Advances in Cardiology最新文献

The unifying basis of acute coronary syndrome (ACS) is the complication of a vulnerable coronary plaque, an event primarily mediated by platelet activation. Three major pathways are predominantly involved in this process: thromboxane A(2) via the thromboxane A(2) receptor, adenosine diphosphate via the P2Y(12) receptor, and thrombin via the protease-activated receptor (PAR)-1, with the latter being the most potent platelet activator. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y(12) inhibitors, respectively, the recurrence of ischemic events in patients with ACS remains high. There is also a growing concern regarding the safety profile in terms of bleeding with more powerful antiplatelet agents, which has tempered expectations of newly developed compounds. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preliminary data indicate that these compounds have the potential to improve ischemic prognosis without increasing the bleeding risk. In this chapter we will discuss the rationale for developing this novel class of antiplatelet agents and specifically, the two compounds in most advanced clinical development, vorapaxar and atopaxar.

For many years clopidogrel was the 'gold standard' ADP receptor antagonist in patients with coronary artery disease in combination with acetylsalicylic acid, i.e. in elective/stable patients after coronary stent implantation and in patients with acute coronary syndromes with/without percutaneous coronary intervention. For the latter group, in which the risk of atherothrombotic events is increased, the new ADP receptor-antagonists, e.g. prasugrel and ticagrelor, have shown their superiority over clopidogrel. This is mainly based on the fact that up to 30% of patients with acute coronary syndromes tend to be low- or non-responders to therapy due to non-genetic and/or genetic causes. Nevertheless, there is still room for the use of clopidogrel in the majority of patients with coronary artery disease. This review summarizes the latest knowledge of clopidogrel and its current indications.

Dual antiplatelet therapy with aspirin and a P2Y(12) receptor antagonist improves outcomes in patients with acute coronary syndrome and in those treated with percutaneous coronary intervention (PCI) and a coronary stent. Candidate gene and genome-wide association studies have found that common genetic polymorphisms of the cytochrome P450 (CYP) 2C19 isoenzyme that result in a loss of functional activity are associated with less exposure of clopidogrel active metabolite and a diminished antiplatelet effect. Meta-analyses of registries and genetic substudies of randomized clinical trials demonstrate that carriers of these polymorphisms who are treated with clopidogrel are at an increased risk of cardiovascular events, particularly stent thrombosis, compared with noncarriers. This deleterious effect appears to be attenuated in patients not treated with PCI. The influence of polymorphisms of other genes, such as ABCB1, is inconsistent across clinical studies. The clinical efficacy of the newer P2Y(12) antagonists prasugrel and ticagrelor do not appear to be affected by the CYP2C19 genotype, but these agents increase major bleeding not related to coronary artery bypass surgery. Although data from randomized clinical trials are currently lacking, these observations suggest that a pharmacogenomic-guided approach to antiplatelet therapy in acute coronary syndrome could potentially maximize ischemic benefit while minimizing bleeding risk.

Atrial fibrillation (AF) is an extremely prevalent dynamic chronic disease often associated with underlying heart disease, making the management of AF challenging. The antithrombotic management - and in particular the use of antiplatelet agents herein - is challenging as it depends on the (adequate) assessment of the risk of stroke and major bleeding. We therefore focus on the current (recommended) use of antiplatelet agents, address the caveats, and provide clinical tools to assess risk of stroke and major bleeding. Furthermore, we discuss novel antithrombotic agents to provide a future perspective of the role of antiplatelet agents in the antithrombotic management of AF patients.

Platelets play a critical role in the pathophysiology of acute coronary syndrome and thromboembolic complications associated with atrial fibrillation. Despite the development of newer and more potent antiplatelet agents, aspirin remains the cornerstone of antithrombotic therapy. Clinical trials conducted over the past decades have clearly established the safety and efficacy of aspirin therapy for the acute treatment and secondary prevention of acute myocardial infarction, ischemic stroke, and vascular death among patients at high risk for cardiovascular events. Although the absolute benefit of aspirin for primary prevention is lower than seen in secondary prevention trials, it is nevertheless an accepted preventive. This chapter provides a comprehensive overview of the clinical utility of aspirin in the setting of acute coronary syndrome and atrial fibrillation.

The antithrombotic activity of dipyridamole was initially discovered in an in vivo experiment about half a century ago. At that time science had not appreciated the complexity of the regulation of local thrombus formation. Inhibition of platelets has been the main focus for the prevention of arterial thrombus formation. Unfortunately, established in vitro test systems have to take away several important components of the hemostatic system. Rather than directly inhibiting platelet aggregation, dipyridamole amplifies endogenous antithrombotic systems and modulates or downregulates prothrombotic processes. While for many years the main focus had been on preventing acute thrombus formation in the case of a rupture of an atherosclerotic plaque in large coronary arteries, it now has been appreciated that perfusion of tissue and patency of small vessels and capillaries is equally important for preventing further damage to the tissue. Here dipyridamole was experimentally shown to improve perfusion and function in chronic hypoperfused tissue unrelated to its vasodilatory properties. Recently, several clinical trials have shown the benefit of dipyridamole when given in a formulation that assures a sufficient plasma concentration. Its potential to scavenge particularly peroxy radicals, its direct reduction of innate inflammation, and a chronic elevation of interstitial adenosine seems to be of more importance for the prevention of vascular and tissue damage than its adenosine- and prostacyclin-mediated antithrombotic effect. In its extended-release preparation with the tartaric acid nucleus, not only does it not seem to add significantly to the risk of bleeding, but seems to hold potential for protecting tissue from oxidative and metabolic stress.

Prasugrel is a third-generation thienopyridine which selectively inhibits the platelet P2Y(12) receptor more rapidly, more potently, and with less interindividual response variability compared with the second-generation thienopyridine clopidogrel. Large-scale phase III clinical testing showed that in high-to moderate-risk acute coronary syndrome patients undergoing percutaneous coronary intervention, prasugrel translates into a greater reduction in ischemic events, including stent thrombosis, in the short and long term compared to clopidogrel. Prasugrel, however, is associated with an increased risk of major bleeding, which is more pronounced in certain patient subgroups. The ideal patient population for prasugrel use are those patients without prior transient ischemic attack/stroke, <75 years of age and >60 kg in whom the greatest ischemic benefit is achieved without a significant increase in major bleeding risk. Dose modifications in specific populations or at given time-points may represent an avenue to minimize bleeding risk and therefore maximize the clinical benefit of prasugrel. Ongoing clinical studies with prasugrel will better define the safety and efficacy profiles of this agent and potentially set the basis for new indications for use.

Antiplatelet therapy serves an important role in the management of acute coronary syndromes and in reducing the risk of thrombotic complications from atrial fibrillation. There has been rapid development of newer and more potent antiplatelet therapies over the last several years that have further reduced ischemic complications, but with a trade-off of increased bleeding risk. Bleeding complications associated with antiplatelet and anticoagulant therapies are associated with significantly increased risk of adverse outcomes, including death. Understanding the risk of bleeding associated with antiplatelet agents is critical to developing strategies to mitigate this risk.

Ischemic stroke is a major cause of death and disability worldwide. Determination of the underlying stroke mechanism is critical for the optimization of treatment. The role of antiplatelet therapy in primary and secondary stroke prevention is of major significance. Antiplatelet agents predominantly in use are aspirin, clopidogrel, and combination regimens. Novel antiplatelet agents either in use or in advance clinical development seek an indication in the management of stroke patients; yet data are limited. The present review focuses on the optimization of antithrombotic therapy in the field of primary and secondary prevention of stroke, based on data obtained from randomized controlled trials and systemic reviews of the literature.