The VITATOPS (vitamins to prevent stroke) Trial: Rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke

Background: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B-12 and vitamin B-6, it is not known whether lowering tHcy, by means of multivitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. Purpose: To determine whether vitamin supplements (folic acid 2 mg, B-6 25 Mg, B-12 500 mug) reduce the risk of stroke, and other serious vascular events, in patients with recent stroke or transient ischaemic attacks of the brain or eye (TIA). Methods: An international, multi-centre, randomised, double-blind, placebo-controlled clinical trial. Results: As of November 2001, more than 1,400 patients have been randomised from 10 countries in four continents. Conclusion: VITATOPS aims to recruit and follow up 8,000 patients between 2000 and 2004, and provide a reliable estimate of the safety and effectiveness of dietary supplementation with folic acid, vitamin B-12, and vitamin B-6 in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke. Copyright (C) 2002 S. Karger AG, Basel.

Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF

Background In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). Methods In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2-0-3.0). Patients and investigators were masked to treatment allocation. Between Dec 18,2006, and June 17,2009,14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767. Findings 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2.79% rivaroxaban vs 2.96% warfarin; hazard ratio [HR] 0-94,95% CI 0.77-1.16) and those without (1.44% vs 1.88%; 0.77, 0.58-1-01; interaction p=0.23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13.31% rivaroxaban vs 13.87% warfarin; HR 0.96,95% CI 0.87-1-07) and those without (16.69% vs 15.19%; 1.10, 0.99-1.21; interaction p=0.08). Interpretation There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF.

Aseptic meningoencephalitis mimicking transient ischaemic attacks.

PURPOSE: To highlight meningoencephalitis as a transient ischaemic attack (TIA) mimic and suggest clinical clues for differential diagnosis. METHODS: This was an observational study of consecutively admitted patients over a 9.75-year period presenting as TIAs at a stroke unit. RESULTS: A total of 790 patients with TIAs and seven with TIA-like symptoms but a final diagnosis of viral meningoencephalitis were recognised. The most frequent presentations of meningoencephalitis patients were acute sensory hemisyndrome (6) and cognitive deficits (5). Signs of meningeal irritation were minor or absent on presentation. Predominantly lymphocytic pleocytosis, hyperproteinorachia and a normal cerebrospinal fluid (CSF)/serum glucose index (in 5 out of 6 documented patients) were present. Meningeal thickening on a brain magnetic resonance imaging (MRI) scan was the only abnormal imaging finding. Six patients received initial vascular treatment; one thrombolysed. Finally, six patients were treated with antivirals and/or antibiotics. Although neither bacterial nor viral agents were identified on extensive testing, viral meningoencephalitis was the best explanation for all clinical and laboratory findings. CONCLUSIONS: Aseptic meningoencephalitis should be part of the differential diagnosis in patients presenting as TIA. The threshold for a lumbar puncture in such patients should be set individually and take into account the presence of mild meningeal symptoms, age and other risk factors for vascular disease, the results of brain imaging and the basic diagnostic work-up for a stroke source.

Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke - a randomized substudy

Background and Purpose - Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine ( total homocysteine [tHcy]) accelerate cardiovascular disease by promoting vascular inflammation, endothelial dysfunction, and hypercoagulability. Methods - We conducted a randomized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg, vitamin B-12 0.5 mg, and vitamin B-6 25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability. Results - At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high-sensitivity C-reactive protein [P = 0.32]; soluble CD40L [ P = 0.33]; IL-6 [P = 0.77]), endothelial dysfunction ( vascular cell adhesion molecule-1 [P = 0.27]; intercellular adhesion molecule-1 [P = 0.08]; von Willebrand factor [P = 0.92]), and hypercoagulability (P-selectin [P = 0.33]; prothrombin fragment 1 and 2 [P = 0.81]; D-dimer [P = 0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7-mumol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy). Conclusions - Lowering tHcy by 3.7 mumol/L with folic acid-based multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation, endothelial dysfunction, or hypercoagulability measured in our study. The possible explanations for our findings are: ( 1) these biomarkers are not sensitive to the effects of lowering tHcy (eg, multiple risk factor interventions may be required); ( 2) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured; or ( 3) elevated tHcy is a noncausal marker of increased vascular risk.

PFO closure vs. medical therapy in cryptogenic stroke or transient ischemic attack: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: This study aims to assess whether patent foramen ovale (PFO) closure is superior to medical therapy in preventing recurrence of cryptogenic ischemic stroke or transient ischemic attack (TIA). METHODS: We searched PubMed for randomized trials which compared PFO closure with medical therapy in cryptogenic stroke/TIA using the items: "stroke or cerebrovascular accident or TIA" and "patent foramen ovale or paradoxical embolism" and "trial or study". RESULTS: Among 650 potentially eligible articles, 3 were included including 2303 patients. There was no statistically significant difference between PFO-closure and medical therapy in ischemic stroke recurrence (1.91% vs. 2.94% respectively, OR: 0.64, 95%CI: 0.37-1.10), TIA (2.08% vs. 2.42% respectively, OR: 0.87, 95%CI: 0.50-1.51) and death (0.60% vs. 0.86% respectively, OR: 0.71, 95%CI: 0.28-1.82). In subgroup analysis, there was significant reduction of ischemic strokes in the AMPLATZER PFO Occluder arm vs. medical therapy (1.4% vs. 3.04% respectively, OR: 0.46, 95%CI: 0.21-0.98, relative-risk-reduction: 53.2%, absolute-risk-reduction: 1.6%, number-needed-to-treat: 61.8) but not in the STARFlex device (2.7% vs. 2.8% with medical therapy, OR: 0.93, 95%CI: 0.45-2.11). Compared to medical therapy, the number of patients with new-onset atrial fibrillation (AF) was similar in the AMPLATZER PFO Occluder arm (0.72% vs. 1.28% respectively, OR: 1.81, 95%CI: 0.60-5.42) but higher in the STARFlex device (0.64% vs. 5.14% respectively, OR: 8.30, 95%CI: 2.47-27.84). CONCLUSIONS: This meta-analysis does not support PFO closure for secondary prevention with unselected devices in cryptogenic stroke/TIA. In subgroup analysis, selected closure devices may be superior to medical therapy without increasing the risk of new-onset AF, however. This observation should be confirmed in further trials using inclusion criteria for patients with high likelihood of PFO-related stroke recurrence.

Nonvitamin-k-antagonist oral anticoagulants in patients with atrial fibrillation and previous stroke or transient ischemic attack: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: To assess whether the combined analysis of all phase III trials of nonvitamin-K-antagonist (non-VKA) oral anticoagulants in patients with atrial fibrillation and previous stroke or transient ischemic attack shows a significant difference in efficacy or safety compared with warfarin. METHODS: We searched PubMed until May 31, 2012, for randomized clinical trials using the following search items: atrial fibrillation, anticoagulation, warfarin, and previous stroke or transient ischemic attack. Studies had to be phase III trials in atrial fibrillation patients comparing warfarin with a non-VKA currently on the market or with the intention to be brought to the market in North America or Europe. Analysis was performed on intention-to-treat basis. A fixed-effects model was used as more appropriate than a random-effects model when combining a small number of studies. RESULTS: Among 47 potentially eligible articles, 3 were included in the meta-analysis. In 14 527 patients, non-VKAs were associated with a significant reduction of stroke/systemic embolism (odds ratios, 0.85 [95% CI, 074-0.99]; relative risk reduction, 14%; absolute risk reduction, 0.7%; number needed to treat, 134 over 1.8-2.0 years) compared with warfarin. Non-VKAs were also associated with a significant reduction of major bleeding compared with warfarin (odds ratios, 0.86 [95% CI, 075-0.99]; relative risk reduction, 13%; absolute risk reduction, 0.8%; number needed to treat, 125), mainly driven by the significant reduction of hemorrhagic stroke (odds ratios, 0.44 [95% CI, 032-0.62]; relative risk reduction, 57.9%; absolute risk reduction, 0.7%; number needed to treat, 139). CONCLUSIONS: In the context of the significant limitations of combining the results of disparate trials of different agents, non-VKAs seem to be associated with a significant reduction in rates of stroke or systemic embolism, hemorrhagic stroke, and major bleeding when compared with warfarin in patients with previous stroke or transient ischemic attack.

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

Cerebral Hypoperfusion in Posterior Reversible Encephalopathy Syndrome is Different from Transient Ischemic Attack on CT Perfusion.

BACKGROUND: PRES is a reversible neurotoxic state presenting with headache, altered mental status, visual loss, and seizures. Delayed diagnosis can be avoided if radiological patterns could distinguish PRES from cerebral ischemia. METHODS: Clinical and radiological data were collected on all hospitalized patients who had (1) discharge diagnosis of PRES and (2) acute CTP/CTA. Data were compared with 10 TIA patients with proven cytotoxic edema on MRI. RESULTS: Of the four PRES patients found, three were correlated with acute blood pressure and one with chemotherapy. At the radiological level, quantitative analyses of the CTP parameters showed that 2 out of 4 patients had bilaterally reduced CBF-values (23.2-47.1 ml/100g/min) in occipital regions, as seen in the pathological regions of TIA patients (27.3 ± 13.5 ml/100g/min). When compared with TIA patients, the pathological ROI's demonstrated decreased CBV-values (3.4-5.6 ml/100g). Vasogenic edema on MRI FLAIR imaging was seen in only one PRES patient, and cytotoxic edema on DWI-imaging was never found. CT angiography showed in one PRES patient a vasospasm-like unilateral posterior cerebral artery. CONCLUSIONS: If confirmed by other groups, CTP and CTA imaging in patients with acute visual loss and confusion may help to distinguish PRES from bi-occipital ischemia. These radiological parameters may identify PRES patients at risk for additional tissue infarction.

Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack

Background-Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages. Methods and Results-We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66-1.13; interaction P=0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42-0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71-1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively). Conclusions-Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality.

Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial

Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of recurrent stroke or other cardiovascular events. We compared the selective thromboxane-prostaglandin receptor antagonist terutroban with aspirin in the prevention of cerebral and cardiovascular ischaemic events in patients with a recent non-cardioembolic cerebral ischaemic event.

Copeptin and risk stratification in patients with ischemic stroke and transient ischemic attack: The CoRisk Study

RATIONALE: Copeptin independently predicts functional outcome and mortality at 90 days and one-year after ischemic stroke. In patients with transient ischemic attack, elevated copeptin values indicate an increased risk of further cerebrovascular events. AIMS: The Copeptin Risk Stratification (CoRisk) study aims to validate the predictive value of copeptin in patients with ischemic stroke and transient ischemic attack. In patients with ischemic stroke, the CoRisk study aims to further explore the effect of treatment (i.e. thrombolysis) on the predictive value of copeptin. DESIGN: Prospective observational multicenter study analyzing three groups of patients, i.e. patients with ischemic stroke treated with and without thrombolysis and patients with transient ischemic attack. OUTCOMES: Primary end-point: In patients with ischemic stroke, the primary end-point includes disability (modified Rankin scale from 3 to 5) and mortality (modified Rankin scale 6) at three-months after stroke. In patients with transient ischemic attack, the primary end-point is a recurrent ischemic cerebrovascular event (i.e. ischemic stroke or recurrent transient ischemic attack). Secondary end-point: In patients with ischemic stroke, the secondary end-points include in-house complications (i.e. symptomatic intracerebral hemorrhage, malignant edema, aspiration pneumonia or seizures during hospitalization, and in-house mortality).

Sleep-disordered breathing in acute ischemic stroke and transient ischemic attack: effects on short- and long-term outcome and efficacy of treatment with continuous positive airways pressure - rationale and design of the SAS CARE study

Sleep-disordered breathing represents a risk factor for cardiovascular morbidity and mortality and negatively affects short-term and long-term outcome after an ischemic stroke or transient ischemic attack. The effect of continuous positive airways pressure in patients with sleep-disordered breathing and acute cerebrovascular event is poorly known. The SAS CARE 1 study assesses the effects of sleep-disordered breathing on clinical evolution, vascular functions, and markers within the first three-months after an acute cerebrovascular event. The SAS CARE 2 assesses the effect of continuous positive airways pressure on clinical evolution, cardiovascular events, and mortality as well as vascular functions and markers at 12 and 24 months after acute cerebrovascular event.

[Management of transient ischemic attack (TIA) and acute stroke]

Patients with a transient ischemic attack and an acute stroke need urgent investigations and therapy in a stroke unit. Immediate investigation of the etiology and early secondary prevention measures reduce the likelihood of recurrent and other vascular events. In selected stroke patients intravenous thrombolysis and/or endovascular therapies lead to a significant reduction of long term disabilities.

Zurich Fabry study - prevalence of Fabry disease in young patients with first cryptogenic ischaemic stroke or TIA

BACKGROUND AND PURPOSE: The etiology of stroke in young patients remains undetermined in up to half of the cases. Data on prevalence of Fabry disease (FD) in young people with cryptogenic ischaemic stroke are limited and controversial. We aimed to evaluate the frequency of unrecognized FD in a cohort of stroke patients at a tertiary stroke center. METHODS: Patients suffering from first cryptogenic ischaemic stroke or transient ischaemic attack (TIA) at the age of 18-55 years were screened for the presence of FD. We measured the serum activity of α-galactosidase (α-GAL) in all patients. In addition, sequencing of α-GAL gene was performed in men with low enzyme activity and in all women. RESULTS: Between January, 2006, and October, 2009, we recruited 150 patients (102 men, 48 women) with a mean age of 43 ± 9 years at symptom onset (135 ischaemic stroke, 15 TIA). The α-GAL activity was low in nine patients (6%; six men and three women). Genetic sequencing in six men with low enzyme activity and all 48 women detected no α-GAL gene mutation. CONCLUSION: Our study suggests that the yield of screening for FD in patients with first cryptogenic ischaemic stroke or TIA is very low. Further large-scale studies are needed to investigate the importance of FD amongst patients with recurrent cryptogenic strokes.