Ischemic stroke patients with atrial fibrillation are at high

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1 Should Stroke Subtype Ifluece Aticoagulatio Decisios to Prevet Recurrece i Stroke Patiets With Atrial Fibrillatio? Adrew Evas, MRCP; Iñigo Perez, MD; Gloria Yu, FRCP; Lalit Kalra, PhD, MRCP Dowloaded from by o September 17, 2018 Backgroud ad Purpose Log-term aticoagulatio is routiely used for secodary stroke prevetio i atrial fibrillatio, ofte regardless of stroke subtype. Although the role of warfari i cardioembolic stroke is established, it may ot prevet recurrece i other stroke subtypes, eve i the presece of atrial fibrillatio. Methods This was a 2-year, prospective, itervetio study coducted i a district geeral hospital. Participats icluded 386 acute stroke patiets with atrial fibrillatio. Subjects were characterized for stroke subtype o cliical, euroimagig, carotid ultrasoographic, ad echocardiographic criteria. Eligible patiets were treated with adjusteddose warfari (iteratioal ormalized ratio, 2.0 to 3.0). Aspiri (75 to 300 mg/d) was used i patiets with cotraidicatios or those who refused aticoagulatio. The mai outcome measures were rate of recurret stroke by subtype ad major ad mior bleedig complicatios. Results The aspiri group ( 172) was comparable to the warfari group ( 214) i terms of age, sex, risk factors, ad iitial stroke subtype. The rate of recurret stroke was higher (9.5% versus 4.9%, P 0.02) but that of major bleedig was lower (0.6% versus 2.5%, P 0.05) with aspiri. The icreased stroke rate with aspiri was due predomiatly to cardioembolic recurrece i patiets presetig iitially with cardioembolic stroke (8.4% versus 1.9%, P 0.01). The recurrece rate i aspiri-treated patiets who preseted with lacuar stroke ad atrial fibrillatio was similar to that see i patiets receivig warfari (8.8% versus 8.9%). Coclusios I this cohort of stroke patiets with atrial fibrillatio, aticoagulatio was superior to aspiri i prevetig cardioembolic but ot lacuar recurrece. Determiatio of stroke subtype may be importat i aticoagulatio decisios for secodary prevetio, ad further studies are required. (Stroke. 2001;32: ) Key Words: aticoagulats atiplatelet agets lacuar ifarctio stroke prevetio stroke, cardioembolic Ischemic stroke patiets with atrial fibrillatio are at high risk of stroke recurrece, which ca be dramatically reduced by log-term aticoagulatio soo after the presetig evet. 1,2 The use of adjusted-dose warfari for stroke patiets with atrial fibrillatio who do ot have sigificat bleedig risk has bee advocated i several professioal guidelies, 3 6 ad the beefit has bee demostrated i cliical practice. 7 However, ot all strokes i patiets with atrial fibrillatio are cardioembolic i origi, 7 9 ad some evidece suggests that warfari may ot prevet ocardioembolic strokes. 7,9,10 It has also bee show that aticoagulatio i patiets with small-vessel cerebrovascular disease carries a higher risk of itracraial hemorrhage. 11 Neither the defiitive study o the effectiveess of aticoagulatio 2 or subsequet recommedatios 3 6 o secodary prevetio of stroke i atrial fibrillatio discrimiate o the basis of stroke subtype, ad it is possible that some patiets who have oembolic strokes may be put at uecessary risk by log-term aticoagulatio. These risks could be sigificatly reduced ad implemetatio i cliical practice could be ehaced by targetig aticoagulatio to those derivig the greatest beefit 12 ad prescribig aspiri to other subtypes despite the presece of atrial fibrillatio. The objective of this prospective cohort study was to determie whether the subtype of the presetig stroke iflueced the effectiveess of log-term aticoagulatio i prevetig recurrece. Subjects ad Methods Patiets This study was udertake i ischemic stroke patiets admitted to a district geeral hospital over 4 years. Iclusio criteria were cliical ischemic stroke cofirmed by CT scaig ad atrial fibrillatio cofirmed o ECG. Patiets who were uwillig to participate or who had cotraidicatios to both aticoagulatio ad aspiri were excluded. Stroke Subtype Assigmet All patiets were assessed by use of stadardized history ad examiatio, CT scaig, extracraial carotid duplex ultrasoography, echocardiography, ad laboratory tests. Stroke subtypes were Received July 3, 2001; fial revisio received August 22, 2001; accepted August 24, From the Departmet of Medicie, Guy s, Kig s & St Thomas School of Medicie, Kig s College, Lodo, UK, ad Quee Mary s NHS Trust, Sidcup, Ket, UK (G.Y.). Correspodece to Dr Adrew Evas, Departmet of Medicie, Guy s, Kig s & St Thomas School of Medicie, Demark Hill Campus, Bessemer Rd, Lodo, UK SE5 8PJ. ady.evas@kcl.ac.uk 2001 America Heart Associatio, Ic. Stroke is available at

2 Evas et al Idex Stroke Type ad Aticoagulatio to Prevet Recurrece 2829 Dowloaded from by o September 17, 2018 based o the Trial of Org i Acute Stroke Treatmet (TOAST) 13 ad the Stroke Prevetio i Atrial Fibrillatio (SPAF) 9 subtype classificatio systems ad defied as follows. Lacuar was defied as a cliical lacuar sydrome 14 with either small, deep, oval white matter or basal gaglia ifarcts 1.5cm i diameter, perivetricular hypodesity, or o lesio o CT scaig. Cardioembolic was defied as a cortical sydrome ad/or ifarct 1.5 cm i diameter o CT sca i the presece of a abormal echocardiogram 3 ad i the absece of a 50% steosis of the relevat carotid artery. Strokes were classified as udetermied whe (1) cortical sydrome was preset with ifarct 1.5 cm i diameter ad 50% steosis of relevat carotid artery, (2) the CT was suggestive of lacuar ifarctio but without classic cliical lacuar sydrome, or (3) 1 cause was equally likely. Stroke subtype was categorized at 2 levels: by the admittig stroke team ad by a idepedet expert o the basis of masked cliical details ad ivestigatios. Patiets i whom it was ot possible or reach cosesus were placed i the udetermied group. Atithrombotic Assigmet Secodary prevetio was udertake i accordace with existig guidelies. 3 6 All patiets were cosidered for adjusted-dose warfari if they did ot have cotraidicatios to aticoagulatio. The cotraidicatios were coagulopathy or thrombocytopeia, gastroitestial bleedig i the 6 moths before stroke, previous cerebral hemorrhage, severe ucotrolled hypertesio, eed for regular osteroidal atiiflammatory drugs, excessive alcohol itake, demetia, recurret falls, severe depedet stroke (modified Raki score 3), 15 ad ucotrolled epilepsy. Patiets with poor drug or cliic compliace or who were uwillig to coset to log-term aticoagulatio were also excluded. Cotraidicatios to aspiri were defied as coagulopathy, thrombocytopeia, recet upper gastroitestial bleedig, active peptic ulceratio, or aspiri allergy. Itervetios Patiets who had o cotraidicatios to aticoagulatio were treated with adjusted-dose warfari with a target iteratioal ormalized ratio (INR) of 2.0 to 3.0. Patiets with mild to moderate eurological deficits ad CT lesios of 2.5 cm were aticoagulated withi 72 hours of stroke oset. Aticoagulatio was begu after 2 weeks i patiets with larger ifarcts. Warfari cotrol was performed by local aticoagulatio services after discharge from the ward. Patiets who had cotraidicatios to warfari but ot to atiplatelet agets were treated with aspiri 75 to 300 mg/d as soo as cerebral hemorrhage had bee excluded o CT scaig. Patiets who were iitially treated with warfari but discotiued for reasos of choice, compliace, or logistics but ot for study ed poits were treated with aspiri ad the followed up i the aspiri group. Follow-Up Patiets were followed up for 2 years after the relevat treatmet was begu. Patiets were assessed every 6 moths for eurological symptoms ad sigs ad for episodes of bleedig. Hospital records were cosulted to documet admissios or evets that may ot have bee recalled by the patiet. Geeral practitioers were cotacted for ay additioal iformatio. Patiets who had defaulted from cliic attedace were cotacted by telephoe ad visited at home if ecessary. This eabled 100% completio of follow-up assessmets. Ed Poits ad Statistical Aalyses Recurret stroke was diagosed o the basis of cliical ad euroimagig examiatios ad were classified by subtype. The classificatio of stroke subtypes was validated by a idepedet observer ot ivolved i origial assessmets. Recurret stroke patiets were assessed for outcome at 3 moths with the modified Raki score (5 ad 6, severe disability or death; 3 ad 4, moderate disability; 0 to 2, o to mild disability). Itracerebral hemorrhages were couted separately. TABLE 1. Baselie Patiet Characteristics Warfari ( 214) All deaths were recorded, ad a cause was assiged o the basis of available cliical iformatio. Deaths resultig from cerebrovascular causes were excluded to prevet double coutig. All bleedig evets were recorded. Major bleedig was defied as fatal bleedig or bleedig leadig to hospitalizatio, emergecy procedures, or urget trasfusio. All other bleeds were classified as mior. Baselie variables were preseted as media or proportio as appropriate. Comparisos betwee groups were made with the Ma-Whitey U test i the case of skewed distributios or the 2 test, as appropriate. The o-treatmet evet rate per patiet-year was calculated, ad the exact Poisso CIs were used for comparisos of cliical outcomes because of the small umbers (resultig from low icidece) i these groups. The differeces i rates, 95% CIs, ad statistical sigificace were calculated with the Z test. Results Aspiri ( 172) Differece % Patiet-years of follow-up Media age (IQR), y 78 (68 81) 78 (76 82) 0 (0 4) Age 70 y, 49 (23) 33 (19) 4 ( 4 12) Male sex, (%) 103 (48) 77 (45) 3 ( 7 13) Hypertesio, (%) 99 (46) 83 (48) 2( 12 8) Diabetes mellitus, (%) 28 (13) 27 (16) 3( 10 4) Curret smokers, (%) 34 (16) 19 (11) 5 ( 2 12) Stroke/TIA i last year 36 (17) 33 (19) 2( 10 6) Cogestive cardiac failure 73 (34) 60 (35) 1( 10 9) Ischemic heart disease 60 (28) 58 (34) 6( 15 3) Cliical stroke subtype Cardioembolic 133 (62) 104 (60) 2 ( 8 12) Udetermied 38 (18) 36 (21) 3( 11 5) Lacuar 43 (20) 32 (19) 7( 7 9) Media duratio of follow-up, y (0 3) IQR idicates iterquartile rage; TIA, trasiet ischemic attack. Baselie Characteristics We treated 214 patiets with warfari ad 172 patiets with aspiri (123 because of defied cotraidicatios; 49 because of choice, compliace, logistics, or patiet/physicia preferece). The 2 treatmet groups were comparable for age, sex, risk factor profile, ad stroke subtype (Table 1). Patiets o warfari had a mea INR of ad spet a average of 66% of the time withi the target INR rage of 2.0 to 3.0. Ed Poits The recurret stroke rate i patiets beig treated with aspiri was sigificatly higher tha i those o warfari (Table 2). There was o sigificat differece i the rate of itracraial hemorrhage o either treatmet. Differeces betwee groups i overall mortality, death from stroke, cardiac death, ocerebral bleedig, or ovascular death were all ot sigificat. There were sigificatly fewer bleedig evets i the aspiri group tha i the warfari group. The differeces were most marked for mior bleeds, but there was still a excess of major bleeds i the warfari group.

3 2830 Stroke December 2001 TABLE 2. Outcome by Treatmet Strategy Warfari (448 patiet-years) Aspiri (358 patiet-years) Evets, Aual Evet % Evets, Aual Evet % Differece % P All strokes ( ) ( ) 4.6 ( ) 0.02 Ischemic Stroke ( ) ( ) 5.0 ( ) 0.01 Fatal/major disability ( ) ( ) 3.0 ( ) 0.01 IS with moderate disability ( ) ( ) 1.5 ( ) NS IS with o/mild disability ( ) ( ) 0.4 ( ) NS Itracraial hemorrhage (0 1.4) (0 0.8) 0.4 ( ) NS Mortality ( ) ( ) 1.6 ( ) NS Vascular deaths ( ) ( ) 1.8 ( ) NS Cerebral (stroke) (0 1.1) ( ) 1.5 ( ) NS Cardiac ( ) ( ) 0.6 ( ) NS Nocerebral bleeds (0 1.4) ( ) NS Other vascular causes (0 1.1) (0 1.8) 0.4 ( ) NS Novascular deaths ( ) ( ) 0.2 ( ) NS Bleedig evets ( ) ( ) 9.0 ( ) 0.01 Major (excludig itracraial ( ) (0 1.3) 1.9 ( ) 0.05 hemorrhage) Mior ( ) ( ) 7.0 ( ) 0.01 Recurret stroke ad major bleed ( ) ( ) 2.7 ( ) 0.05 s ad rate differeces are expressed as evets per hudred patiet-years (%) with exact Poisso 95% CIs. Dowloaded from by o September 17, 2018 Secodary Strokes by Iitial Stroke Subtype Aticoagulatio was most effective i reducig recurret stroke i patiets assiged a cardioembolic stroke iitially (10.7% for aspiri versus 3.3% for warfari, P 0.01). This was almost etirely due to a reductio i cardioembolic recurreces (8.4% versus 1.9%, P 0.01), with o differeces i the rate of recurrece resultig from other causes. Patiets whose iitial stroke was classified as udetermied or lacuar showed o sigificat differeces betwee groups i the rate of stroke recurrece, either overall or betwee subtypes of secod stroke (Table 3). However, patiets presetig with lacuar stroke were more likely to have a lacuar recurrece tha those i whom the first stroke was cardioembolic, TABLE 3. Recurrece by Stroke Subtype ad Treatmet Allocatio Recurret Strokes, Evet rate % regardless of treatmet regime. There were 4 itracraial hemorrhages durig follow-up: 2 i patiets with cardioembolic strokes (1 treated with warfari, 1 with aspiri) ad 2 i patiets with lacuar strokes treated with warfari. Discussio This prospective cohort study cofirms the superiority of warfari over aspiri i prevetig cardioembolic recurrece i stroke patiets with atrial fibrillatio comparable to that see i radomized cotrolled trials. However, log-term aticoagulatio did ot reduce stroke recurrece i patiets presetig with lacuar strokes despite beig i atrial fibrillatio. This observatio is cliically relevat because the Subtype of Recurret Stroke Cardioembolic Udetermied Lacuar Bleed % % % % Iitial Stroke Subtype Treatmet Patiets, Patietyears Cardioembolic Warfari ( ) ( ) (0 1.8) (0 1.1) (0 1.1) Aspiri ( ) ( ) (0 3.0) (0 1.4) (0 1.4) Udetermied Warfari ( ) (0 3.8) (0 3.8) (0 6.2) 0 0 Aspiri ( ) (0 6.0) (0 3.8) (0 6.0) 0 0 Lacuar Warfari ( ) (0 2.9) ( ) 2 2 (0 4.7) Aspiri ( ) (0 7.0) (0 4.4) (0 9.5) 0 0 Total Warfari ( ) ( ) (0 3.3) ( ) (0 1.4) Aspiri ( ) ( ) ( ) ( ) (0 0.8) s expressed as evets per hudred patiet-years (%) with exact Poisso CIs.

4 Evas et al Idex Stroke Type ad Aticoagulatio to Prevet Recurrece 2831 Dowloaded from by o September 17, 2018 prevalece of both atrial fibrillatio 16 ad small-vessel disease 17 icreases with age ad because there is a risk that some patiets may be exposed to the risks of aticoagulatio ad itracerebral hemorrhage 11 without ecessarily beefitig from the treatmet. Although it is widely recogized that stroke is a heterogeeous coditio with diverse origi, little attetio has bee paid to stroke subtypig util recetly. The importace of stroke subtype ad targetig of secodary prevetio to the idividual who has had a relevat stroke rather tha ay stroke has bee recogized i patiets with carotid steosis. 18,19 It is likely that subtypig accordig to possible origi may be equally importat i stroke patiets with atrial fibrillatio. The curret orthodoxy of stroke ad atrial fibrillatio, therefore warfari has the virtue of simplicity, but it may ot be to the beefit of all. The ucertaity of advatages of aticoagulatio over aspiri i patiets with ovalvular atrial fibrillatio ad a presumably ocardioembolic idex stroke would be best addressed by a radomized, cotrolled trial ivolvig this specific patiet group. To have a 90% power to detect a 50% differece (reductio i recurret stroke rate from 10% to 5%), the trial would require 1100 patiets. If the effect of treatmet is smaller (reductio from 10% to 7%), 3600 patiets would be eeded. A radomized, cotrolled study of such a size would preset cosiderable logistical challeges ad expese, beig larger tha ay previous ivestigatio of aticoagulatio i atrial fibrillatio. I additio, it would be uethical to radomize such large umbers of patiets to a less optimal treatmet o the basis of existig evidece ad curret recommedatios that strogly advocate the use of aticoagulatio i all stroke patiets with atrial fibrillatio if there are o cotraidicatios. Observatioal cohort studies may quite ofte be the oly method of idetifyig sigificat differeces i outcome i cliical practice, especially i situatios i which radomizatio would be uethical or ufeasible. Compariso of study desigs has show that well-coducted oradomized trials ca yield iformatio similar to radomized trials without puttig patiets at risk. 20 These studies ca be see as hypothesis geeratig ad are a robust method for gaiig iformatio o patiet characteristics, expected size of effect, ad logistical costraits that ca be used to justify ad desig targeted radomized, cotrolled studies. This strategy was used for the preset study. I view of existig evidece, all eligible patiets were offered aticoagulatio as the treatmet of choice. The use of aspiri was limited to patiets with cotraidicatios to aticoagulatio or those who were uable to take warfari for reasos of choice, compliace, or logistics. Despite beig a oradomized compariso, the ed poits of this study were defied i advace; data were collected prospectively; subtypig of stroke was udertake with appropriate blided cliical, radiographic, ultrasoud, ad echocardiographic assessmets; ad 100% follow-up was achieved to esure that the sources of bias were kept to a miimum. The presece of atrial fibrillatio is a major cofoudig factor i stroke subtype assigmet because most patiets have a potetial embolic source. Recet studies have defied criteria that allow discrimiatio betwee embolic ad oembolic stroke 9,10 that are similar to those used i this study. These studies have show similar proportios of cardioembolic (68%) ad ocardioembolic strokes i patiets with atrial fibrillatio ad foud that warfari did ot reduce ocardioembolic (lacuar ad atheroembolic combied) strokes. 10 It is ackowledged that accurate subtypig of stroke may ot be possible i all cases eve with advaced euroimagig ad vascular imagig techiques ad that some lacuar strokes may have cardioembolic or atheroembolic sources Coversely, because it was ot possible to examie the whole arterial system for every patiet, some cardioembolic strokes may have origiated i the aorta or itracraial vessels. 21 Bias resultig from misclassificatio was reduced by the use of 2 idepedet observers ad categorizig of patiets as udetermied if there were ay doubts about source, a strategy used i other similar studies. 9,10 Previous primary prevetio studies ivolvig atrial fibrillatio ad stroke have idetified secodary variables associated with icreased stroke risk. 1 All patiets icluded i this secodary prevetio study were at high risk because of their idex strokes. The importat cliical ucertaity i the prevetio of recurret stroke is the validity of aticoagulatio i lacuar stroke patiets who have associated atrial fibrillatio. Post hoc aalysis by subtype was ot udertake i the oly large radomized, cotrolled study o secodary prevetio of stroke i patiets with atrial fibrillatio. 2 Although it is possible that patiets with lacuar stroke who have atrial fibrillatio may beefit from the primary prevetive effect of warfari, this remais uproved because of the very small umbers of lacuar stroke i both the placebo ad itervetio groups i primary prevetio studies. 24,25 Oe way i which secodary prevetio may differ from primary prevetio is that stroke recurrece teds to be of the same subtype as the icidet stroke. 26 Patiets with lacuar stroke are at a relatively high risk for recurret stroke, with most of these recurreces beig lacuar. 27 This study suggests that recurrece i patiets with lacuar stroke is uaffected by treatmet with warfari despite the wide CIs (because of a relatively small sample size). It is also iterestig to ote that i the lacuar group, 2 patiets suffered itracraial hemorrhage o warfari ad 2 patiets treated with aspiri had a cardioembolic stroke, suggestig that the beefits of aticoagulatio may be cacelled by the bleedig risk. The higher risk of itracraial bleedig with warfari i patiets with small-vessel cerebrovascular disease has also bee reported i the Stroke Prevetio i Reversible Ischemia Trial (SPIRIT). 11 Although it may be difficult to argue agaist the use of aticoagulatio i patiets with cardioembolic strokes, there is geuie ucertaity as to whether patiets i atrial fibrillatio who have other subtypes of stroke, especially lacuar, beefit to a similar extet. Accurate subtypig of stroke requires cliical expertise ad urestricted, early access to a rage of diagostic facilities, 28 which requires cosiderable ivestmet i stroke services. 29 Similarly, cliical decisios ot to aticoagulate a proportio of patiets who would be cosidered eligible accordig to existig criteria have ethical ad legal implicatios that require hard evidece for support.

5 2832 Stroke December 2001 Dowloaded from by o September 17, 2018 Clearly, this issue eeds to be ivestigated further by welldesiged trials that are iformed by cliical observatios such as those reported i this study. Refereces 1. Hart RG. Halperi JL. Atrial fibrillatio ad thromboembolism: a decade of progress i stroke prevetio. A Iter Med. 1999;131: Europea Atrial Fibrillatio Trial Study Group. Secodary prevetio i o-rheumatic atrial fibrillatio after trasiet ischaemic attack or mior stroke. Lacet. 1993;342: Laupacis A, Albers G, Dale J, Du M, Feiberg W, Jacobso A, Siger D. Atithrombotic therapy i atrial fibrillatio: Fifth ACCP Cosesus Coferece o Atithrombotic Therapy. Chest. 1998;114(suppl): 579S 589S. 4. Lip GY, Lowe GD. ABC of atrial fibrillatio: Atithrombotic treatmet for atrial fibrillatio. BMJ. 1996;312: Ad Hoc Committee o Guidelies for the Maagemet of Trasiet Ischemic Attacks of the Stroke Coucil of the America Heart Associatio. 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