Anticoagulant agents in acute coronary syndromes

There has been substantial interest in novel antiplatelet therapies; yet, despite a growing number of studies with novel anticoagulants, there have been few comprehensive reviews summarizing the data for anticoagulants in acute coronary syndromes. Large-scale trials have demonstrated the efficacy of novel procedural anticoagulants, such as selective Factor-Xa inhibitors and direct thrombin inhibitors. Moreover, with as many as 10% of patients with non-ST-segment elevation acute coronary syndrome experiencing recurrent ischemia or death in the first 30 days, there is continued interest in oral anticoagulants. The purpose of this review is to synthesize the evidence for current anticoagulants, including heparins and more recent Factor Xa inhibitors and direct thrombin inhibitors, as well as oral anticoagulants and newer agents in later phases of clinical testing.     

Bivalirudin: a new approach to anticoagulation

Bivalirudin is one of the first of a new class of anticoagulants known as direct thrombin inhibitors. These drugs are able to overcome many of the shortcomings of traditional heparin anticoagulation by virtue of this unique mechanism of action. Bivalirudin is a semisynthetic derivative of hirudin, a modified component of leech saliva. Hirudin has been plagued by bleeding complications, likely due to its high affinity for thrombin. Bivalirudin has lower thrombin affinity than hirudin and therefore is believed to be a much safer compound. Bivalirudin has been shown to be a very effective anticoagulant in laboratory models, though its clinical efficacy remains to be fully proven. Bivalirudin has been studied in the setting of coronary angioplasty, unstable angina, and acute myocardial infarction and has shown some promise in many of these settings, particularly in preventing complications of percutaneous coronary interventions. Bivalirudin has consistently shown less major bleeding compared with standard heparin, although limitations in study methodologies somewhat hinder an accurate interpretation of this finding. Larger-scale studies are indicated and are currently being performed, the results of which will more definitively define the role of bivalirudin for the treatment of cardiovascular disease.     

Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents

For more than 60 years, heparin and coumarin have been mainstays of anticoagulation therapy. They are widely available, inexpensive, effective, and have specific antidotes but are regarded as problematic because of their need for careful monitoring. In addition, coumarin has a delayed onset of action, interacts with many medications, has a narrow therapeutic window, and is paradoxically prothrombotic in certain settings (ie, can precipitate "coumarin necrosis"). Heparin may require monitoring of its therapeutic effect and can also cause thrombosis (heparin-induced thrombocytopenia/thrombosis syndrome). These limitations have led to the development of new anticoagulants with the potential to replace current agents. These newer agents fall into 2 classes, based on whether they are antithrombin dependent (low-molecular-weight heparin, fondaparinux) or antithrombin independent (direct inhibitors of factor Xa and thrombin [factor IIa]). This paper addresses newer anticoagulants, reviewing their efficacy and limitations, and focuses on the risk of major bleeding that may complicate their use. In contrast to heparin and coumarin, none of these newer agents has a specific antidote that completely reverses its anticoagulant effect. Available data on the efficacy and safety of current and experimental agents for anticoagulant reversal are reviewed, and a plan for management of anticoagulant-induced bleeding is presented.     

Management of bleeding complications in the anticoagulated patient

As new anticoagulants become available, and the number of anticoagulated patients continues to rise, it is necessary to know how to deal with associated bleeding complications. In this review, reversal strategies for traditional anticoagulants (warfarin and heparin) as well as newer anticoagulants are described. Prothrombin complex concentrates (PPCs) can be used to reverse vitamin K antagonists (VKA), and plasma may be used where they are not available. Recombinant activated factor VII (rFVIIa) may be useful to reverse pentasaccharide anticoagulants. 1-Desamino-8-D-arginine vasopressin (DDAVP), cryoprecipitate, PCCs, and dialysis may help to reverse direct thrombin inhibitors, while rFVIIa seems to be ineffective. The effect of direct factor Xa inhibitors may be reversed by PCCs, FVIIa, or factor Xa concentrates.     

REVIEW: New Antithrombotics for Atrial Fibrillation

Atrial fibrillation (AF) is the most commonly occurring arrhythmia, and is a condition of both significant clinical and economic importance. An antithrombotic agent is considered mandatory as part of the management in most patients with AF. It has been conclusively demonstrated that long‐term anticoagulation therapy can significantly reduce the risk of stroke in patients with nonvalvular AF. While vitamin K antagonists (VKAs) such as warfarin are highly effective, they possess numerous limitations that curtail their use, or make their use challenging for clinicians and patients. A new generation of anticoagulants are being investigated in phase III clinical trials in patients with AF. One or more of these agents have the potential to either replace or act as alternatives to VKA therapy in AF. This group includes the direct thrombin inhibitor, dabigatran, the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, and finally, the vitamin K analogue, tecarfarin. Additional agents are being developed in phase I or II clinical trials. The direct thrombin and factor Xa inhibitors are generally small, synthetic molecules with predictable pharmacokinetics, a predictable pharmacodynamic effect, few drug interactions and do not require routine therapeutic drug monitoring. These new anticoagulants may well represent a new era in anticoagulation. However, they do possess their own limitations and will present new challenges for clinicians.     

The future of anticoagulation

The conventional management of thrombotic disorders is based on the use of heparin, oral anticoagulants, and aspirin. The development of low molecular weight heparins and the synthesis of heparinomimetics such as the chemically synthesized pentasaccharide represent a refined use of heparin. Aspirin still remains the lead drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as the adenosine diphosphate receptor inhibitors, glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. The oral anticoagulants such as warfarin provide a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains the approach of choice to manage thrombotic disorders. The new anticoagulant drugs target specific sites in the hemostatic network. There is a major thrust on the development of orally bioavailable anticoagulant drugs to replace oral anticoagulants. Heparin and low molecular weight heparins have been considered with various chemical enhancers for absorption. Both the factor Xa and antithrombin agents have been developed for oral use and some of these agents are in clinical development. Besides the limited bioavailability, the therapeutic indices of some of these drugs have been rather disappointing. Factor Xa inhibitors such as the pentasaccharides have undergone aggressive clinical development. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The newer drugs are attractive for several reasons; however, none of these are expected to completely replace the conventional drugs in polytherapeutic approaches. It is conceivable that some of the newer drugs in combined modalities may mimic the broad therapeutic spectrum of heparins and warfarin. However, clinical validation is required for the therapeutic interchange for specific indications.     

New synthetic antithrombotic agents for venous thromboembolism: pentasaccharides, direct thrombin inhibitors, direct Xa inhibitors

Heparin and low molecular weight heparins have limitations in their efficacy and safety for the prevention and treatment of venous thromboembolism (VTE). New synthetic antithrombotic drugs, designed with the intention of improving the therapeutic window for prophylaxis and treatment, are in various stages of development. Synthetic pentasaccharides include fondaparinux and its long-acting analogue idraparinux. Dabigatran is a direct thrombin inhibitor that has undergone clinical trials for VTE prophylaxis and treatment. Direct factor Xa inhibitors include rivaroxiban, which has shown promising results for VTE prophylaxis and is being studied for VTE treatment, as well as apixaban and betrixaban, which are at earlier stages of clinical validation. These newer agents may represent viable options for prophylaxis and therapy as further clinical studies are performed.     

Anticoagulation strategies for patients undergoing percutaneous coronary intervention: unfractionated heparin, low-molecular-weight heparins, and direct thrombin inhibitors

Low-molecular-weight heparins and direct thrombin inhibitors are emerging as alternative anticoagulants to unfractionated heparin in patients undergoing percutaneous coronary intervention (PCI). This paper reviews the pharmacologic properties of these newer antithrombotic agents and evaluates the clinical data demonstrating their use in patients undergoing PCI.     

New anticoagulants

Anticoagulants are pivotal agents for prevention and treatment of thromboembolic disorders. Limitations of existing anticoagulants, vitamin K antagonist and heparins, have led to the development of newer anticoagulant therapies. These anticoagulants have been designed to target specific coagulation enzymes or steps in the coagulation pathway. New anticoagulants that are under evaluation in clinical trials include: (1) inhibitors of the factor VIIa/tissue factor pathway; (2) factor Xa inhibitors, both indirect and direct; (3) activated protein C and soluble thrombomodulin; and (4) direct thrombin inhibitors. Although most of these are parenteral agents, several of the direct inhibitors of factor Xa and thrombin are orally active. Clinical development of these therapies often starts with studies in the prevention of venous thrombosis before evaluation for other indications, such as prevention of cardioembolism in patients with atrial fibrillation or prosthetic heart valves. At present, the greatest clinical need is for an oral anticoagulant to replace warfarin for long-term prevention and treatment of patients with venous and arterial thrombosis. Ximelagatran, an oral direct thrombin inhibitor, is the first of a series of promising new agents that might fulfill this need. Large phase 3 trials evaluating ximelagatran for the secondary prevention of venous thromboembolism and prevention of cardioembolic events in patients with atrial fibrillation have been completed.     

Pharmacology,benefits, unaddressed questions,and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non-valvular atrial fibrillation and proposal of a management algorithm

This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct thrombin and factor Xa inhibitors, which have emerged for the first time in ~ 60 years as cogent alternatives to warfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common clinical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians' reluctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly; 3) patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary stenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects presented in current guidelines are covered and we also propose an evidence-based anticoagulation management algorithm.     

Drug insight: bleeding after percutaneous coronary intervention-risks, measures and impact of anticoagulant treatment options

In Europe, the use of interventional cardiology, including percutaneous coronary intervention (PCI), is increasing rapidly. The use of anticoagulation agents in PCI procedures is essential, but despite technical improvements, a significant associated bleeding risk still exists: more than 5% of patients are estimated to require transfusion, and around a further 13% experience minor bleeding. The methods used to detect and measure blood loss following PCI, however, vary widely between institutions and clinical trials. The risk of bleeding is influenced by therapeutic options and patient-specific characteristics, such as age, anemia and previous exposure to anticoagulants. Bleeding is associated with death, and also with less severe conditions such as thrombocytopenia, anemia, and hematoma, which have major impacts on patients' welfare and length of hospital stay, and on hospital budgets. Unfractionated heparin is the most widely used anticoagulant during PCI. Heparin, antiplatelet agents and other anticoagulants, however, have limitations that make it difficult to achieve a level of anticoagulation that prevents ischemic events without promoting bleeding. The use of low-molecular-weight heparin and the addition of glycoprotein IIb/IIIa inhibitors offer improved outcomes, but safer and more effective therapeutic agents are still required. New anticoagulants, including direct thrombin inhibitors such as bivalirudin, show similar levels of efficacy to heparin plus glycoprotein IIb/IIIa inhibitors, but with fewer hemorrhagic complications, and might advance clinical practice. This review evaluates the impact of PCI-related bleeding on patients' outcomes and hospital resources, examines methods for the detection and measurement of bleeding, and appraises the therapeutic options--particularly the newer agents--available to minimize hemorrhagic complications.     

Anticoagulants in coronary artery disease

Anticoagulant therapy for acute coronary syndromes is becoming more complex as newer agents are added to unfractionated heparin and warfarin. The anticoagulants used in current clinical practice are low molecular weight heparins, direct thrombin inhibitors, and heparinoids. Properties of and recent clinical trial data regarding these newer anticoagulants are reviewed in reference to current American College of Cardiology/American Heart Association guidelines.     

New antithrombotics in the prevention of thromboembolic disease

New anticoagulants are under development to improve on current ones that, although effective, have limitations in efficacy, safety and convenience. We have reviewed the use of these agents as thromboprophylactic drugs. These new agents have more specific modes of action and can be divided into three groups. Inhibitors of the initiation of coagulation work via inhibition of the factor VIIa/tissue factor complex. Inhibitors of propagation of coagulation include parenteral and oral factor Xa inhibitors, factor IXa inhibitors, inhibitors of factor Va and VIIIa, activated Protein C, soluble thrombomodulin and SNAC-Heparin. Finally, direct inhibitors of thrombin are under development both for parenteral and oral administration. Several new drugs, such as fondaparinux, hirudin, argatroban, bivalirudin and ximelagatran, have already been licensed for specific indications and are being investigated for more general usage. Other drugs reviewed are in much earlier stages of development.     

New oral anticoagulants in atrial fibrillation.

Atrial fibrillation (AF) is a major risk factor for stroke. Currently, acetylsalicylic acid (a platelet inhibitor) and vitamin K antagonists (VKAs; oral anticoagulants), including warfarin, are the only approved antithrombotic therapies for stroke prevention in patients with AF. Although effective, VKAs have unpredictable pharmacological effects, requiring regular coagulation monitoring and dose adjustment to maintain effects within the therapeutic range. The clinical development pathway for novel anticoagulants often involves evaluation of efficacy and safety in a short-term indication, such as the prevention of venous thrombo-embolism (VTE), followed by longer-term VTE treatment studies, and finally chronic indications, including stroke prevention studies in patients with AF. The coagulation pathway provides many targets for novel anticoagulants, including Factor Xa (FXa) and Factor IIa (thrombin). Numerous oral, direct FXa inhibitors are in various stages of clinical development, including rivaroxaban, LY517717, YM150, DU-176b, apixaban, and betrixaban, and are anticipated to overcome the limitations of VKAs. Dabigatran is the only oral direct thrombin inhibitor in late-stage development. Studies of these agents for stroke prevention in patients with AF are planned or ongoing. If approved, they may represent the next generation of anticoagulants, by providing new therapeutic options for stroke prevention in patients with AF.     

The pharmacology of novel oral anticoagulants

Anticoagulation for the prevention of stroke is an important aspect of the management of atrial fibrillation. Novel anticoagulants including oral factor Xa inhibitors rivaroxaban and apixaban and the direct thrombin inhibitor dabigatran have emerged as important therapeutic treatment options for prevention of stroke in non-valvular atrial fibrillation. These agents offer practical advantages over traditional vitamin K antagonists, however an understanding of their individual pharmacokinetic and other agent-specific differences is essential for identifying appropriate candidates for therapy, and for selecting the appropriate agent that will be effective and safe. Here, we review the pharmacokinetic process of oral medication use, summarize the newer anticoagulants, their pharmacology, individual pharmacokinetic features, and explore possible explanations for the differences in bleeding outcomes observed in the clinical trials.     

Methods for the monitoring of direct thrombin inhibitors

Direct thrombin inhibitors are available for prophylactic as well as therapeutic purposes. Application of hirudin in therapeutic doses has been shown to require drug monitoring. Currently, most experience is available for recombinant hirudin, but the principle aspects of drug monitoring are the same for all direct thrombin inhibitors. Most frequently, activated partial thromboplastin time (aPTT) and modifications of the activated clotting time (ACT) have been used for the monitoring of hirudin therapy. However, these methods are insensitive at plasma levels higher than 0.6 mg/L of hirudin, so that overdoses may be missed despite monitoring. Correlations between ecarin clotting time (ECT), enzyme immunoassays, and chromogenic substrate assays on one side and global tests on the other side are poor. Fully automated chromogenic substrate-based assays, also available as point-of-care tests (POCT), are more precise and sensitive and are not disturbed by interferents such as heparin and antithrombin. Good correlations can be observed between chromogenic assays and the ECT performed in plasma or whole blood samples. ECT can also be determined with POCT systems. Test characteristics such as imprecision and measuring range are comparable to those of the chromogenic assays. In conclusion, therapy with direct thrombin inhibitors should be monitored with chromogenic assays or ECT.     

Comparison of Argatroban and Hirudin for the Reperfusion of Thrombotic Arterial Occlusion by Tissue Plasminogen Activator

Despite theoretical advantages of direct thrombin inhibitors, recent clinical studies failed to show the superiority of hirudin over heparin in patients with acute coronary syndromes. However, these inhibitors have important in vitro differences for the inhibition of clot-bound thrombin that may translate into different in vivo relative efficacy. The effects of two direct thrombin inhibitors, argatroban and hirudin, on the reperfusion of thrombotic arterial occlusion by t-PA were compared. In anesthetized rabbits thrombotic occlusion was induced in the femoral artery. t-PA, aspirin, and various doses of argatroban (1.25, 2.5, and 5.0 mg/kg/h) or hirudin (2.5 and 5.0 mg/kg/h) were administered (six animals in each group). Blood flow was measured for 4 hours. Animals treated with 2.5 mg argatroban more rapidly achieved full reperfusion than those treated with high-dose argatroban or hirudin (P < 0.05). At the doses that induced comparable prolongation of bleeding time, argatroban showed a significantly faster and higher level of reperfusion than hirudin. In animals treated with hirudin, there was a positive correlation between the aPTT and the mean reperfusion blood flow (r = 0.70, P < 0.05). In animals treated with argatroban, this correlation did not exist and the high-dose argatroban was paradoxically less effective in promoting thrombolysis despite greater anticoagulation effects. In this animal model of arterial thrombosis, argatroban was more effective than hirudin in inducing rapid, full reperfusion with t-PA. Although they are both direct thrombin inhibitors, these two agents showed important dose-related differences in efficacy and anticoagulant effects.     

New treatments for antiphospholipid syndrome

Challenges in new drug development for APS include the controversy about the strength of association between aPL and thrombotic events, and unknown mechanism of aPL-induced thrombosis. In the long-term management of patients who have APS, controlled studies with warfarin alternatives (such as antiplatelet agents), the new anticoagulant agents (such as direct and indirect thrombin inhibitors), and newer therapeutic agents are vital. It is highly possible that the current "antithrombotic" approach to patients who are aPL-positive will be replaced by a "more specifically targeted, anti-inflammatory or immunomodulatory" approach in the future.     

Antithrombotic therapies for stroke prevention in atrial fibrillation

Atrial fibrillation (AF) is now regarded as the arrhythmia for which patients are hospitalized the most frequently, an arrhythmia that is responsible for significant morbidity and mortality. Of particular importance is that the arrhythmia is associated with a significant incidence of thromboembolism which may induce disabling and incapacitating strokes, sometimes fatal. In the past, it was thought that in patients with AF restoration and maintenance of sinus rhythm prevent the development of strokes, a presumption that has not been vindicated by controlled clinical trials. On the other hand, over many decades, it has been established that appropriate anticoagulation especially with warfarin can reduce stroke rate in nonvalvular AF by about 70%, and mortality by 26%. Aspirin reduces stroke rate by 26%, mortality by about 10%. Thus, in AF oral anticoagulants have become the focal point of therapy for the prevention of strokes and the safety and efficacy of such a therapy has been established by controlled clinical trials; moreover, the subsets of patients with AF in whom anticoagulation is mandatory have been defined on the basis of defined risk factors. Warfarin is now the anticoagulant of choice although its limitations are considerable in terms of drug-drug interactions, narrow range of therapeutic index requiring strict monitoring of intensity of anticoagulation, among other limitations which influence compliance of therapy with the agent. In this review, the continuing role of warfarin in the prevention of stroke in patients with AF is discussed as a background for the development of newer anticoagulants. The issue is of particular importance in the older patients, in whom the development of safer antithrombotic therapies remain a major challenge. In this context, the potential role of the direct thrombin inhibitors hold promise for the future and the evolving data on leading compounds of this class which may be competitive with warfarin are discussed.     

Newer anticoagulants in cardiovascular disease: a systematic review of the literature

Vitamin K antagonists (VKAs) such as warfarin have traditionally been the major therapeutic option for anticoagulation in clinical practice. VKAs are effective and extensively recommended for the prevention of venous and arterial thromboembolism in cardiovascular disease. Despite its effectiveness, warfarin is limited by factors such as a narrow therapeutic index, drug-drug interactions, food interactions, slow onset and offset of action, hemorrhage, and routine anticoagulation monitoring to maintain therapeutic international normalized ratio. During the last 2 decades, the approval of anticoagulants, such as low-molecular-weight heparins, indirect factor Xa inhibitors (eg, fondaparinux), and direct thrombin inhibitors (eg, argatroban, lepirudin, and desirudin), have expanded the number of available antithrombotic compounds with additional targets within the anticoagulation pathway. Although these medications offer several potential therapeutic advantages, they all require parenteral or subcutaneous administration and are substantially more expensive than VKAs. Thus, VKAs, despite several limitations, have remained the major option for most patients requiring chronic anticoagulation. These limitations have prompted interest in the development of newer oral anticoagulants. Novel anticoagulants targeting inhibition of factor Xa and thrombin (factor IIa) have now been incorporated into clinical practice based on the results of large randomized clinical trials, with the recent U.S. Food and Drug Administration approval of dabigatran for stroke prevention in atrial fibrillation and rivaroxaban for deep vein thrombosis and stroke prevention in atrial fibrillation, with multiple other agents in various stages of development for these and other indications. This review discusses the pharmacological properties, clinical results, and therapeutic applications of novel and new anticoagulants, thereby providing an outline for the future of anticoagulation in cardiovascular disease.