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.

The incidence of recurrent cardiovascular events among acute coronary syndrome patients treated with generic or original clopidogrel in relation to their sociodemographic and clinical characteristics. The Aegean study.

INTRODUCTION: The use of generic drugs is continuously growing; however, there are limited epidemiological data regarding the therapeutic equivalence of each original drug formulation with its generic counterparts. We evaluated the 12-month composite endpoint of recurrent acute myocardial infarction, ischaemic stroke, cardiac deaths, or hospitalisation due to a major bleeding in acute coronary syndrome (ACS) patients treated with original clopidogrel or a generic clopidogrel formulation, in relation to sociodemographic and clinical characteristics. MATERIAL AND METHODS: Consecutive Greek ACS patients (n = 1194) hospitalised in the Aegean islands and the Attica region were enrolled. Clopidogrel treatment was recorded either as original clopidogrel hydrogen sulphate (Plavix®/Iscover®) or as a generic clopidogrel besylate formulation (Clovelen®). The composite endpoint was recorded at 12-month follow-up. RESULTS: The 12-month composite endpoint was 3.9% (4.6% in the Aegean islands and 3.5% in the Attica area, p > 0.05). The respective incidence in men was 4.0% and in women 3.8% (p > 0.05). Overall, generic and original clopidogrel use was 87% and 13% of patients, respectively. No significant differences were observed between original and generic clopidogrel use and 12-month composite endpoint incidence. Subgroup analysis with gender, region of residence, and clinical and lifestyle factors as strata did not reveal any significant outcomes. Haemorrhage incidence did not exceed 1% in the total sample. CONCLUSIONS: The use of a generic clopidogrel besylate formulation was quite high in both urban and insular areas of Greece and had similar efficacy and safety profile with the original clopidogrel salt, supporting the routine use of this low-cost generic clopidogrel in the management of cardiovascular disease patients.

Comparison of Triflusal with Aspirin in the Secondary Prevention of Atherothrombotic Events; Α Randomised Clinical Trial.

BACKGROUND: Triflusal has demonstrated an efficacy similar to aspirin in the prevention of vascular events in patients with acute myocardial infarction (ΜΙ) and ischaemic stroke but with less bleeding events. OBJECTIVE: We performed a randomised, multicentre, phase 4 clinical trial to compare the clinical efficacy and safety of triflusal versus aspirin, administered for 12 months in patients eligible to receive a cyclooxygenase-1 (COX-1) inhibitor. METHODS: Patients with stable coronary artery disease or with a history of non-cardioembolic ischaemic stroke were randomly assigned to receive either triflusal 300 mg twice or 600 mg once daily or aspirin 100 mg once daily for 12 months. The primary efficacy endpoint was the composite of: (a) ΜΙ, (b) stroke (ischaemic or haemorrhagic), or, (c) death from vascular causes for the entire follow-up period. The primary safety endpoints were the rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria. RESULTS: At 12-month follow-up, an equivalent result was revealed between the triflusal (n=559) and aspirin (n=560) in primary efficacy endpoint. Specifically, the combined efficacy outcome rate (i.e. MI, stroke or death from vascular causes) difference was equal to -1.3% (95% confidence interval -1.1 to 3.5) and lied within the a-priori defined equivalence interval (p<0.001). Regarding the primary safety endpoints, patients on triflusal treatment were 50% less likely to develop bleeding events according to the BARC criteria, and especially any clinically overt sign of haemorrhage that requires diagnostic studies, hospitalisation or special treatment (BARC type 2). CONCLUSION: The efficacy of triflusal in the secondary prevention of vascular events is similar to aspirin when administered for 12 months. Importantly, triflusal significantly reduced the incidence of ΜΙ and showed a better safety profile compared with aspirin. (ASpirin versus Triflusal for Event Reduction In Atherothrombosis Secondary prevention, ASTERIAS trial; Clinical Trials.gov Identifier: NCT02616497).

Salts of Clopidogrel: Investigation to Ensure Clinical Equivalence: A 12-Month Randomized Clinical Trial.

BACKGROUND: In the present clinical trial, we compared the efficacy and safety of the generic clopidogrel besylate (CB) with the innovator clopidogrel hydrogen sulfate (CHS) salt in patients eligible to receive clopidogrel. METHODS: A prospective 2-arm, multicenter, open-label, phase 4 clinical trial. Consecutive patients (n = 1864) were screened and 1800 were enrolled in the trial and randomized to CHS or CB. Primary efficacy end point was the composite of myocardial infarction, stroke, or death from vascular causes, and primary safety end point was rate of bleeding events as defined by Bleeding Academic Research Consortium criteria. RESULTS: At 12-month follow-up, no differences were observed between CB (n = 759) and CHS (n = 798) in primary efficacy and safety end points (age, sex, history of percutaneous coronary intervention adjusted odds ratio [OR], 0.70; 95% confidence interval [CI], 0.41-1.21 and OR, 0.81; 95% CI, 0.51-1.29, respectively) between CHS and CB. Analyses of efficacy and safety in subgroups that were defined according to the qualifying diagnosis revealed that there was no difference between CHS and CB. CONCLUSION: The efficacy and safety of CB administered for 12 months for the secondary prevention of atherothrombotic events are similar to that of CHS. (Salts of Clopidogrel: Investigation to ENsure Clinical Equivalence, SCIENCE trial; ClinicalTrials.gov Identifier:NCT02126982).

Antiplatelet treatment in the secondary prevention of coronary and cerebrovascular disease: is there any place for novel agents?

Ischemic heart disease and cerebrovascular disease remain major health problems with associated mortality and quality-of-life consequences. Antiplatelet agents, including thienopyridines and the new P2Y12 inhibitors, have been shown to improve survival in the secondary prevention setting. We review the available evidence on the effectiveness and safety of previous established as well as novel antithrombotic agents in the secondary prevention of cardiovascular disease with a special focus on cerebrovascular disease.

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.

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.

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.

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.