Risk Of Ischemic Vascular Events Research Articles

Colchicine pre-treatment and post-treatment does not worsen bleeding or functional outcome after collagenase-induced intracerebral hemorrhage.

Patients with intracerebral hemorrhage (ICH) are at increased risk for major ischemic cardiovascular and cerebrovascular events. However, the use of preventative antithrombotic therapy can increase the risk of ICH recurrence and worsen ICH-related outcomes. Colchicine, an anti-inflammatory agent, has the potential to mitigate inflammation-related atherothrombosis and reduce the risk of ischemic vascular events. Here we investigated the safety and efficacy of colchicine when used both before and acutely after ICH. We predicted that daily colchicine administration would not impact our safety measures but would reduce brain injury and improve functional outcomes associated with inflammation reduction. To test this, 0.05 mg/kg colchicine was given orally once daily to rats either before or after they were given a collagenase-induced striatal ICH. We assessed neurological impairments, intra-parenchymal bleeding, Perls positive cells, and brain injury to gauge the therapeutic impact of colchicine on brain injury. Colchicine did not significantly affect bleeding (average = 40.7 μL) at 48 hrs, lesion volume (average = 24.5 mm3) at 14 days, or functional outcome (median neurological deficit scale score at 2 days post-ICH = 4, i.e., modest deficits) from 1-14 days after ICH. Colchicine reduced the volume of Perls positive cells in the perihematomal zone, indicating a reduction in inflammation. Safety measures (body weight, food consumption, water consumption, hydration, body temperature, activity, and pain) were not affected by colchicine. Although colchicine did not confer neuroprotection or functional benefit, it was able to reduce perihematomal inflammation after ICH without increasing bleeding. Thus, our findings suggest that colchicine treatment is safe, unlikely to worsen bleeding, and is unlikely but may reduce secondary injury after an ICH if initiated early post ICH to reduce the risk of ischemic vascular events. These results are informative for the ongoing CoVasc-ICH phase II randomized trial (NCT05159219).

Low-dose antiplatelet therapy survey after intracerebral hemorrhage in China: a retrospective hospital-based study.

Restarting of antiplatelet therapy (AT) for patients with a history of intracerebral hemorrhage (ICH) is still a clinical dilemma in China. We aimed to investigate the association between low-dose AT and the long-term clinical outcome in Chinese ICH patients. A total of 312 patients with a history of ICH were retrospectively enrolled and followed. The ischemic vascular events, recurrent ICH, and all-cause death were reviewed retrospectively. We explored the predictors of ischemic vascular events and recurrent ICH from all patients using Cox proportional hazard regression model. One hundred fifty-one (48.4%) patients were treated with low-dose AT, and the median duration of follow-up was 4.0 years (interquartile range, 2.5-5 years). Compared to 30 (19.8%) of 151 participants who restarted low-dose AT had ischemic vascular events, 51 (31.7%) of 161 participants who did not receive AT showed ischemic vascular events (p=0.025). Eighteen (11.9%) of 151 participants treated with low-dose AT had recurrent ICH and 21 (13.0%) of 161 in non-AT participants (p=0.830). Cox regression analysis also showed that diabetes mellitus was an independent risk factor for ischemic vascular events (p=0.029). Uncontrolled blood pressure (BP) was independently associated with the risk for both ischemic vascular events (p=0.025) and recurrent ICH (p=0.001). Atrial fibrillation (AF) was an independent risk factor for recurrent ICH among patients with a history of ICH (p=0.018). In a Chinese population of patients with predominantly deep, mild to moderate severity ICH, restarting of low-dose AT at a median of 6.2 months was associated with a lower risk of ischemic vascular events without increased risk of recurrent ICH.

Abstract 528: Correlation Between Expression Level of Platelet Endothelial Aggregation Receptor 1 and On-aspirin Platelet Aggregation

Background: Aspirin is a basilar support in coronary heart disease secondary prevention, patients with high platelet aggregation during aspirin therapy after percutaneous coronary intervention(PCI) may lead to increased risk of ischemic vascular events. Platelet endothelial aggregation receptor 1(PEAR1) is a platelet transmembrane protein which reported play an important role in platelet aggregation. The aim of the study is to analyze the correlation between PEAR1 expression level and on-aspirin platelet aggregation. Methods: Consecutive patients with acute myocardial infarction after PCI under dual antiplatelet with aspirin and clopidogrel were enrolled in the cohort. Blood samples were obtained 3 days after PCI by peripheral venipuncture. On-aspirin platelet aggregation was assessed by VerifyNow Aspirin Assay, results were recorded as aspirin reaction unit(ARU). Expression of PEAR1 on platelet membrane was determined by washed platelet incubated with mouse anti-human PEAR1 phycoerythrin(PE)-conjugated monoclonal antibody for 20 minutes and analyzed by flow cytometry, results were recorded as mean fluorescence intensity(MFI). Results: A total of 131 patients were enrolled in the study, the average age was 59.88±10.84 years, the average ARU was 443.21±65.99, the median MFI was 137.00(interquartile range 105.00 to 226.00). Patients with high platelet aggregation(ARU>550) showed higher expression of PEAR1 on the surface of platelet than those with low platelet aggregation(ARU<400), although did not achieve a significant difference [129.00(interquartile range 116.75 to 215.75) vs 116.00(interquartile range 86.05 to 197.50), P=0.11]. The expression level of PEAR1 showed a poorly positive correlation with platelet aggregation(Spearman r s =0.21, p=0.02). Conclusion: The study showed that elevated expression of PEAR1 was weakly related to increased on-aspirin platelet aggregation after PCI.

A retrospective analysis of triptan and dhe use for basilar and hemiplegic migraine.

Patients with basilar migraine (BM) and hemiplegic migraine (HM) have been excluded from triptan and DHE clinical trials due to a potential risk of ischemic vascular events, and the FDA mandates that package labeling state that they are contraindicated in BM and HM. The objective of this study was to demonstrate that triptans and DHE can be used for the abortive treatment of BM and HM without significant adverse ischemic vascular events. A retrospective chart review of patients with BM features or HM who received acute abortive treatment with either triptans or DHE was conducted at 4 headache centers to assess the frequency of ischemic vascular events after administration. The diagnoses of BM or HM were made by headache specialists based on The International Classification of Headache Disorders, 2nd edition (ICHD-II). Searchable terms included BM, vertigo, dysarthria, diplopia, hemiplegia/hemiparesis, facial droop, weakness, confusion, altered consciousness, confusion, ataxia, and aphasia, as well as all triptans or DHE. The study included 67 patients with BM features and 13 patients with HM. Among those receiving triptans, 40 were in the BM group and 5 were in the HM group. Among those receiving DHE, 27 were included in the BM group and 8 were in the HM group. No side effects of stroke or myocardial infarction were reported. In the triptan group, 5 patients reported adverse effects that included GI upset, rash, neck dystonia, nightmares, and flushing. In the DHE group, 5 patients had adverse events that included chest tightness, dystonic reaction, transient asymptomatic anterior T wave inversion, and agitation. In this retrospective study, triptans and DHE were used with no reported, subsequent acute/subacute ischemic vascular events for the abortive treatment of migraines with basilar and hemiplegic-type features. Although the small sample sizes generated theoretical statistical event rates of 4.5% for BM and 23% for HM, there has been no clear evidence that BM and HM carry an actual elevated risk for vascular events compared with migraine with aura.

Spotlight on the February 3 Issue

#### Notable in Neurology This issue features articles on risk factors for all-cause death after diagnosis of unruptured intracranial aneurysms and on lipid and lipoprotein measurements and the risk of ischemic vascular events. Other featured articles focus on whether the diagnosis of dementia with Lewy bodies is affected by β-amyloid load, predicting progression in mild cognitive impairment with suspected nonamyloid pathology, and dopamine transmission in patients with comorbid REM sleep behavior disorder and major depressive disorder. ### Arterial stiffness and progression of structural brain changes: The SMART-MR study Distension measurements of the common carotid arteries and a brain MRI were performed in 526 patients, followed by a …

Lipid and lipoprotein measurements and the risk of ischemic vascular events: Framingham Study.

To examine the relationship between plasma lipid measurements and incident ischemic vascular events (ischemic stroke [IS], and as a positive control, myocardial infarction [MI]) in a community cohort. In 6,276 stroke-free Framingham participants (aged 64 ± 10 years, 56% female), we related plasma lipid levels (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and TC/HDL-C ratio) measured at the original cohort 15th (1977-1979) and 20th examination cycles (1986-1990) and (TC, HDL-C, TC/HDL-C ratio, triglycerides [TG], and low-density lipoprotein cholesterol [LDL-C]) measured at the offspring fourth examination (1995-1998), to 10-year risk of incident IS and MI. Utilizing genome-wide genotyping in the same subjects, we used mendelian randomization methods to assess whether observed associations were incidental or causal. During a mean follow-up of 9 years, 301 participants experienced incident IS. In multivariable-adjusted analyses, HDL-C ≤40 mg/dL and TC/HDL ratio ≥5 were associated with increased risk of IS (hazard ratio [95% confidence interval]: 1.59 [1.23-2.05], p < 0.001 and 1.47 [1.15-1.87], p < 0.001), but not TC or LDL-C. In adjusted analysis, a strong association between TG and IS was diminished. In the MI-free sample (n = 5,875, aged 64 ± 10 years, 58% female; 403 MI events), all lipid markers were associated with MI risk. A genetic risk score comprising 47 known determinants of circulating HDL-C was not associated with IS. In a middle-aged to elderly community sample, we observed that low HDL-C and high TC/HDL-C ratio, but not LDL-C or TG were associated with risk of incident IS. We observed the usual associations between lipids and risk of MI. Our findings suggest an important, but less likely causal, role of HDL-C over other lipid biomarkers for optimal stroke risk stratification.

Triglycerides and risk of hemorrhagic stroke vs. ischemic vascular events: The Three-City Study

BackgroundFew studies have assessed the relationship between triglycerides and the risk of hemorrhagic stroke, which contrasts the considerable number of studies about triglycerides and ischemic vascular events. We analyzed the association pattern between triglycerides and incident intracerebral hemorrhage as compared with coronary events and ischemic stroke, in a large cohort of elderly. MethodsPopulation-based, prospective cohort study among 8393 men and women participating in the Three-City Study, aged ≥65 years at baseline. Fasting blood lipids, including triglycerides, were measured at baseline. Fatal and non-fatal strokes and coronary events were adjudicated and validated by scientific committees. Cox proportional hazards models were used to adjust for potential confounders. ResultsDuring a mean follow-up of 5.0 years, 36 hemorrhagic strokes, 143 ischemic strokes, and 393 coronary events occurred. An increased level of triglycerides was associated with an increased risk of ischemic vascular events. Conversely, a low level of triglycerides (≤0.94mmol/L) was associated with an increased risk of hemorrhagic stroke (adjusted hazard ratio 2.35; 95% confidence interval 1.18–4.70). The relationship with hemorrhagic stroke was mainly apparent in men, in individuals with high blood pressure, and in those with low levels of cholesterol. ConclusionsIn this large cohort of elderly men and women, low triglycerides levels were associated with an increased risk of hemorrhagic stroke and a decreased risk of ischemic vascular events. The association between triglycerides and hemorrhagic stroke was particularly strong in men, in subjects with high blood pressure and in those with low cholesterol levels.

Tissue factor gene polymorphisms and haplotypes and the risk of ischemic vascular events: four studies and a meta-analysis.

The exposure of tissue factor (TF) to blood flow is the initial step in the coagulation process and plays an important role in thrombogenesis. We investigated the role of genetic polymorphisms and haplotypes of the TF gene in the risk of ischemic vascular disease. Four hundred and twenty-two Italian patients with juvenile myocardial infarction (MI) and 434 controls, 808 US cases with MI and 1005 controls, 267 Italian cases with juvenile ischemic stroke and 209 controls and 148 German cases with juvenile ischemic stroke and 191 controls were studied. rs1361600, rs3917629 (rs3354 in the US population), rs1324214 and rs3917639 Tag single nucleotide polymorphisms were genotyped. Additionally, a meta-analysis of all previous studies on TF loci and the risk of ischemic coronary disease (ICD) was performed. After multivariable analysis none of the SNPs, major SNP haplotypes or haplotype-pairs showed any consistent association with MI. Pooled meta-analysis of six studies also suggested that TF polymorphisms are not associated with CHD. A significant, independent association between SNP rs1324214 (C/T) and juvenile stroke was found in Italian and German populations (OR for TT homozygotes = 0.47, 95% CI 0.24-0.92, in combined analysis). Pooled analysis also showed a significant association for haplotype H3 (OR = 0.76, 95% CI 0.57-1.00) and haplotype-pair H3-H3 (OR = 0.43, 95% CI 0.20-0.92). TF genetic variations were associated with the risk of ischemic stroke at young age, but did not affect ischemic coronary disease.

Comparison of Different Methods to Evaluate the Effect of Aspirin on Platelet Function in High-Risk Patients With Ischemic Heart Disease Receiving Dual Antiplatelet Treatment

Patients with coronary artery disease (CAD) receiving aspirin therapy with a residual platelet reactivity (RPR) may be at increased risk of ischemic vascular events. Point-of-care (POC) methods PFA-100 (Dade-Behring, Marburg, Germany) and VerifyNow (Accumetrics, San Diego, CA) assays have been suggested as rapid tools to evaluate RPR. We compared PFA-100 closure times by collagen/epinephrine and VerifyNow Aspirin assays with light transmission aggregation (LTA) induced by 1 mmol/L of arachidonic acid in 484 patients with CAD undergoing percutaneous coronary intervention and receiving dual antiplatelet therapy. RPR was detected in 30.0% of patients by LTA, in 32.4% by PFA-100, and in 14.3% by VerifyNow. Significant correlations were found among 3 methods (all P < .0001). In relation to the presence or absence of RPR by LTA and PFA-100, by LTA and VerifyNow, and by PFA-100 and VerifyNow, samples were significantly concordant (all P < .0001). Assuming LTA as the reference method, PFA-100 and VerifyNow showed sensitivity of 62.1% and 39.3% and specificity of 80.2% and 96.4%, respectively. The cutoff values for POC methods need to be defined for clinical use.

Screening for Aspirin Responsiveness After Transient Ischemic Attack and Stroke

Recent studies suggest that patients who do not respond to aspirin (ASA) therapy may be at increased risk of ischemic vascular events. The availability of simple to use point-of-care (POC) platelet function tests now potentially allows aspirin nonresponsiveness to be identified in routine clinical practice. However, there are very few data on whether the different tests produce consistent results. We therefore compared 2 POC tests (PFA-100 device and the Ultegra-RPFA [RPFA]) with conventional light transmission aggregometry (LTA). Platelet function was assessed by all 3 tests in 100 patients receiving low-dose ASA therapy after transient ischemic attack (TIA) or ischemic stroke. The incidence of ASA nonresponsiveness was 17% by the RPFA and 22% by the PFA-100, compared with only 5% by LTA (ie, as defined with both arachidonic acid and ADP). Agreement between the RPFA and the PFA-100 and arachidonic acid induced LTA was poor (kappa=0.16, 95% CI, -0.08 to 0.39, P=0.11; and kappa=0.09 -0.12 to 0.30, P=0.32, respectively). Agreement between the 2 POC tests was also poor (kappa=0.14, -0.08 to 0.36, P=0.15). Only 2% of patients were aspirin nonresponders by all 3 tests. The prevalence of apparent ASA nonresponsiveness was higher with both the POC tests than with LTA. However, agreement between the tests was poor and very few patients were ASA nonresponsive by all 3 tests. Aspirin nonresponsiveness is therefore highly test-specific and large prospective studies will be required to determine the prognostic value of each of the separate tests.

The platelet in diabetes: focus on prevention of ischemic events.

Accelerated atherosclerosis and the increased risk of thrombotic vascular events in diabetes may result from dyslipidemia, endothelial dysfunction, platelet hyperreactivity, an impaired fibrinolytic balance, and abnormal blood flow. There is also a correlation between hyperglycemia and cardiovascular (CV) events. The importance of platelets in the atherothrombotic process has led to investigation of using antiplatelet agents to reduce CV risk. A meta-analysis conducted by the Antiplatelet Trialists' Collaboration demonstrated that aspirin reduced the risk of ischemic vascular events as a secondary prevention strategy in numerous high-risk groups, including patients with diabetes. Based on results from placebo-controlled randomized trials, the American Diabetes Association recommends low-dose enteric-coated aspirin as a primary prevention strategy for people with diabetes at high risk for CV events. Clopidogrel is recommended if aspirin allergy is present. There is occasionally a need for an alternative to aspirin or for additive antiplatelet therapy. Aspirin in low doses inhibits thromboxane production by platelets but has little to no effect on other sites of platelet reactivity. Agents such as ticlopidine and clopidogrel inhibit ADP-induced platelet activation, whereas the platelet glycoprotein (Gp) IIb/IIIa complex receptor antagonists block activity at the fibrinogen binding site on the platelet. These agents appear to be useful in acute coronary syndromes (ACSs) in diabetic and nondiabetic patients. A combination of clopidogrel plus aspirin was more effective than placebo plus standard therapy (including aspirin) in reducing a composite CV outcome in patients with unstable angina and non-ST segment elevation myocardial infarction. In a meta-analysis of six trials in diabetic patients with ACSs, intravenous GpIIb-IIIa inhibitors reduced 30-day mortality when compared with control subjects. Results from controlled prospective clinical trials justify the use of enteric-coated low-dose aspirin (81-325 mg) as a primary or secondary prevention strategy in adult diabetic individuals (aged >30 years) at high risk for CV events. Recent studies support the use of clopidogrel in addition to standard therapy, as well as the use of GpIIb-IIIa inhibitors in ACS patients.

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Aspirin resistance and genetic polymorphisms.

Differences in genetic makeup or polymorphisms can affect individual drug response. Detecting genetic variation may help predict how a patient will respond to a drug and could be used as a tool to select optimal therapy, tailor dosage regimens, and improve clinical outcomes. The data are replete relative to the therapeutic efficacy of aspirin (ASA) for the prevention of ischemic events. However, there is a paucity of published data on the relationship between polymorphisms and the clinical effects on ASA. Prothrombotic genetic variations that may contribute to ASA resistance, and increased risk of cardiovascular events may involve: (1) a polymorphism on the cyclooxygenase-1 (COX-1) gene affecting Ser529; (2) overexpression of COX-2 mRNA on platelets and endothelial cells; (3) polymorphism PLA1/A2 of the gene encoding glycoprotein IIIa (GPIIIa); and (4) the homozygous 807T (873A) polymorphism allied with increased density of platelet GP Ia/IIa collagen-receptor gene. Because of the possible increased risk of ischemic vascular events, carriers of these genetic polymorphisms may be resistant to the antithrombotic effects of ASA and should be considered for additional or alternative treatment.