udy 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 No speci ied 300 Asia (ex. Japan) 2006–2011 36 REACH 45 No speci ied 350 Japan 2006–2011 54 REACH 45 No speci ied 6000 Global (ex. Asia) 2006–2011 55 ACC, Ame ican College o Ca diology; ACCP, Ame ican College o Ches Physicians; AF, a ial ib illa ion; AFNET, Cen al Regis y o he Ge man Compe ence NETwo k on A ial Fib illa ion; AHA, Ame ican Hea Associa ion; ATRIUM, Ou pa ien Regis y Upon Mo bidi y o A ial Fib illa ion; CHADS 2 , Conges i e hea ailu e, Hype ension, Age ≥75 yea s, Diabe es melli us, p io S oke/ ansien ischaemic a ack (doubled); ESC, Eu opean Socie y o Ca diology; GARFIELD-AF, Global An icoagulan Regis y in he FIELD; GLORIA-AF, Global Regis y on Long-Te m O al An i h ombo ic T ea men in Pa ien s wi h A ial Fib illa ion; ISAF, I alian Ne wo k o A ial Fib illa ion Managemen su ey; OAC, o al an icoagulan ; ORBIT-AF, Ou comes Regis y o Be e In o med T ea men o A ial Fib illa ion; PREFER AF, PRE en ion oF h omboembolic e en s—Eu opean Regis y in A ial Fib illa ion; REACH, REduc ion o A he o h ombosis o Con inued Heal h; RE-LY AF, Randomized E alua ion o Long- e m an icoagulan The apY. a CHADS 2 sco e ≥2 (includes low molecula weigh hepa in). A.J. Camm e al.1010 Downloaded om h ps://academic.oup.com/eu opace/a icle-abs ac /17/7/1007/2398779 by Faculdade de Medicina de Lisboa use on 13 No embe 2018 o he physicians en olling pa ien s in o he egis ies and he deg ee o awa eness o upda ed guidelines. Pa ien and physician- ela ed ba ie s Regis ies can also p o ide use ul in o ma ion on he easons o non-adhe ence o guidelines and iden i y ba ie s o hei adop- ion. GARFIELD-AF highligh ed ha nea ly hal o pa ien s wi h a CHADS 2 sco e ≥2 we e no ecei ing VKA he apy because o physician choice, speci ically because o conce ns o e bleeding isk, pa ien compliance, unce ain y ega ding guideline ecom- menda ions, all isk o low isk o s oke. 13 Pa ien ac o s, such as alcohol misuse, medica ion e usal, unsui able co-medica ion use, o p e ious bleeding e en s, we e he easons o no ini ia - ing VKA he apy in ,16% o cases. 13 Simila easons we e gi en o wa a in discon inua ion in he Ou comes Regis y o Be e In o med T ea men o A ial Fib illa ion (ORBIT-AF). 46 Simila ly, in he A ial Fib illa ion Clopidog el T ial wi h I besa an o P e- en ion o Vascula E en s (ACTIVE) A ial, which en olled pa ien s who we e conside ed unsui able o VKA he apy, he p ima y eason o en olmen in he ial (accoun ing o 50% o pa ien s) was physician judgemen ha a VKA was inapp op i- a e. Pa ien p e e ence accoun ed o 26% o pa ien s en olled, and speci ic isk o bleeding o 23% o pa ien s. 47 In he Apix- aban s. Ace ylsalicylic Acid o P e en S okes in A ial Fib illa ion Pa ien s Who Ha e Failed o A e Unsui able o Vi amin K An ag- onis T ea men (AVERROES) s udy, he mos equen easons o no p esc ibing VKAs we e physician judgemen ha INR mon- i o ing could no be achie ed a he equisi e equency (43%) and pa ien p e e ence (37%). 48 The S oke and A ial Fib illa ion Ensemble (SAFE) II s udy ound ha ha ing a younge gene al p ac i ione and being ollowed up by a ca diologis we e independen ly associa ed wi h he p esc ip ion o o al an icoagulan s. 49 The p esence o po en ial con aindica ions, lack o an indica ion, low compliance, and ea o bleeding we e easons gi en o non-p esc ip ion. 49 These indings highligh ha he lack o physician awa eness abou o al an icoagula ion and how o manage complica ions is a key ba ie o adop ion o guideline- ecommended he apies. A gene al su ey o Du ch gene al p ac i- ione s also iden i ied en i onmen al ac o s such as o ganiza ional cons ain s, lack o ime, and lack o esou ces as p ominen ba ie s o guideline adhe ence. 50 Fu he mo e, up ake o NOACs may be limi ed by a physician p e e ence o close INR moni o ing, pa icu- la ly in elde ly o ail pa ien s. Ano he ba ie o he adop ion o guidelines a ises when heya e no conside ed applicable a a coun y le el, possibly because o e- gional he e ogenei y in pa ien baseline cha ac e is ics (e.g. a high p opo ion o pa ien s no mee ing he c i e ia o ecommended ea men s o a pe cep ion ha he s udies unde pinning ecommen- da ions a e based on non- ep esen a i e popula ions), di e ences in cu en s anda ds o ca e o cul u al pe cep ions o isk s. bene i o he in e en ion. Fo example, in some Asian coun ies, such as Japan, he ecommended a ge INR in pa ien s wi h AF ≥70 yea s o age is lowe (1.6–2.6) han he ecommended a ge o 2.0–3.0, which is used mo e widely. 51 Simila ly, a lowe 15 mg once-daily dose o i - a oxaban (o 10 mg once-daily in pa ien s wi h c ea inine clea ance 30–49 mL/min) was speci ically es ed in Japanese pa ien s. 52 Access o guideline- ecommended he apies In some coun ies, p esc ibing o he NOACs is es ic ed a a na ion- al, egional, o local le el. Fo example, he Na ional Heal h Se ice o Sco land limi s he p esc ip ion o i a oxaban o pa ien s who appea complian wi h couma in he apy and ye s ill ha e poo INR con ol, as well as o hose who a e alle gic o o a e unable o ole a e couma ins. 53 In he UK, he Depa men o Heal h ollows he NICE guidelines a he han he ESC guidelines. Howe e , e en hough he NOACs a e ecommended as a he apeu ic op ion by NICE, many clinical commissioning g oups o egional p esc ibing g oups in he UK in e p e his ‘op ion’ as second line, wi h wa a in compulso y as i s -line he apy. 54,55 In he UK and I eland, pa ien s who a e close o he hospi al and can a end clinics egula ly o co- agula ion moni o ing and dose adjus men s a e also mo e likely o ecei e VKAs han hose who li e u he away. In Eas e n Eu opean coun ies (e.g. Hunga y), he Na ional Heal h Se ice limi s he p e- sc ip ion o NOACs o pa ien s who ha e had a p e ious s oke o pa ien s wi h poo INR con ol on couma in he apy. 56 This es ic- ion is in place because he i s -line use o he NOACs is conside ed inancially p ohibi i e. Res ic ed access can also be a esul o adminis a i e ba ie s. Fo example, in I aly and Hunga y, a limi ed numbe o specialis s a e allowed o p esc ibe he NOACs; o inalize he p esc ip ion, hese specialis s a e equi ed o ill ou an elec onic case epo o m, con ibu ing o a compulso y na ional su ey (www. agenzia a maco.go .i ). This is a ime-consuming p ocess and, as such, he na ional Regula o y Au ho i ies ha e indi ec ly discou aged ou ine implemen a ion o he ESC guidelines o an i h ombo ic ea men . The bu eauc a ic si ua ion in I aly is mi o ed in o he coun ies: in I eland and some pa s o England, jus i ica ion o ms mus be comple ed o allow physicians o p esc ibe he NOACs and, in Spain, pa ien s mus ha e an INR ha is eco ded o be ou o ange h ee imes in a ow be o e a pa ien can be p esc ibed any o hese d ugs, and his may ake weeks. Access issues can also a ise when upda es o guidelines a e delayed. Fo example, he Eu opean S oke O ganisa ion (ESO) has no upda ed i s guidelines on seconda y s oke p e en ion since 2008, 57 and so he NOACs a e no included. This in luences he daily p ac ice o s oke specialis s: in some Eas e n Eu opean coun ies, o ins ance, physicians ace inancial penal ies o e en imp isonmen i hey a e no complian wi h he guidelines ecommended o hei special y, e en i he guidelines a e ou - da ed and do no e lec he la es clinical ad ances in he ield. In cases such as hese, p e-exis ing guidelines, hough ele an when hey we e published, a e hemsel es a ba ie o adop ing new app oaches o he apies. An upda e o he ESO guidelines is an icipa ed. E en i guidelines a e up o da e, i does no necessa ily gua an ee access o ecommended he apies. Fo example, a g oup o Spanish medical expe s de eloped a consensus documen in line wi h he ESC guidelines ha was app o ed by he Spanish Minis y o Heal h o na ional use. 58 Howe e , access o NOACs is s ill o en es ic ed by local au ho i ies because wa a in is conside ed o be as e ec i e as he NOACs and is a low-cos d ug, albei wi h high moni o ing cos s. The e o e, he newe d ugs a e o en limi ed o pa ien s Non-VKA o al an icoagulan s: ba ie s and s a egies 1011 Downloaded om h ps://academic.oup.com/eu opace/a icle-abs ac /17/7/1007/2398779 by Faculdade de Medicina de Lisboa use on 13 No embe 2018 who a e uns able on wa a in o who ha e had an ischaemic s oke and a e a high isk o ICH. Financial ba ie s o guideline- ecommended he apies One o he majo easons o es ic ed access o new guideline- ecommended he apies is pe cei ed cos . Res ic ions end o be made based on a conside a ion o sho - e m budge impac , such as he lowe acquisi ion cos s o VKAs compa ed wi h he NOACs, a he han he po en ial longe e m economic impac o e en s ha migh ha e been p e en ed. Non- i amin K an agonis o al an ic- oagulan s do no equi e ou ine coagula ion moni o ing, which, in one US s udy, was shown o cos be ween $291 and $943 annually pe pa ien . 59 The Na ional Ins i u e o Heal h and Ca e Excellence has es ima ed he annual cos o INR moni o ing, including anspo cos s,a £656in he i s yea and£540 he ea e . 60 Longe e m cos sa ings ela e o he di ec cos s o managing he consequences o an icoagula ion, which a e summa ized in Table 2. Fo example, con- side ing ha NOACs educe he isk o ICH by a leas hal compa ed wi h wa a in, hei use could con ibu e subs an ially o long- e m cos sa ings (Table 3). A s udy in Denma k published in 1999 es i- ma ed ha ,a e ICH, he mean o al cos o heal hca eandsocialse - ices du ing he i s yea was 123 200 DKK o US$22 000. 63 Mo e ecen ly, a s udy in he USA analysing medicine and pha macy claims o pa ien s wi h AF es ima ed he mean unadjus ed all-cause heal h cos s in he yea a e a wa a in claim o be $41 903 o pa ien s wi h a leas one ICH. 64 Despi e his, i is o en di i- cul in p ac ical e ms o implemen a scheme in which a mo e expen- si e he apy is paid o om one budge (in his case, d ug cos s) o p o ide cos sa ings ha ela e o a sepa a e budge (blood es s and moni o ing). The lack o moni o ing o he NOACs may also ep esen a inan- cial ba ie o hei implemen a ion. In some coun ies, p ima y ca e p ac ices and an icoagula ion clinics ecei e a inancial incen i e o p o iding VKA moni o ing se ices, which could be conside ed unde h ea wi h he in oduc iono he NOACs.Howe e , wi h ap- p op ia e aining o pe sonnel, hese acili ies could be epu posed o ake on a ole in he ini ia ion and managemen o he NOACs and managemen o co-mo bidi ies and o p o ide aluable guidance and eassu ance o pa ien s abou hei an icoagula ion ca e. Indeed, o e all isk ac o con ol, no limi ed o he use o NOACs, is he mos impo an he apeu ic in e en ion o pa ien s wi h AF. Financial ba ie s o app op ia e VKA managemen speci ic o in- di idual coun ies o egions also exis . In many Eas e n and Cen al Eu opean coun ies, bo h INR moni o ing and a el cos s ( o blood sampling) a e co e ed by he heal hca e sys em. Howe e , blood sampling akes place in la ge cen alized labo a o ies ha a e o en a long dis ance om whe e he pa ien li es, meaning ha subs an ial wo k ime is los h ough a elling o and om appoin men s; his can also ha e a nega i e impac on pa ien compliance. ............................................................................................................................................................................... Table 2 O e iew o e en cos s. Adap ed om Klein jens e al. 61 E en a Acu e (pe e en ) (E) Rehabili a ion (pe e en ) b (E) Long- e m ollow-up (pe 3 mon hs) (E) Mino s oke 5946 3204 244 Majo s oke 12 247 17 734 2216 Sys emic embolism 5124 No epo ed No epo ed Clinically ele an non-majo ex ac anial bleeding e en 23 No epo ed No epo ed Majo ex ac anial bleeding e en 3510 No epo ed No epo ed In ac anial bleeding e en c 7699 17 734 2216 Myoca dial in a c ion 7891 No epo ed No epo ed a The ange o e en cos s es ed in sensi i i y analyses was +25% o he mean. b Based on unpublished esul s (K. Pu man, pe sonal communica ion). c Based on ma ke sha e and p ices o locally a ailable b ands. ................................................................................................................... .............................................................................................................................................................................. Table 3 Absolu e pe cen age annual isk o ICH s a i ied by s oke isk in pa ien s wi h non- al ula AF ecei ing o al an icoagula ion he apy o s oke p e en ion. Adap ed om Rognoni e al. 62 In ac anial bleeding, absolu e annual isk (%) CHADS 2 ≤ 1 CHADS 2 52 CHADS 2 ≥ 3 Wa a in 0.48 0.65 1.01 Ri a oxaban (20 mg od) No in es iga ed 0.44 0.68 Apixaban (5 mg bid) 0.2 0.27 0.42 Dabiga an (150 mg bid) 0.2 0.26 0.52 bid, wice daily; CHADS 2 , Conges i e hea ailu e, Hype ension, Age ≥75 yea s, Diabe es melli us, p io S oke/ ansien ischaemic a ack (doubled); od, once daily; ICH, in ac anial haemo hage. A.J. Camm e al.1012 Downloaded om h ps://academic.oup.com/eu opace/a icle-abs ac /17/7/1007/2398779 by Faculdade de Medicina de Lisboa use on 13 No embe 2018 In B azil and many Sou h Eas Asian coun ies, only 30% o pa ien s ha e p i a e heal h insu ance and, he e o e, ha e access o he newe he apies o s oke p e en ioninpa ien swi h AF.Incon as , pa ien s ea ed in he public sec o ypically con inue o ecei ewa - a in o ano he VKA because hese d ug cos s a e suppo ed by he heal hca e sys em. In B azil and Mexico, he local au ho i ies can sub- sidize mo e expensi e medica ions, bu i akes ime o ge new he - apies included on hese lis s and, because i is no a na ional esponsibili y, di e ences in access exis be ween local au ho i ies. In cos -e ec i eness analyses, he NOACs ha e been shown o be cos -e ec i e compa ed wi h wa a in. 61,65–74 Robus and well- designed cos -e ec i eness analyses can be impo an when a guing he case o conside a ion o new he apeu ic op ions wi h policy make s. Howe e , hese analyses a e no wi hou limi a ions. Thei gene al applicabili ycan be limi ed because o di e encesin heal hca e sys ems be ween coun ies. Fu he mo e, cos -e ec i eness analyses may be inadequa e because hey do no ake in o conside a ion all ac o s, pa icula ly indi ec cos s including loss o wo k o pa ien s o ca e sdue oINRclinic isi sandassocia ed a elcos s. 75 Addi ion- ally, e en demons a ing he cos -e ec i eness o a d ug wi hin he pa ame e s de ined in he analysis may no p o ide a compa ison o cos -e ec i eness ela i e o o he es ablished ea men s. In addi ion o hei cos -e ec i eness, he ela i e e ec i eness and sa e y o he NOACs compa ed wi h he VKAs is an impo an bene i . The con enience o pa ien s in e ms o lack o moni o ing and die a y es ic ions, which is likely o imp o e pe sis ence and ad- he ence and he e o e clinical ou comes, should also no be unde - es ima ed. Bes p ac ice in Eu opean Socie y o Ca diology guideline implemen a ion Regis y da a highligh ha i can ake se e al yea s o guideline ecommenda ions o be implemen ed in clinical p ac ice, and e en hen, ecommenda ions may no be applied p ope ly o con- sis en ly. I is also clea ha he e is wide a ia ion be ween coun- ies ega ding which ecommenda ions a e implemen ed and how his is achie ed. When he w i ing commi ee a ed he impo - ance o ce ain ac o s o guideline implemen a ion, a ia ion be ween coun ies did exis , bu ac o s such as AF sc eening, diagnosis, and s oke isk assessmen we e a ed o high impo - ance ac oss he g oup. The ba ie s o guideline implemen a ion ha he g oup iden i ied (summa ized in Table 4) all in o h ee main ca ego ies: p ac ical, edu- ca ional, and access ela ed. P ac ical issues ela e p ima ily no only o op imal diagnosis and isk s a i ica ion o pa ien s wi h AF bu also o he applicabili y o he ESC guidelines o non-Eu opean popula- ions. Lack o awa eness o he ESC guidelines and delays in upda es o local o na ional guidelines a e he key educa ional ba - ie s ha exis , despi e he e o s o he ESC o p omo e i s guide- lines h ough a ious me hods, including ‘ ain he eache ’ p og ammes, ESC guideline implemen a ion oolki s, and mobile pocke guidelines. Ano he educa ional ba ie s ems om he a ie y o in o ma ion a ailable abou he NOACs, which can lead o con usion o e hei speci ic p ope ies and use p o ocols. Access- ela ed issues a e p ima ily due o cos and also include o he ac o s ha ha e been discussed abo e. In ligh o hese ba ie s, he Ac ion o S oke P e en ion alliance w i ing commi ee ecommends se e al bes -p ac ice s a egies (summa ized in Table 5) o imp o e adhe ence o he ESC guidelines (o hei egion-speci ic modi ica ion) and access o guideline- ecommended he apies. Measu ing heal hca e quali y o s oke p e en ion: po en ial ole in guideline implemen a ion Regis ies p o ide in o ma ion on whe he guidelines ha e been implemen ed. Howe e , could heal hca e quali y measu es be used o d i e implemen a ion o , and adhe ence o, guidelines as hey a e issued? Un o una ely, da a on he use o heal hca e quali y mea- su es o imp o e s oke p e en ion in pa ien s wi h AF a e gene ally limi ed, al hough na ional audi da a a e a ailable in some coun ies, highligh ing gaps in ca e o s oke p e en ion. 76,77 In he USA, he e a e se e al ini ia i es aimed a assessing he quali y o s oke ca e, including he S oke P ac ice Imp o emen Ne wo k, The Paul Co e dell Na ional Acu e S oke Regis y, ................................................................................ Table 4 Ba ie s o implemen a ion o ESC 2012 guidelines Ba ie P ac ical †Unde -diagnosiso AFbecauseo lacko access o diagnos ic ools o AF (e.g. Hol e moni o ing) †No sc eening using he mos e icien echnique, e.g. loop moni o ing o pa oxysmal AF †Unde es ima ion o h omboembolic isk †Applicabili y o ESC guidelines o non-Eu opean popula ions Educa ional †Lack o widesp ead awa eness o ESC 2012 Guidelines (coupled wi h use o o he /p e-exis ing guidelines) †Delay in upda es o local guidelines o e lec majo en i onmen al changes o p ac ice †Fea o majo bleeding/lack o alida ed sco es o e alua e bleeding isk (HAS-BLED was de eloped based on VKA s udies) †Lack o echnical expe ise †De elopmen and a ailabili y o mul iple NOACs in a ela i ely sho ime ame has led o con usion abou p o ocols o use and he speci ic p ope ies o each d ug – Exace ba ed by manu ac u e s p o iding di e en in o ma ion abou he d ugs in he p esc ibing in o ma ion s. he summa y o p oduc cha ac e is ics and using di e en ma ke ing app oaches – In luenced by media epo s, e.g. epo s o se e e bleeding when dabiga an was i s in oduced Access †Budge es ic ions and/o eimbu semen issues wi h NOACs †Limi a ions/ es ic ions on pa ien s conside ed eligible o NOACs ha a e inconsis en wi h b oade guideline ecommenda ions †Limi a ions o p esc ibe eligibili y †Adminis a i e hu dles associa ed wi h p esc ip ion o NOACs (e.g. comple ion o pape wo k and jus i ica ion o he clinical decision) AF, a ial ib illa ion; HAS-BLED, Hype ension, Abno mal li e / enal unc ion, S oke his o y, Bleeding p edisposi ion, Labile INR, Elde ly (age .65 yea s), D ug/ alcohol use; NOAC, non- i amin K an agonis o al an icoagulan ; VKA, i amin K an agonis ; INR, in e na ional no malized a io. Non-VKA o al an icoagulan s: ba ie s and s a egies 1013 Downloaded om h ps://academic.oup.com/eu opace/a icle-abs ac /17/7/1007/2398779 by Faculdade de Medicina de Lisboa use on 13 No embe 2018 and he ‘Ge wi h he Guidelines’ p og amme. Likewise, in Aus alia, he na ional p esc ibing se ice MedicineWise is a p og amme ha aims o imp o e ca dio ascula managemen in p ima y ca e. Howe e , al hough he use o heal hca e quali y measu es has shown imp o emen s in ca e and adhe ence o guidelines in some cases, me hods o implemen ing hese imp o emen s ha e a ied and he esul s ha e no been consis en . 78–80 In Japan, he Japanese S oke Da abank is a pa ien o ien ed, academically con- olled da abase aimed a es ablishing igo ous e idence o he quali y imp o emen o s oke ca e (h p://c ddb.med.shimane-u. ac.jp). Physicians egis e da a on hei own academic incen i e and he da abank is endo sed by he ep esen a i e o s oke pa ien s, p o iding a success ul collabo a ion be ween pa ien s and physicians o o e come s oke. In he UK, he Quali y and Ou - comes F amewo k incen i izes p o ide s o he p o ision o high- quali y ca e, agains explici clinical indica o s and de ined a ge s, and helps o s anda dize imp o emen s in he deli e y o p ima y medical se ices. This sys em is cu en ly being used o imp o e eco ds o pa ien s wi h AF and hei ongoing managemen and could be applied o imp o ing he use o NOACs o s oke p e en- ion in pa ien s wi h AF. Un il alida ed and s anda dized heal hca e quali y measu es o s oke p e en ion in pa ien s wi h AF a e de eloped, he ole o such measu es in d i ing ESC guideline implemen a ion is limi ed. Howe e , measu es de eloped a a local o hospi al le el could be o bene i and wa an u he in es iga ion. ............................................................................................................................................................................... Table 5 Bes -p ac ice s a egies o implemen a ion o he ESC 2012 guidelines and a ionale o such s a egies S a egy Ra ionale P ac ical De elop hospi al and depa men p o ocols and checklis s based on na ional/local guidelines and implemen quali y indica o s P o ides clinical p ac ical guidance o day- o-day managemen o pa ien s wi h AF and allows measu emen o guideline adhe ence Regula mul idisciplina y eam mee ings and local quali y audi s Allows assessmen o indi idual pa ien s and can ac as an in e nal check o ensu e hey a e being managed in line wi h guideline ecommenda ions Enhances pee - o-pee lea ning expe ience Plan ollow-up isi s and labo a o y check-ups Ensu es pa ien s a e complian wi h guideline- ecommended he apy and educes he isk o complica ions P o ide clea p ac ical guidance on he use o NOACs P o ides eassu ance o physicians no expe ienced in he use o hese d ugs Implemen CHA 2 DS 2 -VASc and bleeding isk checklis s be o e p esc ibing NOACs and a e e y ollow-up isi Ensu esiden i ica iono pa ien ssui able o an i h ombo ic he apyand hose a inc eased isk o bleeding Implemen compliance checks, e.g. speci ic ques ions, pill ‘coun ing’, dia y comple ion, SMS messages o ala m calls o ake able s Ensu es pa ien s a e complian wi h guideline- ecommended he apy, imp o es adhe ence and educes he isk o complica ions Educa ional Regula ly dissemina e ESC/na ional and local guideline in o ma ion and upda es Raises awa eness o guidelines De elop imely coun y-speci ic/local guidelines based on he ESC ecommenda ions Allows ecogni ion o coun y-speci ic equi emen s, such as access, so ha guidelines a e compa ible wi h local condi ions Re- ain/educa e nu ses cu en ly in ol ed in an icoagula ion/wa a in clinics o ake on a mo e gene al ole in ini ia ion and managemen o NOACs Can p o ide an es ablished poin o con ac h ough which pa ien s can ecei e ad ice on an icoagula ion wi h he NOACs De elop simple algo i hms o speci ic popula ions o pa ien s wi h AF, as pe Figu e 2(e.g. pos -ischaemic s oke, pos -haemo hagic s oke, ge ia ic pa ien s) P o ides guidance on when and how o s a NOACsand o how long in hese pa ien s In o m physicians on how o educa e pa ien s on he impo ance o adhe ence o he apy Limi s he likelihood o non-adhe ence o guideline- ecommended p o ocols Access App oach he esponsible pe son wi hin you heal hca e sys em o: Highligh o key a ge g oups (e.g. budge holde s, policy make s, o mula y ga e keepe s, he media, pa ien g oups) he po en ial impac o no p o iding access o guideline- ecommended he apies, om bo h inancial and clinical pe spec i es Raises awa eness ha AF is a signi ican isk ac o o s oke and ha AF- ela ed s oke is p e en able Pe o m coun y-speci ic cos -e ec i eness analyses o he NOACs Educa e paye s/budge holde s abou be e u iliza ion o an icoagulan s, including NOACs, highligh ing po en ial long- e m cos bene i s P o ides paye s/budge holde s wi h mo e obus e idence o conside he use o he NOACs as i s -line he apy – In o m poli icians, pa ien g oups and he media abou di e ences in access o AF s oke p e en ion ea men wi hin egions o coun ies Lobby pa liamen a y and heal hca e bodies o equali y o access o guideline- ecommended he apies globally o ac oss egions Pu s p essu e on policy make s o p o ide equali y o ca e o s oke p e en ion in pa ien s wi h AF wi h ega ds o medica ion AF,a ial ib illa ion; CHA 2 DS 2 -VASc, Conges i e hea ailu e/le en icula dys unc ion, Hype ension, Age ≥75 yea s (doubled), Diabe es, S oke (doubled), Vascula disease, Age 65–74 yea s, Sex ca ego y ( emale); NOAC, non- i amin K an agonis o al an icoagulan ; SMS, sho message se ice; ESC, Eu opean Socie y o Ca diology. A.J. Camm e al.1014 Downloaded om h ps://academic.oup.com/eu opace/a icle-abs ac /17/7/1007/2398779 by Faculdade de Medicina de Lisboa use on 13 No embe 2018 Limi a ions o hese ecommenda ions I should be no ed ha , al hough he majo i y o he e idence ci ed in his documen comes om published clinical s udies o eal-wo ld in es iga ions, some o he coun y-speci ic in o ma ion, and he ba - ie s iden i ied as a esul , a e based on pe sonal e idence p o ided by w i ing commi ee membe s. The ecommenda ions p o ided e- p esen he opinion o he g oup, and would equi e p ac ical imple- men a ion o es hei obus ness and applicabili y o di e en heal hca escena ios. As no ed abo e, he lacko ce ain s anda dized s uc u es may p e en some ecommenda ions om being imple- men ed in p ac ice a his ime. Conclusions A ial ib illa ion- ela ed s oke is po en ially p e en able and, h ough be e implemen a ion o he 2012 ESC guidelines, i s impac on pa ien s, hei amilies, and ca e s, and heal hca e sys ems can be educed. Howe e , his canno be achie ed wi hou inc eased de ec ion o pa ien s wi h AF and he inc eased use o an icoagula ion in hose assessed o be a mode a e o high s oke isk, using ei he well-con olled wa a in o , p e e ably, NOACs. P o iding pa ien s wi h a choice o he apy and allowing physicians o p esc ibe he mos app op ia e an icoagulan o hei pa ien s will only be possible i he e is access o all guideline- ecommended he apies. In ou lining p ac ical measu es ha physicians and medical heal h socie ies wo king in his ieldcan ins iga e o imp o e guideline implemen a ion, we belie e ha subs an ial bene i s, in e ms o imp o ed pa ien ou comes and educed heal hca e bu den, can be achie ed. Acknowledgemen s The au ho s would like o acknowledge Sa ah A kinson, who p o- ided edi o ial suppo o his manusc ip . Funding This wo k was suppo ed by edi o ial suppo unded by Baye Heal h- Ca e Pha maceu icals and Janssen Scien i ic A ai s, LLC. The sponso s p o ided sugges ions and commen s, bu he con en o his documen ep esen s he wo k o he au ho s. Con lic o in e es : A.J.C.: Speake /consul ing ees om Sano i, Baye , Daiichi Sankyo, Boeh inge Ingelheim, P ize , and B is ol-Mye s Squibb. F.J.P.: Speake /consul ing ees om As aZeneca, Baye , and Boeh inge Ingelheim. G.J.H.: Speake ees om Baye . F.A.: Speake /consul ing ees om Amgen, Baye , B is ol-Mye s Squibb/P ize , Boeh inge Ingel- heim, Daiichi Sankyo, and Eli-Lilly. F.D.R.H.: Speake /consul ing ees om B is ol-Mye s Squibb/P ize , Baye , and Boeh inge Ingelheim; g an s/sponso ship om Baye and Daiichi Sankyo. La ´szlo ´Csiba: Speake /consul ing ees om Baye , Boeh inge Ingelheim, MSD, sano i-a en is, and Egis. 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Apix- aban compa ed wi h wa a in in pa ien s wi h a ial ib illa ion and p e ious s oke o Non-VKA o al an icoagulan s: ba ie s and s a egies 1015 Downloaded om h ps://academic.oup.com/eu opace/a icle-abs ac /17/7/1007/2398779 by Faculdade de Medicina de Lisboa use on 13 No embe 2018