Sheila Cristina Ouriques Martins

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.).

Stroke: Working toward a Prioritized World Agenda

Background and Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent ‘silo’ mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e.g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a ‘Brain Health’ concept that enables promotion of preventive measures. Conclusions: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

Stroke: Working toward a Prioritized World Agenda:

Background and Purpose The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods Preliminary work was performed by seven working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results Recommendations of the Synergium are: Basic Science, Drug Development and Technology : There is a need to develop: (1) New systems of working together to break down the prevalent ‘silo’ mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention : (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management : Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation : (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications :(1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a ***‘Brain Health’ concept that enables promotion of preventive measures. Conclusions To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

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.

New Strategy to Reduce the Global Burden of Stroke

The socioeconomic and health effect of stroke and other noncommunicable disorders (NCDs) that share many of the same risk factors with stroke, such as heart attack, dementia, and diabetes mellitus, is huge and increasing.1–4 Collectively, NCDs account for 34.5 million deaths (66% of deaths from all causes)3 and 1344 million disability-adjusted life years lost worldwide in 2010.2 The burden of NCDs is likely to burgeon given the aging of the world’s population and the epidemiological transition currently observed in many low- to middle-income countries (LMICs).5,6 In addition, there is low awareness in the population about these NCDs and their risk factors,7–10 particularly in LMICs.11 These factors, coupled with underuse of strategies for primary prevention of stroke/NCDs on an individual level and the lack of accurate data on the prevalence and effect of risk factors in different countries and populations have been implicated in the ever-increasing worldwide burden of the NCDs.12–15 Of particular concern is a significant increase in the number of young adults (aged <65 years) affected by stroke,16 and the increasing epidemic of overweight/obesity17 and diabetes mellitus worldwide.18 If these trends continue, the burden of stroke and other major NCDs will increase even faster. The increasing burden of stroke and other major NCDs provide strong support for the notion that the currently used primary prevention strategies for stroke and other major NCDs (business as usual) are not sufficiently effective. The most pertinent solution to this problem is the implementation of new, effective, widely available, and cost-effective prevention and treatment strategies to reduce the incidence and severity distribution of stroke and other major NCDs. The recent INTERSTROKE case-control study, conducted in 22 countries worldwide, provided evidence that, collectively, 10 risk factors accounted …

Past, present, and future of stroke in middle-income countries: the Brazilian experience

Background Stroke is one of the major public health challenges in middle-income countries. Brazil is the worlds sixth largest economy but was clearly behind the milestones in the fight against stroke, which is the leading cause of death and disability in the country. Nevertheless, many initiatives are now reshaping stroke prevention, care, and rehabilitation in the country. Aims The present article discusses the evolution of stroke care in Brazil over the last decade. Methods We describe the main characteristics of stroke care before 2008; a pilot study in a Southern Brazilian city between 2008 and 2010, the Brazilian Stroke Project initiative; and the 2012 National Stroke Policy Act. Results The National Stroke Project was followed by a major increased on the number of stroke center in the country. The key elements of the 2012 National Stroke Policy Act included: definition of the requirements and levels of stroke centers; improved reimbursement for stroke care; promotion of stroke telemedicine; definition of the Line of Stroke Care (to integrate available resources and other health programs); increased funding for stroke rehabilitation; funding for training of healthcare professionals and initiatives to increase awareness about stroke within the population. Conclusions The evolution of stroke care in Brazil over the last decade is a pathway that exemplifies the challenges that middle-income countries have to face in order to improve stroke prevention, treatment and rehabilitation. The reported Brazilian experience can be extrapolated to understand the past, present, and future of stroke care in middle-income countries.

State of acute endovascular therapy: report from the 12th thrombolysis, Thrombectomy, and acute stroke therapy conference

Acute endovascular therapy for ischemic stroke is at a pivotal juncture. Until recently, on the basis of randomized trials comparing devices, we knew that endovascular treatment options were effective in quickly restoring blood flow and that successful early recanalization was associated with better functional outcome when compared with sustained occlusion.1,2 We did not have randomized evidence that available acute endovascular therapy improved patient outcomes; the 3 initial randomized controlled trials of endovascular recanalization treatment published in February of 2013—the Phase II Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), Phase III Interventional Management of Stroke (IMS) III, and Local Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS) trials—failed to demonstrate improved clinical outcomes.3–5 Many factors may have contributed to the failure of these 3 initial trials to show endovascular benefits. These trials were performed during a period of rapid evolution of imaging and treatment options, and used intra-arterial thrombolysis, or first-generation device therapies at best, with little use of newer generation devices, such as stent retrievers, demonstrated to achieve significantly higher rates of recanalization.1,2 Patients with mild or moderate stroke severity may have been less likely to benefit from endovascular reperfusion based on IMS III and Prolyse in Acute Cerebral Thromboembolism (PROACT) II post hoc analyses and others.3,6,7 The power of these trials was diluted by including subjects without intracranial vessel occlusions, and post hoc analyses of IMS III suggested a potential treatment effect among stroke patients with baseline computed tomographic (CT) angiographic occlusions.8 Larger vessel occlusions, which are more resistant to recanalization by intravenous recombinant tissue-type plasminogen activator (r-tPA), such as intracranial internal carotid artery (ICA) location or occlusions >8 mm, may have been more likely to show a treatment effect …

Guidelines for acute ischemic stroke treatment - Part I

Executive Committee: Charles André, Aroldo Luiz Bacellar, Daniel da Cruz Bezerra, Roberto Campos, João José Freitas de Carvalho, Gabriel Rodrigues de Freitas, Roberto de Magalhães Carneiro de Oliveira, Sebastião Eurico Melo de Souza, Soraia Ramos Cabette Fábio, Eli Faria Evaristo, Jefferson Gomes Fernandes, Maurício Friedrich, Marcia Maiumi Fukujima, Rubens José Gagliardi, Sérgio Roberto Haussen, Maria Clinete Sampaio Lacativa, Bernardo Liberato, Alexandre L. Longo, Sheila Cristina Ouriques Martins, Ayrton Roberto Massaro, Cesar Minelli, Carla Heloísa Cabral Moro, Jorge El-Kadum Noujaim, Edison Matos Nóvak, Jamary Oliveira-Filho, Octávio Marques Pontes-Neto, César Noronha Raffin, Bruno Castelo Branco Rodrigues, José Ibiapina Siqueira-Neto, Elza Dias Tosta, Raul Valiente, Leonardo Vedolim, Marcelo Gabriel Veja, Leonardo Vedolin, Fábio Iuji Yamamoto, Viviane Flumignan Zétola. Correspondence: Jamary Oliveira-Filho; Rua Reitor Miguel Calmon s/n; Instituto de Ciências da Saúde / sala 455; 40110-100 Salvador BA Brasil; E-mail: jamaryof@ufba.br Conflict of interest: There is no conflict of interest to declare. Received 18 February 2012; Received in final form 22 February 2012; Accepted 29 February 2012 Guidelines for acute ischemic stroke treatment – Part I

Stroke in Latin America: Burden of Disease and Opportunities for Prevention.

The epidemiological transition in Latin America toward older urban dwelling adults has led to the rise in cardiovascular risk factors and an increase in morbidity and mortality rates related to both stroke and myocardial infarction. As a result, there is an immediate need for effective actions resulting in better detection and control of cardiovascular risk factors that will ultimately reduce cardiovascular disease burden. Data from case-control studies have identified the following risk factors associated with stroke: hypertension; smoking; abdominal obesity; diet; physical activity; diabetes; alcohol intake; psychosocial factors; cardiac causes; and dyslipidemia. In addition to its high mortality, patients who survive after a stroke present quite frequently with marked physical and functional disability. Because stroke is the leading cause of death in most Latin American countries and also because it is a clearly preventable cause of death and disability, simple, affordable, and efficient strategies must be urgently implemented in Latin America.

Thrombolytic Therapy for Acute Stroke in the Elderly: An Emergent Condition in Developing Countries

Elderly patients may represent an important group when considering new stroke treatments, particularly in developing countries. The aim of this study was to analyze the use of recombinant tissue plasminogen activator (rtPA) in elderly Brazilian patients with acute ischemic stroke. Clinical and neuroimaging parameters at admission, frequency of symptomatic intracranial hemorrhage, and outcome were compared between elderly (≥80 years) and nonelderly (<80 years) stroke patients treated with rtPA in the Porto Alegre Stroke Network. We evaluated 183 nonelderly patients (mean age, 63 ± 12 years) and 55 elderly patients (mean age, 84 ± 3 years). Female sex, hypertension, congestive heart failure, atrial fibrillation, and previous history of stroke or transient ischemic attack were more frequent in the elderly patients. Elderly patients also presented with higher mean systolic blood pressure (P = .03) and National Institutes of Health Stroke Scale (NIHSS) score (P < .0001), whereas the nonelderly patients had a higher serum glucose level (P = .03). The rate of symptomatic intracranial hemorrhage was 10.9% in the elderly patients and 6.6% in the nonelderly patients (P = .28), and a substantial proportion of the elderly patients achieved a favorable outcome (modified Rankin Scale score ≤1) at 90 days, although this proportion was lower than that in the nonelderly patients (42% vs 58%; P = .04). Poorer outcomes were generally seen in elderly patients with an anterior circulation stroke, a higher NIHSS score, hypoattenuation in ≥1/3 lf the middle cerebral artery territory, and an Alberta Stroke Program Early CT score of ≤7 on an initial computed tomography scan. Our results support the administration of intravenous rtPA in selected elderly stroke patients presenting early to the hospital in developing countries.