Gregory A. Schulz

Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke: The PROACT II trial

Objective: To analyze the frequency, clinical characteristics, and predictors of symptomatic intracerebral hemorrhage (ICH) after intraarterial (IA) thrombolysis with recombinant pro-urokinase (r-proUK) in acute ischemic stroke. Method: The authors conducted an exploratory analysis of symptomatic ICH from a randomized, controlled clinical trial of IA thrombolysis with r-proUK for patients with angiographically documented occlusion of the middle cerebral artery within 6 hours from stroke onset. Patients (n = 180) were randomized in a ratio of 2:1 to either 9 mg IA r-proUK over 120 minutes plus IV fixed-dose heparin or IV fixed-dose heparin alone. As opposed to intention to treat, this analysis was based on “treatment received” and includes 110 patients given r-proUK and 64 who did not receive any thrombolytic agent. The remaining six patients received out-of-protocol urokinase and were excluded from analysis. The authors analyzed centrally adjudicated ICH with associated neurologic deterioration (increase in NIH Stroke Scale [NIHSS] score of ≥4 points) within 36 hours of treatment initiation. Results: Symptomatic ICH occurred in 12 of 110 patients (10.9%) treated with r-proUK and in two of 64 (3.1%) receiving heparin alone. ICH symptoms in r-proUK–treated patients occurred at a mean of 10.2 ± 7.4 hours after the start of treatment. Mortality after symptomatic ICH was 83% (10/12 patients). Only blood glucose was significantly associated with symptomatic ICH in r-proUK–treated patients based on univariate analyses of 24 variables: patients with baseline glucose >200 mg/dL experienced a 36% risk of symptomatic ICH compared with 9% for those with ≤200 mg/dL (p = 0.022; relative risk, 4.2; 95% CI, 1.04 to 11.7). Conclusions: Symptomatic ICH after IA thrombolysis with r-proUK for acute ischemic stroke occurs early after treatment and has high mortality. The risk of symptomatic ICH may be increased in patients with a blood glucose >200 mg/dL at stroke onset.

Selection of Acute Ischemic Stroke Patients for Intra-Arterial Thrombolysis With Pro-Urokinase by Using ASPECTS

Background— Previous studies have suggested that baseline computed tomographic (CT) scans might be a useful tool for selecting particular ischemic stroke patients who would benefit from thrombolysis. The aim of the present study was to assess whether the baseline CT scan, assessed with the Alberta Stroke Program Early CT Score (ASPECTS), could identify ischemic stroke patients who might particularly benefit from intra-arterial thrombolysis of middle cerebral artery occlusion. Methods— Baseline and 24-hour follow-up CT scans of patients randomized within 6 hours of symptoms to intra-arterial thrombolysis with recombinant pro-urokinase or control in the PROACT-II study were retrospectively scored by using ASPECTS. Patients were stratified into those with ASPECTS >7 or ≤7. Independent functional outcome at 90 days was compared between the 2 strata according to treatment assignment. Results— The analysis included 154 patients with angiographically confirmed middle cerebral artery occlusion. The unadjusted risk ratio of an independent functional outcome, in favor of treatment, in the ASPECTS >7 group was 5.0 (95% confidence interval [CI], 1.3 to 19.2) compared with 1.0 (95% CI, 0.6 to 1.9) in the ASPECTS ≤7 group. After adjustment for baseline characteristics, the risk ratio in the ASPECTS score >7 was 3.2 (95% CI, 1.2 to 9.1). Similar favorable treatment effects were observed when secondary outcomes were used, but these did not reach statistical significance. Conclusions— Ischemic stroke patients with a baseline ASPECTS >7 were 3 times more likely to have an independent functional outcome with thrombolytic treatment compared with control. Patients with a baseline ASPECTS ≤7 were less likely to benefit from treatment. This observation suggests that ASPECTS can be both a useful clinical tool and an important method of baseline risk stratification in future clinical trials of acute stroke therapy.

Computed Tomographic Findings in Patients Undergoing Intra-arterial Thrombolysis for Acute Ischemic Stroke due to Middle Cerebral Artery Occlusion Results From the PROACT II Trial

Background and Purpose— The purpose of this study was to evaluate the role of noncontrast CT in the selection of patients to receive thrombolytic therapy for acute ischemic stroke and to predict radiological and clinical outcomes. Methods— One hundred eighty patients with stroke due to middle cerebral artery (MCA) occlusion were randomized 2:1 within 6 hours of onset to receive intra-arterial recombinant prourokinase plus intravenous heparin or intravenous heparin only. Four hundred fifty-four CT examinations were digitized to calculate early infarct changes, infarct volumes, and hemorrhagic changes among the 162 patients treated as randomized (108 recombinant prourokinase–treated patients and 54 control patients). CT changes were correlated with baseline stroke severity, angiographic clot location, collateral vessels, and outcome at 90 days. Results— Baseline CT scans, 120 (75%) of 159, showed early infarct–related abnormalities. The baseline CT abnormality volume was not correlated with the baseline National Institutes of Health Stroke Scale (NIHSS) score (r =−0.11) but was correlated weakly with the outcome (r =0.17, P <0.05). Compared with patients with M2 occlusions, patients with M1 MCA occlusions had significantly higher baseline NIHSS scores (P <0.05), more basal ganglia involvement on CT, and larger hypodensity volumes on follow-up CTs. Compared with patients with partial or no collateral supply, patients with full collateral supply had lower baseline NIHSS scores, significantly smaller baseline CT infarct volumes, and less cortical involvement (P <0.05). Conclusions— Noncontrast CT is not correlated with baseline stroke severity and does not predict outcome in patients with stroke due to MCA occlusion. However, baseline CT changes, clinical presentation, and the evolution of CT changes are influenced by clot location and the presence of a collateral supply.

Sex-Based Differences in the Effect of Intra-Arterial Treatment of Stroke Analysis of the PROACT-2 Study

Background and Purpose— Sex influences outcome after intravenous thrombolysis. In a combined analysis of the tissue plasminogen activator clinical trials, a sex-by-treatment interaction was observed. We sought to confirm that observation in an independent data set. Methods— Data were from the Pro-Urokinase for Acute Cerebral Thromboembolism-2 (PROACT-2) trial. Baseline factors were compared by sex. The primary outcome was an assessment of a sex-by-treatment interaction term within a logistic regression model, using a modified Rankin Scale score ≤2 at 90 days as the binary outcome. We also assessed whether there were differences in CT-scan appearance and recanalization at 2 hours post-treatment. Results— In the PROACT-2 study of intra-arterial stroke thrombolysis, in both women and men, prourokinase resulted in better outcomes than control. A sex by prourokinase treatment interaction was observed, with women showing a larger treatment effect (20% absolute benefit) compared with men (10% absolute benefit). The reason for this interaction is that thrombolytic treatment nullifies the worse outcome for untreated women compared with men. The reasons for effect modification do not include improved recanalization at 2 hours among women. Conclusions— Women with middle cerebral artery ischemic stroke benefit more from intra-arterial therapy. Further study of how sex affects stroke outcome is needed.

Factors Influencing Outcome and Treatment Effect in PROACT II

Background and Purpose— The PROACT II study demonstrated a significant benefit from treatment with intra-arterial pro-urokinase (r-proUK) in patients with middle cerebral artery occlusion treated within 6 hours of stroke onset. The purpose of the current study was to examine baseline factors to determine predictors of good outcome and response to treatment. Methods— We selected from the baseline clinical, radiologic, and angiographic data variables that considered possibly related to outcome. A univariate analysis was performed to examine the association between these baseline factors and good outcome, defined as a modified Rankin scale score ≤2. A multivariate model then selected the most important variables independently influencing prognosis. A risk score for each patient was constructed on the basis of the patient’s individual values for each independent variable. Patients were stratified into risk quartiles based on their risk scores, and an odds ratio for each risk quartile was calculated. The treatment effects of each quartile were compared. Results— In the univariate analysis, screening National Institutes of Health stroke scale (NIHSS) score and age were strongly associated with good outcome. The multivariate model selected age, NIHSS score, and CT hypodensity as the most important prognostic variables. Dividing patients into quartiles based on risk scores achieved a uniform gradient of probability of good outcomes. A trend toward benefit of r-proUK treatment was seen in all risk quartiles, and no differential treatment effect was observed across risk groups. Conclusions— There was no evidence of differential effect of r-proUK across subgroups of patients stratified by risk.

Recombinant urokinase for restoration of patency in occluded central venous access devices A double-blind, placebo-controlled trial

The interval occlusion of central venous access devices (CVADs) remains a significant clinical problem, often requiring re-intervention for catheter exchange or replacement. The purpose of this Phase 3, multi-center, double-blinded study was to test the hypothesis that instillation of recombinant urokinase (r-UK) 5000 IU/ml is superior to placebo in restoring total catheter patency to an unselected cohort of occluded CVADs. After obtaining informed consent, adult and pediatric patients with occluded, non-hemodialysis CVADs of any duration or type were randomized (2 : 1) to receive either r-UK 5000 IU/ml or placebo instilled into all occluded lumens of their catheter. Catheter function was assessed at 5, 15 and 30 min after the first instillation. If the catheter remained occluded after 30 min, a second dose was instilled with repeat assessments at 5, 15 and 30 min. The primary efficacy variable was the restoration of catheter function to all treated lumens (i.e., total catheter patency) after one or two instillations. Catheters that were not successfully recanalized after two instillations were allowed to receive up to two instillations of open-label r-UK administered in the same manner. The primary safety variable was the occurrence of hemorrhagic and non-hemorrhagic events within 72 hr after instillation. A total of 180 patients were enrolled at 43 sites in the United States and Canada. Most patients were adults, although 20% were </=18 years of age. CVAD types included totally implanted subcutaneous ports (45%), PICC lines (26%), non-tunneled percutaneous catheters (18%), and tunneled percutaneous catheters (10%). All CVADs were occluded by virtue of their inability to withdraw blood (withdrawal occlusion). Additionally, 32% of catheters were completely dysfunctional as blood could not be withdrawn and fluids could not be infused (total occlusion). Analysis of the results showed that r-UK was significantly better than placebo in restoring catheter function (54% versus 30%, p = 0.002). There were no major hemorrhagic events within 72 hr after up to four r-UK instillations, and the incidence of non-hemorrhagic events was similar among the r-UK and placebo groups. In conclusion, r-UK is superior to placebo in restoring total catheter patency to occluded CVADs. In patients with occluded CVADs, intra-catheter thrombolysis can restore patency and may obviate the need for catheter replacement.

Computed Tomographic Findings in Patients Undergoing Intra-arterial Thrombolysis for Acute Ischemic Stroke due to Middle Cerebral Artery Occlusion: Results From the PROACT II Trial * Editorial Comment: Results From the PROACT II Trial

Background and Purpose— The purpose of this study was to evaluate the role of noncontrast CT in the selection of patients to receive thrombolytic therapy for acute ischemic stroke and to predict radiological and clinical outcomes. Methods— One hundred eighty patients with stroke due to middle cerebral artery (MCA) occlusion were randomized 2:1 within 6 hours of onset to receive intra-arterial recombinant prourokinase plus intravenous heparin or intravenous heparin only. Four hundred fifty-four CT examinations were digitized to calculate early infarct changes, infarct volumes, and hemorrhagic changes among the 162 patients treated as randomized (108 recombinant prourokinase–treated patients and 54 control patients). CT changes were correlated with baseline stroke severity, angiographic clot location, collateral vessels, and outcome at 90 days. Results— Baseline CT scans, 120 (75%) of 159, showed early infarct–related abnormalities. The baseline CT abnormality volume was not correlated with the baseline National Institutes of Health Stroke Scale (NIHSS) score (r =−0.11) but was correlated weakly with the outcome (r =0.17, P <0.05). Compared with patients with M2 occlusions, patients with M1 MCA occlusions had significantly higher baseline NIHSS scores (P <0.05), more basal ganglia involvement on CT, and larger hypodensity volumes on follow-up CTs. Compared with patients with partial or no collateral supply, patients with full collateral supply had lower baseline NIHSS scores, significantly smaller baseline CT infarct volumes, and less cortical involvement (P <0.05). Conclusions— Noncontrast CT is not correlated with baseline stroke severity and does not predict outcome in patients with stroke due to MCA occlusion. However, baseline CT changes, clinical presentation, and the evolution of CT changes are influenced by clot location and the presence of a collateral supply.

Dose-Ranging Trial with a Recombinant Urokinase (Urokinase Alfa) for Occluded Central Venous Catheters in Oncology Patients

PURPOSE Recombinant urokinase (r-UK) is a high-molecular-weight urokinase produced in transfected, non-human, mammalian cells. A Phase II, randomized, double-blind, parallel, placebo-controlled, dose-ranging study was performed to compare the safety and efficacy of one or two instillations of three intraluminal concentrations of r-UK (5,000; 15,000; and 25,000 IU/mL) with a placebo for reestablishment of total function to occluded central venous access devices (CVADs). MATERIALS AND METHODS One-hundred eight patients with CVAD withdrawal or total occlusion were enrolled and randomized to treatment; 104 patients received at least one instillation of study drug and 101 patients completed treatment. All but one patient had cancer. RESULTS All three concentrations of r-UK were significantly superior to placebo in restoring total CVAD function (patency of all occluded lumens) after one or two instillations of study medication (25,000 IU/mL r-UK, 68% vs. placebo, 28% [P =.007]; 15,000 IU/mL r-UK, 69% vs. placebo, 24% [P =.004]; 5,000 IU/mL r-UK, 70% vs. placebo, 28% [P =.003]). Comparisons of the three r-UK concentrations indicated no difference after one or two instillations with regards to patency restoration. Treatment-emergent hemorrhagic events occurring within 72 hours after study drug exposure were experienced by four patients (17%) in the 25,000 IU/mL r-UK group, two patients (7%) in the 15,000 IU/mL r-UK group, no patients in the 5,000 IU/mL r-UK group, and no patients in the placebo group. CONCLUSIONS Efficacy and safety results of this study support further evaluation of a 5,000 IU/mL concentration of r-UK for treatment of occluded CVADs in adult and pediatric patients from 1 year of age.

Computed Tomographic Findings in Patients Undergoing Intra-arterial Thrombolysis for Acute Ischemic Stroke due to Middle Cerebral Artery Occlusion

Background and Purpose— The purpose of this study was to evaluate the role of noncontrast CT in the selection of patients to receive thrombolytic therapy for acute ischemic stroke and to predict radiological and clinical outcomes. Methods— One hundred eighty patients with stroke due to middle cerebral artery (MCA) occlusion were randomized 2:1 within 6 hours of onset to receive intra-arterial recombinant prourokinase plus intravenous heparin or intravenous heparin only. Four hundred fifty-four CT examinations were digitized to calculate early infarct changes, infarct volumes, and hemorrhagic changes among the 162 patients treated as randomized (108 recombinant prourokinase–treated patients and 54 control patients). CT changes were correlated with baseline stroke severity, angiographic clot location, collateral vessels, and outcome at 90 days. Results— Baseline CT scans, 120 (75%) of 159, showed early infarct–related abnormalities. The baseline CT abnormality volume was not correlated with the baseline National Institutes of Health Stroke Scale (NIHSS) score (r =−0.11) but was correlated weakly with the outcome (r =0.17, P <0.05). Compared with patients with M2 occlusions, patients with M1 MCA occlusions had significantly higher baseline NIHSS scores (P <0.05), more basal ganglia involvement on CT, and larger hypodensity volumes on follow-up CTs. Compared with patients with partial or no collateral supply, patients with full collateral supply had lower baseline NIHSS scores, significantly smaller baseline CT infarct volumes, and less cortical involvement (P <0.05). Conclusions— Noncontrast CT is not correlated with baseline stroke severity and does not predict outcome in patients with stroke due to MCA occlusion. However, baseline CT changes, clinical presentation, and the evolution of CT changes are influenced by clot location and the presence of a collateral supply.