The in vitro effects of niacin on platelet biomarkers in human volunteers.

Niacin is a natural pyridine derivative, proven to favorably modulate the blood lipid profile by increasing levels of high-density lipoprotein (HDL) cholesterol, and by reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp (a) lipoprotein concentrations. Considering that platelet activity is important in predicting vascular outcomes, and that HDL heavily constitutes platelet cellular membranes, we sought to evaluate the effect of niacin on human platelet activity indices. The blood obtained from 30 aspirin-naïve volunteers was preincubated with escalating concentrations of niacin in vitro.

Aptamers: the emerging class of future anticoagulation for vascular disease.

Anticoagulation is an important therapeutic strategy to treat and prevent recurrent thrombotic events in patients after acute myocardial infarction and ischemic stroke. However, available anticoagulants have numerous shortcomings including hemorrhage risks, limited clinical application including heparin-induced thrombocytopenia and modest therapeutic benefit. Each component of the coagulation cascade is a potential target for new drug developments.

The in vitro effects of Xancor, a synthetic astaxanthine derivative, on hemostatic biomarkers in aspirin-naïve and aspirin-treated subjects with multiple risk factors for vascular disease.

Astaxanthine is a polar carotenoid metabolite derived from a proprietary prodrug, Xancor, which aligns parallel with the membrane phospholipids exhibiting potent antioxidant, anti-inflammatory, and cell protective properties, although the precise mechanism of action is unknown. This prodrug is currently under development for hepatic, neurologic, and vascular disease indications. Considering established links between heart disease and stroke with platelets, coagulation cascade, and fibrinolysis, the aim of the study was to assess the effect of asthaxantine on human biomarkers of hemostasis.

Selective thromboxane inhibition after vascular protectant AGI-1067: results of assessment of lipoprotein profiles (ALPS) biomarkers in vitro and in vivo substudy.

Background: Oxidative stress play an important role triggering platelet/endothelial activation. AGI-1067 is a novel, phenolic antioxidant, and vascular protectant which dose-dependently inhibits PEA biomarkers in vitro. Whether treatment with AGI-1067 alters platelets in vivo is not known.

Bleeding risks of combination vs. single antiplatelet therapy: a meta-analysis of 18 randomized trials comprising 129,314 patients.

A number of antiplatelet drugs, principally aspirin alone or in combination, have been evaluated in randomized trials of survivors of prior occlusive vascular disease events or of individuals at high risk because of multiple cardiovascular risk factors. In this meta-analysis we compare single and dual antiplatelet regimens to quantitate the risks of bleeding. Data from randomized trials published in English in 1988-2006 were retrieved from MEDLINE, OVID, and CARDIOSOURCE.

Antiplatelet profiles of the fixed-dose combination of extended-release dipyridamole and low-dose aspirin compared with clopidogrel with or without aspirin in patients with type 2 diabetes and a history of transient ischemic attack: a randomized, single-blind, 30-day trial.

Background: Clopidogrel, aspirin (ASA), and the fixed-dose combination of extended-release dipyridamole and ASA (ER-DP+ASA) are widely used in post-stroke regimens.

Objective: This study compared serial changes in multiple biomarkers of platelet activation with ER-DP+ASA and clopidogrel with or without ASA in patients with type 2 diabetes mellitus and a history of transient ischemic attack (TIA).

Methods: This was a randomized, single-blind pilot study conducted at an outpatient center in the United States.

Magnitude and time course of platelet inhibition with extended release dipyridamole with or without aspirin in healthy Japanese volunteers. The AGgrenox versus Aspirin Therapy Evaluation (AGATE-Japan).

Randomized trials showed greater stroke prevention with extended release dipyridamole in combination with low dose aspirin than with either aspirin or dipyridamole alone. However, most studies with this formulation (Aggrenox) were carried out in Europe and North America. Considering potential inter-racial differences in drug response, we conducted a small randomized study in healthy Japanese volunteers to compare antiplatelet regimens with regard to the changes in the platelet biomarkers.

Platelet and endothelial activity in comorbid major depression and coronary artery disease patients treated with citalopram: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy Trial (CREATE) biomarker sub-study.

Background And Purpose: Major depression is an independent risk factor for increased morbidity and mortality in patients with coronary artery disease (CAD). Increased platelet activity and vascular endothelial dysfunction are possible pathways through which depression may increase cardiovascular risk. Citalopram exhibits strong selective inhibition of human platelet activation, but little is known about its effects on vascular endothelium.

Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in diabetic patients: the PLavix Use for Treatment Of Diabetes (PLUTO-Diabetes) trial.

Background: Clopidogrel is widely used in diabetic patients after vascular events; however, the ability of this thienopyridine to yield additional antiplatelet protection on top of aspirin has never been explored in a controlled study with comprehensive assessment of platelet activity. The objective of this study was to compare the antiplatelet profiles of clopidogrel + aspirin in combination (C + ASA) versus aspirin alone (ASA) in patients with type 2 diabetes mellitus.

Methods: Seventy patients with documented diabetes already treated with antecedent aspirin were randomly assigned to receive C + ASA or ASA in the PLUTO-Diabetes trial.

AGI-1067, a novel vascular protectant, anti-inflammatory drug and mild antiplatelet agent for treatment of atherosclerosis.

Oxidation-sensitive signals play an important role in platelet activation. AGI-1067 is a novel, phenolic, intra- and extracellular antioxidant that inhibits the expression of a number of proinflammatory genes involved in atherosclerosis. AGI-1067 is the metabolically stable monosuccinic acid ester of probucol, and a potent phenolic antioxidant representing a novel class of orally bioavailable compounds termed vascular protectants.

Patients with metabolic syndrome exhibit higher platelet activity than those with conventional risk factors for vascular disease.

Background: The metabolic syndrome is a matter of ongoing debate with regard to its existence, classification, clinical meaningfulness, and associated risks for vessel occlusion. Considering that persistent platelet activation is a cornerstone for the development of acute vascular events, and that patients with type 2 diabetes consistently exhibit high platelet activity, these characteristics may be critical for distinguishing and triageing specific features of metabolic syndrome among established risk factors for vascular disease.

Methods: We assessed the platelet activity by conventional aggregation, expression of major surface receptors by flow cytometry, and quantitatively by rapid bedside analyzers in 20 aspirin-naïve patients with documented metabolic syndrome, and compared these with 20 untreated subjects with multiple cardiovascular risk factors.

Fluorimetric quantitation of citalopram and escitalopram in plasma: developing an express method to monitor compliance in clinical trials.

Background: Selective serotonin reuptake inhibitors (SSRIs) in general, and citalopram/escitalopram in particular, are widely used to treat clinical depression. However, SSRI bioavailability and non-compliance represent major issues, especially in the clinical trials setting. In this context, frequent drug-level measurements for compliance monitoring would be a desirable tool to improve clinical outcomes with SSRIs.

Antiplatelet properties of escitalopram in patients with the metabolic syndrome: a dose-ranging in vitro study.

There is an increasing body of evidence suggesting that selective serotonin reuptake inhibitors exhibit clinical benefit beyond treating depression, by simultaneously inhibiting platelet activity. We recently demonstrated that escitalopram (ESC), but not its major metabolites, inhibits multiple platelet biomarkers in healthy volunteers. Considering that the metabolic syndrome represents one of the major risk factors for vascular disease, we here determined how ESC affects platelet activity in such patients.

Consistent platelet inhibition during long-term maintenance-dose clopidogrel therapy among 359 compliant outpatients with documented vascular disease.

Background: Numerous reports have dichotomized responses after clopidogrel therapy using varying definitions and platelet tests in patients immediately after acute vascular events; however, no large study has assessed platelet characteristics in outpatients receiving long-term treatment for more than 30 days with the maintenance dose (75 mg/d) of clopidogrel. The aim of this study was to describe the responses of ex vivo measures of platelet aggregation and activation to long-term clopidogrel therapy in a large population of outpatients after coronary stenting or ischemic stroke.

Methods: We conducted a secondary post hoc analysis of a data set represented by presumably compliant patients after coronary stenting (n = 237) or a documented ischemic stroke (n = 122) treated with clopidogrel-and-aspirin combination antiplatelet therapy.

Does heart failure etiology, New York Heart Association class, or ejection fraction affect the ability of clopidogrel to inhibit heightened platelet activity?

The ability of clopidogrel to inhibit platelet function in patients with congestive heart failure (CHF) was proved by the PLUTO-CHF trial. We retrospectively analyzed platelet characteristics with respect to CHF etiology, class, and ejection fraction in patients enrolled in the PLUTO-CHF study. Twenty-five patients were divided by CHF etiology, severity, and ejection fraction.

Combination antiplatelet therapy with aspirin and clopidogrel: the role of antecedent and concomitant doses of aspirin. An analysis of 711 patients.

Background: Numerous randomized studies have shown that the combination of clopidogrel with aspirin yields better clinical outcomes than monotherapy in patients with acute vascular events. However, the impact of the aspirin dose on the antiplatelet potency of clopidogrel is unclear. We sought to compare the antiplatelet profile of aspirin 81 mg (n = 252) versus aspirin 325 mg (n = 459) before and during conventional clopidogrel loading (300 mg), and/or clopidogrel maintenance (75 mg/daily) therapy.

The in vitro effects of a novel vascular protectant, AGI-1067, on platelet aggregation and major receptor expression in subjects with multiple risk factors for vascular disease.

Oxidation-sensitive signals are important in platelet activation. The novel, phenolic, intracellular and extra-cellular antioxidant AGI-1067 inhibits the expression of a number of proinflammatory genes involved in atherosclerosis. The effect of AGI-1067 on human platelets was evaluated.

Paradoxical rebound platelet activation after painkillers cessation: missing risk for vascular events?

Background: Several reliable reports strongly indicate that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors is associated with an increased risk of cardiovascular events. Considering the key role of platelets in coronary atherosclerosis and the fact that antiplatelet therapy with aspirin (and more recently, clopidogrel) has been associated with reduced vascular mortality, we sought to determine the effect of therapy and withdrawal of NSAIDs and COX-2 inhibitors on platelet activity.

Methods: Platelet characteristics from 34 aspirin-naive volunteers who were receiving NSAIDs and COX-2 inhibitors were compared with 138 drug-free controls.

Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study).

We investigated whether, in primary prevention patients with metabolic syndrome, statins affect the platelet protease-activated receptor-1 (PAR-1) thrombin receptor by performing serial measurements of its activity and the antigen expression level by flow cytometry before and during treatment. Recent data from randomized trials of statins are compatible with the possibility of clinically relevant pleiotropic effects. The use of statins is associated with a reduced thrombosis burden and diminished platelet activity, as shown in animal models and in vitro studies.

Escitalopram, but not its major metabolites, exhibits antiplatelet activity in humans.

Background: Clinical depression has been identified as an independent risk factor for increased mortality during follow-up in patients suffered from acute coronary events, whereas increased platelet activity has been proposed as one of the mechanisms for this association. Some evidence suggests that selective serotonin reuptake inhibitors and/or their metabolites exhibit potent antiplatelet properties.

Methods: We assessed the in vitro effects of preincubation with escalating (50-200 nmol/L) concentrations of escitalopram (ESC) S-desmethyl-citalopram (S-DCT), and S-di-desmethyl-citalopram, (S-DCT) on platelet aggregation through the expression of major surface receptors using flow cytometry and quantitatively using platelet function analyzers in 20 healthy volunteers.

Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12(R) rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study.

Introduction: Clopidogrel inhibits platelet P2Y12 ADP receptors, while ADP, as an inductor of aggregation, stimulates both P2Y12 and P2Y1 platelet receptors. Despite a clinical loading dose routine with clopidogrel, some patients still experience coronary stent thrombosis suggesting persistent platelet activation. The VerifyNow-P2Y12 is a rapid assay that test platelet activity over 3 min and uses of the combination of ADP and prostaglandin E1 (PGE1) to directly measure the effects of clopidogrel on the P2Y12 receptor.

Effects of escalating doses of tirofiban on platelet aggregation and major receptor expression in diabetic patients: hitting the TARGET in the TENACITY trial?

Introduction: Ongoing search for the optimal dosing regimens, and valid concerns that some GPIIb/IIIa inhibitors may cause rebound platelet activation are limiting the use of these agents in patients with acute vascular events.

Materials And Methods: We assessed the in vitro effects of preincubation with escalating (12.5-200 ng/mL) concentrations of tirofiban on platelet biomarkers in 20 diabetic patients.

Argatroban, a direct thrombin inhibitor for heparin-induced thrombocytopaenia: present and future perspectives.

Heparin remains the most commonly used anticoagulant in the treatment of patients with acute vascular syndromes, including myocardial infarction, unstable angina and ischaemic stroke. However, heparin therapy is not always associated with a significant improvement of clinical outcomes, is linked with enhanced bleeding risk and can occasionally provoke the development of heparin-induced thrombocytopaenia, the most devastating complication of conventional therapy with unfractioned heparin. Understanding the key role of thrombin in clot formation and platelet activation has stimulated the development of a new class of drugs - direct thrombin inhibitors.

Valsartan inhibits platelet activity at different doses in mild to moderate hypertensives: Valsartan Inhibits Platelets (VIP) trial.

Background: Previous in vitro studies have suggested that valsartan produces significant inhibition of human platelets, probably targeting angiotensin I platelet receptors. To test whether valsartan inhibits platelet activity in mild to moderate hypertensives we conducted the randomized Valsartan Inhibits Platelets (VIP) trial.

Methods And Results: Seventy-five patients with mild to moderate hypertension were randomized to valsartan 80 (n = 25), valsartan 160 (n = 29), or valsartan 320 mg/d (n = 21) for 9 weeks.