Relationship between therapeutic changes in blood pressure and outcomes in acute stroke: a metaregression

Both low and high blood pressure (BP) during the acute phase of stroke are associated independently with a poor outcome. Several small clinical trials have involved the alteration of BP and this study assessed the relationship between change in BP and functional outcome. Randomised controlled trials of interventions that would be expected, on pharmacological grounds, to alter BP in patients within one week of the onset of acute ischaemic or haemorrhagic stroke were sought using electronic searches. Data were collected on BP and clinical outcome. The relationship between the difference in on-treatment BP and odds ratios (OR) for outcomes was assessed using meta-regression. Thirty-seven trials involving 9,008 patients were included. A ‘U’ or ‘J’ shaped relationship were found between on-treatment BP difference and early death, death at the end of 90 day follow up, and combined death or dependency at the end of follow up. Although outcomes were not significantly reduced at any level of change in BP, the lowest odds occurred at: early death (OR 0.87, 95% confidence interval, CI 0.54 to 1.23) - 8.1 mmHg; death at end of follow up (OR 0.96, 95% CI 0.31 to 1.65) - 14.4 mmHg; and combined death or dependency at end of follow up (OR 0.95, 95% CI 0.11 to 1.72) - 14.6 mmHg. Although large falls or increases in BP are associated with a worse outcome, modest reductions may reduce death, and combined death or dependency, although the confidence intervals are wide and compatible with overall benefit or hazard.

Fibrinolysis Versus Primary Pci In Stemi Patients Enrolled In The International Survey Of Acute Coronary Syndromes In Transitional Countries

Primary angioplasty has been shown to be more effective than fibrinolysis in terms of mortality and adverse outcomes. More recent data, however, suggests that timely reperfusion with fibrinolysis is comparable to primary angioplasty. The current study gathered data from the International Survey of Acute Coronary Syndromes in Transitional Countries registry. Among 7406 ST-elevation myocardial infarction patients presenting within 12 hours from symptom onset, 6315 underwent primary percutaneous coronary intervention and 1091 were treated with fibrinolysis. The primary outcome was 30-day mortality, while the secondary outcome was a composite of 30-day incidence of death, severe left ventricular dysfunction, stroke or reinfarction. Patients who underwent primary angioplasty tended to have a greater cardiovascular risk profile and were slightly older. On the other hand, patients treated with fibrinolysis received less anti-platelet medications yet were more often prescribed beta blockers in the acute phase. Among those who received fibrinolysis, 43% underwent coronary angiography while 32.3% were treated with a subsequent angioplasty. Total ischemic time was lower in patients undergoing fibrinolysis (185 minutes) than in those treated with primary angioplasty (258 minutes). Rates of primary and secondary combined endpoints were higher in patients receiving fibrinolysis compared to those receiving primary angioplasty (7.8% vs. 4.1%; p<0.0001; OR 1.97, 95% CI, 1.38-2.81; and 14.8% vs. 10.1%, p<0.0001; OR 1.43, 95% CI, 1.12-1.81). When considering only patients receiving reperfusion within 3 hours, regardless of reperfusion strategy, differences in mortality (6.3% vs. 4%, p=0.094, for fibrinolysis or primary angioplasty, respectively; OR 0.87, 95% CI, 0.35-2.16) and in the combined secondary endpoint were no longer observed (12.9% vs 10.8%, p=0.33; OR 0.98, 95% CI, 0.58-1.64), and female sex was no longer a significant predictor of adverse outcomes. When performed 3 hours from symptom onset, fibrinolysis is safe and feasible, in terms of mortality and adverse outcomes, compared to primary angioplasty.

Contralateral cortical response of a subpopulation of interneurons and the glial glutamate transporter GLT1 to an ischemic core

Introduction: Cerebral ischemia is an important cause of brain lesion in humans. The target in research has been the ischemic core or the penumbra zones; little attention has been given to areas outside the core or the penumbra but connected with the primary site of injury. Objective: Evaluate the laminar response of a subpopulation of gabaergic cells, those that are parvalbumin (PV) positive and the astrocytes through the expression of the glial transporter GLT1 on the contralateral cortex to an ischemic core. Methodology: For this purpose we used the medial cerebral artery occlusion model in rats. The artery was occluded for 90 minutes and the animals were sacrificed at 24 and 72 hours post-ischemia. The brains were removed, cut in a vibratome at 50 microns and incubated with the primary antibodies against PV or GLT1. Sections were developed using the vectastain Kit. In control tissue the primary antibody was omitted. Results: When compared with control animals, treated ones show a decrease in the expression of GLT1, especially in layers III and IV of the contralateral cortex to the ischemic core. PV positive cells increases in layers II and V. Conclusion: Increases in the expression of PV cells could correspond to an adaptation associated with glutamate increases in the synaptic compartment. These increases may be due to decreases in the expression of GLT1 transporter, that could not remove the glutamate present in the synaptic cleft, generating hyperactivity in the contralateral cortex. These changes could represent an example of neuronal and glial plasticity in remote areas to an ischemic core but connected to the primary site of injury.

H-ras activation is an early event in the ptaquiloside-induced carcinogenesis: Comparison of acute and chronic toxicity in rats

Bracken fern (Pteridium spp.) produces cancer of the urinary bladder and oesophagus in grazing animals and is a suspected human carcinogen, The carcinogenic principle ptaquiloside (PT), when activated to a dienone (APT), forms DNA adducts which eventually leads to tumor. Two groups of female Sprague-Dawley rats were given a chronic dose of 3 mg APT weekly for 10 weeks either by intravenous (iv) tail vein or by intragastric (ig) route, A third group was given a weekly dose of 6 mg of APT for 3 weeks by the ig route corresponding to acute dosing. Both chronic iv and ig dosed animals showed ischemic tubular necrosis in the kidney but only iv dosed animals developed adenocarcinomas of the mammary glands. Acutely dosed ig animals produced apoptotic bodies in the liver, necrosis of blood cell precursors in the bone marrow and ischemic tubular necrosis in the kidney but they did not develop tumors, No mutations were found in the H-ras and p53 genes in the mammary glands of either the ig rats or the tumor-bearing iv rats. However, the mammary glands of a fourth group of rats, which received APT by iv and killed before tumor development, carried Pu to Pu and Pu to Py double mutations in codons 58 and 59 of H-ras. This study indicates that the route of administration plays a role in the nature of the disease expression from ptaquiloside exposure. In addition to confirming the role of APT in the PT-induced carcinogenesis our finding suggests that activation of H-ras is an early event in the PT-carcinogenesis model. (C) 1998 Academic Press.

Death and readmission in the year after hospital admission with cardiovascular disease: the Hunter Area Heart and Stroke Register

Objectives: To compare outcomes one year after hospital admission for patients initially discharged with a diagnosis of acute myocardial infarction (AMI), other ischaemic heart disease (other IHD), congestive heart failure (CHF) or stroke. Design: Cohort study. Setting: Hunter Area Heart and Stroke Register, which registers all patients admitted with heart disease or stroke to any of the 22 hospitals in the Hunter Area Health Service in New South Wales. Patients: 4981 patients with AMI, other IHD, CHF or stroke admitted to hospital as an emergency between 1 July 1995 and 30 June 1997 and followed for at least one year. Main outcome measures: Death from any cause or emergency hospital readmission for cardiovascular disease. Results: In-hospital mortality varied from 1% of those with other IHD to 22% of those with stroke. Almost a third of all patients discharged alive (and 38% of those aged 70 or more) had died or been readmitted within one year. This varied from 22% of those with stroke to 49% of those with CHF. The causes of death and readmission were from a spectrum of cardiovascular disease, regardless of the cause of the original hospital admission. Conclusions: Data from this population register show the poor outcome, especially with increasing age, among patients admitted to hospital with cardiovascular disease. This should alert us to determine whether optimal secondary prevention strategies are being adopted among such patients.

Long-term disability after first-ever stroke and related prognostic factors in the Perth Community Stroke Study, 1989-1990

Background and Purpose-Few reliable estimates of the long-term functional outcome after stroke are available. This population-based study aimed to describe disability, dependency, and related independent prognostic factors at 5 years after,a first-ever stroke in patients in Perth, Western Australia. Methods-All individuals with a suspected acute stroke who were resident in a geographically defined region (population, 138 708) of Perth, Western Australia, were registered prospectively and assessed according to standardized diagnostic criteria over a period of 18 months in 1989 to 1990. Patients were followed up prospectively at 4 and 12 months and 5 years after the index event. Results-There were 370 cases of first-ever stroke, and 277 patients survived to 30 days. Of these early survivors, 152 (55%) were alive at 5 years, and among those who were neither institutionalized (n=146) nor disabled (n=129) at the time of their stroke, 21 (14%) were institutionalized in a nursing home, and 47 (36%) were disabled. The most important predictors of death or disability at 5 years were increasing age, baseline disability defined by a Barthel Index score of <20/20 (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.7 to 14), moderate hemiparesis (OR, 2.7. 95% CI, 1.1 to 6.2), severe hemiparesis (OR, 4.5; 95% CI, 1.1 to 19), and recurrent stroke (OR, 9.4; 95% CI, 3.0 to 30). A low level of activity before the stroke was a significant predictor of institutionalization, and subsequent recurrent stroke was a consistent, independent predictor of institutionalization, disability, and death or institutionalization, increasing the odds of each of these 3 adverse outcomes by 5- to 15-fold. Conclusions-Among 30-day survivors of first-ever stroke, about half survive 5 years; of survivors, one third remain disabled, and I in 7 are in permanent institutional care. The major modifiable predictors of poor long-term outcome are a low level of activity before the stroke and subsequent recurrent stroke. Efforts to increase physical activity among the elderly and to prevent recurrent stroke in survivors of a first stroke are likely to reduce the long-term burden of cerebrovascular disease.

Modelling the Distribution of Ischaemic Stroke-Specific Survival Time Using an EM-based Mixture Approach with Random Effects Adjustment

A two-component survival mixture model is proposed to analyse a set of ischaemic stroke-specific mortality data. The survival experience of stroke patients after index stroke may be described by a subpopulation of patients in the acute condition and another subpopulation of patients in the chronic phase. To adjust for the inherent correlation of observations due to random hospital effects, a mixture model of two survival functions with random effects is formulated. Assuming a Weibull hazard in both components, an EM algorithm is developed for the estimation of fixed effect parameters and variance components. A simulation study is conducted to assess the performance of the two-component survival mixture model estimators. Simulation results confirm the applicability of the proposed model in a small sample setting. Copyright (C) 2004 John Wiley Sons, Ltd.

Trends in five-year survival and risk of recurrent stroke after first-ever stroke in the Perth community stroke study

Background: Few studies provide information on trends in the long-term outcome of stroke. We aimed to determine trends in survival and recurrent stroke, over 5 years after first-ever stroke, for 2 cohorts of patients enrolled in the Perth Community Stroke Study in 1989 90 and 1995-96. Methods: For 12-month periods beginning February 1989 and February 1995, all individuals with an acute stroke who were resident in a geographically-defined and representative region of Perth, Western Australia, were registered and followed-up prospectively 5 years after the index event. Results: The 5-year cumulative risk of death was 59% (95% confidence interval (CI) 53%, 65%) and 58% (95% CI 52%, 65%) for the 1989-90 and 1995-96 cohorts, respectively (p = 0.94). The 5-year cumulative risk of first recurrent stroke was 32% (95% CI 25%, 40%) and 23% (95% CI 16%, 30%) for the 1989-90 and 1995-96 cohorts, respectively (p = 0.07). Conclusions: Although no statistically significant improvement occurred in 5-year survival after first-ever stroke in Perth between 1989-90 and 1995-96, there was a statistically nonsignificant trend towards a smaller cumulative risk of recurrent stroke over 5 years after a first-ever stroke. Serial community-based studies of the incidence and outcome of stroke are an important means of monitoring the translation of proven preventive interventions to improvements in population health. Copyright (C) 2005 S. Karger AG, Basel.

Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging

OBJECTIVE. Toxic leukoencephalopathy may present acutely or subacutely with symmetrically reduced diffusion in the periventricular and supraventricular white matter, hereafter referred to as periventricular white matter. This entity may reverse both on imaging and clinically. However, a gathering together of the heterogeneous causes of this disorder as seen on MRI with diffusion-weighted imaging (DWI) and an analysis of their likelihood to reverse has not yet been performed. Our goals were to gather causes of acute or subacute toxic leukoencephalopathy that can present with reduced diffusion of periventricular white matter in order to promote recognition of this entity, to evaluate whether DWI with apparent diffusion coefficient (ADC) values can predict the extent of chronic FLAIR abnormality ( imaging reversibility), and to evaluate whether DWI can predict the clinical outcome ( clinical reversibility). MATERIALS AND METHODS. Two neuroradiologists retrospectively reviewed the MRI examinations of 39 patients with acute symptoms and reduced diffusion of periventricular white matter. The reviewers then scored the extent of abnormality on DWI and FLAIR. ADC ratios of affected white matter versus the unaffected periventricular white matter were obtained. Each patient`s clinical records were reviewed to determine the cause and clinical outcome. Histology findings were available in three patients. Correlations were calculated between the initial MRI markers and both the clinical course and the follow-up extent on FLAIR using Spearman`s correlation coefficient. RESULTS. Of the initial 39 patients, seven were excluded because of a nontoxic cause (hypoxic-ischemic encephalopathy [HIE] or congenital genetic disorders) or because of technical errors. In the remaining 32 patients, no correlation was noted between any of the initial MRI markers (percentage of ADC reduction, DWI extent, or FLAIR extent) with the clinical outcome. Three patients had histologic correlation. However, moderate correlation was seen between the extent of abnormality on initial FLAIR and the extent on follow-up FLAIR (r = 0.441, p = 0.047). Of the 13 patients who underwent repeat MRI at 21 days or longer, the reduced diffusion resolved in all but one. Significant differences were noted between ADC values in affected white matter versus unaffected periventricular white matter on initial (p < 0.0001) but not on follow-up MRI (p = 0.13), and in affected white matter on initial versus follow-up (p = 0.0014) in those individuals who underwent repeat imaging on the same magnet (n = 9), confirming resolution of the DWI abnormalities. CONCLUSION. Acute toxic leukoencephalopathy with reduced diffusion may be clinically reversible and radiologically reversible on DWI, and may also be reversible, but to a lesser degree, on FLAIR MRI. None of the imaging markers measured in this study appears to correlate with clinical outcome, which underscores the necessity for prompt recognition of this entity. Alerting the clinician to this potentially reversible syndrome can facilitate treatment and removal of the offending agent in the early stages.

Histological features of acute tubular necrosis in native kidneys and long-term renal function

There are few studies on the relationship between the morphology of acute tubular necrosis (ATN) in native kidneys and late functional recovery. Eighteen patients with acute renal failure (ARF) who had undergone renal biopsy were studied. All had the histological diagnosis of ATN and were followed for at least six months. Clinical characteristics of ARF were analyzed, and histological features were semi-quantitatively evaluated (tubular atrophy, interstitial inflammatory infiltrate, interstitial fibrosis, and ATN). According to the maximal GFR achieved during the follow-up, patients were divided into two groups: complete recovery (GFR >= 90 mL/min/1.73 m(2)) and partial recovery (GFR < 90 mL/min/1.73 m(2)). Only 39% of the patients achieved complete recovery. Patients with partial recovery achieved their maximal GFR (63 +/- 9 mL/min/1.73 m(2)) 37 +/- 14 months after ARF, a period of time similar to those patients with complete recovery (i.e., 54 +/- 22 months). Patients with partial recovery had more severe ARF: oliguria was more frequent (90 versus 17%, p < 0.01), and they had higher peak creatinine (13.85 +/- 1.12 versus 8.95 +/- 1.30 mg/dL, p = 0.01), and longer hospitalization (45 +/- 7 versus 20 +/- 4 days, p = 0.03). No single histological parameter was associated with partial recovery, but the sum of all was when expressed as an injury index [4.00 (2.73-5.45) versus 2.00 (1.25-3.31), p < 0.05]. In conclusion, among patients with atypical ATN course, those with more severe ARF and tubule-interstitial lesions are more prone to partial recovery.

Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial

Patients with diabetes mellitus (DM) have high platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronary syndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similar rates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelor vs. clopidogrel in patients with DM or poor glycaemic control. We analysed patients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13 951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patients with DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76-1.03), all-cause mortality (HR: 0.82, 95% CI: 0.66-1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36-1.17) with no increase in major bleeding (HR: 0.95, 95% CI: 0.81-1.12) with ticagrelor was consistent with the overall cohort and without significant diabetes status-by-treatment interactions. There was no heterogeneity between patients with or without ongoing insulin treatment. Ticagrelor reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI: 0.70-0.91; HR: 0.78, 95% CI: 0.65-0.93; and HR: 0.62, 95% CI: 0.39-1.00, respectively) with similar bleeding rates (HR: 0.98, 95% CI: 0.86-1.12). Ticagrelor, when compared with clopidogrel, reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, without an increase in major bleeding events.

The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale

Background The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA.CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features. Trial design TRA.CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least I year. The TRA.CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention. Conclusion TRA.CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies. (Am Heart J 2009; 158:327-34.)

Effects of Optimal Medical Treatment With or Without Coronary Revascularization on Angina and Subsequent Revascularizations in Patients With Type 2 Diabetes Mellitus and Stable Ischemic Heart Disease

Background-In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, an initial strategy of coronary revascularization and optimal medical treatment (REV) compared with an initial optimal medical treatment with the option of subsequent revascularization (MED) did not reduce all-cause mortality or the composite of cardiovascular death, myocardial infarction, and stroke in patients with type 2 diabetes mellitus and stable ischemic heart disease. In the same population, we tested whether the REV strategy was superior to the MED strategy in preventing worsening and new angina and subsequent coronary revascularizations. Methods and Results-Among the 2364 men and women (mean age, 62.4 years) with type 2 diabetes mellitus, documented coronary artery disease, and myocardial ischemia, 1191 were randomized to the MED and 1173 to the REV strategy preselected in the percutaneous coronary intervention (796) and coronary artery bypass graft (377) strata. Compared with the MED strategy, the REV strategy at the 3-year follow-up had a lower rate of worsening angina (8% versus 13%; P < 0.001), new angina (37% versus 51%; P = 0.001), and subsequent coronary revascularizations (18% versus 33%; P < 0.001) and a higher rate of angina-free status (66% versus 58%; P = 0.003). The coronary artery bypass graft stratum patients were at higher risk than those in the percutaneous coronary intervention stratum, and had the greatest benefits from REV. Conclusions-In these patients, the REV strategy reduced the occurrence of worsening angina, new angina, and subsequent coronary revascularizations more than the MED strategy. The symptomatic benefits were observed particularly for high-risk patients.

Basilar artery occlusive disease in stroke survivors in a multiethnic population

Objectives: To describe clinical, radiological findings, and outcome in a multiethnic population of stroke survivors with basilar artery occlusive disease (BAOC). Methods: Forty patients with infarcts in the basilar artery (BA) territory, alive 30 days after the ictus, participated in the study. BA stenosis (>50%) or occlusion was shown by magnetic resonance or digital subtraction angiography in all patients. Demographical, clinical and radiological characteristics were described. Modified Rankin Scale (MRS) scores at 30 days and 6 months after the ischemic event were evaluated. Association between demographical, clinical, radiological features and outcome were analyzed with Chi-square and Fisher`s exact tests. MRS scores at 30 days and 6 months were compared with the Wilcoxon test. Results: Sixty percent of the patients were men, and 33% were Afro-Brazilian. Mean age was 55.8 +/- 12.9 years. Most (90%) had multiple vascular risk factors. Stroke was preceded by TIA in 48% of the patients, and 80% had a history of arterial hypertension. The most common neurological symptom was vertigo/dizziness (60%) and the sign, hemiparesis (60%). Most of the infarcts were located in the pons (85%) and the BA middle third was the most frequently affected segment (33%). BA occlusion occurred in 58% of the patients. More severe vascular occlusive lesions were present in Whites (p = 0.002) and in patients with involvement of the middle third of the BA (p = 0.021). Large-artery atherosclerosis was the most common stroke etiology (88%) and was more frequent in older patients (p < 0.001). Most patients were treated with anticoagulation. MRS scores improved significantly at 6 months (p < 0.001): at this time, 78% of the patients had MRS scores between 0 and 2. Conclusions: We observed different results compared with other series: greater proportion of Afro-descendents, higher frequency of atherosclerosis and BA occlusion. Rates of preceding TIAs and good outcome at 6 months were similar to previously published data. These results represent a step forward towards understanding BAOC in a multiethnic context. (C) 2009 Elsevier B.V. All rights reserved.