Nicola Logallo

Safety of off-label stroke treatment with tissue plasminogen activator

Many patients with acute ischaemic stroke do not receive intravenous thrombolysis due to contraindications. We aimed to assess safety, short‐term clinical development, short‐term outcome and mortality in patients treated off‐label with tissue plasminogen activator (tPA).

Serum uri acid: neuroprotection in thrombolysis. The Bergen NORSTROKE study

BackgroundA possible synergic role of serum uric acid (SUA) with thrombolytic therapies is controversial and needs further investigations. We therefore evaluated association of admission SUA with clinical improvement and clinical outcome in patients receiving rt-PA, early admitted patients not receiving rt-PA, and patients admitted after time window for rt-PA.MethodsSUA levels were obtained at admission and categorized as low, middle and high, based on 33° and 66° percentile values. Patients were categorized as patients admitted within 3 hours of symptom onset receiving rt-PA (rt-PA group), patients admitted within 3 hours of symptom onset not receiving rt-PA (non-rt-PA group), and patients admitted after time window for rt-PA (late group). Short-term clinical improvement was defined as the difference between NIHSS on admission minus NIHSS day 7. Favorable outcome was defined as mRS 0 - 3 and unfavorable outcome as mRS 4 - 6.ResultsSUA measurements were available in 1136 patients. Clinical improvement was significantly higher in patients with high SUA levels at admission. After adjustment for possible confounders, SUA level showed a positive correlation with clinical improvement (r = 0.012, 95% CI 0.002-0.022, p = 0.02) and was an independent predictor for favorable stroke outcome (OR 1.004; 95% CI 1.0002-1.009; p = 0.04) only in the rt-PA group.ConclusionsSUA may not be neuroprotective alone, but may provide a beneficial effect in patients receiving thrombolysis.

Mild stroke: safety and outcome in patients receiving thrombolysis

The aim of this study was to compare the short‐term clinical outcome of patients with acute cerebral ischemia and mild symptoms receiving rt‐PA with that of patients with acute cerebral ischemia and mild symptoms not treated with rt‐PA, and to investigate the frequency of symptomatic intracranial hemorrhage (sICH) in these patients.

Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial

BACKGROUND Tenecteplase is a newer thrombolytic agent with some pharmacological advantages over alteplase. Previous phase 2 trials of tenecteplase in acute ischaemic stroke have shown promising results. We aimed to investigate the safety and efficacy of tenecteplase versus alteplase in patients with acute stroke who were eligible for intravenous thrombolysis. METHODS This phase 3, randomised, open-label, blinded endpoint, superiority trial was done in 13 stroke units in Norway. We enrolled adults with suspected acute ischaemic stroke who were eligible for thrombolysis and admitted within 4·5 h of symptom onset or within 4·5 h of awakening with symptoms, or who were eligible for bridging therapy before thrombectomy. Patients were randomly assigned (1:1) to receive intravenous tenecteplase 0·4 mg/kg (to a maximum of 40 mg) or alteplase 0·9 mg/kg (to a maximum of 90 mg), via a block randomisation schedule stratified by centre of inclusion. Patients were not informed of treatment allocation; treating physicians were aware of treatment allocation but those assessing the primary and secondary endpoints were not. The primary outcome was excellent functional outcome defined as modified Rankin Scale (mRS) score 0-1 at 3 months. The primary analysis was an unadjusted and non-stratified intention-to-treat analysis with last observation carried forward for imputation of missing data. This study is registered with ClinicalTrials.gov, number NCT01949948. FINDINGS Between Sept 1, 2012, and Sept 30, 2016, 1107 patients met the inclusion criteria and seven patients were excluded because informed consent was withdrawn or eligibility for thrombolytic treatment was reconsidered. 1100 patients were randomly assigned to the tenecteplase (n=549) or alteplase (n=551) groups. The median age of participants was 77 years (IQR 64-79) and the median National Institutes of Health Stroke Scale score at baseline was 4 points (IQR 2-8). A final diagnosis other than ischaemic stroke or transient ischaemic attack was found in 99 (18%) patients in the tenecteplase group and 91 (17%) patients in the alteplase group. The primary outcome was achieved by 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group (odds ratio 1·08, 95% CI 0·84-1·38; p=0·52). By 3 months, 29 (5%) patients had died in the tenecteplase group compared with 26 (5%) in the alteplase group. The frequency of serious adverse events was similar between groups (145 [26%] in the tenecteplase group vs 141 [26%] in the alteplase group; p=0·74). INTERPRETATION Tenecteplase was not superior to alteplase and showed a similar safety profile. Most patients enrolled in this study had mild stroke. Further trials are needed to establish the safety and efficacy in patients with severe stroke and whether tenecteplase is non-inferior to alteplase. FUNDING Research Council of Norway.

Elevated Admission Blood Pressure and Stroke Severity in Acute Ischemic Stroke: The Bergen NORSTROKE Study

Background: Transient elevated blood pressure (BP) is frequent in patients presenting with acute ischemic stroke. The pathophysiology of this response is not clear and its effect on clinical outcome has shown contradictory results. Some studies have suggested that BP elevation may represent a protective response to enhance perfusion in ischemic brain tissue. In this study, we aimed to explore the association between elevated admission BP and stroke severity in the acute phase of ischemic stroke. If it is true that elevated BP represents a protective response in acute ischemia, we expected an inverse association between elevated BP and admission stroke severity, and a positive association between elevated BP and complete neurological recovery within 24 h and/or favorable short-term outcome. Methods: Patients with ischemic stroke with hospital admission <6 h after symptom onset were prospectively included in a stroke registry (Bergen NORSTROKE Registry). BP was measured immediately after admission in all patients. Elevated BP was defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg. The National Institutes of Health Stroke Scale (NIHSS) was used to assess stroke severity upon admission. Mild stroke was defined as NIHSS score <8, moderate stroke as NIHSS score 8-14, and severe stroke as NIHSS score ≥15. Complete neurological recovery (CNR) was defined as no persistent ischemic stroke symptoms at 24 h after admission. Favorable short-term outcome was defined as a modified Rankin Scale score of 0 or 1 at day 7. Results: A total of 749 patients with ischemic stroke were included, of which 621 patients (82.9%) presented with elevated BP. Elevated BP was independently associated with mild stroke (odds ratio, OR: 2.12; 95% CI: 1.39-3.24; p < 0.001), whereas lack of elevated BP was independently associated with severe stroke (OR: 0.41; 95% CI: 0.25-0.68; p < 0.001). There was a nonsignificant association between elevated BP and CNR (OR: 2.11; 95% CI: 0.96-4.68; p = 0.063), yet no association between elevated BP and favorable short-term outcome (OR: 0.97; 95% CI: 0.59-1.59; p = 0.906) when adjusted for confounders. Conclusion: Our study showed an inverse association between elevated BP and stroke severity on admission, where elevated BP was associated with mild stroke and lack of elevated BP was associated with severe stroke. This could be explained by a protective effect of elevated BP in the acute phase of ischemic stroke, although the absence of association between elevated BP and favorable outcome argues against this hypothesis.

Body temperature and major neurological improvement in tPA‐treated stroke patients

Major neurological improvement (MNI) at 24 hours represents a marker of early recanalization in ischaemic stroke. Although low body temperature is considered neuroprotective in cerebral ischaemia, some studies have suggested that higher body temperature may promote clot lysis in the acute phase of ischaemic stroke. We hypothesized that higher body temperature was associated with MNI in severe stroke patients treated with tPA, suggesting a beneficial effect of higher body temperature on clot lysis and recanalization.

NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study): Randomized controlled contrast-enhanced sonothrombolysis in an unselected acute ischemic stroke population

Background and Purpose— The NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) aimed to assess effect and safety of contrast-enhanced ultrasound treatment in an unselected acute ischemic stroke population. Methods— Patients treated with intravenous thrombolysis within 4.5 hours after symptom onset were randomized 1:1 to either contrast-enhanced sonothrombolysis (CEST) or sham CEST. A visible arterial occlusion on baseline computed tomography angiography was not a prerequisite for inclusion. Pulse-wave 2 MHz ultrasound was given for 1 hour and contrast (SonoVue) as an infusion for ≈30 minutes. Magnetic resonance imaging and angiography were performed after 24 to 36 hours. Primary study end points were neurological improvement at 24 hours defined as National Institutes of Health Stroke Scale score 0 or reduction of ≥4 National Institutes of Health Stroke Scale points compared with baseline National Institutes of Health Stroke Scale and favorable functional outcome at 90 days defined as modified Rankin scale score 0 to 1. Results— A total of 183 patients were randomly assigned to either CEST (93 patient) or sham CEST (90 patients). The rates of symptomatic intracerebral hemorrhage, asymptomatic intracerebral hemorrhage, or mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days was similar in the 2 groups both in the intention-to-treat analysis and in the per-protocol analysis. Conclusions— CEST is safe among unselected ischemic stroke patients with or without a visible occlusion on computed tomography angiography and with varying grades of clinical severity. There was, however, statistically no significant clinical effect of sonothrombolysis in this prematurely stopped trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01949961.

Is smoking associated with favourable outcome in tPA-treated stroke patients?

Smoking has been associated with improved outcome in thrombolysed patients with myocardial infarction and higher recanalization rates in stroke patients treated with tissue plasminogen activator (tPA). We hypothesized a positive association between smoking and favourable outcome in stroke patients treated with tPA and no such association in acute stroke patients not treated with tPA, suggesting a beneficial effect of smoking on thrombolysis with tPA.

Clinical implications of increased use of MRI in TIA

Transient ischemic attack has been redefined as a tissue‐based diagnosis and MRI recommended as the preferred imaging modality. We aimed to investigate whether an increased use of MRI leads to a decrease in the proportion of TIA as compared to cerebral infarction. We also sought to see whether DWI‐positive patients with transient ischemic symptoms <24 h differ from DWI‐negative TIA patients in terms of performed diagnostic investigations and clinical characteristics.

Diffusion-Weighted Lesions in Stroke Patients with Transient Symptoms - Where Are They Located?

Background: MR diffusion-weighted imaging (DWI) has revolutionized neuroimaging and contributed to a tissue-based redefinition of transient ischemic attack (TIA). Stroke patients with DWI lesions may have neurological symptoms that resolve completely within 24 h, suggesting successful vessel recanalization. Prior studies of stroke patients with transient symptoms have not found any predilection for DWI lesions in any specific territory. Other studies have, however, reported an association between higher brain dysfunction and presence of DWI lesions in patients with transient ischemic symptoms, suggesting a high rate of cortical affection in these patients. We sought to see whether DWI location in stroke patients with transient symptoms <24 h differed from those with persistent symptoms ≥24 h. We hypothesized an association between transient symptoms <24 h and cortical DWI lesion localization due to a possible higher rate of vessel recanalization in patients with transient symptoms causing distal cortical infarctions. Methods: Ischemic stroke patients examined with DWI and admitted within 24 h after symptom onset between February 2006 and November 2013 were prospectively registered in a database (The Bergen NORSTROKE Registry). Based on neurological examination 24 h after admission, patients were classified as having either transient symptoms <24 h (DWI <24) or persistent symptoms ≥24 h (DWI ≥24). DWI lesions were classified into different groups depending on lesion location: cortical lesions, confined to the supratentorial cortex; large subcortical lesions, located in the hemispheric white matter, basal ganglia, internal capsule, thalamus or corona radiate with a diameter ≥15 mm; lacunar lesions, located in the same territory as large subcortical lesions with a diameter <15 mm; mixed cortical-subcortical lesions, located in both supratentorial cortex and subcortex; cerebellar lesions, confined to the cerebellum; brain stem lesions, confined to the brain stem; multiple locations, located in more than one of the above defined areas. Results: A total of 142 ischemic stroke patients had DWI <24 and 830 DWI ≥24. Cortical DWI location was more frequent in patients with DWI <24 (54.2% vs. 29.5%, p < 0.001), while proportions of mixed cortical-subcortical lesions (13.4% vs. 26.5%, p = 0.001) and lesions with multiple locations (5.6% vs. 11.1%, p = 0.048) were less frequent as compared to DWI ≥24. Cortical DWI location was independently associated with DWI <24 when adjusted for confounders in multiple regression analyses (OR 1.89, 95% CI 1.28-2.81, p = 0.001). Conclusion: Cortical DWI location was independently associated with transient stroke symptoms <24 h. This may be explained by vessel recanalization, resulting in upstream transportation of remaining particles and distal cortical lesions.