Current Pharmaceutical Design - Volume 18, Issue 33, 2012

The crucial role of platelets in primary hemostasis and repair of injured endothelium is well established, as is their role in atherothrombosis. No other single cell type is responsible for as much morbidity and mortality, since death from ischemic heart disease or stroke is by far the leading cause of death worldwide. There is no doubt that our understanding of atherothrombosis has guided current antithrombotic strategies that have dramatically reduced ischemic complications and cardiovascular mortality within the last decades. Yet the rate of ischemic complications after optimal revascularization therapy remains disappointingly high. There is still a strong need for new and smart antiplatelet drugs. The ideal antithrombotic drug would spare physiological platelet function, hemostasis and vascular repair in order to avoid bleeding complications, but would exclusively target the pathological atherothrombotic process. As platelet activity might be determined early in the bone marrow, this review starts with insights into the birth of platelets, describes the essential and primary role of platelets in hemostasis with new evidence in signaling cascades, and closes with the deleterious role of platelets in atherosclerosis and atherothrombosis, with a focus on acute coronary syndromes.

Aspirin is an antiplatelet drug, inhibiting the cyclooxygenase activity of platelet prostaglandin H synthase-1 and almost complete suppressing platelet capacity to generate the prothrombotic and proatherogenic thromboxane A2. Antiplatelet therapy with aspirin reduces the risk of serious vascular events by about a quarter in patients who are at high risk because they already have occlusive vascular disease. However, the inhibition of thromboxane-dependent platelet function by aspirin is effective for the prevention of thrombosis, but is also associated with excess bleeding, although the absolute increase in major gastrointestinal or other major extracranial bleeds is an order of magnitude smaller. For secondary prevention of vascular events, the benefits of aspirin therapy substantially exceed the risks. Therefore, aspirin is a cornerstone of antithrombotic therapy in acute coronary syndromes, in chronic ischemic heart disease and in percutaneous coronary intervention. On the other hand, the role of aspirin in primary prevention remains uncertain and it is still debated, because the absolute risk of vascular complications is the major determinant of the absolute benefit of antiplatelet prophylaxis and the reduction in vascular events needs to be weighed against any increase in major bleeds. Future data from ongoing studies will help us to identify people at high vascular risk who take advantage from aspirin therapy for primary prevention or will indicate if specific category of high risk patients, like patients with diabetes, could be better protected from an increase in the frequency of aspirin administration.

In patients with stable and unstable coronary disease and those undergoing coronary stenting, the activation of platelets plays a central role in the occurrence of major thrombotic events such as death, myocardial infarction and stent thrombosis. Antiplatelet therapy for primary and secondary prevention of thromboembolic events is a cornerstone for the management of these patients and for many years the cyclooxygenase-1 (COX-1) inhibitor aspirin and the second generation thienopyridine clopidogrel which targets the ADP P2Y12 receptor on platelets served as the main antiplatelet agents for these indications. Clopidogrel in particular is very efficient in reducing ischemic cardiovascular events but exposes patients to an increased risk of bleeding. Therefore the optimal dosage and duration of clopidogrel therapy is of utmost importance. Furthermore, platelet function studies have revealed that responsiveness to clopidogrel is not uniform and that a low response is linked to a higher incidence of thrombotic events. Causes are multifactorial and several genetic and non-genetic factors including patients' co-morbidities and co-medications have been identified. As a result clopidogrel's long lasting monopole as the only antiplatelet agent in patients undergoing coronary stenting is currently challenged by the newer P2Y12 blockers such as prasugrel and ticagrelor, which provide a stronger and more consistent inhibition of platelets. In the setting of acute coronary syndromes, this more potent platelet inhibition led to less thrombotic events with these newer agents, but at the cost of a higher bleeding risk. This review provides an overview of the indication, dosage and duration of clopidogrel therapy and discusses its role in light of the recent introduction of newer P2Y12 receptor antagonists, the combination with newer oral anticoagulants such as dabigatran, apixaban and rivaroxaban as well as the emerging use of platelet function testing in clinical practice.

Anti-platelet agents have left an indelible impression in the management of a wide range of pathologies. From the earliest therapeutic agents such as aspirin, to the cutting edge agents still undergoing development, they have the capability to powerfully manipulate platelet biology, a central player in thrombosis. The use of these agents is still subject to a number of important limitations that two newer agents, prasugrel and ticagrelor, aim to address. Both have recently received licensing for use in acute coronary syndromes and promise to improve outcomes for patients. Here, we examine the rationale for the development and clinical integration of antiplatelet agents focusing upon prasugrel and ticagrelor.

Stroke prevention is highly effective but underutilized in medical care. Lifestyle modification, in the form of diet, exercise, smoking cessation, antihypertensive therapy, close control of diabetes and hyperlipidemia, can prevent most strokes. Selected subgroups can benefit from carotid surgery or stenting, anticoagulation for atrial fibrillation, and antiplatelet therapy. Evidence for these approaches and alternative management strategies are discussed.

Patients with diabetes mellitus (DM) have accelerated atherosclerosis, which explains their high risk of cardiovascular disease and atherothrombotic complications. Among the several factors contributing to the prothrombotic condition which characterize patients with DM, platelet hyperreactivity is of major relevance since platelets play a key role in the development of atherosclerosis and its atherothrombotic complications. A number of mechanisms contribute to platelet dysfunction and affect the adhesion, activation and, aggregation phases of platelet-mediated thrombosis. In addition, DM is associated with a high prevalence of reduced pharmacodynamic response to standard oral antiplatelet treatment regimens. The latter may contribute to explain the fact that despite the use of recommended antiplatelet treatment strategies, the presence of DM has been consistently associated with a high rate of adverse recurrent cardiovascular events. Therefore, several new antiplatelet treatment strategies have been developed in order to optimize platelet inhibition: a) modification of dosing of commonly used agents; b) use of new agents; and c) addition of a third antiplatelet drug (triple therapy). The present review manuscript aims to provide an overview on the current status of knowledge on platelet abnormalities that characterize patients with DM, focusing on the challenges and perspectives of antiplatelet treatment strategies in this population.

The concept of “pharmacogenetics” addresses genetically determined variation in how individuals respond to drugs. Accordingly, specific genetic variants have been suggested as contributors to a reduced response to various antiplatelet drugs. Aspirin is a cornerstone in secondary cardiovascular prevention and has been thoroughly investigated. The efficacy of aspirin is well documented, although with considerable interindividual variation. According to meta-analyses, a reduced antiplatelet effect of aspirin confers an increased risk of cardiovascular events. The platelet response to aspirin is assessed by in vitro evaluation of thromboxane-dependent platelet function. A reduced antiplatelet effect of aspirin can be explained by several mechanisms, which are largely determined by clinical, pharmacodynamic, biological and genetic factors. During the past decade, numerous studies have identified genetic polymorphisms significantly associated with cardiovascular events and modulating the antiplatelet effect of aspirin. However, results have been contradictory allowing only few firm conclusions to be drawn. Polymorphisms in genes encoding glycoproteins (IIb/IIIa, Ia/IIa, VI and Ibα), cyclooxygenases (1 and 2), adenosine diphosphate receptors (P2Y1 and P2Y12) and proteins of importance for haemostasis (thromboxane A2 receptor, coagulation factor XIII, etc.) have been investigated. In particular, a polymorphism in the gene encoding glycoprotein IIb/IIIa has been associated with a reduced antiplatelet effect of aspirin. The additive value of an individual's genetic makeup in predicting the antiplatelet effect of aspirin and the risk of cardiovascular events remains controversial. The present review outlines the pharmacology of aspirin and provides an overview of specific genetic variations considered to influence the antiplatelet effect of aspirin.

Clopidogrel used in conjunction with aspirin has a central role in the treatment of patients with an acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI). The pharmacokinetic and pharmacodynamic responses to this drug are highly variable leaving up to one third of patients with inadequate platelet inhibition or high on-treatment platelet reactivity (HPR), and subsequent increased ischemic cardiovascular events. Genetic variability in drug absorption and metabolism is a key factor responsible for the inefficient generation of the active drug metabolite. The two-step hepatic cytochrome P450 (CYP)-dependant oxidative metabolism of the prodrug appears to be of particular importance. Pharmacogenomic analyses have identified loss-of-function variant alleles of CYP 2C19 and specifically the 2C19*2 allele, to be the predominant genetic mediators of the antiplatelet effect of clopidogrel. Carriers were have been shown to have lower active metabolite levels of clopidogrel, higher platelet reactivity and associated poorer outcomes. Rapid and accurate point-of-care genetic tests to identify these alleles are currently in development but several questions about the role of such testing remain such as patient selection and whether personalized treatment based on genotype has a positive impact on clinical outcome. At present, genetic testing cannot be recommended in routine clinical practice due to insufficient prospective data. However, the significant body of research published to date suggests a likely role when used in combination with platelet function analysis in ACS patients undergoing stenting who have other known risk factors for recurrent ischemic events.

Platelets play a pivotal role in primary hemostasis where their rapid response to vascular injury prevents excessive bleeding. To accomplish this, platelets are enriched in membrane receptors and cytoplasmic enzymes with often redundant and self-amplifying functions leading to platelet activation, release into the bloodstream of hemostatically active compounds and culminating with thrombus formation. However, the same process in the pathological state of atherosclerosis can lead to thrombotic complications such as an acute coronary syndrome or stroke. The role of platelets in this process is more extensive than previously believed. Several lines of evidence suggest that platelets contribute not only to the acute thrombotic events in atherosclerosis, but also to disease initiation and progression. This review focuses on the role of platelet heterogeneity and turnover in atherothrombotic disease. Specifically, this article covers (a) the regulation of platelet formation; (b) the role of the heterogeneity of platelets in atherothrombotic diseases; (c) the disease-modifying effect of platelets on the development of atherosclerosis; and (d) the modifying effect of atherosclerotic disease on platelet production and function; (e) the platelet indices influencing platelet responsiveness to antiplatelet therapies; and finally (f) the potential novel therapeutic modalities that could be applied in atherothrombosis.

The modern era of antiplatelet therapy was founded by large clinical trials demonstrating the benefit of aspirin and clopidogrel in the treatment and prevention of acute coronary syndromes. The concept of antiplatelet drug “resistance” emerged during the 1990s with studies revealing considerable residual platelet aggregation in some patients despite aspirin treatment. In the wake of these reports, larger studies established an association between high on-treatment platelet reactivity and thrombotic events. The possible mechanisms explaining this phenomenon are manifold and reflect the complexity of platelet function, thrombus formation and cardiovascular disease. Some mechanisms apply to both drugs, while others apply only to one of them. In recent years, efforts have been made to translate this information into an improved clinical outcome by modifying antiplatelet drug regimens. Several studies investigated measurements of on-treatment platelet reactivity, but large clinical trials have failed to demonstrate substantial clinical benefit of individually tailored antiplatelet therapy according to platelet function tests. This article provides an integrated review of interindividual variability in the efficacy of aspirin and clopidogrel with particular emphasis on possible effect-modifying mechanisms and clinical implications.

Antithrombotic therapy is a cornerstone of treatment in patients with cardiovascular disease with bleeding being the most feared complication. This review describes the risk of bleeding related to different combinations of antithrombotic drugs used for cardiovascular disease: acute coronary syndrome (ACS), atrial fibrillation (AF), cerebrovascular (CVD) and peripheral arterial disease (PAD). Different risk assessment schemes and bleeding definitions are compared. The HAS-BLED risk score is recommended in patients with AF and in ACS patients with AF. In patients with ACS with or without a stent dual antiplatelet therapy with a P2Y12 receptor antagonist and acetylsalicylic acid (ASA) is recommended for 12 months, preferable with prasugrel or ticagrelor unless there is an additional indication of warfarin or increased risk of bleeding. In patients with AF, warfarin is recommended if the risk of stroke is moderate to high, but newer emerging antithrombotic drugs will be recommended along with/or preferred to warfarin in the nearby future. Patients with CVD (without cardiogenic causes) are recommended clopidogrel treatment for secondary prevention, where as patients with PAD are recommended ASA or clopidogrel. With future implementation of new antithrombotic treatment regimens as monotherapy and in combinations with antiplatelet therapy, increased focus on risk of thromboembolic events and bleeding and individual tailoring of antithrombotic therapy is warranted.

Platelet function testing was introduced more than a century ago with the invention of bleeding time; a test which has now been replaced by more accurate methods. Light transmittance aggregometry is traditionally regarded as the gold standard for evaluating platelet function. However, lately the position of light transmittance aggregometry has been challenged by a panel of new instruments. Aspirin and P2Y12-inhibitors are antiplatelet drugs used for secondary prevention of cardiovascular disease. However, an increasing recognition of the fact that not all patients respond adequately to these agents has prompted a focus on individualising antiplatelet treatment. Platelet function testing enables the detection of patients with high on-treatment platelet reactivity and facilitates individually tailored antiplatelet therapy, yet platelet function tests have still not been adopted into routine clinical practice. The present review outlines key milestones of the development of platelet function testing and provides an up-to-date overview of currently available tests and important studies evaluating their strengths and limitations in a clinical context.

P2Y12 adenosine di-phosphate (ADP) receptor antagonists are critical to reduce thrombotic recurrences in acute coronary syndromes patients and for those undergoing percutaneous coronary revascularization. Multiple lines of evidence suggest that the level of on-treatment platelet reactivity inhibition with P2Y12 ADP receptor antagonists correlates with thrombotic recurrences. Recent studies observed a relationship between excessive platelet reactivity inhibition and bleedings. Together these data support the potential of platelet reactivity measurement to prevent thrombotic events without increasing bleeding. In the present review we aimed to summarize evidences of a therapeutic window for P2Y12-ADP receptor antagonists and the potential of platelet reactivity monitoring and individualized antiplatelet therapy to optimize the clinical outcome in patients suffering from an acute coronary syndrome or undergoing percutaneous coronary intervention.