Diagnostic and Interventional Imaging (2014) 95, 1129—1133

CONTINUING EDUCATION PROGRAM: FOCUS. . .

Intravenous thrombolysis for acute ischemicstroke

G. Turca,b,c,∗, C. Isabela,b, D. Calveta,b,c

a Stroke unit, Sainte-Anne hospital, 1, rue Cabanis, 75014 Paris, Franceb Université Paris Descartes, Sorbonne Paris Cité, Francec Inserm UMR S894, France

KEYWORDSStroke;Ischemia;Thrombolysis;Interventionalradiology;

Abstract Intravenous thrombolysis (IVT) with alteplase remains the standard treatment foracute ischemic stroke. Although IVT can be started up to 4.5 hours after symptoms’ onset, it isall the more effective and safe when started early. It allows a 10% absolute reduction in the riskof handicap or death at 3 months, despite a 2—7% risk of symptomatic intracranial hemorrhage.Current research efforts involve firstly trying to treat a larger proportion of patients by over-coming some of the contraindications to IVT and secondly assessing combined or alternative

Thrombectomy treatments to achieve a higher early recanalization rate.© 2014 Éditions francaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is intended to produceearly arterial recanalization, allowing reperfusion of the ischemic penumbral tissue, toavoid its progression to infarction [1]. IVT with alteplase remains the standard treatmentwithin the 4.5 hours window after symptoms’ onset [2].

Pivotal clinical trials

The clinical efficacy of IVT with alteplase was demonstrated as early as 1995 in the NINDSrandomized controlled trial, which compared IVT to placebo within 3 hours after symptoms’

onset [3]. The diagnosis of AIS was based on the results of a non-contrast brain CT. Withinthe 3-hours’ time hours’ time window, IVT allowed a 50% relative increase in the proportionof patients without disability at 3 months (modified Rankin scale [mRS] ≤ 1): 39% vs. 26%,i.e. a 13% absolute increase as compared to placebo (number needed to treat = 8). The

∗ Corresponding author. Department of neurology, Sainte-Anne hospital center, 1, rue Cabanis, 75014 Paris, France.E-mail address: g.turc@ch-sainte-anne.fr (G. Turc).

http://dx.doi.org/10.1016/j.diii.2014.10.0022211-5684/© 2014 Éditions francaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

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Despite major advances, less than 10% of all ischemic

130

isk of symptomatic intracranial hemorrhage (sICH) was 6% inhe first 36 hours after IVT (compared to 0.6% in the placeborm). Three-month mortality rates did not differ betweenhe two arms.

In 2008, the ECASS 3 randomized controlled trial demon-trated the clinical efficacy of IVT within the 3—4.5 hourime window [4]. Compared to placebo, IVT allowed a 16%elative increase in the proportion of patients without dis-bility (mRS ≤ 1) at 3 months: 52% vs. 45% (absolute increase%, number needed to treat = 14). The rate of sICH was 8%sing the same definition as in the NINDS study and mortalityates were similar in both arms.

unctional prognosis, hemorrhagicransformation and mortality rates inlinical registries

ecause patients included in clinical trials might differ fromhose seen in everyday practice, the SITS (Safe Implemen-ation of Thrombolysis in Stroke) European registries haveeen set up since 2002 to assess the outcome of patientsreated by IVT for AIS. Three months after AIS, 40 to 45%f patients were free of any handicap (mRS ≤ 1) and 55 to0% were independent in activities of daily living (mRS ≤ 2)5,6].

Independent predictors of poor functional outcomemRS > 2) at 3 months despite IVT are age, clinical severityt baseline (NIHSS score), blood glucose level on admission,nset-to-treatment time, pre-existing handicap, proximalrtery occlusion, initial lesion volume and lack of earlyecanalization [7,8].

In the SITS registries, the rate of sICH after IVT was 7%ccording to the NINDS study definition and 2 to 5% usinglternative, more conservative definitions requiring a proba-le causal relationship between the hemorrhage and clinicaleterioration [5]. Predictors of sICH are age, baseline NIHSScore, blood glucose level on admission, blood pressure,nset-to-treatment time, proximal artery occlusion and ini-ial lesion volume [9]. Overly late recanalisation may also be

predisposing factor, although this is still debated [10,11].Three-month mortality in the SITS registries was 12%, vs.

8% in randomized trials.

atients aged over 80

he findings described in the previous paragraphs led toarket authorization being granted for IVT with alteplase

Activase®) within 4.5 hours after symptoms’ onset of AIS,ut only in patients under 80 years old. Less than 100 elderlyatients were included in the randomized trials comparingVT to placebo before publication of the IST-3 study in 201212,13]. IST-3 was an open, randomized study intended toompare IVT with control treatment (mostly aspirin) in the—6 hour time window [12]. Although IST-3 failed to demon-trate the superiority of IVT regarding the primary end pointabsent or mild functional disability at 6 months), proba-

ly because the treatment window was too wide, this is anmportant study as it included over 1600 patients who were0 years old or older, which represent half of all enrolled

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G. Turc et al.

atients. This study established that the clinical efficacy ofVT did not decrease with age in the 0—3 hour time win-ow. This result was confirmed in a meta-analysis showinghat IVT allowed a 10% absolute increase in the proportionf patients who were independent in activities of daily liv-ng (mRS ≤ 2) at 3 or 6 months. The effect size was similarn patients under 80 years old (mRS ≤ 2: 50% vs. 40% in thelacebo arm) and in those ≥ 80 years old (mRS ≤ 2: 29% vs.9% in the placebo arm) [13].

Regarding the 3—4.5 hour time window, published datare less clear-cut for older patients. Although an individualatient data meta-analysis from 9 randomized placebo-ontrolled trials suggested that IVT had a similar effect sizen patients under 80 years old (mRS ≤ 1: OR 1.26 CI95%:.04—1.54) and ≥ 80 years old (mRS ≤ 1: OR 1.36 CI95%:.87—2.14), this meta-analysis was inadequately poweredo formally confirm the clinical efficacy of IVT between 3nd 4.5 hours in elderly patients [14]. Despite the fact thatVT is not currently licensed for use in AIS patients ≥ 80ears old, age is not considered to be an exclusion crite-ion for IVT in most stroke units, in accordance with Frenchnd international guidelines [15—17].

he importance of early treatment

lthough IVT may be started up to 4.5 hours after symptoms’nset, several meta-analyses and registries have shown thatt is all the more effective when administered early [18,19].he ‘‘Get With The Guidelines—Stroke Program’’ Northmerican registry showed that faster onset-to-treatmentime, per 15 minutes increment, was associated with a 4%ncrease in achievement of independent ambulation at hos-ital discharge, a 4% decrease in the risk of sICH, and a 4%eduction in the risk of death [18]. These results are consis-ent with the pathophysiology of AIS, as firstly the conversionf the penumbral tissue into necrotic core depends directlyn the duration of severe hypoperfusion and secondly therobability to achieve arterial recanalisation increases witharlier obstruction as the thrombus is potentially less orga-ized [20].

The median onset-to-treatment time is approximately40 minutes in industrialized countries [6,18]. Furthereducing this time would help to improve the prognosisf patients who are treated, but also allow more patientso be treated [21]. Optimizing each stage in AIS manage-ent is therefore a major objective, requiring education

f the general public (through national campaigns) andurther reduction of the pre-hospital and hospital patientanagement times. Specifically, although the recommendedoor-to-needle time is under 60 minutes, several centersave reduced it to approximately 20 minutes using specificrganization [2,22,23].

uture prospects: treating more patients

trokes are treated by IVT in industrialized countries, mostlyecause they arrive too late in hospital [24]. Several strate-ies are currently being assessed in order to increase the

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proportion of patients who are treated. Some of the manycontraindications of IVT for AIS are now deemed to beobsolete or minor thanks to observational studies and ran-domized data showing that, in several situations, off-labelIVT is not associated with poorer clinical outcome [14,25].These findings relate to age, epileptic seizures, improving orminor neurological deficit, or conversely very severe neuro-logical deficit [14]. Although lack of visible arterial occlusionis considered by some groups to be a non-indication for IVT,no arterial occlusion was deemed necessary in the pivotalstudies, and observational data suggest that these patientsmay also benefit from IVT [26].

Extending the treatment window for IVT beyond 4.5 hourshas been a long-standing goal. However, all of the random-ized trials which have assessed IVT beyond 4.5 hours havebeen negative or neutral so far [14]. Perfusion-weightedimaging may help to identify patients with a persistentischemic penumbra beyond the 4.5 hour time window, andtherefore to select potentially good candidates for lateIVT [10]. This approach is currently being assessed in arandomized trial based on the existence of an MRI diffusion-perfusion mismatch (ECASS 4-Extend study). Brain MRI mayalso allow some of the wake-up or unknown time onsetAIS (which represents approximately 15% of all AIS) to betreated by IVT [27]. Diffusion-FLAIR mismatch (i.e. AIS vis-ible on diffusion weighted imaging but not yet on FLAIR)has positive and negative predictive values > 90% to deter-mine that symptoms are recent (less than 3 hours or evenless than 4.5 hours) [28,29]. One randomized trial compar-ing IVT to placebo in patients suffering wake-up stroke witha diffusion-FLAIR mismatch is currently ongoing (Wake-upstudy), following encouraging observational findings [30].

Telemedicine (telestroke) is bringing the expertise ofstroke physicians and neuroradiologists to help emergencydepartment physicians to start IVT in hospitals lacking adedicated stroke unit [31].

An original approach has been recently proposed by twoGerman groups, which involves ‘‘bringing the hospital to thepatient’’ via a mobile stroke unit (MSU), in order to startIVT directly at the site of the AIS [21,32]. The MSU is adedicated ambulance equipped with a CT, a point-of-carelaboratory, a telemedicine solution and involving an onboardstroke neurologist and radiology technician. This strategyhas been assessed on a randomized basis in a semi-rural set-ting and then in Berlin and has allowed a 25-min medianonset-to-IVT time reduction compared to usual care [21].Moreover, the Berlin (PHANTOM-S) study showed that theMSU helped increase the proportion of patients treated withIVT for AIS by over 50%. Several clinical trials are now ongo-ing in Europe and the United States in order to demonstratethat this approach reduces long-term disability.

Future prospects: improving thebenefit/risk balance of IVT

Although unquestionable, the efficacy of IVT remains

limited, as almost 50% of treated patients still have sig-nificant functional disability at 3 months [6]. The arterialrecanalisation rate after IVT is no more than 50% [33], andadditional endovascular treatment (‘‘stentrievers’’) may be

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key option. However, whilst combined treatment with IVTnd endovascular approach (bridging therapy) allows highecanalization rates, no randomized trial have yet demon-trated bridging therapy to be superior to IVT alone inerms of long-term disability [34,35]. Subgroup analysesrom the IMS-3 trial suggest that trials assessing bridgingherapy should focus on patients with severe neurologicaleficit, proximal arterial occlusion and treated very early34]. Thanks to dedicated scores, identifying on hospitaldmission patients likely to have poor long-term functionalrognosis despite IVT is feasible and could help selecting theest candidates to assess bridging therapy [7,8]. Several ran-omized trials of bridging therapy are ongoing (MR CLEAN,HRACE, SWIFT PRIME, BASICS trial, etc.).

Apart from endovascular strategies, three mainpproaches have been proposed to improve the effec-iveness of IVT: reducing the onset-to-treatment timewhich would also reduce the risk of sICH), using next-eneration thrombolytics instead of alteplase, or carryingut sonothrombolysis.

Two recent thrombolytics, desmoteplase andenecteplase, have theoretical advantages over alteplase,articularly greater affinity for fibrin, reduced neurotoxicitynd administration as a single one-minute bolus rather than

one-hour infusion [36,37]. Unfortunately, desmoteplaseas not been shown to be superior to placebo in the—9 hours time window (DIAS 3 trial, intention-to-treatnalysis). Tenecteplase, however, has been shown to beuperior to alteplase in a phase IIb randomized study inhe 0—6 hours time window [37]. This trial involved highlyelected patients with intracranial artery occlusion andersistent ischemic penumbra, both of which were deter-ined on CT. Administration of tenecteplase was associatedith a significant short-term and 3-month clinical benefitompared to alteplase, and a non-significant trend towardsower risk of sICH. However, this study should be considereds preliminary because of the small number of patients andifferent proximal middle cerebral artery occlusion ratesetween the tenecteplase and alteplase arms. Severallinical trials comparing tenecteplase and alteplase arengoing.

Sonothrombolysis has been proposed for patients with aiddle cerebral artery occlusion. It involves applying low

ntensity, high frequency ultrasounds to the occlusion sitever 2 hours via a transcranial Doppler to increase the throm-olytic effect, by allowing better exposure of the thrombuso alteplase. One phase II randomized study has shownonothrombolysis to be superior to IVT alone in terms of com-lete recanalization rates (assessed by transcranial Dopplerltrasonography) two hours after starting IVT [38]. A non-ignificant trend in favor of sonothrombolysis was observedor 3-month functional outcome. No significant differenceas shown between the two groups in terms of sICH. Oneouble-blind, phase III randomized controlled trail is ongoingCLOTBUST-ER).

Reducing the risk of IVT-related hemorrhage would alsomprove the benefit/risk balance for this therapy. Thenchanted randomized trial is currently comparing the usualose of alteplase (0.9 mg/kg) to a lower dose (0.6 mg/kg,hich is used routinely in Japan) in order to establishhether the lower dose reduces the risk of sICH without

educing the effectiveness of IVT.

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n conclusion, IVT with alteplase within 4.5 hours after AISnset is currently the only treatment proven to be clin-cally effective and which is currently approved for theanagement of this condition. It allows an approximately

0% absolute reduction in the risk of disability or death at months, despite a 2—7% risk of sICH, depending on theefinitions used. The contribution of additional endovascu-ar therapy or next-generation thrombolytics will need to beetermined in randomized trials using IVT with alteplase ashe control group, and long-term functional disability as therimary outcome.

TAKE-HOME MESSAGES

• Intravenous thrombolysis with alteplase is currentlythe standard treatment for acute ischemic stroke.

• It allows a 10% absolute reduction in the risk ofdisability or death at 3 months.

• The earlier intravenous thrombolysis is started, themore effective it will be.

• It has clearly been shown to be beneficial under theage of 80 years old within 4.5 hours after symptoms’onset.

• After the age of 80 years old, intravenousthrombolysis is currently given off-label in France,as randomized control trials did not show reducedbenefits of treatment based on age.

• Approximately 55% of all patients treated withintravenous thrombolysis are independent inactivities of daily living 3 months after the ischemicstroke.

• The incidence of symptomatic intracranialhemorrhage after intravenous thrombolysis is 2to 7%, depending on the definitions used.

• Bridging therapy (intravenous thrombolysis followedby an endovascular procedure) may be superiorto intravenous thrombolysis alone in patients withproximal arterial obstruction treated early, althoughthis point needs to be demonstrated formallyin randomized controlled trials using long-termfunctional disability as the primary outcome.

• Other new approaches are currently assessed inclinical studies:◦ using the diffusion-FLAIR mismatch or penumbra

imaging to treat some patients despite wake-upstroke, or beyond the 4.5 hour time window,

◦ next-generation thrombolytics,◦ telestroke,◦ pre-hospital thrombolysis using a mobile

neurovascular unit,◦ sonothrombolysis.

isclosure of interest

he authors declare that they have no conflicts of interestoncerning this article.

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