Associations of Early Systolic Blood Pressure Control and Outcome After Thrombolysis-Eligible Acute Ischemic Stroke: Results From the ENCHANTED Study.

BACKGROUND AND PURPOSE: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. METHODS: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150-180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1-24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage. RESULTS: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71-0.82]; P<0.001 and 0.86 [95% CI, 0.76-0.98]; P=0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93-1.04]; P=0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06-1.31]; P=0.002 and 1.34 [1.11-1.62]; P=0.002) but not with magnitude of SBP reduction (1.05 [0.98-1.14]; P=0.184). CONCLUSIONS: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616.

Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial.

BACKGROUND: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. METHODS: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. FINDINGS: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. INTERPRETATION: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. FUNDING: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

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.).

[Correlation between socioeconomic factors and in-hospital mortality from ischemic stroke in a hospital cohort in Colombia, 2003-2006]. / Asociación entre factores socioeconómicos y mortalidad intrahospitalaria por accidente cerebrovascular isquémico en una cohorte hospitalaria de Colombia, 2003-2006.

OBJECTIVE: To determine if there is a correlation between socioeconomic conditions and in-hospital mortality (IHM) from ischemic stroke in a sample of the Colombian population and identify the chain of events that determine that association. METHODS: Prospective study of a hospital cohort of patients with ischemic stroke in four Colombian clinical referral institutions-located in Floridablanca, Bucaramanga, Bogotá, and Medellín-between February 2003 and December 2006. Hierarchical analysis was used to group the socioeconomic variables into three levels, and their relationship to IHM due to ischemic stroke was assessed in a Cox proportional hazards model. RESULTS: The IHM rate was 9.4% in the 253 patients included in the study. In the analysis by levels, mortality was inversely associated with educational level (advanced to primary), monthly income (≥ minimum wage), and participation in the contributory health system. When the three levels were combined in the hierarchical analysis, affiliation with the contributory system was the only association that maintained its statistical significance (RR 0.35; CI 95%: 0.13-0.96; P = 0.04). CONCLUSIONS: The results indicate that, in Colombia, being affiliated with the contributory health system is an independent protective factor against IHM after an ischemic stroke. The education-income-access to health services sequence is a possible explanation for the relationship between socioeconomic conditions and the clinical outcome of these events. Strategies should be designed to mitigate the differences in the quality and distribution of health services in the Colombian population.

Efficacy and Safety of Text Messages Targeting Adherence to Cardiovascular Medications in Secondary Prevention: TXT2HEART Colombia Randomized Controlled Trial.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide, with a prevalence of approximately 100 million patients. There is evidence that antiplatelet agents and antihypertensive medications could reduce the risk of new vascular events in this population; however, treatment adherence is very low. An SMS text messaging intervention was recently developed based on behavior change techniques to increase adherence to pharmacological treatment among patients with a history of ASCVD. OBJECTIVE: This study aims to evaluate the efficacy and safety of an SMS text messaging intervention to improve adherence to cardiovascular medications in patients with ASCVD. METHODS: A randomized controlled clinical trial for patients with a prior diagnosis of cardiovascular events, such as acute myocardial infarction, unstable angina, cerebrovascular disease, or peripheral artery disease, in one center in Colombia was conducted. Patients randomized to the intervention arm were assigned to receive SMS text messages daily for the first 4 weeks, 5 SMS text messages on week 5, 3 SMS text messages each in weeks 6 and 7, and 1 SMS text message weekly from week 8 until week 52. In contrast, patients in the control arm received a monthly SMS text message reminding them of the next study appointment and the importance of the study, requesting information about changes in their phone number, and thanking them for participating in the study. The primary endpoint was the change in low-density lipoprotein cholesterol (LDL-C) levels, whereas the secondary endpoints were the changes in thromboxane B2 levels, heart rate, systolic and diastolic blood pressure, medication adherence, cardiac and noncardiac mortality, and hospitalization. Linear regression analyses and bivariate tests were performed. RESULTS: Of the 930 randomized patients, 805 (86.5%) completed follow-up and were analyzed for the primary endpoint. There was no evidence that the intervention changed the primary outcome (LDL-C levels; P=.41) or any of the secondary outcomes evaluated (all P>.05). There was also no evidence that the intervention was associated with adverse events. CONCLUSIONS: In this study, there was no evidence that a behavior modification intervention delivered by SMS text messaging improved LDL-C levels, blood pressure levels, or adherence at 12 months. More research is needed to evaluate whether different SMS text messaging strategies, including personalized messages and different timings, are effective; future studies should include mixed methods to better understand why, for whom, and in which context (eg, health system or social environment) SMS text messaging interventions work (or not) to improve adherence in patients with ASCVD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03098186; https://clinicaltrials.gov/ct2/show/NCT03098186. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2018-028017.

Benefit, risk and cost of new oral anticoagulants and warfarin in atrial fibrillation; A multicriteria decision analysis.

INTRODUCTION: Warfarin and new oral anticoagulants are effective in reducing stroke in atrial fibrillation; however, the benefits and risks rates in clinical trials show heterogeneity for each anticoagulant, and is unknown the cost influence on a model considering most of the treatment consequences. We designed a benefit-risk and cost assessment of oral anticoagulants. DESIGN: We followed the roadmap proposed by IMI-PROTECT and the considerations of emerged good practice to perform Multi-Criteria Decision Analysis (MCDA). The roadmap defines the following steps: (1) planning, (2) evidence gathering and data preparation, (3) analyses, (4) explorations, and (5) conclusions. We defined two reference points (0-100) to allocate numerical values for scores and weights, and used an analogue numeric scale to assess physicians' preferences. As benefits of the anticoagulant therapy, we included reductions in stroke and all-cause mortality; intracranial haemorrhage, gastrointestinal haemorrhage, minor bleeding and myocardial infarction were considered risks. We also made an estimation of the annual drug cost per person. MAIN RESULTS: The scores were: Apixaban 33, Dabigatrán 25, warfarin 18 and Rivaroxaban 14 this score reveals the most preferred up to the less preferred option, considering the benefit-risk ratio and drug costs altogether. The relative model weights were: 51.1% for risks, 40.4% for benefits and 8.5% for cost. The sensitivity analysis confirms the model robustness. CONCLUSIONS: From this analysis, apixaban should be considered as the preferred anticoagulant option -due to a better benefit-risk balance and a minor cost influence- followed by dabigatran, warfarin and rivaroxaban.

Raised C-reactive protein and impaired flow-mediated vasodilation precede the development of preeclampsia.

BACKGROUND: The aim of this study was to investigate whether impaired flow mediated vasodilation precedes the clinical manifestations of preeclampsia and whether is associated with inflammation. METHODS: We conducted a nested case-control study in a prospective cohort of 506 normotensive women recruited before the 30th week of gestation (mean gestational age of 21.8 weeks). At enrollment, flow-mediated dilation was measured in the brachial artery using a 7.5-MHz transducer. C-reactive protein plasma concentrations and leukocyte count were also determined at study entry. Patients were followed until delivery, and medical records were reviewed for each patient to confirm the presence or absence of preeclampsia or gestational hypertension. RESULTS: Of the women studied, 14 developed preeclampsia, 18 developed gestational hypertension, and 474 remained normotensive. Two normotensive pregnant control subjects were randomly selected for each case, matched by maternal age, gestational age, and body mass index at enrollment. Women who subsequently developed preeclampsia had lower flow-mediated dilation (13.4% +/- 4.3% v 18.2% +/- 7.2, P = .026), higher C-reactive protein plasma concentrations (8.7 +/- 5.5 mg/dL v 5.3 +/- 4.3 mg/dL, P = .022) and leukocyte count (10.3 +/- 2.0 x 10(9)/L v 9.1 +/- 2.0 x 10(9)/L, P = .036) at study entry. CONCLUSIONS: Decreased flow-mediated vasodilation and higher levels of CRP are present in early stages of gestation in women who subsequently develop preeclampsia. These alterations occur before the onset of clinical symptoms of PE. Further studies are needed to confirm that flow-mediated dilation and C-reactive protein could be useful methods to screen women at risk of developing preeclampsia.

Olive, soybean and palm oils intake have a similar acute detrimental effect over the endothelial function in healthy young subjects.

BACKGROUND AND AIM: Currently, more than 30% of the caloric intake in the Colombian population comes from vegetable oil consumption mainly by the ingestion of deep-fried foods. Recently, it has been reported that unsaturated fatty acid rich oils have a beneficial effect on the endothelial function. Nevertheless, it is well know that the deep-frying process alters the chemical composition of vegetable oils and can produce adverse effects in the endothelial function. OBJECTIVE: To evaluate the acute effect of the ingestion of large amounts of olive, soybean and palm oils, fresh and at two different deep-fry levels, on the glucose and lipid profiles and the endothelial function. METHODS AND RESULTS: Ten healthy young volunteers were included in the study. After performing a baseline evaluation of cardiovascular risk factors and drawing a fasting blood sample, subjects were exposed to a randomly assigned potato soup meal containing 60 mL of one of three different vegetable oils (olive, soybean and palm), either fresh or at one of two different deep-fry levels (10 and 20 fries, respectively). Flow-mediated vasodilation (FMD) was performed in fasting conditions and 3h after the intake of the oil rich meal. Furthermore, blood samples were taken at these stages for the lipid profiles and plasma glucose determinations. All the meals resulted in a similar acute endothelial impairment (FMD decrease of 32.1%, confidence interval [CI] 95%, 28.0-36.2) and postprandial increase in triglycerides (27.03%, CI 95%, 20.5-33.3), independently of the type of oil ingested (p=0.44) and regardless of its deep-fry level (p=0.62). No correlation was found between endothelial impairment and postprandial triglyceride increment (r=-0.22, p=0.09). CONCLUSIONS: No difference was found in the acute adverse effect of the ingestion of different vegetable oils on the endothelial function. All the vegetable oils, fresh and deep-fried, produced an increase in the triglyceride plasma levels in healthy subjects.

Repetitive Transcranial Magnetic Stimulation for Phantom Limb Pain in Land Mine Victims: A Double-Blinded, Randomized, Sham-Controlled Trial.

UNLABELLED: We evaluated the effects of repetitive transcranial magnetic stimulation (rTMS) in the treatment of phantom limb pain (PLP) in land mine victims. Fifty-four patients with PLP were enrolled in a randomized, double-blinded, placebo-controlled, parallel group single-center trial. The intervention consisted of real or sham rTMS of M1 contralateral to the amputated leg. rTMS was given in series of 20 trains of 6-second duration (54-second intertrain, intensity 90% of motor threshold) at a stimulation rate of 10 Hz (1,200 pulses), 20 minutes per day, during 10 days. For the control group, a sham coil was used. The administration of active rTMS induced a significantly greater reduction in pain intensity (visual analogue scale scores) 15 days after treatment compared with sham stimulation (-53.38 ± 53.12% vs -22.93 ± 57.16%; mean between-group difference = 30.44%, 95% confidence interval, .30-60.58; P = .03). This effect was not significant 30 days after treatment. In addition, 19 subjects (70.3%) attained a clinically significant pain reduction (>30%) in the active group compared with 11 in the sham group (40.7%) 15 days after treatment (P = .03). The administration of 10 Hz rTMS on the contralateral primary motor cortex for 2 weeks in traumatic amputees with PLP induced significant clinical improvement in pain. PERSPECTIVE: High-frequency rTMS on the contralateral primary motor cortex of traumatic amputees induced a clinically significant pain reduction up to 15 days after treatment without any major secondary effect. These results indicate that rTMS is a safe and effective therapy in patients with PLP caused by land mine explosions.

Serie de Casos de Leishmaniasis Detectados en Centros Hospitalarios del Departamento de Caaguazú, Paraguay en 2019

Resumen La leishmaniasis es la tercera de las enfermedades de transmisión vectorial a humanos en importancia por el número de casos y la población en riesgo. En Paraguay la leishmaniasis cutánea es una enfermedad endémica atribuida en casi todos los casos a Leishmania (Viannia) braziliensis. El objetivo del artículo es describir las características demográficas y clínicas de una serie de casos de pacientes con leishmaniasis en el V departamento de Caaguazú y departamentos cercanos, epidemiológicamente endémicos. Se reportan casos diagnosticados en los meses enero a diciembre del año 2019. Los casos se presentaron en el departamento de Caaguazú, abarcando los diferentes distritos que componen y departamentos cercanos como Canindeyú, Alto Paraná y Guaira. De los casos registrados (9 casos) fueron hombres y (6 casos) tuvieron entre 50 a 70 años de edad. La lesión estuvo situada mayormente en el tabique nasal en 8 casos, con una evolución de menos de 10 años (6 casos) y en 4 casos dejo cicatriz. Solo 3 casos completaron su tratamiento. Se sugiere realizar el reporte de casos para tener un panorama de los casos de leishmaniasis en Paraguay como vigilancia sanitaria de la enfermedad y localizar focos de contagio.

Abstract Leishmaniasis is the third most important vector-borne diseases in humans due to the number of cases and the population at risk. In Paraguay, cutaneous leishmaniasis is an endemic disease attributed in almost all cases to Leishmania (Viannia) braziliensis. The objective of the article was to describe the demographic and clinical characteristics of a series of cases of patients with leishmaniasis in the V department of Caaguazú and nearby departments, epidemiologically endemic. Cases diagnosed in the months of January to December of the year 2019 are reported. The cases occurred in the department of Caaguazú, covering the different districts that make up and nearby departments such as Canindeyú, Alto Paraná and Guaira. Of the registered cases (9 cases) were men and (6 cases) were between 50 and 70 years of age. The lesion was located mainly in the nasal septum in 8 cases, with an evolution of less than 10 years (6 cases) and in 4 cases it left a scar. Only 3 cases completed their treatment. It is suggested to carry out the case report to have an overview of Leishmania cases in Paraguay as a health surveillance of the disease and to locate sources of contagion.

[Extrapontine osmotic myelinolysis]. / Mielinólisis osmótica extrapóntica.

Extrapontine osmotic myelinolysis is a rare nervous system complication. Symptoms of this malady were presented during the clinical examination of a 49-year-old alcoholic male, who arrived at the hospital emergency room in a state of cardiorespiratory arrest. After resuscitation methods were applied, the patient was found in metabolic acidosis (pH 7.014) and was treated with sodium bicarbonate. Forty-eight hours later, sodium levels in the patient had risen from 142 to 174 mEq/l. During the period of clinical observation, the patient showed signs of cognitive impairment, disartria, bilateral amaurosis, hyporeflexia and right-half body hemiparesias. After 72 hours, computer tomography was applied; this showed a bilateral lenticular hypodensity with internal and external capsule compromise. One month later, when the patient was referred to another institution for rehabilitation, the patient showed cognitive impairment, bilateral optic atrophy, residual disartria, bradikynesia and double hemiparesia.

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 (i.v.) 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) i.v. rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of i.v. 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) i.v. 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) i.v. 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 i.v. rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. CONCLUSIONS: Low-dose i.v. rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.

[Autonomic dysfunction syndromes associated with orthostatic intolerance]. / Síndromes de disfunción autonómica asociados con intolerancia ortostática.

In recent years increased interest has focused on the nature and pathophysiology of orthostatic intolerance and syndromes associated with autonomic disorders. Understanding the pathophysiology underlying these syndromes has led to the recognition of several distinct clinical entities with overlapping features and the associated need to reclassify many of the previously unrecognized syndromes. Among the clinical manifestations, syncope and near syncope are frequently associated with orthostatic intolerance. In addition, however, a wide spectrum of symptoms have been described ranging from chronic fatigue to recurrent neurally mediated vasodepressor reactions. The present review focuses on the pathophysiology and classification of syndromes of autonomic dysfunction associated with orthostatic intolerance. Primary and secondary causes of dysautonomia as well as therapeutic approach to these frequently unrecognized syndromes is presented.

[Fundamentals and Clinical Applications of Transcranial Magnetic Stimulation in Neuropsychiatry]. / Fundamentos y aplicaciones clínicas de la estimulación magnética transcraneal en neuropsiquiatría.

Transcranial Magnetic Stimulation (TMS) is a non-invasive method for stimulation of brain that is based on the ability of a generated magnetic field to penetrate skull and brain meninges, inducing an electric current in the brain tissues that produces neuronal depolarization. TMS can be applied as single pulse of stimulation, pairs of stimuli separated by variable intervals to the same or different brain areas, or as trains of repetitive stimuli at various frequencies. Its mechanism of action is currently unknown. Repetitive TMS can modify the excitability of the cerebral cortex, and has been postulated as a diagnostic and therapeutic tool in the area of neuropsychiatry. The aim of this article is to review the knowledge of the TMS as regards its basic principles, pathophysiological mechanism, and its usefulness in clinical practice.

Cost-effectiveness of new oral anticoagulants and warfarin in atrial fibrillation from adverse events perspective / Análisis de costo-efectividad de los nuevos anticoagulantes orales y la warfarina en fibrilación auricular desde la perspectiva de los eventos adversos

Abstract Objective: new oral anticoagulants (apixaban, dabigatran and rivaroxaban) are the newest advance for stroke's risk reduction in atrial fibrillation. These are as effective as warfarin in preventing stroke/systemic embolism, but exists heterogenic outcomes as gastrointestinal hemorrhage, mortality reduction, minor and major haemorrhage (adverse events). Despite of this, there is a lack of cost-effectiveness models focused on adverse events. Methods: a cost-effectiveness analysis with a third payer perspective, interventions included were apixaban, dabigatran, warfarin and rivaroxaban. Discount rate of 3%, and 10 years of temporal horizon. The Markov model is an international, validated, and modified to assess better adverse events. Major assumptions, patients with mild and moderate stroke returns to oral anticoagulation, patients with moderate and severe hemorrhage do not returns to oral anticoagulation. Probabilities and QALYs, taken from a cost-effectiveness analysis published. Costs, information from a cohort of stroke patients. Software, TreeAge pro( and Excel(. Results: overall results, 1.48 QALYs, $17 916 USD for apixaban, 1.49 QALYs, $18 122 USD for dabigatran, 1.32 QALYs, $21 966 USD for warfarin and 1.24 QALYs, $24 547 USD for rivaroxaban. The ICER for apixaban compared to dabigatran was $12 988 USD. Negative ICER for warfarin and rivaroxaban, shows that are dominated alternatives (less benefits and more costs). Apixaban is cost-effective at 70% and dabigatran at 30% of iterations in the probabilistic sensitivity analysis. Conclusions: apixaban and dabigatran are cost-effective alternatives, apixaban is the most cost-effective alternative from adverse events perspective. Warfarin shows better results than rivaroxaban to prevent stroke in atrial fibrillation from adverse events perspective.

Resumen Introducción: los nuevos anticoagulantes orales (apixabán, dabigatrán y rivaroxabán) son el avance más reciente para la reducción del riesgo de accidente cerebrovascular en la fibrilación auricular. Estos son tan efectivos como la warfarina en la prevención del accidente cerebrovascular/embolia sistémica, pero existen resultados heterogéneos como hemorragia gastrointestinal, reducción de la mortalidad y hemorragia menor y mayor (eventos adversos). Pese a ello, se carece de modelos de costo-efectividad enfocados en eventos adversos. Materiales y métodos: se hizo un análisis de costo-efectividad con una perspectiva de tercer pagador, en el que se incluyeron intervenciones como apixabán, dabigatrán, warfarina y rivaroxabán. La tasa de descuento fue del 3% y 10 años de horizonte temporal. El modelo de Markov es internacional, validado y modificado para evaluar mejor eventos adversos. Las principales suposiciones, los pacientes con accidente cerebrovascular leve y moderado vuelven a la anticoagulación oral, los pacientes con hemorragia moderada y grave no regresan a la anticoagulación oral. Probabilidades y AVAC, tomados de un análisis de costo-efectividad publicado. Los costos, información de una cohorte de pacientes con accidente cerebrovascular. Software, TreeAge pro y Excel. Resultados: resultados generales, 1.48 QALYs, $ 17 916 USD para apixabán, 1.49 QALYs, $ 18 122USD para dabigatrán, 1.32 QALYs, $ 21 966 USD para warfarina y 1.24 QALYs, $ 24 547 USD para rivaroxabán. El ICER para apixabán en comparación con dabigatrán fue de $ 12 988 USD. El ICER negativo para warfarina y rivaroxabán muestra que son alternativas dominadas (menos beneficios y más costos). Apixabán es rentable en 70% y dabigatrán en 30% de las iteraciones en el análisis de sensibilidad probabilístico. Conclusión: apixabán y dabigatrán son costo-efectivos; apixabán es la alternativa más costo-efectiva desde la perspectiva de los eventos adversos. Warfarina mostró mejores resultados que rivaroxabán para prevenir accidentes cerebrovasculares en fibrilación auricular desde la perspectiva de los eventos adversos.

Modelo de costos asociados al ataque cerebrovascular y los eventos adversos en pacientes con fibrilación auricular no valvular tratados con warfarina / Model of costs associated with stroke and adverse events in patients with non-valvular atrial fibrillation treated with warfarin

Resumen Objetivo: estimar el número y el costo médico directo del accidente cerebrovascular y los eventos adversos en usuarios de warfarina por fibrilación auricular. Métodos: se utilizó la metodología del análisis de impacto presupuestario para estimar el número de casos y el costo de los eventos. Se calculó la población diana con base en información poblacional de Colombia, así como las tasas de uso de warfarina según el riesgo y la distribución del tiempo en rango terapéutico de la misma. Se estimaron los eventos con base en probabilidades reportadas, y los costos utilizados en el modelo fueron calculados con información de una cohorte de pacientes con accidente cerebrovascular que se lleva a cabo en la Fundación Cardiovascular de Colombia. Resultados: la población diana fue de 84 623 pacientes en 1 año. El costo total de los accidentes cerebrovasculares y los sangrados fue de $36 852 236 476 millones COP. El costo total de los accidentes cerebrovasculares fue $5 004 588 241 COP; el costo total de las hemorragias intracraneales fue $11 875 730 234 COP y el de las hemorragias gastrointestinales fue $19 246 023 614 COP. El sangrado retroperitoneal, la epistaxis y el sangrado del tracto urinario fueron $735 894 387COP. El análisis de sensibilidad mostró que un ajuste en 10% de los tiempos en rango terapéutico podría ahorrar $4 211 957 037 COP. Conclusiones: el costo del accidente cerebrovascular y de los eventos adversos por warfarina es grande. Sin embargo, un ajuste de los tiempos en rango terapéutico podría ahorrar costos, lo que significa vidas de pacientes.

Abstract Objective: The aim of this study is to estimate the number and direct medical cost of cerebrovascular accident (stroke) and the adverse events in patients on warfarin due to atrial fibrillation. Methods: A budget impact analysis methodology was used to estimate the number of cases and cost of the events. The target population was based on Colombian population information, as well as the rates of use of warfarin according to risk and the distribution of its therapeutic time range. The events were estimated base on reported probabilities, and the costs used in the model were calculated from a cohort of stroke patients that was performed in the Cardiovascular Foundation of Colombia. Results: The target population consisted of 84,623 patients in 1 year. The total cost the strokes and bleeding was €10,426,275.28 ($36 852 236 476 million COP (Note: 3,500 /3,000Colombian Pesos (COP) = 1 Euro approx). The total cost strokes was €1,415,903.61 ($5 004 588 241 COP). The total costs of intracranial and gastrointestinal bleeding was €3,359,894.66 ($11 875 730 234 COP) and €5,445,106.17 ($19 246 023 614 COP), respectively. Retroperitoneal bleeding, epistaxis (nosebleeds) and urinary tract bleeding was €208,200.05 ($735 894 387 COP). The sensitivity analysis showed that an adjustment of 10% in the therapeutic time ranges could save €1,191,651.52 ($4 211 957 037 COP). Conclusions: The cost of the cerebrovascular accident and the adverse effects due to warfarin is large. However, an adjustment in the therapeutic range times could save costs, which means patient lives.

Revisión sistemática de nuevos anticoagulantes orales frente a warfarina en fibrilación auricular no valvular / Systematic review of new oral anticoagulants versus warfarin in non valvular atrial fibrillation

RESUMEN INTRODUCCIÓN: Los nuevos anticoagulantes orales son el más reciente avance en anticoagulación oral. Existen suficientes estudios publicados, pero muy poca síntesis de la información. MÉTODOS: Se realizó una búsqueda sistemática de los estudios en Medline, Cochrane y Embase con los términos predefinidos. Se aplicaron los criterios de inclusión y exclusión definidos, se definieron las variables utilizadas en este estudio según el beneficio (reducción de la mortalidad y reducción del ACV) y el riesgo en la anticoagulación (sangrado intracraneal, sangrado gastrointestinal, sangrado mayor y otros sangrados). Se seleccionaron los artículos y se extrajo la información en una hoja de cálculo para análisis. RESULTADOS: Se incluyeron 24 meta-análisis y 62 subanálisis; 77 % de los meta-análisis mostraron reducción de ACV, 65 % mortalidad, 71 % reportó disminución de hemorragia intracraneal y 45 % de sangrado mayor, pero hubo aumento de sangrado gastrointestinal en el 5 4% de los estudios. En relación a los resultados de los subanálisis, 4 estudios mostraron algún dato estadísticamente significativo para apixabán, 5 para dabigatrán, 3 para edoxabán y 5 estudios para rivaroxabán. Existen diferencias en algunas variables como sexo, riesgo de ACV, resultados a 30 días, función renal; diferentes dosis (dabigatrán y edoxabán), según la edad, síntomas gastrointestinales, relación con el INR; niveles séricos del medicamento, uso de amiodarona, uso previo de warfarina; enfermedad arterial periférica, transición a warfarina; factores de riesgo de HGI y sangrado mayor para cada anticoagulante en particular. CONCLUSIONES: Los nuevos anticoagulantes orales muestran mejor perfil de seguridad y de eficacia frente a warfarina.

SUMMARY INTRODUCTION: New oral anticoagulants are the latest advancement in oral anticoagulation. Several studies are published, but a few studies of synthesis information. METHODS: A systematic review of the studies in MEDLINE, COCHRANE and EMBASE was performed with the predefined terms. The defined inclusion and exclusion criteria were applied; variables used in this study were defined according to benefits (reduction of mortality and reduction of stroke) and anticoagulation risks (intracranial bleeding, gastrointestinal bleeding, major bleeding and other bleeding). Articles were selected and information was extracted into a spreadsheet for analysis. RESULT: Were included 24 meta-analyzes and 62 sub-analyzes; 77% of meta-analyzes showed stroke reduction, 65% in mortality, 71% reported decreased of intracranial hemorrhage and 45% in major bleeding, but there was an increase in gastrointestinal bleeding in 54% of the studies. Regarding the results of the sub-analysis, 4 studies for apixaban, 5 for dabigatran, 3 for edoxaban and 5 studies for rivaroxaban showed some statistically significant data. There are differences in some variables such as sex, stroke risk, 30-day results, renal function; Different doses (dabigatran and Edoxaban), according to age, gastrointestinal symptoms, relation with INR; Serum levels of the drug, use of amiodarone, prior use of warfarin; Peripheral arterial disease, transition to warfarin; Risk factors for gastrointestinal bleeding and major bleeding for each particular anticoagulant. CONCLUSION: The new oral anticoagulants shows better safety and efficacy profile against Warfarin.

Asociación entre niveles de proteína C-reactiva y óxido nítrico con el pronóstico de pacientes con infarto cerebral agudo / Association of C-reactive protein and nitric oxide levels with the prognosis of acute ischemic stroke

Introducción: La inflamación y alteraciones en la biodisponibilidad del óxido nítrico (NO) han sido involucradas en la fisiopatología de la enfermedad cerebrovascular. Objetivo: El objetivo del estudio fue determinar el valor pronóstico de la medición de metabolitos del NO y marcadores inflamatorios en pacientes con infarto cerebral agudo. Materiales y métodos: Se incluyeron 158 pacientes con diagnóstico de infarto cerebral agudo en un estudio observacional de cohorte. Entre 48 y 72 horas del inicio de los síntomas se tomó una muestra de sangre para determinación del perfil bioquímico, marcadores inflamatorios (PCR, IL1-β, IL6, TNF-α) y nitritos/nitratos plasmáticos. Se realizó seguimiento durante 2 años para determinar la aparición de un nuevo evento (infarto cerebral, infarto de miocardio, falla cardiaca) o muerte de origen vascular. Un análisis de regresión multivariada de Cox permitió determinar los factores asociados independientemente con el desenlace. Resultados: La edad promedio fue 70,5 ± 12,8 años. El 39,2% de los sujetos incluidos presentó el desenlace durante los primeros 24 meses de seguimiento. Los niveles de PCR > 12 mg/L (HR 2,22, IC 95% 1,07-4,59) y el puntaje > 13 en la escala NIHSS al ingreso (HR 2,81 IC 95% 1,46-5,41) se encontraron significativamente asociados con mayor riesgo de presentar un nuevo evento. La combinación de niveles de PCR < 12 mg/L y nitritos/nitratos < 35,5 µmol/L se identificó como un factor protector (HR 0,21, IC 95% 0,06-0,71). Conclusión: Este estudio sugiere que la determinación de nitritos/nitratos en conjunto con los niveles de PCR puede ser de utilidad para estratificar el riesgo de nuevos eventos en pacientes con infarto cerebral agudo.

Introduction: Inflammation and alterations in the bioavailability of nitric oxide (NO) have been involved in the pathophysiology of cerebrovascular disease. Objective: The aim of the study was to determine the prognostic value of measuring NO metabolites and inflammatory markers in patients with acute ischemic stroke. Materials and methods: A total of 158 patients with acute ischemic stroke were included in an observational cohort study. Between 48 and 72 hours post admission, a fasting blood sample was taken to determine the biochemical profile, inflammatory markers (CRP, IL1-β, IL6, TNF-α) and nitrites/nitrates plasma levels. The cohort's follow-up was conducted for two years to determine the occurrence of a new event (stroke, myocardial infarction, heart failure) or death of vascular origin. Comparisons between groups were made using the log-rank test. A Cox multivariate regression analysis permitted to determine factors independently associated with the outcome. Result: The mean age was 70.5 ± 12.8 years. 39.2% of the subjects presented the outcome during the first 24 months of follow-up. CRP levels > 12 mg/L (HR 2.22, 95% CI 1.07-4.59) and a score > 13 on the NIHSS scale at admission (HR 2.81 95% CI 1.46-5.41) were significantly associated with an increased risk of a new event. The combination of CRP levels < 12 mg/L and nitrites/nitrates levels < 35.5 mmol/L was identified as a protective factor (HR 0.21, 95% CI 0.06-0.71). Conclusion: This study demonstrates that the determination of CRP and NOx levels could be beneficial in clinical practice to stratify the risk of future events or death of vascular origin in acute ischemic stroke patients.

Fundamentos y aplicaciones clínicas de la estimulación magnética transcraneal en neuropsiquiatría / Fundamentals and Clinical Applications of Transcranial Magnetic Stimulation in Neuropsychiatry

La estimulación magnética transcraneal (EMT) es una herramienta no invasiva de estimulación cerebral que se basa en la capacidad de un campo magnético generado para penetrar el cráneo y las meninges y originar una corriente eléctrica secundaria en el tejido cerebral que produce despolarización neuronal. Esta técnica se puede aplicar en un solo estímulo, en pares de estímulos separados por intervalos o en trenes de estímulos repetidos a varias frecuencias. Si bien el mecanismo de acción exacto se desconoce, la EMT repetitiva puede modular la excitabilidad de la corteza cerebral, por lo cual se ha vislumbrado como una posible herramienta diagnóstica y terapéutica en el área de neuropsiquiatría. El objetivo de este artículo es revisar el conocimiento actual de la EMT en cuanto a principios básicos, mecanismos fisiopatológicos y utilidad en la práctica clínica de la neuropsiquiatría.

Transcranial Magnetic Stimulation (TMS) is a non-invasive method for stimulation of brain that is based on the ability of a generated magnetic field to penetrate skull and brain meninges, inducing an electric current in the brain tissues that produces neuronal depolarization. TMS can be applied as single pulse of stimulation, pairs of stimuli separated by variable intervals to the same or different brain areas, or as trains of repetitive stimuli at various frequencies. Its mechanism of action is currently unknown. Repetitive TMS can modify the excitability of the cerebral cortex, and has been postulated as a diagnostic and therapeutic tool in the area of neuropsychiatry. The aim of this article is to review the knowledge of the TMS as regards its basic principles, pathophysiological mechanism, and its usefulness in clinical practice.

Respuesta inflamatoria en pacientes con un primer ataque cerebrovascular isquémico: evaluación por género / Inflammatory response in a first ischemic stroke: differences by gender

Introducción. Se han descrito diferencias por género en la incidencia, la severidad y mortalidad asociadas al ataque cerebrovascular isquémico. Objetivo. Describir el comportamiento de la respuesta inflamatoria en hombres y mujeres con un primer episodio de ACV isquémico. Material y Métodos. Se incluyeron 50 mujeres postmenopáusicas mayores de 45 años y 50 hombres mayores de 45 años con un primer episodio de ataque cerebrovascular isquémico. Se evaluaron y analizaron diferencias en la presentación de síntomas, antecedentes, severidad, respuesta inflamatoria y mortalidad entre ambos géneros. Resultados. Las mujeres tuvieron un promedio de edad mayor al momento de presentar un primer ataque cerebrovascular isquémico (72,9 ± 9,8 años vs. 69,7 ± 9,03 años; p= 0,09), sin diferencias en la severidad del evento (mediana NIHSS 10,4 ± 7,61 en mujeres vs. 10,46 ± 4,96 en hombres), con mayores niveles de colesterol total (216,39 ± 50,61 vs. 188,76 ± 49,56; p=0,007), LDL (140,40 ± 39,57 vs. 121,3 ± 45,36; p=0,032), HDL (44,69 ± 15,52 vs. 37,67 ± 12,23; p= 0,013), triglicéridos (158,03 ± 74,65 vs. 144,05 ± 55,64; p=0,291) y glicemia (142,77 ± 71,60 vs. 138,16 ± 115,75; p=0,826), menor respuesta inflamatoria evaluada por PCR ultrasensible, IL-6 y TNFα, y mortalidad hospitalaria que los hombres (6,52% vs. 14%; p=0,231). Conclusión. Se propone que las diferencias por género en el comportamiento del ACV isquémico observadas en este estudio podrían ser explicadas por la protección cardiovascular hormonal extendida o la existencia de factores inherentes en las mujeres que les confieren un estado de protección ante un ACV isquémico.

Introduction. Controversy persists regarding gender differences in the incidence, severity and mortality associated with ischemic stroke. Objective. To describe the inflematory response in patients with a first ischemic stroke behavior in women and men over 45 year-old. Materials and Methods. 50 postmenopausal women and 50 men, over 45 years old with a first-ever ischemic stroke were included. Differences in symptoms, medical history, severity, inflammatory response and mortality were evaluated and analyzed among both genders. Results: Postmenopausal women were older at the first-ever ischemic stroke (72,9 + 9,8 years vs. 69,7 + 9,03 years, p=0,09), with no differences in stroke severity (NIHSS median score 10,4 + 7,61 in women vs. 10,46 + 4,96 in men), with higher levels of total cholesterol (216,39 + 50,61 vs. 188,76 + 49,56; p=0,007), LDL cholesterol (140,40 + 39,57 vs. 121,3 + 45,36; p=0,032), HDL cholesterol (44,69 + 15,52 vs. 37,67 + 12,23; p= 0,013), triglycerides (158,03 + 74,65 vs. 144,05 + 55,64; p=0,291) and blood glucose (142,77 + 71,60 vs. 138,16 + 115,75; p=0,826); less inflammatory response assessed by CRP, IL-6 and TNF-α, and hospital mortality than men (6,52% vs. 14%, p=0,231). Conclusion. Gender differences in ischemic stroke behavior observed in this study could be explained by the cardiovascular protection of premenopausal hormonal factors or inherent factors in women that confers a protection state against ischemic stroke.