A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation.

Background: The aim of this study was to compare rate of onset, magnitude, and consistency of platelet inhibition after administration of prasugrel or clopidogrel and to relate platelet inhibition to systemic exposure to each active metabolite. Thienopyridines are prodrugs, metabolized in vivo to active metabolites that inhibit the platelet P2Y12 adenosine diphosphate (ADP) receptor.

Methods: This was an open-label, 2-way, crossover study that randomized healthy subjects (n = 68) to an oral loading dose (LD) of prasugrel 60 mg or clopidogrel 300 mg.

Clopidogrel response variability, resistance, or both?

Dual antiplatelet therapy represents an important advance for patients with established cardiovascular disease. Variable platelet response and potential resistance to therapy have emerged with aspirin and clopidogrel. There is no clear and accepted definition of clopidogrel resistance, but patients with lower responses to clopidogrel are at risk for ischemic events, particularly when they undergo percutaneous coronary intervention.

The safety and efficacy of achieving very low LDL-cholesterol concentrations with high dose statin therapy.

Purpose Of Review: The benefits of lipid lowering with statins are established in patients with or at risk for coronary artery disease. Recent trials with high doses of potent statins have examined treating to very low levels of LDL-cholesterol. Concerns have been raised about the safety of this strategy.

Clinical applications of antiplatelet therapy.

Dual antiplatelet therapy with aspirin and a thienopyridine has become the standard of care for patients undergoing percutaneous intervention with stenting, regardless of indication. This article will examine the evidence for and against the use of aspirin and thienopyridines, with emphasis on platelet resistance and nonresponsiveness. Data suggest that in some patients, clopidogrel plus aspirin is not superior to aspirin alone.

Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38).

Background: Dual antiplatelet therapy with aspirin and clopidogrel is standard for prevention of thrombotic complications of percutaneous coronary intervention (PCI). Prasugrel is a thienopyridine that is more potent, more rapid in onset, and more consistent in inhibition of platelets than clopidogrel. TRITON-TIMI 38 is designed to compare prasugrel with clopidogrel in moderate to high-risk patients with acute coronary syndrome (ACS).

Evaluation of the National Cholesterol Education Program Adult Treatment Panel III algorithm for selecting candidates for statin therapy: insights from the A to Z trial.

The National Cholesterol Education Program Adult Treatment Panel III recommends an algorithm to integrate iterative risk-stratification information with low-density lipoprotein (LDL) cholesterol levels to identify candidates for statin therapy. We used the Aggrastat to Zocor (A to Z) trial, in which all patients presented with an acute coronary syndrome (ACS) event in the absence of previous statin therapy, to evaluate the performance of this algorithm. Of 1,750 patients with ACS included in this analysis, 1,126 (64%) had an indication for statin therapy before enrollment and 624 (36%) did not have a statin indication before enrollment.

Benefits of achieving the NCEP optional LDL-C goal among elderly patients with ACS.

Aims: To assess the efficacy and safety of the achievement of the NCEP goal of LDL-C <1.8 mmol/L in elderly patients with ACS.

Methods And Results: The relationship between LDL-C at 30 days after ACS and subsequent clinical outcomes were compared among elderly patients (aged > or =70 years) vs.

Update on lipid-lowering therapy and LDL-cholesterol targets.

Serum cholesterol has long been recognized as an important risk factor for the development and progression of atherosclerotic vascular disease. For more than 30 years, improved outcomes with lipid lowering have been demonstrated. As a result of these data, the National Heart, Lung, and Blood Institute (NHLBI) convened the National Cholesterol Education Program-Adult Treatment Panel I (NCEP ATP I).

Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial.

Background: Elevated levels of high-sensitivity C-reactive protein (hsCRP) are associated with higher risk of adverse outcomes in patients at risk for or with established coronary artery disease. Retrospective analyses suggest that this risk may be modified with statin therapy. However, a role for hsCRP in monitoring the success of therapy remains uncertain.

The role of clopidogrel in early and sustained arterial patency after fibrinolysis for ST-segment elevation myocardial infarction: the ECG CLARITY-TIMI 28 Study.

Objectives: This study was designed to determine the relationship between clopidogrel and early ST-segment resolution (STRes) and the interaction of the two with clinical outcomes after fibrinolysis.

Background: ST-segment resolution is an early noninvasive marker of coronary reperfusion.

Methods: The CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28) trial randomized 3,491 patients with ST-segment elevation myocardial infarction (STEMI) undergoing fibrinolysis to clopidogrel versus placebo.

Application of the Thrombolysis in Myocardial Infarction risk index in non-ST-segment elevation myocardial infarction: evaluation of patients in the National Registry of Myocardial Infarction.

Objectives: The purpose of this research was to evaluate the Thrombolysis In Myocardial Infarction risk index (TRI) to characterize the risk of death among patients with non-ST-segment elevation myocardial infarction (NSTEMI).

Background: The TRI, calculated from baseline age, systolic pressure, and heart rate, was established in patients with ST-segment elevation myocardial infarction (STEMI) and is predictive of mortality. Patients presenting with NSTEMI are increasing compared to STEMI and constitute a group with varied risk.

A tale of two trials: a comparison of the post-acute coronary syndrome lipid-lowering trials A to Z and PROVE IT-TIMI 22.

Background: The Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trials compared intensive and moderate statin therapy after acute coronary syndromes, with seemingly disparate results. We analyzed the design, implementation, and results of the two trials in an attempt to clarify the effects of early intensive statin therapy.

Methods And Results: Study design, end points, and definitions were compared.

Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy.

Objectives: This study sought to evaluate the safety and efficacy of achieving very low calculated low-density lipoprotein (LDL) levels with intensive statin therapy.

Background: Intensive statin therapy reduces clinical events occurring after acute coronary syndrome (ACS) and may result in LDL levels markedly lower than guideline levels. Prior epidemiologic and preclinical studies raise concerns about the safety of very low cholesterol levels.

Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial.

Background: Despite the current standard antiplatelet regimen of aspirin and clopidogrel (with or without glycoprotein IIb/IIIa inhibitors) in percutaneous coronary intervention patients, periprocedural and postprocedural ischemic events continue to occur. Prasugrel (CS-747, LY640315), a novel potent thienopyridine P2Y(12) receptor antagonist, has the potential to achieve higher levels of inhibition of ADP-induced platelet aggregation than currently approved doses of clopidogrel.

Methods And Results: Joint Utilization of Medications to Block Platelets Optimally-Thrombolysis In Myocardial Infarction 26 (JUMBO-TIMI 26) was a phase 2, randomized, dose-ranging, double-blind safety trial of prasugrel versus clopidogrel in 904 patients undergoing elective or urgent percutaneous coronary intervention.

Association of glomerular filtration rate on presentation with subsequent mortality in non-ST-segment elevation acute coronary syndrome; observations in 13,307 patients in five TIMI trials.

Aims: To determine the association of glomerular filtration rate (GFR) with clinical outcomes in the setting of non-ST-segment elevation acute coronary syndromes (NSTE-ACS).

Methods And Results: Data were pooled from five NSTE-ACS TIMI trials (TIMI 11A and B, TIMI 12, OPUS-TIMI 16 and TACTICS-TIMI 18) and were available in 13 307 patients. GFR was assessed as a continuous and a categorical variable (normal: > or = 90 mL/min/1.

Enoxaparin versus unfractionated heparin in patients treated with tirofiban, aspirin and an early conservative initial management strategy: results from the A phase of the A-to-Z trial.

Aims: In high risk patients with non-ST elevation acute coronary syndromes (ACS), enoxaparin is generally preferred to unfractionated heparin (UFH). However, less is known about the relative merits of these two forms of heparin in patients receiving concomitant glycoprotein IIb/IIIa inhibitors.

Methods And Results: The A phase of the A-to-Z trial was an open label non-inferiority trial in which 3987 patients with non-ST elevation ACS were randomised to receive either enoxaparin or UFH in combination with aspirin and tirofiban.

Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.

Context: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome.

Objective: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS.

Design, Setting, And Participants: International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003.

Unstable angina and non-ST-segment elevation myocardial infarction: part II. Coronary revascularization, hospital discharge, and post-hospital care.

In the guideline developed by the American College of Cardiology and the American Heart Association, the management of suspected unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) has four components: initial evaluation and management; hospital care; coronary revascularization; and hospital discharge and post-hospital care. Part II of this two-part article discusses coronary revascularization, hospital discharge, and post-hospital care. Decisions must be made about the use of coronary angiography and coronary revascularization in patients hospitalized with UA/NSTEMI.

Unstable angina and non-ST-segment elevation myocardial infarction: part I. Initial evaluation and management, and hospital care.

Each year, more than 1 million patients are admitted to U.S. hospitals because of unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI).

Performance of the thrombolysis in myocardial infarction risk index in the National Registry of Myocardial Infarction-3 and -4: a simple index that predicts mortality in ST-segment elevation myocardial infarction.

Objectives: We sought to evaluate a simple risk index based on age and vital signs in a community sample of patients with ST-segment elevation myocardial infarction (STEMI).

Background: A simple risk index based on age and vital signs (heart rate x [age/10](2)/systolic blood pressure) developed from patients with STEMI accurately predicts mortality in clinical trials of fibrinolysis. The application of such a tool in an unselected population is necessary to evaluate its utility in clinical practice.

Pathophysiology, prognostic significance and clinical utility of B-type natriuretic peptide in acute coronary syndromes.

The natriuretic hormones are a family of vasoactive peptides that can be measured circulating in the blood. Because they serve as markers of hemodynamic stress, the major focus of the use of natriuretic peptide levels [predominantly B-type natriuretic peptide (BNP) and N-terminal (NT)-pro-BNP] has been as an aid to the clinical diagnosis and management of congestive heart failure (CHF). Recently, however, the measurement of natriuretic peptides in the acute coronary syndromes (ACS) has been shown to provide information complementary to traditional biomarkers (of necrosis) such as cardiac troponins and creatine kinase (CK).

Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST-elevation myocardial infarction: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) substudy.

Background: Diagnosis of coronary artery disease in women is more difficult because of lower specificity of symptoms and diagnostic accuracy of noninvasive testing. We sought to examine the relationship between gender and cardiac biomarkers in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI).

Methods And Results: In the TACTICS-TIMI 18, OPUS-TIMI 16, and TIMI 11 studies, baseline samples were analyzed in the Thrombolysis In Myocardial Infarction (TIMI) biomarker core laboratory.

Association of creatinine and creatinine clearance on presentation in acute myocardial infarction with subsequent mortality.

Objectives: We hypothesized that impaired renal function would also be associated with poorer clinical outcomes among patients with ST-segment elevation myocardial infarction (STEMI) treated with fibrinolysis.

Background: Previous studies have demonstrated that impaired renal function is associated with poorer clinical outcomes in the setting of unstable angina and non-STEMI and after percutaneous coronary intervention.

Methods: Data were drawn from the Thrombolysis In Myocardial Infarction (TIMI)-10, TIMI-14, and Intravenous nPA for the Treatment of Infarcting Myocardium Early (InTIME-II) trials.