Verónica V. Olavarría

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

BACKGROUND Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. METHODS Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. RESULTS The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). CONCLUSIONS This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.).

Rationale, Design, and Progress of the ENhanced Control of Hypertension ANd Thrombolysis Stroke Study (ENCHANTED) Trial: An International Multicenter 2 × 2 Quasi-Factorial Randomized Controlled Trial of Low- vs. Standard-Dose rt-PA and Early Intensive vs. Guideline-Recommended Blood Pressure Lowering in Patients with Acute Ischaemic Stroke Eligible for Thrombolysis Treatment

Rationale Controversy exists over the optimal dose of intravenous (iv) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) iv rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of iv rt-PA, despite observational studies indicating better outcomes at much lower (<140 mmHg) systolic BP levels in this patient group. Aims The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight; maximum 60 mg) iv rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight; maximum 90 mg) iv rt-PA; and (ii) early intensive BP lowering (systolic target 130–140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg). Design The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent, 2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] ‘rt-PA dose’ and/or Arm [B] ‘BP control’, using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. Study outcomes The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2–6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift (‘improvement’) in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. Results Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose iv rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. Conclusions Low-dose iv rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.

Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke

BACKGROUND The role of supine positioning after acute stroke in improving cerebral blood flow and the countervailing risk of aspiration pneumonia have led to variation in head positioning in clinical practice. We wanted to determine whether outcomes in patients with acute ischemic stroke could be improved by positioning the patient to be lying flat (i.e., fully supine with the back horizontal and the face upwards) during treatment to increase cerebral perfusion. METHODS In a pragmatic, cluster‐randomized, crossover trial conducted in nine countries, we assigned 11,093 patients with acute stroke (85% of the strokes were ischemic) to receive care in either a lying‐flat position or a sitting‐up position with the head elevated to at least 30 degrees, according to the randomization assignment of the hospital to which they were admitted; the designated position was initiated soon after hospital admission and was maintained for 24 hours. The primary outcome was degree of disability at 90 days, as assessed with the use of the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death). RESULTS The median interval between the onset of stroke symptoms and the initiation of the assigned position was 14 hours (interquartile range, 5 to 35). Patients in the lying‐flat group were less likely than patients in the sitting‐up group to maintain the position for 24 hours (87% vs. 95%, P<0.001). In a proportional‐odds model, there was no significant shift in the distribution of 90‐day disability outcomes on the global modified Rankin scale between patients in the lying‐flat group and patients in the sitting‐up group (unadjusted odds ratio for a difference in the distribution of scores on the modified Rankin scale in the lying‐flat group, 1.01; 95% confidence interval, 0.92 to 1.10; P=0.84). Mortality within 90 days was 7.3% among the patients in the lying‐flat group and 7.4% among the patients in the sitting‐up group (P=0.83). There were no significant between‐group differences in the rates of serious adverse events, including pneumonia. CONCLUSIONS Disability outcomes after acute stroke did not differ significantly between patients assigned to a lying‐flat position for 24 hours and patients assigned to a sitting‐up position with the head elevated to at least 30 degrees for 24 hours. (Funded by the National Health and Medical Research Council of Australia; HeadPoST ClinicalTrials.gov number, NCT02162017.)

Exclusion Criteria for Intravenous Thrombolysis in Stroke Mimics: An Observational Study

BACKGROUND Stroke mimics (SMs) are frequent in emergency departments (EDs), but are treated infrequently with intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis. We aimed at identifying the factors that lead to the exclusion of SMs from thrombolytic therapy. METHODS Consecutive patients presenting to the ED between December 2004 and March 2011 with symptoms that suggested acute ischemic stroke were included. RESULTS Eight hundred forty-two patients were included in this study; 113 (13.4%) were considered SMs; these patients were younger (P = .01), more frequently diabetic (P = .001), arrived later to the ED (P = .03), had lower National Institutes of Health Stroke Scale scores (P < .001), and higher frequencies of negative diffusion-weighted imaging studies (P = .002). The most common causes of cases of SM were toxic metabolic disorders (n = 34 [30.1%]) and seizures (n = 22 [19.5%]). The most frequent cause of consultation was aphasia (n = 43 [37.6%]). SM patients had a total of 152 contraindications for rt-PA, with 34 (30%) patients having >1 contraindication. The most frequent of these were being beyond the therapeutic window for thrombolysis (n = 96) and having deficits not measurable by the National Institutes of Health Stroke Scale or very mild symptoms before the start of rt-PA (n = 37). Twenty-four (21.2%) patients had both contraindications simultaneously. Two patients (1.76%) in the SM group were candidates for rt-PA but did not receive this treatment because they or their family rejected it. Of 729 stroke patients, 87 (11.9%) did receive rt-PA. CONCLUSIONS SM patients frequently had exclusion criteria for systemic thrombolysis, the most frequent being presenting beyond the established thrombolytic window.

Head Position in Stroke Trial (HeadPoST)--sitting-up vs lying-flat positioning of patients with acute stroke : study protocol for a cluster randomised controlled trial

BackgroundPositioning a patient lying-flat in the acute phase of ischaemic stroke may improve recovery and reduce disability, but such a possibility has not been formally tested in a randomised trial. We therefore initiated the Head Position in Stroke Trial (HeadPoST) to determine the effects of lying-flat (0°) compared with sitting-up (≥30°) head positioning in the first 24 hours of hospital admission for patients with acute stroke.Methods/DesignWe plan to conduct an international, cluster randomised, crossover, open, blinded outcome-assessed clinical trial involving 140 study hospitals (clusters) with established acute stroke care programs. Each hospital will be randomly assigned to sequential policies of lying-flat (0°) or sitting-up (≥30°) head position as a ‘business as usual’ stroke care policy during the first 24 hours of admittance. Each hospital is required to recruit 60 consecutive patients with acute ischaemic stroke (AIS), and all patients with acute intracerebral haemorrhage (ICH) (an estimated average of 10), in the first randomised head position policy before crossing over to the second head position policy with a similar recruitment target. After collection of in-hospital clinical and management data and 7-day outcomes, central trained blinded assessors will conduct a telephone disability assessment with the modified Rankin Scale at 90 days. The primary outcome for analysis is a shift (defined as improvement) in death or disability on this scale. For a cluster size of 60 patients with AIS per intervention and with various assumptions including an intracluster correlation coefficient of 0.03, a sample size of 16,800 patients at 140 centres will provide 90 % power (α 0.05) to detect at least a 16 % relative improvement (shift) in an ordinal logistic regression analysis of the primary outcome. The treatment effect will also be assessed in all patients with ICH who are recruited during each treatment study period.DiscussionHeadPoST is a large international clinical trial in which we will rigorously evaluate the effects of different head positioning in patients with acute stroke.Trial registrationClinicalTrials.gov identifier: NCT02162017 (date of registration: 27 April 2014); ANZCTR identifier: ACTRN12614000483651 (date of registration: 9 May 2014). Protocol version and date: version 2.2, 19 June 2014.

Accuracy of Diffusion-Weighted Imaging in the Diagnosis of Stroke in Patients With Suspected Cerebral Infarct

Background and Purpose— The accuracy of diffusion-weighted imaging (DWI) for the diagnosis of acute cerebral ischemia among patients with suspected ischemic stroke arriving to an emergency room has not been studied in depth. Methods— DWI was performed in 712 patients with acute or subacute focal symptoms that suggested an acute ischemic stroke (AIS), 609 of them with AIS. Results— DWI demonstrated a sensitivity of 90% and specificity of 97%, a positive likelihood ratio of 31 and a negative likelihood ratio of 0.1 for detecting AIS. The overall accuracy was 95%. Of those patients who demonstrated abnormal DWI studies, 99.5% were AIS patients, and of those patients with normal DWI studies 63% were stroke mimics. Conclusions— DWI is accurate in detecting AIS in unselected patients with suspected AIS; a negative study should alert for nonischemic conditions.

Socioeconomic and Cardiovascular Variables Explaining Regional Variations in Stroke Mortality in Chile: An Ecological Study

Background: Regional differences in stroke mortality rates have been described in Chile. These could be related to the distribution of cardiovascular risk factors, the quality of medical care or socioeconomic status influencing incidence or case fatality rates. Our objective was to investigate variables explaining the variability in stroke mortality rates in the different regions of Chile. Methods: Adjusted stroke mortality rates in different regions were calculated for the year 2003. Variables were added from three sources: the National Death Certificate Database, the National Socioeconomic Characterization Survey and the National Health Survey. A logistic regression model was used to investigate regions, demographic variables and socioeconomic variables associated with the risk of death from stroke. A linear regression model was used to study the association of socioeconomic variables and cardiovascular risk factors with the standardized mortality rate by region and the contribution of these to the variability. Results: A twofold increase was found in adjusted stroke mortality rates among regions. Greater risk was associated with older age, female gender and residence in regions V, VII, VIII and IX. Sixty-two percent of the regional variability rate was explained by the combined prevalence of poverty (34%), diabetes (17%), sedentarism (8%) and overweight (3%). Conclusion: The risk of death from stroke in Chile is associated with age, sex and living in four specific regions of the country. The majority of the increased risk in these regions is explained by the prevalence of poverty, diabetes, a sedentary lifestyle and overweight.

Additional Information Given to a Multimodal Imaging Stroke Protocol by Transcranial Doppler Ultrasound in the Emergency Room: A Prospective Observational Study

Background: Transcranial Doppler (TCD) ultrasound can demonstrate dynamic information. We aimed to evaluate whether TCD generates useful additional information in the emergency room after a multimodal stroke imaging protocol and also whether this modified the management of patients with cerebral infarction. Methods: Patients admitted between April 2006 and June 2007 with ischemic stroke of less than 24 h were subjected to a protocol consisting of noncontrast brain CT, computed tomography angiography, diffusion-weighted magnetic resonance imaging and then TCD within the following 6 h by an observer blinded to the results of imaging studies. Results: Seventy-nine patients were included. The imaging protocol was performed 457 (±346) min after stroke symptoms and TCD after 572 (±376) min. TCD provided additional information in 28 cases (35.4%, 95% CI 25.7–46.4). More that one piece of additional information was obtained in 6 patients. The most frequent additional information was collateral pathways. Multivariate analysis demonstrated that intracranial vessel occlusion was the variable most associated with additional information. In 7 patients (8.8%, 95% CI 4.3–17.1), additional information changed management: in 4 an additional angiography was performed, in 2 patients angiography was suspended and in 1 aggressive neurocritical care was indicated. Patients with NIHSS >10 were significantly more likely to have their initial treatment changed (p = 0.004). Conclusions: TCD can provide additional information to a multimodal acute ischemic stroke imaging protocol in a third of patients. This can result in changes in the management in some of these patients.

Low- Versus Standard-Dose Alteplase in Patients on Prior Antiplatelet Therapy: The ENCHANTED Trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study).

Background and Purpose— Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study). Methods— Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2–6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria. Results— There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01; 95% confidence interval [CI], 0.81–1.26; P=0.953), 3 to 6 (OR, 0.95; 95% CI, 0.75–1.20; P=0.662), or ordinal mRS shift (OR, 1.03; 95% CI, 0.87–1.21; P=0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82; 95% CI, 1.00–3.30; P=0.051) according to the safe implementation of thrombolysis in stroke-monitoring study definition. Although not significant (P-trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2–6; OR, 0.84; 95% CI, 0.62–1.12 versus OR, 1.16; 95% CI, 0.99–1.36). Conclusions— Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic stroke patients on prior APT, but this requires further evaluation in a randomized controlled trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Transcranial Doppler in a Hispanic-Mestizo population with neurological diseases: a study of sonographic window and its determinants.

Between 5% and 37% of patients are not suitable for transtemporal insonation with transcranial Doppler (TCD). This unsuitability is particularly frequent in elderly females and non‐Caucasians. We aim to evaluate TCD efficiency in a mixed Hispanic population in Santiago, Chile and to determine whether factors associated with the presence of optimal windows depend exclusively on patient‐related elements. Seven hundred forty‐nine patients were evaluated with power mode TCD. Optimal temporal windows (TWs) included detection of the middle, anterior, posterior cerebral arteries and terminal carotid. The patients age and sex, the location of the examination, the time of day, whether the test was conducted on weekends and whether mechanical ventilation was used were recorded. Percentages of optimal windows were calculated. Examinations were deemed ideal if both TWs were optimal. TWs were obtained in 82% of cases. In univariate analyses, male sex (P < 0.001), an age below 60 years (P < 0.0001) and mechanical ventilation (P= 0.04) correlated with ideal TWs. Using logistic regression where dependent variable was a non‐ideal window only male sex odds ratio (OR) 2.3 (1.51–3.45) and age below 60 OR 13.8 (7.8–24.6) were statistically significant. Our findings indicate that Hispanic populations have detection rates for TWs similar to Europeans and are affected by patient‐related elements.