High Risk Of Atherothrombosis Research Articles

Experience with Prasugrel in the Treatment of Patients with Acute Coronary Syndrome

Dual antiplatelet therapy (DAPT) with aspirin and one of inhibitors of P2Y12receptors (clopidogrel, ticagrelor, prasugrel) is an international standard of receptors (clopidogrel, ticagrelor, prasugrel) is an international standard of is an international standard of treatment strategy in patients with acute coronary syndrome (ACS). to analyze experience of prasugrel use in the National Medical Cardiology Research Center in comparison to similar groups of patients treated with other P2Y12inhibitors for determination of optimal place of DAPT with prasugrel in ACS patients.Materials and methods.We included in this retrospective study 40 patients who received therapy with prasugrel, ticagrelor, or clopidogrel in connection with urgent percutaneous coronary intervention (PCI) performed in the Department of Urgent Cardiology from May to December 2018. We analyzed specific characteristics of prasugrel treated patients including disease history, features of clinical presentation and coronary anatomy, use of strategies of escalation and de-escalation, as well as inhospital mortality, development of complications and side effects.Results.New P2Y12inhibitors were more effective in patients with higher risk of atherothrombosis compared with risk of bleeding. Median of implanted stents in ticagrelor and clopidogrel groups was equal to 1, in the prasugrel group - 2 stents per PCI. When multivascular stenting was performed the choice usually was made in favor of prasugrel or ticagrelor, excluding cases with presence of limiting factors - use of oral anticoagulants (OAC) (n=4) and prehospital thrombolytic therapy (n=5). Of note was close to statistical significance high number of side effects related to ticagrelor use (n=3, 23.08%, p=0.057). There were no significant differences between groups in rates of unfavorable outcomes and complications.Conclusion.Administration of prasugrel can be considered in patients with high risk of atherothrombosis: with diabetes, with large number of implantable stents. The choice between ticagrelor and prasugrel can be made with consideration of the potential for side effects that significantly impair the quality of life of patients. Main limitations for application of both prasugrel and ticagrelor are the need to permanent use of OAC, prehospital thrombolytic therapy, and higher cost compared to clopidogrel.

Dual Antiplatelet Therapy Cessation and Adverse Events After Drug-Eluting Stent Implantation in Patients at High Risk for Atherothrombosis (from the PARIS Registry)

The impact of dual antiplatelet therapy (DAPT) cessation after percutaneous coronary intervention with drug eluting stent implantation in patients at high atherothrombotic risk remains unclear. We aimed to characterize the risk for adverse events, and its relation with the mode of DAPT cessation in patients at high atherothrombotic risk (HATR). Considering patients treated with drug-eluting stents among those enrolled in the Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients registry, we defined subjects with prior myocardial infarction (MI), prior stroke or peripheral vascular disease at HATR, while patients without any of these conditions were classified as atherothrombotic risk (LATR). DAPT cessation-modes were defined as physician-recommended discontinuation, temporary interruption, and disruption due to bleeding or poor compliance. Compared to patients with LATR (n = 2867; 68.2%), patients with HATR (n = 1340; 31.8%) were older with a higher prevalence of cardiovascular risk factors. Over 2 years, HATR patients had lower rates of physician-recommended discontinuation (32.5% vs 39.4%; p = 0.002) and trend for disruption (11.5% vs 13.7%, p = 0.051), though no significant difference in the rate of DAPT interruption. Patients with HATR had higher 2-year rates of cardiac death, MI, or stent thrombosis compared with those at LATR (8.7% vs 4.0%; adjusted hazard ratio [aHR]: 1.80; 95% confidence interval [CI]: 1.36-2.39; p < 0.0001). Disruption of DAPT was associated with greater risk for cardiac death, MI, or stent thrombosis in both HATR (aHR: 1.86; 95% CI: 1.05 to 3.46) and LATR (aHR: 2.84; 95% CI: 1.68 to 4.80) patients (pinteraction = 0.40). The degree of atherothrombotic risk influences the pattern and mode of DAPT cessation with less discontinuation among patients considered HATR. Atherothrombotic risk status does not influence the association between DAPT cessation and cardiac risk.

Safety and Efficacy of New-Generation Drug-Eluting Stents in Women at High Risk for Atherothrombosis: From the Women in Innovation and Drug-Eluting Stents Collaborative Patient-Level Pooled Analysis.

The safety and efficacy of new-generation drug-eluting stents (DES) in women with multiple atherothrombotic risk (ATR) factors is unclear. We pooled patient-level data for women enrolled in 26 randomized trials. Study population was categorized based on the presence or absence of high ATR, which was defined as having history of diabetes mellitus, prior percutaneous or surgical coronary revascularization, or prior myocardial infarction. The primary end point was major adverse cardiovascular events defined as a composite of all-cause mortality, myocardial infarction, or target lesion revascularization at 3 years of follow-up. Out of 10,449 women included in the pooled database, 5333 (51%) were at high ATR. Compared with women not at high ATR, those at high ATR had significantly higher risk of major adverse cardiovascular events (15.8% versus 10.6%; adjusted hazard ratio: 1.53; 95% confidence interval: 1.34-1.75; P=0.006) and all-cause mortality. In high-ATR risk women, the use of new-generation DES was associated with significantly lower risk of 3-year major adverse cardiovascular events (adjusted hazard ratio: 0.69; 95% confidence interval: 0.52-0.92) compared with early-generation DES. The benefit of new-generation DES on major adverse cardiovascular events was uniform between high-ATR and non-high-ATR women, without evidence of interaction (Pinteraction=0.14). At landmark analysis, in high-ATR women, stent thrombosis rates were comparable between DES generations in the first year, whereas between 1 and 3 years, stent thrombosis risk was lower with new-generation devices. Use of new-generation DES even in women at high ATR is associated with a benefit consistent over 3 years of follow-up and a substantial improvement in very-late thrombotic safety.

TCT-577 Early- Versus New-Generation Drug-Eluting Stents in Women at High Risk for Atherothrombosis: Results froma Patient-Level Pooled Analysis of Randomized Controlled Trials

TCT-577 Early- Versus New-Generation Drug-Eluting Stents in Women at High Risk for Atherothrombosis: Results froma Patient-Level Pooled Analysis of Randomized Controlled Trials

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Impact of Diabetes Mellitus on Hospitalization for Heart Failure, Cardiovascular Events, and Death: Outcomes at 4 Years From the Reduction of Atherothrombosis for Continued Health (REACH) Registry.

Despite the known association of diabetes mellitus with cardiovascular events, there are few contemporary data on the long-term outcomes from international cohorts of patients with diabetes mellitus. We sought to describe cardiovascular outcomes at 4 years and to identify predictors of these events in patients with diabetes mellitus. The Reduction of Atherothrombosis for Continued Health (REACH) registry is an international registry of patients at high risk of atherothrombosis or established atherothrombosis. Four-year event rates in patients with diabetes mellitus were determined with the corrected group prognosis method. Of the 45 227 patients in the REACH registry who had follow-up at 4 years, 43.6% (n=19 699) had diabetes mellitus at baseline. The overall risk and hazard ratio (HR) of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were greater in patients with diabetes compared with patients without diabetes (16.5% versus 13.1%; adjusted HR, 1.27; 95% confidence interval [CI] 1.19-1.35). There was also an increase in both cardiovascular death (8.9% versus 6.0%; adjusted HR, 1.38; 95% CI, 1.26-1.52) and overall death (14.3% versus 9.9%; adjusted HR, 1.40; 95% CI, 1.30-1.51). Diabetes mellitus was associated with a 33% greater risk of hospitalization for heart failure (9.4% versus 5.9%; adjusted odds ratio, 1.33; 95% CI, 1.18-1.50). In patients with diabetes mellitus, heart failure at baseline was independently associated with cardiovascular death (adjusted HR, 2.45; 95% CI, 2.17-2.77; P<0.001) and hospitalization for heart failure (adjusted odds ratio, 4.72; 95% CI, 4.22-5.29; P<0.001). Diabetes mellitus substantially increases the risk of death, ischemic events, and heart failure. Patients with both diabetes mellitus and heart failure are at particularly elevated risk of cardiovascular death, highlighting the need for additional therapies in this high-risk population.

The Impact of Lost Therapeutic Benefit (LTB) in High‐Risk Hypertensive Patients: 2‐Year Follow‐Up Data from the Australian REACH Registry

The aim of the study is to determine the extent of lost therapeutic benefit (LTB) in the hypertensive patients, and to determine the relationship between the presence of LTB and clinical outcomes. Prospective-cohort study of n=2856 patients with or at high risk of atherothrombosis. LTB was calculated as the proportion of patients receiving blood pressure medication who were not attaining guideline blood pressure (BP) control targets (<140/90mmHg). Logistic regression analysis was performed to identify predictors of LTB at baseline, and propensity score matching (PSM) was undertaken to estimate the treatment effects by matching case LTB and control non-LTB cohorts based on the nearest neighbor matching. Of the total sample of 2856, 45.6% had uncontrolled BP, and LTB was present in 46.7% patients. The likelihood of LTB was less in males (OR=0.78 [95% CI; 0.64-0.97]), and those with a previous myocardial infarction (OR=0.66 [0.53-0.81]) or heart failure (OR=0.58 [0.42-0.82]). LTB was more common in those with diabetes (OR=1.44 [1.16-1.79]), aged >65years (OR=1.36 [1.06-1.75]) and having an ABI<0.09 in either leg at rest (OR=1.30 [1.02-1.75]). Following PSM, the combination of ischemic events (55-64 age category) was more likely to occur in the LTB compared with non-LTB group (4.38% and 0.68%, respectively [P=0.046]). Presence of HF, previous MI and being male decreased the likelihood of LTB, while presence of diabetes, age>65 and ABI<0.09 increased the risk of LTB. Patients with LTB in age category 55-64 had higher incidence of vascular events compared with those with non-LTB.

The rationale for pre-race aspirin to protect susceptible runners from sudden cardiac death during marathons: Deconstructing the Pheidippides conundrum

Objectives: While endurance exercise such as training for marathons is cardioprotective, cardiac arrests and sudden death occur in previously healthy runners during races predominantly in middle-aged males due to atherosclerotic heart disease. Recent evidence related to this problem is reviewed herein including epidemiologic studies and findings related to acute cardiac risk in asymptomatic middle-aged male runners during races. Method: Literature review related to the above. Findings: The risks of cardiac arrest and sudden death were 1 in 57,002 and 1 in 171,005 respectively in runners with a mean age of 49.7 years among 1,710,052 participants in marathons in the United States since 1980. Atherosclerotic heart disease was the cause of death in over 90% of cases in two retrospective studies and a greater than two-fold increase in cardiac arrests was observed in middle-aged men in the latter half of a 10-year prospective registry beginning in the year 2000. Asymptomatic middle-aged male runners showed elevated biomarkers of inflammation such as interleukin-6, C-reactive protein together with procoagulant effects including in vivo platelet activation, indicating susceptibility to atherothrombosis. Conclusions: Antithrombotic prophylaxis is evidence-based by validated clinical paradigms to prevent cardiac arrest and sudden death in susceptibile marathon runners at high risk for atherothrombosis during races.

Relation between body mass index, waist circumference, and cardiovascular outcomes in 19,579 diabetic patients with established vascular disease: the REACH Registry

Obesity is frequent in type 2 diabetic patients with myocardial infarction (MI) or established cardiovascular disease. Earlier studies suggest that elevated body mass index (BMI) is associated with a favorable prognosis for persons with established vascular disease. We sought to analyse the associations between raised BMI and waist circumference with the 2-year event rate in type 2 diabetic patients with established vascular disease. Patients from the Reduction of Atherothrombosis for Continued Health (REACH) Registry, an international, prospective cohort of patients at high risk of atherothrombosis, were selected if they were diabetic and had established atherosclerotic arterial disease (n = 19,579). The main outcomes after 2-year follow-up were: all-cause death, cardiovascular death, MI, stroke, cardiovascular death/MI/stroke, and cardiovascular death/MI/stroke/rehospitalization. The rates of all-cause death, cardiovascular death, and cardiovascular death/MI/stroke decreased across increasing BMI quintile categories, whereas the same rates were stable across waist categories. The hazard ratios, adjusted for confounders, decreased significantly with increasing BMI for all-cause death (p < 0.0001), cardiovascular death (p = 0.0009), cardiovascular death/MI/stroke (p = 0.0004), and all events (p = 0.002), but not for greater waist circumference. There is an apparent obesity paradox (better outcome with increasing obesity) when obesity is measured by BMI but not when measured by waist circumference in diabetic subjects.

Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin generation assay

Diabetes is a risk factor for the development of atherothrombosis and venous thromboembolism (VTE). We investigated whether plasma from patients with type 2 diabetes has an imbalance of pro- versus anti-coagulation resulting in hypercoagulability despite normal conventional coagulation tests. We analyzed blood samples from 60 patients with type 2 diabetes and 60 gender- and age-matched healthy subjects (controls) for the levels of pro- and anti-coagulant factors, for thrombin generation and for the numbers of cell-derived circulating microparticles bearing such pro-coagulant triggers as tissue factor and negatively charged phospholipids. The levels of pro- or anti-coagulants as measured with conventional coagulation tests or single factor measurements were similar to those of the control population. In contrast, the median (range) of the height of the thrombin peak (taken as an index of thrombin generation) was higher in patients [205 nM (126-352)] than controls [151 nM (41-289)], P < 0.001. The median numbers of circulating microparticles were higher for patients [5,041/μl (1,821-13,132)] than for controls [1,753/μl (554-13,308)], P < 0.001 and their values were correlated with the height of the thrombin peak (ρ = 0.66, P < 0.001). In conclusion, plasma from patients with type 2 diabetes possesses an imbalance of pro- versus anti-coagulation resulting in hypercoagulability that can be detected by thrombin generation tests, but not by the measurement of the single pro- or anti-coagulant factors. This hypercoagulability is associated with increased numbers of circulating microparticles bearing endogenous pro-coagulant triggers. These findings might explain the relatively high risk of atherothrombosis and VTE described in these patients.

Prevalence, clinical profile, and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis

Atrial fibrillation (AF) is a major risk factor (RF) for ischemic stroke. Its prevalence and prognostic impact in patients with atherothrombosis are unclear. Risk factors, drug usage, and 1-year cardiovascular (CV) outcomes (CV death, myocardial infarction [MI], and stroke) were compared in AF and non-AF patients from the REduction of Atherothrombosis for Continued Health (REACH) Registry, an international, prospective cohort of 68,236 stable outpatients with established atherothrombosis or>or=3 atherothrombotic RFs. Atrial fibrillation and 1-year follow-up data are available for 63,589 patients. The prevalence of AF was, 12.5%, 13.7%, 11.5%, and 6.2% among coronary artery disease, CV disease, peripheral artery disease, and RF-only patients, respectively. Of the 6,814 patients with AF, 6.7% experienced CV death, nonfatal MI, or nonfatal stroke within a year. The annual incidence of nonfatal stroke (2.4% vs 1.6%, P<.0001) and unstable angina (6.0% vs 4.0%, P<.00001) was higher, and CV death was more than double (3.2% vs 1.4%, P<.0001), in AF versus non-AF patients. In these patients with or at high risk of atherothrombosis, most patients with AF received antiplatelet agents, but only 53.1% were treated with oral anticoagulants. Even with high CHADS2 (congestive heart failure, hypertension, aging, diabetes mellitus, and stroke) scores, anticoagulant use did not exceed (59%). The rate of bleeding requiring hospitalization was higher in AF versus non-AF patients (1.5% vs 0.8%, P<.0001), possibly related to the more frequent use of anticoagulants (53.1% vs 7.1%). Atrial fibrillation is common in patients with atherothrombosis, associated with more frequent fatal and nonfatal CV outcomes, and underuse of oral anticoagulants.

Cardiovascular risk factors in patients at high risk of atherothrombosis: What can be learned from registries?

Cardiovascular risk factors in patients at high risk of atherothrombosis: What can be learned from registries? -

Safety of Clopidogrel and Aspirin for??Stroke Prevention

Antiplatelet therapy is universally recommended for the prevention of recurrent events in patients with noncardioembolic ischaemic stroke or transient ischaemic attack (TIA), acute and chronic coronary artery disease, or peripheral arterial disease. However, choosing which antiplatelet agents to use in these situations remains controversial. The use of aspirin, aspirin plus extended-release dipyridamole, or clopidogrel is recommended as initial therapy in patients with noncardioembolic ischaemic stroke or TIA to reduce the risk of recurrent stroke and other cardiovascular events. Based on the results of the MATCH trial, combination therapy with aspirin plus clopidogrel is not recommended for patients with ischaemic stroke or TIA due to the increased risk of haemorrhage. The results of the CHARISMA trial support this recommendation; despite previous data demonstrating a favourable benefit-risk profile of aspirin plus clopidogrel in patients with acute coronary syndrome, this combination should not be used in patients at high risk for atherothrombosis and those with previous stroke or TIA. In these patients, the CHARISMA trial demonstrated a lack of significant clinical efficacy and an increased risk of bleeding with clopidogrel plus aspirin compared with aspirin alone. Further research is needed to assess the benefit-risk ratio of clopidogrel plus aspirin in specific subpopulations of patients at high risk for atherothrombotic events, and to determine the role of clopidogrel plus aspirin in preventing cardioembolic stroke or early recurrent stroke after symptomatic large-vessel atherostenosis. Recent and ongoing studies are seeking to better define the roles of different antiplatelet regimens in preventing recurrent stroke.

Role of Microparticles in Thrombin Generation in Patients at Risk for Atherothrombosis.

We have shown recently (Hron et al. JAMA 2006) that measuring thrombin generation can identify patients at low risk for recurrent venous thromboembolism and that peak thrombin is a suitable parameter to differentiate low risk from high risk patients. In this study we used the same assay (Technothrombin®TGA) to analyze patients at high risk of atherothrombosis (a swiss study of patients with a history of myocardial infarction). Moreover, we investigated the influence of microparticles on thrombin generation in these patients. Thrombin generation was measured using Technothrombin®TGA. The reagent used contained low levels of phospholipid and 5 pM tissue factor. Platelet poor plasma from 178 patients (n=178, age =55±8 ys, male/female = 157/21) who had a previous myocardial infarction and 79 normal age and sex matched controls. (n=79, age = 55±8 ys, male/female = 70/9) was analyzed. Microparticle-free plasma was generated from PPP plasma by filtration through a membrane (0.2 μm pore size) using a standardized filtration device (Ceveron®MFU 500, Technoclone). In the control group the mean value for peak thrombin in platelet poor plasma was 252±7.7 nM (mean±SD). A significantly higher (p< 0,05) peak thrombin was found in the group of patients (355±49 nM) when patients without medication were analyzed. In patients on aspirin (n=109) the peak thrombin was not significantly different from untreated patients (297±10 nM) while in patients on oral anticoagulation (n=34) peak thrombin was significantly lower (225±27 nM). In the group of patients on oral anticoagulation also the lag period was significantly longer as compared to controls or patients without medication (21.9±2 minutes versus 14.8±0.2 minutes) whereas aspirin treatment did not affect the lag period significantly. After removing microparticles from the samples, the peak thrombin values between patient and control group were no longer significantly different. The difference between microparticle free plasma and platelet poor plasma was significantly higher (p<0.05) in the patient groups without therapy (304±39nM) and in patients on Aspirin therapy (257±23nM) as compared to the normal controls(182.6±10.4nM). These data indicate that thrombin generation is significantly increased in patients with previous myocardial infarction and that this increased thrombin generation is likely due to microparticles contained in these samples.

Control de factores de riesgo y tratamiento de la aterotrombosis. Registro REACH España

The REACH Registry is the largest worldwide registry designed to obtain information on cardiovascular risk factor control and preventive treatment in a population who have, or are at high risk of having, symptoms of atherothrombosis. The objective of this study is to show the results obtained in a sample of the Spanish population included in that registry. Registry of consecutive patients who have risk factors only (RFO) for atherothrombosis or who have symptomatic vascular disease (VD): coronary heart disease (CHD) and/or cerebrovascular disease (CVD) and/or peripheral artery disease (PAD). Cardiovascular risk factor control and the use of antithrombotic and lipid lowering therapy were evaluated. In Spain 2,515 patients were recruited; 297 had RFO and 2,218 had VD: 61.4% with CHD, 36.6% with CVD and 18.7% with PAD. The rates of noncontrolled blood pressure, glycemia, total cholesterol and triglyceride levels in the RFO group compared to those of the VD group were: 76.5% vs 57.1% (p < 0.005), 61.6% vs 30.9% (p < 0.005), 55.7% vs 41.3% (p < 0.005) and 45.5% vs 35.1% (p < 0.005), respectively. The antiplatelet therapy rate in these two groups was 44.1% vs 86.5% (p < 0.005), the anticoagulant therapy rate was 11.4% vs 12.6% (no significant difference) and statin therapy rate was 65.2% vs 65.6% (no significant difference). Significant differences were found among the CHD, CVD and PAD groups as regards noncontrolled blood pressure rate (49.8%. 57.1% and 67.1%, respectively p < 0.005), total cholesterol control rate (41.3%, 48.2% and 50.2% respectively, p < 0.005) as well as antiplatelet therapy rate (86.5%. 83.2% and 81.6% respectively p < 0.005) and statin therapy rate (78.2%. 51.9% and 57.8% respectively p < 0.005). Cardiovascular risk factor control in subjects at high risk of atherothrombosis or who have established VD is poor. It is poorer in primary prevention and in PAD patients. Whilst the use of statins is insufficient, the use of antithrombotic medication is acceptable in secondary prevention but considerably lacking in primary prevention.

Prevalence, Awareness and Treatment of Cardiovascular Risk Factors in Patients at High Risk of Atherothrombosis in Japan Results From Domestic Baseline Data of the REduction of Atherotherombosis for Continued Health (REACH) Registry

The REduction of Atherothrombosis for Continued Health (REACH) Registry is an international observational study of patients with, or at risk of, atherothrombotic disease. Japanese patients were analyzed to clarify national prevalence and treatment. Almost 68,000 outpatients were recruited worldwide with 5,193 in Japan. Among the Japanese patients, 83.7% had established vascular disease (symptomatic) and 16.3% had risk factors only (asymptomatic). Of the symptomatic patients, 14.0% had atherothrombotic lesions in more than 1 vascular bed, with 0.8% having lesions in 3 areas: brain, heart, and peripheral arteries. The prevalence of additional atherothrombotic risk factors among symptomatic patients was independent of the vascular lesion. Obesity was recorded in 10.6% and 42.1% of patients according to the National Cholesterol Education Program and Japanese guidelines, respectively. Pharmacologic intervention for risk factors was inadequate: only 37.7% of diabetic patients received antidiabetic medication, 79.6% of hypertensive patients used antihypertensives, and 74.0% received antiplatelet agents. The use of statins (44.1%) and aspirin (54.7%) was less common than seen in REACH globally. Japanese patients enrolled in REACH share many similarities with the global population, but with some important differences. Long-term follow-up will determine the impact of these factors on the development of atherothrombotic events.

Risk Factor Control in Patients at High-Risk of Atherothrombosis in Australian General Practice—Local Results from the Reach Registry

Risk Factor Control in Patients at High-Risk of Atherothrombosis in Australian General Practice—Local Results from the Reach Registry

Failure of aspirin to prevent atherothrombosis: potential mechanisms and implications for clinical practice.

Aspirin (acetylsalicylic acid) reduces the odds of serious atherothrombotic vascular events and death in a broad category of high risk patients by about one-quarter. The mechanism is believed to be inhibition of thromboxane biosynthesis by inactivation of platelet cyclo-oxygenase-1 enzyme. However, aspirin is not that effective; it still fails to prevent the majority of serious vascular events. Mechanisms that may account for the failure of aspirin to prevent vascular events include non-atherothrombotic causes of vascular disease, non-adherence to aspirin therapy, an inadequate dosage, alternative "upstream" pathways of platelet activation (e.g. via stimulation of the ADP, collagen or thrombin receptors on platelets), aspirin-insensitive thromboxane biosynthesis (e.g. via monocyte cyclo-oxygenase-2), or drugs that interfere with the antiplatelet effects of aspirin. Genetic or acquired factors may further modify the inhibitory effects of aspirin on platelets (e.g. polymorphisms involving platelet-associated proteins, increased platelet turnover states). Identification and treatment of the potential causes of aspirin failure could prevent at least another 20% of serious vascular events (i.e. over and above those that are currently prevented by aspirin). There is currently no role for routine laboratory testing to measure the antiplatelet effects of aspirin. Clinicians should ensure that patients at high risk of atherothrombosis (>3% risk over 5 years) are compliant with aspirin therapy and are taking the correct dosage (75-150 mg/day). Patients who cannot tolerate aspirin, are allergic to aspirin, or have experienced recurrent serious atherothrombotic events whilst taking aspirin, should be treated with clopidogrel, and patients with acute coronary syndromes benefit from the combination of clopidogrel plus aspirin. Future research is required to standardize and validate laboratory testing of the antiplatelet effects of aspirin and to identify treatments that can both improve these laboratory measures and reduce the risk of future atherothrombotic events.

Up-Regulated Expression of Plasminogen Activator Inhibitor-1 in Hep G2 Cells: Interrelationship between Insulin and Insulin-Like Growth Factor 1

Insulin resistance represents a situation with a high risk of atherothrombosis and is accompanied by increased plasma plasminogen activator inhibitor-1 (PAI-1) levels. Fasting insulin level is highly correlated with PAI-1 levels in plasma. It has been shown that insulin increases PAI-1 synthesis by the human hepatoma cell line Hep G2. Moreover when Hep G2 cells expressing a down-regulation of insulin receptors by incubation with 10(-7) M insulin, were stimulated by 10(-9) M insulin, an overexpression of PAI-1 synthesis was observed despite a reduced number of insulin receptors. Insulin-like growth factor 1 (IGF-1) shares many properties with insulin. The aim of the present study was to evaluate the effect of IGF-1 on PAI-1 synthesis by Hep G2 cells down-regulated either by insulin or IGF-1. Incubation of Hep G2 cells with increasing doses from 10(-9) to 10(-7) M IGF-1 induced a dose-dependent stimulation of PAI-1 synthesis up to 4.5-fold the control level. When cells were first pre-incubated with 10(-7) M IGF-1 for 18 h, acid washed, and then stimulated with 10(-9) M IGF-1, the expression of IGF-1 receptors was greatly reduced (up to 70%). In contrast PAI-1 secretion was increased 3.4-fold the level of control cells and by 1.9-fold the level of cells first stimulated with 10(-9) M IGF-1. Both transcripts of PAI-1 mRNA were also increased.(ABSTRACT TRUNCATED AT 250 WORDS)