KISSIMMEE, FLA—Combining IV and intra-arterial (IA) recombinant tissue plasminogen activator (t-PA) therapy is feasible and reasonably safe and may be of benefit in selected acute stroke patients, preliminary results of the second Interventional Management of Stroke (IMS II) study have shown. In IMS I, conducted to help define revascularization end points in stroke interventional trials, investigators found that recanalization of the primary arterial occlusive lesion and global reperfusion of the distal vascular bed resulted in similar good clinical outcomes.

"The primary goal of the IMS II study was to evaluate the risks and benefits of combining reduced-dose t-PA IV therapy, followed by additional IA delivery of t-PA at the site of an arterial blockage in eligible ischemic stroke patients, using the EKOS Micro-Infusion Catheter MicroLysus infusion system delivering low-energy ultrasound to accelerate clot lysis," said principal investigator Thomas A. Tomsick, MD, at the American Stroke Association’s 2006 International Stroke Conference.

Patients ages 18 to 80 were enrolled at one of 13 participating clinical centers from December 2003 through April 2005. IV t-PA was initiated within three hours of symptom onset. An NIH Stroke Scale (NIHSS) score of 10 at time of t-PA administration was required for patients to be included in the study. Excluded patients were those with hypertension (systolic blood pressure > 185 mm Hg and diastolic > 110 mm Hg), those taking oral anticoagulants and with an international normalized ratio greater than 1.5, and those with large regions (one third of the middle cerebral artery) of clear hypodensity on baseline CT.

t-PA AT A REDUCED DOSE

"The t-PA was administered at a reduced dose, 0.6 mg/kg, with 15% as bolus infused over 30 minutes," said Dr. Tomsick, Professor and Director of Neuroradiology at the University of Cincinnati. Patients then went immediately to the angiographic suite. If no thrombus or arterial occlusive lesions were identified, treatment was stopped. If a thrombus was identified, patients eligible for the EKOS catheter received a 2-mg hand bolus of drug "administered into the proximal portion of the thrombus, and an infusion was begun at 10 mg an hour for two hours of treatment until the clot resolved." Maximum IA administration of t-PA was 22 mg, and no clot manipulation was allowed with the EKOS microcatheter.

"If the catheter could not reach the clot, regional infusion was allowed," said Dr. Tomsick. If a patient was not EKOS eligible, treatment was initiated with a standard microcatheter, using the IMS I protocol, "which was 2 mg distal, 2 mg intraclot, and proximal infusion 9 mg an hour for up to two hours, 22 mg maximum, with clot manipulation allowed every 15 minutes at the time of the requisite control angiogram. And regional infusion was allowed then, if the catheter could not access the site."

The mean age of the 73 patients enrolled in the trial was 64.1. Patients were predominantly white (81%), with more males than females (56% versus 44%). Mean baseline NIHSS score was 18.4 (range, 10 to 32).

IV AND IA TREATMENT

The median time from symptom onset to IV t-PA was 141 minutes, and median time to IA therapy was 239.5 minutes, which represents some degree of delay compared with median time in IMS I (212 minutes). Compared with patients in IMS I, the NINDS t-PA Stroke Trial, and the NINDS placebo study, "we see this was a fairly sick group of patients, with the median baseline stroke scale score of 19," Dr. Tomsick said. The NIHSS score was 18 in IMS I and 17 in the two NINDS studies.

Of the 73 patients, 22 received IV treatment only. "Of these 22 patients, approximately half had distal or no arterial occlusive lesion," noted Dr. Tomsick. "There were a number of subjects with major arterial occlusive changes who were not treated intra-arterially, because they may have been too late in the study. IA treatment had to begin within five hours." These patients had a lower baseline median NIHSS score (15.5) but did not differ in age or time to IV treatment.

Fifty-one patients received IV and IA treatment, 30 in conjunction with the EKOS microcatheter and 18 with a standard microcatheter. Three patients were treated with the EKOS without ultrasound, predominantly due to a regional infusion. Median NIHSS score was 21 in the standard microcatheter group and 20 in the EKOS microcatheter group. There was a slight trend toward difference in onset to IA therapy—246.5 minutes for the standard microcatheter group versus 224.0 minutes for the EKOS microcatheter group. "Several patients [were] treated with standard microcatheter after the EKOS microcatheter could not be delivered, suggesting that there could have been a time delay in that treatment," Dr. Tomsick noted.

"The primary end point shows more complete recanalization at 60 minutes with the EKOS ultrasound microcatheter compared to 23 subjects in the IMS I trial for whom data were available," he said. "At two hours or at completion of procedure, total recanalization of the primary lesion [was] seen in 69% of IMS II [patients] treated with the EKOS ultrasound microcatheter compared to 50.5% in IMS I. So it did seem to have more complete and potentially faster recanalization."

TRIAL COMPARISON

Twelve patients (16.4.%) died, according to Dr. Tomsick. "In terms of comparison of those safety factors to previous studies, if we look at the NINDS t-PA–treated group and the previous IMS I study, the mortality remains the same, with the trend toward reduced mortality compared to NINDS t-PA," he said. Symptomatic hemorrhages were greater in the IMS II trial (11%) compared with in IMS I (6.3%) and the NINDS t-PA trials (6.6%). Asymptomatic intracerebral hemorrhage less than 36 hours from onset occurred in 23 patients (31.5%).

Using the modified Rankin scale score of 0 to 2, 45% of patients in IMS II had good outcomes at three months, compared with 43% in IMS I, 39% in the NINDS t-PA Stroke trial, and 28% in the NINDS placebo study. After adjustment for differences in baseline stroke severity, age, and time-to-treatment, the IMS II patients were 65% more likely to attain functional independence at three months, compared with patients treated with only IV t-PA in the NINDS t-PA Stroke Trial.

The temperature of the microcatheter ultrasound tip was also evaluated, because cooling may identify recanalization. Of 93 data points available with arteriographic and temperature data for retrospective analysis, 40 temperature decreases and 45 recanalizations or retractions were identified. "We found out that a temperature decrease has an 81% sensitivity identifying recanalization, 90% specificity excluding recanalization, 85% positive predictive value, 87% negative predictive value, and an 85% accuracy," Dr. Tomsick said. In IMS IIb, investigators will determine whether real-time monitoring of temperature changes at the catheter tip can identify changes prospectively and thus accelerate recanalization.

IMS III STUDY DESIGN OUTLINED

Also at the Stroke Conference, Joseph Broderick, MD, Professor and Chairman of the Department of Neurology and Director of the Greater Cincinnati/Northern Kentucky Stroke Team at the University of Cincinnati, presented the scientific rationale and design for IMS III. "This is going to be the largest interventional study that has been done yet in stroke—900 patients with moderate to severe stroke," Dr. Broderick said. IV t-PA 0.9 mg/kg, 10% as a bolus, will be infused over 40 minutes, during which time the patient will be required to meet all inclusion and exclusion criteria and consent will be obtained. The patient will then be randomized two to one to the IA or IV approach.

"The IA therapy will include the choice of a catheter device—which at this point will include the Concentric retriever, the EKOS catheter, and the standard microcatheter—and additional IA t-PA, depending on the lesion, experience, and training of the investigators," Dr. Broderick continued. "We also built into the trial a mechanism by which future devices, if they meet FDA approval and are accepted by the study steering committee and NIH, may be incorporated at a later date. The bottom line is we have no ‘Goldilocks’ catheter that is just right. We probably are never going to have a Goldilocks catheter for every indication, but we want to make sure that this approach can stay current with what is best. We are testing an approach, not a specific device, and that’s something to keep in mind," he said.

The primary efficacy outcome is a modified Rankin score of 0 to 2 at three months. "We think IMS III will address a question that has already been answered in cardiology: How does an interventional approach compare to standard dose of an IV thrombolytic?" Dr. Broderick said. "We hope that the answer is the same, but we don’t know the answer. That’s why you randomize trials, and it’s time to get started."

NR

—Debra Hughes

Suggested Reading
Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Thrombolytic Therapy in Acute Ischemic Stroke Study Investigators. Stroke. 2000;31:811-816.
IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke study. Stroke. 2004;35:904-911.
Khatri P, Neff J, Broderick JP, et al. Revascularization end points in stroke interventional trials: recanalization versus reperfusion in IMS-I. Stroke. 2005;36:2400-2403.
Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.

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