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5.2.1 In Observational Studies 9 5.3 IST-3 9 5.4 Pooled/Meta-Analyses 9 6. Dosage an d Administration 9 7. PlaceofAlteplase in the Mana gem ent ot Acu te Ischaemic Stroke 9

bstr ct AU eplase Actilyse, Activase)is a recombinant tissue-type plasminogenactivator that activates plasminogen directly to plasmin.It is the only pharmacological treatment currently approved for patients with acute ischaemic strokeThis article reviews the efficacy and tolerability of alteplase, focusing on datrelevant to treatment between 0 and 4.5hours after onset ofstroke, and summarizesitspharm acological properties.Well designed clinical trials showed that alteplase administered within 3hour intheNI ND S t rial )andbetween 3 and 4.5hours(in theECASSIII trial) aftestroke onset significantly improved clinical outcomes at 90days relative to placebo. Alteplase was generally well tolerated in these trials, with no significandifference observed between alteplaseand placebo recipientsin the90-daymortality rates, despite significantly higher incidences of any and symptomatiintracranial haem orrhages in alteplase recipients.These results were generally supp orted bythoseofthe SITS-MO STandSITSISTR observational studies, which showed that alteplase was effective and generallywell tolerated when administered within 4.5 hours ofstroke onsetinroutine clinica

practice. However, results from SITS-IST R indicated that the safety an d functionaoutcomes were generally less favourable when alteplase wasadministered3-4.5hours after stroke onset than within 3hoursof stroke onset. Add itionally, resultfrom pooled analysesof randomized clinical trials indicated that thebenefit ofalteplase therapy over placebo decreasedas thetime between stroke onsetandtreatment initiation increased, with nosignificant benefit observed w hen trea tm entwasinitiated >4.5 hour s after s troke onset. M oreover, the odds of mortality increasedasthe time between stroke onset andtreatme nt initiation increased. Thus, the greatesbenefitofalteplase thera pyisgained with early trea tmen t.Based on these results, current EUlabellingand treatment guidelines recommend that alteplase should be administered as early as possible within 4.5 hours o

symptom onset in patients with acute ischaemic stroke. However, recent resultfrom a meta-analysis and IST-3 suggest that some patients maybenefit fromtreatmentup to 6hours after stroke onset. Patientsforwhom alteplase therapyiscontraindicated as per currentEUlicensing criteria, suchasthose aged >80 yearsmay also benefit from therapy. Further randomized trials of alteplase administered >4.5hours after stroke in selected patients are required toconfirm thesfindings.

ntroduction

Intravenous alteplase (Actilyse, Activase)dations were updated * ^ and the window of trment with alteplase was extended until 4.5 hafter onset of symptoms; however, governm

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s.t '^1 In oth er c ou ntr ies , such as th e USf'' and

Th is article reviews the efficacy and tolerab ility

2 Pharmacodynamic PropertiesAiteplase, a recombinant tissue-type plasmino-t activates plasm inogen directly to plasmin.t^' '

In the plasma, tPA is thought to have a plas-

In the brain, tPA is believed to play a cruciale in the control of homeostasis of the C N S,' '^ '

oede m a a nd ischaemic cell dea th).t' '12.1 Fibrlnolytic EffectOwing to the relative fibrin-specificity of aite-

100mg intravenous

decrease from baseline in absolute plasma levelsof fibrinogen).['^1 Plasma plasminogen levels alsodecreased after alteplase treatment, with meanresidual levels being 52% and 61%of baseline at 3and 5 hours, which recovered to a mean residuallevel of69%at 27 hours after treatment (p< 0.001for the decrease from baseline in absolute plasmalevels of plasminogen).t'^l In an oth er study in pa -tients (n =73valuable) who received in trave nou salteplase 1.25mg/kg over 3 hours, mean residualfibrinogen levels were 64% at 6 ho urs a nd 84% at24 hours (values estimated from a graph); onlyeight (11%) alteplase recipients had fibrinogenlevels of

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[58% vs 2 3% of p atien ts; p = 0.037] in alteplaserecipients than in control patients. ' '^' See table IIIfor the definitions and descriptions of efficacymeasures.Arterial recanalization was also observed in asubgro up of pafients (n = 79) who h ad hyperdenseartery sign (H A S; a mar ker of clot in the prox imalmiddle cerebral artery) on the baseline com putedtomography (CT) scan in the NINDS clinicaltrial in patients with acute ischaemic stroke (seesection 4 for study design details). ' '^' At 24 hoursafter treatment, significantly (p 0.03) more al-teplase (0.9 mg /kg; n = 37) tha n placeb o (n 42)recipients had resolution of HAS (38% vs 17%).Moreover, alteplase recipients with resolution ofH A S had significantly (p = 0.004) sm aller infarctvolumes than those who had persistence of HAS.However, resolution of HAS was not associatedwith significant improvem ent in functional outcom es(as assessed by the mRS and Barthel Index).' '*'The thrombolytic efficacy of intravenous alte-plase in other large clinical trials in patients withacute ischaemic stroke is discussed in section 4.

2.3 Other EffectsStudies have suggested that alteplase mediatesa cerebral ischaemia-induced increase in the per-meability of the neurovascular unit, which mayresult in the passage of fluids from the intra-vascular space into the ischaemic brain, leadingto the development of oedema and haemorrhagictrans form ation . ' ' For example, after adm inis-tration of alteplase in rodent models of emboliefocal ischaemia, the blood-brain barrier perme-ability (as assessed by the extravasation of Evansblue dye) and matrix metalloproteinase-9 levelswere increased in both the central and peripheralischaemic regions. ' '^ 'Trea tme nt w ith alteplase in patients with acuteischaemic stroke was also shown to increase thepermeability of the neurovasc ular unit.'^'^'' In one

study, patients receiving alteplase (n = 15) had sig-nificantly (p 0.008) more blood-brain barrier

0.56 ml/100 g/min].'2' In ano the r study, hyintense acute injury marker (thought to repredelayed contrast enhancement on MRI becof blood-brain barrier disruption) was foun50% of alteplase recipients (n = 24) com pwith 30% of pafients who received no acute tapy (n=60) . '2 ' '

tPA has also been associated with neuroteffects (e.g. synaptic plasticity and cell deaththe brain paren chym a.' ' ' ' Anim al studies suggethat the presence of tPA in the brain p arenchwas a ssoc iated with ne uro na l death' ^ ^''' several plasminogen-dependent and -indedent mechanisms have been proposed to expthese effects. For example, the generationplasmin via tPA may have deleterious effsuch as degradation of the components ofextracellular matrix (thereby disrupting neuextracellular matrix interaction, which sensihippocampal neurons to cell death), '^^' activaof microglial cells (thought to partly reguneuronal death via excitotoxicity)'^^' and int ion of chemokine macrophage chemoattracprotein (a key downstream effector of the extoxicity pathway believed to recruit micro

(26]Studies in animals have also suggested th at may play a role in nitric oxide-dependent extoxicity. It is thought that tPA may interact the NMDA receptor, resulting in the producof nitric oxide, leading to n euron al cell death , may activate microglia, which can release varneurotoxic factors including nitric oxide.'^^Additionally, tPA may have pro-apoptodc'^and-apoptotic effects, '^ ' according to data f

in vitro studies, with the reason for these trasting effects currently being u ncle ar. ' ' ' 'No studies have been undertaken to assessinteracdon between alteplase and other drugse.g. cardioactive or cerebroactive drugs.'*' risk of bleeding may be increased if heparintamin K antagonists or drugs that alter pla

funcdon are administered prior to, during or aalteplase treatment.'^'^-^' Concomitant admini

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Pharmacokinetics of intravenous aiteplase in patients with n= 12) who received a 10 mg bolus overinutes (infusion A) , followed by a 50 mg dose over 60 minutes

Mean values

s2 (ng/m L)

(%) {%)

s (L)

331022109303833.615.53.7663132.89.3

a and y t^ and AUC values were calculated after infusion C.Proportion of total AU C.C=area under the plasma concentration-time curve of the a (AUCp) and y (AUCy) phases; CL=total clearance;

he a (t ^ J , (t^p) andy (ty^)phases; V|=vo lum e of distribution ofvolume of distribution at steady state.

3 Pharmacoicinetic PropertiesThe pharm acokinetics of intravenou s alteplase

Alteplase is cleared rapidly from circulating a and half-lives accounting formajority of clearance (97 of the area under I P^^

ear in the urine within day.'^^'

when administered between 0 and 4.5 hours afterischaemic stroke onset. Key trials assessing itsefficacy within 3 hou rs of sympto m onset a rediscussed briefly (section 4.1), followed by a dis-cussion of results from trials assessing its efficacybetween 3 and 4.5 hours after symptom onset(section 4.2). Also discussed are several pooledanalyses and meta-analyses (section 4.4), whichincluded data from trials assessing the efficacy ofalteplase administered 0-4.5 hours or 0-6 hoursafter symptom onset. Data from the latter studiesare briefly summ arized in section 7 and w ill not bediscussed here, as these studies included data rel-evant to the adm inistration of alteplase beyond thecurrently app roved treatment window (section 6).

In add ition , the recently published IST-3 study' '*'is discussed, although it should be noted that themajority (95 ) of valuable patien ts in this studydid no t meet current EU licensing criteria.Trial acronyms/abbreviations are presented intable II and the definitions/descriptions of keyefficacy measures used in these trials are pre-sented in table III.4.1 Treatmenf wifhin 3 Hours of Stroke Onset4.1.1 heNINDS rialThe thrombolytic efficacy of alteplase admin-istered within 3 hours of acute ischaemic strokeversus that of placebo was assessed in the N IN D S

Table ii Trial acronyms/abbreviations and definitionsAcronym/abbreviationATLANTIS

CASESECASSEPITHETIST-3NINDSSITS-ISTR

DefinitionAlteplase ThromboLysis for AcuteNoninterventional Therapy in IschaemicStrokeCanadian Alteplase for StrokeEffectiveness StudyEuropean Cooperative Acute Stroke StudyEchoplanar Imaging ThrombolyticEvaluation TrialThird international Stroke TrialNational Institute of Neurologic Disordersand StrokeSafe Implementation of Thrombolysis in

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Table III Definitions/descriptions of outcome measuresMeasure Definition/descriptionBl Asse sses the ability to perform activities of daily living (score range: 0 [complete dependence ] to 100 [independence ]); whe

repo rted, ^' pts who died were also scored as 0GOS A 5-point scale on which1= independence,3 =severe disability and 5= dea thmRS A measure of disability (score range: 0 [no symptom s at all] to 6 [death]; a score of 5 indicates severe disability)NIHSS A 15-item scale measuring the level of neurological impairmen t (total score range: 0 to 42, with higher values indicating mosevere infarct [scores 25 indicate very severe impairment]) l= Barthel Index; GOS =Glasgow Outcome Scale;mRS= modified Rankin scale; NIHSS=National Institutes of Health Stroke pts= patients.

trial, which was carried out in two parts. '^^' Pa rt 1was designed to assess the improvement in N IH SSscores 24 hours after stroke onset, while part 2assessed the chnical outcome at 90 days afterstroke onset, with a favourable outcome definedas minimal or no disabihty as measured by fourassessment scales (NIHSS, Barthel Index, Glas-gow Outcome Scale and mRS) representing dif-ferent aspects of stroke recovery. Key inclusionand exclusion criteria and baseline characteristicsof patients participating in this study are sum-marized in table IV. ' ^'

In patients with acute ischaemic stroke, treat-men t with alteplase within 3 hours of symp tomonset significantly improved clinical outcome at90 days, but no t 24 hou rs, after stroke onset. '^^' Inpar t of the NINDS trial, at 24 hours, there wasno significant difference between alteplase andplacebo recipients in terms of the proportion ofpatients who had an improvement from baselineof>4points in the NIHSS score or complete res-olution of neurological deficit (i.e. NIHSS scoreof 0) [primary outcome; table V]. However, inpart 2 of the trial, 90 days after treatment, a sig-nificant benefit of alteplase therapy over placebowas observed in terms of the global test statistic(primary outcome), with significantly more alte-plase than placebo recipients achieving favour-able outcomes as assessed by the four individualmeasures (Barthel Index, Glasgow OutcomeScale, mRS and NIHSS) [table V\ Fur thermore ,the treatment effect remained significant when

The benefit of alteplase therapy over placwas maintained during a 12-month followwith significantly more alteplase than plarecipients likely to have minimal or no disab(as assessed by the global test statistic) at 6 12 months (primary outcome; tableV).'^^'In addition, a post hoc subgroup analysis gested that alteplase therapy was benefacross a broad range of subgroups (stratified

cording to baseline and demographic characistics), as there were no significant subgrouptreatment interactions. '^ ' Another post hocgroup analysis suggested that the benefit of

Table IV Key eligibility criteria and baseline characteristpatients in the NINDS trial, a 2-part, randomized, doubleInclusion criteriaR s w ith ischaemic stroke with a clearly defined time of onset neurological deficit measurable on the NIHSS who receivedtreatment 185/110 mmHBaseline characteristicsMean age" (y)Median NIHSS scoreMean glucose (mg/dL)Mean bodyweight (kg)

Alteplase681414976

Placebo66=15=15180

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Thrombolytic eff icacy of intravenous alteplase administered within 3 hours of symptom onset in patients with acute ischaemic(0.9mg/kg;m aximum 90 mg) or placebo in the NINDStrial,a 2-part, rand om ized, double-blind trial (parts 1

udy Favourable outcom e Tim e ofassessment24 h24 h90 d

90 d

6 m o

1 2 m o

Proportion of ptsALT*4748NR54474738NR50394431NR504143NR504143

PL3939NR39273121NR38263220NR372931NR382832

O R (95%C l)

NRNR2.1 (1 .3 ,3 .2 ) *1 .8(1.1 ,2 .8)*2 . 3 ( 1 . 4 , 3 . 6 ) *2 . 0 ( 1 . 2 , 3 . 1 )2 . 2 ( 1 . 3 , 3 . 7 )1.7(1.2 ,2 .6)*1 .6(1.1 ,2 .5)*1 .7(1.1 ,2 .6)*1 .6(1.1 ,2 .5)*1 .7(1.0 ,2 .8)*1 .7 (1 .3 , 2 .3 ) *1 .7 (1 .2 , 2 .4 ) *1 .8 (1 .3 , 2 .5 ) *1 .6(1.2 ,2 .3)* *1 .7 (1 .2 , 2 .3 ) *1 .6 (1 .1 , 2 .1 )1 .8 (1 .3 , 2 .5 ) *1 .6(1.1 ,2 .2)*

RR (95%C l)

1 .2(0.9 ,1 .6)1.2(0.9 ,1 .5)NR1.4 (1 .1 , 1.8)1.7(1.3 ,2 .3)1.5(1.1 ,2 .0)1.8(1.2 ,2 .6)NR1.3(1.0, 1.7)1.5(1.1 ,2 .0)1.4(1.0, 1.8)1.5(1.0 ,2 .2)NR1.4(1.1 ,1 .6)1.4(1.2 ,1 .8)1.4(1.1 ,1 .7)NR1.3(1.1 ,1 .5)1.5(1.2 ,1 .8)1.3(1.1 ,1 .6)

rt 1 ' ^ ' NIHSS score of 0 or >4 pnt improvement from BL 24 hNIHSS score of 0 or >4 pnt improvement from BLGlobal test statistic

Bl score of 295mRS score 95mRS score of 95mRS score of

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NIHSS score of >25); stroke w ithin previous3 mon ths; history of prior stroke and concom itantdiabetes meilitus and mRS score of >1 . Baselinecharacteristicsofpatients inSITS-M OST wereroughly similartothose inpooled randomized

Results from SITS-MOST supported the find-ings of the pooled randomized, controlled trialsand showed that alteplase treatment was effectivewhen administered within 3 hours of stroke onsetin routi ne clinical practice.'"*' A t 90 da ys, 54.8%of patients in SITS-MOST and 49.0% of patientsin randomized, controlled trials (pooled data)had functional independence (mRS score of 0-2)and 38.9% and 42.3%ofpatie nts, respectively,had complete recovery (mRS score of or I).'"*'

A multivariate analysis of data from SITS-M OS T showed th at older age, high blood glucose,diastolic BP >90 mm Hg , high N IHS S scores, cur-rent infarction on imaging scans, disability beforecurrent stroke (mRS scoreof2-5) and previousstroke were relatedtolower functional indepen-denceat90 days.'' '^' After adju stm ent forthesevariables, the rate of functional independenceat90 days in SITS -MO ST was 50.4% compared with50.1% (unadjusted analysis) in the pooled ran-domized '^

4.2 Treatmeint 3-4.5 Hours After Stroke O nse t4 2 1The EC SSIIITrialThe thrombolytic efficacy of alteplase adminis-tered between 3 and 4.5 hours after acute ischaemicstroke versus that ofplaceb o was assessedinthe large, randomized, double-blind, ECASS IIItrial.[^^' Key inclusion and exclusion criteria andbaseline characteristicsofpatients participatingin this study are summarizedintable V I. T herewere no significant differences between the twogroups in terms ofdem ographics andclinicalcharacteristics, apart from significantly (beforeadjustment for multiple comparisons) more pla-

cebo than alteplase recipients having greaterneurological impairment (i.e. severityofstroke)

outcomes relative to placebo.'^^ Significmore alteplase than placebo recipients hadvourable outcomeat90 days, as assessed b yprop ortion of patients with m RS scores of 0(^primary endpoint; table VII). Furthermore,tre atm en t effect re ma ined significant (p = 0.0apost hoc, intent-to-treat (ITT) analysis adjufor confounding baseline variables (alteplasplacebo O R 1.42 [95% C I, 1.02,1.98]).t35]

Alteplase was also associated w ith a signifimprovementinthe secondary endp oint (goutcomeatday 90), with the relative od dsfavourable outcome (the abihtytoreturntindependent lifestyle) being 28% higher withteplase than with placebo (table VII). '^^ In ation, patients treated with alteplase had shtowardsabetter health state (as assessed by mby day30,''*^'with the shift being significant bodays 30'''^ and 90'^^ post hoca nalyses; figurFor the extended treatment window (i.e. betw3 and 4.5 hou rs after symptom onset), the nu mneeded to treat for one patient to achieve a favable ou tcom e w as 14.' ^

Additional analyses in the ITT population shed that significant (p

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Thrombolytic efficacy of intravenous alteplase administered between 3 and 4.5 hours after symptom onset in patients with acutemg/kg;maxim um 90 mg ) or placebo in the random ized, double-blind, multicentre, phase III, t r ia l . i ^ ' Results at day 90 in the intent-to-treat population, with the worst possible outcome score assigned for missing data in

(% of pts)core of

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30M 25m 2 0Q.? 15o 1o

22 22 ,

15

0 Aiteplase (n = 418)D Placebo (n = 403)

16 1611 11 12

15

30 1M 25cQH 2L

10

2823

16 14

0 1 2 3 4 5 6Modified Rankin scale scoresFig 1 . A post hoc assessment of the distribution of scores on themodified Rankin scale in patients receiving treatment for acuteischaemic stroke in the randomized, double-blind ECASS iii trial.Patients received alteplase (0.9 mg/kg) or placebo between 3.5 and4 hours of symptom onset. Presented are the scores at (a) day 3O'^ Iand (b) day 90 '^ 'inthe intant-to-treat popu lation. Scores indicate thefollowing: 0=no symptoms at all;1 =no significant disability despitesymptoms;2 = slight disability; 3=moderate disability; 4=moderatelysevere disability; 5=severe disability; 6=death. Score distribution atboth timepoints showed a significant difference between the treatmentgroups, favouring aiteplase over placebo (p

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during the two periods (63 minutes

0.03).''*5]In addition to the SITS-ISTR study, a prospec-ve, multicentre Canad ian co hort study (CASES )pared the benefits of alteplase (0.9 mg/kg)ceived treatmen t 3-4.5

ved treatm ent within 3 hours oft of sy m pto m s (n = 983).''*^l R esu lts show ed

of patients treated within the 3-hour window;d relative risk 0.98 [95% C I 0.8, 1.2] . At

to 4.5-hour window and 148 minutes in thosewithin the 3 -hour w indow (p < 0.0001).

y bec ause they were aged >80 years

4.3 IST-3IST-3 was undertaken to determine whether a

open , blinded e ndp oint) trial,'*^' which originallyplann ed to enrol 6000 patients.' '*' Howev er, becauseof difficulties in recruiting patients, the samplesize was revised, with a target of 3100 patientsestimated to yield 80% power to detect an abso-lute difference o4.7 in the prim ary outcome.'^'*IST-3 enrolled 3035 patients who were random-ized to receive alteplase (0.9mg/kg; n=1515) orcontrol treatment (n=1520) within 6 hours ofstroke onset.'^'*' The study had an initial double-blind, placebo-controlled, pilot phase in which276 patients received treatment.'^''^ This was fol-lowed by the main phase, in which patients allo-cated to the control group were to avoid alteplasetreatment, receive stroke care in the same clinicalenvirotiment as alteplase recipients and start aspirintherapy immediately.'^'*' The mean time from onsetof stroke to treatment initiation was 4.2 hours.'-''*'

Notab ly ,95%of patie nts in IST-3 did not meetcurrent EU licensing criteria (section 6),'^'*' in-cluding patients aged >80 years (53% of patients)and those who received treatment 4.5-6 hoursafter onset of stroke (33%).'-''*''*^ Some patients alsodid not meet current US licensing criteria (sec-tion 6),'^'*'including those who received trea tm ent>3 hours after stroke onset (72% of patients).''*^'Recently published results of the study showedthat a t 6 m on ths , there was no significant differ-ence between the alteplase and control groups inthe proportion of patients alive and independent(Oxford Handicap Scale [OHS] score of 0-2;prim ary ana lysis; 37% vs 35%; adjusted OR 1.13

[95% CI 0.95, 1.35] . However, a secondary or-dinal analysis showed a favourable shift in thedistribution of OHS scores with alteplase relativeto cont rol (co m m on O R 1.27 [95% CI 1.10, 1.47];p = 0.001), suggesting tha t, on average, patie ntstreated within 6 hours after stroke survived withless disability.'^'*' In addition, significantly morepatients in the alteplase group th an in the co ntrolgroup were alive with favourable outcome (OHSscore of 0 or 1) at 6 mo nth s (24% vs21%; adjustedO R 1.26 [95% C I 1.04, 1.53]; p =0.018). Oddsratios and p-values were adjusted for age, time,

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prognostic subgro ups, there was little variation inthe adjusted effects of treatment in most subgroups(including those based on gender, time to rand om -ization and baseline BP and glucose levels).'^'*^However, the adjusted treatment effect differedsignificantly between patients aged >80 years andthose aged

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Odds of favourable outco mes w ith aiteplase reiative to piacebo at 90 days and the estimated numbe r needed to treat with aitepiasee (modified R ankin scaie score of 0 or1 .Data were adjusted for variables, inciuding time betweenent initiation,'"31 Nationai institutes of Heaith Stroke Scaie scoref^^''^ and agei'^'' '^'

Time from onset of stroke to treatment initiation0-90 min 91-180 min 181-270 min 271-360 min 0-360 min

outcom e" 2.81 (1.75, 4.50)R (95% CI)]

pooied analysisl )score of 0 or1 2 .55(1.44,4.52) 'R (95% Ci)]

ai outcome" 2.84 (1.75, 4. 60 )' "R (95% Ci)]

1.55(1.12,2.15)'= 1.4 0(1 .05, 1.85 ) 1.15(0.90,1.47)"= NR

1.64(1.12,2.40)* 1.34(1.06 ,1.68)' 1.22(0.92,1.61) 1.40(1.20 ,1.63)"1.52(1.10,2.11 )' 1.32 (1.09 ,1.61 )" 1.22(0.96,1.54) 1.36(1.22 ,1.58)"9.0 14.1 21.4 12.6

Pooied anaiysis of data from NiNDS (parts1and 2),Pl ECASS i'^"' and ii,P'l ATUVNTiS (A'^^l and B^^^ triais, in which pts received AL0.9 or 1.1 mg/kg n=1391 )or PL (n = 1384) between 0 and 6hafter symptom onset. The median age of pts was 68 y and the median time tonset of treatment was 243 min.A composite of mRS score of 0 or 1,Bartinei index score 95 or 100, and NIHSS score of 0 or 1.No p-value reported.Pooied anaiysis of data from NiNDS (parts1and 2),1361EC ASS i,P

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Table XI. Clinical efficacy of alteplase as assess ed by the proportion of patients alive and independent (m odified Rankin scale score of 0alive with favourable outcome (modified Rankin scale score of 0 or1 )at finai follow-up (4 weeks to 6 months) in an updated systematic rand meta-analysis'^'PAg e Outcome Time from onset of stroke to treatment initiation

0-180 min 180-360 min 0-360min">18y mRS score of 0-2

>18y mRS score of 0 or1 ^

Subgroup analysis80 y" mRS score of 0-2

of ALT/CT ptsOR (95% CI)TE/1000pts% of ALT/CT ptsOR (95% CI)TE/1000pts

% of ALT/CT ptsOR (95% C I)TE/1000pts% of ALT/CT ptsOR (95% C I)TE/1000pts

40.7/31.71.53(1.26,1.86)*+9031.6/22.91.61 (1.30, 1.99)*+87

49.6**/40.11.51 (1.18, 1.93)+9528.9*/19.31.68(1.20,2.34)+96

47.5/45.71.07(0.96, 1.20)+18NRNRNR

52.6/50.31.09(0.96, 1.24)+2325.9/26.40.97(0.73, 1.30)-5

46.3/42.11.17(1.06, 1.2+4234.8/29.31.29(1.16, 1.4+5552.5*/48.31.16(1.04, 1.2+4327.2/23.41.22(0.98,1.5+3 8

a The analysis included 12 randomized studies (NIND S [parts 1 and 2]P^' ECASS 1 1 1 11,^'' and 111,^=1 ATLANTIS [A'^^l andEPITHETl^l IST-3'*'l and four earlier studies'""^ ) in pts with acute ischaemic stroke (n= 7012) who received ALT 0.6-1.1mgPL/open CT (referred to as CT in the table) within 6 hof stroke ons et. Data for all outcomes were not prov ided in all trials, but all avadata were used for the analyses of individual outcom es.'^^b Primary analysis.c For this measu re, significant(p=0.01 )heterogeneity was obse rved between a ll trials, but not between IST-3 and the previously conductedd Three trials (NINDS, EPITHET and IST-3) included a total of 1711 pts aged >80y.e Minus indicates fewer events per 1000 pts treated with ALT.ALT=alteplase; CT=control;mRS =modified Rankin scale; NR = not reported; OR = odds ratio; PL =pla ceb o; ts=patients; T E=treateffect;* p l/100 to

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b

20H

(ope

8 10 i

H 5n -

DOS20.5

D Alteplase (n = 312)D Placebo (n = 312)

*

*

6.43D

1.3 5.10.6

m 5.4All-cause 90 d Any ICHmortality Symptomatic Asymptomatic Symptomatic New ischaemicICH ICH ICH

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91 4 D

occurred in 34 patien ts, 24 (12 and 12 in the alte-plase and placebo groups, respectively) eventsoccurring within 3 months, 7 (4 and 3) eventsoccurring between 3 and 6 mo nths , and 3 (1 and2) events occurring between 6 and 12 months.'^*'

5 1 1 Intt^e SITS MOSTObservational StudyIn the SITS-MOST observational study (seesection 4.1.2 for study design details), which wasundertaken to compare the safety of alteplase0.9 mg/kg in routine chnical practice with that inrandomized trials, the primary safety outcomeswere symptomatic ICH (see table XII for defini-tion) and d eath w ithin 90 days.''*'' Res ults show edtha t 1.7 of alteplase recipients had sym ptom aticIC H w ithin 36 hou rs as per SITS -MO ST definition,and 7.3 (vs 8.6 of patie nts in pooled rando m -ized, controlled trials) of patients had sympto-matic ICH within 90 days as per N IN D S definition(see table XII for definition).''*'' The 90-daymo rtality rate in SITS -MO ST was 11.3 com-pared with 17.3 in the pooled random ized,controlled trials.' '*'' These findings suggested tha tthe safety profile of the drug was generally similarto that in randomized chnical trials. ' '*' '

A multivariate analysis of data from SMOST showed that several baseline variabincluding older age, high blood glucose and N IH SS scores, were related to high mortality symptomatic ICH.' '*^' After adjusting for tvariables, the incidence of sym ptomatic IC H (arandomized, controlled trials definition [table Xin SIT S-M OS T was 8.5 versus 8.6 in porandomized trials, and the 90-day mortality rate15.5 versus 17.3 (the data for pooled randized tria ls were unad justed for baseline variables

5.2 In the Extencded Treatm ent WindowThe tolerabihty profile of alteplase admtered during the extended treatment windowbetween 3 and 4.5 hours after stroke onseECASS III (see section 4.2.1 for study dedetails) was generally similar to that of altepadm inistered w ithin 3 hou rs of stroke onseNTND S. Any IC H and sym ptomatic ICH (asse

according to the definition used in ECASS III other studies; table XII) occurred in significamore alteplase than placebo recipients (figurehowever, there were no significant between-g1.73 1.24,2.42)

30.0 n El Alteplase (n = 418)D Placebo (n = 403)

0.90(0.54,1.49)0.96(0.56,1.64) I |

Any ICH Symptomatic ICH Fatal ICH Sym ptomaticoedema 90 dmortality

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teplase: A Review 9t5

patien ts (2.9% of alteplase and 3.2% of place bos, 18 pat ien ts (2.4% and0%) died 8-30 days , 16 patients (1.4% and 2.5%)d 31-90 days and 7 patients (1 % and 0.7%)days after treatment. '^^l All sy mp tom atic

There were no significant differences between

(25.1% vs 24.6%), of which theical (14.4% vs11.9%),cardiac(5.3%

vs 6.0%) adverse events.'^^lSubgroup analyses of ECASS III suggestedt the morta lity ra te in alteplase relative to placebo

sm oking history.''*^ C urre nt sm oking (O R 0.27 CI 0.10, 0.78]) relative to no smoking (OR [95%CI 0.57, 2.58]) or a p ast h istory of smo k-[95%C I0.71,5.87]) app eare d to have=0.02) p rotec tive effect aga instrtality in alteplase relative to placebo recipients.

signif- p-0.004) higher in patien ts aged >65 years1.96]).[ 3]

istered between December 2002 and November2007 showed no significant differences betweenpatients who received alteplase between 3 and4.5 hou rs (n = 664) after stroke onset and thosewho received treatment within 3 hours of strokeonset (n = 865) in terms of mortality (at 7 daysor 90 days after treatment) or symptomatic ICH(as per SITS-MOST, ECASS II or NINDS defi-nitions; see table XII for definitions).''*'*'

However, an updated analysis of this study,which included patients registered between De-cember 2002 and F ebrua ry 2010, showed th at thesafety of alteplase administered between 3 and4.5 h our s after stroke onset (n = 2376) was gen-erally less favourable than that of alteplaseadministered within 3 hours of stroke onset(n =2 566).''*51 Th e u nad juste d rate of s ym pto -matic ICH as per SITS-MOST definition wassignificantly (p = 0.04) higher in p atie nts wh o re-ceived alteplase in the extended treatment win-dow than in those who received treatment within3 ho urs of strok e onset (2.2% vs 1.7%; O R 1.36[95% CI 1.01,1.83]), b ut the rates of sym ptom aticICH as per ECASS II(5.3%vs 4 .8%) and N IN D S(7.4%vs 7.1%) definitions a nd m orta hty at 7 days(5.8%vs 6.2%) and 90 days (12.0% vs 12.3%) didnot differ significantly between the two patientgroups. However, after adjustment for baselinevariables, symptomatic ICH as per SITS-MOST(O R 1.44 [95% C I 1.05, 1.97])and E CASS II (OR1.27 [95% CI1.03,1.55])definitions and mortalityat 90 days (OR 1.26 [95% CI 1.07, 1.49]) weresignificantly (p

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symptomatic ICH in the extended treatme ntwindow relativeto theearlier treatm ent window(p = 0.009for thex^ tes tfor trend). *^

5 .3 IST-3In IST-3 seesection 4.3 for study design de-tails), although significantly more alteplase thancontrol recipientshad anysymptomatic ICH ordeath within 7days of stroke, there were fewerdeathsin the alteplase group between 7daysand6 months, such that by 6 months, there was no

significant between-group difference in mortalityrates (table X III). * As noted previously in section4.3,thevast majority ofpatien ts included inIST-3did not meet current EU/US licensing criteria;these criteria varied between countries (section6).5.4 Pooled/Meta-AnalysesAn earlier pooled analysisof six, randomizedtrials had shown that alteplase and placebo re-cipients did not differ significantly in termsofthe risk of death when treatment was adminis-tered between0 and 4.5hou rs after s troke onset(table XrV; see section4.4 for further detailsoftheanalysis); however, the risk ofdeath washigherwith alteplase than with placebo when treatmentwas initiated >4.5 ho ur s after stro ke onset. *^Parenchymal haemorrhage type 2 occurred sig-nificantly more frequently with alteplase than

T abi e X I I I . Safety outcomes that differed significantiy betweentheaitepiase (0.9 mg/kg) and controi groups in iS T -3 .'*'' Odds ratios andp-values were adjustedfor age. National institutesof Heaith StrokeScaie score, t ime, and presence or absence of visibie acuteischaemic change on baseiine scanOutcome Assessed %o fALT /CT AdjOR T E/1000(95% Ci) ptsS y m p i C H

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eview 917

Mortality and symptomatic intracranial haemorrhage with alteplase (0.6-1.1 mg/kg) relative to control (placebo or open control) in

% of ALT/CT ptsOR (95%CI)TE/1000pts% of ALT/CT ptsOR (95%CI)TE/1000pts

Time from onset of stroke to treatment initiation0-180min

24.6/26.00.91 (0.73, 1.13)-15=8.0/1.24.55 (2.92, 7.09)***+68

180-360 min

17.8/15.91.16(1.00,1.35)+187.7/1/83.73 (2.86 , 4.86)***+58

0-360 min(

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(3.6% vs 0.6%; OR 4.18 [95% CI 2.99, 5.84]);p< 0.001), but there was no significant between-group difference in the incidence of death fromother causes w ithin 7 days(5.3%vs 5.7%; OR 0.93[0.73, 1.18] , indicating that the excess of earlydeaths was largely because of ICH.'^^' There wasan absolute increase of 9 fatal ICH/1000 patientstreated and an absolute decrease of4death s fromother causes/1000 patients treated. SymptomaticICH within 7 days was also significantly higherwith alteplase than with control (table XV), whilethere was no significant between-group differencein symptomatic oedema within 7 days (10.2% vs10.4%; OR 0.97 [0.79, 1.19]; absolute decrease of2 events/1000 patien ts tre ate d). "' It should benoted that for the outcomes of deaths from othercauses and symptomatic oedema, there was sig-nificant (p80 years, it is recommended the risks of alteplase therapy should be weigcarefully against the anticipated benefits, as of bleeding may be increased in these patiAlteplase is not indicated for the treatmenacute strok e in pa tients aged

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Review 919

^^' In th e U S , =795 000 people experience

ke being 115/100 000 and 75/100 000,

ect and indirect cost of stroke

Besides stroke unit care, decompressive sur-

signif-

5.1.1 of alteplase inHowever, other trials (ECASS 1'^' and 11,'^

NINDS trial was that in the negative trials, only14% of patients had received alteplase therapywithin 3 hours, whereas in the NINDS trial allbut two patients were enrolled within 3 hours and48% of patients were enrolled within 1 ho ur ofsymptom onset. '^*'A subsequent pooled analysis''*^' of six ran-domized trials suggested a potential benefit ofalteplase therapy up to 4.5 hours after strokeonset (section 4.4), with no significant increasein the risk of death (section 5.4). This was con-firmed in the ECASS III trial, '^^' which showedthat patients who received treatment between3 and 4.5 hou rs after stroke o nset experienced sig-nificant benefit with alteplase relative to placebo,as assessed by the proportion of patients withm RS scores of 0 or 1 (section 4.2.1). M oreov er,the tolerability profile of alteplase administeredbetween 3 and 4.5 hours after stroke onset wasgenerally similar to that of alteplase administeredwithin 3 hours of stroke onset (section 5.2), withno significant differences between alteplase andplacebo recipients in the 90-day mortality rates,despite higher incidences of any or symptomaticICH in alteplase recipients.

Results from the SITS-ISTR observationalstudy,''*^' an u pd ate d poo led an alysis''*'' an d m eta-analyses'^^'^*' also showed that patients who re-ceived alteplase in the extended tr eatm ent windowbenefited from therapy; however, the functional(sections 4.2.2 and 4.4) and safety (sections 5.2.1and 5.4) outcomes were generally less favourablewhen treatment was administered 3-4.5 hoursafter stroke onset than within the 3-hour treat-ment window. Taken together, these findings in-dicate that alteplase therapy administered within4.5 hours of stroke onset was effective and gen-erally safe, but in order to gain maximum benefitof therapy, treatment should be initiated as earlyas possible after onset of symptoms.' '*' ' It shouldbe noted that these studies have various inherenthmitations, such as the observational design ofthe SITS -MO ST''* and SITS-ISTRt'*^' studies,differing methodologies of the trials included in

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lteplase: A Review 921

ts favoured treat m ent with alteplase in the 3- to, with an 88% probability that

0 000/quality-adjusted life-years gained.f'^'In addition to the efficacy and safety studies

at some patients in the VISTA

(also excluded from treatm ent as per current

irmed, p robably because of the small samplets with d iabetes (n = 5411) or s troke alone= 5019),^'^' no interaction of alteplase treatm ent

Another study, IST-3, was undertaken to de-

at 6 months did not differ significantly betweenthe alteplase and control groups, a secondaryordinal analysis suggested that patients treatedwith alteplase within 6 hours of stroke survivedwith less disability (section 4.3). Mortality at6 months did not differ significantly between thealteplase and con trol groups, despite more deathsand symptomatic ICH within 7 days in the alte-plase group (section 5.3).^^'*'

Furthermore, subgroup analyses of IST-3suggested that patients aged >80 years and thosewith more severe stroke may experience greaterbenefit of treatment than patients aged 80 years,^'*''provided valuable randomized evidence of thebenefit/risk of alteplase therapy in this importantage-group that had been under-represented inprevious trials of treatments for acute stroke.t'^'The study authors note that most patients whoreceived treatment within 3 hours of stroke onsetwere aged >80 years (n =726), yet the treatmentbenefit achieved was similar to that in patientsaged

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up to 12 randomized trials was conducted to as-sess the overall effect of alteplase administeredwithin 6 hours of stroke onset. '^^' In additionto supporting the findings of the earlier pooledanalyses, indicating that the benefit of alteplasetherapy was greater the sooner treatment was ad-ministered, results suggested that treatment ben-efit may extend up to 6 hours, i.e. beyond thecurrently recommended treatment winclow (sec-don 6). The analysis showed that for every 1000padents treated with alteplase, 42 more patientswere likely to be alive and independent and 55mo re pade nts were likely to have a favourable out-come at final follow-up (80 yearsmay benefit from alteplase, especially when ad-ministered within 3 hours of stroke onset (secdon4.4); however, it should be noted that the meta-analysis did not present any tolerability datafor the subgroups of patients aged >80 years or4.5 hours after stroke inselected patients are required to confirm thesefindings;'^ *' however, as the magnitude of benefitin such padents is expected to be low, such trialswould require a very large sample size or screen-ing of padents based on modern neuroimagingtechniques.It has been suggested that with the findings of

IST-3 and the updated meta-analysis, more pa-tients aged >80 years are likely to receive alteplas e

dechne often have white matter lesions, silenfarcts and brain m icrobleeds (which m ay predispatients to haemorrhages) and elderly patimay be more sensidve to the toxic effects of plase on ischaemic dssue.'^^' A recent mu lticenretrospecdve cohort study of patients (mean82 years) with acute stroke with or withoutme ntia who received alteplase therap y (n propensity-matched patients per group) shothat pre-existing demen tia was not independeassociated with mortality, disability or insdonalizadon after ischaemic stroke, suggesthat this pre-exisdng cond idon may not necesily preclude padents from thrombolytic therand specialized care.'^' '

Based on results from these and similar sies, it has been suggested in literature thatexclusion criteria for alteplase therapy, wwere derived from medical opinion at the of the NINDS study and based on no or wscientific e vidence,''*'^ ' should be re-ev aluand streamlined.'^'^' ' This could potendallycrease the number of padents qualifying for trment, '^' ' with some experts suggesdng that stand emergency physicians should class all padas candidates for throm bolysis an d idendfy thepade nts w ho will not receive treatm ent rather idendfying those who will receive therapy.'^*'

Since IST-3 was underpowered to detect portant subgroup effects, a collaborative indiual patient da ta m eta-analysis (STT C [the StThrombolysis Trialists Collaboration]) has bestablished, with the aim of exploring which bline factors, other than dme to treatment, modify the effects of alteplase on major outco(e.g. funcdonal outcome, death and ICH).'^'*addidon, the WAKE-UP study plans to asthe efficacy and safety of MRI-based intraventhrombo lysis with alteplase in patients wakingwith stroke symptoms or patients with otherwunknown symptom onset. '*^' Other ongoing tinclude TESPI (Thrombolysis in Elderly StrPadents in I ta ly) , '^ ' EXTEND (Extendingtime for Thrombolysis in Emergency Neurolog

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inistered at later times (

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12. Benchenane K, Lpez-Atalaya JP, Fernndez-Monreal M,et al. Equivocal roles of tissue-type plasminogen activatorin stroke-induced injury. Trends Neurosci 2004 Mar; 273):155-6013. Hoylaerts M, Rijken DC, Lijnen HR, et al. Kinetics of theactivation of plasminogen by human tissue plasminogenactivator: role of fibrin. J Biol Chem 1982 M ar 25; 257 6):2912-914. CoUen D. Molecular mechanisms of fibrinolysis and theirapplication to fibrin-specific thrombo lytic therapy. J CellBiochem 1987 Feb; 33 2): 77-8615. Mueller HS, Rao AK, Forman SA, on behalf of the TIMIinvestigators. Thrombolysis In Myocardial Infarction TIMI): comparative studies of coronary reperfusion andsystemic fibrinogenolysis with two forms of recombinanttissue-type plasminogen activator. J Am Coll Cardiol 1987Sep; 10 3): 479-9016. Topol EJ, Morris DC, Smalling RW, et al. A multicenter,randomized, placebo-controlled trial of a new form of in-travenous recombinant tissue-type plasminogen activator activase) in acute myocardial infarction. J Am Coll Car-diol 1987 Jun ; 9 6): 1205-1317.Molina CA, Montaner J, Abilleira S, et al. Time course oftissue plasminogen activator-induced recanalization inacute cardioembolic stroke: a case-control study. Stroke2001 Dec 1; 32 12): 2821-718. Nichols C, Kh oury J, Brott T, et al. Intravenous re-combinant tissue plasminogen activator improves arterialrecanalization rates and reduces infarct volumes in patientswith hyperdense artery sign on baseline computed tomo-grap hy. J Stroke Cerebrov asc Dis 2008; 17 2): 64-819. Aoki T, Sumii T, Mori T, et al. Blood-brain barrier disrup-tion and matrix metalloproteinase-9 expression during re-perfusion injury: mechanical versus embolie focal ischemiain spontaneously hypertensive rats. Stroke 2002 Nov; 33 11):2711-720. Kassner A, Roberts TPL, Moran B, et al. Recombinanttissue plasminogen activator increases blood-brain barrierdisruption in acute ischmie stroke: an MR imagingpermeability study. Am J Neuroradiol 2009; 30 10):1864-921. Kidwell CS, Latour L, Saver JL, et al. Thrombolytic toxi-city: blood-brain barrier disruption in human ischmiestrok e. Cerebrovasc D is 2008; 25 4): 338-4322. Chen ZL, Strickland S. Neuron al death in the hippocampusis promoted by plasmin-catalyzed degradation of laminin.Cell 1997 Dec 26; 91 7): 917-2523. Nagai N , De Mol M, Lijnen H R, et al. Role of plasminogensystem components in focal cerebral ischmie infarction: agene targeting and gene transfer study in mice. Circulation

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tab To xicol 2012; 8 2): 271-8132. Seifried E, Tanswell P, Ellbruck D , et al. Pharm acokiand haemostatic status during consecutive infusions combinant tissue-type plasminogen activator in pawith acute myocardial infarction. Thromb Haemost Jun 30; 61 3): 497-50133. Nilsson T, Wallen P, Mellbring G. In vivo metabolishuman tissue-type plasminogen activator. Scand J mato l 1984 Jul; 33 I): 49-5334. The IST-3 collaborative group. The benefits and hof intravenous throm bolysis with recombinant tissueminogen activator within6h of acute ischaemic strokthird international stroke trial [IST-3]): a random

controlled trial. Lancet 2012 Jun 23; 379 9834): 235235. Hacke W, Kaste M, Bluhmki E, et al. on behalf oECASS investigators. Thrombolysis with alteplase 3 hours after acute ischmie stroke. New Engl J Med 359 13): 1317-2936. The N ational Institute of Neurological D isordersStroke rt-PA Stroke Study Group. Tissue plasminactivator for acute ischmie stroke. N Engl J Med 19914;333 24): 1581-737. Wardlaw JM , M urray V, Berge E, et al. Recombinant plasminogen activator for acute ischaemic stroke: adated systematic review and meta-analysis. Lancet Jun 23; 379 9834): 2364-7238. Kwiatkowski TG, Libman RB, Frankel M, et al. on bof the National Institute of Neurological DisordersStroke Recomb inant Tissue Plasminogen A ctivator S

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