Sònia Abilleira

Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke

BACKGROUND We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry. METHODS During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials. RESULTS Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals. CONCLUSIONS Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT ClinicalTrials.gov number, NCT01692379.).

Matrix Metalloproteinase-9 Pretreatment Level Predicts Intracranial Hemorrhagic Complications After Thrombolysis in Human Stroke

Background—Matrix metalloproteinase (MMP) expression is related to blood brain barrier disruption after cerebral ischemia. Moreover, MMP inhibitors reduce hemorrhagic transformation (HT) after embolic ischemia in tissue plasminogen activator (t-PA)–treated animals. We aimed to correlate plasmatic MMP levels with the appearance of intracranial bleeding complications in stroke patients treated with t-PA. Methods and Results—Serial MMP-2 and MMP-9 determinations were performed (ELISA, ng/mL) in 41 strokes involving the middle cerebral artery territory in patients who received t-PA within 3 hours of stroke onset. Blood samples were obtained at baseline (pretreatment) and at 12 and 24 hours after symptom onset. Hemorrhagic events were classified according to CT criteria (petechial hemorrhagic infarctions [HI, 1 to 2] and large parenchymal hemorrhages [PH, 1 to 2]). Brain CT scan was obtained at 48 hours or when a neurological worsening occurred. HT was present in 36.5% of the patients (24.4% HI and 12.1% PH). MMP-2 values were unrelated to any subtype of HT. The highest baseline MMP-9 level (normal range <97 ng/mL) corresponded to patients who later developed a PH (PH: 270.2±87.8, non-HT: 126.3±127.5, HI: 94.6±88.7;P =0.047). A graded response was found between mean baseline MMP-9 levels and the degree of bleeding (HI-1=37.4; HI-2=111.0; PH-1=202.5; PH-2=337.8). Baseline MMP-9 was the most powerful predictor of PH appearance in the multiple logistic regression model (OR= 9.62; CI 1.31 to 70.26;P =0.025). Conclusions—Baseline MMP-9 level predicts PH appearance after t-PA treatment. Therefore, we suggest that MMP determination may increase the safety profile for thrombolysis and, in the future, anti-MMP drugs might be combined with t-PA to prevent hemorrhagic complications.

Matrix Metalloproteinase Expression After Human Cardioembolic Stroke Temporal Profile and Relation to Neurological Impairment

Background and Purpose— Uncontrolled expression of matrix metalloproteinases (MMPs) can result in tissue injury and inflammation. In animal models of cerebral ischemia, the expression of MMP-2 and MMP-9 was significantly increased. However, their role in human stroke in vivo remains unknown. Therefore, we sought to determine the temporal profile of MMP expression in patients with acute ischemic stroke and to investigate its relationship to stroke severity, location of arterial occlusion, and total infarct volume. Methods— Serial MMP-2 and MMP-9 determinations were made in 39 patients with cardioembolic strokes that involved the middle cerebral artery territory by means of enzyme-linked immunosorbent assay. Blood samples, transcranial Doppler recordings, and National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and at 12, 24, and 48 hours after stroke onset. Infarct volume was measured with CT scanning at 48 hours. Results— No correlation was found between MMP-2 and NIHSS score at any time point, although a close relation appeared between mean MMP-9 and final NIHSS score (r =0.486, P =0.002). MMP-9 value was the only factor associated with the final NIHSS score in the multiple logistic regression model (OR 4.54, 95% CI 1.5 to 13.75). A cut-point of MMP-9 142.18 ng/mL had a positive predictive value of 94.4% to assess a patient’s NIHSS (<8 or ≥8) by the end of the study. Final MMP-2 and MMP-9 levels were significantly lower when recanalization occurred (528±144.3 versus 681.4±239.2 ng/mL, P =0.031 for MMP-2; 110.2±100.9 versus 244.8±130 ng/mL, P =0.004 for MMP-9). A positive correlation was found between mean MMP-9 and infarct volume (r =0.385, P =0.022). Conclusions— MMPs are involved in the acute phase of human ischemic stroke. MMP-9 levels are associated with neurological deficit, middle cerebral artery occlusion, and infarct volume.

Timing of Spontaneous Recanalization and Risk of Hemorrhagic Transformation in Acute Cardioembolic Stroke

Background and Purpose The relationship between reperfusion and hemorrhagic transformation (HT) remains uncertain. Therefore, we aimed to clarify the relationship between the time course of recanalization and the risk of HT in patients with cardioembolic stroke studied within 6 hours of symptom onset. Methods Fifty-three patients with atrial fibrillation and nonlacunar stroke in the middle cerebral artery (MCA) territory admitted within the first 6 hours after symptom onset were prospectively studied. Serial TCD examinations were performed on admission and at 6, 12, 24, and 48 hours. CT was performed within 6 hours after stroke onset and again at 36 to 48 hours. Results Proximal and distal MCA occlusions were detected in 32 patients (60.4%) and 18 patients (34%), respectively. Early spontaneous recanalization occurring within 6 hours was identified in 10 patients (18.8%). Delayed recanalization (>6 hours) occurred in 28 patients (52.8%). HT on CT scan was detected in 17 patients (32%) within the first 48 hours. Only large parenchymal hemorrhage (PH2) was significantly associated with an increase (P =0.038, Kruskal-Wallis test) in the National Institutes of Health Stroke Scale (NIHSS) score compared with the other subtypes of HT. Univariate analysis revealed that an NIHSS score of >14 on baseline (P =0.001), proximal MCA occlusion (P =0.004), hypodensity >33% of the MCA territory (P =0.012), and delayed recanalization occurring >6 hours of stroke onset (P =0.003) were significantly associated with HT. With a multiple logistic regression model, delayed recanalization (OR 8.9; 95% CI 2.1 to 33.3) emerged as independent predictor of HT. Conclusions Delayed recanalization occurring >6 hours after acute cardioembolic stroke is an independent predictor of HT.

Thrombolysis-Related Hemorrhagic Infarction A Marker of Early Reperfusion, Reduced Infarct Size, and Improved Outcome in Patients With Proximal Middle Cerebral Artery Occlusion

Background and Purpose— The role of early and delayed recanalization after thrombolysis in the development of hemorrhagic transformation (HT) subtypes remains uncertain. We sought to explore the association between the timing of recanalization and HT risk in patients with proximal middle cerebral artery (MCA) occlusion treated with intravenous recombinant tissue plasminogen activator (rtPA) <3 hours of stroke onset and to investigate the relationship between HT subtypes, infarct volume, and outcome. Methods— Thirty-two patients with acute stroke caused by proximal MCA occlusion treated with rtPA <3 hours of symptom onset were prospectively studied. Serial transcranial Doppler examinations were performed on admission and at 6, 12, 24, and 48 hours. Presence and type of HT were assessed on CT at 36 to 48 hours. Modified Rankin scale was used to assess outcome at 3 months. Results— Early and delayed recanalization was identified in 17 patients (53.1%) and 8 patients (25%), respectively. HT was detected in 14 patients (43.7%): 4 (12.5%) with hemorrhagic infarction (HI1), 5 (15.6%) with HI2, 3 (9.3%) with parenchymal hematoma (PH1), and 2 (6.8%) with PH2. Distribution of HT subtypes differed significantly (P =0.025), depending on the time to artery reopening. Eight of 9 (89%), 1 of 5 (20%), and 8 of 18 (44.4%) with HI1-HI2, with PH1-PH2, and without HT, respectively, recanalized in <6 hours. Delayed recanalization was observed in 1 patient with HI1-HI2 (11%), 4 with PH1-PH2 (80%), and 3 without HT (16.6%). Neurological improvement was significantly (P <0.001) more frequent in patients with HI1-HI2 (88%) than in those without HT (39%). Infarct volume was significantly (P <0.031) lower in patients with HI1-HI2 (51.4±42 cm3) than in patients with PH1-PH2 (83.8±48 cm3) and those without HT (98.4±84 cm3, P =0.021). The modified Rankin scale score was significantly lower in HI1-HI2 compared with PH1-PH2 patients (1.9±1.1 versus 4.6±1.2, P <0.001) and with those without HT (1.9±1.1 versus 3.5±2.0, P =0.009.). Conclusions— Thrombolysis-related HI (HI1-HI2) represents a marker of early successful recanalization, which leads to a reduced infarct size and improved clinical outcome.

Impaired cerebrovascular reactivity as a risk marker for first-ever lacunar infarction: A case-control study.

BACKGROUND AND PURPOSE Functional assessment of small arteries and arterioles could provide valuable information regarding the extent of diffuse arteriolosclerosis in patients with small-vessel disease. Therefore we attempted to clarify the role of cerebrovascular reactivity (CVR) as a risk marker for first-ever symptomatic lacunar infarction. METHODS Forty-six patients with lacunar infarction and 46 sex- and age-matched control subjects were prospectively evaluated. Cerebral hemodynamics were studied with transcranial Doppler ultrasonography. CVR was examined by calculating the percent increase in mean flow velocity occurring after 15 mg/kg acetazolamide administration (Diamox test). RESULTS CVR was significantly (P<0.0001, Students t test) lower in cases (50.0+/-12. 7%) as compared with control subjects (65.2+/-12.4%). A multiple logistic regression analysis identified male sex (odds ratio [OR] 2. 3, P=0.02), age (OR 3.6, P<0.005), and the presence of lacunar infarction on magnetic resonance imaging (OR 5.3, P<0.001) as significant and independent factors associated with a reduction of CVR. Moreover, a cut-point of 55.6% (sensitivity 67%, specificity 82%) was established as the threshold value for distinguishing between pathological and normal CVR. CVR was significantly (P=0.02) lower in patients with multiple (46.38+/-12.6%) than with single (54. 83+/-11.58%) lacunar infarction. In addition, a trend of negative correlation was found between CVR and the number of lacunar infarctions (r=-0.26, P=0.08). In the multiple logistic model, history of hypertension (OR 7.24; 95% confidence interval 2.95 to 17. 79) and CVR (OR 0.8; 95% confidence interval 0.81 to 0.93) emerge as significant and independent predictors of first-ever lacunar infarction. CONCLUSIONS These data suggest that impaired CVR is a risk marker for first-ever lacunar infarction.

The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis

Current evidence suggests that matrix metalloproteinases (MMPs) have a role in early atherosclerosis, plaque rupture and myocardial infarction. Polymorphisms in MMP genes have been examined for associations with atherosclerosis, but interpretation is complicated by methodological issues. This article presents a systematic review of these association studies and a meta-analysis of available data for polymorphisms where a sufficient number of studies was available. The 5A allele of the MMP3 5A/6A polymorphism was associated with acute myocardial infarction (odds ratio (OR) 1.26, 95% confidence interval (CI) 1.1 to 1.4, p<0.001), suggesting its role in plaque rupture. There was no association with the functional MMP9 −1562C/T polymorphism (OR 1.11, 95% CI 1.0 to 1.3, p = 0.18). Current data provide evidence for the role of MMP3 polymorphism in plaque destabilisation, but elucidation of the role of other MMP gene variants in atherosclerosis will depend on better study design, including a larger sample size, extensive screening of individual genes with haplotype analysis and replication of studies to avoid publication bias.

INFLUENCE OF THE STROKE CODE ACTIVATION SOURCE ON THE OUTCOME OF ACUTE ISCHEMIC STROKE PATIENTS

Introduction: In our metropolitan area, the Stroke Code (SC) system allows immediate transfer of patients with acute stroke to a stroke center. It may be activated by community hospitals (A), emergency medical services (EMS, B), or the emergency department of the stroke center (C). Our aim was to analyze whether the SC activation source influences the access to thrombolytic therapy and outcome of patients with ischemic stroke. Methods: We prospectively registered patients with ischemic stroke admitted to the acute stroke unit who arrived through the SC system. The primary outcome variable was good outcome at discharge (Rankin Scale ≤ 2). Secondary outcome was neurologic improvement ≥4 in National Institutes of Health Stroke Scale (NIHSS) score or NIHSS score 0 to 1 at 24 hours. Results: A total of 262 consecutive patients with hyperacute ischemic stroke were studied; the SC source was A in 112, B in 57, and C in 92. Median time from onset to admission was longer in Group A and stroke severity higher in Groups B and C. Percentage of tPA administration was higher in patients from Groups B and C (27%, 54%, and 46% of patients; p = 0.001). With respect to Group A, Group B was associated with good outcome with an odds of 2.9 (1.2–6.6; p = 0.01), and Group C with an odds of 2.4 (1.1–4.9; p = 0.01) after adjustment for age and stroke severity at baseline. Patients coming via levels B and C were more likely to improve at 24 hours. Conclusions: Patients arriving directly to the stroke center via emergency medical services or on their own receive neurologic attention sooner, are more frequently treated with tPA, and have better clinical outcome than those patients who are first taken to a community hospital.

Polymorphisms in MMP Family and TIMP Genes and Carotid Artery Intima-Media Thickness

Background and Purpose— Genetic variation in a number of MMP and TIMP genes have been implicated as risk factors for atherosclerosis, although such studies have been generally small and produced conflicting results. We have therefore sought to address this issue in a large, well-phenotyped community population to assess the effect of a number of polymorphisms in both MMP and TIMP genes on carotid artery intima-media thickness (IMT). Methods— In a community population (n=1000), IMT was determined using ultrasound in the common carotid artery, carotid bulb, and bifurcation. Eight polymorphisms in 6 MMP genes were genotyped (MMP1 A-519G, MMP2 C-1306T, MMP2 C-735T, MMP3 -1171 5A/6A, MMP9 R279Q, TIMP2 G853A, TIMP3 A-915G, and T-1296C) and assessed for their effect on carotid IMT alone and by interaction with common cardiovascular risk factors. Results— An association was found between MMP9 R279Q and internal carotid artery bulb IMT (P=0.002), but there was no linear trend between allele number and IMT and no association with common carotid artery or bulb IMT. In addition, 3 interactions were found between polymorphisms and hypertension (MMP1 A-519G, MMP3 5A/6A, TIMP3 T-1296C), the latter 2 of which showed a significant trend test for linearity with increasing copy number and increased internal carotid artery bulb IMT. All remained significant after correction for multiple testing. Conclusions— Our findings provide little support for genetic variants of MMP as direct risk factors for IMT. However, the interaction findings between MMP variants and hypertension suggest that hypertensive carriers of these alleles may be at greater risk for increased IMT and future cardiovascular disease. These findings need replication in hypertensive populations to assess their effects more fully.

Outcomes of a contemporary cohort of 536 consecutive patients with acute ischemic stroke treated with endovascular therapy.

Background and Purpose— We sought to assess outcomes after endovascular treatment/therapy of acute ischemic stroke, overall and by subgroups, and looked for predictors of outcome. Methods— We used data from a mandatory, population-based registry that includes external monitoring of completeness, which assesses reperfusion therapies for consecutive patients with acute ischemic stroke since 2011. We described outcomes overall and by subgroups (age ⩽ or >80 years; onset-to-groin puncture ⩽ or >6 hours; anterior or posterior strokes; previous IV recombinant tissue-type plasminogen activator or isolated endovascular treatment/therapy; revascularization or no revascularization), and determined independent predictors of good outcome (modified Rankin Scale score ⩽2) and mortality at 3 months by multivariate modeling. Results— We analyzed 536 patients, of whom 285 received previous IV recombinant tissue-type plasminogen activator. Overall, revascularization (modified Thrombolysis In Cerebral Infarction scores, 2b and 3) occurred in 73.9%, 5.6% developed symptomatic intracerebral hemorrhages, 43.3% achieved good functional outcome, and 22.2% were dead at 90 days. Adjusted comparisons by subgroups systematically favored revascularization (lower proportion of symptomatic intracerebral hemorrhages and death rates and higher proportion of good outcome). Multivariate analyses confirmed the independent protective effect of revascularization. Additionally, age >80 years, stroke severity, hypertension (deleterious), atrial fibrillation, and onset-to-groin puncture ⩽6 hours (protective) also predicted good outcome, whereas lack of previous disability and anterior circulation strokes (protective) as well as and hypertension (deleterious) independently predicted mortality. Conclusions— This study reinforces the role of revascularization and time to treatment to achieve enhanced functional outcomes and identifies other clinical features that independently predict good/fatal outcome after endovascular treatment/therapy.