Risk Of Major Ischemic Events Research Articles

Dual antiplatelet therapy improves functional recovery and inhibits inflammation after cerebral ischemia/reperfusion injury

BackgroundDual antiplatelet therapy with aspirin and clopidogrel (ASA + CPG) during the first 21 days has been shown to reduce the risk of major ischemic events in patients with transient ischemic attack (TIA) or minor stroke. However, the mechanisms underlying combination treatment with ASA + CPG in experimental ischemic stroke has not been fully elucidated.MethodsMinor cerebral ischemia was induced in mice by transient distal middle cerebral artery occlusion (tdMCAO). Two doses of ASA + CPG (12 and 24 mg/kg/day) or vehicle were administered by gavage daily. Neurological behaviors were assessed using the modified Garcia scores, Rotarod test, Y maze, and open field test. Platelet function was assessed in vitro by flow cytometry and in vivo by bleeding and clotting time. The neutrophil ratio and the levels of inflammatory cytokines were measured by flow cytometry and the Meso Scale Discovery (MSD) electrochemilunimescence, respectively.ResultsSensorimotor function was partially recovered with ASA + CPG treatment after ischemia. Anxiety levels and cognitive functions showed improvement in the ASA + CPG group at 12 mg/kg/day after 21 days. Both tail bleeding time and flow cytometry showed significantly decreased platelet function after ASA + CPG treatment. Notably, ASA + CPG at 12 mg/kg/day prolonged clotting time at 28 days after injury. Furthermore, the ratio of neutrophils, an indicator of inflammation, was reduced with 12 mg/kg/day ASA + CPG treatment in the bone marrow (BM) at 21 days and in the peripheral blood (PB) at 21 and 28 days after tdMCAO. Both doses of ASA + CPG decreased pro-inflammatory cytokine interleukin (IL)-6 expression 21 days after stroke. Taken together, these results demonstrated that combination treatment with ASA + CPG improved long-term neurological function after stroke and may inhibit platelet-neutrophil interaction by decreasing the concentration of pro-inflammatory cytokine, IL-6.ConclusionsThese findings indicate a neuroprotective effect of combination treatment with ASA + CPG for a duration of 21 days in an experimental acute minor stroke model. These findings provide further evidence that dual antiplatelet therapy may be a viable neuroprotective treatment to decrease the recurrence of stroke.

Higher neutrophil-to-lymphocyte ratio (NLR) increases the risk of suboptimal platelet inhibition and major cardiovascular ischemic events among ACS patients receiving dual antiplatelet therapy with ticagrelor

BackgroundNeutrophil to lymphocyte ratio (NLR) has emerged as a useful and easy-to-assess prognostic tool and biomarker of cardiovascular risk. However, few studies have evaluated its role on platelet inhibition among patients on dual antiplatelet therapy (DAPT), and especially in the settings of acute coronary syndromes (ACS). We aimed at assessing the impact of NLR on platelet reactivity and the risk of major ischemic events at long-term follow-up among ACS patients on DAPT with ticagrelor. MethodsPatients on dual antiplatelet therapy with ASA + ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30–90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition (HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome, target vessel revascularization) at longest available follow-up. ResultsWe included 397 patients, that were divided according to NLR tertiles. Patients with higher NLR were older (p < .001), less frequently smokers (p = .03), with higher rates of renal failure (p = .001), previous bypass surgery (p = .05) and use of statins (p = .03) and diuretics (p = .01). Higher white blood cells count and C-reactive protein (p < .001) and lower haemoglobin (p = .001) were associated with NLR. Mean platelet reactivity and the prevalence of high platelet reactivity (HRPR) on ticagrelor were significantly associated to higher NLR tertiles values (7% vs 12% vs 14.3%, p = .04), with a significant relationship between NLR and platelet reactivity being confirmed for all the different activating stimuli.At a mean follow-up of 939 ± 581.4 days, 21.2% of the patients experienced the primary composite endpoint, with a trend for a higher risk of events across NLR tertiles (15.4% vs 24.2% vs 24.4%, p = .09), that became statistically significant after correction for baseline confounders (adjusted HR[95%CI] = 1.13[1.008–1.26], p = .036). Moreover, NLR was significantly associated to overall mortality and recurrent ACS (adjusted p = .008, p = .06 and p = .02 respectively). ConclusionsIn the present study we found that among ACS patients treated with ASA and ticagrelor after PCI, suboptimal platelet inhibition despite DAPT was significantly increased for higher values of Neutrophil-to-Lymphocyte Ratio. Moreover, mortality and the risk of recurrent major ischemic events at long-term were associated to NLR.

P651Prevalence of hypertriglyceridemia in statin treated high risk patients who might benefit from treatment with icosapent ethyl for secondary prevention in clinical practice - Results of DYSIS

Abstract Background Patients with elevated triglyceride (TG) levels are at increased risk for ischemic events. In the recently published REDUCE-IT-Study among patients with elevated triglyceride levels who were receiving statin therapy, the risk of major ischemic events, including cardiovascular death, was significantly lower with 2 g of icosapent ethyl twice daily than with placebo. Little is known about how many patients in clinical practice might benefit from this additional treatment. Methods The cross sectional, observational Dyslipidemia International Study (DYSIS) examined lipid goal attainment among statin-treated very high cardiovascular risk patients (defined as per 2011 EAS/ESC guidelines, including patients suffering from coronary heart disease, diabetes, chronic kidney disease or peripheral atherosclerotic disease) in Canada, Europe, Middle East countries and China. Data were collected under real life conditions in physicians' offices and hospital outpatient wards between 2008–2012. We examined the prevalence of mixed dyslipidemia with TG &gt;135 mg/dl in high statin treated high risk patients in clinical practice. Results Of a total of 44,593 patients on very high cardiovascular risk, all on chronic statin treatment, 21,312 (47.8%) had mixed dyslipidemia with TG values &gt;135mg/dl. Patients with elevated TG also had higher levels of total and LDL-cholesterol. The overall use of additional fibrates on top of statins was low (4.0%), but more frequent in patients with TG &gt;135 mg/dl. CVD patients with TG&gt;135 mg/dl Pts with TG &gt;135 mg/dl Pts with TG ≤135 mg/dl p-value OR (95% CI) n=21,312 (47.8%) n=23,281 (52.2%) Age (years) 65.4±10.1, 68.1±10.2 &lt;0.0001 Females 42.2% 38.6% &lt;0.0001 1.16 (1.12–1.21) Sedentary lifestyle 43.0% 37.6% &lt;0.0001 1.25 (1.20–1.30) Risk factors/CV-disease Hypertension 79.0% 74.9% &lt;0.0001 1.26 (1.21–1.32) Diabetes mellitus 56.3% 45.3% &lt;0.0001 1.55 (1.50–1.61) Ischemic heart disease 50.6% 54.4% &lt;0.0001 0.86 (0.83–0.89) Cerebrovascular disease 16.1% 17.7% &lt;0.0001 0.90 (0.85–0.94) Peripheral artery disease 8.1% 6.9% &lt;0.0001 1.18 (1.10–1.27) Lipid lowering therapy Rosuvastatin 11.3% 11.8% 0.13 0.95 (0.90–1.01) Atorvastatin 38.2% 40.9% &lt;0.0001 0.89 (0.86–0.93) Simvastatin 41.9% 38.9% &lt;0.0001 1.13 (1.09–1.18) Other statins 8.6% 8.4% 0.12 0.96 (0.88–1.05) Fibrates 5.5% 1.5% &lt;0.0001 3.86 (3.40–4.37) Lipid Profile Total Cholesterol (mg/dl) 185.6 159.0 &lt;0.0001 LDL-Cholesterol (mg/dl) 102.1 88.9 &lt;0.0001 Triglyderides (mg/dl) 189.5 95.7 &lt;0.0001 Conclusion Almost half of consecutive patients with cardiovascular disease treated with statins for secondary prevention in clinical practice suffer from TG levels &gt;135 mg/dl and might benefit from additional treatment with icosapent ethyl with further reduction in subsequent major ischemic events, including cardiovascular death. Acknowledgement/Funding MSD

Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic Attack

Dual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about the optimal duration of dual antiplatelet therapy for minor stroke or TIA. To obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA. This analysis pooled individual patient-level data from 2 large-scale randomized clinical trials that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor stroke or high-risk TIA. The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial enrolled patients at 114 sites in China from October 1, 2009, to July 30, 2012. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial enrolled patients at 269 international sites from May 28, 2010, to December 19, 2017. Both were followed up for 90 days. Data analysis occurred from November 2018 to May 2019. In the 2 trials, patients with minor stroke or high-risk TIA were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset. The primary efficacy outcome was a major ischemic event (ischemic stroke, myocardial infarction, or death from ischemic vascular causes). The primary safety outcome was major hemorrhage. The study enrolled 5170 patients (CHANCE) and 4881 patients (POINT). Analysis included individual data from 10 051 patients (5016 in the clopidogrel-aspirin treatment group and 5035 in the control group) with a median age of 63.2 (interquartile range, 55.0-72.9) years; 6106 patients (60.8%) were male. Clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (328 of 5016 [6.5%] vs 458 of 5035 [9.1%]; hazard ratio [HR], 0.70 [95% CI, 0.61-0.81]; P < .001), mainly within the first 21 days (263 of 5016 [5.2%] vs 391 of 5035 [7.8%]; HR, 0.66 [95% CI, 0.56-0.77]; P < .001), but not from day 22 to day 90. No evidence of heterogeneity of treatment outcome across trials or prespecified subgroups was observed. Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was nonsignificant. In this analysis of the POINT and CHANCE trials, the benefit of dual antiplatelet therapy appeared to be confined to the first 21 days after minor ischemic stroke or high-risk TIA.

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA

BackgroundCombination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population.MethodsIn a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days.ResultsA total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02).ConclusionsIn patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029.)

Positive trials in ischaemic stroke reported at ESOC 2018.

BACKGROUND: Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS: In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS: A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS: In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Nonalcoholic Fatty Liver Disease and Severity of Cardiovascular Disease Manifestations

Nonalcoholic fatty liver disease (NAFLD), characterized by the accumulation of fat in the liver cells in the absence of excessive alcohol intake and other liver disease, affects approximately 15% to 30% of the general population in various countries; its prevalence increases up to 70% to 90% in people with obesity, metabolic syndrome (MetS), or type 2 diabetes mellitus (T2DM). The histological manifestations of NAFLD range from simple steatosis, steatohepatitis (nonalcoholic steatohepatitis [NASH]), liver fibrosis, cirrhosis, and, rarely, hepatocellular carcinoma. The NAFLD is considered to be the hepatic manifestation of the MetS. The NAFLD is strongly associated with increased risk of cardiovascular disease (CVD), and NAFLD is not only a marker but also an early mediator of atherosclerosis. The risk of clinical manifestations of CVD is significantly higher in individuals with NASH than in those with simple steatosis, and the histological severity of NAFLD (ie, steatosis, necroinflammation, and fibrosis) predicts CVD independent of classical risk factors, insulin resistance, and components of the MetS. This suggests that NAFLD might itself confer a degree of CVD risk above and beyond that associated with the individual components of MetS. Key issues remaining to be investigated are the association of NAFLD presence and/or grade (stage) with the severity, and therefore, the prognosis of CVD manifestations (coronary artery disease [CAD], stroke, and peripheral arterial disease [PAD]) and our ability to tackle the negative effect of NAFLD on CVD morbidity and mortality. The results of the study by Agac et al, published in this issue of Angiology, suggest that the prevalence of NAFLD was very high (81.2%) among subjects with acute coronary syndromes (ACS) and that the SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score (SS) may represent a prognostic marker in patients with both non-ST and ST segment elevation ACS. The SS is an angiographic variable that predicts 1-year mortality rates, cardiac death, myocardial infarction, and target vessel revascularization in patients undergoing percutaneous coronary intervention (PCI) and its value is significantly higher in patients with NAFLD than in those without NAFLD (18 + 8 vs 11+ 5, P 1⁄4 .001). Furthermore, in multivariate analysis, increased age (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.00-1.10) and the presence of NAFLD (OR, 13.20; 95% CI, 2.52-69.15) were independent factors associated with the SS value. This suggests that the presence of NAFLD was associated with a more severe CAD, which is bound to have a worse prognosis. Among the limitations of this study are the cross-sectional design and therefore its inability to confirm findings on the rate of CVD events. Moreover, the use of the SS has been mainly validated in the Acute Catheterization and Urgent Intervention Triage StrategY trial only in patients with a non-ST-segment elevation ACS undergoing PCI, and its use in patients with ST elevation ACS might be challenged. Initially, the SS was shown to be an effective tool for predicting the risk of major ischemic events in patients with stable CAD and multivessel or left main disease undergoing PCI, and there are data suggesting a moderate intraobserver reproducibility (its calculation relies on the subjective assessment of lesions using coronary angiography). Nevertheless, the findings of this study are adequate to act as hypothesis generating and should encourage the design of bigger and long-term studies that will prospectively investigate the relationship between the presence and the histological stage of NAFLD with actual midor long-term prognosis of CVD. Moreover, these results might motivate the initiation of interventions to control and, if possible, to reverse the progress of NAFLD from steatosis to a more advanced stage, given that at present time, there is no globally accepted effective intervention for NAFLD. There are some data suggesting a close relationship of NAFLD with the severity of CAD. To begin with, there are very few data on NAFLD and ACS. The most common cause of ACS appears to be vulnerable plaque rupture. These are related to a positive remodeling of the vessel, a large lipid

Clinical update on the therapeutic use of clopidogrel: treatment of acute ST-segment elevation myocardial infarction (STEMI)

The pathogenesis of ST-elevation myocardial infarction (STEMI) involves plaque disruption, platelet aggregation and intracoronary artery thrombus formation. Aspirin is the cornerstone of antiplatelet therapy in patients with STEMI, reducing the risk of recurrent myocardial infarction or death during the acute phase and long term by about one-quarter. Recent large randomized trials have demonstrated that the addition of clopidogrel to aspirin reduces the risk of major ischemic events by up to a further one-third in patients with STEMI treated with fibrinolytic therapy and undergoing percutaneous coronary intervention, with no significant increase in bleeding. Thus, dual antiplatelet therapy with the combination of clopidogrel and aspirin is becoming the new standard of care for the management of patients with STEMI.

Antithrombotic therapy in acute coronary syndromes: Key notes from ESSENCE and TIMI 11B

Platelet activation and thrombus formation are key events in the pathogenesis of acute coronary syndromes (unstable angina and non-Q-wave myocardial infarction). Therefore, current management of these conditions consists of antithrombotic and antiplatelet therapy, principally heparin and oral aspirin. However, such treatment is unsuccessful in a significant proportion of patients. Two recent large studies with the low-molecular-weight heparin (LMWH) enoxaparin have shown that this agent significantly reduces the risk of major ischemic events compared with unfractionated heparin. In the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) study, treatment with enoxaparin for 2 to 8 days reduced the risk of death, myocardial infarction, or recurrent angina by 20% at 14 days compared with treatment with unfractionated heparin. In the Thrombolysis in Myocardial Infarction (TIMI) 11B study, enoxaparin was associated with a significant reduction in the risk of death, myocardial infarction, or urgent revascularization compared with unfractionated heparin, which became apparent within 48 hours; this benefit was maintained during outpatient treatment for 5 weeks. A meta-analysis of these two studies showed that the risk of death or myocardial infarction was consistently approximately 20% lower in enoxaparin-treated patients than in heparin-treated patients. In contrast, studies with other LMWHs have not shown consistent superiority over unfractionated heparin. This may reflect the pharmacologic heterogeneity of LMWH and/or differences in trial design.

Reduction of ischemic events with angiotensin-converting enzyme inhibitors: lessons and controversy emerging from recent clinical trials.

Angiotensin-converting enzyme (ACE) inhibitor therapy has been associated with a substantial (> or = 20%) reduction in the risk of major ischemic events in two recent clinical trials with long-term follow-up: Studies of Left Ventricular Dysfunction (SOLVD) and the Survival and Ventricular Enlargement (SAVE) study. Participants in these studies included patients with a low ejection fraction (< or = 0.35 in SOLVD and < or = 0.40 in SAVE), generally without symptoms of congestive heart failure. Approximately 80% of patients enrolled in SOLVD and all participants in SAVE had histories of ischemic heart disease or acute myocardial infarction (SAVE). In both SOLVD and SAVE the risk of experiencing a major ischemic event such as myocardial infarction was reduced significantly following prolonged ACE inhibitor therapy. In the SOLVD trial, this effect was evident across a range of patient subgroups, including varying concomitant drug therapies. In both studies, several months elapsed before this benefit became apparent, suggesting an effect on underlying ischemic pathophysiology. A third trial of ACE inhibitor therapy postinfarction, the Acute Infarction Ramipril Efficacy (AIRE) Study, demonstrated a 27% reduction in all cause mortality but no effect on myocardial infarction after a 15-month mean follow-up. No effect of ACE inhibition on risk of survival or reinfarction was reported in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS-II), which began the drug within 24 hours of infarction and terminated follow-up at 6 months, a time not likely to demonstrate infarction reduction benefit based on the SOLVD and SAVE observations. Neither AIRE nor CONSENSUS-II had objectively determined left ventricular dysfunction as an entry criterion, as did SOLVD and SAVE, but AIRE mandated "clinical" congestive heart failure prior to randomization. More recently, preliminary results from the third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3), the Fourth International Study of Infarct Survival (ISIS-4), and the Chinese Captopril Trial suggested that angiotensin-converting enzyme (ACE) inhibitor mortality benefits post-myocardial infarction would be detected in these megatrials as early as 35 days after the event.(ABSTRACT TRUNCATED AT 400 WORDS)