Deposited on: 8 May 2008 Glasgow eprints Service

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1 Assenburg C. and Bravo-Vergel Y. and Palmer S. and Fenwck E. and de Belder M. and Abrams K.R. and Sculpher M. (2007) Assessng the effectveness of prmary angoplasty compared wth thrombolyss and ts relatonshp to tme delay: a Bayesan evdence synthess. Heart 93:pp Deposted on: 8 May 2008 Glasgow eprnts Servce

2 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. Assessng the Effectveness of Prmary Angoplasty Compared to Thrombolyss and ts Relatonshp to Tme Delay: A Bayesan Evdence Synthess Chrstan Asseburg 1 Yolanda Bravo Vergel 1 Stephen Palmer 1 Elsabeth Fenwck 2 Mark de Belder 3 Keth R Abrams 4 Mark Sculpher 1 1 Centre for Health Economcs Unversty of York UK 2 Publc Health & Health Polcy Dvson of Communty Based Scences Unversty of Glasgow UK 3 The James Cook Unversty Hosptal Mddlesbrough UK 4 Centre for Bostatstcs and Genetc Epdemology Department of Health Scences Unversty of Lecester UK Correspondence: Mark Sculpher PhD Centre for Health Economcs Unversty of York Heslngton York YO10 5DD UK. 1

3 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. Abstract Background: Meta-analyses of trals comparng thrombolyss and prmary angoplasty followng an acute myocardal nfarcton (AMI) have shown benefts for angoplasty. Choce of therapy needs to consder the relatonshp between ths beneft and any tme delay n ntatng angoplasty. Obectve: To etend earler meta-analyses of these alternatve forms of reperfuson by consderng both 1- and 6-month outcome data. To use Bayesan statstcal methods to quantfy more fully the uncertanty assocated wth the estmated relatonshps. Methods: A systematc revew and meta-analyss publshed n 2003 was updated wth recently publshed trals. Data on key clncal outcomes and the dfference between tme-to-balloon and tme-to-needle were ndependently etracted by two researchers. Bayesan statstcal methods were used to synthesse evdence despte dfferences between trals n follow-up tmes and reported outcomes. Outcomes are presented as absolute probabltes of specfc events and odds ratos (wth 95% credble ntervals (CrI)) as a functon of the addtonal tme-delay assocated wth angoplasty. Results: A total of 22 studes were ncluded n the meta-analyss wth 3760 and 3758 patents randomsed to prmary angoplasty and thrombolyss respectvely. The mean angoplasty-related tme delay (over and above tme to thrombolyss) was 54.3 mnutes (S.E. 2.2). For ths average delay the mean event probabltes are lower for prmary angoplasty for all outcomes. Mortalty wthn 1 month s 4.5% followng angoplasty and 6.4% after thrombolyss (odds rato of 0.68 (95% CrI )). For non-fatal re-nfarcton the odds rato s 0.32 (95% CrI ); and for non-fatal stroke t s 0.24 (95% CrI ). For all outcomes the beneft of angoplasty decreases wth longer delay from ntaton. Conclusons: The beneft of prmary angoplasty over thrombolyss depends on the former s addtonal tme delay. For delays between 30 and 90 mnutes angoplasty s superor on average for 1-month fatal and non-fatal outcomes. Thrombolyss may be the preferred opton n terms of 6-month mortalty only for delays at around 90 mnutes and beyond but there s consderable uncertanty for longer tme delays. Keywords: Acute myocardal nfarcton prmary coronary angoplasty thrombolytcs meta-regresson. 2

4 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. INTRODUCTION In the UK at least ndvduals under the age of 75 years suffer an acute myocardal nfarcton (AMI) each year. 1 The relatonshp between normal coronary artery blood flow and mortalty after MI s well documented 2 so early restoraton of normal myocardal blood flow s a prme therapeutc goal for the management of MI. Pharmacologcal treatment wth thrombolytc therapy and prmary angoplasty are two dfferent modes of reperfuson therapy for ST elevaton AMI (STEMI). Meta-analyses of the varous randomsed trals comparng thrombolyss and prmary angoplasty have shown substantal benefts from angoplasty n terms of mortalty non-fatal re-nfarcton and stroke; 2-5 and they have also shown that angoplasty has lower recurrence rates and less resdual stenoss. 67 Despte the apparent clncal superorty of prmary angoplasty thrombolytc treatment s the default treatment opton n many countres because of practcal lmtatons on the use of percutaneous nterventons ncludng a shortage of cardac catheter facltes and approprately sklled staff. The choce of approprate management also needs to consder the possble tme delay n ntatng reperfuson wth prmary angoplasty compared to thrombolyss. The effect of ths angoplasty-related tme delay n reducng the mortalty beneft of angoplasty relatve to thrombolyss has been demonstrated usng metaregresson methods. 89 Ths work has been nfluental n clncal gudelnes for the management of AMI For eample European gudelnes suggest that prmary angoplasty s the preferred treatment f performed by an eperenced team less than 90 mnutes after frst medcal contact. 11 However there are some lmtatons n the analyses nformng these gudelnes. A key meta-analyss only had abstracts avalable for some trals 2 and naccuracy n data etracton has been observed. 12 The quantfcaton of the relatonshp between the beneft of angoplasty and tme delay untl ts ntaton dd not quantfy the uncertanty around ths relatonshp and the analyss was restrcted to a sub-set of maor clncal events. 8 Ths paper seeks to buld on these prevous analyses by etendng ther scope and statstcal rgor. It assesses how the treatment effect of angoplasty on fatal and non-fatal outcomes (re-nfarctons and strokes) relates to the addtonal delay nvolved n ntatng angoplasty. It also consders both the 1-month and the 6-month outcome data reported n randomsed clncal trals. Furthermore n usng Bayesan statstcal methods the paper s able to quantfy more fully the uncertanty assocated wth the estmated relatonshps. 3

5 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. METHODS Search strategy and data etracton To dentfy trals comparng ntravenous thrombolyss and prmary angoplasty n patents wth STEMI the analyss used an earler revew 2 as a startng pont. To update ths revew the followng databases were searched: Cochrane Controlled Trals Regster UK Natonal Research Regster Medlne Embase Database of Abstracts of Revews of Effects UK Natonal Health Servce Economc Evaluaton Databases and Health Technology Assessment Database. The searches were restrcted to Englsh-language studes publshed between 2002 and The ncluson crtera were consstent wth those used prevously. 25 Full detals of the search strategy are avalable n a techncal report {note to the edtor: a techncal report s submtted wth ths paper wth a vew to web-based publcaton}. Two researchers (YB CA) ndependently etracted the clncal data. Outcomes of nterest were mortalty non-fatal re-nfarctons fatal and non-fatal strokes and hemorrhagc strokes as well as any data regardng tme delay to treatment ntaton. Dscrepances were resolved by consensus and a thrd researcher (SP) was consulted when necessary. Data were also etracted on the dfference between tme-to-balloon n angoplasty and tme-to-needle n thrombolytc therapy. Ths defnton emphasses the dfferences n tmes to ntaton of treatment between the two reperfuson strateges thus avodng the problem of dfferent tmng defntons across studes. Mean tmes to treatment together wth ther standard devatons were preferred n the analyss but medans and quartles were used when these were not avalable. Where the earler revew 2 had used prelmnary data from conference abstracts these were updated wth fnal tral reports; the earler data etracton was also checked and any naccuraces were corrected. Statstcal methods The comparson n the meta-analyss was between prmary angoplasty and thrombolyss (regardless of type of drug). Because only a lmted number of trals reported 6-month data on fatal or hemorrhagc strokes these endponts were ecluded from the meta-analyss. Thus three outcomes (death non-fatal strokes and non-fatal re-nfarctons) for whch suffcent data were avalable were analysed usng an ntenton-to-treat prncple. The analyss was undertaken usng Bayesan statstcal methods These methods were used because they are more sutable for synthessng evdence when there are dfferences between trals n for eample follow-up tmes and reported outcomes. An mportant feature of Bayesan methods s that they use eternal evdence (so called pror dstrbutons ) whch represent belefs about the evdence and ts uncertanty eternal to the data etracted from the trals. Ths analyss has used non-nformatve pror dstrbutons so that the data are domnant n the results presented. A senstvty analyss was undertaken to verfy that changng the specfcaton of the pror dstrbuton dd not alter the results substantally. Bayesan methods also enable drect probablty 4

6 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. statements to be made about quanttes of clncal nterest e.g. the probablty that an nterventon s superor to another Full detals of the statstcal methods are presented n the techncal report. Brefly the meta-analyss models all outcomes of nterest as probabltes on the log-odds scale and results are reported n terms of the absolute probablty of specfc events and odds ratos (wth 95% credble ntervals (CrI)). It s assumed that baselne event rates (.e. clncal events n the thrombolyss arms) vary randomly between trals where the degree of varaton s estmated from the data (a random effect assumpton). That s although the patent populatons n dfferent trals are not dentcal they are smlar to each other. So the results of the analyss are only vald for patent populatons smlar to a hypothetcal average tral populaton. For each outcome measure the relatve treatment effect of prmary angoplasty compared to thrombolytc treatment s modelled as a random effect ; smlar but not dentcal between trals. Ths relatve treatment effect s estmated as a functon of the tme delay related to the ntaton of angoplasty. Ths relatonshp s used to establsh the etent to whch any addtonal effectveness of angoplasty s affected by the addtonal tme t takes to delver the nterventon compared to thrombolyss whlst takng nto account the uncertanty surroundng the average delay n each tral. When nterpretng the results of such a meta-regresson cauton s needed n etrapolatng the relatonshp beyond the data on tme delay observed n the trals. Also t should be recognsed that at the etremes of the tme delay data uncertanty n the estmates relatonshp wll be greater than around the md-pont. A feature of the evdence base s that some trals report outcomes at 1 month follow-up some at 6 months follow-up and some at both. In order that all these data can be used outcomes at 1 month and 6 months are assumed to dffer by a random effect. 16 Ths reflects the fact that clncal events are more lkely to occur wthn the frst month followng AMI and by allowng a relatonshp between outcomes at the two tme-ponts more of the data can be used n the analyss. Thus those studes whch do not report at 6 months can borrow strength both from those that do and from ther own results at 1 month. RESULTS Summary of the tral evdence A total of 24 studes met the ncluson crtera. Two of the studes were subsequently ecluded from the meta-analyss. One of these was ecluded because t dd not report tmes to treatment and as such could not provde data on the delay to prmary angoplasty. 17 The SHOCK study 18 was also ecluded because the prmary comparson was between emergency revascularzaton wthout dfferentatng results by type of nterventon (angoplasty 64% surgery 36%) and hence ths treatment strategy s not drectly comparable wth prmary angoplasty n the other trals. Table 1 lsts the remanng 22 studes ncluded. In comparson wth the earler revew 2 one addtonal tral 19 was dentfed whch had not been publshed at the 5

7 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. tme. In addton full tral results were avalable for three studes that had prevously been reported n abstract form only Table 1 lsts the data etracted from the 22 trals. In total these trals ncluded 3760 and 3758 patents randomsed to prmary angoplasty and thrombolyss respectvely. Eght of the 22 trals used streptoknase as the form of thrombolyss and 14 used t-pa. For angoplasty 13/22 trals used coronary stents and 8 studes used glycoproten IIb/IIIa antagonsts. The mean value of angoplasty-related tme delay (over and above tme to thrombolyss) was 54.3 mnutes (S.E. 2.2). All trals reported outcomes at between 30 days and 6 weeks (both are referred to as 1 month n the meta-analyss results) after the ntal MI; 10 out of the 22 trals also reported outcomes at 6 months follow-up. 6

8 Study Zlstra et al Table 1. Overvew of trals and key endponts and tme to treatment for prmary angoplasty (A) and thrombolyss (T). 1 month (4-6 weeks) 6 months N (A) (T) Death N (A)/(T ) / 4 Rbero et al / 1 Zwolle / 11 Berrocal et al / 6 Zlstra et al / 0 Wdmsky 10 et al / 14 de Boer et al / 8 Wdmsky et al / 42 O.R. (95% CrI) 0.1 (0 7.7) ) 0.3 2) 0.9 ( ) 2.3 (0 43) 0.5 ( ) 0.3 ( ) 0.7 (0.5 NF Renfarcton N O.R. (A)/(T (95% ) CrI) /9 4.8) / 5 3.5) / ) / 2 8.6) / 8 5.2) / ) / 6 6 / ) 0.4 NF Stroke N Death NF Renfarcton NF Stroke N (A)/(T ) 0 / 2 O.R. (95% CrI) ) 7 (A) (T) N (A)/(T ) O.R. (95% CrI) N (A)/(T ) O.R. (95% CrI) N (A)/(T ) O.R. (95% CrI) Tme (mnutes) Mea Mea n n (A) (A) / ) / 2 0 / 0 1 / 2 1 / ) ) ) / ) 0 / ) 1 / ) Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only

9 ) 1.8) 3.0) DeWood et al / 2 Grnes et al / 13 Gbbons et al / 2 Rbchn et al / 3 Garca et al GUSTO IIb / / 40 Le May et al / 2 Bonnefoy 42 et al / 16 Schomg et al / 5 Vermeer et al / ) ) 1.2 (0.1 8) 0.3 ( ) 0.2 ( ) 0.8 ( ) ) 1.3 ( ) ) 1 ( ) / ) 0 / ) / / 2 1 / 2 4 / 6 25 / 37 3 / 5 7 / 15 2 / 4 1 / ) ) 0.6 ( ) 0.5 ( ) ) 0.4 ( ) ) 0 / 0 0 / 2 1 / 5 1 / 1 0 / ) ) ) ) ) / / / / 9 2 / 1 2 ( ) ) ) ) ) / 2 2 / 2 6 / ) 1 ( ) ) ( ) 4 / ( ) 1 / ) ( ) Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only

10 Kastrat et al / 5 Aversano 22 et al / 16 Grnes et al / 8 Andersen 56 et al 2003: Referral 22* 7 Andersen 22 et al 2003: Invasve 22* / / ( ) 0.7 ( ) 0.7 ( ) 0.7 ( ) 1.1 ( ) 0 / 4 11 / 20 1 / 0 11 / 35 2 / ) 0.5 ( ) 1.8 (0 39.7) ) ) 1 / 1 3 / 8 0 / 3 9 / 11 0 / ) 0.3 ( ) ) 0.8 ( ) ) / / ) 0.8 ( ) / ( ) 5 / ) Renf. = renfarcton; SD = standard devaton; CrI = credblty nterval * Ths tral conssted of two sub-trals labelled Referral and Invasve and these are analysed as f they are two separate studes. Includes a thrd group of patents who receved thrombolytc therapy followed by transfer to angoplasty; these thrd comparators were ecluded from the present analyss. Tral used streptoknase as part the thrombolytc arm all other trals used t-pa. 9 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only.

11 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. Meta-analyss Table 2 shows the estmated probablty of each outcome occurrng wthn 1 month or 6 months after ntal treatment wth prmary angoplasty or thrombolytcs. These results are based on the average angoplasty-related tme delay of 54.3 mnutes reported n the trals estmated as a weghted average the weghts beng the total number of patents n each tral. For all outcomes the mean probablty of an event occurrng s lower for patents randomsed to prmary angoplasty. In partcular mortalty wthn 1 month s estmated to be 4.5% followng angoplasty and 6.4% after thrombolyss wth an odds rato of 0.68 (95% CrI ). For non-fatal renfarcton the odds rato s 0.32 (95% CrI ); and for non-fatal stroke t s 0.24 (95% CrI ). Table 2 also shows estmated results for the 6-month endponts whch are very smlar to those at 1 month ndcatng that the maorty of events happen n the frst month after randomsaton. As the addtonal tme delay to ntaton of prmary angoplasty s modelled eplctly t s possble to predct how partcular angoplasty-related tme delays nfluence the clncal superorty of angoplasty. For angoplasty delays of or 90 mnutes the absolute probablty dfferences and the odds-ratos of angoplasty versus thrombolytc therapy are shown n Table 3. If angoplasty could be ntated wthn 30 mnutes of possble thrombolyss the absolute probabltes of mortalty non-fatal renfarcton and non-fatal stroke at 6 months would be respectvely 3.7% 4.6% and 1.7% lower than those wth thrombolyss. For any of these outcomes the beneft of angoplasty decreases wth longer delay untl ts ntaton. Ths effect s shown n more detal n Fgure 1. In terms of mortalty angoplasty s superor to thrombolyss on average at tme delays up to 90 mnutes. Moreover n terms of the 1-month outcome of mortalty the probablty that t s superor s 97% for an addtonal delay of up to around 60 mnutes. For the 6-month outcome of mortalty there s over 95% probablty that angoplasty s superor for delays of up to around 45 mnutes and 87% for delays up to around 60 mnutes. However ths probablty goes below 50% for delays at 90 mnutes and beyond where thrombolyss could therefore be the preferred opton at least for the 6-month mortalty outcome. For non-fatal re-nfarcton and non-fatal stroke prmary angoplasty s superor on average even f t requres an addtonal tme of up to 2 hours to acheve reperfuson wth that method. For both non-fatal outcomes at one month there was over 95% probablty that angoplasty s superor at addtonal delays of up to 90 mnutes. For the correspondng 6-month outcomes there was over 95% probablty that angoplasty was superor at delays up to 80 mnutes. 10

12 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. Table 2. Estmated absolute probabltes of the occurrence of varous endponts 1 month or 6 months after angoplasty or thrombolytc therapy (mean and 95% CrI) together wth the odds ratos (95% CrI) comparng prmary angoplasty and thrombolyss and probabltes that angoplasty s superor. The results are for the average observed angoplasty-related tme delay (.e mnutes). 1-month endponts Probablty (angoplasty) Death 4.5% (3.0% 6.5%) Non-fatal renfarcton Non-fatal stroke 2.0% (1.2% 3.1%) 0.5% (0.2% 0.9%) Probablty (thrombolytcs) Odds rato 6.5% (4.5% 9.0%) 6.1% (4.1% 8.5%) 1.9% (1.0% 3.2%) 0.68 ( ) 0.33 ( ) 0.26 ( ) Probablty angoplasty superor month endponts Probablty (angoplasty) Death 5.5% (3.4% 8.8%) Non-fatal renfarcton Non-fatal strokes 2.6% (1.4% 4.8%) 0.8% (0.2% 1.0%) Probablty (thrombolytcs) 7.7% (5.0% 11.8%) 6.9% (4.4% 10.7%) 2.8% (1.1% 6.9%) Odds rato 0.70 ( ) 0.33 ( ) 0.26 ( ) Probablty angoplasty superor

13 Table 3. Absolute probablty dfferences (thrombolyss mnus angoplasty) odds ratos for the 6-month treatment effects of angoplasty compared to thrombolytc therapy (mean and 95% CrI) and probablty that angoplasty s superor at assumed angoplasty-related tme delays of and 90 mnutes. Endpont Death Non-fatal renfarcton Non-fatal stroke Prmary angoplasty-related tme delay 30 mnutes 60 mnutes 90 mnutes Probablty Odds Probablty Odds Probablty dfference rato dfference rato dfference (95% CrI) (95% CrI) (95% CrI) 3.5% ( 7.2% 0.5%) 4.8% ( 8.2% 2.2%) 2.1% ( 5.8% 0.5%) 0.54 ( ) 0.30 ( ) 0.47 ( ) Probablty angoplast y s a superor treatment % ( 5.6% +1.7%) % ( 7.5% 1.6%) % ( 5.6% 0.4%) ( ) 0.39 ( ) 0.56 ( ) Probablty angoplasty s a superor treatment % ( 4.6% +8.1%) % ( 7.1% +1.6%) % ( 5.3% +0.8%) Odds rato Probablty angoplasty s a superor treatment ( ) ( ) 0.79 ( ) 0.93 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only.

14 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. Fgure 1. Treatment effect of prmary angoplasty relatve to thrombolytc therapy n terms of the absolute probablty dfferences for each key outcome (death non-fatal re-nfarctons non-fatal strokes) and pont of follow-up (1- month 6-month). The graphs show means and 95% CrIs plotted aganst the addtonal tme delay to ntatng prmary angoplasty. Values above the -as ndcate that angoplasty results n fewer clncal events. Each pont represents a tral and ther sze s proportonal to the tral sample sze. DISCUSSION The contrbuton of ths revew s twofold. Frstly t updates the most comprehensve recent meta-analyss of randomsed trals comparng prmary angoplasty and thrombolyss n patents wth STEMI. 2 Secondly t etends the evdence synthess by evaluatng the relatonshp between the treatment effects of angoplasty and tme delay epressed as the dfference n tmes to ntaton of treatment between the two reperfuson strateges. Furthermore to our knowledge ths s the frst study that eplctly models the measurement uncertanty assocated wth angoplasty-related tme delay. Although Keeley et al 2 do not drectly address the ssue of tme delay the man results n that study can be compared wth those presented here for the average tme delay of 54.3 mnutes. For mortalty at 1 month Keeley et al found an odds rato of 0.70 (95% confdence nterval ) whch s smlar to that reported here although our estmate does not reach statstcal sgnfcance. Ths lack of statstcal sgnfcance s lkely to be due to dfferences n the data etracton 12 the ncluson of addtonal evdence and also because the measurement uncertanty n the tme delay covarate s eplctly consdered here. For the outcome of non-fatal re-nfarcton the results here are smlar to those of Keeley et al n terms of both the magntude and uncertanty of the odds rato. The analyss of the stroke outcome s not comparable to that n Keeley et al whch ncluded all strokes compared to the non-fatal strokes consdered here. Although a separate analyss of the longerterm follow-up data was undertaken by Keeley et al these results were not presented n suffcent detal to allow a relable comparson between the two sets of analyses at 6 months. Another reason why there wll be slght dfferences between the two meta-analyses s that n ours the uncertanty n the between-study varablty of the effect s approprately taken n to account thus producng slghtly wder CrIs than those obtaned usng Classcal metaanalyss methods Based on research undertaken durng a smlar perod to our own Boersma et al. 41 have also recently demonstrated usng ndvdual patent data from 22 trals that angoplasty s assocated wth sgnfcantly lower 30-day mortalty re-nfarcton and stroke relatve to thrombolyss regardless of delay n presentaton. The man results n that study for the overall angoplasty-related delay of 55 mnutes can be compared wth those presented here for the average tme delay of 54.3 at 1-month (Table 2) although there were mnor dfferences n the trals ncluded n the two studes. The absolute dfferences 13

15 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. n the rsks of non-fatal MI and stroke between angoplasty and thrombolyss at one month were very smlar (4.3% vs 4.1% for non-fatal MI and 1.7% vs 1.4% for non-fatal stroke n Boersma et al and the current study respectvely). The estmated absolute reducton n mortalty rsk wth angoplasty at one month was hgher n the Boersma et al study: 2.6% versus 2%. As seen n prevous studes 842 the beneft of angoplasty n terms of mortalty decreases the longer the tme delay to ntaton of angoplasty. However none of these studes (ncludng Boersma et al. 41 ) quantfy the uncertanty n ths relatonshp fully. The comprehensve handlng of uncertanty n the current analyss allows the precson assocated wth the relatonshp to be presented (Fgure 1). The Bayesan approach also facltates the presentaton of results n terms of the probablty of one nterventon of beng the superor treatment. Ths s the frst study to lnk eplctly short-term (1 month) wth longer-term (6 months) outcomes usng as much of the avalable clncal evdence as possble. Although none of the tral data ndcate systematc dfferences between the relatve treatment effect of prmary angoplasty at 1 month and at 6 months fewer data are generally avalable at 6 months resultng n greater uncertanty. It s therefore not surprsng that the pont estmates of the relatve treatment effect of angoplasty are smlar at the two tme-ponts but wth greater uncertanty at 6-month endponts. Thus a probablty of superorty of angoplasty n terms of the 6-month mortalty endpont of greater than 0.95 can be dentfed for delays of up to around 45 mnutes only whlst for delays at around 90 mnutes thrombolyss appears to be superor. However angoplasty appears to be superor for 6-month non-fatal outcomes on average for delays up to around 90 mnutes. It should be noted however that the uncertanty n these relatonshps shown here s less than t would have been had only 6 month follow-up data been used n the analyss due to the paucty of the data. The analyss suggests therefore that angoplasty performs better than thrombolytc therapy but ths superorty s related to angoplasty-related tme delay. It should be emphassed however that no trals have been dentfed whch show a statstcally sgnfcant advantage for thrombolyss at very long angoplasty-related tme delays. Moreover the PRAGUE-2 tral ndcates that angoplasty performs better than thrombolyss even when t nvolves a patent transfer of up to 3 hours. 21 Wthout more evdence at long angoplasty-related tme delays the lnear regresson model estmated here wll nevtably ndcate that the relatve treatment effect of prmary angoplasty becomes negatve at an unspecfed delay. Ths s not because of data showng ths effect but smply because a consstent relatonshp has been observed for a range of relatvely short tme delays. In realty for delays approachng 2 hours ths study can nether confrm nor refute whether angoplasty s better than thrombolytc treatment. Ths study has some lmtatons. Frstly the lack of ndvdual patent data precludes the analyss of how the relatve effect of angoplasty vares between patent sub-groups and whlst ths analyss has taken account of the uncertanty n the average tme delay thus reducng the possblty of ecologcal fallacy 43 the presence of an ecologcal bas cannot be entrely 14

16 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. elmnated. However ths s less of an ssue when t s recognzed that the am of ths study s to provde evdence to support populaton-based decsons usng cost-effectveness analyss as reported n the companon paper {ref to CE paper}. However an analyss of ndvdual patent data would also enable a more approprate estmate of the mpact or otherwse of tme delay on outcome to be obtaned Secondly tme-to-needle s a predctor of the success of thrombolytc treatment but ths effect could not be ncluded n the analyss eplctly due to nconsstent reportng of the data n the trals. Hence the results are based on the average tme-to-needle n the studes consdered whch at 75 mnutes was shown to be smlar to the medan call to needle tme (67 mnutes) n the UK (personal communcaton Dr John Brkhead UK Myocardal Infarcton Natonal Audt Proect). Further research would be desrable to dentfy all eternal evdence on the effect of tme-to-needle on outcomes and ncorporate ths nto our analyss va approprate pror dstrbutons takng account of relevance and qualty. 15 Thrdly gven ths revew was an update of those publshed earler nether the effect of publcaton bas study qualty or the nfluence of ndvdual studes were formally assessed on the overall meta-analyss results. Fourthly further eploraton of whether the potental relatonshp between tme-delay and effect (log odds rato) s lnear may be of mert. The fnal lmtaton concerns the use of older streptoknase trals n the metaanalyss. Keeley et al were crtcsed 46 for ncludng these trals n ther metaanalyss because by effectvely averagng across the thrombolytc trals the addtonal beneft of angoplasty may have been over-estmated. However streptoknase s the most common form of thrombolytc therapy used n many countres and s used n about a thrd of patents n the UK (personal communcaton Dr John Brkhead UK Myocardal Infarcton Natonal Audt Proect). In the present meta-analyss the dfferences between thrombolytc drugs were gnored wth a focus on prmary angoplasty or thrombolyss as two treatment groups. If only t-pa trals were analysed the relatve beneft of prmary angoplasty s attenuated: 1-month odds-ratos for mortalty are found to be 0.71 (95% CrI ); for non-fatal re-nfarcton 0.41 (95% CrI ); and for non-fatal strokes 0.23 (95% CrI ). Full detals of ths senstvty analyss are reported n the techncal report. The polcy mplcatons of ths analyss should be seen n the contet of the relevant health care system. For eample US gudelnes currently recommend that prmary angoplasty should be used only wthn an angoplasty-related delay of less than 60 mnutes. 10 The gudelnes however seem to be based largely on the work of Nallamothu and Bates 8 and may be premature because angoplasty appears to convey health benefts even when the delay s longer than 60 mnutes. Even at delays longer than 1 hour angoplasty s superor on average for all the 1-month outcomes ncluded n ths study although there s consderable uncertanty assocated wth these estmates. What sze of treatment effect would be necessary wth prmary angoplasty to be consdered worthwhle gven the maor changes n servce organzaton necessary for ts mplementaton? Ths ssue s consdered drectly n the cost- 15

17 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. effectveness analyss submtted as a companon paper whch addresses whether the health benefts of prmary angoplasty are suffcent to ustfy ts addtonal cost. Wth respect to the absolute sze of treatment effect wth prmary angoplasty our analyss shows that the probablty that prmary angoplasty reaches at least a 1% 2% and 3% mprovement n survval at 1- month relatve to thrombolyss s and 0.15 respectvely at the average angoplasty-related tme delay. In short the beneft of tmely treatment s the key: If prmary angoplasty can be delvered n a tmely fashon current evdence supports ts use; f not the choce of treatment probably depends on tme from onset of symptoms to presentaton and the avalablty of pre-hosptal thombolyss. 35 Decsons about approprate methods of reperfuson should consder not only the effectveness of each treatment opton but also ther cost-effectveness. Wth the quantfcaton of both the epected treatment effects of angoplasty wth regard to several possble outcomes and the uncertantes assocated wth these predctons ths meta-analyss usng Bayesan methods lays the foundatons for a robust cost-effectveness analyss n whch other treatment strateges may be consdered and n whch approprate account s taken of statstcal clncal and methodologcal heterogenety and all sources of uncertanty

18 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. Techncal Append [Note to edtor: ths append could be web-based or publshed wth the paper.] The results of the 22 trals dentfed were formally combned usng metaanalytc approaches. A Bayesan evdence synthess s mplemented 48 usng specalst software (WnBUGS). 49 A random-baselne random-effects approach s adopted for each outcome measure 5051 that ncorporates a lnear regresson of the treatment effect (log odds rato) on the covarate PCIrelated tme delay. 52 The model assumptons are descrbed step by step below. Multple outcomes In the tral search strategy we dentfed three clncal outcomes that are reported by a suffcent number of trals to nform an evdence synthess: death non-fatal strokes and non-fatal re-nfarctons. Wth such bnomal outcomes where an event ether happens or does not happen treatment effects can be modelled as absolute or relatve rsk dfferences or as logodds. 53 For numercal convenence we model all treatment effects on the logodds scale. To reflect slght dfferences n recrutment crtera and patent m for each outcome the baselne event rates are assumed to vary randomly around a common mean. Multple tme-ponts Whle all trals report outcomes at the 1-month endpont a number of trals also report clncal events at the 6-month endpont. However any event that has occurred by 1 month wll stll have occurred by 6 months so these endponts are clearly related. Statstcally such a stuaton can be modelled by assumng that for each treatment arm and outcome the 1-month and the 6- month endponts dffer by a random effect addtve on the log-odds scale. We assume that these random effects are unrelated to the covarates that may eplan some of the varaton n the treatment effect of PCI compared to thrombolytc therapy. Treatment effect of PCI relatve to thrombolyss For each tral and outcome we model the treatment effect of PCI relatve to thrombolyss as a random effect addtve on the log-odds scale respectng both the randomsaton n the clncal tral and the heterogenety of treatment effects measured by dfferent trals. We assume that the same mean treatment effect of PCI relatve to thrombolyss apples at both the 1-month and the 6-month tme-pont of each tral. Ths assumpton s supported n the tral reports whch show that most clncal events occur wthn a few days from the ntal epsode (e.g. Aversano et al 39 Schomg et al 54 Le May et al 34 García et al 32 ). We do not attempt to mpute the 6-month data for those trals that dd not report t and therefore the average treatment effect of PCI relatve to thrombolytc therapy wll be nformed more strongly by the 1-month data that are reported more commonly. The mean treatment effect of PCI relatve to thrombolyss s modelled n terms of the covarate PCI-related tme 17

19 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. delay (.e. the addtonal tme to PCI over and above thrombolyss) by lnear regresson [e. g. Berkey et al ]. Correlated outcomes We dentfy and model two sources of correlaton between event rates. Baselne log-odds for the three outcomes are correlated across trals (e. g. hgh baselne mortaltes may systematcally concde wth elevated or reduced rates of non-fatal strokes). Also wthn each outcome we model correlaton of the four endponts (1-month and 6-month endponts on two treatment arms) but we allow the eact nature of these correlatons to vary dependent on outcome [e. g. van Houwelngen et al ]. We parameterse all the above correlatons by multvarate normal dstrbutons (on the log-odds scale). Covarate PCI-related tme delay To model the measurement error n the covarate PCI-related tme delay we model ndependently the delays assocated wth each treatment (tme to needle/balloon) as measured n each tral and calculate the value of the covarate by subtracton. For each treatment arm the tral reports gve a summary statstc (.e. mean wth standard error or medan wth confdence nterval) whch we have nterpreted to obtan a pror mean and varance under the assumpton of normalty. For those trals that do not report the varablty n tmes to treatment we used the correspondng average values from the other trals. Because treatment effect n our model only depends on the PCIrelated tme delay.e. the dfference between the delays n the two arms of each tral t s rrelevant whether a tral measures the tme from occurrence of symptoms to reperfuson or from randomsaton to begnnng of treatment as long as both arms of the tral are consstent and assumng that there s no wthn-tral correlaton. Statstcal Model Table A1 shows the equatons used n the analyss for each component of the model. Throughout let nde the trals and nde the clncal endponts. Also let captal letters N R stand for the 6-month endpont data and small letters n r denote 1-month endpont data from the trals for the two arms = P T (PCI or thrombolytcs). Probabltes π are estmated on the log-odds scale. Baselne probablty log-odds are denoted by µ. Random effects are modelled as addtve on the log-odds scale and the mean underlyng probabltes shall be denoted by λ. The log-odds dfferences between 1- month and 6-month probabltes are denoted by ω. Tme delays as measured n each tral arm shall be wrtten as δ ther means as δ and the observed varance as v. The covarate PCI-related tme delay s denoted by and the coeffcents of the lnear regresson by α (ntercept) and β (slope). Wshart pror dstrbutons were used for the covarance matrces n whch the degrees of freedom were set to the rank of the covarance matr whlst for means and regresson parameters Normal or half-normal pror dstrbutons were assumed n whch hyper-pror unform dstrbutons for the correspondng standard devaton were used. 18

20 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. Parameter Estmaton The parameters of the model were estmated usng Markov Chan Monte Carlo (MCMC) methods as mplemented n WnBUGS software Convergence was assessed va senstvty analyses wth respect to ntal values length of burn-n and length of sample usng both vsual nspecton of trace plots and by runnng multple chans assessed by the Gelman-Rubn convergence statstc. 55 Fnal parameter estmates are based on a burn n of 5000 and a sample of teratons. Senstvty analyses wth respect to pror dstrbutons especally for the covarance matrces were also undertaken. 19

21 20 Table A1. The equatons used n the analyss for each component of the model Model component Equatons (for all where approprate) Tral data ( ) n Bn r ~ π and ( ) N Bn R ~ Π Probabltes on logt scale 1 log λ π π = and 1 log Λ = Π Π Correlated wthnoutcome errors Λ Λ Λ Λ P T P T P T P T X MVN ~ λ λ λ λ where X s the between-tmepont covarance matr for the th outcome and s assumed constant across trals. Eplan treatment effects ω = λ + Λ to relate 1-month and 6-month outcomes T P + + = β α λ λ for the treatment effect Random baselnes = = = Y MVN T T T ~ µ µ µ λ λ λ where Y s the betweenoutcome covarance matr for thrombolytc therapy and s assumed constant across trals. tme delay covarate T P δ = δ Measurement error n tme delay ( ) v N ~ δ δ For Evaluaton Only. Copyrght (c) by Fot Software Company Edted by Fot PDF Edtor

22 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. Acknowledgements The authors gratefully acknowledge the contrbuton of our clncal Epert Advsory Group consstng of Drs. Davd Gray Rob Henderson and Jm McLenachan. The vews epressed are those of the authors who are also responsble for any errors. Competng nterests All authors declare that the answer to the questons on your competng nterest form ( are all No and therefore have nothng to declare wth the ecepton of Mark Sculpher and Mark de Belder who have receved research fundng and consultancy fees from varous manufacturers of medcal devces such as coronary stents. The Correspondng Author has the rght to grant on behalf of all authors and does grant on behalf of all authors an eclusve lcence (or non eclusve for government employees) on a worldwde bass to the BMJ Publshng Group Ltd and ts Lcensees to permt ths artcle (f accepted) to be publshed n HEART and any other BMJPGL products to eplot all subsdary rghts as set out n our lcence ( Sources of fundng Ths study was funded by an unrestrcted educatonal grant from Cords Ltd whch played no part n the desgn eecuton or dssemnaton of the research. Mark Sculpher also receves fundng va a Career Award n Publc Health funded by the NHS Research and Development Programme. 21

23 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. References 1. Brtsh Heart Foundaton. Incdence of myocardal nfarcton. Accessed Keeley EC Boura JA Grnes CL. Prmary angoplasty versus ntravenous thromblytc therapy for acute myocardal nfarcton: a quanttatve revew of 23 randomzed trals. Lancet 2003;361(9351): Dalby M Bouzamondo A Lechat P Montalescot G. Transfer for prmary angoplasty versus mmedate thrombolyss n acute myocardal nfarcton: a meta-analyss.[see comment]. Crculaton 2003;108(15): PCAT. Prmary coronary angoplasty compared wth ntravenous thrombolytc therapy for acute myocardal nfarcton: s-month follow up and analyss of ndvdual patent data from randomzed trals. Amercan Heart Journal 2003;145(1). 5. Cucherat M Bonnefoy E Tremeau G. Prmary angoplasty versus ntravenous thrombolyss for acute myocardal nfarcton.[update of Cochrane Database Syst Rev. 2000;(2):CD001560; PMID: ]. Cochrane Database of Systematc Revews 2004;3. 6. Zlstra F. Acute myocardal nfarcton: prmary angoplasty. Heart 2001;85(6): Smth D Channer KS. Prmary angoplasty should be frst lne treatment for acute myocardal nfarcton. For and aganst. BMJ 2004;328: Nallamothu BK Bates ER. Percutaneous coronary nterventon versus fbrnolytc therapy n acute myocardal nfarcton: s tmng (almost) everythng? Amercan Journal of Cardology 2003;92(7): Kent DM Lau J Selker HP. Balancng the benefts of prmary angoplasty aganst the benefts of thrombolytc therapy for acute myocardal nfarcton: the mportance of tmng. Effectve Clncal Practce 2001;4: Antman EM Anbe DT Armstrong PW et al 2004;110: ACC/AHA gudelnes for the management of patents wth ST-elevaton myocardal nfarcton - eecutve summary: a report of the Amercan College of Cardology/Amercan Heart Assocaton Task Force on Practce Gudelnes. Crculaton 2004;110: Slber S Albertsson P Avlés FF et al. Gudelnes for percutaneous coronary nterventons: the Task Force for Percutaneous Coronary Interventons of the European Socety of Cardology. European Heart Journal 2005;26:

24 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. 12. Nallamothu BK Antman EM Bates ER. Prmary percutaneous coronary nterventon versus fbrnolytc therapy n acute myocardal nfarcton: does the choce of fbrnolytc agent mpact on the mportance of tme-to-treatment? The Amercan Journal of Cardology 2004;94: Spegelhalter DJ Myles JP Jones DR Abrams KR. An ntroducton to Bayesan methods n health technology assessment. Brtsh Medcal Journal 1999;319: Sutton AJ Abrams KR. Bayesan methods n meta-analyss and evdence synthess. Statstcal Methods n Medcal Research 2001;10: Spegelhalter DJ Abrams KR Myles JP. Bayesan approaches to clncal trals and health-care evaluaton. Chchester: Wley Larose DT Dey DK. Grouped random effects models for Bayesan metaanalyss. Statstcs In Medcne 1997;16: Akhras F Abu Ousa A Swann G et al. Prmary coronary angoplasty or ntravenous thrombolyss for patents wth acute myocardal nfarcton? Acute and late follow-up results n a new cardac unt. J Am Coll Cardol 1997;29 (suppl):a Hochman JS Sleeper LA Webb JG Sandborn TA Whte HD Talley JD et al. Early revascularzaton n acute myocardal nfarcton complcated by cardogenc shock. New England Journal of Medcne 1999;341(9): de Boer M Hoornte JCA Ottervanger JP et al. Immedate coronary angoplasty versus ntravenous streptoknase n acute myocardal nfarcton: left ventrcular eecton fracton hosptal mortalty and renfarcton. JACC 1994;23: Berrocal DH Cohen MG Spnetta AD Ben MG Roas Matas CA Gabay JM et al. Early reperfuson and late clncal outcomes n patents presentng wth acute myocardal nfarcton randomly assgned to prmary percutaneous coronary nterventon or streptoknase. Amercan Heart Journal 2003;146(6). 21. Wdmsky P Budesnsky T Vorac D Groch L Zelzko M Aschermann M et al. Long dstance transport for prmary angoplasty vs mmedate thrombolyss n acute myocardal nfarcton. Fnal results of the randomzed natonal multcentre tral--prague-2. European Heart Journal 2003;24(1): Andersen HR Nelsen TT Rasmussen K Thuesen L Kelbaek H Thayssen P et al. A comparson of coronary angoplasty wth fbrnolytc therapy n acute myocardal nfarcton. New England Journal of Medcne 2003;349(8):

25 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. 23. Zlstra F de Boer MJ Hoornte JC et al. A comparson of mmedate coronary angoplasty wth ntravenous streptoknase n acute myocardal nfarcton. N Engl J Med 1993;328: Rbero EE Slva LA Carnero R et al. Randomzed tral of drect coronary angoplasty versus ntravenous streptoknase n acute myocardal nfarcton. J Am Coll Cardol 1993;22: Zlstra F Beukema WP van't Hof AWJ Lem A Reffers S Hoornte JCA et al. Randomzed comparson of prmary coronary angoplasty wth thrombolytc therapy n low rsk patents wth acute myocardal nfarcton. Journal of the Amercan College of Cardology 1997;29(5): Wdmsky P Groch L Zelzko M et al. Multcentre randomzed tral comparng transport to prmary angoplasty vs mmedate thrombolyss vs. combned strategy for patents wth acute myocardal nfarcton presentng to a communty hosptal wthouth a catheterzaton laboratory. The PRAGUE study. Eur Heart J 2000;21: de Boer MJ Ottervanger JP van't Hof AW Hoornte JC Suryapranata H Zlstra F et al. Reperfuson therapy n elderly patents wth acute myocardal nfarcton: a randomzed comparson of prmary angoplasty and thrombolytc therapy. [see comments.]. Journal of the Amercan College of Cardology 2002;39(11): DeWood D et al. Drect PTCA vs ntravenous t-pa n acute myocardal nfarcton: results from a prospectve radomzed tral. Thrombolyss and Interventonal Therapy n Acute Myocardal Infarcton Symposum VI. Washngton George Washngton Unversty Grnes CL Browne KF Marco J et al. A comparson of mmedate angoplasty wth thrombolytc therapy for acute myocardal nfarcton. N Engl J Med 1993;328: Gbbons RJ Homes DR Reeder GS et al. Immedate angoplasty compared wth the admnstraton of a thrombolytc agent followed by conservatve treatment for myocardal nfarcton. N Engl J Med 1993;328: Rbchn F Steffenno G Dellavalle A Ferrero V Vado A Feola M et al. Comparson of thrombolytc therapy and prmary coronary angoplasty wth lberal stentng for nferor myocardal nfarcton wth precordal ST-segment depresson: mmedate and long-term results of a randomzed study. Journal of the Amercan College of Cardology 1998;32(6):

26 Edted by Fot PDF Edtor Copyrght (c) by Fot Software Company For Evaluaton Only. 32. Garca E Elzaga J Sorano J et al. Prmary angoplasty versus thrombolyss wth t-pa n anteror myocardal nfarcton: results from a sngle tral. J Am Coll Cardol 1999;33: GUSTO Investgators. A clncal tral comparng prmary coronary angoplasty wth tssue plasmnogen actvator for acute myocardal nfarcton. The Global Use of Strateges to Open Occluded Coronary Arteres n Acute Coronary Syndromes (GUSTO IIb) Angoplasty Substudy Investgators [publshed erratum appears n N Engl J Med 1997 Jul 24;337(4):287]. New England Journal of Medcne 1997;336(23): Le May MR Labnaz M Daves RF Marqus JF Laramee LA O'Bren ER et al. Stentng versus thrombolyss n acute myocardal nfarcton tral (STAT). Journal of the Amercan College of Cardology 2001;37(4): Bonnefoy E Lapostolle F Lezorovcz A Steg G McFadden EP Duben PY et al. Prmary angoplasty versus prehosptal fbrnolyss n acute myocardal nfarcton: a randomsed study. Lancet 2002;360(9336): Schomg A Kastrat A Drschnger J Mehll J Schrcke U Pache J et al. Coronary stentng plus platelet glycoproten IIb/IIIa blockade compared wth tssue plasmnogen actvator n acute myocardal nfarcton. New England Journal of Medcne 2000;343(6): Vermeer F Oude Ophus AJ van der Berg EJ et al. Prospectve randomsed comparson between thrombolyss rescue PTCA and prmary PTCA n patents wth etensve myocardal nfarcton admtted to a hosptal wthout PTCA facltes: a safety and feasblty study. Heart 1999;82: Kastrat A Mehll J Drschnger J Schrcke U Neverve J Pache J et al. Myocardal salvage after coronary stentng plus abcmab versus fbrnolyss plus abcmab n patents wth acute myocardal nfarcton: a randomsed tral. Lancet 2002;359(9310): Aversano T Aversano LT Passaman E Knatterud GL Terrn ML Wllams DO et al. Thrombolytc therapy vs prmary percutaneous coronary nterventon for myocardal nfarcton n patents presentng to hosptals wthout on-ste cardac surgery: a randomzed controlled tral. [see comments.]. Jama 2002;287(15): Grnes CL Westerhausen DR Jr. Grnes LL Hanlon JT Logemann TL Nemela M et al. A randomzed tral of transfer for prmary angoplasty versus on-ste thrombolyss n patents wth hgh-rsk myocardal nfarcton: the Ar Prmary Angoplasty n Myocardal Infarcton study. [see comments.]. Journal of the Amercan College of Cardology 2002;39(11):