Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a Novel Risk Factor-Based Approach

Transcription

1 CHEST Originl Reserch Refining Clinicl Risk Strtifiction for Predicting Stroke nd Thromboembolism in Atril Fibrilltion Using Novel Risk Fctor-Bsed Approch The Euro Hert Survey on Atril Fibrilltion THROMBOEMBOLISM Gregory Y. H. Lip, MD ; Robby Nieuwlt, PhD ; Ron Pisters, MD ; Deirdre A. Lne, PhD ; nd Hrry J. G. M. Crijns, MD Bckground: Contemporry clinicl risk strtifiction schemt for predicting stroke nd thromboembolism (TE) in ptients with tril fibrilltion (AF) re lrgely derived from risk fctors identified from tril cohorts. Thus, mny potentil risk fctors hve not been included. Methods: We refined the 2006 Birminghm/Ntionl Institute for Helth nd Clinicl Excellence (NICE) stroke risk strtifiction schem into risk fctor-bsed pproch by reclssifying nd/or incorporting dditionl new risk fctors where relevnt. This schem ws then compred with existing stroke risk strtifiction schem in rel-world cohort of ptients with AF (n 5 1,084) from the Euro Hert Survey for AF. Results: Risk ctegoriztion differed widely between the different schemes compred. Ptients clssified s high risk rnged from 10.2% with the Frminghm schem to 75.7% with the Birminghm 2009 schem. The clssic CHA (Congestive hert filure, Hypertension, Age. 75, Dibetes, prior Stroke/trnsient ischemic ttck) schem ctegorized the lrgest proportion (61.9%) into the intermedite-risk strt, wheres the Birminghm 2009 schem clssified 15.1% into this ctegory. The Birminghm 2009 schem clssified only 9.2% s low risk, wheres the Frminghm scheme ctegorized 48.3% s low risk. Clculted C-sttistics suggested modest predictive vlue of ll schem for TE. The Birminghm 2009 schem fred mrginlly better (C-sttistic, 0.606) thn CHA. However, those clssified s low risk by the Birminghm 2009 nd NICE schem were truly low risk with no TE events recorded, wheres TE events occurred in 1.4% of low-risk CHA subjects. When expressed s scoring system, the Birminghm 2009 schem (CHA 2 -VASc cronym) showed n increse in TE rte with incresing scores ( P vlue for trend 5.003). Conclusion: Our novel, simple stroke risk strtifiction schem, bsed on risk fctor pproch, provides some improvement in predictive vlue for TE over the CHA schem, with low event rtes in low-risk subjects nd the clssifiction of only smll proportion of subjects into the intermedite-risk ctegory. This schem could improve our pproch to stroke risk strtifiction in ptients with AF. CHEST 2010; 137(2): Abbrevitions: ACC/AHA/ESC 5 Americn College of Crdiology/Americn Hert Assocition/ Europen Society of Crdiology; ACCP 5 Americn College of Chest Physicins; AF 5 tril fibrilltion; BAFTA 5 Birminghm Atril Fibrilltion Tretment of the Aged; CHADS 5 Congestive hert filure, Hypertension, Age. 75, Dibetes, prior Stroke/TIA; NICE 5 Ntionl Institute for Helth nd Clinicl Excellence; OR 5 odds rtio; ROC 5 receiver-operting chrcteristic; SPAF 5 Stroke Prevention in Atril Fibrilltion; TE 5 thromboembolism; TIA 5 trnsient ischemic ttck; VKA 5 vitmin K ntgonist Atril fibrilltion (AF) is the most common sustined crdic rhythm disorder, which is ssocited with substntil risk of mortlity nd morbidity from stroke nd thromboembolism (TE). A substntil evidence bse is in fvor of nticogultion with the vitmin K ntgonists (VKAs, eg, wrfrin), which reduce this risk by two-thirds, wheres ntipltelet therpy decreses stroke risk only by 22%. 1 VKAs re CHEST / 137 / 2 / FEBRUARY,

2 clerly superior to spirin for stroke prevention, even in ptients with AF ged 75 yers. For exmple, in the Birminghm Atril Fibrilltion Tretment of the Aged (BAFTA) Study, the use of VKA (INR 2-3) reduced the primry end point of TE by 52% compred with spirin 75 mg dily, with no difference in mjor bleeding events between VKA or spirin. 2 Even in lowrisk subjects with AF, spirin my be no better thn control for reducing TE events, with tendency to more dverse effects (especilly bleeding) with spirin. 3 The risk of stroke nd TE in AF is not homogeneous, nd vrious clinicl nd echocrdiogrphic fetures hve been identified to help strtify risk into high-, intermedite-, or low-risk ctegories. 1 However, contemporry clinicl risk strtifiction schem for predicting stroke, trnsient ischemic ttck (TIA), or TE for ptients with AF re lrgely derived from risk fctors identified from non-vka rms of tril cohorts, nd one cohort study (Frminghm). Thus, mny potentil risk fctors hve not been dequtely ssessed, s not ll potentil risk fctors hve been systemticlly documented in the clinicl tril popultions. The Stroke in AF Working Group 4 performed systemtic review of these stroke risk fctors nd concluded tht only four clinicl fetures (prior stroke/tia, dvncing ge, hypertension, nd dibetes) were consistent independent risk fctors. Also, existing stroke risk strtifiction schem hve widely vrying proportions ctegorized into high-, intermedite-, nd low-risk strt, nd re generlly of modest predictive vlue in predicting stroke nd TE (C-sttistics of pproximtely 0.6). 5 Agin, some of the vlidtion studies compring the performnce of different schem re limited by hving been performed in nticogulted tril cohorts, 6 retrospective nlyses of nticogulted AF registries, 7 nd in some, non-vka rms of tril cohorts whereby ntipltelet therpy nd/or subtherpeutic VKA (eg, INR, 1.5) were used. 8 Mnuscript received July 4, 2009; revision ccepted July 31, Affilitions: From the University of Birminghm Centre for Crdiovsculr Sciences (Drs Lip nd Lne), City Hospitl, Birminghm, UK; nd the Deprtment of Crdiology (Drs Nieuwlt, Pisters, nd Crijns), Mstricht University Medicl Centre, The Netherlnds. Funding/Support: The Euro Hert Survey is funded by industry sponsors AstrZenec, Snofi-Aventis, nd Eucomed, nd by the Austrin Hert Foundtion, Austrin Society of Crdiology, French Federtion of Crdiology, Hellenic Crdiologicl Society, Netherlnds Hert Foundtion, Portuguese Society of Crdiology, Spnish Crdic Society, Swedish Hert nd Lung Foundtion nd individul centers. Correspondence to: Professor G.Y.H. Lip, MD, University of Birminghm Centre for Crdiovsculr Sciences, City Hospitl, Birminghm B18 7QH, UK; e-mil: g.y.h.lip@bhm.c.uk. Reproduction of this rticle is prohibited without written permission from the Americn College of Chest Physicins ( site/misc/reprints.xhtml ). DOI: /chest Other dt on rel life AF popultions were provided in the ATRIA study, 9 but this study did not compre some contemporry risk strtifiction schem s used in current guidelines Nonetheless, there re incresing dt tht other risk fctors should be considered in refining stroke nd TE risk strtifiction for AF. For exmple, femle gender incresed TE risk in the Euro Hert Survey nd other cohorts Also, vsculr diseses, including myocrdil infrction, peripherl rtery disese, nd complex ortic plque, ll increse TE risk in AF Furthermore, stroke risk in AF increses t ge. 65 yers onwrds, nd ge s risk fctor is not yes/no phenomenon. Indeed, the BAFTA tril showed tht VKA ws clerly superior thromboprophylxis to spirin in elderly (ged 75 yers) subjects with AF in primry cre setting, which shows tht the frequently reported fer of bleeding s n excuse for not prescribing wrfrin to elderly ptients is not justified. 1,2 In 2006, the Birminghm stroke risk strtifiction schem ws compred ginst the CHA (Congestive hert filure, Hypertension, Age. 75, Dibetes, prior Stroke/trnsient ischemic ttck) schem in cohort of 994 ptients with AF, nd it ws found tht the ccurcy of both clinicl risk strtifiction schemes ws similr for predicting ischemic strokes nd vsculr events. 8 The Birminghm schem ws subsequently refined for the evidence-bsed UK Ntionl Institute for Helth nd Clinicl Excellence (NICE) guidelines on AF mngement, which formulted n lgorithm-bsed pproch to stroke risk strtifiction. 12 Since 2006, it is pprent tht stroke risk strtifiction needs to be simple, yet consider new dt on other risk fctors (femle gender, ge, vsculr disese, nd so forth) tht hve emerged, nd recognize tht n rtificil ctegoriztion into high-, intermedite-, nd low-risk ctegories per se my be less helpful. Current tretment guidelines recommend VKA for high-risk subjects nd (usully) spirin for lowrisk subjects, but for intermedite risk, mny guidelines stte either wrfrin or spirin cn be used The ltter cn sometimes cuse uncertinty for clinicins mnging such ptients, especilly if lrge proportion of prticulr cohort of ptients with AF re clssified into this intermedite-risk ctegory. This either wrfrin or spirin recommendtion is lso sometimes used s n excuse not to prescribe wrfrin in intermedite-risk ptients. Also, clinicins need ressurnce tht those clssified s low risk re truly low risk, with no TE events in such ptients. The objective of this nlysis is to refine the 2006 Birminghm/NICE stroke risk strtifiction schem into risk fctor-bsed pproch, by reclssifying nd/or incorporting dditionl new risk fctors s relevnt. This novel schem (Birminghm 2009) ws 264 Originl Reserch

3 then compred with existing schem in rel world AF ptient cohort in the Euro Hert Survey for AF, where longitudinl dt on outcomes hve previously been published. 21 Vlidtion Cohort Methods To test the predictive bility of the refined Birminghm schem, nd to compre this with the performnce of other schem, we used the Euro Hert Survey on AF popultion. Survey methods, center prticiption, ptient chrcteristics, mngement nd definitions of the bseline nd follow-up survey of the Euro Hert Survey on AF hve previously been described. 21,22 In summry, 5,333 mbulnt nd hospitlized ptients with AF were enrolled from the crdiology prctices of 182 hospitls mong 35 countries in 2003 to Ptients were enrolled if they were 18 yers old nd if they hd n ECG or Holter recording showing AF during the qulifying dmission/consulttion or in the preceding 12 months. A follow-up ws performed to ssess mortlity nd incidence of mjor dverse events during 1 yer. For the current nlysis we selected 1,577 ptients without mitrl stenosis or previous hert vlve surgery nd who did not use either VKA or heprin t dischrge of the qulifying visit. We hd survivl sttus during 1 yer for 1,150 (73%) of these ptients nd the TE sttus for 1,084 (69%). Compred with ptients with known survivl sttus t follow-up, ptients with unknown survivl sttus were t bseline of similr ge ( vs yers; P 5.624), were s often femle (45% vs 40%; P 5.103), nd eqully s often hd dibetes (15% vs 17%; P 5.244) or prior stroke/tia (9% vs 8%; P 5.359), wheres they more often hd hert filure (41% vs 24%; P,.001) nd less often vsculr disese (35% vs 42%; P 5.015) nd hypertension (62% vs 67%; P 5.032). Ptients with known survivl sttus t follow-up but unknown TE sttus were more often decesed compred with ptients who hd both survivl nd TE sttus known (24% vs 4%; P,.001). Description of Stroke Risk Strtifiction Schem The vrious stroke risk schem compred nd/or vlidted in this rel world Europen cohort re summrized in Tble 1. In cse of multiple vilble schem, we chose to use the most recent one: for exmple, the Stroke Prevention in Atril Fibrilltion (SPAF) 1999 schem (rther thn the SPAF 1995 schem), 23 the second Americn College of Crdiology/Americn Hert Assocition/ Europen Society of Crdiology (ACC/AHA/ESC) guidelines (2006), 11 nd the eighth Americn College of Chest Physicins (ACCP) guidelines (2008). 10 We did use the AF Investigtors 1994 schem, 24 since the 1998 nlysis explored the dditionl vlue of echocrdiogrphy prmeters, but did not explicitly recommend new schem. The Frminghm nd CHA schem re point-bsed scores, with the Frminghm bsed on mthemticl eqution 25 nd the CHA bsed on one point for CHAD nd two points for stroke/tia. 26 In order to compre their predictive bility with other schem for distinguishing low, intermedite, nd high risk, we ctegorized the scores into three groups. We defined the CHA score in two wys: (1) clssic, whereby scores of 0 5 low, 1 to 2 5 intermedite,. 2 5 high risk; or (2) revised, whereby scores of 0 5 low, 1 5 intermedite, 2 5 high risk. We ctegorized the Frminghm score in similr mnner to tht proposed by Fng et l, 9 s follows: score 0 to 7 5 low, 8 to 15 5 intermedite, 16 to 31 5 high risk. In ddition to these ctegorized definitions (commonly used in clinicl prctice), the Frminghm nd CHA scores were lso tested s continuous vribles. We refined the 2006 Birminghm (or NICE) TE risk schem into risk fctor-bsed pproch, by defining definitive risk fctors (previous stroke/tia/te nd ge 75 yers) nd combintion risk fctors (hert filure/moderte-severe crdic dysfunction, hypertension, dibetes, vsculr disese, femle gender, nd ge yers). If we wished to rtificilly ctegorize these subjects, high risk ws defined s one definitive or two or more combintion risk fctors, intermedite risk ws essentilly defined s one combintion risk fctor, nd low risk ws defined s no risk fctors being present. This refined (2009) Birminghm schem ws lso tested with point-bsed scoring system, the CHA 2 -VASc score (see Tble 2 for definition), whereby scores of 0 5 low, 1 5 intermedite, nd 2 5 high risk. Definitions of End Points nd Risk Fctors Ischemic stroke ws defined s focl neurologic deficit of sudden onset s dignosed by neurologist, lsting. 24 h nd cused by ischemi. TIA ws defined s focl neurologic deficit of sudden onset s dignosed by neurologist, lsting, 24 h. Peripherl embolism ws defined s TE outside the brin, hert, eyes, nd lungs. Pulmonry embolism ws defined by the responsible physicin. TE s outcome vrible of the vlidtion nlysis ws defined s either n ischemic stroke, peripherl embolism, or pulmonry embolism. Definitions of risk fctors, such s dibetes, hypertension, hert filure, peripherl rtery disese, nd so forth, re provided in the online supplement. Sttisticl Anlysis We used descriptive nlyses with proportions nd mens ( 6 SD) to describe the vlidtion cohort, ctegoriztion of the three risk groups per schem, nd the event rtes per risk group. We clculted the 95% CI of event rtes using the binomil pproximtion. We performed logistic regression with ech schem, contining three risk groups, s independent vrible nd TE during 1 yer s dependent vrible. The probbility tht this model predicted the correct clssifiction of ech ptient (TE or not) ws sved. Following this we plotted this probbility in receiveroperting chrcteristic (ROC) curve ginst TE s dependent vrible. The re under the curve for this ROC curve represents the bility of schem to correctly clssify risk for TE, which is lso referred to s the C-sttistic (Hrrell s C). As subsidiry nlysis, we lso rn the sme nlyses on 843 ptients within this group who were not on nticogultion t both bseline nd 1-yer follow-up. To ssess the effect of individul risk fctors on the occurrence of TE in this cohort, we performed multivrible logistic regression with the following independent vribles: ge, gender, dibetes, coronry rtery disese, hert filure, hypertension, prior stroke/tia, prior other thromboembolism, nd peripherl vsculr disese. To ssess whether the effect of systolic blood pressure t bseline ws different thn tht of hypertension, we performed the sme nlysis while replcing systolic blood pressure for hypertension nd we report these results in the text only. Further, since recent echocrdiogrphy ws not vilble for 400 (37%) ptients, we repeted the initil nlysis with the ddition of left ventriculr ejection frction to ssess its effect nd whether other effects were chnged by this ddition. Vribles were removed stepwise from the model when the P vlue exceeded.10. Vribles with P vlue, 0.05 in the finl model were considered to be significnt contributors to TE prediction nd we report the net odds rtio (OR), 95% CI, nd P vlue for these vribles. Vribles in the finl model were tested for interction(s), if ny. CHEST / 137 / 2 / FEBRUARY,

4 Tble 1 Risk Strtifiction Schemes Used To Predict Thromboembolism in Atril Fibrilltion Risk Scheme Low Risk Intermedite Risk High Risk AFI Investigtors (1994) 24 Age, 65 y nd no risk Age. 65 y nd no other risk Prior stroke/tia, hypertension, dibetes fctors fctors SPAF investigtors 23 No risk fctors Hypertension, dibetes Prior stroke/tia, women. 75 y, men. 75 y with hypertension CHA (2001) clssic26 Score 0 Score 1-2 Score 3-6 CHA revised Score 0 Score 1 Score 2-6 Frminghm (2003) 25 Score 0-7 Score 8-15 Score NICE guidelines (2006) 12 Age, 65 y with no moderte/high-risk fctors Age 65 y with no high-risk fctors Previous stroke/tia or thromboembolic event ACC/AHA/ESC guidelines (2006) 11 Eighth ACCP guidelines (2008) 10 No risk fctors No risk fctors Age, 75 y with hypertension, dibetes, or vsculr disese Age 75 y, or hypertension, or hert filure, or LVEF 35%, or dibetes Age. 75 y, or hypertension, or modertely or severely impired LVEF nd/or hert filure, or dibetes Birminghm (2009) No risk fctors One combintion risk fctor: hert filure/lvef 40, hypertension, dibetes, vsculr disese, femle gender, ge Age 75 y with hypertension, dibetes, or vsculr disese Clinicl evidence of vlve disese or hert filure, or impired left ventriculr function Previous stroke, TIA or embolism, or 2 moderte risk fctors: ge 75 y, hypertension, hert filure, LVEF 35%, dibetes Previous stroke, TIA or embolism, or 2 moderte risk fctors: ge 75 y, hypertension, modertely or severely impired LVEF nd/or hert filure, dibetes Previous stroke, TIA or embolism, or ge 75 y, or 2 combintion risk fctors: hert filure/lvef 40, hypertension, dibetes, vsculr disese, femle gender, ge ACC 5 Americn College of Crdiology; ACCP 5 Americn College of Chest Physicins; AFI 5 Atril Fibrilltion Investigtors; AHA 5 Americn Hert Assocition; CHA 5 Congestive hert filure, Hypertension, Age. 75, Dibetes, prior Stroke/TIA; ESC 5 Europen Society of Crdiology; LVEF 5 left ventriculr ejection frction; NICE 5 Ntionl Institute for Helth nd Clinicl Excellence; SPAF 5 Stroke Prevention in Atril Fibrilltion; TIA 5 trnsient ischemic ttck. Myocrdil infrction, peripherl rtery disese, or ortic plque. Results The 1,084 ptients with nonvlvulr AF, who were not on nticogultion t bseline nd for whom we knew TE sttus t 1 yer, were on verge 66 yers old nd 40.8% were women ( Tble 3 ). Hypertension ws the most prevlent stroke risk fctor (67.3%), followed by coronry rtery disese (38.4%). Antipltelet drugs were tken by 74.0%. In univrite nlyses, Tble 2 The 2009 Birminghm Schem Expressed s Point-Bsed Scoring System, With the Acronym CHA 2 -VASc Risk Fctor Score C ongestive hert filure/lv dysfunction 1 H ypertension 1 A ge 75 y 2 D ibetes mellitus 1 S troke/tia/te 2 V sculr disese (prior myocrdil infrction, peripherl rtery 1 disese, or ortic plque) A ge y 1 S ex c tegory (ie femle gender) 1 LV 5 left ventriculr; TE 5 thromboembolism. See Tble 1 for expnsion of other bbrevitions. femle gender, history of vsculr disese, prior stroke/tia, nd dibetes were ssocited with n incresed incidence of TE (ll P,.05; Tble 4 ). When ssessing the independent effect of ll potentil risk fctors on TE occurrence in multivrite nlysis, femle gender (OR [ ]; P 5.029) ws the only significnt ssocited fctor, wheres the effect of vsculr disese ws ner significnt (OR [ ]; P 5.064) ( Tble 4 ). Tking into ccount systolic blood pressure t bseline, rther thn the dignosis of hypertension, showed tht lso systolic blood pressure ws not significntly ssocited with TE occurrence (OR [ ] per mm Hg increse; P 5.319). The proportions of ptients ctegorized s high, intermedite or low risk re shown in Tble 5. Risk ctegoriztion differed widely between the different schemes. Ptients clssified s high risk rnged from 10.2% with the Frminghm schem to 75.7% with the Birminghm 2009 schem. The clssic CHA ctegorized the lrgest proportion (61.9%) of subjects into the intermedite-risk strt, wheres the AF Investigtors nd Birminghm 2009 schem clssified 12.2% nd 15.1%, respectively, into this ctegory. 266 Originl Reserch

5 Tble 3 Clinicl Chrcteristics of 1,084 Nonvlvulr Atril Fibrilltion Ptients Not Receiving Orl Anticogultion nd Heprin t Dischrge of the Bseline Euro Hert Survey nd With Known Thromboembolic Follow-up Sttus During 1 Yer Clinicl Chrcteristic No. (%) or Men 6 SD Age, y Age 75 y 309 (28.5) Women 442 (40.8) Pst medicl history Stroke 45 (4.2) TIA 46 (4.3) Other systemic embolism 6 (0.6) CAD 412 (38.4) Peripherl vsculr disese 62 (5.8) Hypertension 729 (67.3) Dibetes 187 (17.3) Hert filure 253 (23.5) Systolic blood pressure, mm Hg LVEF, % Drugs ACEI 480 (44.3) ARB 139 (12.8) ACEI/ARB 607 (56.0) Sttins 252 (23.2) Antipltelet drugs 802 (74.0) ACEI 5 ACE inhibitor; ARB 5 ngiotensin II receptor blocker; CAD 5 coronry rtery disese. See Tble 1 for expnsion of other bbrevitions. The Birminghm 2009 schem clssified only 9.2% s low risk, wheres the Frminghm scheme ctegorized 48.3% s low risk. The C-sttistics ll suggested modest predictive vlue of ll schem for TE, with C-sttistics rnging from (SPAF) to (Frminghm), whereby the Frminghm schem ws the only one to predict TE better thn chnce in this cohort. If Frminghm nd CHA scores were tested s continuous vribles slightly improved C-sttistic ws obtined compred with their respective ctegorized scores. The Birminghm 2009 schem fred mrginlly better (C-sttistic, 0.606) thn CHA, whether clssic (0.561) or revised (0.586), or s continuous vrible (0.602) ( Tble 5 ). Those clssified s low risk by Birminghm 2009 nd the NICE schem were truly low risk, with no TE events recorded, wheres TE events occurred in 1.4% of low-risk CHA subjects nd 1.8% of SPAF low-risk subjects. Also, where most intermedite-risk groups hd n event rte round 3%, the intermediterisk group using the Birminghm 2009 schem hd only 1 event (0.6%). When expressed s scoring system ( Tble 6 ), the Birminghm 2009 schem (with the CHA 2 -VASc cronym) showed n increse in TE rte with incresing scores ( P vlue for trend 5.003); those with score of 0 (ie, low risk) hd no TE events, wheres score of 1 (ie, intermedite risk) hd TE events in 0.6% A secondry nlysis of cohort of subjects who were not treted with nticogultion t bseline nd t follow-up re presented in the online supplement, nd ccepting the cvet of lower study numbers, this does not substntilly chnge our observtions. Discussion In this rticle, we hve provided vlidtion for novel risk fctor-bsed pproch to stroke risk strtifiction (Birminghm 2009), in comprison with other published schem, in rel world Europen cohort. This Birminghm 2009 schem considers ptients with prior stroke/tia or ptients 75 yers s high risk nd s cndidtes for wrfrin. Furthermore, combintion of t lest two risk fctors from hypertension, hert filure, dibetes, ge 65 to 75, femle gender, nd vsculr disese re lso considered to be high risk; we provide strong evidence from the Euro Hert Survey for the ddition of the ltter two risk fctors. To id risk scoring, we lso provide risk score for the Birminghm 2009 schem, using the CHA 2 -VASc cronym, with cler increse in stroke risk with n incresing score, wheres those with score of 0 to 1 (tht is, low to moderte risk) hd low event rtes. We lso confirm the results of recent comprisons 5-9,14 showing modest predictive Tble 4 Univrite nd Multivrite Predictive Power of Risk Fctors for Thromboembolic Events Event Rte With Risk Fctor Event Rte Without Risk Fctor Univrite P Vlue OR Multivrite P Vlue Age (3.6) 14 (1.8) ( ).383 Femle 16 (3.6) 9 (1.4) ( ).029 Stroke/TIA/TE 5 (5.9) 20 (2.0) ( ).163 Hypertension 19 (2.6) 6 (1.7) ( ).992 Dibetes 8 (4.3) 17 (1.9) ( ).220 Hert filure 6 (2.4) 19 (2.3) ( ).493 LVEF, 40 1 (0.8) 12 (2.1) ( ).243 Vsculr disese b 16 (3.6) 9 (1.5) ( ).063 OR 5 odds rtio. See Tbles 1 nd 2 for expnsion of other bbrevitions. All results other thn LVEF from model without LVEF. b Coronry rtery disese, peripherl vsculr disese, or previous thromboembolism other thn stroke/tia. CHEST / 137 / 2 / FEBRUARY,

6 Tble 5 Risk Ctegoriztion, Incidence of TE, nd Predictive Ability for Contemporry Risk Strtifiction Schem Among Euro Hert Survey Ptients Who Did not Receive Anticogultion t Bseline Ctegoriztion of TE Risk Predictive Ability Low Intermedite High C Sttistic (95% CI) P Vlue AFI % in risk ctegory TE events, No. (%) 1 (0.6) 4 (3.0) 20 (2.6) ( ) SPAF % in risk ctegory TE events, No. (%) 5 (1.8) 11 (2.3) 9 (2.9) ( ) CHA clssic.296 % in risk ctegory b TE events, No. (%) 3 (1.4) 16 (2.4) 6 (3.2) ( ) CHA revised.140 % in risk ctegory b TE events, No. (%) 3 (1.4) 7 (1.9) 15 (3.1) ( ) Frminghm.018 % in risk ctegory b TE events, No. (%) 6 (1.2) 14 (3.2) 5 (4.6) ( ) NICE % in risk ctegory TE events, No. (%) 0 (0.0) 13 (3.1) 12 (2.3) ( ) ACC/AHA/ESC % in risk ctegory TE events, No. (%) 3 (1.4) 7 (2.0) 15 (2.9) ( ) ACCP % in risk ctegory TE events, No. (%) 3 (1.4) 7 (1.9) 15 (3.0) ( ) Birminghm % in risk ctegory TE events, No. (%) 0 (0.0) 1 (0.6) 24 (3.0) ( ) See Tbles 1 nd 2 for expnsion of bbrevitions. Ischemic stroke, pulmonry embolism, or peripherl embolism. b The C sttistics for the Frminghm nd CHA scores, if tested s continuous vribles, re s follows: Frminghm: ( ); P 5.001; nd CHA : ( ); P vlue of older published stroke risk strtifiction schem for stroke nd TE in ptients with AF, but extend this work by showing the modest performnce of the most recent ACC/AHA/ESC, ACCP, nd NICE schemt. There is some justifiction for the ddition of femle gender, vsculr disese, nd ge 65 to 74 yers into the combintion risk fctor ctegory. The impct of femle gender on stroke nd TE risk hs recently been reviewed by us. 15 Compred with men, women Tble 6 Stroke or Other TE t 1 Yer Bsed on the 2009 Birminghm (CHA 2 -VASc) Scoring System CHA 2 -VASc Score No. Number of TE Events TE Rte During 1 y (95% CI) TE Rte During 1 y, Adjusted for Aspirin Prescription, % % (0-0) % ( ) % ( ) % ( ) % ( ) % ( ) % ( ) % ( ) % ( ) % ( ) 100 Totl 1, P Vlue for trend See Tbles 1 nd 2 for expnsion of bbrevitions. Theoreticl TE rtes without therpy: corrected for the % of ptients receiving spirin within ech group, ssuming tht spirin provides 22% reduction in TE risk, bsed on Hrt et l Originl Reserch

7 re more likely to suffer TE event or ischemic stroke when not tking wrfrin, but when they re prescribed wrfrin they hve comprble INR control, re not more likely to suffer mjor bleed, nd demonstrte greter TE risk reduction. 15 The impct of vsculr disese, prticulrly myocrdil infrction, on incresing TE risk in AF hs lso been systemticlly reviewed Furthermore, the presence of AF in ssocition with peripherl rtery disese is ssocited with substntil mortlity nd morbidity, nd the impct of therothrombotic disese is lso clerly illustrted by the presence of complex ortic plque on the descending ort being n independent predictor for stroke nd TE in AF. 17,20 Lst, stroke incidence increses with dvncing ge, nd in AF this is no exception. Given tht ge is not yes/no effect on stroke, nd tht nticogultion hs mrked benefit in elderly subjects 2 our proposl is tht ge 75 yers is definitive (high) risk fctor, nd ge 65 to 74 plus one dditionl combintion risk fctor lso merits nticogultion, thus improving thromboprophylxis for lrge bsolute numbers of AF ptients who would otherwise be t risk. Our proposl is supported by dt tht the reltive ischemic stroke risk re duction of ntipltelet drugs decreses with ging, wheres orl nticogultion mintins its preventive power.27 The Frminghm schem 25 hd the highest C-sttistic (0.638) but is bsed on complicted mthemticl formul nd hs not been incorported into current tretment guidelines. In ddition, it clssified most ptients of our cohort into low nd moderte risk ctegories. Thus, mny ptients could hve been denied VKA tretment on this bsis, exposing them to the risk of stroke nd TE. The AF Investigtors schem 24 is bsed on the originl (nd now, historicl) plcebo-controlled trils of wrfrin vs control, nd gin, represents historicl interest given tht mny schem (eg, Birminghm/NICE nd CHA ) hve since evolved from this schem. Similrly, the SPAF risk strtifiction schem is of historicl interest nd the CHA schem ws n mlgmtion of the AF Investigtors nd SPAF schem, but the SPAF schem ws the only one to hve previously included femle gender s risk fctor. 23 Since publiction of the Stroke in AF Working Group nlysis, 5 the eighth ACCP guidelines hve been published, 10 nd the current nlysis provides comprison of this ginst other schem. Becuse the eighth ACCP schem is brodly similr to the revised CHA schem (score 1 s intermedite risk group), it is unsurprising tht the performnce of this schem is comprble to CHA. The CHADS2 schem is widely used due to its simplicity nd ese. The CHA schem hs been vlidted in its clssic form, nd we re unwre of forml vlidtion or comprison ginst other published schem with its revised (0, 1,. 1) form. 9,26 As our nlysis (nd tht of others 5-9 ) hs shown, the clssic CHA version generted lrge intermedite risk group (. 60%) for whom it is uncler which tretment (wrfrin or spirin) to pply. The revised CHA provided some improvement, with low proportion clssified s intermedite risk, but with the ddition of vsculr disese, femle gender, or ge 65 to 74 yers to risk fctor-bsed schem (Birminghm 2009) there ws further refinement of TE risk strtifiction for AF with n improved C-sttistic. Current guidelines divide subjects into high-, intermedite-, nd low-risk strt, but one dvntge of risk fctor-bsed pproch s proposed in the current nlysis is the possibility to stte consider nticogultion if AF present with one or more TE risk fctors. Indeed, the presence of one definitive fctor merits orl nticogultion with (for exmple) n orl VKA (to trget INR 2-3). Ptients with two or more combintion risk fctors should ll be considered for orl nticogultion. Thus, those with one definitive fctor or two or more combintion risk fctors represent the old-style high-risk ctegory. The smll group of ptients with one combintion risk fctor (15% of this cohort) would represent the old-style intermediterisk ctegory nd should be mnged with ntithrombotic therpy, either s orl nticogultion therpy (eg, VKA, trget INR 2-3) or s spirin 75 to 325 mg dily, lthough the recent ACCP guidelines suggest considering VKA rther thn spirin if possible. 10 In Figure 1, we propose clinicl flowchrt, bsed on the Birminghm 2009 schem. Our refined schem cn thus be presented in three wys: (1) in nrrtive mnner (high risk is one definitive risk fctor, or two or more combintion risk fctors), (2) scoring system (CHA 2 -VASc score 2 is high risk), or (3) s lgorithm-bsed flow digrm. Where possible, ptients t intermedite risk should be considered for orl nticogultion rther thn spirin, since undertretment is more hrmful thn overtretment.28,29 Full discussion with the ptient with one combintion risk fctor would enble greement to use orl nticogultion insted of spirin to llow greter protection ginst ischemic stroke, especilly if these ptients vlue stroke prevention much more thn the (theoreticl) lower risk of hemorrhge with spirin nd the inconvenience of nticogultion monitoring. 10 As mentioned, the BAFTA tril found no difference in mjor bleeding between wrfrin (INR 2-3) nd spirin 75 mg in n elderly AF popultion in primry cre, 2 nd spirin cnnot be regrded s much sfer lterntive to VKA. Ptients with no risk fctors re t low risk (essentilly ptients ged, 65 yers with lone AF, with CHEST / 137 / 2 / FEBRUARY,

8 Figure 1. Proposed clinicl flowchrt for the use of orl nticogultion for stroke prevention in tril fibrilltion. none of the risk fctors, whether high, moderte, or less vlidted), s confirmed by the bsence of TE events in this group in our nlysis, nd cn be mnged with spirin 75 to 325 mg dily or no ntithrombotic therpy, given the limited dt on the benefits of spirin in this ptient group (tht is, lone AF) nd the potentil for dverse effects. 3 Indeed, the 22% reduction in stroke risk with ntipltelet therpy in the ltest metnlysis is lrgely driven by the SPAF-I clinicl tril, in which internl inconsistencies in TE events with the spirin vs control rms re pprent. 30 Also, it is likely tht the mgnitude of spirin effect is relted to the stroke prevention seen by giving ntipltelet therpy in ptients with vsculr disese. 1,27,31 It is notble tht if trils with spirin lone (nd not other ntipltelet drugs) re considered in the recent metnlysis by Hrt et l, 28 the 95% confidence intervls of the spirin effect lso include zero. Interestingly, more recent trils in vsculr disese hve not shown ny significnt benefit for spirin in the primry prevention of vsculr disese. 32,33 Hesitnce to prescribe VKA to ptients t high or intermedite risk is substntilly relted to the need for monitoring VKA nd the mny interctions of food nd drugs with VKAs. These limittions cn cuse ptient to spend low proportion of time within the therpeutic trget INR rnge, which is ssocited with n increse TE risk. 34 Implementtion of methods shown to improve qulity of VKA mngement, such s n nticogultion clinic, nd the development of new orl nticogulnts tht cn be given s fixed dose with few food/drug interctions nd no requirement for monitoring, provide n opportunity for guidelines to dopt this risk fctor-bsed pproch to simply stte consider orl nticogultion if AF is present with one or more TE risk fctors (ie, CHA 2 -VASc score of 1 or more). The Birminghm 2009 schem lso llows identifiction of truly low-risk popultion, in whom no TE events were recorded in the low-risk subjects clssified s no risk fctors (ie, CHA 2 -VASc score 5 0) nd such ptients my not need ny ntithrombotic therpy. This nlysis is limited by its dependence upon survey dtbse, nd lthough we hve mde efforts to ensure ccurte coding nd vlidtion, ll possible sources of bis nd recording errors cnnot be excluded. An importnt limittion is the bsence of informtion on TE occurrence during 1 yer for 31% of ptients from the bseline survey. Also, we hve bsed our primry nlysis on 1,084 subjects who 270 Originl Reserch

9 were not nticogulted t bseline, but during the 1 yer of follow-up, smll proportion (18%) were strted on VKA, which could hve influenced TE end points. However, confining our nlysis to secondry cohort of subjects who were not treted with nticogultion t bseline or during follow-up does not chnge our conclusions. Also, these nlyses my hve included some ptients who were not strted on VKA becuse of comorbidities, poor complince (or inbility to hve dequte monitoring), nd/or intolernce of nticogultion, nd furthermore, the numbers of end points in this subset re much lower. We recognize our modest follow-up period (1 yer) in contemporry rel life clinicl prctice survey, but follow-up durtions in other nlyses re only mrginlly better. For exmple, the (older) CHA vlidtion exercise only hd n verge of 1.25 yers of follow-up. 26 In conclusion, our novel, simple stroke risk strtifiction schem, bsed on risk fctor pproch, provides some improvement in predictive vlue for TE over the CHA schem, with low event rtes in low risk subjects nd the clssifiction of only smll proportion of subjects into the intermedite risk ctegory. This schem could improve our pproch to stroke risk strtifiction in ptients with AF. Ongoing vlidtions of the Birminghm 2009 risk schem in other AF popultions from different rce/ethnic groups will confirm its true vlue. Acknowledgments Author contributions: Dr Lip: contributed to study design nd hypothesis, dt interprettion, nd drfting nd revisions of the mnuscript. Dr Nieuwlt: contributed to sttisticl nlyses, dt interprettion, nd drfting of the mnuscript. Dr Pisters: contributed to drfting nd revision of the mnuscript. Dr Lne: contributed to drfting nd revision of the mnuscript. Dr Crijns: contributed to drfting nd revision of the mnuscript. Finncil/nonfinncil disclosures: The uthors hve reported to CHEST the following conflicts of interest: Dr Lip hs served s consultnt for Byer, Astells, Merck, AstrZenec, Snofi, Aryx, nd Boehringher nd hs been on the spekers bureu for Byer, Boehringher, nd Snofi. Dr Pisters hs served on the Roche dvisory bord. Dr Lne hs received ssistnce to trvel to the Europen Society of Crdiology from AstrZenec. Drs Nieuwlt nd Crijns hve reported no potentil conflicts of interest exist with ny compnies/orgniztions whose products or services my be discussed in this rticle. Other contributions: We thnk the Euro Hert Survey tem, ntionl coordintors, investigtors, nd dt collection officers for performing the survey. References 1. Lip GY, Lim HS. Atril fibrilltion nd stroke prevention. Lncet Neurol ;6(11): Mnt J, Hobbs FD, Fletcher K, et l ; BAFTA investigtors ; Midlnd Reserch Prctices Network (MidReC). Wrfrin versus spirin for stroke prevention in n elderly community popultion with tril fibrilltion (the Birminghm Atril Fibrilltion Tretment of the Aged Study, BAFTA): rndomised controlled tril. Lncet ;370(9586): Sto H, Ishikw K, Kitbtke A, et l ; Jpn Atril Fibrilltion Stroke Tril Group. Low-dose spirin for prevention of stroke in low-risk ptients with tril fibrilltion: Jpn Atril Fibrilltion Stroke Tril. Stroke ;37 (2 ): Stroke Risk in Atril Fibrilltion Working Group. Independent predictors of stroke in ptients with tril fibrilltion: systemtic review. Neurology ;69 (6 ): Stroke Risk in Atril Fibrilltion Working Group. Comprison of 12 risk strtifiction schemes to predict stroke in ptients with nonvlvulr tril fibrilltion. Stroke ;39 (5 ): Bruch L, Gge BF, Horrow J, et l. Cn ptients t elevted risk of stroke treted with nticogulnts be further risk strtified? Stroke ;38(9): Poli D, Antonucci E, Grifoni E, Abbte R, Gensini GF, Prisco D. Stroke risk in tril fibrilltion ptients on wrfrin. Predictive bility of risk strtifiction schemes for primry nd secondry prevention. Thromb Hemost ;101 (2 ): Lip GY, Lne D, Vn Wlrven C, Hrt RG. Additive role of plsm von Willebrnd fctor levels to clinicl fctors for risk strtifiction of ptients with tril fibrilltion. Stroke ;37 (9 ): Fng MC, Go AS, Chng Y, Borowsky L, Pomerncki NK, Singer DE ; ATRIA Study Group. Comprison of risk strtifiction schemes to predict thromboembolism in people with nonvlvulr tril fibrilltion. J Am Coll Crdiol ; 51 (8 ): Singer DE, Albers GW, Dlen JE, et l ; Americn College of Chest Physicins. Antithrombotic therpy in tril fibrilltion: Americn College of Chest Physicins evidence-bsed clinicl prctice guidelines (8th edition). Chest ;133 (6 suppl ):546S-592S. 11. Fuster V, Rydén LE, Cnnom DS, et l ; Tsk Force on Prctice Guidelines, Americn College of Crdiology/Americn Hert Assocition ; Committee for Prctice Guidelines, Europen Society of Crdiology ; Europen Hert Rhythm Assocition ; Hert Rhythm Society. ACC/AHA/ESC 2006 guidelines for the mngement of ptients with tril fibrilltion-executive summry: report of the Americn College of Crdiology/ Americn Hert Assocition Tsk Force on Prctice Guidelines nd the Europen Society of Crdiology Committee for Prctice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Mngement of Ptients with Atril Fibrilltion). Eur Hert J ;27 (16 ): Ntionl Collborting Centre for Chronic Conditions. Atril Fibrilltion: Ntionl Clinicl Guideline for Mngement in Primry nd Secondry Cre. London : Royl College of Physicins ; Dgres N, Nieuwlt R, Vrds PE, et l. Gender-relted differences in presenttion, tretment, nd outcome of ptients with tril fibrilltion in Europe: report from the Euro Hert Survey on Atril Fibrilltion. J Am Coll Crdiol ;49 (5 ): Fng MC, Singer DE, Chng Y, et l. Gender differences in the risk of ischemic stroke nd peripherl embolism in tril fibrilltion: the AnTicogultion nd Risk fctors In Atril fibrilltion (ATRIA) study. Circultion ;112 (12 ): Lne DA, Lip GYH. Femle gender is risk fctor for stroke nd thromboembolism in tril fibrilltion ptients. Thromb Hemost. 2009;101(5): Schmitt J, Dury G, Gersh BJ, Hohnloser SH. Atril fibrilltion in cute myocrdil infrction: systemtic review of the incidence, clinicl fetures nd prognostic implictions. Eur Hert J ;30(9): Conwy DS, Lip GY. Comprison of outcomes of ptients with symptomtic peripherl rtery disese with nd without CHEST / 137 / 2 / FEBRUARY,

10 tril fibrilltion (the West Birminghm Atril Fibrilltion Project). Am J Crdiol ;93 (11 ): , A Siu CW, Jim MH, Ho HH, et l. Trnsient tril fibrilltion complicting cute inferior myocrdil infrction: implictions for future risk of ischemic stroke. Chest ;132 (1 ): Lip GYH. Coronry rtery disese nd ischemic stroke in tril fibrilltion. Chest ;132 (1 ): The Stroke Prevention in Atril Fibrilltion Investigtors Committee on Echocrdiogrphy. Trnsesophgel echocrdiogrphic correltes of thromboembolism in high-risk ptients with nonvlvulr tril fibrilltion. Ann Intern Med ;128 (8 ): Nieuwlt R, Prins MH, Le Heuzey JY, et l. Prognosis, disese progression, nd tretment of tril fibrilltion ptients during 1 yer: follow-up of the Euro Hert Survey on tril fibrilltion. Eur Hert J ;29 (9 ): Nieuwlt R, Cpucci A, Lip GY, et l; Euro Hert Survey Investigtors. Antithrombotic tretment in rel-life tril fibrilltion ptients: report from the Euro Hert Survey on Atril Fibrilltion. Eur Hert J. 2006;27(24): Hrt R, Perce L, McBride R, Rothbrt R, Asinger R. Fctors ssocited with ischemic stroke during spirin therpy in tril fibrilltion: nlysis of 2012 prticipnts in the SPAF I-III clinicl trils. Stroke ;30 (6 ): Atril Fibrilltion Investigtors. Risk fctors for stroke nd efficcy of ntithrombotic therpy in tril fibrilltion nlysis of pooled dt from five rndomised clinicl trils. Arch Intern Med ;154 (13): Wng TJ, Mssro JM, Levy D, et l. A risk score for predicting stroke or deth in individuls with new-onset tril fibrilltion in the community: the Frminghm Hert Study. JAMA ;290 (8 ): Gge BF, vn Wlrven C, Perce L, et l. Selecting ptients with tril fibrilltion for nticogultion: stroke risk strtifiction in ptients tking spirin. Circultion ;110 (16 ): vn Wlrven C, Hrt RG, Connolly S, et l. Effect of ge on stroke prevention therpy in ptients with tril fibrilltion. The Atril Fibrilltion Investigtors. Stroke ; 40 ( 4 ): Hrt RG, Perce LA, Aguilr MI. Met-nlysis: ntithrombotic therpy to prevent stroke in ptients who hve nonvlvulr tril fibrilltion. Ann Intern Med ;146 (12 ): Nieuwlt R, Olsson SB, Lip GY, et l ; Euro Hert Survey Investigtors ; The Euro Hert Survey on Atril Fibrilltion. Guideline-dherent ntithrombotic tretment is ssocited with improved outcomes compred with undertretment in high-risk ptients with tril fibrilltion. Am Hert J ; 153 (6 ): Stroke Prevention in Atril Fibrilltion investigtors. A differentil effect of spirin in prevention of stroke on tril fibrilltion. J Stroke Cerebrovsc Dis ;3 (X ): Antithrombotic Trilists Collbortion. Collbortive metnlysis of rndomised trils of ntipltelet therpy for prevention of deth, myocrdil infrction, nd stroke in high risk ptients. BMJ ;324 (7329 ): Belch J, McCuish A, Cmpbell I, et l ; Prevention of Progression of Arteril Disese nd Dibetes Study Group ; Dibetes Registry Group; Royl College of Physicins Edinburgh. The prevention of progression of rteril disese nd dibetes (POPADAD) tril: fctoril rndomised plcebo controlled tril of spirin nd ntioxidnts in ptients with dibetes nd symptomtic peripherl rteril disese. BMJ. 2008;337: Ogw H, Nkym M, Morimoto T, et l ; Jpnese Primry Prevention of Atherosclerosis With Aspirin for Dibetes (JPAD) Tril Investigtors. Low-dose spirin for primry prevention of therosclerotic events in ptients with type 2 dibetes: rndomized controlled tril. JAMA ;300 (18 ): Connolly SJ, Pogue J, Eikelboom J, et l ; ACTIVE W Investigtors. Benefit of orl nticogulnt over ntipltelet therpy in tril fibrilltion depends on the qulity of interntionl normlized rtio control chieved by centers nd countries s mesured by time in therpeutic rnge. Circultion ;118 (20 ): Originl Reserch