Professional guideline versus product label selection for treatment with IV thrombolysis: An analysis from SITS registry

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1 Origial research article Professioal guidelie versus product label selectio for treatmet with IV thrombolysis: A aalysis from SITS registry Europea Stroke Joural 0(0) 1 8! Europea Stroke Orgaisatio 2017 Reprits ad permissios: sagepub.co.uk/jouralspermissios.av DOI: / jourals.sagepub.com/home/eso Ala C Camero 1, James Bogie 1, Azmil H Abdul-Rahim 2, Niaz Ahmed 3,4, Michael Mazya 3,4, Robert Mikulik 5, Werer Hacke 6 ad Keedy R Lees 1 ; for the Safe Implemetatio of Treatmets i Stroke (SITS) Ivestigators Abstract Itroductio: Thrombolysis usage i ischaemic stroke varies across sites. Diverget advice from professioal guidelies ad product labels may cotribute. Patiets ad methods: We aalysed SITS-Iteratioal registry patiets erolled Jauary 2010 through Jue We grouped sites ito orgaisatioal tertiles by umber of patiets arrivig 2.5 h ad treated 3 h, percetage arrivig 2.5 h ad treated 3 h, ad umbers treated 3 h. We assiged scores of 1 3 (lower/middle/upper) per variable ad 2 for osite thrombectomy. We classified sites as lower efficiecy (summed scores 3 5), medium efficiecy (6 8) or higher efficiecy (9 11). Sites were also grouped by adherece with Europea product label ad ESO guidelie: label adheret (>95% o-label), guidelie adheret (5% off-label, 95% o-guidelie) or guidelie o-adheret (>5% off-guidelie). We cross-tabulated site-efficiecy ad adherece. We estimated the potetial beefit of uiversally selectig by ESO guidace, usig oset-to-treatmet time-specific umbers eeded to treat for day 90 mrs 0 1. Results: A total of 56,689 patiets at 597 sites were icluded: 163 sites were higher efficiecy, 204 medium efficiecy ad 230 lower efficiecy. Fifty-six sites were label adheret, 204 guidelie adheret ad 337 guidelie o-adheret. There were strog associatios betwee site-efficiecy ad adherece (P < 0.001). Almost all label adheret sites (55, 98%) were lower efficiecy. If all patiets were treated by ESO guidelies, a additioal 17,031 would receive alteplase, which traslates ito 1922 more patiets with favourable three-moth outcomes. Discussio: Adherece with product labels is highest i lower efficiecy sites. Closer aligmet with professioal guidelies would icrease patiets treated ad favourable outcomes. Coclusio: Product labels should be revised to allow treatmet of patiets 4.5 h from oset ad aged 80 years. Keywords Alteplase, product label, professioal guidelie, thrombolysis Date received: 17 September 2017; accepted: 30 October 2017 Backgroud Thrombolysis with itraveous recombiat tissue plasmioge activator (IV rt-pa) (alteplase; Actilyse or Activase) is effective ad safe for patiets with acute ischaemic stroke, ad yet oly a fractio of 1 Istitute of Cardiovascular ad Medical Scieces, Uiversity of Glasgow, Glasgow, UK 2 Istitute of Neurosciece ad Psychology, Uiversity of Glasgow, Glasgow, UK 3 Departmet of Neurology, Karoliska Uiversity Hospital, Stockholm, Swede 4 Departmet of Cliical Neurosciece, Karoliska Istitute, Stockholm, Swede 5 Iteratioal Cliical Research Cetre, Neurology Departmet, St Ae s Hospital ad Masaryk Uiversity, Bro, Czech Republic 6 Departmet of Neurology, Uiversity of Heidelberg, Heidelberg, Germay Correspodig author: Ala C Camero, Istitute of Cardiovascular ad Medical Scieces, Uiversity of Glasgow, 126 Uiversity Place, Glasgow G12 8TA, UK. ala.camero.2@glasgow.ac.uk

2 2 Europea Stroke Joural 0(0) patiets receive treatmet. 1 9 The product labels for IV rt-pa i Europe (EU) ad the Uited States (US) are derived from early radomised cotrolled trials, which excluded importat groups. 10 The EU label restricts treatmet to patiets uder 80 years, whilst the US label excludes patiets greater tha 3 h from symptom oset. IV rt-pa is effective ad safe withi 4.5 h of symptom oset, ad there is clear treatmet beefit i the elderly. 9,14 18 Professioal guidace from the Europea Stroke Orgaisatio (ESO) ad America Stroke Associatio (ASA) better reflects the evidece base for alteplase The ESO recommed treatmet withi 4.5 h with o age limit, whilst ASA guidace i 2013 excluded patiets aged >80 years beyod 3 h, although a update i 2016 ackowledged alteplase is effective withi 4.5 h i the elderly. 9,19 21 Thus, patiets are ofte treated off-label, 22 although this practice is ot permitted i may coutries ad the curret product labels therefore restrict the umber of patiets who ca be treated. 1,22 We aimed to assess variatio i the use of IV rt-pa withi the Safe Implemetatio of Treatmets i Stroke Iteratioal Stroke Thrombolysis Registry (SITS-ISTR), i relatio to the pricipal criteria that differ betwee regioal product labels ad professioal guidelies. Our objective was to assess whether cetres expertise, measured i terms of efficiet patiet throughput ad treatmet logistics, is associated with closer adherece to the EU/US drug labels ad professioal guidelies ad to estimate the potetial impact o treatmet rates ad cliical outcomes if there were greater aligmet of the product labels ad professioal guidelies. We hypothesised that cetres which achieve excellet treatmet logistics will adhere more closely with professioal guidelies rather tha strictly observig the product label for IV alteplase. Methods We coducted a retrospective aalysis o idividual patiet data obtaied from the SITS-ISTR betwee Jauary 2010 ad Jue 2016 (Figure 1). SITS-ISTR is a multiatioal ope registry of patiets with acute ischaemic stroke who received IV rt-pa. 23 Patiets from 597 participatig cetres were icluded, who had complete iformatio o treatig hospital ad coutry, age, geder, oset-to-treatmet time (OTT), total Natioal Istitutes of Health Stroke Scale (NIHSS), history of diabetes ad stroke. We excluded patiets o direct oral aticoagulats or with OTT recorded as >6 h. Baselie characteristics icluded data o pre-stroke modified Raki Scale (mrs), medical history ad medicatios. We also gathered data for osite use of thrombectomy. We grouped sites accordig to their selectio adherece of alteplase use: label adheret (>95% of patiets treated withi label), guidelie adheret (5% of patiets treated off-label but 95% of patiets treated withi guidelie) or guidelie o-adheret (>5% of patiets treated off-guidelie). We assessed site quality usig a tertile-based scorig algorithm. Sites were grouped ito tertiles accordig to (i) the volume of patiets arrivig withi 2.5 h ad treated withi 3 h, (ii) the percetage of patiets arrivig withi 2.5 h ad treated withi 3 h, ad (iii) the volume of patiets treated withi 3 h of stroke oset. We assiged sites a score for each variable: 1 poit if the site was withi the lower tertile, 2 poits for the middle tertile or 3 poits for the upper tertile. A additioal 2 poits were allocated for osite use of thrombectomy. This resulted i a total score betwee 3 ad 11 for each site. We classified sites with scores of 3 to 5 as lower efficiecy, 6 to 8 as medium efficiecy ad 9 to 11 as higher efficiecy. We tested associatios betwee site efficiecy ad selectio adherece of alteplase use by cross-tabulatio ad Chi-squared aalyses performed i SPSS versio 22.0, with a sigificace level of 5%. We estimated the potetial for cliical beefit if treatmet for all patiets withi our cohort was by the professioal guidelie versus product label for alteplase. We performed this aalysis by applyig guidelie criteria for treatmet with IV rt-pa to our etire cohort, ad compared this to the umber of patiets who would have bee treated if the product label criteria were applied. We coducted separate aalyses for both Europea (ESO guidelie ad EU label) ad America (ASA guidelie ad FDA label) criteria applied to the etire dataset. We calculated the umber of patiets for whom treatmet would have bee cotraidicated by the product label but recommeded by professioal guidelie. We stratified such patiets accordig to OTT: withi 90 mi, 91 to 180 mi or 181 to 270 mi. We used OTT-specific umbers eeded to treat (NNT) for a day 90-modified Raki Scale (mrs) of 0 1 to estimate the umber of additioal patiets who would achieve a favourable outcome if treatmet was provided uiversally by professioal guidelie rather tha by product label (NNT of 4.5 if OTT was 0 to 90 mi, NNT of 9.0 if OTT 91 to 180 mi ad NNT of 14.1 if OTT 181 to 270 mi). We divided the umber of additioal patiets who would be treated withi each time widow by the correspodig NNT to estimate the umber of patiets who would achieve a favourable outcome. Results We aalysed data from 56,689 patiets treated at 597 sites durig the study period. Baselie characteristics of

3 Camero et al. 3 Figure 1. Selectio process of the study populatio. the patiets are show i Table 1. By our predefied criteria, 163 sites (27%) were classified as higher efficiecy, 204 sites (34%) as medium efficiecy ad 230 sites (39%) as lower efficiecy. Whe aalysig selectio adherece across all sites by the EU product label ad ESO guidelie, we foud that 56 sites (9%) were label adheret, 204 sites (34%) were guidelie adheret ad 337 sites (56%) were guidelie o-adheret. Site efficiecy was strogly associated with selectio adherece by Europea criteria (p < 0.001) (Figure 2). Amog the 56 labeladheret sites, 55 (98%) were lower efficiecy ad oe oly (2%) was medium efficiecy. Of the 204 guidelieadheret sites, 92 (45%) were lower efficiecy, 75 (37%) were medium efficiecy ad 37 (18%) were higher efficiecy. Amog the 337 guidelie o-adheret sites, 126 (37%) were higher efficiecy, 128 (38%) were medium efficiecy ad 83 (25%) were lower efficiecy. Whe we judged use i our maily Europea dataset agaist US product label ad ASA guidelie criteria, a similar patter emerged except that guidelie oadherece rose (see olie Appedix). IV rt-pa was admiistered to 5770 patiets (10%) beyod Europea guidelie recommedatios. This was due to patiets treated with a BP greater tha guidelie recommedatios i 4618 patiets (8%), a OTT greater tha 4.5 h i 1047 patiets (2%) ad a combiatio of elevated BP with a OTT greater tha 4.5 h i 105 patiets (0.2%). Amog the 5770 patiets admiistered IV rt-pa beyod Europea guidelie recommedatios, 3845 (67%) were treated i a higher efficiecy site, 1644 (28%) i a medium efficiecy site ad 281 (5%) i a lower efficiecy site (Figure 3).

4 4 Europea Stroke Joural 0(0) Withi our cohort, 50,919 patiets (90%) would receive thrombolysis if treatmet was uiversally delivered by the ESO guidelie, compared to 33,888 patiets (60%) by the Europea product label. Thus, a Table 1. Baselie characteristics of the cohort. Characteristic Age (years) Sex (male) Baselie NIHSS Oset-to-treatmet time (mi) Atrial fibrillatio Hypertesio Diabetes mellitus Hypercholesterolaemia Heart failure Smoker Previous stroke or TIA Measure Mea (SD) Media (IQR) Media (IQR) Etire cohort N ¼ 56, (13.1) 30,969 (55%) 10 (6 16) 151 ( ) 11,947 (21%) 37,641 (66%) 10,604 (19%) 16,455 (29%) 4702 (8%) 9347 (17%) 9067 (16%) IQR: iterquartile rage; NIHSS: Natioal Istitutes of Health Stroke Scale; TIA: trasiet ischaemic attack. additioal 17,031 patiets (30%) would receive thrombolysis if treatmet was uiversally delivered accordig to ESO guidace. This traslates ito 1922 patiets who would achieve a favourable outcome whe measured by OTT-specific NNT for a day 90 mrs of 0 1 (Figure 4). Discussio We have demostrated that strict adherece with the product label for IV rt-pa is greatest i sites that treat lower volumes of patiets, have fewer facilities or achieve less impressive i-hospital timelies. Strict adherece with the product label restricts use of IV rt-pa, reducig the umber of patiets who ca be treated ad, by implicatio, who may achieve favourable outcomes. If treatmet decisios withi our cohort were based o ESO guidelies rather tha the Europea drug label, a additioal 2620 patiets would be treated aually across the 6.5 years studied. This traslates ito a additioal 296 patiets each year with favourable outcomes. Evidece supportig the selectio criteria described i the ESO ad ASA professioal guidelies is robust, ad the coclusios of these orgaisatios agree o all major poits The drug product labels for alteplase require review i both Europe ad America, to reflect evidece highlightig the efficacy ad safety of IV rt-pa i circumstaces that were origially cosidered cotraidicatios for thrombolysis. 1,24,25 The key issue is that these labels, which simply cotrol marketig activities ad ot prescribig per se, should permit the maufacturers to discuss ad educate cliicias o the safe treatmet of Key Guidelie No-Adheret (>5% off guidelie) Guidelie Adheret ( 5% off label, 95% o guidelie) Label Adheret (>95% o label) Figure 2. Site efficiecy ad selectio adherece with EU Product Label ad ESO Guidelie.

5 Camero et al. 5 Figure 3. The percetages of patiets treated off-guidelie grouped by site efficiecy, accordig to ESO guidelie criteria ( ¼ 5770). Key Treatmet with IV alteplase NOT recommeded Treatmet with IV alteplase recommeded Figure 4. The percetage of patiets who would be treated if the decisio was based o ESO guidace versus EU product label: a additioal 17,031 patiets (30%) would be treated if the decisio was based o ESO guidace, which traslates ito 1922 patiets achievig favourable outcomes whe estimated usig OTT-specific NNT for a day 90 mrs of 0 1. patiets withi 4.5 h of symptom oset or aged over 80 years. Revisig the Europea ad America product labels to this effect would deliver cliical outcomes cosistet with those obtaied whe treatig withi the curret drug labels, with o adverse effect o mortality. 26 Aligmet of educatioal messages is desirable ad should be coveyed amog the medical commuity. 9 Our data demostrate that less efficiet sites have the lowest rates of treatmet with alteplase off-label, which may i part be attributable to less developed regios beig uable to treat off-label. 27 This is cosistet with fidigs from a previous study usig SITS-ISTR data, which demostrated that higher volume cetres have the greatest rates of treatmet with alteplase offlabel. 28 Improvig the quality of treatmet for every patiet with acute stroke is a priority of the ESO ad World Stroke Orgaisatio (WSO), with the Agels Iitiative recetly itroduced to help achieve this goal. Educatio of cliicias ad revisio of the product labels for alteplase will help our effort to deliver excellet care for patiets with acute ischaemic stroke worldwide. It is cocerig that we observed high rates of treatmet with alteplase beyod professioal guidelies. Offguidelie treatmet was admiistered to 10% of patiets by Europea criteria, which was drive by treatmet above BP recommedatios ad beyod 4.5 h. Treatmet with alteplase off-guidelie exposes patiets to a icreased risk of mortality that is ot offset by potetial for cliic beefit 26 ad cliicias should avoid this practice. Violatios of pre-treatmet BP parameters

6 6 Europea Stroke Joural 0(0) are associated with a icreased risk of bleedig, ad BP should be cotrolled before treatmet with IV rt-pa to reduce the risk of symptomatic itracerebral haemorrhage. 24,25 Most off-guidelie treatmets were i higher efficiecy sites, ad programmes discouragig this approach should iclude all the stroke commuity. We desiged a measure of site efficiecy that acts as a marker of site quality. We allocated poits for efficiet treatmet logistics, the volume ad proportio of patiets treated promptly ad osite use of thrombectomy. Our aim was to stratify sites accordig to treatmet logistics, patiet volume ad delivery of comprehesive acute stroke care. Various idicators ca be used to assess quality of acute stroke uit care, 29 although ot all of these data are available withi SITS-ISTR. Our measure of site quality is arbitrary ad uses objective iformatio available withi SITS-ISTR defied before we accessed the data, which is thus a weakess of our study. The criterio for site quality icludes measures derived maily from OTT ad volume of patiets, which may disadvatage cetres with loger out-of-hospital trasportatio logistics ad smaller sites. We defied BP based o that recorded at baselie withi the SITS registry ad caot be certai that BP was ot lowered prior to thrombolysis, which is a limitatio. A further limitatio is the retrospective ad observatioal desig, although the large volume ad accuracy of data collected withi SITS-ISTR allow for robust statistical aalyses. 23 SITS-ISTR is a predomiatly Europea cohort which is importat whe cosiderig the geeralisability of our fidigs. Patiets maaged outside Europe are ofte i coutries with less experieced cetres, ad our results are relevat to these regios. Fially, SITS-ISTR icludes patiets volutarily registered by participatig cetres which could cotribute to selectio bias, although data from SITS are robust ad have bee used i similar studies. 14,23,28 Coclusio We cofirmed that strict adherece with the more restrictive product label for alteplase was cocetrated amog the least active or efficiet hospitals, whereas more experieced sites offer treatmet based o professioal guidelie criteria. However, we foud that the busiest ad most efficiet sites are treatig beyod eve the professioal guidelies, potetially exposig these patiets to a risk of icreased mortality that is ot offset by potetial for cliical beefit. We coclude that review ad aligmet of the marketig approvals for alteplase i acute ischaemic stroke with the curret recommedatios of the professioal guidelies, to allow treatmet of patiets 4.5 h from oset ad aged 80 years, should be coupled with ehaced educatio to operate withi those guidelies to maximise the populatio safety ad effectiveess of thrombolysis for stroke. Ackowledgemets We would like to thak the Safe Implemetatio of Treatmets i Stroke (SITS) Registry ad Scietific Committee for their assistace with this research. Declaratio of Coflictig Iterests The author(s) declared the followig potetial coflicts of iterest with respect to the research, authorship, ad/or publicatio of this article: KRL is a member of the Stroke Thrombolysis Trialists Collaboratio that has published pooled idividual patiet data aalyses of the effects of rt- PA i acute ischaemic stroke; a member of the Scietific Committee of SITS; is Past Presidet of the Europea Stroke Orgaisatio that publishes guidelies o stroke maagemet ad coordiates the ESO-Agels project; ad has received fees ad expeses for data moitorig committees from Boehriger Igelheim. WH reports o curret coflicts. He declares that he served at the SCs of the ECASS 1 4 trials ad has bee compesated for work i the SCs ad for lectures i the past. NA is the Vice Chairma ad MM is a Researcher at SITS Iteratioal, which receives a urestricted grat from Boehriger Igelheim for the SITS-Iteratioal Stroke Thrombolysis Register. Fudig The author(s) disclosed receipt of the followig fiacial support for the research, authorship, ad/or publicatio of this article: SITS (Safe Implemetatio of Treatmets i Stroke) is fiaced directly ad idirectly by grats from Karoliska Istitutet, Stockholm Couty Coucil, the Swedish Heart- Lug Foudatio, the Swedish Order of St. Joh, Frieds of Karoliska Istitutet, ad private doors, as well as from a urestricted sposorship from Boehriger- Igelheim. SITS has previously received grats from the Europea Uio Framework 7, the Europea Uio Public Health Authority ad Ferrer Iteratioal. SITS is curretly coductig studies supported by Boehriger-Igelheim ad EVER Pharma, as well as i collaboratio with Karoliska Istitutet, supported by Stryker, Covidie ad Pheox. N Ahmed is supported by grats provided by the Stockholm Couty Coucil ad the Swedish Heart-Lug Foudatio. RM has bee supported by the project o. LQ1605 from the Natioal Program of Sustaiability II (MEYS CR) ad by the project FNUSA-ICRC o. CZ.1.05/1.1.00/ (OP VaVpI). Iformed coset Not applicable. Ethical approval Ethical approval for this study was obtaied from the Safe Implemetatio of Treatmets i Stroke (SITS) Scietific Committee.

7 Camero et al. 7 Guarator KRL. Cotributorship KRL, ACC, JB ad AHAR researched literature ad coceived the study. KRL, ACC, JB ad AHAR were ivolved i protocol developmet, gaiig SITS Scietific Committee approval ad data aalysis. ACC, JB ad AHAR wrote the first draft of the mauscript. All authors reviewed ad edited the mauscript ad approved the fial versio of the mauscript. Refereces 1. Meretoja A, Putaala J, Tatlisumak T, et al. Off-label thrombolysis is ot associated with poor outcome i patiets with stroke. Stroke 2010; 41: The Natioal Istitute of Neurological Disorders ad Stroke rt-pa Stroke Study Group. Tissue plasmioge activator for acute ischemic stroke. N Egl J Med 1995; 333: Hacke W, Kaste M, Fieschi C, et al. Itraveous thrombolysis with recombiat tissue plasmioge activator for acute hemispheric stroke. The Europea Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274: Hacke W, Kaste M, Fieschi C, et al. Radomised doubleblid placebo-cotrolled trial of thrombolytic therapy with itraveous alteplase i acute ischaemic stroke (ECASS II). Lacet 1998; 352: Wardlaw JM, Zoppo G, Yamaguchi T, et al. Thrombolysis for acute ischaemic stroke. Cochrae Database Syst Rev 2003; 12: CD Meretoja A ad Tatlisumak T. Thrombolytic therapy i acute ischemic stroke basic cocepts. Curr Vasc Pharmacol 2006; 4: Meretoja A ad Tatlisumak T. Novel thrombolytic drugs: will they make a differece i the treatmet of ischaemic stroke? CNS Drugs 2008; 22: Schumacher HC, Batema BT, Bode-Albala B, et al. Use of thrombolysis i acute ischemic stroke: aalysis of the Natiowide Ipatiet Sample 1999 to A Emerg Med 2007; 50: Demaerschalk BM, Kleidorfer DO, Adeoye OM, et al. Scietific ratioale for the iclusio ad exclusio criteria for itraveous alteplase i acute ischemic stroke: a statemet for healthcare professioals From the America Heart Associatio/America Stroke Associatio. Stroke 2016; 47: Gumbiger C, Reuter B, Stock C, et al. Time to treatmet with recombiat tissue plasmioge activator ad outcome of stroke i cliical practice: retrospective aalysis of hospital quality assurace data with compariso with results from radomised cliical trials. BMJ 2014; 348: g Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Egl J Med 2008; 359: Wahlgre N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase h after acute ischaemic stroke (SITS- ISTR): a observatioal study. Lacet 2008; 372: Lees KR, Bluhmki E, Kummer vo R, et al. Time to treatmet with itraveous alteplase ad outcome i stroke: a updated pooled aalysis of ECASS, ATLANTIS, NINDS, ad EPITHET trials. Lacet 2010; 375: Mishra NK, Ahmed N, Aderse G, et al. Thrombolysis i very elderly people: cotrolled compariso of SITS Iteratioal Stroke Thrombolysis Registry ad Virtual Iteratioal Stroke Trials Archive. BMJ 2010; 341: c6046 c Karli ski M, Kobayashi A, Litwi T, et al. Itraveous thrombolysis for acute ischaemic stroke i patiets ot fully adherig to the Europea licece i Polad. Neurol Neurochir Pol 2014; 46: Ford GA, Ahmed N, Azevedo E, et al. Itraveous alteplase for stroke i those older tha 80 years old. Stroke 2010; 41: Meseguer E, Labreuche J, Olivot JM, et al. Determiats of outcome ad safety of itraveous rt-pa therapy i the very old: a cliical registry study ad systematic review. Age Ageig 2008; 37: Egelter ST, Boati LH ad Lyrer PA. Itraveous thrombolysis i stroke patiets of > or ¼80 versus <80 years of age a systematic review across cohort studies. Age Ageig 2006; 35: Europea Stroke Orgaisatio (ESO) Executive Committee, ESO Writig Committee. Guidelies for maagemet of ischaemic stroke ad trasiet ischaemic attack Cerebrovasc Dis 2008; 25: ESO Guidelie Update (Abstract) Jauary 2009, Europea Stroke Orgaisatio. ESO_Guidelie_Update_Ja_2009.pdf (accessed 28 August 2017). 21. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelies for the early maagemet of patiets with acute ischemic stroke: a guidelie for healthcare professioals from the America Heart Associatio/America Stroke Associatio. Stroke 2013; 44: Cappellari M, Moretto G, Micheletti N, et al. Off-label thrombolysis versus full adherece to the curret Europea Alteplase licese: impact o early cliical outcomes after acute ischemic stroke. J Thromb Thrombolysis 2013; 37: Scheitz JF, Abdul-Rahim AH, MacIsaac RL, et al. Cliical selectio strategies to idetify ischemic stroke patiets with large aterior vessel occlusio. Stroke 2017; 48: Tsivgoulis G, Safouris A ad Alexadrov AV. Safety of itraveous thrombolysis for acute ischemic stroke i specific coditios. Expert Opi Drug Saf 2015; 14: Frak B, Grotta JC, Alexadrov AV, et al. Thrombolysis i stroke despite cotraidicatios or warigs? Stroke 2013; 44:

8 8 Europea Stroke Joural 0(0) 26. Hacke W, Lyde P, Emberso J, et al. Effects of alteplase for acute stroke accordig to criteria defiig the Europea Uio ad Uited States marketig authorizatios: Idividual-patiet-data meta-aalysis of radomized trials. It J Stroke. Epub ahead of prit doi: / Nomai AZ, Nabi S, Badshah M, et al. Review of acute ischaemic stroke i Pakista: progress i maagemet ad future perspectives. Stroke Vasc Neurol 2017; 2: Aai N, Mazya MV, Bill O, et al. Chages i Europea Label ad guidelie adherece after updated recommedatios for stroke thrombolysis: results from the safe implemetatio of treatmets i stroke registry. Circ Cardiovasc Qual Outcomes 2015; 8: S155 S Wiedma S, Norrvig B, Nowe T, et al. Variatios i quality idicators of acute stroke care i 6 Europea coutries. Stroke 2012; 43: