Joaquín Serena

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.).

Perfusion-CT Assessment of Infarct Core and Penumbra: Receiver Operating Characteristic Curve Analysis in 130 Patients Suspected of Acute Hemispheric Stroke

Background and Purpose— Different definitions have been proposed to define the ischemic penumbra from perfusion-CT (PCT) data, based on parameters and thresholds tested only in small pilot studies. The purpose of this study was to perform a systematic evaluation of all PCT parameters (cerebral blood flow, volume [CBV], mean transit time [MTT], time-to-peak) in a large series of acute stroke patients, to determine which (combination of) parameters most accurately predicts infarct and penumbra. Methods— One hundred and thirty patients with symptoms suggesting hemispheric stroke ≤12 hours from onset were enrolled in a prospective multicenter trial. They all underwent admission PCT and follow-up diffusion-weighted imaging/fluid-attenuated inversion recovery (DWI/FLAIR); 25 patients also underwent admission DWI/FLAIR. PCT maps were assessed for absolute and relative reduced CBV, reduced cerebral blood flow, increased MTT, and increased time-to-peak. Receiver-operating characteristic curve analysis was performed to determine the most accurate PCT parameter, and the optimal threshold for each parameter, using DWI/FLAIR as the gold standard. Results— The PCT parameter that most accurately describes the tissue at risk of infarction in case of persistent arterial occlusion is the relative MTT (area under the curve=0.962), with an optimal threshold of 145%. The PCT parameter that most accurately describes the infarct core on admission is the absolute CBV (area under the curve=0.927), with an optimal threshold at 2.0 ml×100 g−1. Conclusion— In a large series of 130 patients, the optimal approach to define the infarct and the penumbra is a combined approach using 2 PCT parameters: relative MTT and absolute CBV, with dedicated thresholds.

Blood Pressure Decrease During the Acute Phase of Ischemic Stroke Is Associated With Brain Injury and Poor Stroke Outcome

Background and Purpose— Studies on the relation between blood pressure (BP) and stroke outcome have shown contradictory results. We explored the association of systolic (SBP) and diastolic (DBP) BP during acute stroke with early neurological deterioration, infarct volume, neurological outcome, and mortality at 3 months. Methods— We included 304 patients with acute ischemic stroke. SBP and DBP on admission and on the first day were the average values of all readings obtained in the emergency department and during a 24-hour period after patient allocation in the stroke unit. Results— A U-shaped effect was observed: for every 10 mm Hg ≤180 mm Hg of SBP, the risk of early neurological deterioration, poor outcome, and mortality increased by 6%, 25%, and 7%, respectively, whereas for every 10 mm Hg >180 mm Hg, the risk of early neurological deterioration increased by 40% and the risk of poor outcome increased by 23%, with no effect on mortality. Mean infarct volume increased 7.3 and 5.5 cm3 for every 10 mm Hg ≤180 and >180 mm Hg. A similar pattern was found in patients with DBP ≤100 or >100 mm Hg. These effects disappeared after adjustment for the use of antihypertensive drugs and BP drop >20 mm Hg within the first day, with the latter being the more important prognostic factor of poor outcome. Conclusions— High and low SBP and DBP, as well as a relevant drop in BP, are associated with poor prognosis in patients with ischemic stroke.

Plasma Metalloproteinase-9 Concentration Predicts Hemorrhagic Transformation in Acute Ischemic Stroke

Background and Purpose— Matrix metalloproteinase-9 (MMP-9) activity has been associated with hemorrhagic transformation (HT) in experimental models of cerebral ischemia. Our aim was to investigate the relationship between MMP-9 concentrations in blood within 24 hours of stroke onset and subsequent HT of cerebral infarction. Methods— We studied 250 patients with a hemispheric ischemic stroke of 7.8±4.5 hours’ duration. Early CT signs of cerebral infarction were evaluated on admission. The HT and infarct volume were analyzed from the CT performed on days 4 through 7. MMP-9 levels were determined by enzyme-linked immunosorbent assay in blood samples obtained on admission. Results— HT was observed in 38 patients (15.2%): 24 (63.2%) had a hemorrhagic infarction, and 14 (36.8%) had a parenchymal hematoma. A total of 108 patients (43%) received anticoagulants before the second CT scan. Systolic and diastolic blood pressures, body temperature, frequency of early CT signs of ischemia (92% versus 22%), and treatment with anticoagulants (79% versus 37%) were significantly higher in the group with HT (P <0.001). Mean infarct volume was 126±60 cm3 in the HT group and 90±68 cm3 in the group without HT (P =0.003). Median (quartiles) plasma MMP-9 concentrations were higher in the HT group (193 [163, 213] versus 62 [40, 93] ng/mL, P <0.001), even in the 24 patients seen within 3 hours of symptom onset (P =0.014). MMP-9 levels ≥140 ng/mL had a positive and negative predictive value of HT of 61% and 97%, respectively. MMP-9 ≥140 ng/mL was associated with HT (odds ratio, 12; 95% confidence interval, 3 to 51;P <0.001) after adjustment for potential confounders and final infarct volume. Conclusions— High plasma MMP-9 concentration in the acute phase of a cerebral infarct is an independent biochemical predictor of HT in all stroke subtypes.

Statin treatment withdrawal in ischemic stroke A controlled randomized study

Background: Pretreatment with statins has been shown to reduce brain injury in cerebral ischemia. In this controlled randomized study, we investigated the influence of statin pretreatment and its withdrawal on the outcome of acute ischemic stroke patients. Methods: From 215 patients admitted within 24 hours of a hemispheric ischemic stroke, 89 patients on chronic statin treatment were randomly assigned either to statin withdrawal for the first 3 days after admission (n = 46) or to immediately receive atorvastatin 20 mg/day (n = 43). The primary outcome event was death or dependency (modified Rankin Scale [mRS] score > 2) at 3 months. Early neurologic deterioration (END) and infarct volume at days 4 to 7 were secondary outcome variables. In a secondary analysis, outcome variables were compared with the nonrandomized patients without previous statin therapy (n = 126). Results: Patients with statin withdrawal showed a higher frequency of mRS score > 2 at the end of follow-up (60.0% vs 39.0%; p = 0.043), END (65.2% vs 20.9%; p < 0.0001), and greater infarct volume (74 [45, 126] vs 26 [12, 70] mL; p = 0.002) compared with the non–statin-withdrawal group. Statin withdrawal was associated with a 4.66 (1.46 to 14.91)–fold increase in the risk of death or dependency, a 8.67 (3.05 to 24.63)–fold increase in the risk of END, and an increase in mean infarct volume of 37.63 mL (SE 10.01; p < 0.001) after adjusting for age and baseline stroke severity. Compared with patients without previous treatment with statins, statin withdrawal was associated with a 19.01 (1.96 to 184.09)–fold increase in the risk of END and an increase in mean infarct volume of 43.51 mL (SE 21.91; p = 0.048). Conclusion: Statin withdrawal is associated with increased risk of death or dependency at 90 days. Hence, this treatment should be continued in the acute phase of ischemic stroke.

Frequency of Atrial Septal Aneurysms in Patients With Cerebral Ischemic Events

BACKGROUND Atrial septal aneurysm (ASA) is a putative risk factor for cardioembolism. However, the frequency of ASA in the general population has not been adequately determined. Therefore, the frequency in patients with cerebral ischemic events, compared with the frequency in the general population, is poorly defined. We sought to determine the frequency of ASA in the general population and to compare the frequency of ASA in patients with cerebral ischemic events with the frequency in the general population. METHODS AND RESULTS The frequency of ASA in the population was determined in 363 subjects, a sample of the participants in the Stroke Prevention: Assessment of Risk in a Community study (control subjects), and was compared with the frequency in 355 age- and sex-matched patients undergoing transesophageal echocardiography in search of a cardiac source of embolism after a focal cerebral ischemic event. The proportion with ASA was 7.9% in patients versus 2.2% in control subjects (P=0.002; odds ratio of ASA, 3.65; 95% CI, 1.64 to 8.13, in patients versus control subjects). Patent foramen ovale (PFO) was detected with contrast injections in 56% of subjects with ASA. The presence of ASA predicted the presence of PFO (odds ratio of PFO, 4.57; 95% CI, 2.18 to 9.57, in subjects with versus those without ASA). In 86% of subjects with ASA and cerebral ischemia, transesophageal echocardiography did not detect an alternative source of cardioembolism other than an associated PFO. CONCLUSIONS The prevalence of ASA based on this population-based study is 2.2%. The frequency of ASA is relatively higher in patients evaluated with transesophageal echocardiography after a cerebral ischemic event. ASA is frequently associated with PFO, suggesting paradoxical embolism as a mechanism of cardioembolism. In patients with cerebral ischemia and ASA, ASA (with or without PFO) commonly is the only potential cardioembolic source detected with transesophageal echocardiography.Background—Atrial septal aneurysm (ASA) is a putative risk factor for cardioembolism. However, the frequency of ASA in the general population has not been adequately determined. Therefore, the frequency in patients with cerebral ischemic events, compared with the frequency in the general population, is poorly defined. We sought to determine the frequency of ASA in the general population and to compare the frequency of ASA in patients with cerebral ischemic events with the frequency in the general population. Methods and Results—The frequency of ASA in the population was determined in 363 subjects, a sample of the participants in the Stroke Prevention: Assessment of Risk in a Community study (control subjects), and was compared with the frequency in 355 age- and sex-matched patients undergoing transesophageal echocardiography in search of a cardiac source of embolism after a focal cerebral ischemic event. The proportion with ASA was 7.9% in patients versus 2.2% in control subjects (P=0.002; odds ratio of A...

The clinical-DWI mismatch: a new diagnostic approach to the brain tissue at risk of infarction.

Objective: To evaluate the usefulness of a mismatch between the severity of acute clinical manifestations and the diffusion-weighted imaging (DWI) lesion in predicting early stroke outcome and infarct volume. Methods: One hundred sixty-six patients with a hemispheric ischemic stroke of <12 hours’ duration were studied. The NIH Stroke Scale (NIHSS) score and the volume of DWI lesion were measured on admission and at 72 ± 12 hours. Infarct volume was measured on T2-weighted or fluid-attenuated inversion recovery images at day 30. Early neurologic deterioration (END) was defined as an increase of ≥4 points between the two NIHSS evaluations. Thirty-eight patients received IV thrombolysis or abciximab. Clinical–DWI mismatch (CDM) was defined as NIHSS score of ≥8 and ischemic volume on DWI of ≤25 mL on admission. The adjusted influence of CDM on END, DWI lesion enlargement at 72 hours, and infarct growth at day 30 was evaluated by logistic regression analysis and generalized linear models. Results: CDM was found in 87 patients (52.4%). Patients with CDM had a higher risk of END than patients without CDM because NIHSS < 8 (odds ratio [OR], 9.0; 95% CI,1.9 to 42) or DWI lesion > 25 mL (OR, 2.0; 95% CI, 0.8 to 4.9). CDM was associated with an increase of 46 to 68 mL in the mean volume of DWI lesion enlargement and infarct growth in comparison with non-CDM. All the effects were even greater and significant in patients not treated with reperfusion therapies. Conclusions: Acute stroke patients with an NIHSS score of ≥8 and DWI volume of ≤25 mL have a higher probability of infarct growth and early neurologic deterioration. The new concept of CDM may identify patients with tissue at risk of infarction for thrombolytic or neuroprotective drugs.

An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke

Objective: We aimed to create an index to stratify cryptogenic stroke (CS) patients with patent foramen ovale (PFO) by their likelihood that the stroke was related to their PFO. Methods: Using data from 12 component studies, we used generalized linear mixed models to predict the presence of PFO among patients with CS, and derive a simple index to stratify patients with CS. We estimated the stratum-specific PFO-attributable fraction and stratum-specific stroke/TIA recurrence rates. Results: Variables associated with a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or TIA. The 10-point Risk of Paradoxical Embolism score is calculated from these variables so that the youngest patients with superficial strokes and without vascular risk factors have the highest score. PFO prevalence increased from 23% (95% confidence interval [CI]: 19%–26%) in those with 0 to 3 points to 73% (95% CI: 66%–79%) in those with 9 or 10 points, corresponding to attributable fraction estimates of approximately 0% to 90%. Kaplan-Meier estimated stroke/TIA 2-year recurrence rates decreased from 20% (95% CI: 12%–28%) in the lowest Risk of Paradoxical Embolism score stratum to 2% (95% CI: 0%–4%) in the highest. Conclusion: Clinical characteristics identify CS patients who vary markedly in PFO prevalence, reflecting clinically important variation in the probability that a discovered PFO is likely to be stroke-related vs incidental. Patients in strata more likely to have stroke-related PFOs have lower recurrence risk.

Recurrent Stroke and Massive Right-to-Left Shunt Results From the Prospective Spanish Multicenter (CODICIA) Study

Background and Purpose— Few studies have prospectively examined the risk of recurrent stroke associated with patent foramen ovale. We present the results of the Spanish right-to-left shunt (RLSh) multicenter study. Methods— Four hundred eighty-six patients with cryptogenic stoke were included at 17 participating hospitals. Patients were examined by contrast transcranial Doppler methods at baseline. The magnitude of RLSh was quantified during the Valsalva maneuver. Transthoracic and/or transesophageal echocardiography, computed tomography scan, or magnetic resonance imaging was performed. Functional outcome and stroke recurrence were evaluated at 3 months and yearly thereafter. The independent relation between RLSh magnitude and stroke recurrence was analyzed by logistic-regression analysis in the whole group and in the younger subgroup (<55 years). Results— Massive RLSh was detected in 200 patients (41.2%). The mean follow-up was 729±411 days. Stroke recurrence was low (5.8%, n=28) and similar in patients with massive RLSh, with nonmassive RLSh, and with no RLSh, in both the younger group (3.4% vs 2.3% vs 4.5%, respectively; P=0.75) and in the whole population (5.0% vs 6.2% vs 6.3%, respectively; P=0.58). Regression analysis found no association between massive RLSh and recurrent stroke in either group (in the whole population, odds ratio=0.94; 95% CI, 0.36 to 2.40; P=0.89; in the younger population, odds ratio=0.93; 95% CI, 0.18 to 4.91; P=0.93). These results were similar when concurrent atrial septal aneurysm and massive RLSh were analyzed and when antithrombotic treatment and concomitant stroke risk factors were included. Conclusions— These results suggest that neither massive RLSh nor massive RLSh with concurrent atrial septal aneurysm is an independent risk factor for recurrent stroke, in either the general or younger stroke populations.

Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)

BACKGROUND Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. METHODS We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. RESULTS 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events. INTERPRETATION Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke. FUNDING Ferrer Grupo.