Recanalization

Several studies have validated the ability of CTP to distinguish between core and penumbra. In one study, Wintermark et al. found that the volumes of early infarcts in CTP CBV maps were highly correlated with volumes of early DWI lesions, whereas volumes of lesions seen in CTP CBF maps were close to those seen in the corresponding MRP MTT maps. In another study, the volume of the CBF abnormahty in an acute-stage infarct was highly correlated with final infarct volume in patients who did not exhibit recanalization after thrombolysis, consistent with extension of infarction into the penumbra. However, in patients who did exhibit recanalization after thrombolysis, final infarct volume was highly correlated with the initial CBV abnormality, consistent with failure of infarcts to extend into the ischemic penumbra. ... 

The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic rt-PA (CLOTBUST) study was a phase II randomized trial which compared continuous transcranial Doppler ultrasound insonation, in subjects with ultrasound evidence of MCA occlusion being given IV rt-PA, to sham insona-tion. ° There was an increased rate of arterial recanalization with the continuous insonation (49% vs. 30%, p = 0.03) and no increased risk of sICH. 

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

Local intra-arterial thrombolysis (lAT) has several theoretical advantages over IV thrombolysis. For instance, by using coaxial microcatheter techniques, the occluded intracranial vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombus. This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic infusion, and ideally it allows for more complete recanalization with lower total doses of thrombolytic. With the smaller dose, complications from systemic fibrinolytic effects, including ICH, can theoretically be reduced. 

Much like the experience with IV thrombolysis, the majority of the early work in lAT has been reported in nonrandomized case series. Reports of successful lAT go back to the late 1950s, when Sussmann and Fitch described the recanalization of an acutely occluded ICA with an intra-arterial injection of plasmin. Nonetheless, it was not until the early 1990s that this approach was studied in a more systematic manner. 

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,... 

The PRO ACT-11 trial was designed to assess the clinical efficacy and safety of lA r-pro-UK. In this study, 180 patients were enrolled in a 2 1 randomization scheme to receive either 9 mg lA r-pro-UK plus 4 hours of low-dose IV heparin, or low-dose IV heparin alone. The primary clinical outcome, the proportion of patients with slight or no disability at 90 days (mRS of < 2), was achieved in 40% of the 121 patients in the r-pro-UK treatment group, compared to 25% of the 59 patients in the control group (absolute benefit 15%, relative benefit 58%, number need to treat = 7 p = 0.04). The recanalization rate (TlMl 2 and 3) was 66% for the r-pro-UK group and 18% for the control group (p < 0.001). Symptomatic ICH within 24 hours occurred in 10% of r-pro-UK patients and 2% of control patients (p = 0.06). All symptomatic ICHs occurred in patients with a baseline NIHSS... 

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. 

Lindsberg and Mattle ° recently analyzed published case series reporting on the outcome of basilar artery occlusion (BAO) after lAT or IV thrombolysis. In 420 BAO patients treated with IV thrombolysis (76) and lAT (344), death or dependency was equally common 78% (59 of 76) and 76% (260 of 344). Recanalization was achieved more frequently with lAT (225 of 344 65%) than with IV thrombolysis (40 of 76 53% p = 0.05), but survival rates after IV thrombolysis (38 of 76 50%) and lAT (154 of 344 45%) were equal (p = 0.48). A total of 24% of patients treated with lAT and 22% treated with IV thrombolysis reached good outcomes (p = 0.82). Without recanalization, the likelihood of achieving a good outcome was close to nil (2%). The authors conclude that recanalization occurs in more than half of BAO patients treated with lAT or IV thrombolysis, and 45-55% of survivors regain functional independence. They advised that hospitals not equipped for lAT should consider setting up IV thrombolysis protocols for BAO since the effect of IVT did not appear to be much different from the effect of lAT. 

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. 

In a prospective, open-label study, Hill et al. assessed the feasibility of a bridging approach using full-dose IV rt-PA. Following IV infusion of 0.9 mg/kg rt-PA, six patients underwent lAT with rt-PA (maximum dose 20 mg) and one underwent intracranial angioplasty. TIMI 2 or 3 recanalization was achieved in three of these patients. There were no symptomatic ICHs. 

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... 

After a baseline angiogram confirms the presence and location of the vascular occlusion, a microcatheter is navigated over a microwire into the occluded vessel, traversing the thrombus. Once the microcatheter is positioned immediately distal to the clot, thrombolytic infusion begins the microcatheter is then pulled back through the clot while dmg is infused. Dose adjustments and total dose calculations are made depending on the clinical circumstances, pretreatment dose of rt-PA received, degree of recanalization, and relative size and function of the territory at risk. 

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... 

FIGURE 4.2 (Continued) A compliant balloon was used to perform angioplasty (c). Postangioplasty angiogram demonstrated complete recanalization of the basilar artery and its major branches (d and e). MRI performed 2 days later demonstrated only small areas of infarction in the cerebellar hemispheres (arrows—f and g) but no brainstem or occipital infarcts. 

Stenting of an acutely occluded intracranial vessel may provide fast recanalization by entrapping the thrombus between the stent and the vessel wall. A recent study in which 19 patients with acute occlusions at the ICA terminus n = 8), M1/M2 (n = 7), or basilar artery (n = 4) were treated with balloon-expandable stents showed a TIMI 2 and 3 recanalization rate of 79% and no symptomatic intracranial hemorrhages (Fig. 4.5). ... 

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. 

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