Stroke recanalization

IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke the Interventional Management of Stroke study. Stroke. 2004 35 904-911. 

A single-center review of 350 acute stroke patients treated with lAT using urokinase showed recanalization rates greater than 75% when additional endovascular techniques (such as mechanical fragmentation of the thrombus, thromboaspiration,... 

Internal Carotid Artery Occlusion Acute stroke due to a distal ICA T (T = terminus) occlusion carry a much worse prognosis than MCA occlusions. In a recent analysis of 24 consecutive patients (median NIHSS 19) presenting with T occlusions of the ICA who were treated by lAT using urokinase at an average of 237 minutes from symptom onset, only four patients (16.6%) had a favorable outcome at 3 months. Partial recanalization of the intracranial ICA was achieved in 15 (63%), of the MCA in 4 (17%), and of the ACA in 8 patients (33%). Complete recanalization did not occur. The presence of good leptomeningeal collaterals and age <60 years were the only predictors of a favorable clinical outcome. New treatment strategies, such as the combination of IV rt-PA and lAT, or the use of new mechanical devices may improve the outcome in these patients. 

Some studies have evaluated the feasibility, safety, and efficacy of combined IV rt-PA at a dose of 0.6 mg/kg with lAT in patients presenting with acute strokes within 3 hours of symptom onset. This approach has the potential of combining the advantages of IV rt-PA (fast and easy to use) with the advantages of lAT (directed therapy, titrated dosing, mechanical aids to recanalization, and higher rates of recanalization), thus improving the speed and frequency of recanalization. 

Ernst et al. performed a retrospective analysis of 20 consecutive patients (median NIHSS 21) who presented within 3 hours of stroke symptoms and were treated using IV rt-PA (0.6 mg/kg) followed by LA rt-PA (up to 0.3 mg/kg or 24 mg, whichever was less, over a maximum period of 2 hours) in 16 of the 20 patients. Despite a high number of ICA occlusions (8/16), TIMI 2 and 3 recanalization rates were... 

Suarez et al. smdied bridging therapy in 45 patients using IV rt-PA at 0.6 mg/kg within 3 hours of stroke onset. Patients exhibiting evidence of PWI/ DWI mismatch on MRI underwent subsequent lAT. Eleven patients received lAT with rt-PA (maximum dose 0.3 mg/kg) and 13 patients received lAT with urokinase (maximum dose 750,000 units). Symptomatic ICH occurred in 2 of the 21 patients in the IV rt-PA-only group but in none of the patients in the IV rt-PA/IAT group. Of the 24 patients in the IV rt-PA/IAT group, 21 had MCA occlusions, 2 had ACA occlusions, and 1 had a PCA occlusion. Complete recanalization occurred in 5 of the 13 IV rt-PA/IA urokinase-treated patients, and in 4 of the IIIV rt-PA/IA rt-PA-treated patients. Partial recanalization also occurred in 5 of the 13 IV rt-PA/IA urokinase-treated patients and 4 of the 11 IV rt-PA/IA rt-PA-treated patients. Favorable outcomes (BI > 95) were seen in 92%, 64%, and 66% of the IV rt-PA/IA urokinase, IV rt-PA/IA rt-PA, and IV rt-PA-only-treated patients, respectively. 

A reversed bridging approach has been proposed by Keris et al. In this study, 12 patients (three ICA occlusions and nine MCA occlusions) out of the 45 enrolled (all with an NIHSS score >20) were randomized to receive an initial lA infusion of 25 mg of rt-PA over 5-10 minutes, followed by IV infusion of another 25 mg over 60 minutes, within 6 hours of stroke onset (total combined dose 50 mg with a maximum dose of 0.7 mg/kg). The remaining 33 patients were assigned to a control group and did not undergo any thrombolysis. TIMI 2 and 3 recanalization occurred in 1 of 12 and 5 of 12 of the patients, respectively. There were no symptomatic ICHs. At 12 months, 83% of the patients in the thrombolysis group were functionally independent, whereas only 33% of the control subjects had a good outcome. 

The Interventional Management of Stroke (IMS I) Study was a multicenter, open-labeled, single-arm pilot study in which 80 patients (median NIHSS 18) were enrolled to receive IV rt-PA (0.6 mg/kg, 60 mg maximum, 15% of the dose as a bolus with the remainder administered over 30 minutes) within 3 hours of stroke onset (median time to initiation 140 minutes). " Additional rt-PA was subsequently administered via a microcatheter at the site of the thrombus in 62 of the 80 patients, up to a total dose of 22 mg over 2 hours of infusion or until complete recanalization. Primary comparisons were with similar subsets of the placebo and rt-PA-treated subjects from the NINDS rt-PA Stroke Trial. The 3-month mortality in IMS I subjects (16%) was numerically lower but not statistically different than the mortality of the placebo (24%) or rt-PA-treated subjects (21%) in the NINDS rt-PA Stroke Trial. The rate of symptomatic ICH (6.3%) in IMS I subjects was similar to that of the rt-PA-treated subjects (6.6%) but higher than the rate in the... 

No direct comparison trials have been reported between the different thrombolytic agents in acute ischemic stroke. In a retrospective review of the results for acute stroke lAT performed at our center, we have found significantly higher rates of recanalization and good clinical outcome in the era in which lA UK was used versus the era in which UK was not available and lAT with rt-PA was the primary treatment. Conversely, in another retrospective study, Eckert et al. found no major difference between the recanalization rates of UK and rt-PA. 

Direct Fibrinolytics Alfimeprase is a recombinant tmncated form of fibrolase, a fibrinolytic zinc metalloproteinase isolated from the venom of the Southern copperhead snake. It degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This may result in faster recanalization and a decreased risk of hemorrhagic conversion. The initial data on the safety and efficacy of alfimeprase in peripheral arterial occlusion disease appeared very promising, but recent communication from the sponsor revealed that the phase III trials of the drug in peripheral arterial disease and catheter obstruction (NAPA-2 and SONOMA-2) failed to meet their primary and key secondary endpoints of revascularization. A trial for I AT in acute stroke (CARNEROS-1) is planned to begin soon. 

The data for the use of GP Ilb/Illa inhibitors in conjunction with lAT are even more scant, and are limited to case reports. Intravenous abciximab has been successfully used as adjunctive therapy to lA rt-PA or UK in cases of acute stroke. Desh-mukh et al. reported on 21 patients with large vessel occlusion refractory to lAT with rt-PA who were treated with IV and/or lA abciximab, eptifibatide, or tirofiban. Twelve patients also received IV rt-PA and 18 patients underwent balloon angioplasty. Complete or partial recanalization was achieved in 17 of 21 patients. Three patients (14%) had asymptomatic ICH, but there were no cases of symptomatic ICH. Mangiafico et al. described 21 stroke patients treated with an intravenous bolus of tirofiban and heparin followed by lA urokinase. Nineteen of these patients also underwent balloon angioplasty. TIMI 2-3 flow was achieved in 17 of 21 patients. ICH occurred in 5 of 21 patients (3 symptomatic ICH and 2 SAH), and was fatal in 3... 

Self-expanding stents with a higher radial force (e.g., WingSpan, Boston Scientific Corp.) will probably play a key role in acute stroke cases related to intracranial atherosclerotic disease. Antegrade flow is essential for the maintenance of vascular patency, as particularly evident in patients with severe proximal stenoses who commonly develop rethrombosis after vessel recanalization. Furthermore, stenting of the proximal vessels may be required in order to gain access to the intracranial thrombus with other mechanical devices or catheters. In a recent series, 23 of 25 patients (92%) with acute n = 15) or subacute n = 10) ICA occlusions were successfully revascularized with this technique. " ... 

The Penumbra stroke system (Penumbra Inc., San Leandro, CA) includes two different revascularization options (1) thrombus debulking and aspiration may be achieved by a reperfusion catheter that aspirates the clot while a separator device fragments it, and (2) direct thrombus extraction may be performed by a ring retriever while a balloon guide catheter is used to temporarily arrest flow. This system has been tested in a pilot trial in Europe. Twenty patients (mean NIHSS 21) with a total of 21 vessel occlusions (7 ICA, 5 MCA, and 9 Basilar) were treated up to 8 hours after symptom onset. Recanalization prior to lA lysis was achieved in all cases (48% TIMI 2 52% TIMI 3). Seven patients were also treated with lA UK or rt-PA. Good outcome at 30 days (defined as mRS < 2 or NIHSS 4-point improvement) was demonstrated in 42%. The mortality rate was 45%, but there were no device-related deaths. There was one asymptomatic SAH and three symptomatic ICHs. A prospective, single-arm, multicenter trial is being conducted in the United States and Europe currently. 

The efficacy of IV thrombolysis in patients with moderate-to-severe strokes due to proximal arterial occlusions is restricted by several factors, including the relatively short therapeutic window, poor recanalization rates as the clot burden increases, restrictive eligibility criteria, and the risk of intracerebral hemorrhage. Endovascular techniques improve the rates of recanalization in this patient population, and appear to increase the likelihood of a good functional outcome. Intravenous thrombolysis... 

Qureshi Al, Siddiqui AM, Kim SH, Hanel RA, Xavier AR, Kirmani JF, Suri ME, Boulos AS, Hopkins LN. Reocclusion of recanalized arteries during intra-arterial thrombolysis for acute ischemic stroke. AJNR Am J Neuroradiol 2004 25 322-328. 

Berlis A, Lutsep H, Barnwell S, Norbash A, Wechsler L, Jungreis CA, Woolfenden A, Redekop G, Hartmann M, Schumacher M. Mechanical thrombolysis in acute ischemic stroke with endovascular photoacoustic recanalization. Stroke 2004 35 1112-1116. 

Levy El, Ecker RD, Horowitz MB, Gupta R, Hanel RA, Sauvageau E, Jovin TG, Guterman LR, Hopkins LN. Stent-assisted intracranial recanalization for acute stroke early results. Neurosurgery 2006 58 458-463 [discussion 458 63]. 

Early studies indicate that combined GP Ilb/IIIa inhibition with rt-PA thrombolysis may improve clinical and MRI outcomes after acute ischemic stroke, with an acceptable safety prohle. The dual targeting of platelets and hbrin by combination therapy may provide synergistic benefits, including increased arterial recanalization, reduced microvascular thrombosis, reduced arterial reocclusion, and less rt-PA-mediated blood-brain barrier injury and secondary activation of the coagulation system. 

Mokri B, Silbert PL, Schievink WI et al (1996) Cranial nerve palsy in spontaneous dissection of the extracranial internal carotid artery. Neurology 46 356-359 Molina CA, Montaner J, Abilleira S et al (2001) Timing of Spontaneous Recanalization and Risk of Hemorrhagic Transformation in Acute Cardioembolic Stroke. Stroke 32 1079-1084 Molina CA, Alvarez-Sabin J, Montaner J et al (2002) Thrombolysis-related hemorrhagic infarction a marker of early reperfusion, reduced infarct size, and improved outcome in patients with proximal middle cerebral artery occlusion. Stroke 33 1551-1556... 

MR and recanalization of stroke clots using embolectomy (MR RESCUE) Yes Yes Yes... 

The concept of critical flow thresholds provides the rational basis for attempts to salvage the ischemic penumbra. In the clinical environment, the successful application of thrombolysis in stroke patients (NINDS Study Group 1995) could be shown to be related to this issue fair clinical outcome correlated positively with early recanalization (von Kummer et al. 1995) and even small improvements of local CBF in the 10% range predicted the reversibility of ischemic tissue changes (Butcher et al. 2003). 

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