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

CONTINUING EDUCATION PROGRAM: FOCUS. . .

Intravenous thrombolysis for acute ischemic stroke G. Turc a,b,c,∗, C. Isabel a,b, D. Calvet a,b,c a

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

KEYWORDS Stroke; Ischemia; Thrombolysis; Interventional radiology; Thrombectomy

Abstract Intravenous thrombolysis (IVT) with alteplase remains the standard treatment for acute ischemic stroke. Although IVT can be started up to 4.5 hours after symptoms’ onset, it is all the more effective and safe when started early. It allows a 10% absolute reduction in the risk of 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 overcoming some of the contraindications to IVT and secondly assessing combined or alternative treatments to achieve a higher early recanalization rate. ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved. © 2014 Éditions franc

Intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is intended to produce early arterial recanalization, allowing reperfusion of the ischemic penumbral tissue, to avoid its progression to infarction [1]. IVT with alteplase remains the standard treatment within 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 NINDS randomized 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. Within the 3-hours’ time hours’ time window, IVT allowed a 50% relative increase in the proportion of 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: [email protected] (G. Turc).

http://dx.doi.org/10.1016/j.diii.2014.10.002 2211-5684/© 2014 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

1130 risk of symptomatic intracranial hemorrhage (sICH) was 6% in the first 36 hours after IVT (compared to 0.6% in the placebo arm). Three-month mortality rates did not differ between the two arms. In 2008, the ECASS 3 randomized controlled trial demonstrated the clinical efficacy of IVT within the 3—4.5 hour time window [4]. Compared to placebo, IVT allowed a 16% relative increase in the proportion of patients without disability (mRS ≤ 1) at 3 months: 52% vs. 45% (absolute increase 7%, number needed to treat = 14). The rate of sICH was 8% using the same definition as in the NINDS study and mortality rates were similar in both arms.

Functional prognosis, hemorrhagic transformation and mortality rates in clinical registries Because patients included in clinical trials might differ from those seen in everyday practice, the SITS (Safe Implementation of Thrombolysis in Stroke) European registries have been set up since 2002 to assess the outcome of patients treated by IVT for AIS. Three months after AIS, 40 to 45% of patients were free of any handicap (mRS ≤ 1) and 55 to 60% were independent in activities of daily living (mRS ≤ 2) [5,6]. Independent predictors of poor functional outcome (mRS > 2) at 3 months despite IVT are age, clinical severity at baseline (NIHSS score), blood glucose level on admission, onset-to-treatment time, pre-existing handicap, proximal artery occlusion, initial lesion volume and lack of early recanalization [7,8]. In the SITS registries, the rate of sICH after IVT was 7% according to the NINDS study definition and 2 to 5% using alternative, more conservative definitions requiring a probable causal relationship between the hemorrhage and clinical deterioration [5]. Predictors of sICH are age, baseline NIHSS score, blood glucose level on admission, blood pressure, onset-to-treatment time, proximal artery occlusion and initial lesion volume [9]. Overly late recanalisation may also be a predisposing factor, although this is still debated [10,11]. Three-month mortality in the SITS registries was 12%, vs. 18% in randomized trials.

Patients aged over 80 The findings described in the previous paragraphs led to market authorization being granted for IVT with alteplase (Activase® ) within 4.5 hours after symptoms’ onset of AIS, but only in patients under 80 years old. Less than 100 elderly patients were included in the randomized trials comparing IVT to placebo before publication of the IST-3 study in 2012 [12,13]. IST-3 was an open, randomized study intended to compare IVT with control treatment (mostly aspirin) in the 0—6 hour time window [12]. Although IST-3 failed to demonstrate the superiority of IVT regarding the primary end point (absent or mild functional disability at 6 months), probably because the treatment window was too wide, this is an important study as it included over 1600 patients who were 80 years old or older, which represent half of all enrolled

G. Turc et al. patients. This study established that the clinical efficacy of IVT did not decrease with age in the 0—3 hour time window. This result was confirmed in a meta-analysis showing that IVT allowed a 10% absolute increase in the proportion of patients who were independent in activities of daily living (mRS ≤ 2) at 3 or 6 months. The effect size was similar in patients under 80 years old (mRS ≤ 2: 50% vs. 40% in the placebo arm) and in those ≥ 80 years old (mRS ≤ 2: 29% vs. 19% in the placebo arm) [13]. Regarding the 3—4.5 hour time window, published data are less clear-cut for older patients. Although an individual patient data meta-analysis from 9 randomized placebocontrolled trials suggested that IVT had a similar effect size in patients under 80 years old (mRS ≤ 1: OR 1.26 CI95%: 1.04—1.54) and ≥ 80 years old (mRS ≤ 1: OR 1.36 CI95%: 0.87—2.14), this meta-analysis was inadequately powered to formally confirm the clinical efficacy of IVT between 3 and 4.5 hours in elderly patients [14]. Despite the fact that IVT is not currently licensed for use in AIS patients ≥ 80 years old, age is not considered to be an exclusion criterion for IVT in most stroke units, in accordance with French and international guidelines [15—17].

The importance of early treatment Although IVT may be started up to 4.5 hours after symptoms’ onset, several meta-analyses and registries have shown that it is all the more effective when administered early [18,19]. The ‘‘Get With The Guidelines—Stroke Program’’ North American registry showed that faster onset-to-treatment time, per 15 minutes increment, was associated with a 4% increase in achievement of independent ambulation at hospital discharge, a 4% decrease in the risk of sICH, and a 4% reduction in the risk of death [18]. These results are consistent with the pathophysiology of AIS, as firstly the conversion of the penumbral tissue into necrotic core depends directly on the duration of severe hypoperfusion and secondly the probability to achieve arterial recanalisation increases with earlier obstruction as the thrombus is potentially less organized [20]. The median onset-to-treatment time is approximately 140 minutes in industrialized countries [6,18]. Further reducing this time would help to improve the prognosis of patients who are treated, but also allow more patients to be treated [21]. Optimizing each stage in AIS management is therefore a major objective, requiring education of the general public (through national campaigns) and further reduction of the pre-hospital and hospital patient management times. Specifically, although the recommended door-to-needle time is under 60 minutes, several centers have reduced it to approximately 20 minutes using specific organization [2,22,23].

Future prospects: treating more patients Despite major advances, less than 10% of all ischemic strokes are treated by IVT in industrialized countries, mostly because they arrive too late in hospital [24]. Several strategies are currently being assessed in order to increase the

Intravenous thrombolysis for acute ischemic stroke proportion of patients who are treated. Some of the many contraindications of IVT for AIS are now deemed to be obsolete or minor thanks to observational studies and randomized data showing that, in several situations, off-label IVT is not associated with poorer clinical outcome [14,25]. These findings relate to age, epileptic seizures, improving or minor neurological deficit, or conversely very severe neurological deficit [14]. Although lack of visible arterial occlusion is considered by some groups to be a non-indication for IVT, no arterial occlusion was deemed necessary in the pivotal studies, and observational data suggest that these patients may also benefit from IVT [26]. Extending the treatment window for IVT beyond 4.5 hours has been a long-standing goal. However, all of the randomized trials which have assessed IVT beyond 4.5 hours have been negative or neutral so far [14]. Perfusion-weighted imaging may help to identify patients with a persistent ischemic penumbra beyond the 4.5 hour time window, and therefore to select potentially good candidates for late IVT [10]. This approach is currently being assessed in a randomized trial based on the existence of an MRI diffusionperfusion mismatch (ECASS 4-Extend study). Brain MRI may also allow some of the wake-up or unknown time onset AIS (which represents approximately 15% of all AIS) to be treated by IVT [27]. Diffusion-FLAIR mismatch (i.e. AIS visible on diffusion weighted imaging but not yet on FLAIR) has positive and negative predictive values > 90% to determine that symptoms are recent (less than 3 hours or even less than 4.5 hours) [28,29]. One randomized trial comparing IVT to placebo in patients suffering wake-up stroke with a diffusion-FLAIR mismatch is currently ongoing (Wake-up study), following encouraging observational findings [30]. Telemedicine (telestroke) is bringing the expertise of stroke physicians and neuroradiologists to help emergency department physicians to start IVT in hospitals lacking a dedicated stroke unit [31]. An original approach has been recently proposed by two German groups, which involves ‘‘bringing the hospital to the patient’’ via a mobile stroke unit (MSU), in order to start IVT directly at the site of the AIS [21,32]. The MSU is a dedicated ambulance equipped with a CT, a point-of-care laboratory, a telemedicine solution and involving an onboard stroke neurologist and radiology technician. This strategy has been assessed on a randomized basis in a semi-rural setting and then in Berlin and has allowed a 25-min median onset-to-IVT time reduction compared to usual care [21]. Moreover, the Berlin (PHANTOM-S) study showed that the MSU helped increase the proportion of patients treated with IVT for AIS by over 50%. Several clinical trials are now ongoing in Europe and the United States in order to demonstrate that this approach reduces long-term disability.

Future prospects: improving the benefit/risk balance of IVT Although unquestionable, the efficacy of IVT remains limited, as almost 50% of treated patients still have significant functional disability at 3 months [6]. The arterial recanalisation rate after IVT is no more than 50% [33], and additional endovascular treatment (‘‘stentrievers’’) may be

1131 a key option. However, whilst combined treatment with IVT and endovascular approach (bridging therapy) allows high recanalization rates, no randomized trial have yet demonstrated bridging therapy to be superior to IVT alone in terms of long-term disability [34,35]. Subgroup analyses from the IMS-3 trial suggest that trials assessing bridging therapy should focus on patients with severe neurological deficit, proximal arterial occlusion and treated very early [34]. Thanks to dedicated scores, identifying on hospital admission patients likely to have poor long-term functional prognosis despite IVT is feasible and could help selecting the best candidates to assess bridging therapy [7,8]. Several randomized trials of bridging therapy are ongoing (MR CLEAN, THRACE, SWIFT PRIME, BASICS trial, etc.). Apart from endovascular strategies, three main approaches have been proposed to improve the effectiveness of IVT: reducing the onset-to-treatment time (which would also reduce the risk of sICH), using nextgeneration thrombolytics instead of alteplase, or carrying out sonothrombolysis. Two recent thrombolytics, desmoteplase and tenecteplase, have theoretical advantages over alteplase, particularly greater affinity for fibrin, reduced neurotoxicity and administration as a single one-minute bolus rather than a one-hour infusion [36,37]. Unfortunately, desmoteplase has not been shown to be superior to placebo in the 3—9 hours time window (DIAS 3 trial, intention-to-treat analysis). Tenecteplase, however, has been shown to be superior to alteplase in a phase IIb randomized study in the 0—6 hours time window [37]. This trial involved highly selected patients with intracranial artery occlusion and persistent ischemic penumbra, both of which were determined on CT. Administration of tenecteplase was associated with a significant short-term and 3-month clinical benefit compared to alteplase, and a non-significant trend towards lower risk of sICH. However, this study should be considered as preliminary because of the small number of patients and different proximal middle cerebral artery occlusion rates between the tenecteplase and alteplase arms. Several clinical trials comparing tenecteplase and alteplase are ongoing. Sonothrombolysis has been proposed for patients with a middle cerebral artery occlusion. It involves applying low intensity, high frequency ultrasounds to the occlusion site over 2 hours via a transcranial Doppler to increase the thrombolytic effect, by allowing better exposure of the thrombus to alteplase. One phase II randomized study has shown sonothrombolysis to be superior to IVT alone in terms of complete recanalization rates (assessed by transcranial Doppler ultrasonography) two hours after starting IVT [38]. A nonsignificant trend in favor of sonothrombolysis was observed for 3-month functional outcome. No significant difference was shown between the two groups in terms of sICH. One double-blind, phase III randomized controlled trail is ongoing (CLOTBUST-ER). Reducing the risk of IVT-related hemorrhage would also improve the benefit/risk balance for this therapy. The Enchanted randomized trial is currently comparing the usual dose of alteplase (0.9 mg/kg) to a lower dose (0.6 mg/kg, which is used routinely in Japan) in order to establish whether the lower dose reduces the risk of sICH without reducing the effectiveness of IVT.

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Conclusion

References

In conclusion, IVT with alteplase within 4.5 hours after AIS onset is currently the only treatment proven to be clinically effective and which is currently approved for the management of this condition. It allows an approximately 10% absolute reduction in the risk of disability or death at 3 months, despite a 2—7% risk of sICH, depending on the definitions used. The contribution of additional endovascular therapy or next-generation thrombolytics will need to be determined in randomized trials using IVT with alteplase as the control group, and long-term functional disability as the primary outcome.

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TAKE-HOME MESSAGES • Intravenous thrombolysis with alteplase is currently the standard treatment for acute ischemic stroke. • It allows a 10% absolute reduction in the risk of disability or death at 3 months. • The earlier intravenous thrombolysis is started, the more effective it will be. • It has clearly been shown to be beneficial under the age of 80 years old within 4.5 hours after symptoms’ onset. • After the age of 80 years old, intravenous thrombolysis is currently given off-label in France, as randomized control trials did not show reduced benefits of treatment based on age. • Approximately 55% of all patients treated with intravenous thrombolysis are independent in activities of daily living 3 months after the ischemic stroke. • The incidence of symptomatic intracranial hemorrhage after intravenous thrombolysis is 2 to 7%, depending on the definitions used. • Bridging therapy (intravenous thrombolysis followed by an endovascular procedure) may be superior to intravenous thrombolysis alone in patients with proximal arterial obstruction treated early, although this point needs to be demonstrated formally in randomized controlled trials using long-term functional disability as the primary outcome. • Other new approaches are currently assessed in clinical studies: ◦ using the diffusion-FLAIR mismatch or penumbra imaging to treat some patients despite wake-up stroke, or beyond the 4.5 hour time window, ◦ next-generation thrombolytics, ◦ telestroke, ◦ pre-hospital thrombolysis using a mobile neurovascular unit, ◦ sonothrombolysis.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

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