Combined Intravenous and Intra Arterial Thrombolysis

Some studies have evaluated the feasibility, safety, and efficacy of combined IV rt-PA at a dose of 0.6 mg/kg with IAT in patients presenting with acute strokes within 3 hours of symptom onset.31-34 This approach has the potential of combining the advantages of IV rt-PA (fast and easy to use) with the advantages of IAT (directed therapy, titrated dosing, mechanical aids to recanalization, and higher rates of recanalization), thus improving the speed and frequency of recanalization.

The Emergency Management of Stroke (EMS) Bridging Trial was a doubleblind, randomized, placebo-controlled, multicenter phase I study of IV rt-PA or IV placebo followed by immediate IAT with rt-PA.31 Seventeen patients were randomly assigned to the IV/IA group and 18 to the placebo/IA group. Clot was found in 22 of 34 patients. TIMI 3 flow recanalization occurred in 6 of 11 IV/IA patients versus 1 of 10 placebo/IA patients (p = 0.03), and correlated with the total dose of rt-PA (p = 0.05). However, no difference in the 7- to 10-day or 3-month outcomes was found, and there were more deaths in the IV/IA group. Eight intraparenchymal hemorrhages occurred. Symptomatic ICH occurred in one placebo/IA patient and two IV/IA patients. Life-threatening bleeding complications occurred in two patients, both in the IV/IA group.

Ernst et al.32 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 IA 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 obtained in 50% (8/16) and 19% (3/16) of the patients, respectively. One patient (5%) developed a fatal ICH. Ten patients (50%) recovered to an mRS score of 0-1, three patients (15%) to an mRS score of 2, and five patients (25%) to an mRS score of 4-5.

Suarez et al.33 studied "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 IAT. Eleven patients received IAT with rt-PA (maximum dose 0.3 mg/kg) and 13 patients received IAT 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 11 IV rt-PA/IA rt-PA-treated patients. Partial recanalization also occurred in 5 of the 13 IV rt-PA/IA uro-kinase-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.35 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 IA 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.36 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 IAT with rt-PA (maximum dose 20 mg) and one underwent intracranial angioplasty. TIMI2 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).34 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 reca-nalization. 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 placebo-treated subjects (1.0%, p = 0.018) in the NINDS rt-PA Stroke Trial. IMS I subjects had a significantly better outcome at 3 months than NINDS placebo-treated subjects for all outcome measures (OR > 2). For the 62 subjects who received IA rt-PA in addition to IV rt-PA, the rate of complete recanalization (TIMI 3 flow) was 11% (7/62), and the rate of partial or complete recanalization (TIMI 2 or 3 flow) was 56% (35/62).

The IMS II objective was to continue investigating the feasibility of the combined IV and IA approach to restore cerebral blood flow in acute stroke patients.37 The difference between IMS I and IMS II is that IMS II used the EKOS microcath-eter to deliver the rt-PA into the clot, using microcatheter ultrasound technology. The rationale is that the ultrasound energy delivered in the clot loosens the fibrin strands, increasing the permeability and penetration of the thrombolytic agents. In IMS II, patients aged 18-80 years with a baseline NIHSS >10 were given IV rt-PA (0.6 mg/kg, 60 mg maximum over 30 minutes) within 3 hours of stroke onset. Patients with eligible clot in extra- or intracranial cerebral vessels were subsequently administered up to 22 mg IA rt-PA, as well as low-energy ultrasound energy at the clot site using the EKOS ultrasound catheter for a maximum period of 2 hours of infusion or until thrombolysis was achieved. If the EKOS catheter could not access the clot, standard microcatheters were used as per the IMS I protocol. Primary comparisons were made with similar subsets of placebo and rt-PA-treated subjects from the NINDS rt-PA Stroke Trial, as well as subjects from IMS I. Seventy-three subjects were enrolled with a median baseline NIHSS score of 19 and a median time from symptom onset to initiation of IV rt-PA of 141 minutes. In IMS II, 45% of patients had an mRS score of 0-2 at 90 days, compared to 43% in the IMS I and 39% in the NINDS IV rt-PA Stroke Trial. After adjustment for baseline NIHSS, age, and time-to-treatment, the OR of IMS II subjects attaining an mRS of 0-2 at 3 months was 1.65 (95% CI 0.88, 3.07) compared to rt-PA-treated subjects in the NINDS rt-PA Stroke Trial. Compared to the IMS I, the IMS II trial demonstrated a higher rate of recanalization (69%). The mortality and the symptomatic ICH rates in IMS II were 16% and 11%, respectively.

The ongoing IMS III trial is a randomized, multicenter, phase III trial continuing the investigation into the efficacy of the combined IV and IA approach to treat acute stroke. Patients are being randomized to IV/IA therapy and IV rt-PA alone in a 2:1 ratio. In the group allocated to combination IV/IA therapy, the physician will select either the EKOS microcatheter or a standard microcatheter to infuse rt-PA, or select the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) clot retrieval device. The primary outcome is the percentage of patients with an mRS score of 0-2 at 90 days.38

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