Current Pharmaceutical Design - Volume 23, Issue 9, 2017

Anaxagoras and Empedocles both established during the Presocratic era a pioneering theory for the creation of everything in the universe. Macrocosmos' impact through the “Four Elements Theory” explained the conglomeration of the blood inside the vessels. Hippocrates, who instituted the “Four Humours theory”, clearly understood blood's coagulation and introduced the term “thrombus”. Plato, Aristotle and Galen, all engaged with the clotting phenomenon trying to interpret it. After eons of inquiry, it was the innovative thinking of the ancient Greek medico philosophers that set the scientific bases towards the understanding of a process that had been analyzing until our era.

Thrombosis is the formation of potentially deadly blood clots in the artery (arterial thrombosis) or vein (venous thrombosis). Since thrombosis is one of the main causes of death worldwide, the development of antithrombotic agents is a global medical priority. They are subdivided into antiplatelet agents and anticoagulants. Antiplatelet agents inhibit clot formation by preventing platelet activation and aggregation, while anticoagulants primarily inhibit the coagulation cascade and fibrin formation. Therapeutics within each category differs with respect to the mechanism of action, time to onset, duration of effect and route of administration. In this review, we critically discuss their main pharmacodynamic and pharmacokinetic characteristics as well as recent advances in daily clinical practice.

The efficacy of antiplatelet therapy for the secondary prevention of cardiovascular disease after an ischemic event is well established. However, the role for antiplatelet therapy for the primary prevention of cardiovascular disease is more complex because of the interplay of efficacy vs safety in individuals without established cardiovascular disease who have a relatively low, but linear trajectory of cardiovascular risk. Several large randomized trials have investigated the efficacy and safety of antiplatelet therapy (primarily aspirin) for patients without established cardiovascular disease. The pharmacological profile of the most commonly used primary prevention antiplatelet agent, aspirin, has been delineated by randomized clinical trials and showcased in practice guidelines for reducing cardiovascular risk. For this indication, aspirin has been consistently shown to reduce the risk of non-fatal myocardial infarction with little impact on cardiovascular death, but with a consistent increased risk of bleeding. These divergent results have contributed to differences in the recommendations from international practice guidelines and highlight controversy at the forefront of considerations for anti-platelet therapy for primary prevention. However, further studies in specific sub-groups of patients without established cardiovascular disease such as those with Diabetes Mellitus, chronic kidney disease, or the elderly may clarify which patient groups will benefit the most from aspirin treatment for the primary prevention of a cardiovascular event.

Background: Coronary artery disease remains the leading cause of death globally. Dual antiplatelet treatment with aspirin and aP2Y12 receptor significantly reduces thrombotic events. However, antiplatelet drug response displays considerable interindividual variability. Methods: Genetic factors account for up to 70% of impaired drug response. A number of genes encoding proteins involved in the pharmacokinetic pathway have been found to alter drug response. Results: According to most studies, CYP2C19 gene is the strongest genetic determinant. The novel antiplatelet agents prasugrel and ticagrelor, seem to overcome genetic restrictions but in expense of increased bleeding rates. Achieving a balance between adequate platelet inhibition and bleeding complications is challenging. Conclusion: Genetic screening may provide valuable guidance towards an efficient antiplatelet treatment. However, the lack of randomized controls trials testing the effect of a genotype-guided therapy, forbids the implementation of genetic testing into clinical practice.

Whilst there exist general guidelines regarding administration of antiplatelet therapy to prevent thrombotic events in patients with cardiovascular disease, the optimal therapy for a particular individuals in particular settings remains unclear. For patients with acute coronary syndrome (ACS) or those undergoing percutaneous coronary intervention (PCI), the use of potent antiplatelet agent combinations is recommended. However, some patients continue to have thrombotic events or experience bleeding events, which have been linked to the widely known variability in individual response to antiplatelet therapy, particularly to clopidogrel. Platelet function tests (PFTs) have been used in an attempt to predict ongoing thrombotic risk and to monitor the response to antiplatelet drugs. Although the cause of both thrombotic and bleeding events is multifactorial in origin, the observation that enhanced platelet reactivity is associated with recurrent thrombosis and reduced platelet reactivity with bleeding has raised hopes of identifying those at risk through the use of PFTs. Consequently, there was initial enthusiasm for the use of PFTs to guide individualized antiplatelet therapy. Few studies have been conducted, but the alteration of treatment based on the results of PFTs has not been shown to influence outcomes. Inherent limitations of the studies utilizing PFTs may indeed have contributed to the failure of this approach. Further, there are important limitations to the relevance of currently available PFTs to the in vivo situation. Refinement of existing techniques to allow the use of native blood, high shear, use of a global stimulus instead of individual agonists, assessment of thrombin generation by activated platelets, and assessment of fibrinolytic potential, should be considered to make these tests more physiological. Perhaps the results of PFTs need to be considered in combination with other prognostic factors in a more complex prediction model. The present manuscript provides an overview on the role of and value of available PFTs in contemporary clinical practice, with particular focus on possible individualized antiplatelet regimens in high risk patients.

Transcatheter interventions for structural heart disease represent an emerging field in interventional cardiology. Undoubtedly, there is an absolute necessity for antiplatelet and/or anticoagulation treatment prior, during and post such interventions. However, currently administered regimens are mainly based in expert consensus recommendations. In the present review we aim to summarize data regarding anti platelet and/or anticoagulation treatment in the following transcatheter structural heart interventions: left atrial appendage closure, atrial septal defect closure, patent foramen oval closure, paravalvular leak closure.

Catheter ablation for rhythm control in atrial fibrillation has been recognized as an established treatment. Patients with atrial fibrillation suffer from an increased risk of thromboembolic events. Long-term stroke risk and mortality have been shown to be reduced after catheter ablation, still the procedure per se is associated with an additive peri-procedural thromboembolic risk. Maintenance of the thrombotic - bleeding equilibrium in such patients during interventional procedures is compelling. Lack of data from randomized studies along with the recent introduction of novel oral anticoagulants in clinical practice has resulted in a wide variance of antithrombotic treatment approaches. Procedural interruption of anticoagulants, switching of anticoagulation scheme (i.e. from novel oral anticoagulants to vitamin K antagonists), bridging with heparin, timing of re-initiation of therapy and/or utilization of novel oral anticoagulants have all been points of dispute. In the present review we present the available data regarding optimal peri-procedural anticoagulation strategies in patients undergoing catheter ablation for atrial fibrillation.

The liver represents the site of synthesis of most procoagulant and anticoagulant factors, fibrinolytic proteins and thrombopoetin while being also involved in the clearance of hemostatic and fibrinolyic proteins. Therefore in patients with liver insufficiency a great variety of disturbances can be documented resulting however in a new “rebalanced” hemostatic system with a labile equilibrium between thromboses or bleeding. Interestingly patients with liver insufficiency may present with arterial or venous thrombotic episodes requiring antiplatelet and/or antithrombotic therapy despite low platelet count or prolonged INR. The aim of this review is to point on the current knowledge regarding hemostasis in patients with liver insufficiency underlining practical recommendations of the use of antiplatelet and anticoagulant drugs in this setting.

Thrombocytopenia (TP) is a common finding in patients hospitalized for cardiovascular causes and needing antiplatelet and anticoagulant therapies. However, TP is not only a numeric parameter, but mostly a dynamic condition affected by the patients' underlying disorders and concomitant treatments. Platelets are important players in the hemostatic process, taking part to both primary and secondary hemostasis. Although both TP and antithrombotic treatment contribute to the risk of bleeding, the complexity of the pathogenesis of bleeding events makes it difficult to predict them accurately simply based on these two parameters. It should be considered that, under certain clinical conditions, TP may be associated with an increased risk of thrombosis. In order to manage antithrombotic therapies in patients with TP, the frail balance between bleeding and thrombotic complications needs to be estimated. A joint hematological and cardiological evaluation is mandatory in order to avoid stopping an otherwise lifesaving treatment and to decrease the individual patient risk for both thrombotic and/or bleeding events, in each different setting. The purpose of this review is to describe an operative work flow aimed at helping clinicians to face this challenging issue.

Progressive impairment of renal function can lead to uremia, which is associated with an increased risk of bleeding as well as thrombosis. Furthermore, many patients with chronic kidney disease (CKD) have an indication for an anticoagulation or antiplatelet therapy due to atrial fibrillation, coronary artery disease, thromboembolic disease, or peripheral artery disease. The treatment usually includes vitamin-K antagonists (VKAs) and/or platelet aggregation inhibitors. The direct oral anticoagulants (DOACs) inhibiting factor Xa or thrombin activity represent an alternative for heparins and VKAs. However, DOACs can further aggravate the bleeding risk in CKD patients. This is related to a combination of an accumulation of the substance due to the reduced renal clearance, an inhibition of thrombin-mediated platelet activation, and uremia associated factors such as impaired coagulation, platelet function, and platelet-vessel wall interactions. Furthermore, platelet aggregation inhibitors can also influence the bleeding risk, particularly if they are administered in combination with anticoagulants in patients with advanced CKD. In this review we discuss the different mechanisms leading to the increased risk of bleeding and thrombosis as well as the different options and problems related to an antiplatelet or anticoagulation therapy in CKD patients.

Despite numerous advances over the last 50 years, stroke continues to be a leading cause of death and disability worldwide. The treatment and prevention of stroke has undergone extensive study, and significant advances in medical management have occurred within the past decade principally with the development of new classes of orally active anticoagulant drugs. Here we review these recent breakthroughs and the varying roles of anticoagulants and antiplatelet agents in the prevention and management of different ischemic stroke subtypes, as well as describe the benefits and ongoing challenges to incorporating the novel oral anticoagulants (NOACs) into clinical management guidelines. Current guidelines recommend (a) administration of the antiplatelet agent aspirin in the acute management of ischemic stroke, (b) antiplatelet therapy - aspirin, clopidogrel, dypiridamole - in the secondary prevention of noncardioembolic (large artery atherosclerosis) ischemic stroke, and (c) anticoagulants - warfarin and the NOACs - in the secondary prevention of cardioembolic (atrial fibrillation related) ischemic stroke. In phase III clinical trials of the NOACs, dabigatran 150mg BID and apixaban 5mg BID were superior to warfarin in the prevention of stroke/systemic embolism while rivaroxaban 20mg QD demonstrated noninferiority. Both dabigatran and rivaroxaban had similar rates of major bleeding as warfarin but apixaban showed significantly reduced incidence of this complication. As application of novel anticoagulant agents increases, with concomitant study in a variety of clinical settings; their promise in reducing the incidence of stroke, as well as that of therapeutic complications related to warfarin, should be further elaborated.

Background: Intracerebral hemorrhage is the pathological accumulation of blood within the brain. It is a type of stroke more likely to be lethal or to severely disable the patient and results from a wide variety of causes. On the other hand antithrombotic therapy is used for the prevention or/and the therapy of thromboembolic episodes. Antithrombotic drugs are very effective in reducing risk or mortality rate after a thromboembolic event, yet they are associated with significant hemorrhages. Objective: The aim of this article is to review current literature for intracerebral hemorrhage and antithrombotic therapy and offer recommendations on the reversal, the discontinuation and the resumption of antithrombotic therapy. Methods and Materials: Current literature has been reviewed for intracerebral hemorrhage associated with three major categories of patients, those with atrial fibrillation, those with prosthetic mechanical valves and those with venous thromboembolism. Antithrombotic therapy is categorized in antiplatelet agents and anticoagulants. The risk of intracerebral hemorrhage, of a thromboembolic event and of a rebleeding with or without antithrombotic therapy was also reported. Conclusion: Although no one can deny the usefulness of antithrombotic therapy a therapeutic strategy should be developed in order to optimize the clinical decision of stopping, reversing and restarting antithrombotic treatment. This review concludes in strong recommendations, yet a multidisciplinary panel by a stroke physician or neurologist, a cardiologist, a neuroradiologist and a neurosurgeon should evaluate the benefits and the risks for each patient and decide the best therapeutic strategy.

There is an increasing prevalence of cardiovascular diseases that warrant antithrombotic therapy. Antithrombotic therapy includes antiplatelet agents and anticoagulation therapy with vitamin K antagonists (VKAs) or non-Vitamin K oral anticoagulants (NOACs). Antithrombotic therapy is associated with increased rates of bleeding. In this review we summarize the evidence and provide strategies for the management of severe bleeding in the setting of antithrombotic therapy. There is limited data on the management of bleeding in the setting of antiplatelet therapy. We recommend discontinuation of the antiplatelet, as well as administration of platelet transfusions and desmopressin only in the setting of life-threatening bleeding. For patients presenting with severe bleeding in the setting of VKAs, we recommend discontinuation of VKA and prompt administration of 10 mg intravenous vitamin K plus 50 units/kg 4-factor prothrombin complex concentrate (PCC). If 4-factor PCC is not available 3-factor PCC or fresh frozen plasma (FFP) can be used, but these are inferior to 4-factor PCC. For patients presenting with severe bleeding while on dabigatran, we recommend discontinuation of dabigatran and intravenous administration of 5g idarucizumab. There is currently no available reversal agent for factor Xa inhibitors. Andexanet alpha is a factor Xa-specific inhibitor that is currently undergoing FDA review. Until andexanet alpha becomes available we recommend discontinuation of the factor Xa inhibitor and administration of 50 units/kg 4- factor PCC. The decision to discontinue and/or reverse antithrombotic therapy should be made on a case-by-case basis and the competing risk from discontinuation and/or reversal of antithrombotic therapy should be taken into consideration.