Antoni Dávalos

Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.

BACKGROUND Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke. METHODS After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events. CONCLUSIONS As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)

Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II)

Summary Background Thrombolysis for acute ischaemic stroke has been investigated in several clinical trials, with variable results. We have assessed the safety and efficacy of intravenous thrombolysis with alteplase (0·9 mg/kg bodyweight) within 6 h of stroke onset. Methods This non-angiographic, randomised, double-blind, trial enrolled 800 patients in Europe, Australia, and New Zealand. Computed tomography was used to exclude patients with signs of major infarction. Alteplase (n=409) and placebo (n=391) were randomly assigned with stratification for time since symptom onset (0–3 h or 3–6 h). The primary endpoint was the modified Rankin scale (mRS) at 90 days, dichotomised for favourable (score 0–1) and unfavourable (score 2–6) outcome. Analyses were by intention to treat. Findings 165 (40·3%) alteplase-group patients and 143 (36·6%) placebo-group patients had favourable mRS outcomes (absolute difference 3·7%, p=0·277). In a post-hoc analysis of mRS scores dichotomised for death or dependency, 222 (54·3%) alteplase-group and 180 (46·0%) placebo-group patients had favourable outcomes (score 0–2; absolute difference 8·3%, p=0·024). Treatment differences were similar whether patients were treated within 3 h or 3–6 h. 85 (10·6%) patients died, with no difference between treatment groups at day 90·14 days (43 alteplase, 42 placebo). Symptomatic intracranial haemorrhage occurred in 36 (8·8%) alteplase-group patients and 13 (3·4%) placebo-group patients. Interpretation The results do not confirm a statistical benefit for alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials. Despite the increased risk of intracranial haemorrhage, thrombolysis with alteplase at a dose of 0·9 mg/kg in selected patients may lead to a clinically relevant improvement in outcome.

Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study.

BACKGROUND The aim of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was to assess the safety and efficacy of intravenous alteplase as thrombolytic therapy within the first 3 h of onset of acute ischaemic stroke. Under European Union regulations, SITS-MOST was required to assess the safety profile of alteplase in clinical practice by comparison with results in randomised controlled trials. METHODS 6483 patients were recruited from 285 centres (50% with little previous experience in stroke thrombolysis) in 14 countries between 2002 and 2006 for this prospective, open, monitored, observational study. Primary outcomes were symptomatic (a deterioration in National Institutes of Health stroke scale score of >or=4) intracerebral haemorrhage type 2 within 24 h and mortality at 3 months. We compared mortality, the proportion of patients with symptomatic intracerebral haemorrhage as per the Cochrane definition, and functional outcome at 3 months with relevant pooled results from randomised controlled trials. FINDINGS Baseline characteristics of patients in SITS-MOST were much the same as those in the pooled randomised controlled trials. At 24 h, the proportion of patients with symptomatic intracerebral haemorrhage (per the SITS-MOST protocol) was 1.7% (107/6444; 95% CI 1.4-2.0); at 7 days, the proportion with the same condition as per the Cochrane definition was 7.3% (468/6438; 6.7-7.9) compared with 8.6% (40/465; 6.3-11.6) in the pooled randomised controlled trials. The mortality rate at 3 months in SITS-MOST was 11.3% (701/6218; 10.5-12.1) compared with 17.3% (83/479; 14.1-21.1) in the pooled randomised controlled trials. INTERPRETATION These data confirm that intravenous alteplase is safe and effective in routine clinical use when used within 3 h of stroke onset, even by centres with little previous experience of thrombolytic therapy for acute stroke. The findings should encourage wider use of thrombolytic therapy for suitable patients treated in stroke centres.

Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials

BACKGROUND In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included. METHODS We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation. FINDINGS We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2.49, 95% CI 1.76-3.53; p<0.0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2.6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction=0.43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3.68, 95% CI 1.95-6.92), those randomised more than 300 min after symptom onset (1.76, 1.05-2.97), and those not eligible for intravenous alteplase (2.43, 1.30-4.55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations. INTERPRETATION Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion. FUNDING Medtronic.

Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study.

BACKGROUND Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). METHODS In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 microg/kg desmoteplase, 125 microg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. FINDINGS Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 microg/kg desmoteplase; 66 received 125 microg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 microg/kg desmoteplase, 36% (24 of 66) for 125 microg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 microg/kg desmoteplase 14.0% (0.5 cm(3)); 125 microg/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 microg/kg desmoteplase, 4.5% (3 of 66) for 125 microg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 microg/kg desmoteplase; 21% [14 of 66] for 125 microg/kg desmoteplase; and 6% [4 of 63] for placebo). INTERPRETATION The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. FUNDING PAION Deutschland GmbH; Forest Laboratories.

Thrombolysis with alteplase 3–4·5 h after acute ischaemic stroke (SITS-ISTR): an observational study

BACKGROUND Intravenous alteplase is approved for use within 3 h of ischaemic stroke onset, although a meta-analysis of randomised controlled trials suggests treatment benefit up to 4.5 h. We compared outcome in patients treated between 3 h and 4.5 h versus those treated within 3 h, who were recorded in the in the Safe Implementation of Treatments in Stroke (SITS), a prospective internet-based audit of the International Stroke Thrombolysis Registry (ISTR). METHODS We compared 664 patients presenting with ischaemic stroke and given intravenous altepase (0.9 mg/kg total dose) between 3 h and 4.5 h with 11 865 patients treated within 3 h. All patients were otherwise compliant with European summary of product characteristics criteria and had been documented in the international stroke treatment registry between Dec 25, 2002, and Nov 15, 2007. Outcome measures were symptomatic intracerebral haemorrhage within 24 h (haemorrhage type 2 associated with National Institutes of Health Stroke Scale [NIHSS] > or = 4 points deterioration), and mortality and independence (modified Rankin scale of 0-2) at 3 months. FINDINGS In the 3-4.5-h cohort, treatment was started at a median of 55 min later after symptom onset (195 min [IQR 187-210] vs 140 min [115-165], p<0.0001), median age was 3 years younger (65 years [55-73] vs 68 years [58-74], p<0.0001), and stroke severity was lower (NIHSS score 11 [7-16] vs 12 [8-17], p<0.0001) than in the 3-h cohort. We recorded no significant differences between the 3-4.5-h cohort and the within 3-h cohort for any outcome measure--rate of symptomatic intracerebral haemorrhage: 2.2% (14 of 649) versus 1.6% (183 of 11 681) (odds ratio [OR] 1.18 [95% CI 0.89-1.55], p=0.24; adjusted OR 1.32 [1.00-1.75], p=0.052); mortality: 12.7% (70 of 551) versus 12.2% (1263 of 10 368) (OR 1.02 [0.90-1.17]; p=0.72; adjusted OR 1.15 [1.00-1.33]; p=0.053); and independence: 58.0% (314 of 541) versus 56.3% (5756 of 10231) (OR 1.04 [0.95-1.13], p=0.42; adjusted OR 0.93 [0.84-1.03], p=0.18). INTERPRETATION Alteplase remains safe when given at 3-4.5 h after ischaemic stroke, offering an opportunity for patients who cannot be treated within the standard 3-h timeframe. FUNDING Boehringer-Ingelheim, European Union Public Health Executive Authority.

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.

Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST).

Background and Purpose— The Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) unadjusted results demonstrated that intravenous alteplase is well tolerated and that the effects were comparable with those seen in randomized, controlled trials (RCTs) when used in routine clinical practice within 3 hours of ischemic stroke onset. We aimed to identify outcome predictors and adjust the outcomes of the SITS-MOST to the baseline characteristics of RCTs. Methods— The study population was SITS-MOST (n=6483) and pooled RCTs (n=464) patients treated with intravenous alteplase within 3 hours of stroke onset. Multivariable, backward stepwise regression analyses (until P≤0.10) were performed to identify the outcome predictors for SITS-MOST. Variables appearing either in the final multivariable model or differing (P<0.10) between SITS-MOST and RCTs were included in the prediction model for the adjustment of outcomes. Main outcome measures were symptomatic intracerebral hemorrhage, defined as National Institutes of Health Stroke Scale deterioration ≥1 within 7 days with any hemorrhage (RCT definition), mortality, and independency as defined by modified Rankin Score of 0 to 2 at 3 months. Results— The adjusted proportion of symptomatic intracerebral hemorrhage for SITS-MOST was 8.5% (95% CI, 7.9 to 9.0) versus 8.6% (6.3 to 11.6) for pooled RCTs; mortality was 15.5% (14.7 to 16.2) versus 17.3% (14.1 to 21.1); and independency was 50.4% (49.6 to 51.2) versus 50.1% (44.5 to 54.7), respectively. In the multivariable analysis, older age, high blood glucose, high National Institutes of Health Stroke Scale score, and current infarction on imaging scans were related to poor outcome in all parameters. Systolic blood pressure, atrial fibrillation, and weight were additional predictors of symptomatic intracerebral hemorrhage. Current smokers had a lower rate of symptomatic intracerebral hemorrhage. Disability before current stroke (modified Rankin Score 2 to 5), diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers, and male sex were related to high mortality at 3 months. Conclusions— The adjusted outcomes from SITS-MOST were almost identical to those in relevant RCTs and reinforce the conclusion drawn previously in the unadjusted analysis. We identified several important outcome predictors to better identify patients suitable for thrombolysis.

Mechanical Thrombectomy With the Solitaire AB Device in Large Artery Occlusions of the Anterior Circulation: A Pilot Study

Background and Purpose— To describe the safety and effectiveness of a self-expanding and fully retrievable stent (Solitaire AB; ev3 Inc, Plymouth, MN) in revascularization of patients with acute ischemic stroke. Methods— Prospective, single-center study of 20 patients with an acute ischemic stroke attributable to a large artery occlusion of the anterior circulation within the first 8 hours from symptoms onset (median National Institutes of Health Stroke Scale, 19 [interquartile range, 15–23]). The occlusion site was middle cerebral artery in 12 patients, proximal internal carotid artery/middle cerebral artery tandem occlusion in 3 patients, and terminus internal carotid artery in 5 patients. Thrombectomy was used as rescue therapy in 2 patients who were refractory to intra-arterial plasminogen activator, and in 3 patients in whom successful recanalization with the MERCI retriever was not achieved. Results— Successful revascularization defined as thrombosis in cerebral ischemia grade 2b or 3 was achieved in 18 of 20 (90%) treated vessels, and 16 patients showed immediate restoration of flow after stent deployment. The mean number of passes for maximal recanalization was 1.4, and the median (quartiles) time from groin puncture to recanalization was 50 (38–71) minutes. No case required adjuvant therapy after deployment of the embolectomy device. No significant procedural events occurred. Symptomatic intracranial hemorrhage was found in 2 (10%) patients, 4 (20%) patients died during the 90-day follow-up period, and 45% of patients showed good functional outcome at 3 months (modified Rankin Scale score ≤2). Conclusions— These results suggest that the Solitaire AB device can rapidly, safely, and effectively retrieve clots from the middle cerebral artery and terminus internal carotid artery within 8 hours from symptoms onset.

Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis

IMPORTANCE Endovascular thrombectomy with second-generation devices is beneficial for patients with ischemic stroke due to intracranial large-vessel occlusions. Delineation of the association of treatment time with outcomes would help to guide implementation. OBJECTIVE To characterize the period in which endovascular thrombectomy is associated with benefit, and the extent to which treatment delay is related to functional outcomes, mortality, and symptomatic intracranial hemorrhage. DESIGN, SETTING, AND PATIENTS Demographic, clinical, and brain imaging data as well as functional and radiologic outcomes were pooled from randomized phase 3 trials involving stent retrievers or other second-generation devices in a peer-reviewed publication (by July 1, 2016). The identified 5 trials enrolled patients at 89 international sites. EXPOSURES Endovascular thrombectomy plus medical therapy vs medical therapy alone; time to treatment. MAIN OUTCOMES AND MEASURES The primary outcome was degree of disability (mRS range, 0-6; lower scores indicating less disability) at 3 months, analyzed with the common odds ratio (cOR) to detect ordinal shift in the distribution of disability over the range of the mRS; secondary outcomes included functional independence at 3 months, mortality by 3 months, and symptomatic hemorrhagic transformation. RESULTS Among all 1287 patients (endovascular thrombectomy + medical therapy [n = 634]; medical therapy alone [n = 653]) enrolled in the 5 trials (mean age, 66.5 years [SD, 13.1]; women, 47.0%), time from symptom onset to randomization was 196 minutes (IQR, 142 to 267). Among the endovascular group, symptom onset to arterial puncture was 238 minutes (IQR, 180 to 302) and symptom onset to reperfusion was 286 minutes (IQR, 215 to 363). At 90 days, the mean mRS score was 2.9 (95% CI, 2.7 to 3.1) in the endovascular group and 3.6 (95% CI, 3.5 to 3.8) in the medical therapy group. The odds of better disability outcomes at 90 days (mRS scale distribution) with the endovascular group declined with longer time from symptom onset to arterial puncture: cOR at 3 hours, 2.79 (95% CI, 1.96 to 3.98), absolute risk difference (ARD) for lower disability scores, 39.2%; cOR at 6 hours, 1.98 (95% CI, 1.30 to 3.00), ARD, 30.2%; cOR at 8 hours,1.57 (95% CI, 0.86 to 2.88), ARD, 15.7%; retaining statistical significance through 7 hours and 18 minutes. Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 [95% CI, 0.76 to 0.93]; ARD, -6.7%) and less functional independence (OR, 0.81 [95% CI, 0.71 to 0.92], ARD, -5.2% [95% CI, -8.3% to -2.1%]), but no change in mortality (OR, 1.12 [95% CI, 0.93 to 1.34]; ARD, 1.5% [95% CI, -0.9% to 4.2%]). CONCLUSIONS AND RELEVANCE In this individual patient data meta-analysis of patients with large-vessel ischemic stroke, earlier treatment with endovascular thrombectomy + medical therapy compared with medical therapy alone was associated with lower degrees of disability at 3 months. Benefit became nonsignificant after 7.3 hours.