Antithrombotic Therapy in Peripheral Artery Disease : Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American

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1 Antithromboti Therpy in Peripherl Artery Disese : Antithromboti Therpy nd Prevention of Thrombosis, 9th ed: Amerin College of Chest Physiins Clinil Prtie Guidelines Evidene-Bsed Pblo Alonso-Coello, Sergi Bellmunt, Ctherine MGorrin, Soni S. Annd, Rndolph Guzmn, Mihel H. Criqui, Elie A. Akl, Per Olv Vndvik, Mrten G. Lnsberg, Gordon H. Guytt nd Frederik A. Spener Chest 2012;141;e669S-e690S DOI /hest The online version of this rtile, long with updted informtion nd servies n be found online on the World Wide Web t: Supplementl mteril relted to this rtile is vilble t: e669s.dc1.html Chest is the offiil journl of the Amerin College of Chest Physiins. It hs been published monthly sine Copyright2012by the Amerin College of Chest Physiins, 3300 Dundee Rod, Northbrook, IL All rights reserved. No prt of this rtile or PDF my be reprodued or distributed without the prior written permission of the opyright holder. ( ISSN:

2 CHEST Supplement ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES Antithromboti Therpy in Peripherl Artery Disese Antithromboti Therpy nd Prevention of Thrombosis, 9th ed: Amerin College of Chest Physiins Evidene-Bsed Clinil Prtie Guidelines Pblo Alonso-Coello, MD, PhD ; Sergi Bellmunt, MD ; Ctherine MGorrin, MBBCh, BAO ; Soni S. Annd, MD, PhD ; Rndolph Guzmn, MD, RVT ; Mihel H. Criqui, MD, MPH ; Elie A. Akl, MD, MPH, PhD ; Per Olv Vndvik, MD, PhD ; Mrten G. Lnsberg, MD, PhD ; Gordon H. Guytt, MD, FCCP ; nd Frederik A. Spener, MD Bkground: This guideline fouses on ntithromboti drug therpies for primry nd seondry prevention of rdiovsulr disese s well s for the relief of lower-extremity symptoms nd ritil ishemi in persons with peripherl rteril disese (PAD). Methods: The methods of this guideline follow those desribed in Methodology for the Development of Antithromboti Therpy nd Prevention of Thrombosis Guidelines: Antithromboti Therpy nd Prevention of Thrombosis, 9th ed: Amerin College of Chest Physiins Evidene- Bsed Clinil Prtie Guidelines in this supplement. Results: The most importnt of our 20 reommendtions re s follows. In ptients ged 50 yers with symptomti PAD or symptomti rotid stenosis, we suggest spirin ( mg/d) over no therpy (Grde 2B) for the primry prevention of rdiovsulr events. For seondry prevention of rdiovsulr disese in ptients with symptomti PAD (inluding ptients before nd fter peripherl rteril bypss surgery or perutneous trnsluminl ngioplsty), we reommend long-term spirin ( mg/d) or lopidogrel (75 mg/d) (Grde 1A). We reommend ginst the use of wrfrin plus spirin in ptients with symptomti PAD (Grde 1B). For ptients undergoing peripherl rtery perutneous trnsluminl ngioplsty with stenting, we suggest single rther thn dul ntipltelet therpy (Grde 2C). For ptients with refrtory ludition despite exerise therpy nd smoking esstion, we suggest ddition of ilostzol (100 mg bid) to spirin ( mg/d) or lopidogrel (75 mg/d) (Grde 2C). In ptients with ritil limb ishemi nd rest pin unble to undergo revsulriztion, we suggest the use of prostnoids (Grde 2C). In ptients with ute limb ishemi due to ute thrombosis or embolism, we reommend surgery over peripherl rteril thrombolysis (Grde 1B). Conlusions: Reommendtions ontinue to fvor single ntipltelet therpy for primry nd seondry prevention of rdiovsulr events in most ptients with symptomti PAD, symptomti PAD, nd symptomti rotid stenosis. Additionl therpies for relief of limb symptoms should be onsidered only fter exerise therpy, smoking esstion, nd evlution for peripherl rtery revsulriztion. CHEST 2012; 141(2)(Suppl):e669S e690s Abbrevitions: ABI 5 nkle brhil index; CAD 5 oronry rtery disese; CAPRIE 5 Clopidogrel vs Aspirin in Ptients t risk for Ishemi Events; MI 5 myordil infrtion; MWD 5 mximum wlking distne; PAD 5 peripherl rteril disese; PTA 5 perutneous trnsluminl ngioplsty; RCT 5 rndomized ontrolled tril; RR 5 risk rtio; rt-pa 5 reombinnt tissue-type plsminogen tivtor CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e669s

3 Summry of Reommendtions Note on Shded Text: Throughout this guideline, shding is used within the summry of reommendtions setions to indite reommendtions tht re newly dded or hve been hnged sine the publition of Antithromboti nd Thrombolyti Therpy: Amerin College of Chest Physiins Evidene- Bsed Clinil Prtie Guidelines (8th Edition). Reommendtions tht remin unhnged re not shded For persons with symptomti peripherl rteril disese (PAD), we suggest spirin 75 to 100 mg dily over no spirin therpy (Grde 2B). Remrks: Aspirin slightly redues totl mortlity regrdless of rdiovsulr risk profile if tken over 10 yers. In people t moderte to high risk of rdiovsulr events, the redution in myordil infrtion (MI) is losely blned with n inrese in mjor bleeds. Whtever their risk sttus, people who re verse to tking medition over prolonged time period for very smll benefits will be disinlined to use spirin for primry prophylxis. Individuls who Revision epted August 31, Affilitions: From the Iberomerin Cohrne Centre (Dr Alonso-Coello), CIBERESP-IIB Snt Pu, Brelon, Spin; Angiology (Dr Bellmunt), Vsulr nd Endovsulr Surgery Deprtment, Hospitl de l Snt Creu i Snt Pu, Brelon, Spin; The Hert House (Dr MGorrin), Mter Miseriordie University Hospitl, Dublin, Irelnd; Deprtments of Mediine nd Clinil Epidemiology nd Biosttistis (Drs Annd nd Guytt), MMster University, Hmilton, ON, Cnd; Setion Vsulr Surgery (Dr Guzmn), University of Mnitob, St Bonife Hospitl, Winnipeg, MB, Cnd; Deprtment of Fmily nd Preventive Mediine (Dr Criqui), University of Cliforni Sn Diego Shool of Mediine, L Joll, CA; Deprtment of Mediine (Dr Akl), Stte University of New York t Bufflo, Bufflo, NY; Norwegin Knowledge Centre for the Helth Servies nd Deprtment of Mediine Gjøvik (Dr Vndvik), Innlndet Hospitl Trust, Gjøvik, Norwy; Stnford Stroke Center (Dr Lnsberg), Stnford University Medil Center, Plo Alto, CA; nd Deprtment of Mediine (Dr Spener), MMster University, Hmilton, ON, Cnd. Funding/Support: The Antithromboti Therpy nd Prevention of Thrombosis, 9th ed: Amerin College of Chest Physiins Evidene-Bsed Clinil Prtie Guidelines reeived support from the Ntionl Hert, Lung, nd Blood Institute [R13 HL104758] nd Byer Shering Phrm AG. Support in the form of edutionl grnts were lso provided by Bristol-Myers Squibb; Pfizer, In; Cnyon Phrmeutils; nd snofi-ventis US. Dislimer: Amerin College of Chest Physiin guidelines re intended for generl informtion only, re not medil dvie, nd do not reple professionl medil re nd physiin dvie, whih lwys should be sought for ny medil ondition. The omplete dislimer for this guideline n be essed t hestjournl.hestpubs.org/ontent/141/2_suppl/1s. Correspondene to: Frederik A. Spener, MD, Deprtment of Mediine, MMster University, St Joseph s Helth Cre, 50 Chrlton Ave E, Hmilton, ON, L8N 4A6, Cnd; e-mil: fspene@mmster Amerin College of Chest Physiins. Reprodution of this rtile is prohibited without written permission from the Amerin College of Chest Physiins ( site/mis/reprints.xhtml ). DOI: /hest vlue preventing n MI substntilly higher thn voiding GI bleed, if they re in the moderte or high rdiovsulr risk group, will be more likely to hoose spirin For seondry prevention ptients with symptomti PAD, we reommend one of the two following ntithromboti regimens to be ontinued long term over no ntithromboti tretment: spirin 75 to 100 mg dily or lopidogrel 75 mg dily (ll Grde 1A). We suggest not to use dul ntipltelet therpy with spirin plus lopidogrel (Grde 2B). We reommend not to use n ntipltelet gent with moderte-intensity wrfrin (Grde 1B) For ptients with intermittent ludition refrtory to exerise therpy (nd smoking esstion), we suggest the use of ilostzol in ddition to previously reommended ntithromboti therpies (spirin mg dily or lopidogrel 75 mg dily) (Grde 2C) ; we suggest ginst the use of pent oxifylline, heprinoids, or prostnoids (Grde 2C) For ptients with symptomti PAD nd ritil leg ishemi/rest pin who re not ndidtes for vsulr intervention, we suggest the use of prostnoids in ddition to previously reommended ntithromboti therpies (spirin mg dily or lopidogrel 75 mg dily) (Grde 2C). Vlues nd preferenes: Ptients who do not vlue unertin relief of rest pin nd uler heling greter thn voidne of high likelihood of drug-relted side effets will be disinlined to tke prostnoids In ptients with ute limb ishemi due to rteril emboli or thrombosis, we suggest immedite systemi ntiogultion with unfrtionted heprin over no ntiogultion (Grde 2C) ; we suggest reperfusion therpy (surgery or intrrteril thrombolysis) over no reperfusion therpy (Grde 2C) ; we reommend surgery over intrrteril thrombolysis (Grde 1B). In ptients undergoing intrrteril thrombolysis, we suggest reombinnt tissuetype plsminogen tivtor (rt-pa) or urokinse over streptokinse (Grde 2C) For ptients undergoing peripherl rtery perutneous trnsluminl ngioplsty (PTA) with or without stenting, we reommend longterm spirin ( mg/dy) or lopidogrel (75 mg/dy) (Grde 1A). For ptients undergoing peripherl rtery PTA with stenting, we suggest e670s Antithromboti Therpy in Peripherl Artery Disese

4 single rther thn dul ntipltelet therpy (Grde 2C). Vlues nd preferenes: Ptients who ple high vlue on n unertin redution in the risk of limb loss nd reltively low vlue on voiding definite inresed risk of bleeding re more likely to hoose to use dul ntipltelet therpy We reommend one of the following ntithromboti regimens to be ontinued longterm following peripherl rtery bypss grft surgery over no ntithromboti tretment: spirin 75 to 100 mg dily or lopid ogrel 75 mg dily (ll Grde 1A). We reommend single ntipltelet therpy over ntipltelet therpy nd wrfrin (Grde 1B). In ptients undergoing below-knee bypss grft surgery with prostheti grfts, we suggest lopidogrel 75 mg/d plus spirin ( mg/d) over spirin lone for 1 yer (Grde 2C). For ll other ptients, we suggest single over dul ntipltelet therpy (Grde 2B) For persons with symptomti rotid stenosis, we suggest spirin 75 to 100 mg dily over no spirin therpy (Grde 2B). Remrks: Aspirin slightly redues totl mortlity regrdless of rdiovsulr risk profile if tken over 10 yers. In people t moderte to high risk of rdiovsulr events, the redution in MI is losely blned with n inrese in mjor bleeds. Whtever their risk sttus, people who re verse to tking medition over prolonged time period for very smll benefits will be disinlined to use spirin for primry prophylxis In ptients with symptomti rotid stenosis (inluding reent rotid endrteretomy), we reommend long-term ntipltelet therpy with lopidogrel (75 mg one dily) or spirinextended-relese dipyridmole (25 mg/200 mg bid) or spirin ( mg one dily) over no ntipltelet therpy (Grde 1A). We suggest either lopidogrel (75 mg one dily) or spirin-extendedrelese dipyridmole (25 mg/200 mg bid) over spirin ( mg) (Grde 2B). T his rtile fouses on the use of ntithromboti drugs in ptients with peripherl rteril disese (PAD). PAD is ssoited with high prevlene of theroslerosis in other vsulr beds. The leding uses of morbidity nd mortlity in ptients with PAD re myordil infrtion (MI) nd stroke; therefore, s in ptients with oronry rtery disese (CAD), the primry benefit of ntithromboti therpy in this ptient popultion is prevention of vsulr events nd mortlity. The ptient-importnt outomes (ie, totl mortlity, nonftl MI, nonftl stroke, mjor nonftl extrrnil bleed) re the sme outomes onsidered for reommendtions for CAD nd stroke. However, we review the effets of ntithromboti therpy on outomes speifi to PAD (eg, rest pin of the limbs, qulity of life, or mputtion). Studies evluting ntithromboti therpy immeditely following peripherl bypss grft surgery or perutneous endovsulr proedures generlly hve used grft pteny or reolusion s the primry end point. These outomes re surrogtes for ptientimportnt outomes of qulity of life nd limb mputtion, whih re seldom reported. We onsider the desirble nd undesirble onsequenes of ntithromboti therpy in the following popultions or ptient groups: (1) persons with symptomti PAD, (2) ptients with symptomti PAD (inluding those with ludition or ritil [hroni] limb ishemi nd rest pin or prior peripherl rteril revsulriztion), (3) ptients with ute limb ishemi nd thretened limb loss, (4) ptients following peripherl rteril revsulriztion, nd (5) persons with symptomti nd symptomti rotid stenosis. Tble 1 nd Tble S1 desribe both the question definition (ie, popultion, intervention, omprtor, nd outome) nd the study types onsidered for eh question. (Tbles tht ontin n S before the number denote supplementry tbles not ontined in the body of the rtile nd vilble insted in n online dt supplement. See the Aknowledgments for more informtion.) High-qulity evidene supports n effet of spirin on vsulr mortlity. In ddition, reent metnlysis provided moderte-qulity evidene tht long-term use of spirin redues mortlity from speifi ner types. 1 In popultion of ptients with symptomti vsulr disese, vsulr disese nd ner re the leding uses of deth. Therefore, we hve hosen totl mortlity over 10-yer period s the min outome of interest. When dt re vilble, we inluded ftl intrrnil or extrrnil bleeding with vsulr deth or totl mortlity under the generl tegory of ntithromboti therpy-relted deths. Nonftl hemorrhgi strokes nd ishemi strokes re inluded together s nonftl strokes. Although the former is omplition nd derese in the ltter is benefiil effet of ntithromboti therpy, their impt on ptient morbidity is similr. 1.0 Methods Estimtion of Bseline Risks nd Absolute Effets of Tretment In order to estimte bsolute benefits nd hrms ssoited with given therpy, we performed the following steps. First, CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e671s

5 Tble 1 [Introdution] Strutured Clinil Questions PICO Question Setion Informl Question Popultion Intervention Comprtor Outome 2.1 Choie of ntithromboti therpy 3.1 Choie of ntithromboti therpy 2.0 Asymptomti PAD Ptients with Aspirin Plebo Totl mortlity symptomti PAD Nonftl MI (eg, ABPI, 0.9 Nonftl stroke Mjor nonftl extrrnil bleeding 3.0 Symptomti PAD: prevention of rdiovsulr events Ptients with symptomti PAD Aspirin Plebo Totl mortlity Nonftl MI Nonftl stroke Mjor nonftl extrrnil bleeding 3.2 Clopidogrel Aspirin 3.3 Aspirin 1 lopidogrel Aspirin 3.4 Aspirin 1 orl ntiogulnts Aspirin 4.0 Symptomti PAD: mngement of ludition 4.1 Choie of ntithromboti therpy Ptients with ludition Heprins Plebo Qulity of life Mximum wlking distne Mjor nonftl extrrnil bleeding Mortlity Adverse events 4.2 Cilostzol Plebo or pentoxifylline 4.3 Pentoxifylline Plebo 4.4 Prostglndins Plebo 5.1 Choie of ntithromboti therpy 6.1 Choie of ntithromboti therpy 5.0 Symptomti PAD: mngement of ritil limb ishemi Ptients with ritil limb ishemi unble to undergo revsulriztion Ptients with ute limb ishemi Prostglndins Plebo Rest-pin relief Uler heling Amputtions Mortlity Adverse events 6.0 Aute limb ishemi Unfrtionted heprin No ntiogultion Deth Amputtion Nonftl stroke Mjor nonftl extrrnil bleeding 6.2 Intrrteril thrombolyti therpy Surgery 6.3 Urokinse or rt-pa Streptokinse 7.0 Endovsulr surgery 7.1 Choie of ntithromboti therpy post-pta stent Ptients undergoing PTA Aspirin plus dipyridmole Plebo Vessel restenosis/olusion Aspirin/dipyridmole Phenprooumon Tilopidine Phenprooumon Unfrtionted heprin Subutneous ndroprin (LMWH) (Continued) e672s Antithromboti Therpy in Peripherl Artery Disese

6 Tble 1 Continued PICO Question Setion Informl Question 8.1 Choie of ntithromboti therpy Popultion Intervention Comprtor Outome Ptients undergoing ny grft 8.0 Open lower-limb vsulr surgery Aspirin or spirin/dipyridmole Plebo Vsulr mortlity Nonftl MI Nonftl stroke Mjor nonftl extrrnil bleeding Aspirin plus lopidogrel Aspirin Amputtion 8.2 Aspirin or spirin/dipyridmole Other gents 8.3 Clopidogrel plus spirin Aspirin 8.4 Orl ntiogulnts spirin Aspirin 8.5 Ptients undergoing below-knee prostheti grft 9.1 Choie of ntithromboti therpy Ptients with symptomti rotid stenosis 9.2 Ptients with symptomti rotid stenosis 9.3 Ptients with rotid stenosis undergoing endrteretomy 9.0 Crotid stenosis Aspirin Plebo Totl mortlity Nonftl MI Nonftl stroke Antipltelet gents post Plebo Mjor nonftl extrrnil bleeding endrteretomy ABPI 5 nkle-brhil pressure index; LMWH 5 low-moleulr-weight heprin; MI 5 myordil infrtion; PAD 5 peripherl rteril disese; PICO 5 popultion, intervention, omprtor, outome; PTA 5 perutneous trnsluminl ngioplsty; rt-pa 5 reombinnt tissue-type plsminogen tivtor. CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e673s

7 we generted reltive effet estimtes (reltive risks) from the highest-qulity published met-nlysis of rndomized ontrolled trils (RCTs). If no suh met-nlyses were vilble or were out of dte, we onduted our own met-nlyses of relevnt RCTs or used reltive risk estimtes from single RCTs in the bsene of other relevnt RCTs. Idelly, in order to pproximte the benefit of given therpy in the rel world, estimtes of bseline risk (ontrol group risks) would be derived from popultion-bsed observtionl studies. Unfortuntely, for most of our linil questions, we were unble to identify observtionl studies of suffiient qulity tht reported ll relevnt outomes. In suh ses, we derived ontrol group risk estimtes from representtive ontrol rm of relevnt metnlysis or RCT nd djusted them to our speified time frme. Detiled explntions of our hoies re presented in eh setion. Vlues nd Preferenes The reltive weight given to outomes (eg, n extrrnil bleed ompred with n MI or stroke) gretly ffets the trde-offs between desirble nd undesirble onsequenes of ntithromboti therpy. Unfortuntely, limited dt guide us with respet to the reltive impt of these events on ptient s qulity of life. 2 As desribed in Guytt et l, 3 in this supplement we hve used rtings from prtiipting guideline pnelists estimtes of ptient vlution of the outomes of interest. The rtings suggest tht nonftl mjor extrrnil bleeding (whih is usully redily treted nd with few long-lsting onsequenes) rries only slightly less weight thn nonftl MI (whih lso often hs limited long-term onsequenes) but substntilly less weight thn stroke (whih often is ssoited with long-term disbility). Our deisions re bsed on disutility or negtive weight of stroke of three times the disutility of mjor extrrnil bleed. Trde-offs between desirble nd undesirble onsequenes of lterntive mngement strtegies sometimes represent losell situtions. In mking reommendtions in suh situtions, we hve tken primum non noere (first do no hrm) pproh, pling the burden of proof with those who would lim benefit of tretment. In other words, when tretment is ssoited with unertin benefit nd n ppreible probbility of importnt hrm, we reommend ginst suh tretment. We identified the relevnt evidene for our linil questions with the ssistne of tem of methodologists nd medil librrins s outlined in Guytt et l. 3 Systemti literture serhes for systemti reviews nd originl studies were performed until the dte of Jnury 15, After tht dte, we snned the literture regulrly, lthough this ws not performed s systemti literture serhes. 2.0 Primry Prevention of Crdiovsulr Events in Ptients With Asymptomti PAD As in the rtile by Vndvik et l 4 of this supplement, primry prevention refers to the use of n intervention to prevent events prior to ny linilly mnifested disese. Hene, even though nerly every 70-yer-old mn or womn hs signifint vsulr hnges, they re ndidtes for primry (s opposed to seondry) prevention unless they hve linilly mnifested vsulr disese (ie, ludition; history of peripherl vsulr proedures; known history of CAD, MI, or stroke). Most symptomti ptients with PAD will be identified through nkle-brhil index (ABI) sreening. The ABI is the rtio of the highest systoli BP in e674s the lower limb to tht of the rm. This reltively simple linil test ws originlly used to onfirm the dignosis of PAD nd ssess its severity. Low ABI (, 0.90) hs been shown to be n independent preditor of MI, stroke, nd vsulr mortlity independent of other rdiovsulr risk ftors. 5-9 The ABI, therefore, hs been promoted s simple, inexpensive, noninvsive sreening tool for the ssessment of future rdiovsulr risk. In met-nlysis of 48,000 helthy men nd women, ABI, 0.90 t bseline ws ssoited with n pproximte doubling of the 10-yer mortlity, rdiovsulr mortlity, nd mjor oronry event rte fter djusting for the Frminghm risk sore. 10 Therefore, when evluting ptient for primry prevention with spirin, we suggest using risk strtifition tool suh s the Frminghm risk sore, whih provides estimtes of low (, 10%), moderte (10%-20%), nd high risk (. 20%) of rdiovsulr events over 10 yers. If, in ddition, the ptient hs n ABI, 0.90, we suggest doubling this sore, thus possibly inresing the ptient s risk from low to moderte or moderte to high tegory Aspirin We onsider the evidene for spirin therpy for the primry prevention of CAD (see setion 1.1 in Vndvik et l 4 in this supplement) pplible to ptients with symptomti PAD. On the bsis of n individul prtiipnt dt met-nlysis, 11 spirin would be expeted to prevent 19 nd 31 nonftl MIs nd led to 16 nd 22 mjor extrrnil bleeding events per 1,000 moderte- nd high-risk ptients treted, respetively (Tble S2). In ddition, long-term spirin use hs been ssoited with signifint derese in ner mortlity, 12 likely ontributing to the derese in totl mortlity ssoited with longterm spirin therpy observed in nother metnlysis. 13 On the bsis of these dt nd regrdless of vsulr risk, spirin use in 60-yer-old men would lso result in six fewer deths (12 fewer to 0 fewer) per 1,000 ptients treted for 10 yers. The overll qulity of evidene is moderte given the in the estimtes for totl mortlity. The reltive effet of spirin on prevention of vsulr events, bleeding, nd totl mortlity re likely similr in ptients with rdiovsulr risk ftors, symptomti PAD, nd symptomti rotid stenosis. Our reommendtions for primry prevention in symptomti ptients with PAD re therefore identil to those desribed in Vndvik et l. 4 Reommendtion 2.1. For persons with symptomti PAD, we suggest spirin 75 to 100 mg dily over no spirin therpy (Grde 2B). Antithromboti Therpy in Peripherl Artery Disese

8 Remrks: Aspirin slightly redues totl mortlity regrdless of rdiovsulr risk profile if tken over 10 yers. In people t moderte to high risk of rdiovsulr events, the redution in MI is losely blned with n inrese in mjor bleeding events. Whtever the risk sttus, people verse to tking medition over prolonged time period for very smll benefits will be disinlined to use spirin for primry prophylxis. Individuls who vlue preventing n MI substntilly higher thn voiding GI bleed, if they re in the moderte or high rdiovsulr risk strt, will be more likely to hoose spirin. 3.0 Seondry Prevention of Crdiovsulr Events in Ptients With Symptomti PAD Antipltelet Therpies for Seondry Prevention of Crdiovsulr Events in Ptients With Symptomti PAD Beuse ntipltelet therpy would be expeted to result in similr reltive redutions in vsulr events suh s MI or stroke in ptients with PAD or CAD, we onsidered RCTs enrolling ptients with PAD, CAD, or both to support our reommendtions for both onditions. Although mny of the inluded studies onduted post ho nlyses limited to ptients enrolled for symptomti PAD, we did not find these subgroup nlyses redible bsed on riteri proposed by Sun et l. 14 Therefore, our reommendtions for ntipltelet therpy s seondry prevention of rdiovsulr events in symptomti ptients with PAD re identil to those desribed in setions 2.1.1, 2.1.2, 2.1.3, nd of Vndvik et l. 4 For the reder s interest, we briefly review the pertinent evidene in the following setions. 3.1 Aspirin Tble S3 summrizes the qulity of evidene nd min findings from met-nlysis of individul prtiipnt dt from 16 rndomized trils with 17,000 ptients with estblished vsulr disese (six trils of ptients with previous MI nd 10 of ptients with previous trnsient ishemi ttk or stroke).11 In this popultion t high risk for serious vsulr event (8.2% yerly risk), spirin signifintly redued totl mortlity, nonftl MI, nd nonftl stroke but inresed nonftl extrrnil bleeding events. The number of vsulr events nd totl deths prevented ws fr greter thn the number of bleeding events tht resulted from spirin. 3.2 Clopidogrel vs Aspirin The Clopidogrel vs Aspirin in Ptients t Risk for Ishemi Events (CAPRIE) tril is the only rn- domized tril tht diretly ompred lopidogrel nd spirin in seondry prevention of rdiovsulr events, nd we onsider this tril to be the most redible soure of evidene. 15 More thn 19,000 ptients with therosleroti vsulr disese mnifested s reent stroke, reent MI, or symptomti PAD reeived lopidogrel or spirin. After men follow-up of 1.9 yers, lopidogrel ws ssoited with possible redution in nonftl MI nd nonftl extrrnil bleeding nd little or no effet on totl mortlity. Tble S4 summrizes the qulity of evidene nd min findings of the CAPRIE tril. The results indite no effet of lopidogrel on totl mortlity ompred with spirin. These results re onsistent with met-nlysis of 10 studies exmining the effets of thienopyridine derivtives (eg, lopidogrel, tilopidine) vs spirin in ptients t high vsulr risk Dul Antipltelet Therpy With Clopidogrel nd Aspirin vs Single Antipltelet Therpy A Cohrne systemti review evluted shortnd long-term dul ntipltelet therpy in ptients with estblished CAD. 17 Only one lrge-sle RCT, the Clopidogrel for High Atherothromboti Risk nd Ishemi Stbiliztion, Mngement, nd Avoidne (CHARISMA) tril, hs evluted the long-term effiy of lopidogrel nd spirin vs spirin lone. 18 This tril followed 15,603 ptients with estblished vsulr disese or multiple risk ftors for men period of 28 months. Tble S5 summrizes the qulity of evidene nd findings from this tril. Results of the study filed to demonstrte or exlude n effet of dul ntipltelet therpy reltive to spirin on totl mortlity or nonftl MI. Dul ntipltelet therpy ws ssoited with possible redution in nonftl stroke nd possible inrese in nonftl extrrnil bleeding. We onsidered the qulity of evidene to be moderte beuse of impreise effet estimtes for ll outomes. Although this study inluded ptients with other vsulr diseses, we onsidered its findings diretly pplible to ptients with symptomti PAD. We did not deem subgroup nlyses suggesting different effets of dul ntipltelet therpy in symptomti vs symptomti ptients to be redible Wrfrin Plus Aspirin vs Aspirin Alone Although studies ompring wrfrin to plebo or spirin hve been onduted in ptients with PAD, these hve been smll in size nd foused on PADspeifi outomes (eg, lower-extremity pin, bypss grft pteny) rther thn on rtes of subsequent stroke, MI, or vsulr deth. Subsequent setions summrize these studies. Of the vilble trils of ptients with symptomti CAD ompring wrfrin plus spirin to spirin CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e675s

9 lone, ll were in the setting of reent ute oronry syndrome, nd number hd only short-term follow-up. It is unknown whether the response to wrfrin therpy, prtiulrly with respet to bleeding, might differ in ptients with symptomti CAD vs symptomti PAD. Therefore, we used only RCTs speifilly enrolling ptients with symptomti PAD for our evlution of wrfrin therpy. For the omprison of wrfrin plus spirin vs spirin lone for nonftl vsulr outomes, we used the event rtes from prtiipnts tking spirin in metnlysis of 16 RCTs evluting spirin use vs no spirin use in ptients with vsulr disese djusted to 5-yer time intervl s our bseline risk estimte. 10 Beuse this met-nlysis does not provide dt on totl mortlity or nonftl mjor extrrnil bleeds, we derived bseline risk estimtes from the spirin rm in the CHARISMA tril (totl mortlity) nd CAPRIE tril (mjor nonftl extrrnil bleeding events). 15,18 We identified three RCTs evluting wrfrin (interntionl normlized rtio, ) plus spirin vs spirin lone in 3,048 ptients with estblished PAD Tble 2 nd Tble S6 provide detils bout the qul ity of evidene nd findings from our metnlysis of the three inluded studies. Results filed to demonstrte or exlude n effet of wrfrin plus spirin vs spirin lone on mortlity, nonftl MI, or nonftl stroke. However, there ws signifint inrese in mjor bleeding events with wrfrin plus spirin ompred with spirin lone. The overll qulity of evidene is low. Reommendtion For seondry prevention in ptients with symptomti PAD, we reommend one of the two following ntithromboti regimens to be ontinued long term over no ntithromboti tretment: spirin 75 to 100 mg dily or lopidogrel 75 mg dily (ll Grde 1A). We suggest not to use dul ntipltelet therpy with spirin plus lopidogrel (Grde 2B). We reommend not to use n ntipltelet gent with moderteintensity wrfrin (Grde 1B). 4.0 Antithromboti Therpy for the Mngement of Ptients With Cludition In the previous setion, we reommended spirin or lopidogrel for the prevention of nonftl MI, nonftl stroke, or vsulr deth for ll ptients with symptomti PAD. In this setion, we evlute other therpies with ntipltelet nd ntithromboti properties (eg, ilostzol, pentoxifylline, prostnoids) for their effet on qulity of life. Unfortuntely, most studies hve not evluted qulity of life s n outome e676s diretly nd often used wlking distne s surrogte. We mke inferenes regrding qulity of life bsed on these dt, inferenes tht re less ertin beuse of. Beuse these therpies hve not been shown to hve n impt on rdiovsulr events, they re onsidered only s possible dditions to previously reommended ntipltelet tretments. Ptients with intermittent ludition hve lowerextremity disomfort with wlking, thereby limiting tivity. In generl, ludition itself is not ssoited with limb loss nd is responsive to smoking esstion nd exerise therpy. Cesstion of tobo use n signifintly redue lower-extremity symptoms nd progression of PAD. 22,23 One systemti review suggested tht strutured exerise progrms n improve mximl wlking distne (MWD). 24 Therefore, dditionl drug therpy should be onsidered only in ptients who hve troubling limittions even fter smoking esstion nd exerise therpy. Seletion of Bseline Risk For the three omprisons of ilostzol, pentoxifylline, nd prostnoids vs plebo, beuse ontrolled trils showed lrge improvements in wlking test distne in ptients in plebo groups, for the surrogte outome of MWD, we used ontrol response rte of 80%; tht is, we ssumed tht 80% of untreted ptients would show improvements in qulity of life. We lulted the stndrdized men differenes, nd when needed, we imputed SDs from other trils. We then onverted stndrdized men differenes into risk differenes 25,26 nd present the results s the proportion of ptients who experiene n importnt benefit in qulity of life (inferred from MWD). For evlution of bleeding risk ssoited with ilostzol ompred with no ilostzol or plebo, we used the ontrol group risk estimte from systemti review of 10 RCTs evluting ilostzol in ddition to dul ntipltelet therpy in oronry perutneous trnsluminl ngioplsty (PTA) nd stenting Cilostzol Cilostzol is phosphodiesterse III inhibitor of pltelet tivtion nd relxes vsulr smooth musle. Ten RCTs tht ompred ilostzol 100 mg bid to plebo hve been loted in two systemti reviews.28,29 Pooling dt from seven studies ompring ilostzol vs plebo suggested tht regrding helth-relted qulity of life (s inferred from MWD), ptients reeiving ilostzol re more likely to experiene n importnt benefit thn those reeiving plebo (79 more per 1,000 [55 more to 100 more]) ( Tble 3, Tble S7). Chnges in qulity of life were evluted diretly in four of the studies Antithromboti Therpy in Peripherl Artery Disese

10 Tble 2 [Setion ] Summry of Findings: Moderte-Intensity Wrfrin (INR ) Plus Aspirin vs Aspirin Alone for Seondry Prevention of Crdiovsulr Events in Ptients With Symptomti PAD 20,21,22 Antiipted Absolute Effets Over 5 y Outomes Prtiipnts (Studies), Follow-up Qulity of the Evidene (GRADE) Reltive Effet Risk With Aspirin Risk Differene With Wrfrin + Aspirin Totl mortlity 3,048 (3 RCT), mo Low due to nd b MI nonftl events 3,048 (3 RCT), mo Stroke, inluding nonftl ishemi nd hemorrhgi strokes e Mjor extrrnil bleed nonftl events 3,048 (3 RCT), mo RR 1.11 ( ) 120 per 1, more per 1,000 (from 25 fewer to 66 more) RR 0.95 ( ) 80 per 1,000 d 4 fewer per 1,000 (from 28 fewer to 32 more) RR 0.92 ( ) 110 per 1,000 d 8 fewer per 1,000 (from 39 fewer to 36 more) 2,994 (2 RCT), mo High RR 2.39 ( ) 40 per 1,000 f 55 more per 1,000 (from 20 more to 112 more) Burden of tretment N/A g High Wrfrin. spirin Wrfrin: dily medition, dietry nd tivity restritions, frequent blood testing/monitoring, inresed hospitl/lini visits d Aspirin: dily medition only CAPRIE 5 Clopidogrel vs Aspirin in Ptients t Risk for Ishemi Events; CHARISMA 5 Clopidogrel for High Atherothromboti Risk nd Ishemi Stbiliztion, Mngement, nd Avoidne; GRADE 5 Grdes of Reommendtions, Assessment, Development, nd Evlution; INR 5 interntionl normlized rtio; N/A 5 not pplible; RCT 5 rndomized ontrolled tril; RR 5 risk rtio. See Tble 1 legend for expnsion of other bbrevitions. The 95% CI for bsolute effet inludes benefit nd hrm. b Exess ner deths in one study with wrfrin nd spirin. Control group risk estimtes for totl mortlity ome from the spirin rm of the CHARISMA tril. d Control group risk estimtes for nonftl MI nd nonftl stroke (ishemi, hemorrhgi, nd unknown use) ome from observed events in met-nlysis of 16 RCTs in seondry prevention. 11 e Of totl nonftl strokes, two of 48 (4%) with spirin nd 17 of 50 (34%) with wrfrin plus spirin were hemorrhgi. f Control group risk estimtes for mjor bleeds ome from the observed events in the spirin-lone rm of the CAPRIE tril. 15 g As fr s we re wre, no studies hve evluted differenes in burden of tretment between ptients with PAD tking wrfrin vs spirin. There re studies evluting qulity of life in ptients during wrfrin tretment (with disprte findings), but these re limited by smll smple size, lk of omprtor, nd other design issues. CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e677s

11 Tble 3 [Setion ] Summry of Findings: Cilostzol vs Plebo in Ptients With Symptomti PAD nd Cludition 28 Outomes Prtiipnts (Studies), Follow-up Qulity of the Evidene (GRADE) Reltive Effet Antiipted Absolute Effets Risk Without Cilostzol Risk Differene With Cilostzol Totl mortlity 1,439 (1 RCT 30 ), 34 mo Low due to bis nd b RR 0.94 ( ) 68 per 1,000 4 fewer per 1,000 (from 27 fewer to 26 more) MI nonftl events Stroke, inluding nonftl ishemi nd hemorrhgi strokes Mjor extrrnil bleed 2,273 (6 RCT), 1-6 mo Low due to d nd e Qulity of life s inferred from mximum wlking distne (importnt outome) 1,890 (7 RCT), 3-6 mo Low due to bis, f g nd h RR 0.89 ( ) 44 per 1,000 5 fewer per 1,000 (from 24 fewer to 32 more) 1.09 ( ) 800 per 1, more per 1,000 (55 more to 100 more) i See Tble 1 nd 2 legends for expnsion of bbrevitions. Unler onelment of llotion. b CI inludes importnt benefit nd hrm; only 101 events. Control group risk estimtes ome from observed events reported in plebo rms of inluded studies. d Dt from studies ompring ilostzol vs plebo in ddition to spirin nd lopidogrel following perutneous oronry intervention. e CIs inlude protetive effet nd hrm. f Unler onelment of llotion in four of seven studies. gmoderte heterogeneity (I %). h Use of surrogte end point (wlking distne for qulity of life). i Clulted from pooled stndrdized men differenes, onverted into risk differene (ssumed ontrol response rte of 80%). e678s Antithromboti Therpy in Peripherl Artery Disese

12 ompring ilostzol 100 mg bid to plebo All four trils reported results onsistent with our inferenes from MWD: signifint improvement in the physil helth subsle of the SF-36 (Short Form Helth Survey ), suggesting n improvement in overll physil funtion. However, the overll helthrelted qulity of life ws not improved, with no hnges in the mentl helth omponents (eg, soil funtioning, role-emotionl subsle). In the lrgest of the trils, the results filed to demonstrte or exlude n effet of ilostzol on totl mortlity. 30 Regrding qulity of life (s inferred from MWD), ptients reeiving ilostzol 100 mg bid were more likely to experiene n importnt benefit thn those reeiving pentoxifylline. 35 There were no signifint differenes in totl mortlity or dverse events (ny dverse event or serious dverse events). A seprte review of phrmeutil sfety dtbse inluded eight RCTs of ptients with symptomti PAD. 36 The uthors did not list the individul trils inluded in this dtbse. There were 1,374 prtiipnts rndomized to ilostzol (475 ptient-yers exposure) nd 973 rndomized to plebo (357 ptient-yers exposure). Although forml met-nlysis does not pper to hve been undertken, the review reported no differene in rtes of MI (1.0% vs 0.8%), stroke (0.5% vs 0.5%), or deth (0.6% vs 0.5%) between ptients with symptomti PAD tking ilostzol or those tking plebo. 36 Mjor or minor bleeding rtes were not reported. As we onsidered whether to dd ilostzol to existing ntithromboti therpy, we relied on bleeding dt from studies ompring ilostzol to no ilostzol in ptients undergoing oronry stenting (nd lredy tking spirin nd lopidogrel) to estimte bleeding risk ssoited with this therpy. A systemti review of ilostzol in ptients undergoing perutneous oronry intervention inluded 10 RCTs (2,809 ptients) ompring triple therpy with spirin, lopidogrel, nd ilostzol to spirin plus lopidogrel.27 Results filed to demonstrte or exlude n effet of ilostzol on mjor bleeding (risk rtio [RR], 0.89; 95% CI, ). 4.2 Pentoxifylline Pentoxifylline ws ompred with plebo in six smll RCTs in ptients with intermittent ludition. A pooled nlysis of these trils filed to demonstrte differene between pentoxifylline nd plebo in qulity of life s inferred from MWD (31 more per 1,000 [47 less to 94 more]). 29 Pentoxifylline ws ssoited with more dverse events (96 more per 1,000 [21 more to 181 more]). The studies inluded hd limittions in design nd exeution nd showed mrked vribility, nd there ws n importnt risk of publition bis; thus, the overll qulity of the evidene ws deemed to be low. 4.3 Heprins (Inluding Low-Moleulr Weight Heprins) A Cohrne systemti review of the use of heprin produts in ptients with intermittent ludition 37 identified five eligible studies (Tble S8) In the pooled dt, there were no deths, no bleeding events, nd nine rdiovsulr events with no signifint differenes between heprins nd plebo. Effets of heprin on wlking distne were only evluble from one RCT in whih heprin 12,500 units subutneously dily or plebo were dministered for two 3-month periods followed by 6 months of observtion in rossover design. Aspirin ws dministered throughout the 18-month period. 38 Results filed to estblish or exlude benefit or hrm from heprin (112 more with improvement in qulity of life per 1,000 [58 fewer to 149 more]) (Tble S8). 4.4 Prostnoids Prostglndins (prostglndin E1, prostglndin I2, nd their derivtives) re potent inhibitors of pltelet tivtion, dhesion, nd ggregtion nd hve vsodiltory nd ntithromboti effets. A metnlysis of five studies (1,636 ptients) suggested tht with regrd to qulity of life s inferred from MWD, ptients reeiving prostglndins re more likely to experiene n importnt benefit thn those reeiving plebo (79 more per 1,000 [58 more to 98 more]) but hve higher risk of dverse events (RR, 2.61; 95% CI, ). 43 There ws substntil heterogeneity between study results ( I 2 564%). Results filed to demonstrte or exlude n effet of prostglndins vs plebo on nonftl stroke, nonftl MI, revsulriztion, or deth. The overll qulity of the evidene is low due to nd nd for qulity of life, (Tble S9). Reommendtion For ptients with intermittent ludition refrtory to exerise therpy nd smoking esstion, we suggest the use of ilostzol in ddition to previously reommended ntithromboti therpies (spirin mg dily or lopidogrel 75 mg dily) (Grde 2C) ; we suggest ginst the use of pentoxifylline, heprinoids, or prostnoids (Grde 2C). 5.0 Critil Limb Ishemi Ptients with ritil limb ishemi hve indequte resting blood flow to the lower limbs, resulting CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e679s

13 in rest pin, ulertion, nd eventully gngrene nd limb loss. Suh ptients re ndidtes for prompt revsulriztion. Pertinent outomes inlude relief of pin, qulity of life, nd limb slvge. 5.1 Prostnoids Investigtors hve lso dministered prostglndins to ptients with ritil limb ishemi in hopes of relieving rest pin nd heling ishemi ulers. A Cohrne systemti review identified 13 studies ompring prostnoids to plebo in ptients with ritil limb ishemi without hne of resue or reonstrutive intervention. 44 These studies mesured outomes in different wys. The uthors of the review delt with this vribility by dihotomizing the ontinuous results. Pin relief ws defined s ny improvement on vlidted pin sle. Uler heling ws defined s ny derese in lesion surfe re nd presene of grnultion tissue. The overll qulity of the evidene is low beuse of limittions in design,, nd. Prostnoids improved rest pin nd uler heling (77 nd 136 ptients per 1,000 treted, respetively) but did not signifintly prevent mputtions or derese mortlity ( Tble 4, Tble S10). Prostnoids were poorly tolerted, with 75% of subjets experiening t lest one dverse event ompred with 31% of ontrols (the most ommonly reported dverse effets were hedhe, nuse, vomiting, dirrhe, nd fil flushing). A sensitivity nlysis restrited to the eight highest-qulity studies found similr results with respet to the five outome vribles. Reommendtion 5.1. For ptients with symptomti PAD nd ritil leg ishemi/rest pin who re not ndidtes for vsulr intervention, we suggest the use of prostnoids in ddition to previously reommended ntithromboti therpies (spirin mg dily or lopidogrel 75 mg dily) (Grde 2C). Vlues nd preferenes: Ptients who do not vlue unertin relief of rest pin nd uler heling greter thn voidne of high likelihood of drug-relted side effets will be disinlined to undergo prostnoid therpy. e680s 6.0 Aute Limb Ishemi Aute limb ishemi results from sudden interruption of blood flow to n extremity. 45 The most ommon uses of nontrumti ute rteril olusion re embolism nd thrombosis Approximtely 80% of peripherl emboli originte in the hert (eg, left tril ppendge, left ventriulr pex, ntive nd prostheti rdi vlves). In the remining ses, emboli originte from the ort or peripherl vessels themselves or re of venous origin (prdoxil with migrtion through ptent formen ovle nd tril septl defet). Thromboti olusion is most ommonly ssoited with dvned theroslerosis, with slow progression of disese. 47 The limb typilly hs developed ollterl blood supply, nd the finl olusion of the stenoti vessel often is not immeditely limb thretening. 45, Antiogultion for Aute Limb Ishemi Regrdless of the use nd level of ute limb ishemi, ptients usully reeive short-term ntiogultion tretment with therpeuti doses of heprin to redue the extent of ishemi injury by preventing lot propgtion nd further embolism. Although the logi of this pproh is widely epted, there re no forml studies demonstrting improved outomes with ntiogultion. The expeted dverse effet of preopertive ntiogulnt therpy is n inresed risk of bleeding, inluding wound hemtoms. To our knowledge, there re no rndomized trils diretly ompring unfrtionted heprin with other ntiogulnts in this setting. 6.2 Thrombolysis vs Surgery for Aute Limb Ishemi Tretment of ute limb ishemi is direted t restortion of flow to the oluded rtery, whih is now ommonly omplished by either surgery or theter-direted intrrteril thrombolysis. Although no forml dt support either reperfusion therpy over ntiogultion lone or supportive re, the high risk of limb loss (nd subsequent ssoited morbidity nd mortlity) without blood flow restortion hs led to widespred use of both modlities. Tble 5 nd Tble S11 summrize the results from met-nlysis tht provides the best evidene regrding the omprtive benefits nd hrms of intrrteril thrombolysis vs surgery. 48 This metnlysis presented dt from five rndomized trils of 1,180 ptients We provide bsolute effet estimtes bsed on ontrol (surgil rm) event rtes from these trils. In summry, thrombolysis ompred with surgery ppered to hve little or no effet on limb slvge but ws ssoited with n inrese risk in stroke (10 per 1,000 treted) nd mjor bleeding (16 per 1,000 treted) t 30 dys. Results filed to demonstrte or exlude n effet of thrombolysis vs surgery on mputtion or deth. We onsider the overll qulity of evidene to be moderte beuse of nd. Antithromboti Therpy in Peripherl Artery Disese

14 Tble 4 [Setion 5.1] Summry of Findings: Prostnoids vs Plebo in Ptients With Critil Limb Ishemi Ineligible for Revsulriztion 44 Outomes Prtiipnts (Studies), Follow-up Qulity of the Evidene (GRADE) Reltive Effet Antiipted Absolute Effets Risk Without Prostnoids Risk Differene With Prostnoids Totl mortlity 1,391 (5 RCT), 32 wk Low due to, RR 1.07 ( ) 121 per 1,000 d 8 more per 1,000 (from 42 fewer to,b nd 90 more) MI nonftl events Stroke, inluding nonftl ishemi nd hemorrhgi strokes Mjor extrrnil bleed Rest pin relief (ny improvement 1,116 (9 RCT), 21.4 wk RR 1.32 ( ) 243 per 1,000 d 77 more per 1,000 (from 24 more to on vlidted sle) 138 more) Uler heling (ny derese in size or grnultion tissue) Amputtions (mjor or minor mputtions) 1,132 (8 RCT), 17.5 wk Low due to nd e 1,790 (9 RCT), 23.1 wk Low due to nd f RR 1.54 ( ) 253 per 1,000 d 136 more per 1,000 (from 55 more to 242 more) RR 0.89 ( ) 313 per 1,000 d 34 fewer per 1,000 (from 75 fewer to 12 more) Adverse events 716 (8 RCT), 14.4 mo RR 2.35 ( ) 77 per 1,000 g 103 more per 1,000 (from 76 more to 137 more) 394 per 1,000 g 531 more per 1,000 (from 390 more to 701 more) See Tble 1 nd 2 legends for expnsion of bbrevitions. Unler llotion of onelment nd blinding onerns. b I %. CIs inlude both importnt benefit nd hrm. Smll number of events (145). d Control group risk estimtes ome from medin ontrol group rtes or representtive ontrol group risk of the inluded studies. e I %. f CIs inlude importnt benefit nd hrm. g Representtive ontrol group risk. CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e681s

15 Tble 5 [Setion ] Summry of Findings: Thrombolysis vs Surgery for the Tretment of Aute Limb Ishemi 48 Antiipted Absolute Effets Outomes Prtiipnts (Studies), Follow-up Qulity of the Evidene (GRADE) Reltive Effet Risk With Surgery Risk Differene With Thrombolysis Totl mortlity t 1 y 768 (3 RCTs), b 12 mo Low due to RR 0.74 ( ) 169 per 1,000 e 43 fewer per 1,000 (from 109 fewer to nd d 98 more) MI nonftl events Strokes t 30 d inludes nonftl ishemi 1,180 (5 RCTs), b,g 1-12 mo nd hemorrhgi strokes f h Mjor extrrnil bleed t 30 d 1,070 (4 RCTs), b 1-12 mo j Limb slvge t 1 y 654 (2 RCTs), b 12 mo Low due to nd k Amputtion t 1 y 768 (3 RCTs), 12 mo 0.01 ( ) i 0 per 1,000 e 10 more per 1,000 (from 0 fewer to 20 more) RR 2.34 ( ] 12 per 1,000 e 16 more per 1,000 (from 3 more to 37 more) RR 1.00 ( ) 754 per 1,000 e 0 fewer per 1,000 (from 106 fewer to 128 more) RR 1.10 ( ) 190 per 1,000 e 19 more per 1,000 (from 22 fewer to 72 more) See Tble 1 nd 2 legends for expnsion of bbrevitions. Ouriel et l48 reported tht one of 54 deths in the thrombolysis group ws from intrrnil hemorrhge, wheres none of 46 in the surgery group were from intrrnil hemorrhge. b For one study using three different doses of the thrombolyti gent, only the optiml dose is used for omprison with surgery. Control group risk estimtes ome from ontrol event rtes in the medin study (fter rrnging risks in inresing order). The 95% CI for bsolute effet inludes importnt benefit nd hrm. d I %. e Control risk estimtes from medin or representtive ontrol group risk of inluded studies. f Of reported nonftl strokes, ll hppened in the thrombolysis group, nd ll were intrrnil hemorrhges (eight of eight [100%]). gwever et l53 inluded ptients with both ute nd hroni limb ishemi. h The 95% CI for bsolute effet inludes importnt benefit nd hrm; low number of events (eight). i Pooled risk differene presented insted of reltive risk. j The 95% CIs re wide, low number of events (60). k I %. e682s Antithromboti Therpy in Peripherl Artery Disese

16 6.3 Comprison of Intrrteril Thrombolyti Agents for Aute Limb Ishemi In the pst, thrombolysis for ute limb ishemi ws dministered by IV; now this strtegy hs been repled by theter-direted thrombolysis. Evidene ompring the effiy of different intrrteril thrombolyti gents for ute limb ishemi is limited. However, in Cohrne systemti review, Robertson et l 54 identified four rndomized trils ompring reombinnt tissue-type plsminogen tivtor (rt-pa), urokinse, or streptokinse for the mngement of ute lower-limb ishemi Inluded ws one smll RCT ompring intrrteril streptokinse to intrrteril rt-pa in 40 ptients with ute limb ishemi. 55 With streptokinse, there ws n inresed rte of mputtion t 30 dys (seven of 20 vs one of 20; RR, 7.0; 95% CI, ). Results filed to demonstrte or exlude n effet of streptokinse vs intrrteril rt-pa on symptomti limb slvge, mjor hemorrhge, or deth. Initilly, streptokinse ws the most widely used gent, but sine this study 55 nd beuse of other sfety onerns (eg, llergi retions), it hs lrgely been repled by urokinse nd rt-pa. 54 Three RCTs ompred intrrteril urokinse to rt-pa for ute peripherl rteril olusion The overll qulity for this omprison is low beuse of in outome estimtes s well s limittions in design nd exeution. Results filed to demonstrte or to exlude n effet of intrrteril rt-pa vs intrrteril urokinse on mputtion, limb slvge, mjor hemorrhge, or deth (Tble S12). Reommendtion In ptients with ute limb ishemi due to rteril emboli or thrombosis, we suggest immedite systemi ntiogultion with unfrtionted heprin over no ntiogultion (Grde 2C) ; we suggest reperfusion therpy (surgery or intrrteril thrombolysis) over no reperfusion therpy (Grde 2C) ; nd we reommend surgery over intrrteril thrombolysis (Grde 1B). In ptients undergoing intrrteril thrombolysis, we suggest rt-pa or urokinse over streptokinse (Grde 2C). 7.0 Endovsulr Revsulriztion in Ptients With Symptomti PAD Ptients with refrtory ludition, rest pin, nd ishemi often require revsulriztion for symptomti relief nd limb slvge. Inresingly, ptients re undergoing PTA with or without stent plement. Few studies guide liniins regrding type nd durtion of ntithromboti therpy following suh proe- dures. Current prtie is very heterogeneous nd often is bsed on indiret evidene from studies in ptients undergoing oronry stenting. 7.1 Antithromboti Therpy Following PTA With nd Without Stent Proedures A Cohrne review 59 pooled dt from two erly studies, inluding 356 ptients undergoing lowerextremity PTA without stent plement, nd found possible redution in reolusion t 6 months in ptients tking spirin plus dipyridmole ompred with plebo (OR, 0.69; 95% CI, ). 60,61 Two other studies filed to demonstrte or exlude n effet of spirin nd dipyridmole vs phenprooumon (vitmin K ntgonist) in reolusion t 6 months following PTA (OR, 0.78; 95% CI, ). 62,63 One study filed to demonstrte or exlude n effet on 12-month reolusion in ptients tking tilopidine ompred with phenprooumon (OR, 0.71; 95% CI, ). 64 An dditionl study rndomized 179 ptients following PTA (pelvi or lower extremity) omplited by extensive dissetion to IV unfrtionted heprin vs subutneous ndroprin ( lowmoleulr-weight heprin) dministered for 1 week postproedure (followed by 6 months of spirin in eh rm). 65 Ndroprin ws ssoited with redution in vessel restenosis/olusion t 6 months (OR, 0.35; 95% CI, ) but filed to demonstrte or exlude n effet on mputtion (OR, 1.0; 95% CI, ). We hve identified no RCTs ompring ntithromboti gents post-pta with stent plement. Indeed, it remins unler whether PTA with stent plement is superior to PTA lone with respet to ptient-importnt outomes. In reent metnlysis of 10 RCTs, PTA plus routine stenting for superfiil femoropoplitel rteril disese ws ssoited with possible redution in restenosis (RR, 0.85; 95% CI, ) ompred with PTA without routine stenting but filed to demonstrte or exlude n effet on need for trget vessel revsulriztion (RR, 0.98; 95% CI, ). 66 Nevertheless, stenting is performed frequently. Despite low-qulity evidene regrding thienopyridines in ptients undergoing PTA with stent plement for PAD, mny interventionists provide loding dose of lopidogrel in ddition to spirin preproedure nd then ontinue dul ntipltelet therpy for 1 to 3 months post-pta (prtiulrly if stent is pled in smll peripherl vessel). The rtionle for this prtie is bsed on the results from oronry rtery stenting trils (see setion 3 of Vndvik et l 4 in this supplement). We re skeptil bout extrpolting these dt to ll ptients with PAD given differenes in the CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e683s