Ioannis Goudevenos

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 A2 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.

Short-term outcome and attainment of secondary prevention goals in patients with acute coronary syndrome--results from the countrywide TARGET study.

BACKGROUND/OBJECTIVES Acute coronary syndromes (ACS) continue to pose a significant medical and socioeconomic burden worldwide. Optimal management strategy aims to improve short and long-term outcome. The present study aims to assess short-term outcome of real-world ACS patients and evaluate the achievement rate of secondary prevention goals. METHODS The TARGET study is an observational study enrolling 418 consecutive ACS patients from 17 centers countrywide (78.0% males, 63.9 ± 12.9 years). After the in-hospital phase, patients were followed for 6 months. In total, 366 patients were included in the prospective phase of the study. At the end of the follow-up, mortality, major adverse cardiovascular events (MACE), prescription pattern of cardiovascular medications, lipid levels, adherence rate to treatment and behavioral recommendations were measured. RESULTS The overall mortality was 4.8% and the rate of MACE was 17.5%. At 6 months, a significantly lower proportion of patients received antiplatelet agents and statins as compared to hospital discharge. At the end of the follow-up, 87.7% of patients remained on statin treatment, yet only 18.2% of patients had LDL cholesterol levels less than 70 mg/dL. The adherence pattern to lifestyle and dietary recommendations remained low (66.2% quit smoking, 55.8% and 81.3% followed physical activity and dietary recommendations respectively). CONCLUSION Despite the low rate of mortality and MACE occurrence rate in this countrywide observational study, the attainment rate of secondary prevention goals is relatively poor. Improvement interventions focusing in these gaps of optimal care provision are expected to have a favorable impact on the prognosis of real world ACS patients.

Influence of high‐density lipoprotein and paraoxonase‐1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy

Summary.  Background: The paraoxonase activity of the enzyme paraoxonase‐1 (PON‐1) associated with high‐density lipoprotein (HDL) may significantly influence clopidogrel’s antiplatelet and clinical efficacy as a result of its involvement in the clopidogrel biotransformation to the pharmacologically active thiol metabolite. We evaluated the possible relationships of HDL levels as well as PON‐1 activities and the Q192R genotype with clopidogrel’s antiplatelet efficacy in acute coronary syndrome (ACS) patients. Methods and results: The platelet aggregation, P‐selectin expression and platelet/leukocyte conjugates as well as the clopidogrel response variability (evaluated by the VASP phosphorylation test and expressed as platelet reactivity index, PRI) were assessed in 74 ACS patients undergoing percutaneous coronary intervention (PCI) in relation to the PON‐1 Q192R genotype and to serum HDL‐cholesterol levels, and PON‐1 (paraoxonase and arylesterase) activities. Patients were loaded with 600 mg of clopidogrel followed by 75 mg per day. HDL‐cholesterol levels and PON‐1 activities at baseline (before clopidogrel loading) were not altered at 5‐ and 30‐day post‐clopidogrel loading, whereas baseline platelet activation parameters were significantly attenuated. At 5 days, 17 patients were clopidogrel non‐responders (PRI: 64.2 ± 11.1%). HDL‐cholesterol was inversely associated with platelet activation parameters independently on platelet response variability to clopidogrel whereas a negative association between platelet activation parameters and paraoxonase activity was observed in patients adequately responding to clopidogrel but not in clopidogrel non‐responders. Similarly, the platelet activation markers were significantly higher in PON‐1 Q192Q genotype carriers compared with those having one or two R alleles only in patients adequately responding to clopidogrel. Conclusions: PON‐1 is an important determinant of clopidogrel antiplatelet efficacy only in patients adequately responding to clopidogrel. These findings may be clinically important in ACS patients receiving clopidogrel therapy, especially the first days after the episode.

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.

Clopidogrel differentially affects platelet-mediated thrombosis and inflammatory response in patients with acute coronary syndromes.

1 Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979; 59: 8–13. 2 Grundy SM, Howard B, Smith S, Eckel R, Redberg R, Bonow RO. Prevention Conference VI: Diabetes and Cardiovascular Disease: executive summary: conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 2002; 105: 2231–9. 3 Carr ME. Diabetes mellitus: a hypercoagulable state. J Diab Complic 2001; 15: 44–54. 4 ZumbachM, HofmannM, Borcea V, Luther T, KotzschM, MulleM, Hergesell O, Andrassy K, Ritz E, Ziegler R, Wahl P, Nawroth PP. Tissue factor antigen is elevated in patients with microvascular complications of diabetes mellitus. Exp Clin Endocrinol Diabetes 1997; 105: 206–12. 5 Abdel-Hafiz E, Vaidyula VR, Bagga S, London FS, Boden G, Rao AK. Elevated whole blood tissue factor procoagulant activity in diabetes mellitus. Vitamin E inhibits glucose induced tissue factor activity in vitro. Blood 2002; 100: 496a. 6 Reverter JL, Reverter JC, Tassies D, Rius F, Monteagudo J, Rubies-Prat J, Escolar G, Ordinas A, Sanmarti A. Thrombomodulin and induced tissue factor expression on monocytes as markers of diabetic microangiopathy: a prospective study on hemostasis and lipoproteins in insulin-dependent diabetes mellitus. Am J Hematol 1997; 56: 93–9. 7 Diamant M, Nieuwland R, Pablo RF, Sturk A, Smit JW, Radder JK. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106: 2442–7. 8 Sommeijer DW, Hansen HR, van Oerle R, Hamulyak K, van Zanten AP, Meesters E, Spronk HM, ten Cate H. Soluble tissue factor is a candidate marker for progression of microvascular disease in patients with type 2 diabetes. J Thromb Haemost 2006; 4: 574–80. 9 Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V, Crandall J, Badimon JJ. Role of risk factors in themodulation of tissue factor activity and blood thrombogenicity. Circulation 2003; 107: 973– 7. 10 Gerrits AJ, Koekman CA, Yildirim C, Nieuwland R, Akkerman JW. Insulin inhibits tissue factor expression in monocytes. J Thromb Haemost 2009; 7: 198–205. 11 Ollivier V, Houssaye S, Ternisien C, Léon A, de Verneuil H, Elbim C, Mackman N, Edgington TS, de Prost D. Endotoxin-induced tissue factor messenger RNA in human monocytes is negatively regulated by a cyclic AMP-dependent mechanism. Blood 1993; 81: 973–9. 12 Bajaj MS, Ghosh M, Bajaj SP. Fibronectin-adherent monocytes express tissue factor and tissue factor pathway inhibitor whereas endotoxin-stimulated monocytes primarily express tissue factor: physiologic and pathologic implications. J Thromb Haemost 2007; 5: 1493–9. 13 Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest 2005; 115: 3355–62.

Expert consensus on the rational clinical use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

Two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab and alirocumab, have recently been approved by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. These fully human monoclonal antibodies selectively block PCSK9, thus permitting the low-density lipoprotein (LDL) receptor to effectively recycle to the surface of liver cells. The administration of these antibodies leads to robust LDL cholesterol (LDL-C) lowering by 50-60% on top of maximum hypolipidemic treatment. At least 4 randomized, placebo-controlled studies are under way and will address the question of whether the administration of these PCSK9 inhibitors is associated with a significant reduction of cardiovascular events. Because of the high cost associated with the use of these medications it is very important to consider which patients may gain the most benefit, at least until the results of outcome studies are available. In this Consensus paper, 34 clinicians/scientists define 3 groups of patients that should be currently considered as candidates for the use of these novel drugs. These include: 1a. Adults with established cardiovascular disease and LDL-C≥100 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe, 1b. Adults with diabetes and established cardiovascular disease or chronic kidney disease or target organ damage and LDL-C ≥100 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe, 2. Adults with familial hypercholesterolemia (FH) without established cardiovascular disease and LDL-C ≥130 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe (evolocumab is also indicated in children above 12 years with homozygous FH), and 3. Adults at high or very high cardiovascular risk who are statin intolerant and have an LDL-C ≥100 and ≥130 mg/dL, respectively, while on any tolerated hypolipidemic treatment.

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.

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.