Prospective Validation of Computed Tomography to Identify Patients at High Risk for Stroke After Transient Ischemic Attack or Minor Stroke.

The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia

Background: Conflicting data exists surrounding whether or not the effect of clopidogrel on risk reduction of cardiovascular outcomes, including stroke, is more pronounced in smokers. The aim of this study was to determine the effect of smoking status on subsequent stroke risk in all patients with minor ischemic stroke or TIA, as well as subgroups that may be particularly impacted by an effect, and determine whether smoking improves the effect of clopidogrel treatment on subsequent stroke risk reduction. Subgroup analysis included those of older age, black race, and female gender, as these groups may have higher risk of clopidogrel non-response and subsequently poor outcomes. Methods: This was a post-hoc analysis of the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial. The POINT trial compared clopidogrel plus aspirin (DAPT) to aspirin alone for prevention of recurrent stroke, myocardial infarction, or vascular death within 3 months of a high-risk TIA or minor ischemic stroke. We used multivariable cox-regression models to determine the effect of smoking on the efficacy of DAPT in reducing the risk of subsequent ischemic stroke in all patients and prespecified subgroups stratified based on age, sex, race, and diabetes. We also performed interaction analyses to determine whether the effect of clopidogrel on subsequent ischemic stroke differed with respect to smoking status. Results: Data from 4,877 participants enrolled in the POINT trial were analyzed. Among these, 1,004 were current smokers and 3,873 were non-smokers. Smoking was associated with a non-significantly increased risk of recurrent ischemic stroke during follow up (hazard ratio, 1.31 [95% CI, 0.97 - 1.78], P=0.076). The effect of clopidogrel on ischemic stroke was not significantly different in non-smokers (hazard ratio, 0.74 [95% CI, 0.56 - 0.98], P=0.03) compared to smokers (adjusted hazard ratio, 0.63 [95% CI, 0.37 - 1.05], P=0.078), P for interaction = 0.572. In addition, the effect of clopidogrel on major hemorrhage was not significantly different in current smokers (hazard ratio, 2.59 [95% CI, 1.08 - 6.21], P=0.032) compared to non-smokers (hazard ratio, 1.67 [95% CI, 0.40 - 7.00], P=0.481), P for interaction = 0.613. This finding was maintained across different subgroups: males, females, blacks, whites, those with and without diabetes, and those aged < 60 and ≥ 60 years. Conclusions: Cigarette smoking was associated with a non-significantly higher risk of subsequent ischemic stroke and smoking did not modify the effect of clopidogrel-based dual antiplatelet therapy on subsequent ischemic stroke risk reduction, even in the subgroups of stratified based on age, sex, race, and diabetes, where greater likelihood of effect was theorized. Every effort should be made to encourage tobacco dependence treatment and cessation in patients with minor ischemic stroke and TIA.

Background: Most prior estimates of transient ischemic attack (TIA) incidence and post-TIA stroke risk are derived from case-based cohorts recruited in hospitals or TIA clinics, but are less well described in population-based cohorts. We report the incidence, clinical features of first-ever TIA, risk and timing for subsequent stroke in the community-based Framingham Study (FHS) cohort. Methods: Longitudinal follow-up (1948-2015) of all FHS participants free of stroke or TIA at age 35-94. Medical records, evaluation by a study neurologist and review of brain imaging were used to establish diagnosis of TIA and stroke. We examined the annual age- and sex-specific incidence rates of TIA. Each case was randomly assigned 5 age- and gender- matched controls, stroke- and TIA-free prior to the date of TIA. Cox models were used to examine the risk of subsequent stroke. Results: 435 participants (229 women, 71.9±11.2 years) suffered a first-ever TIA over 366,209 person-years of follow-up. The overall crude incidence was 1.19/1,000 person-years. Incidence increased with age, peaking in the 85-94 years group (4.88/1,000 person-years). Age-adjusted annual incidence was 1.04/1,000 person-years for women and 1.41 for men. The most common symptom was unilateral weakness (47.4%) followed by sensory (36.5%) disturbances. Most TIAs were referable to the anterior circulation (~69%), 13% to retinal ischemia, 18% to the vertebrobasilar distribution. Symptoms lasted < 1hour in 66% of subjects. Over 4.27±6.18 years of follow-up 149 patients (34.3%) had a stroke, occurring within the first week in 18.8%, 1 week-3 months in 16%, 3-12 months in 10%, and ~50% beyond 12 months. Compared to controls, persons with TIA had a 4-fold higher 5-year risk of stroke, adjusting for age, sex, hypertension, diabetes, atrial fibrillation, coronary artery disease and current smoking (Odds Ratio 4.45, 95% CI 3.28-6.03, p<0.001). Conclusion: TIA incidence increases with age, is higher in men, and is a strong independent predictor of subsequent stroke which occurs in >30% of TIA patients. Although the risk is high early on, ~50% of strokes occur beyond 12 months. Our findings highlight the need for both early intervention but also continued surveillance in this high-risk patient population.

Transient Ischemic Attacks—Populations and Prognosis

Antithrombotic therapy for intracranial arterial stenosis was recently evaluated in the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial. A prespecified aim of WASID was to identify patients at highest risk for stroke in the territory of the stenotic artery who would be the target group for a subsequent trial comparing intracranial stenting with medical therapy. WASID was a randomized, double-blinded, multicenter trial involving 569 patients with transient ischemic attack or ischemic stroke due to 50% to 99% stenosis of a major intracranial artery. Median time from qualifying event to randomization was 17 days, and mean follow-up was 1.8 years. Multivariable Cox proportional hazards models were used to identify factors associated with subsequent ischemic stroke in the territory of the stenotic artery. Subsequent ischemic stroke occurred in 106 patients (19.0%); 77 (73%) of these strokes were in the territory of the stenotic artery. Risk of stroke in the territory of the stenotic artery was highest with severe stenosis > or =70% (hazard ratio 2.03; 95% confidence interval 1.29 to 3.22; P=0.0025) and in patients enrolled early (< or =17 days) after the qualifying event (hazard ratio 1.69; 95% confidence interval 1.06 to 2.72; P=0.028). Women were also at increased risk, although this was of borderline significance (hazard ratio 1.59; 95% confidence interval 1.00 to 2.55; P=0.051). Location of stenosis, type of qualifying event, and prior use of antithrombotic medications were not associated with increased risk. Among patients with symptomatic intracranial stenosis, the risk of subsequent stroke in the territory of the stenotic artery is greatest with stenosis > or =70%, after recent symptoms, and in women.

Location of Cerebral Microbleeds May Predict Subsequent Stroke after Transient Ischemic Attack

Abstracts of literature

Transient ischemic attack and minor ischemic stroke are associated with early recurrence and deterioration respectively. There is a high risk of stroke after TIA ranging between 10-20% in the ensuing 90 days in the various studies. There are various clinical and imaging factors which predict the early risk of stroke after a TIA. To evaluate the short term and long term risk of ischemic stroke following early treatment of TIA and minor stroke. TIA is defined as sudden focal neurologic deficit of presumed vascular origin lasting less than 24 hours. Minor ischemic stroke is defined as National institute of Health Stroke scale score of ≤5. TIA mimics were excluded from the study. The patients were followed up till 1 year. In patients with minor ischemic stroke, a 2-point worsening in the NIHSS was considered as an event. Modified Rankin score at 3 months was assessed. Total 320 patients were analysed with a mean age of 60.6 ± 13.6 years. Out of the them 20.7% were females, 78% of patients had minor stroke. There is significant association of lacunar stroke in minor stroke patients (p&amp;#60;0.01), whereas most TIA patients, etiology remained undetermined. In multiple regression analysis, both diabetes [p&amp;#60;0.05] and significant vessel stenosis (&amp;#62;50%) [p&amp;#60;0.05] were found to be an independent predictor of recurrent stroke in TIA and minor stroke patients. Urgent treatment after TIA and minor ischemic stroke is associated with reduced risk of ischemic stroke recurrence. Both diabetes mellitus and significant vessel stenosis are independent predictor of stroke recurrence.

ImportanceThere is growing recognition that patients may respond differently to therapy and that the average treatment effect from a clinical trial may not apply equally to all candidates for a therapy.ObjectiveTo determine whether, among patients with an ischemic stroke or transient ischemic attack and insulin resistance, those at higher risk for future stroke or myocardial infarction (MI) derive more benefit from the insulin-sensitizing drug pioglitazone hydrochloride compared with patients at lower risk.Design, Setting, and ParticipantsA secondary analysis was conducted of the Insulin Resistance Intervention After Stroke trial, a double-blind, placebo-controlled trial of pioglitazone for secondary prevention. Patients were enrolled from 179 research sites in 7 countries from February 7, 2005, to January 15, 2013, and were followed up for a mean of 4.1 years through the study’s end on July 28, 2015. Eligible participants had a qualifying ischemic stroke or transient ischemic attack within 180 days of entry and insulin resistance without type 1 or type 2 diabetes. InterventionsPioglitazone or matching placebo.Main Outcomes and MeasuresA Cox proportional hazards regression model was created using baseline features to stratify patients above or below the median risk for stroke or MI within 5 years. Within each stratum, the efficacy of pioglitazone for preventing stroke or MI was calculated. Safety outcomes were death, heart failure, weight gain, and bone fracture.ResultsAmong 3876 participants (1338 women and 2538 men; mean [SD] age, 63 [11] years), the 5-year risk for stroke or MI was 6.0% in the pioglitazone group among patients at lower baseline risk compared with 7.9% in the placebo group (absolute risk difference, –1.9% [95% CI, –4.4% to 0.6%]). Among patients at higher risk, the risk was 14.7% in the pioglitazone group vs 19.6% for placebo (absolute risk difference, –4.9% [95% CI, –8.6% to 1.2%]). Hazard ratios were similar for patients below or above the median risk (0.77 vs 0.75; P = .92). Pioglitazone increased weight less among patients at higher risk but increased the risk for fracture more.Conclusions and RelevanceAfter an ischemic stroke or transient ischemic attack, patients at higher risk for stroke or MI derive a greater absolute benefit from pioglitazone compared with patients at lower risk. However, the risk for fracture is also higher.Trial Registrationclinicaltrials.gov Identifier: NCT00091949

Background and Purpose: Transient ischemic attack (TIA) and minor ischemic stroke is critical warning sign of following disabling stroke. Recently, the concept of acute cerebrovascular syndrome (ACVS) is advocated for early diagnosis and management of TIA or minor stroke. We thought to determine whether the early examination findings at admission can predict the recurrent stroke or death during 1 year after the qualifying event. Methods: Between April 2006 and July 2009, 621patients with TIA or minor ischemic stroke (defined as an National Institutes of Health Stroke Scale [NIHSS] score ≤3) were admitted to our stroke center within 7 days after the onset. Among them, 494 patients obtained outcome at 1year were analyzed. Background data including the findings of laboratory examination, brain MRI diffusion weighted image (DWI), brain MRA and carotid ultrasound were obtained within 3 days after the admission. Information about recurrent stroke and/or death from any cause within 1 year after the qualifying event was obtained from clinical record or telephone interview. Results: During 1 year after the qualifying events, further stroke were identified in 46 (9.3%) patients, 19 (3.9%) patients died, and a total of 60 (12.2%) patients had composite incident of recurrent stroke or death. Multivariate logistic regression analysis showed that age ≥ 60 years old (hazard ratio, 3.00), female sex (hazard ratio, 1.98), history of previous stroke (hazard ratio, 2.10), serum CRP level ≥ 0.2mg/dL (hazard ratio, 2.59), intracranial or carotid artery stenosis ≥ 50% (hazard ratio, 1.76) and acute infarction on DWI (hazard ratio, 3.62) were found to be independent risk factors for recurrent stroke or death. A four-point score derived from these results (acute infarction on DWI [present = 1], CRP level [≥ 0.2mg/dL = 1], vascular stenosis of intracranial or carotid artery [≥ 50% = 1], and stroke history [present = 1]: ACVS) was highly predictive of 1-year risk of recurrent stroke or death (p &lt; 0.001, Figure ). Conclusions: Risk of stroke or death during 1 year after TIA or minor stroke seemed to be highly predictable. Although further validations are needed, the ACVS score may be useful in clinical practice to identify high-risk individuals who need careful treatment and follow up.

Response

This study was designed to evaluate intra-arterial thrombolytic therapy as part of a treatment strategy for patients requiring revascularization for lower limb ischemia caused by nonembolic arterial and graft occlusion. Patients with native arterial or bypass graft occlusion were randomized prospectively to either optimal surgical procedure or intra-arterial, catheter-directed thrombolysis with recombinant tissue plasminogen activator (rt-PA) or urokinase (UK). Thrombolysis patients required successful catheter placement into the occlusion before infusion of either rt-PA at 0.05 mg/kg/hr for up to 12 hours or UK of 250,000 units bolus followed by 4000 units/min x 4 hours, then 2000 units/min for up to 36 hours. A composite clinical outcome of death, ongoing/recurrent ischemia, major amputation, and major morbidity was the primary endpoint. Additional endpoints were reduction in surgical procedure, clinical outcome classification, length of hospitalization, and outcome by duration of ischemia. Randomization was terminated at 393 patients because a significant primary endpoint occurred by the first interim analysis. Failure of catheter placement occurred in 28% of patients who were randomized to lysis, and thus, were considered treatment failures. Thirty-day outcomes demonstrated significant benefit to surgical therapy compared with thrombolysis (p < 0.001), primarily because of a reduction in ongoing/recurrent ischemia (p < 0.001). However, clinical outcome classification at 30 days was similar. Stratification by duration of ischemia indicated that patients with ischemic deterioration of 0 to 14 days had lower amputation rates with thrombolysis (p = 0.052) and shorter hospital stays (p < 0.04). Patients with ischemic deterioration of > 14 days who who were treated surgically had less ongoing/recurrent ischemia (p < 0.001) and trends toward lower morbidity (p = 0.1). At 6-month follow-up, there was improved amputation-free survival in acutely ischemic patients treated with thrombolysis (p = 0.01); however, chronically ischemic patients who were treated surgically had significantly lower major amputations rates (p = 0.01). More than half of thrombolysis patients (55.8%) had a reduction in magnitude of their surgical procedure (p < 0.001). There was no difference in efficacy or safety between rt-PA and UK; however, in the thrombolysis group as a whole, fibrinogen depletion predicted hemorrhagic complications (p < 0.01). Surgical revascularization of patients with < 6 months of ischemia is more effective and safer than catheter-directed thrombolysis. Although ongoing/recurrent ischemia is greater in the patients undergoing thrombolysis, 30-day clinical outcomes are similar, probably because of cross-over treatment to surgery. There is no difference in efficacy or safety between rt-PA and UK, although bleeding occurs in patients with greater fibrinogen depletion. A significant reduction in planned surgical procedure is observed after thrombolysis. Patients with acute ischemia (0-14 days) who were treated with thrombolysis had improved amputation-free survival and shorter hospital stays. However, for patients with chronic ischemia (> 14 days), surgical revascularization was more effective and safer than thrombolysis. Combining a treatment strategy of catheter-directed thrombolysis for acute limb ischemia with surgical revascularization for chronic limb ischemia offers the best overall results.

Cell therapy has shown beneficial effects on ventricular function and tissue regeneration in patients with acute and chronic myocardial infarction, although with diverse grades of variability in the results, possibly by proportion, subtype and cell cycle status. Objective: Identify and phenotypically characterize, via CXCR4 and SDF-1 expression, the bone marrow cell subpopulations that are mobilized into the bloodstream in patients with Acute Myocardial Infarction (AMI) and Acute Ischemia (AI) such as acute angina and Chronic Ischemia (CI) such as chronic stable angina, and also determine the cell cycle status of these cells. Method: Patients with AMI and AI were recruited in the ICCU, and patients with CI in the departments of cardiology and cardiovascular surgery. The quantification of cellular subpopulations was made by cytofluorometry with a FACS caliburcyto fluorometry (Becton Dickinson) with specific FITC-labeled anti human monoclonal antibodies against CD34, CD133, CD117, CD48, CXCR4, SDF-1 and Ki67 (Becton Dickinson). Serum concentration of IL-6 and IL-8 were determined by a sequential solid phase chemiluminescent assay performed in a SIEMENS IMMULITE 1000 Analyzer. Statistical analysis was made with the SPSS version 20.0 for Windows. A p value 3/ml) than that in AI (9.2 ± 1.3 × 103/ml) and CI (6.6 ± 1.1 × 103/ml) patients (p p = 0.22 to 0.39), but interestingly in AMI and AI patients, cells were CXCR4+ in almost half of these mobilized cells, although the proportion was significantly higher in AMI patients (46.8% ± 7.1% to 55.7% ± 6.3% vs 23% ± 1.6% to 28.4% ± 2.1%, p = 0.03 to 0.05). A similar behavior was observed with the Ki67 antibody (29.9% ± 2.1% to 36.1% ± 6.3% vs 10% ± 1.2% to 24% ± 1.1%, p = 0.001 to 0.05). Bivariate analysis of the results showed a significant correlation of the cell proportion in AMI but not in AI and CI patients (p = 0.001 to 0.05; 0.12 to 0.87 and 0.17 to 0.92 respectively). The amount of myocardial tissue infarcted did not show any correlation with the amount of cellular subpopulations mobilized to peripheral blood (r = 0.10 to 0.20; p = 0.21 to 0.64) from the bone marrow. Conclusion: The proportion of cellular subpopulations with regenerative potential mobilized to circulation during an event of Acute Myocardial Infarction is significantly higher than during an event of acute angina and chronic stable angina, with a significant proportion of mobilized cells that expressed CXCR4, most of which were already in some of the cell cycle phases.

Recent advances in management of transient ischaemic attacks and minor ischaemic strokes

Background: Patients after a transient ischemic attack (TIA) are at high risk of subsequent stroke. There are various scores that aim to accurately identify patients at the highest risk of stroke. However, without comparisons between these scores, it is still unknown which is the score with the best predictive utility. Our study aims to identify the risk stratification score with the highest utility to identify patients at high risk for stroke within 90 days after a TIA. Methods: The MEDLINE and Scopus databases were systematically searched on 1 December 2023 for observational cohort studies assessing the ability of a score to predict a stroke within the first 90 days from the index TIA event. Only studies that had a direct comparison of at least two scores were included. A random-effects network meta-analysis was performed. Sensitivity and specificity, along with relevant 95% credible intervals, and between-score and between-study heterogeneity were estimated. We also estimated relative sensitivities and relative specificities compared with the ABCD2 score. We ranked each score according to its predictive accuracy based on both sensitivity and specificity estimates, using the diagnostic odds ratio (DOR) and the summary receiver operating characteristic (SROC) curve. Results: Our systematic review highlighted 9 studies including 14 discrete cohorts. The performance of all scores to identify patients at high risk for stroke recurrence within 90 days following a TIA was low (pooled sensitivity range 48-64%, pooled specificity range 59-72%). In the network meta-analysis, we analyzed 6 studies with 11 discrete cohorts, including data from 8217 patients. The ABCD3-I score demonstrated the highest DOR, followed by the ESRS, ABCD, California, and ABCD2. The SROC curves demonstrate no significant differences in the performance of the scores, using the ABCD score as the common comparator. Conclusions: In this systematic review and network meta-analysis of observational cohort studies of patients who experienced TIA and were followed for the occurrence of subsequent stroke, we failed to identify a score performing significantly better for the prediction of stroke at 90 days. New models are needed for the prediction and stroke risk stratification following a TIA.