Events In Acute Coronary Syndrome Patients Research Articles

The platelet hyporesponsiveness to clopidogrel in acute coronary syndrome patients treated with 75 mg/day clopidogrel may be overcome within 1 month of treatment

Platelets are involved in thrombus formation and inflammation following vascular injury, while clopidogrel exerts antithrombotic and anti-inflammatory actions. We investigated various platelet-derived prothrombotic and proinflammatory mediators as well as the platelet aggregatory response in patients with acute coronary syndromes (ACS) receiving clopidogrel, as a function of the patient responsiveness to drug treatment. Blood samples were obtained from 40 patients with recent (<24 h) ACS before clopidogrel loading 600 mg (followed by a maintenance dose of 75 mg/day) as well as 5-days and 30-days afterwards. Twelve patients exhibited platelet reactivity index (PRI) values higher than 50% evaluated by the Vasodilator Stimulated Phosphoprotein (VASP) test at 5 days and were characterized as nonresponders. The platelet response to adenosine diphosphate (ADP) and thrombin receptor agonist peptide-14 (TRAP) was studied by flow cytometry and light transmission aggregometry. A maximum reduction of ADP- or TRAP-induced platelet aggregation in 28 clopidogrel responding patients was observed at 5 days postclopidogrel loading, whereas in nonresponders, it was achieved at 30-days along with a significant decrease in the PRI values. Similar results were obtained for the membrane expression of CD40L and the production of platelet-derived microparticles. By contrast, the maximum inhibition of P-selectin expression and platelet–leukocyte conjugate formation was observed at 30-days in both patient groups. A maintenance dose of 75 mg clopidogrel differentially affects the platelet aggregation and platelet-derived prothrombotic and proinflammatory mediators in ACS patients within the first month of the treatment, a phenomenon that is highly influenced by the drug response variability. Since these factors may be involved in the major adverse cardiovascular events in ACS patients, especially in those undergoing percutaneous coronary intervention, the above findings may be clinically important.

Association of microalbuminuria and insulin resistance with acute coronary syndrome

Objective To investigate relationship of microalbuminuria (MAU) and insulin resistance (IR) to severity of coronary lesions in patients with acute coronary syndrome (ACS), and its predictive value for short-term prognosis in then.Methods In total, 162 ACS patients admitted to the department of cardiology, Guangzhou First People's Hospital, Guangzhou, Guangdong province during January 2008 to June 2009 were selected and divided into three groups according to their urine albumin excretion rate (UAER): 54 cases in normal group with UAER less than 20 μg/min, 62 cases in microalbuminuria group with UAER of (20-200)μg/min, and 46 cases in mass-albuminuria group with UAER more than 200 μg/min.Difference in IR (by homeostasis model assessment, HOMA ) and severity of coronary lesions among the three groups was assessed.Effects of baseline MAU and IR on main adverse cardiac events within the recent six months were observed in ACS patients after percutaneous coronary intervention (PCI).Results IR increased and coronary lesions aggravated as UAER increasing in all the three groups of ACS patients (P＜0.05 or P＜0.01).MAU associated with IR, with a coefficient of correlation of 0.366 (P＜0.01).Results of multivariate logistic regression analysis showed that both MAU and IR were strong independent predictors for main adverse cardiac events in ACS patients within six months after PCI.Conclusions MAU and IR associate with severity of coronary lesions in ACS patients, suggesting certain predictive value for main adverse cardiac events in short-term after PCI. Key words: Albuminuria; Insulin resistance; Coronary disease

Recenti progressi nello studio dell’attivazione e dell’aggregazione delle piastrine

The interaction of ADP with its platelet receptor P2Y12 plays a crucial role in platelet activation and thrombogenesis. This article reviews the pharmacology and clinical trials of specific antagonists of P2Y12. Clopidogrel is a thienopyridine with proven antithrombotic efficacy, but it has some important drawbacks: i) it is a pro-drug that needs to be metabolized to its active metabolite; ii) it has a delayed onset and offset of action; iii) there is high inter-individual variability in pharmacological response. Prasugrel is also a thienopyridine, with faster onset of action and more uniform inhibition of platelet function compared to clopidogrel, accounting for lower incidence of ischemic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and higher incidence of both non-CABG (Coronary Artery Bypass Grafting) related bleeding complications. Two direct and reversible P2Y12 antagonists, cangrelor and ticagrelor, are characterized by rapid onset and reversal of platelet inhibition. Cangrelor did not prove superior to clopidogrel in preventing thrombotic events in patients undergoing PCI. Ticagrelor proved to be superior to clopidogrel in preventing major adverse cardiac events in ACS patients, but was, like prasugrel, was associated with higher frequency of non-CABG-related bleeding complications. A shorter period of drug discontinuation before surgery was necessary in ticagrelor-treated patients compared to clopidogrel-treated patients to limit the severity of post-surgical bleeding.

Current Antithrombotic Therapy in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Interventions.

Acute coronary syndromes (ACS) represent a life-threatening complication of the systemic atherosclerotic process, affecting the coronary circulation. Thrombosis, defined as an uncontrolled activation of the endogenous thrombogenetic reparative process, often follows atherosclerotic plaque damage and is mainly engaged by two main pathways: platelet aggregation and coagulation. Therefore, antithrombotic therapy to modulate either pathway plays an important role for the reduction of ischaemic adverse events in ACS patients. Since the advent of aspirin and warfarin, numerous antiaggregant and anticoagulant molecules have been developed to achieve this goal, but their anti-ischaemic efficacy is often obtained at the price of augmented bleedings, which are known to be strong predictors of adverse outcome. This article briefly reviews the physiopathological mechanisms of thrombosis and presents an overview of the available literature supporting the use of these major drugs, as well as the European Society of Cardiology recommendations for their utilisation in the setting of non-ST and ST-elevation myocardial infarction undergoing invasive treatment.

State of the art of new P2Y12 antagonists

The interaction of ADP with its platelet receptor P2Y12 plays a crucial role in platelet activation and thrombogenesis. This article reviews the pharmacology and clinical trials of specific antagonists of P2Y12. Clopidogrel is a thienopyridine with proven antithrombotic efficacy, but it has some important drawbacks: (a) it is a pro-drug that needs to be metabolized to its active metabolite; (b) it has a delayed onset and offset of action and (c) there is high inter-individual variability in pharmacological response. Prasugrel is also a thienopyridine, with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel, accounting for lower incidence of ischemic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and higher incidence of both non-CABG-related bleeding complications. Two direct and reversible P2Y12 antagonists, Cangrelor and ticagrelor, are characterized by rapid onset and reversal of platelet inhibition. Cangrelor is not superior to clopidogrel in preventing thrombotic events in patients undergoing PCI. Ticagrelor is superior to clopidogrel in preventing major adverse cardiac events in ACS patients, but, like prasugrel, is associated with a higher frequency of non-CABG-related bleeding complications. A shorter period of drug discontinuation before surgery is necessary in ticagrelor-treated patients compared to clopiodgrel-treated patients to limit the severity of post-surgical bleeding.

Impact of Statin Therapy on Renal Function and Long-Term Prognosis in Acute Coronary Syndrome Patients With Chronic Kidney Disease

A recent study showed that statins reduce cardiovascular events in stable coronary artery disease patients with chronic kidney disease (CKD). However, it remains unclear whether acute coronary syndrome (ACS) patients with CKD benefit from statins. A total of 501 patients with ACS who underwent successful percutaneous coronary intervention were investigated and CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73 m(2) at discharge. Three hundred and twenty-four of 501 patients (64.7%) had CKD and 173 patients (34.5%) received statins. The patients with CKD were older and had higher blood pressure than those without CKD. With a mean follow-up of 5.2 years, irrespective of treatment assignment, 74 patients with CKD experienced cardiac events (22.8%) in comparison to 25 without CKD (14.1%, HR 1.81; 95% CI 1.15-2.84, P = 0.0095). Cardiac events occurred in only 18 of the patients with CKD treated with statins (16.2%) and in 56 of those treated with CKD without statins (26.3%, HR 0.58; 95% CI 0.34-0.98, P = 0.039), whereas, no significant reduction of the events was observed in the patients without CKD treated with statins versus without having statins (P = 0.130). These data indicate that statin therapy reduces cardiac events in ACS patients with CKD.

Comparison of Low vs Moderate Dose of Atorvastatin in Clopidogrel Resistance After Coronary Stenting in Korean Patients With Acute Coronary Syndrome

The effect of atorvastatin 10 mg vs 40 mg in clopidogrel resistance and clinical events after coronary stenting was compared in patients with acute coronary syndrome (ACS). Platelet aggregation was measured before clopidogrel administration and 4 h, 24 h, 5 days, and 8 months later in 130 ACS patients. Stented patients were randomly assigned to atorvastatin either 10 mg (n=65) or 40 mg (n=65), and received an oral loading dose of 300 mg of clopidogrel followed by 75 mg/day for 8 months. Measurement of platelet aggregation was done by the turbimetric method. The mean % changes in inhibition of platelet aggregation were 35.5 +/-8.3, 50.9 +/-10.1, 38.3 +/-8.3, 40.0 +/-6.8 in the Atorvastatin 10 mg Group and 31.0 +/-7.6, 43.7 +/-9.8, 45.0 +/-10.3, 43.5 +/-7.8 (4 h, 24 h, 5 days, and 8 months, respectively, after 300 mg of clopidogrel pretreatment) in the Atorvastatin 40 mg Group with no significant differences between the 2 groups. Cardiovascular events showed no significant differences during the follow-up. Atorvastatin 10 mg or 40 mg co-administered with clopidogrel for 8 months did not affect the antiplatelet potency of clopidogrel and showed no significant differences in the clinical events in ACS patients.

Prasugrel: a novel platelet ADP P2Y12 receptor antagonist. A review on its mechanism of action and clinical development

Antiplatelet therapy is the cornerstone of treatment for patients who present with acute coronary syndrome (ACS) or undergo percutaneous coronary intervention (PCI). Clopidogrel, in combination with aspirin, is associated with improvement in long-term clinical outcomes in these patients and is currently the antiplatelet therapy of choice. However, a significant number of patients experience recurrent ischemic events, which have been in part attributed to variability in individual response profiles to currently recommended treatment regimens. The presence of variable degrees of responsiveness, thus inadequate platelet inhibition in some patients, underscores the need for novel agents with more potency and less variable platelet inhibitory effects. Prasugrel (CS-747; LY640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate (ADP) P2Y12 receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower interindividual variability in platelet response, and faster onset of activity compared with clopidogrel. Recent findings from large-scale Phase III testing showed prasugrel to be more efficacious in preventing ischemic events in ACS patients undergoing PCI; however, this is achieved at the expense of an increased risk of bleeding. This article reviews the currently available data regarding the efficacy and safety of prasugrel.

Risks and Benefits of Antiplatelet Therapy in Uremic Patients

Patients with renal insufficiency are at an increased risk for cardiovascular morbidity and mortality. Despite being at a substantial risk for thrombotic events, patients with renal insufficiency also experience a greater number of hemorrhagic complications associated with antiplatelet therapy than individuals with normal renal function. This review focuses on the benefits and risks of antiplatelet therapy in patients with impaired kidney function suffering from an acute coronary syndrome.

Inflammatory and anti-inflammatory variable clusters and risk prediction in acute coronary syndrome patients: A factor analysis approach

Background Numerous inflammatory mediators such as C-reactive protein (CRP), fibrinogen, interleukin-18 (IL-18), and inter-cellular adhesion molecule-1 (ICAM-1) have been proposed for risk stratification in acute coronary syndrome (ACS) patients. However, interactions between these markers have made it difficult to assess their true role in risk prediction. Factor analysis is a multivariable statistical technique that reduces a large number of intercorrelated variables to a smaller set of independent clusters, underlining physiological relationships. The aim of this study was to investigate, using factor analysis, a clustering of pro-inflammatory markers, anti-inflammatory cytokines such as interleukin-10 (IL-10) and HDL cholesterol, and to determine their role in prediction of risk of recurrent coronary events in ACS patients. Methods We assessed 320 consecutive patients (236 men; 67 years; IQ 58–74 years) admitted with ACS. The composite of cardiac death and re-hospitalization with non-fatal myocardial infarction, or unstable angina, was the pre-specified study end-point. Serum CRP, fibrinogen, HDL cholesterol, IL-10, IL-18 and ICAM-1 levels were measured at study entry. We assessed independent predictors of the combined end-point during a 1-year follow-up using multiple logistic regression analysis. Results Factor analysis identified three clusters which were arbitrarily interpreted as (1) a “systemic inflammation” cluster with positive loadings of CRP and fibrinogen, (2) a “local inflammation–endothelial dysfunction” cluster with positive loadings of IL-18 and ICAM-1 and (3) an “anti-inflammation” cluster comprising IL-10 and HDL cholesterol. Only the “anti-inflammation” cluster was a significant predictor (OR 0.66, 95% CI: 0.49–0.89) of adverse cardiac events during a 1-year follow-up and remained significant (OR 0.65, 95% CI: 0.48–0.88) in a multivariate model that included all three factors. Conclusions Although inflammatory markers such as CRP predict future cardiovascular events in ACS patients, when all inflammatory mediators are taken into account in a prospective analysis of risk, markers reflecting anti-inflammatory mechanisms are better prognostic markers.

The changes of electrocardiogram and impact of early invasive strategy in patients with acute coronary syndromes without ST-segment elevation

To investigate the changes of electrocardiogram (ECG) and impact of early invasive strategy in patients with acute coronary syndrome (ACS) without ST-segment elevation. Five hundred and forty-five consecutive ACS patients without ST-segment elevation were randomly assigned to early conservative treatment group and early invasive treatment group. The combined cardiovascular events, including cardiac death, nonfatal myocardial infarction, nonfatal heart failure, and re-hospitalization due to recurrent ischemia angina, within 30 days and 6 months were analyzed and the effects of varied ECG changes and different intervention strategies on outcomes of patients were evaluated. The incidences of each and combined cardiovascular events were higher in the patients with ST-segment depression than in those without ST-segment depression. ST-segment depression was one of independent predictive factors for an increase in cardiovascular events within 6 months (OR 3.864, 95% CI: 1.668 approximately 9.451, P < 0.001). Early invasive strategy was associated with a lower rate of re-hospitalization due to recurrent ischemia angina within 30 days and a decreased incidence of combined cardiovascular events within 30 days and 6 months in comparison with the early conservative treatment group (all P < 0.05). Subgroup analysis implied that incidences of combined cardiovascular events within 30 days and 6 months decreased significantly only in patients with ST-segment depression treated with early invasive strategy, and no such benefit was seen in the patients without ST-segment depression. ST-segment depression is an effective indicator for identifying those patients with non-ST segment elevation ACS most likely to benefit from early invasive strategy. Early invasive strategy markedly decreases the cardiovascular events in ACS patients with ST-segment depression than early conservative strategy.

Intensive statin therapy in acute coronary syndromes: clinical benefits and vascular biology

The results of a landmark clinical study comparing intensive statin therapy with conventional statin therapy, in patients with acute coronary syndromes (ACS), are reviewed. The mechanisms behind these results are analysed drawing data from vascular and cell biology. The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) study showed that intensive statin therapy with 80 mg of atorvastatin to achieve a low-density lipoprotein cholesterol of 62 mg/dl resulted in a 3.9% absolute and a 16% relative risk reduction in death or major cardiovascular events up to 2 years, compared to 40 mg of pravastatin, in patients with ACS. The results were especially significant as intensive statin therapy resulted in a very early benefit (<30 days) and occurred against a background of percutaneous coronary intervention (69%) for the index admission and high use of medications for secondary prevention. The PROVE IT and the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) C-reactive protein sub-study also showed that atorvastatin (80 mg) resulted in a significant reduction in markers of inflammation, whilst the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study showed that intensive statin therapy was associated with reduced progression of atherosclerosis compared with conventional doses of statins. Intensive statin therapy results in a significant early reduction in adverse cardiac events in ACS patients which are sustained over 2 years. The early benefits seen are likely to result from modulation of inflammation, endothelial function and coagulation, i.e. the pleiotropic effects, whereas the greater reduction in low-density lipoprotein cholesterol results in reduced long-term events.