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Anticoagulant drugs are used to prevent and treat thrombotic disorders in millions of patients worldwide. This Milestone plots the history of anticoagulant drugs on an interactive Timeline, starting with the discovery and clinical trials of heparin and warfarin. The synthesis of low-molecular-weight heparins enabled more convenient, outpatient treatment of thrombosis. Since 2000, the development of direct oral factor Xa and thrombin inhibitors as well as antidotes to reverse the effects of these drugs has revolutionized the practice of anticoagulation. Nevertheless, the delicate cost–benefit balance between bleeding and prevention of clotting continues to drive research into novel agents and optimal dosing regimens.
The non-vitamin K antagonist oral anticoagulants (NOACs) include direct inhibitors of factor Xa or thrombin. In this Review, Levy and colleagues describe the mechanism of action of the NOAC-reversal strategies, provide guidance on potential indications for reversal, and offer a management approach for patients treated with NOACs who present with serious bleeding or require urgent surgery.
Novel oral anticoagulants (direct thrombin or factor Xa inhibitors) have become alternative options to vitamin K antagonists owing to their predictable and safe pharmacological profiles. In this Review, Baber and colleagues discuss the overall clinical effect of these drugs, which is a balance between ischaemic benefit and bleeding risk, in patients with atrial fibrillation, venous thromboembolism, or acute coronary syndrome.
Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the cornerstone of pharmacological treatment to optimize clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). In this Review, Franchi et al. provide an overview of currently available antithrombotic therapies used in these patients, results from pivotal clinical trials and their implications for guidelines, as well as recommendations for clinical practice.
Atherothrombosis underlies numerous manifestations of cardiovascular disease, including coronary artery disease (CAD) and cerebrovascular disease (CVD). Treatment of patients with concomitant CAD and CVD is complex, owing to their increased risk of both ischaemia and bleeding. Capodanno et al. review the use of antithrombotic drugs for the secondary prevention of atherothrombotic events in patients with concomitant CAD and CVD, particularly those with a history of noncardioembolic stroke or transient ischaemic attack.
Venous thromboembolism, including deep-vein thrombosis and pulmonary embolism, is a common, often-recurring condition that is occurring with increasing frequency, despite the availability of prophylactic treatments. The epidemiology of VTE involves interactions between predispositions to thrombosis and a range of risk factors, including hospitalization, cancer, and pregnancy.
Asian individuals have a higher risk of stroke associated with atrial fibrillation (AF) than white patients. The use of the vitamin K antagonist warfarin is low in Asian countries, owing to the challenge of controlling anticoagulation and the high-risk of haemorrhage with warfarin in Asians. The non-vitamin K antagonist, oral anticoagulant drugs offer a solution to these challenges. In this article, Sabir et al. discuss the use of these agents in the management of AF in Asian populations.
A number of gene variants that cause hypercoagulability, and can lead to venous thromboembolism, have been identified. The two main mechanisms are loss-of-function of anticoagulant proteins and gain-of-function of procoagulants. In this Review, Ida Martinelli and colleagues discuss the main causes of inherited thrombophilia, the associated clinical manifestations, and the implications for screening and antithrombotic prophylaxis in affected individuals and their families.
The novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban have been examined for efficacy and safety in the prophylaxis and treatment of venous thromboembolism. In this Review, these clinical trials are summarized, and practical considerations in the use of these drugs are discussed.
Novel, oral, direct inhibitors of factor Xa are valuable additions to anticoagulation therapy in patients with various thrombotic disorders, but have shown mixed results in trials for secondary prevention in patients with an acute coronary syndrome. Drs Wisler and Becker review the available data, with particular emphasis on the phase III APPRAISE 2 and ATLAS ACS 2–TIMI 51 trials of apixaban and rivaroxaban.
Oral direct factor Xa inhibitors, particularly apixaban and rivaroxaban, are novel and promising alternatives to warfarin for stroke prevention in patients with atrial fibrillation. Drs Cabral and Ansell review the data from clinical trials of these drugs, and also discuss the challenges of reversing their anticoagulant effects, interactions with other medications, patient compliance, and therapeutic monitoring.
Direct inhibitors of thrombin are a novel class of anticoagulant. The authors critically review the data from clinical trials on the use of the parenteral and oral forms of these drugs for primary or secondary prevention or treatment in patients with acute coronary syndrome, atrial fibrillation, or venous thromboembolism, or those undergoing percutaneous coronary intervention or orthopedic surgery.
Oral anticoagulation therapy is the most effective strategy for preventing thromboembolic complications in pregnant women with prosthetic heart valves. However, this therapy is associated with increased fetal morbidity and mortality. The authors discuss the controversies surrounding the choice of prosthetic heart valve in women of childbearing age and the advantages and disadvantages of various anticoagulation strategies during pregnancy.
Dual and triple antiplatelet therapies prevent ischemic events in high-risk patients with coronary artery disease or during percutaneous coronary interventions, but can cause bleeding complications. In this Review, Dr. Tantry and Dr. Gurbel discuss the utility of platelet function assays for the assessment of ischemic and bleeding risk to personalize antithrombotic combination therapies.
In the second part of their Review on pulmonary embolism (PE), van Es and colleagues discuss risk stratification of patients with this condition, the short-term and long-term treatment options, and introduce some of the novel therapeutic agents under investigation for PE.
In this comprehensive Review, Drs Stashenko and Tapson examine the literature on the use of venous thromboembolism prophylaxis in hospitalized medical patients, and evaluate the available data for the outpatient setting. The authors also discuss the potential strategies for improving venous thromboembolism prophylaxis rates in these groups of patients.
Renal dysfunction and atrial fibrillation (AF) share common risk factors and often coexist. Here, the authors discuss the risks and benefits of use of vitamin K antagonists (VKAs) and non-VKA oral anticoagulants for thromboprophylaxis in patients with coexistent AF and renal dysfunction.
The anticoagulant rivaroxaban is the first approved direct inhibitor of the serine protease factor Xa. This article presents the history of rivaroxaban's development, from its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development.
Venous thrombosis and its potentially debilitating or even fatal consequences can pose diagnostic and therapeutic challenges. Here, Mackman and colleagues discuss not only the clinical implications of thrombosis but also new insights into thrombogenesis and how to inhibit this process.
Disseminated intravascular coagulation can be caused by various infectious and non-infectious insults, such as sepsis and trauma, respectively. It is characterized by the widespread activation of coagulation and, depending on the underlying condition, can manifest as bleeding and/or thrombosis.
Venous thromboembolism (VTE) is a major cause of morbidity and mortality in patients with cancer. Treatment with low-molecular-weight heparin is the recommended first-line approach for treating cancer patients with newly diagnosed VTE. The authors of this Review discuss the optimal duration of anticoagulant therapy, treatment of recurrent VTE, the role of vena cava filters, the effects of VTE and its treatment on quality of life, and the impact of anticoagulants on survival.
Portal vein thrombosis (PVT) is a fairly common complication of liver cirrhosis. In this Review, the authors discuss the evidence regarding the management of PVT in patients with liver cirrhosis and propose an exploratory and preliminary algorithm, noting the limited data and low-quality evidence available to date.
The authors of this Review present what is known about the pathophysiology of increased coagulation in patients with cancer and how it applies to pancreatic carcinoma. The relationship between the activation of coagulation or symptomatic thromboembolic disease and the development of pancreatic carcinoma is explored. In addition, the relationship between thromboembolic disease and prognosis, and the rationale and evidence for the use of anticoagulants in patients with pancreatic carcinoma are considered.
The association between coagulation and the immune system has been increasingly recognised to have a role in the development of inflammatory rheumatic diseases. The fact that the risk of venous thromboembolism is increased in patients with rheumatoid arthritis (RA) and citrullinated fibrinogen is an early autoantigen in RA indicates an adaptive immune response to coagulation factors in inflammatory rheumatic diseases. In this article, Hoppe and Dörner describes the pathophysiology of an induced procoagulatory state in inflammatory rheumatic diseases, discussing the roles of endothelial cell and platelet activation, and coagulation and fibrinolytic systems, and providing insights into future research for innovative therapeutic interventions.
Coagulation factor Xa is targeted by a new generation of antithrombotic drugs such as rivaroxaban. However, as excessive factor Xa inhibition can cause bleeding, the clinical use of factor Xa inhibitors would be enhanced by the availability of a specific antidote. Uma Sinha and her colleagues devise such an antidote, an inactive form of recombinant factor Xa that can bind to and neutralize factor Xa inhibitors, and demonstrate its efficacy in animal models.
A new generation of target-specific inhibitors of the coagulation enzymes thrombin and factor Xa has been approved for a number of indications, but the clinical use of these drugs is hindered by the lack of a way to reverse bleeding, should it occur. An antidote to these new oral anticoagulants has now been designed and shows promise in small-animal models of blood loss (pages 446–451).
A major drawback in the clinical use of the oral anticoagulants that directly inhibit factor Xa in order to prevent blood clot formation is the potential for life threatening bleeding events. Here the authors describe factor Xa variants that are refractory to inhibition by these anticoagulants and could serve as rescue agents in treated patients.
A variant of coagulation factor Xa reverses the anticoagulant effects of clinically used inhibitors of factor Xa and thrombin in mice, pointing to the potential use of this agent as a general reversal agent for direct oral anticoagulants.
The inorganic procoagulant polymer polyphosphate participates in thrombosis via factor XII. Here the authors use recombinant probes that specifically bind or degrade circulating polyphosphate to protect mice in arterial and venous thrombosis models without an increased bleeding risk, the primary complication of all currently used anticoagulants.
An siRNA targeting antithrombin promotes hemostasis in mouse and nonhuman primate models of hemophilia and could represent a new therapeutic option for this disease.