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1 Focused Issue of This Month Thrombolytic Treatment of Acute Stroke Sung-Il Sohn, MD Department of Neurology, Keimyung University School of Medicine E - mail : docsohn@dsmc.or.kr A -Hyun Cho, MD Department of Neurology, The Catholic University of Korea, St. Mary s Hospital, Seoul, Korea E - mail : ahyun@catholic.ac.kr J Korean Med Assoc 2009; 52(4): Abstract For the patients suffering from acute ischemic infarct from abrupt occlusion of vessels, prompt reperfusion is necessary to save the ischemic penumbra, eventually leading to a good prognosis. Regarding this, intravenous (IV) recombinant tissue plasminogen activator (rt-pa) thrombolysis as a reperfusion therapy is the only approved method. The IV rt-pa therapy gives us a clinical benefit of 30% or more likelihood of favorable outcome compared to the placebo. However, there is about 6% symptomatic intracranial hemorrhagic risk. Therefore, prudent decision-making by selecting of indicated patients is the role of neurologists. Besides intravenous rt-pa thrombolysis, application of intra-arterial therapy or bridging concept of intra-arterial combined with IV rt-pa is promising. They showed better recanalization rate than that of IV therapy according to the controlled studies. Although the clinical evidence is lacking, they have been performed occasionally in well-facilitated institutions. The results of ongoing trials to support the clinical benefit of these active therapies are expected. In this article, we reviewed the major clinical trials for thrombolytic treatment of acute ischemic stroke and various trials which are under investigation for the extension of the time window for thrombolysis. Keywords: Acute stroke; Thrombolysis; Tissue-plasminogen activator; Intra-arterial therapy 340

2 Thrombolytic Treatment of Acute Stroke Table 1. Factors related to symptomatic intracerebral hemorrhage after intravenous thrombolysis or intra-arterial thrombolysis Clinical (4~6, 53, 55, 56) Radiological (7, 8, 53, 57, 75) CT MRI Angiography Procedural (53, 56, 58) Old age Initial stroke severity Higher systolic blood pressure Higher body temperature Higher glucose level Parenchymal hypoattenuation exceeding one third of middle cerebral artery territory on CT Large ischemic lesion volume on baseline diffusion-weighted imaging Low apparent diffusion coefficient values Presence of leukoaraiosis Focal FLAIR hyperintensity within acute diffusion-weighted image lesions Tandem occlusion Poor collateral circulation Higher urokinase dose Longer time to recanalization 341

3 Sohn SICho AH Table 2. Summary of major clinical trials of intravenous thrombolysis for acute ischemic stroke NINDS (1) ECASS II (11) ATLANTIS (20) ECASS III (22) Year Study design Placebo-controlled, Placebo-controlled, Placebo-controlled, Placebo-controlled, double-blind double-blind double-blind double-blind randomized study randomized study randomized study randomized study Subject number Imaging method Exclusion ICH by CT CT criteria CT criteria Exclusion ICH by CT for decision Initial NIHSS (median) Time window < 3 h < 6 h 3~5 h 3~4.5 h Thrombolysis IV rt-pa vs. placebo IV rt-pa vs. placebo IV rt-pa vs. placebo IV rt-pa vs. placebo method Primary outcome Global test statistic Disability at 3 mo NIHSS 1 at 3mo Disability at 3 mo (Barthel index, mrs, (mrs 0~1) (mrs 0~1) NIHSS at 3 mo) 3mo mrs 0~1 (%) 39 vs. 26* 40.4 vs vs vs. 45.1* Recanalization NA NA NA NA rate (%) Symptomatic 6.4 vs. 0.6* 8.1 (PH2) 4.7 vs. 11.4* 7.9 (NINDS) ICH (%) Mortality (%) 21 vs vs vs vs. 8.4 NIHSS, national institute of health stroke scale; rt-pa, recombinant tissue plasminogen activator; mrs, modified Rankin Scale; GCS, Glasgow coma scale; NA, non-applicable; PH, parenchymal hemorrhage. *Comparison between treatment group and placebo group, statistical significance at P <

4 Thrombolytic Treatment of Acute Stroke Table 2 CLOBUST (17) DIAS II (30) EPITHET (35) Placebo-controlled, Placebo- controlled, Placebo-controlled randomized study double-blind double-blind randomized randomized study study Exclusion ICH by CT MRI or CT criteria MRI criteria < 3 h 3~9 h 3~6 h IV rt-pa vs. IV rt- IV desmoteplase 90 IV rt-pa vs. placebo PA /Ultrasound ug/kg vs. 125 ug/kg vs. placebo Complete recanalization, Global test statistic Infarct growth Dramatic clinical (Barthel index, mrs, on imaging recovery GCS, NIHSS at 3 mo) 42 vs. 29* 58 vs. 50 vs vs vs. 13 at 2h (TCD)* NA 74 vs vs. 4.8 (NINDS) 3.5 vs. 4.5 vs vs. 0 * 29 vs vs. 21 vs vs

5 Sohn SICho AH Figure 1. Model estimating odds ratio for favorable outcome at 3 months in rt-patreated patients compared with controls by onset to treatment (OTT, min). Lancet 2004; 363:

6 Thrombolytic Treatment of Acute Stroke Table 3. Characteristics of patients with ischemic stroke who could be treated with rt - PA Diagnosis of ischemic stroke causing measurable neurological deficit The neurological signs should not be clearing spontaneously The neurological signs should not be minor and isolated Caution should be exercised in treating a patient with major deficits The symptoms of stroke should not be suggestive of subarachnoid hemorrhage Onset of symptoms < 3hours before beginning treatment No head trauma or prior stroke in previous 3months No myocardial infarction in the previous 3months No gastrointestinal or urinary tract hemorrhage in previous 21days No major surgery in the previous 14days No arterial puncture at a noncompressible site in the previous 7days No history of previous intracranial hemorrhage Blood pressure not elevated (systolic < 185mmHg and diastolic < 110mmHg) No evidence of active bleeding or acute trauma (fracture) on examination Not taking an oral anticoagulant or, if anticoagulant being taken, INR 1.7 If receiving heparin in previous 48 hours, aptt must be in normal range Platelet count 100,000 3 mm Blood glucose concentration 50 mg/dl (2.7mmol/L) No seizure with postictal residual neurological impairments CT does not show a multilobar infarction (hypodensity > 1/ 3 cerebral hemisphere) The patient or family members understand the potential risks and benefits from treatment INR indicates international normalized ratio; aptt, activated partial thromboplastin time. 345

7 Sohn SICho AH Table 4. Summary of major prospective trials for combined intravenous/intra-arterial thrombolysis and endovascular treatment of acute ischemic stroke PROACT II (47) MELT (48) EMS (76) IMS II (41) Year Study design Placebo-controlled, Placebo-controlled Placebo- controlled, Open labeled open label randomized study double blind single arm study randomized study randomized study Subject number Initial NIHSS (median) Time window < 6 h < 6 h < 3 h < 3 h Treatment methods IA pro-uk IA urokinase IV rt-pa/ IA rt-pa IV rt-pa /IA rt-pa vs. IV placebo/ia rt-pa Primary outcome Disability at 3 mo Disability at 3 mo NIHSS 7 at 7~10 days Disability at 3 mo (mrs 0~2) (mrs 0~2) (mrs 0~1) 33% 3mo mrs 0~2 (%) 40 vs. 25* 49.1 vs vs Recanalization rate 66 vs. 18* vs (TIMI 2, 3) (%) Symptomatic 10 vs. 2 9 vs vs ICH (%) Mortality (%) 25 vs vs vs NIHSS: National Institute of Health Stroke Scale, mrs: modified Rankin Scale, TIMI: Thrombolysis in myocardial infarction, ICH: Intracerebral hemorrhage. *Comparison between treatment group and placebo group, statistical significance at P <

8 Thrombolytic Treatment of Acute Stroke MERCI (59) Multi-MERCI II (60) PENUMBRA (62) Single arm, Single arm, Single arm, multicenter study multicenter study multicenter study < 8 h < 8 h < 8 h MERCI concentric MERCI concentric Penumbra embolectomy retriever device retriever device with device or without IV rt-pa Disability at 3 mo Disability at 3 mo Disability at 1 mo (mrs 0~2), recanalization (mrs 0~2), recanalization (mrs 0~2), 45% NA (82)

9 Sohn SICho AH A B C D E F G H Figure 2. A 55 -year -old man was admitted with a sudden onset of right hemiplegia and global aphasia within 5 hours after symptom onset. There was large diffusion-perfusion mismatch because diffusion-weighted image showed multiple small lesions on the left middle cerebral artery (MCA) territory (A) and perfusion-weighted image showed large perfusion defects on the left MCA territory (B). MR angiography demonstrated occlusion of the M1 portion of left MCA (C). Emergent conventional angiography was performed revealing the proximal portion of the left MCA (D). Through the microcatheter, 200,000 IU of urokinase was infused and followed by mechanical disruption of the clot using a micro-guide wire was done (E). Although slight recanalization was achieved after intra-arterial thrombolysis, the MCA was reoccluded within 10 minutes. Although we attempted to recanalize by use of balloon catheter (F), improvement of flow was not seen. After placement of coronary stent across clot followed by infusion of 14 mg of abciximab (G), the MCA was kept up the good flow (H). His symptoms were completely recovered after 3 days. 348

10 Thrombolytic Treatment of Acute Stroke *Perfusion area 20% greater than diffusion area or NIHSS score 8 and diffusion-imaging lesion 25 cm 3 Figure 3. Proposed algorithm for treatment of patients with acute ischemic stroke. 349

11 Sohn SICho AH 350

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16 Thrombolytic Treatment of Acute Stroke Peer Reviewers Commentary 355