Clopidogrel generic formulations in the era of new antiplatelets: a systematic review.

Clopidogrel is a thienopyridine that selectively and irreversibly inhibits the ADP purinergic receptor P2Y12 and the subsequent ADP-mediated platelet activation. Clopidogrel has been approved for clinical use as clopidogrel hydrogen sulfate (bisulfate) salt. The clinical usefulness of clopidogrel bisulfate salt has been proved in a wide variety of large scale clinical trials, thus clopidogrel bisulfate has been extensively used in a large spectrum of patients been under thrombotic risk. Recently, several generic clopidogrel formulations have been approved for clinical use. Consequently, clopidogrel is currently a cost-effective antiplatelet agent. Only small studies have compared the pharmacokinetic and pharmacodynamic properties of various clopidogrel generic salt formulations with the innovator bisulfate salt. In addition few data are available concerning the clinical efficacy and safety of these generic clopidogrel formulations in order to guide clinicians in deciding when generic substitution is appropriate. The aim of this review is to summarize the physicochemical properties as well as the pharmacokinetic and pharmacodynamic characteristics of the generic clopidogrel salts. We also critically present existing data on the clinical efficacy and safety of the generic clopidogrel formulations compared with the innovator clopidogrel bisulfate salt in patients with cardiovascular disease.

Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives.

Platelets play an important role in atherothrombotic disease. The currently available antiplatelet drugs target key steps of platelet activation including thromboxane A(2) synthesis, ADP-mediated signaling, and glycoprotein IIb/IIIa-mediated platelet aggregation. The improvement of our understanding on the pharmacokinetic and pharmacodynamic characteristics of these drugs enables the tailoring of the most appropriate anti-thrombotic therapy to the individual patient and risk situation in the daily clinical practice. However, current antiplatelet therapies are associated with increased bleeding risk. Thus, further research on platelet functions may give rise to numerous new antiplatelet agents with high anti-thrombotic efficiency and low adverse hemorrhagic side effects.

Platelet-mediated inflammation in cardiovascular disease. Potential role of platelet-endothelium interactions.

Inflammation of the vascular wall is considered as the principal underlying mechanism in the development of atherosclerosis. Besides their specific functions in haemostasis via thrombus formation after an endothelial injury, a growing body of evidence indicates that platelets play an important role in the inflammatory reactions occurring in the vascular wall as well as in the subsequent tissue repair mechanisms. Platelets interact with activated endothelium as well as with circulating leukocytes and progenitor cells. These interactions, involve direct cell-to-cell interactions as well as autocrine and paracrine pathways, which lead to activation of platelets and their respective cellular counterpart. An increasing body of evidence suggests that antiplatelet therapy may reduce vascular inflammation primarily by inhibiting platelet activation. The aim of the present review is to highlight the molecular basis of platelet-mediated inflammatory response, focusing on the mechanisms underlying the platelet-endothelial cell interaction. The anti-inflammatory effects of current antiplatelet therapies will be also discussed.

Effect of clopidogrel besylate on platelet reactivity in patients with acute coronary syndromes. Comparison with clopidogrel hydrogen sulfate.

OBJECTIVE: The efficacy of clopidogrel therapy in patients with an acute coronary syndrome (ACS) has been established using the clopidogrel hydrogen sulfate (CHS) formulation. In this study we compared the antiplatelet effectiveness of a generic clopidogrel salt, clopidogrel besylate (CB), with the original CHS in patients with an ACS. RESEARCH DESIGN AND METHODS: Ninety-six ACS patients were randomized to receive a 600-mg loading dose of either CHS (n = 45) or CB (n = 51), followed by 75 mg/day. Sixty-eight patients underwent a percutaneous coronary intervention (PCI), whereas 28 were treated conservatively. Platelet aggregatory response, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, P-selectin expression and platelet-leucocyte conjugates were determined before clopidogrel loading (baseline), as well as at 5 days and at 1 month afterwards. RESULTS: No difference in the clopidogrel response variability was observed between patients receiving CHS or CB either at 5 days or at 1 month of follow-up. Similarly, no difference in the inhibition of platelet aggregation, P-selectin expression or in the platelet-leucocyte conjugates was observed between CHS and CB group during the follow-up. CONCLUSIONS: There is no overall significant difference in the antiplatelet efficacy between CB and CHS during their administration in ACS patients for up to 1 month after the episode.

Antiplatelet efficacy of long-term treatment with clopidogrel besylate in patients with a history of acute coronary syndrome: comparison with clopidogrel hydrogen sulfate.

The efficacy of clopidogrel therapy in patients with an acute coronary syndrome (ACS) has been established using the clopidogrel hydrogen sulfate (CHS) formulation. We compared the antiplatelet effectiveness of long-term administration of the original CHS with a generic clopidogrel besylate (CB) salt formulation in 86 patients with a history of an ACS. At 1 month after the episode, patients receiving 75 mg/d CHS were randomized to continue with CHS (n = 41) or to switch to 75 mg/d CB (n = 45). Platelet aggregation, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, P-selectin expression, and platelet-leucocyte conjugates were determined before randomization and at 6 months afterward. No difference in any platelet parameter studied was observed between the 2 groups either before randomization or after 6 months of treatment with CHS or CB. We conclude that there is no difference in the antiplatelet efficacy between CB and CHS during long-term administration in patients with a history of an ACS.

Therapeutic modulation of lipoprotein-associated phospholipase A2 (Lp-PLA2).

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a calcium-independent phospholipase A2 that circulates in plasma in association with lipoprotein particles, whereas in atherosclerotic plaques it is co-localized with macrophages. Lp-PLA2 generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. Epidemiologic studies demonstrate that increased circulating levels of Lp-PLA2 predict an increased risk of myocardial infarction, stroke and cardiovascular mortality. Furthermore, histologic examination of diseased human coronary arteries reveals intense presence of the enzyme in atherosclerotic plaques that are prone to rupture. These considerations suggest Lp-PLA2 as a promising therapeutic target in cardiovascular disease. Plasma levels of Lp-PLA2 are increased in various types of hyperlipidemias, while hypolipidemic drugs reduce plasma Lp-PLA2 activity and mass along with the improvement of plasma lipid profile. A selective inhibitor of Lp-PLA2 activity, darapladib, has been developed and studies in animal models and humans have shown that it effectively and safely reduces Lp-PLA2 activity in plasma and in atherosclerotic plaques. Furthermore, in animal models darapladib decreases plaque area and necrotic core area whereas in humans it prevents the expansion of necrotic core volume. Whether the results obtained from the use of darapladib in studies in vitro, as well as in preclinical and clinical studies would translate into benefits on cardiovascular event outcomes, awaits to be proved in 2 ongoing phase 3 trials.

Analysis of the composition of plasma lipoproteins in patients with extensive coronary heart disease using 1H NMR spectroscopy.

INTRODUCTION: Alterations in the lipid composition and overall structure of plasma lipoproteins have been correlated with pathological situations such as dyslipidaemia, coronary heart disease (CHD), hypertension, and renal disease. In the present study 1H NMR spectroscopy was used to analyse the lipid composition of HDL and nonHDL lipoproteins in patients with triple vessel CHD and in patients with normal coronary arteries. METHODS: Serum samples were collected from 50 patients with triple vessel CHD and 41 patients with normal coronary vessels, both documented angiographically. The classical risk factors for CHD were recorded and each patient's standard lipid profile was determined. HDL and nonHDL lipoprotein particles were separated by precipitation with Dextran Sulphate/MgCl2. HDL and nonHDL lipid fractions were extracted with chloroform:methanol (1:2, v/v). 1H NMR spectra were recorded on a Bruker DRX-600 spectrometer. RESULTS: In the HDL fraction of patients with triple vessel disease the percentage of triglycerides was significantly higher than in those with normal coronary arteries, whereas the percentages of cholesterol esters, phosphatidylcholine and sphingomyelin, as well as polyunsaturated fatty acids, such as linoleic, arachidonic, and eicosapentaenoic, were significantly lower. In the nonHDL fraction significantly higher levels of triglycerides and lower levels of polyunsaturated fatty acids were observed. CONCLUSIONS: Patients with established CHD show significant alterations in the composition of plasma lipoproteins compared to those with normal coronary arteries. Further study of plasma lipoprotein composition might be able to identify components as indexes for the existence of CHD.

Prevalence of vascular disease in metabolic syndrome using three proposed definitions.

BACKGROUND: There are a number of definitions available for the diagnosis of the metabolic syndrome (MetS). The MetS-associated increase in cardiovascular disease (CVD) risk may depend on the definition used. AIM: To investigate which of the 3 recently proposed definitions of MetS [the National Cholesterol Education Program-Adult Treatment Panel-III (NCEP-ATP-III), the International Diabetes Federation (IDF) and the American Heart Association/National Heart Lung and Blood Institute (AHA/NHLBI)] is related to excessive CVD risk and thus may be more appropriate to implement in clinical practice. METHODS: A cross-sectional analysis of a representative sample of Greek adults (n=9669). RESULTS: The age-adjusted CVD prevalence was 11.4% in the whole study population, 23.3% in the NCEP-ATP-III (+) subjects, 22.6% in AHA/NHLBI (+) subjects and 18.3% in IDF (+) subjects [p<0.001 for the comparison between the whole study population and all MetS groups and p<0.0001 for the comparison between IDF (+) and either NCEP-ATP-III (+) or AHA/NHLBI (+) MetS]. However, the CVD prevalence was only 11.2% in the IDF (+) but NCEP-ATP-III (-)/AHA/NHLBI (-) MetS subjects [p<0.0001 vs. either NCEP-ATP-III (+) or AHA/NHLBI (+)], which was not different compared with the whole study population. Furthermore, subjects with NCEP ATP III (+) or AHA/NHLBI (+) MetS but not diabetes (DM) had a persistently higher prevalence of CVD compared with the whole study population. However, there was no significant difference regarding CVD prevalence between the whole study population and IDF (+)/DM (-) MetS subjects. CONCLUSIONS: CVD prevalence was increased in the presence of MetS irrespective of the definition used. However, this increase was more pronounced when the NCEP-ATP-III and AHA/NHLBI criteria were implemented compared with the IDF definition. Furthermore, the IDF definition included a large proportion of subjects who did not have increased CVD prevalence compared with the whole study population. These findings may have implications regarding which definition should we use to diagnose the MetS.

Rare association of diffused coronary ectasia and anomalous origin of left circumflex coronary artery in a man with heterozygous familial hypercholesterolemia: a case report.

Coronary artery ectasia (CAE) is an uncommon form of coronary artery disease. It has been reported in association with a variety of pathological conditions, such as isolated congenital heart disease and Kawasaki disease. CAE is more relevant in young adults with multiple predisposing risk factors, especially familial hypercholesterolemia, and is usually considered a form of atherosclerotic coronary artery disease. A case of CAE is reported with familial hypercholesterolemia and diffuse ectasia of the coronary vessels in association with anomalous origin of the left circumflex coronary artery, which lacked ectatic segments. This combination has not been reported previously.

Awareness, treatment and control of the metabolic syndrome and its components: a multicentre Greek study.

INTRODUCTION: There are no data concerning the degree of awareness, treatment and control of the metabolic syndrome (MetS) and its components or associated vascular risk in the general population. METHODS: A cross-sectional analysis was made of a representative sample of Greek adults (n=9669, 49% men and 51% women), living in urban, semi-urban and rural areas (55%, 23% and 22%, respectively). The National Cholesterol Education Program (NCEP-ATP III) and the International Diabetes Federation (IDF) definitions for the MetS were used. RESULTS: The age-standardised prevalence of the MetS in the general population was 24.5% [95% CI 23.4-25.7%] (n=2369). This was similar in men and women and increased with age. Among subjects with the NCEP MetS the prevalence of hypertension was 71%, elevated blood glucose 55%, low high-density lipoprotein cholesterol 58%, high triglycerides 63% and abdominal obesity 82%. Only one third of subjects were aware of the MetS component conditions, less than one quarter were on treatment, and very few (< or =10%) were controlled for MetS components. Awareness of MetS individual component conditions (e.g. arterial hypertension), and consequently effective control, was lower than that reported in other cohorts, including subjects without MetS. Only 5% of subjects were aware of MetS as an entity, 2% were treated for all component conditions and only 1% were controlled. Using the IDF definition, the prevalence of MetS was higher (43.4%) and awareness, treatment and control of MetS and its components were significantly lower. CONCLUSIONS: The prevalence of MetS is high in Greece but is not recognised among the general population. Therefore, treatment and control of MetS and component conditions are extremely low. If the situation does not improve soon, MetS will cause a further increase in the vascular disease epidemic in the years to come. This calls for urgent education of the public and the medical community.