Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial.

Importance: Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone because mutant prourokinase is designed to act only on degraded fibrin without affecting circulating fibrinogen. Objective: To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase. Design, Setting, and Participants: This controlled, open-label randomized clinical trial with a blinded end point was conducted from August 10, 2019, to March 26, 2022, with a total follow-up of 30 days. Adult patients with ischemic stroke from 4 stroke centers in the Netherlands were enrolled. Interventions: Patients were randomized (1:1) to receive a bolus of 5 mg of intravenous alteplase and 40 mg of an intravenous infusion of mutant prourokinase (intervention) or usual care with 0.9 mg/kg of intravenous alteplase (control). Main Outcomes and Measures: The primary outcome was any intracranial hemorrhage (ICH) on neuroimaging at 24 hours. Secondary outcomes included functional outcome at 30 days, symptomatic ICH, and fibrinogen levels within 24 hours. Analyses were by intention to treat. Treatment effects were adjusted for baseline prognostic factors. Results: A total of 268 patients were randomized, and 238 (median [IQR] age, 69 [59-77] years; 147 [61.8%] male) provided deferred consent and were included in the intention-to-treat population (121 in the intervention group and 117 in the control group). The median baseline score on the National Institutes of Health Stroke Scale was 3 (IQR, 2-5). Any ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) in the control group (adjusted odds ratio, 0.98; 95% CI, 0.46-2.12). Mutant prourokinase led to a nonsignificant shift toward better modified Rankin Scale scores (adjusted common odds ratio, 1.16; 95% CI, 0.74-1.84). Symptomatic ICH occurred in none of the patients in the intervention group and 3 of 117 patients (2.6%) in the control group. Plasma fibrinogen levels at 1 hour remained constant in the intervention group but decreased in the control group (ß = 65 mg/dL; 95% CI, 26-105 mg/dL). Conclusions and Relevance: In this trial, dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion. Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed. Overall, in patients with minor ischemic stroke who met indications for treatment with intravenous thrombolytics but were not eligible for treatment with endovascular therapy, dual thrombolytic therapy with intravenous mutant prourokinase was not superior to treatment with intravenous alteplase alone. Trial Registration: ClinicalTrials.gov Identifier: NCT04256473.

Dual thrombolytic therapy with mutant pro-urokinase and small bolus alteplase for ischemic stroke (DUMAS): study protocol for a multicenter randomized controlled phase II trial.

BACKGROUND: The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke. METHODS: DUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5-7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure. DISCUSSION: When dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke. TRIAL REGISTRATION: NL7409 (November 26, 2018)/NCT04256473 (February 5, 2020).

Impact of the lockdown on acute stroke treatments during the first surge of the COVID-19 outbreak in the Netherlands.

INTRODUCTION: We investigated the impact of the Corona Virus Disease 2019 (COVID-19) pandemic and the resulting lockdown on reperfusion treatments and door-to-treatment times during the first surge in Dutch comprehensive stroke centers. Furthermore, we studied the association between COVID-19-status and treatment times. METHODS: We included all patients receiving reperfusion treatment in 17 Dutch stroke centers from May 11th, 2017, until May 11th, 2020. We collected baseline characteristics, National Institutes of Health Stroke Scale (NIHSS) at admission, onset-to-door time (ODT), door-to-needle time (DNT), door-to-groin time (DGT) and COVID-19-status at admission. Parameters during the lockdown (March 15th, 2020 until May 11th, 2020) were compared with those in the same period in 2019, and between groups stratified by COVID-19-status. We used nationwide data and extrapolated our findings to the increasing trend of EVT numbers since May 2017. RESULTS: A decline of 14% was seen in reperfusion treatments during lockdown, with a decline in both IVT and EVT delivery. DGT increased by 12 min (50 to 62 min, p-value of < 0.001). Furthermore, median NIHSS-scores were higher in COVID-19 - suspected or positive patients (7 to 11, p-value of 0.004), door-to-treatment times did not differ significantly when stratified for COVID-19-status. CONCLUSIONS: During the first surge of the COVID-19 pandemic, a decline in acute reperfusion treatments and a delay in DGT was seen, which indicates a target for attention. It also appeared that COVID-19-positive or -suspected patients had more severe neurologic symptoms, whereas their EVT-workflow was not affected.

Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial.

IMPORTANCE: Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known. OBJECTIVE: To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT. DESIGN, SETTING, AND PARTICIPANTS: The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015. MAIN OUTCOMES AND MEASURES: Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion. RESULTS: Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours. CONCLUSION AND RELEVANCE: For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1804.

A randomized trial of intraarterial treatment for acute ischemic stroke.

BACKGROUND: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking. METHODS: We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis). RESULTS: We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage. CONCLUSIONS: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).

[Mazabraud syndrome--benign intramuscular myxoma with fibrous skeletal dysplasia]. / Het syndroom van Mazabraud. Benigne intramusculaire myxomen met fibreuze skeletdysplasie.

A 51-year-old woman presented with a soft-tissue swelling of the thigh. A MRI scan of the thigh showed an intramuscular lesion and bone-marrow abnormalities in the femur. A bone scintigraphy and PET/CT-scan showed multiple hotspots in the skeleton. The soft-tissue swelling was excised. Although we initially suspected a malignancy of the thigh with diffuse skeletal metastases, this proved to be a benign myxoma which, together with the skeletal abnormalities, corresponded with a diagnosis of Mazabraud syndrome. This is a rare benign disorder in which intramuscular myxomas are associated with fibrous dysplasia of the skeleton. In the case of asymptomatic fibrous dysplasia a conservative approach is sufficient. In the case of fibrous dysplasia associated with pain, or imminent fracture, a prophylactic surgical intervention is indicated. To avoid anxiety, unnecessary diagnostic procedures and surgery Mazabraud syndrome should be always be considered in the case of an intramuscular tumour associated with concurrent skeletal abnormalities.

New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a substudy of the International Carotid Stenting Study (ICSS).

BACKGROUND: The International Carotid Stenting Study (ICSS) of stenting and endarterectomy for symptomatic carotid stenosis found a higher incidence of stroke within 30 days of stenting compared with endarterectomy. We aimed to compare the rate of ischaemic brain injury detectable on MRI between the two groups. METHODS: Patients with recently symptomatic carotid artery stenosis enrolled in ICSS were randomly assigned in a 1:1 ratio to receive carotid artery stenting or endarterectomy. Of 50 centres in ICSS, seven took part in the MRI substudy. The protocol specified that MRI was done 1-7 days before treatment, 1-3 days after treatment (post-treatment scan), and 27-33 days after treatment. Scans were analysed by two or three investigators who were masked to treatment. The primary endpoint was the presence of at least one new ischaemic brain lesion on diffusion-weighted imaging (DWI) on the post-treatment scan. Analysis was per protocol. This is a substudy of a registered trial, ISRCTN 25337470. FINDINGS: 231 patients (124 in the stenting group and 107 in the endarterectomy group) had MRI before and after treatment. 62 (50%) of 124 patients in the stenting group and 18 (17%) of 107 patients in the endarterectomy group had at least one new DWI lesion detected on post-treatment scans done a median of 1 day after treatment (adjusted odds ratio [OR] 5.21, 95% CI 2.78-9.79; p<0.0001). At 1 month, there were changes on fluid-attenuated inversion recovery sequences in 28 (33%) of 86 patients in the stenting group and six (8%) of 75 in the endarterectomy group (adjusted OR 5.93, 95% CI 2.25-15.62; p=0.0003). In patients treated at a centre with a policy of using cerebral protection devices, 37 (73%) of 51 in the stenting group and eight (17%) of 46 in the endarterectomy group had at least one new DWI lesion on post-treatment scans (adjusted OR 12.20, 95% CI 4.53-32.84), whereas in those treated at a centre with a policy of unprotected stenting, 25 (34%) of 73 patients in the stenting group and ten (16%) of 61 in the endarterectomy group had new lesions on DWI (adjusted OR 2.70, 1.16-6.24; interaction p=0.019). INTERPRETATION: About three times more patients in the stenting group than in the endarterectomy group had new ischaemic lesions on DWI on post-treatment scans. The difference in clinical stroke risk in ICSS is therefore unlikely to have been caused by ascertainment bias. Protection devices did not seem to be effective in preventing cerebral ischaemia during stenting. DWI might serve as a surrogate outcome measure in future trials of carotid interventions. FUNDING: UK Medical Research Council, the Stroke Association, Sanofi-Synthélabo, European Union, Netherlands Heart Foundation, and Mach-Gaensslen Foundation.

Assessment of feasibility of endovascular treatment of ruptured intracranial aneurysms with 16-detector row CT angiography.

BACKGROUND: It is unclear whether 16-detector row CT angiography (CTA) can replace digital subtraction angiography (DSA) to assess the feasibility of endovascular treatment (EVT) in the acute phase after aneurysmal subarachnoid hemorrhage. METHODS: We studied 80 consecutive patients with aneurysmal subarachnoid hemorrhage, who underwent both CTA and DSA. Two interventional neuroradiologists independently scored CTA and, immediately thereafter, DSA with respect to feasibility of EVT. We determined whether CTA without DSA was sufficient for a definite judgment. We also assessed interobserver agreement. RESULTS: The 2 readers judged EVT to be feasible in 24 and 37 patients with CTA alone and not feasible in 34 and 20 patients. In these patients, DSA yielded additional information in 6 (reader 1) and 5 patients (reader 2), which did not affect treatment decision. In 19 and 7 patients, DSA was considered inferior to CTA. In the remaining patients (n = 22 and 23, respectively), feasibility of EVT could not be judged with CTA alone, and DSA results were required in addition for a treatment decision. Interobserver agreement on feasibility of EVT was just fair (kappa <0.40). CONCLUSIONS: In our series of patients, 16-detector row CTA was a reliable investigation to assess feasibility of EVT of ruptured intracranial aneurysms in most patients. Further, we found that interobserver disagreement on feasibility of EVT was considerable.

Carotid plaque composition and cerebral infarction: MR imaging study.

BACKGROUND AND PURPOSE: Besides the severity of carotid artery stenosis, atherosclerotic plaque composition is an important determinant of cerebral symptoms. We analyzed the relationship between the composition of the atherosclerotic plaque at the carotid artery bifurcation and ipsilateral ischemic cerebral lesions on MR imaging. METHODS: Forty-one patients with symptomatic carotid artery stenosis (>70%) underwent black-blood, fast spin-echo imaging of the carotid artery and turbo fluid-attenuated inversion recovery (t-FLAIR) imaging of the brain. Plaque regions with a relative decrease in signal intensity in the plaque from proton density-weighted (TE = 14 ms) to T2-weighted (TE = 50 ms) imaging were considered to be lipid cores. We assessed the number and location of infarcts in the ipsilateral cortex, basal ganglia, and centrum semiovale, and hyperintense white matter lesions on t-FLAIR images. RESULTS: Lipid in the atherosclerotic plaque at the carotid bifurcation was seen in 25 patients. Ipsilateral infarctions were seen in 22 (54%); most often, it involved the centrum semiovale. Patients with a lipid core had an ipsilateral infarct more often than patients without a lipid core (68% vs. 31%; P = .03). Centrum semiovale infarcts were more frequent (56% vs. 25%, P = .06) and the median number of centrum semiovale infarcts was higher P = .04) in patients with a lipid core than in patients without a lipid core. CONCLUSION: Ischemic cerebral lesions were common in patients with symptomatic carotid artery disease. Plaque composition, as assessed with MR imaging, is related to the presence and extent of ischemic cerebral lesions.

Cerebral ischemia after carotid intervention.

PURPOSE: To determine the incidence of symptomatic and asymptomatic cerebral ischemic lesions found on diffusion-weighted magnetic resonance imaging (DW-MRI) after carotid interventions. METHODS: A prospective study was conducted to assess new cerebral ischemic lesions using DW-MRI in symptomatic patients with carotid artery disease undergoing protected carotid artery stenting (CAS) or carotid endarterectomy (CEA). DW-MRI was performed before and after the intervention in 44 patients (21 CAS and 23 CEA). Two experienced radiologists not involved in the carotid procedures or neurological assessment compared the postprocedural DW-MR images with those acquired before the intervention. RESULTS: Three (6.8%) of the 44 patients suffered strokes: 1 major and 1 minor stroke after CEA and 1 minor stroke after CAS. DW-MRI showed 15 new hyperintense lesions in 2 (9%) of 23 CEA patients; 31 new hyperintense lesions were found in 9 (43%) of the 21 CAS patients. The majority of new lesions were located in the ipsilateral vascular territory; 2 CAS patients also showed 6 new hyperintense lesions in the cerebellum. The mean lesion load per patient was 2.52 cm(3) (range 0.31-4.74) in the CEA group and 1.74 cm(3) (0.03-9.72) in the CAS group (p=0.35). The volume of the individual lesions in CEA patients was 0.39 cm(3) (range 0.01-2.16) compared to 0.52 cm(3) (range 0.01-5.47) in the CAS group (p=0.23). Patients who were asymptomatic after the intervention had fewer lesions (p=0.03) and a smaller lesion load than symptomatic patients. CONCLUSIONS: Ischemic lesions were more frequently seen on DW-MRI after carotid stenting than after endarterectomy. The majority of the detected lesions did not cause neurological deficits.