[Show abstract][Hide abstract] ABSTRACT: Context
Intravenous tissue-type plasminogen activator can be beneficial to some
patients when given within 3 hours of stroke onset, but many patients present
later after stroke onset and alternative treatments are needed.Objective
To determine the clinical efficacy and safety of intra-arterial (IA)
recombinant prourokinase (r-proUK) in patients with acute stroke of less than
6 hours' duration caused by middle cerebral artery (MCA) occlusion.Design
PROACT II (Prolyse in Acute Cerebral Thromboembolism II), a randomized,
controlled, multicenter, open-label clinical trial with blinded follow-up
conducted between February 1996 and August 1998.Setting
Fifty-four centers in the United States and Canada.Patients
A total of 180 patients with acute ischemic stroke of less than 6 hours'
duration caused by angiographically proven occlusion of the MCA and without
hemorrhage or major early infarction signs on computed tomographic scan.Intervention
Patients were randomized to receive 9 mg of IA r-proUK plus heparin
(n = 121) or heparin only (n = 59).Main Outcome Measures
The primary outcome, analyzed by intention-to-treat, was based on the
proportion of patients with slight or no neurological disability at 90 days
as defined by a modified Rankin score of 2 or less. Secondary outcomes included
MCA recanalization, the frequency of intracranial hemorrhage with neurological
deterioration, and mortality.Results
For the primary analysis, 40% of r-proUK patients and 25% of control
patients had a modified Rankin score of 2 or less (P
= .04). Mortality was 25% for the r-proUK group and 27% for the control group.
The recanalization rate was 66% for the r-proUK group and 18% for the control
group (P<.001). Intracranial hemorrhage with neurological
deterioration within 24 hours occurred in 10% of r-proUK patients and 2% of
control patients (P = .06).Conclusion
Despite an increased frequency of early symptomatic intracranial hemorrhage,
treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke
caused by MCA occlusion significantly improved clinical outcome at 90 days.
Figures in this Article
Intravenous (IV) tissue-type plasminogen activator (tPA) improves outcomes
after acute ischemic stroke but must be given within 3 hours of onset.1 Six randomized trials have failed to show an overall
benefit for IV thrombolytic therapy initiated within 6 hours of stroke onset.2- 7
A number of factors have contributed to this failure, but stroke heterogeneity
has been cited as a main cause.8- 9
A focused trial of a homogeneous stroke population provides an alternative
to the traditional large, randomized clinical trial.9
Intra-arterial (IA) thrombolysis lends itself to such a design in selected
patients with acute ischemic stroke.10- 16
The recanalization efficacy and safety of IA recombinant prourokinase
(r-proUK) in patients with acute ischemic stroke of less than 6 hours' duration
caused by middle cerebral artery (MCA) occlusion were demonstrated in the
first Prolyse in Acute Cerebral Thromboembolism (PROACT I) trial.17 Prolyse (nasaruplase beta) is a glycosolated 411–amino
acid single-chain proenzyme precursor of urokinase (UK) derived from transfected
murine SP2/0 hybridoma cells.18 Single-chain
r-proUK is activated to 2-chain UK at the thrombus surface by fibrin-associated
plasmin.19 The thrombolytic effect of r-proUK
is augmented by heparin, possibly through thrombin neutralization or by stimulating
tPA release from the endothelium.20- 21
Based on PROACT I, we performed a multicenter, randomized trial to determine
the clinical efficacy and safety of IA r-proUK in patients with acute ischemic
stroke of less than 6 hours duration caused by MCA occlusion. In PROACT II,
we increased the total dose of r-proUK from 6 mg to 9 mg given over 2 hours
while using the same low heparin dose as in PROACT I in an attempt to improve
recanalization while limiting symptomatic brain hemorrhages.
JAMA The Journal of the American Medical Association 11/1998; 282(21):2003-2011. DOI:10.1001/jama.282.21.2003 · 30.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To report the result of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) 1 study, a phase 1 trial to evaluate the safety and efficacy of mechanical embolectomy in the cerebral vasculature.
MERCI 1 enrolled 30 patients in 7 US centers. Main inclusion criteria were: National Institutes of Health Stroke Scale score (NIHSS) > or =10; treatment performed within 8 hours from symptoms onset and contra-indication to intravenous thrombolysis; no large hypodensity on computed tomography; and occlusion of a major cerebral artery on the angiogram. Safety was defined by the absence of vascular injury or symptomatic intracranial hemorrhage. Efficacy was assessed by recanalization rate and clinical outcome at 1 month. Significant recovery was defined as 30-day modified Rankin of 0 to 2 in patients with baseline NIHSS 10 to 20 and 30-day modified Rankin of 0 to 3 in patients with baseline NIHSS >20. The procedures were performed with the Merci Retrieval System, a system specially designed for intracranial embolectomy.
Twenty-eight patients were treated. Median NIHSS was 22. Median time from onset to completion of treatment was 6 hours and 15 minutes. Successful recanalization with mechanical embolectomy only was achieved in 12 (43%) patients, and with additional intra-arterial tissue plasminogen activator in 18 (64%) patients. There was one procedure related technical complication, with no clinical consequence. Twelve asymptomatic and no symptomatic intracranial hemorrhages occurred. At 1 month, 9 of 8 revascularized patients and 0 of 10 nonrevascularized patients had achieved significant recovery.
This phase 1 study shows that cerebral embolectomy with the Merci Retriever was safe and that successful recanalization could benefit a significant number of patients, even when performed in an extended 8-hour time window.
[Show abstract][Hide abstract] ABSTRACT: Data from recent reports have indicated that mechanical thrombectomy may have potential as a treatment for acute ischemic stroke. The purpose of this study was to assess the safety and performance of the Penumbra System (PS): a novel mechanical device designed to reduce clot burden in acute stroke due to large-vessel occlusive disease.
A prospective, single arm, independently monitored and core laboratory adjudicated trial enrolled subjects with an acute neurologic deficit consistent with acute stroke, presenting within 8 hours of symptom onset and an angiographically verified occlusion (Thrombolysis in Myocardial Infarction [TIMI] grade 0 or 1) of a treatable intracranial vessel. The primary end point was revascularization of the target vessel to TIMI grade 2 or 3. Secondary end points were the proportion of subjects who achieved a modified Rankin Scale (mRS) score of 2 or less or a 4-point improvement on the National Institutes of Health Stroke Scale (NIHSS) score at 30-day follow-up, as well as all-cause mortality.
Twenty-three subjects were enrolled, and 21 target vessels were treated in 20 subjects by the PS. At baseline, mean age was 60 years, mean mRS score was 4.6, and mean NIHSS score was 21. Postprocedure, all 21 of the treated vessels (100%) were successfully revascularized by the PS to TIMI 2 or 3. At 30-day follow-up, 9 subjects (45%) had a 4-point or more NIHSS improvement or an mRS of 2 or less. The all-cause mortality rate was 45% (9 of 20), which is lower than expected in this severe stroke cohort, where 70% of the subjects at baseline had either an NIHSS score of more than 20 or a basilar occlusion.
Thus, early clinical experience suggests that the PS allows revascularization in certain subjects experiencing acute ischemic stroke.
American Journal of Neuroradiology 06/2008; 29(7):1409-13. DOI:10.3174/ajnr.A1110 · 3.68 Impact Factor
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