Current Pharmaceutical Design - Volume 14, Issue 12, 2008

The success of percutaneous coronary interventions depends on a number of variables. Clearly, all starts with appropriate patient and lesion selection for an interventional approach as compared to medical therapy or bypass surgery. A deep understanding of the sometimes complex material as well as broad experience in handling the available technology is also extremely important. A third variable relates to adjunct anticoagulant (antiplatelet and antithrombotic) pharmacological interventions. In recent years, use of acetylsalicylic acid (ASA), thienopyridines and- to a lesser extent, glycoprotein IIb/ IIIa receptor antagonists- has been turned out as the cornerstone of antiplatelet therapy. Regarding antithrombotic interventions, the picture is not so clear. Historically, unfractionated heparin (UFH) has been used for a long time in most centers worldwide. In recent years, however, limitations of UFH like the occurence of heparin- induced thrombocytopenia (HIT) have been disclosed. Furthermore, as the prognostic importance of periprocedural bleeding events has become apparent, the search for alternatives to UFH has become even more important. During the last decade, a number of new antithrombotic drugs have been developed and clinically evaluated, but there is also more to come. In this edition of “Drugs in interventional cardiology”, a variety of antithrombotic drugs in the context of percutaneous coronary interventions will be discussed. In the first article, Susanne Alban will provide an overview on the pharmacology of different antithrombotic drug classes [1]. Thereafter, the specific problem of anticoagulation in patients with confirmed or suspected HIT will be adressed by Alexander Joost and co- workers [2], before two manuscripts will focus on anticoagulation in the large number of patients with acute coronary syndromes using factor Xa inactivation [3] or direct thrombin inhibition [4]. Due to restricted budgets in most health care systems as well as different reimbursement policies between countries and even between states, pharmacoeconomic considerations of anticoagulants are relevant and will be discussed in the last manuscript [5]. I would like to thank all authors for their contribution. References [1] Alban S. Pharmacological strategies for inhibition of thrombin activity. Curr Pharm Des 2008; 14(12): 1152-1175. [2] Joost A, Kurowski V, Radke PW. Anticoagulation in patients with heparin-induced thrombocytopenia undergoing percutaneous coronary angiography and interventions. Curr Pharm Des 2008; 14(12): 1176-1185. [3] Barantke M, Bonnemeier H. Factor Xa Inactivation in Acute Coronary Syndrome. Curr Pharm Des 2008; 14(12): 1186-1190. [4] Hartmann F. Safety and Efficacy of Bivalirudin in Acute Coronary Syndromes. Curr Pharm Des 2008; 14(12): 1191-1196. [5] Houston S, Hawkins SA. Pharmacoeconomics of Anticoagulants in Acute Coronary Syndrome and Percutaneous Coronary Intervention. Curr Pharm Des 2008; 14(12): 1197-1204.

For decades, the options for therapeutic anticoagulation were limited to unfractionated heparin (UFH) and vitamin K antagonists (VKA), and their well-known limitations had to be accepted. With the introduction of the various LMWHs, the short-term anticoagulation could be much improved. The heparins delivered the proof of concept that FXa and thrombin represent suitable targets for therapeutic anticoagulation. Consequently, the search for new anticoagulants focus on inhibitors of thrombin or FXa. Apart from the VKA, the anticoagulants presently available or in an advanced stage of development can thus be divided in two classes: One are the glyco-anticoagulants with the natural sulfated glycosaminoglycans (GAGs) (UFH, LMWHs, and danaparoid) and the synthetic oligosaccharides (OS) (fondaparinux, idraparinux, and SR123781A). The other class are the xenobiotic anticoagulants, i.e. proteins and synthetic chemical entities. Die glyco-anticoagulants act partially (GAGs) or exclusively (oligosaccharides) by catalysing antithrombin, whereas the xenobiotic anticoagulants are direct inhibitors of either thrombin or FXa. At present, three direct thrombin inhibitors (DTI) (lepirudin, argatroban, and bivalirudin) are clinically used for limited indications, whereas there is still no direct FXa inhibitor available. The DTI ximelagatran represented the first oral anticoagulant since the introduction of VKA, but was withdrawn due to safety concerns. Among numerous drug candidates in the clinical development, two orally active anticoagulants dabigatran etexilate, a DTI, and rivaroxaban, the direct FXa inhibitor, are in the most advanced stage of development and may allow a paradigm change in anticoagulation in the foreseeable future. This review describes the pharmacological profile of all these anticoagulants.

The administration of heparins (unfractionated or fractionated) represents the current standard as anticoagulant treatment during percutaneous coronary intervention in different clinical settings (elective cases and acute coronary syndrome). Since the incidence of heparin-induced thrombocytopenia (HIT) is expected to range between 0.1 and 5%, the application of an appropriate anticoagulant agent has become a mandatory issue. This review will provide current pathophysiological insights of HIT as well as contemporary alternative anticoagulant strategies during PCI in patients with or at risk of HIT.

The increasing incidence of patients who develop acute coronary syndrome (ACS) stresses the importance of effective initial treatment to reduce morbidity and mortality. The recommended initial therapeutic regimen for patients with ACS includes both anticoagulants and antiplatelet agents to prevent excessive coronary thrombosis, stroke, and further coronary events. Most commonly, unfractionated heparin (UFH) is used for initial antithrombotic treatment of ACS, despite limited published evidence regarding effectiveness and safety (bleeding complications). Therefore, this treatment regimen is primarily based upon expert opinion rather than evidence-based medicine. Studies addressing the dilemma of effectiveness and increased risk of bleeding when using UFH and low molecular weight heparin (LMWH) in patients with ACS showed superior clinical outcome in patients treated with LMWH. Nevertheless, the concurrent increased risk of bleeding while using anticoagulants is a severe problem and negatively impacts upon clinical outcome. Furthermore, non-hemorrhagic side effects of heparin such as heparin-induced thrombocytopenia (HIT), and skin reactions at the site of subcutaneous injection are reduced but not abolished by replacing UFH with LMWH. The limitations of UFH and LWMH as outlined above provided the impetus for the development of a pentasaccharide, called fondaparinux, which inhibits facor Xa selectively. Fondaparinux has been shown to be as effective as enoxaparin in the prevention of thrombosis in patients undergoing orthopedic surgery and showed similar results compared to enoxaparin or UFH in patients with deep-vein-thrombosis or pulmonary embolism. Recently, a large clinical study addressed the dilemma of the effectiveness and adverse effects of anticoagulation in ACS by comparing fondaparinux and LMWH such as enoxaparin in patients with unstable angina or non ST-segment elevation myocardial infarction (NSTEMI).

Antithrombotic and powerful antiplatelet therapies, in addition to early percutaneous coronary intervention (PCI) are considered the treatment of choice for moderate- to high-risk patients with acute coronary syndromes (ACS; unstable angina and non-STsegment elevation myocardial infarction). However, despite the integration of newer therapies including stents, glycoprotein IIb/IIIa inhibitors (GPI), and thienopyridines, the rate of adverse ischemic events still remains unacceptably high. Intensive pharmacologic regimens used to stabilize the disrupted atherosclerotic plaque and support angioplasty as well as surgical revascularization procedures, elicit a high rate of bleeding complications. Recent trials (ACUITY and HORIZONS studies) added evidence regarding safety and efficacy of bivalirudin use in acute coronary syndromes. In summary, is has been shown that bivalirudin alone is safe and effective in the vast majority of patients suffering from acute coronary syndromes and being treated invasively. The cost-effectiveness of such an approach will have to be determined. It remains to be a matter of discussion whether there are still patient subgroups being in need of more aggressive treatment strategies including GPI. In practice, it might be reasonable to perform a baseline assessment of hemorrhagic risk facilitating the choice of an antithrombotic regimen with a favourable safety and efficacy profile. With this tailored therapy it might be possible to further improve outcomes for individual patients with ACS.

Economic evaluation plays an important role during almost all stages of pharmaceutical design and use. This paper reviews the recent pharmacoeconomic literature on the use of anticoagulants for acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI). Both ACS and PCI are common reasons for hospitalization and contribute significantly to costs of care. ACS and PCI practice standards are still evolving. For ACS enoxaparin does appear to be more cost-effective around the globe than unfractionated heparin (UFH) when clopidrogel and glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors are not used. With the high prevalence of clopidrogel and GP IIb/IIIa use, the question may be moot. Since the cost of UFH therapy, including the cost of anticoagulant monitoring, is less expensive than enoxaparin therapy, UFH is probably the more cost-effective strategy. For PCI, as ischemic complications were reduced during the mid'90's, bleeding complications have become the most common problem and a major cost driver. Other complications that can drive costs include the occurrence of MI and revascularization procedures (repeat PCI or CABG). Results suggest that bivalirudin plus a provisional GP IIb/IIIa inhibitor is the most cost-effective strategy for patients undergoing elective PCI. There is no clear evidence regarding its use in urgent PCI. ACS and PCI practice standards are still evolving. It would be useful to embed economic studies within new clinical trials. Full economic analysis of groups at high risk for bleeding while undergoing PCI is needed.

Myocardial infarction necessitates new therapeutic interventions, since it still results in high morbidity and mortality worldwide. Reperfusion therapy itself results in (acceleration of) apoptosis, called myocardial ischemia/reperfusion (I/R) injury. For several decades it is known that the inflammatory response during reperfusion is the major cause of myocardial I/R injury. Therapeutic options are limited by lack of (detailed) understanding of intra- and intercellular mechanisms between inflammatory cells and cardiomyocytes. Furthermore, clinical trials generally fail to reproduce experimental successes, because essential factors are not taken into account in animal studies: risk factor for coronary artery disease, duration of ischemia and reperfusion, time of intervention. Above all, there is no specific therapeutic target for inhibiting the inflammatory response, in which cardiomyocytes are involved. The identification of Toll-like receptors (TLRs) on cardiomyocytes, has given rise to, not only new insights on the inflammatory response initiated by cardiomyocytes themselves, but also provided potential targets to reduce myocardial I/R injury. Experimental and clinical studies show that inflammatory responses are also involved in tissue repair responses. Since certain TLRs are expressed on inflammatory cells and cardiomyocytes, it ensures specific targeting of either detrimental effects or tissue repair responses in the inflammatory response during reperfusion. Which TLRs are involved in the ‘good’ and which in the ‘bad’ effects of the inflammatory response remains to be addressed. This review will discuss both experimental and clinical research on inflammatory reactions that occur after myocardial ischemia/ reperfusion (I/R). Data and conclusions concerning potential therapeutic targets in both experimental as clinical research settings will be reviewed.

After three decades from the development of the hybridoma technology, a monoclonal antibody-based therapy targeting the inflammatory cytokine has been established as an ultimate treatment for chronic inflammatory diseases. Interleukine-6 (IL-6) is one of the inflammatory cytokines playing a pivotal role in these conditions, and strategies targeting IL-6 signal show promise in the treatment of chronic inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, and Crohn's disease. Although many groups have been exploring the approach to block the IL-6 signal, tocilizumab, a humanized monoclonal antibody of the IL-6 receptor, has been the most intensively studied agent for clinical use. Clinical trials regarding chronic inflammatory diseases described above have demonstrated efficacy of tocilizumab, however, this treatment has limitations in terms of economic costs and ease of administration, and further advances are necessary to expand the concept of IL-6-specific therapeutics. In this review, we discuss targeting IL-6 in a rational drug design and present the various strategies to achieve this.

Obesity was first described as a low-grade inflammatory condition more than a decade ago. However, it is only relatively recently that obese individuals have been described with increased macrophage infiltration of adipose tissue, as well as an increase in the number of “M1” or “classically activated” macrophages. Furthermore, macrophages have been identified as the primary source of many of the circulating inflammatory molecules that are detected in the obese state and are postulated to be causal both in the development of insulin resistance and in the progression to type 2 diabetes. There is also novel evidence to suggest that macrophages inhibit adipocyte differentiation, potentially leading to adipocyte hypertrophy, altered secretion of adipokines and ectopic storage of lipid within liver, muscle and other non-adipose tissues. Currently, it is not clear what causes increased macrophage infiltration of adipose tissue in obese individuals. Theories include altered signalling by adipocytes, nutritional induction of metabolic endotoxemia or reduced angiogenesis and local adipose cell hypoxia. Importantly, PPAR-gamma agonists have been shown to alter macrophage phenotype to “M2” or an “alternatively activated” anti-inflammatory phenotype and may induce macrophage specific cell death. Consequently, excitement surrounds the potential for specific inhibition of macrophage infiltration of adipose tissue via pharmacotherapy for obese patients and more particularly as adjunct therapy to improve insulin sensitivity in obese individuals with insulin resistance and overt type 2 diabetes.

Human interleukin 5 (IL5) is the major hematopoietin that stimulates the proliferation, migration and activation of eosinophils and is implicated in the pathogenesis of inflammatory and other myeloproliferative diseases. IL5 functions through the signaling of a common receptor subunit β (βc), in a receptor activation process that requires initial recruitment of an IL5 specific receptor subunit α (IL5Rα), for cytokine presentation to βc. Important advances have been made to understand molecular mechanisms of cytokine recognition and receptor antagonism. Mutational studies indicate that a pair of charge complementary regions play an essential role in specific interaction between IL5Rα and IL5. Moreover, peptide studies with the IL5 system have identified a cyclic peptide inhibitor, AF17121, which binds specifically to IL5Rα by mimicking the cytokine. A key receptor-recognition pharmacophore has been identified in this peptide inhibitor, and sites of inhibitor recognition can be proposed in the homology-deduced structural model of IL5Rα. These results provide an experimental platform to derive enhanced-potency peptidomimetic inhibitors. Such inhibitors have potential use as tools to evaluate the role of eosinophilia in disease and as potential leads to antagonists to treat hyper-eosinophilic diseases such as eosinophilic esophagitis, asthma and chronic myeloproliferative leukemias.