New and Emerging Anticoagulant Therapy for Atrial Fibrillation and Acute Coronary Syndrome

Estella M. Davis, Pharm.D.; Kathleen A. Packard, Pharm.D.; Jon T. Knezevich, Pharm.D.; Jennifer A. Campbell, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(10):975-1016. 

In This Article

Abstract and Introduction

Abstract

Thrombosis is an underlying cause of many cardiovascular disorders, and generation of thrombi in the arterial circulation can lead to unstable angina, myocardial infarction, or ischemic stroke. Antithrombotic therapy is widely used, with proven benefit to prevent ischemic stroke and thromboembolic events in patients with atrial fibrillation (AF) or to prevent further ischemic complications in patients with acute coronary syndrome (ACS). Traditional anticoagulants (including unfractionated heparin, low-molecular-weight heparin, and warfarin) and antiplatelet agents (including aspirin, clopidogrel, and prasugrel) are typically used for these indications. Limitations to their use include variable pharmacokinetic and pharmacodynamic profiles, inability to inhibit fibrin-bound thrombin, risk of heparin-induced thrombocytopenia, delayed onset of action, numerous drug interactions, need for substantial laboratory monitoring and dosage titrations, hyporesponsiveness or resistance, hypersensitivity, adverse events, and bleeding. To overcome some of the limitations of traditional agents, new antithrombotic agents under development are highly selective for specific coagulation factors blocking the synthesis of thrombin. Clinicians must have an understanding of the new anticoagulants to aid in the selection of appropriate therapies for patients. We describe the most relevant phases II and III clinical trials that evaluated several recent emerging anticoagulant drugs for use in patients with AF or ACS. The advantages of many new agents include predictable pharmaco-dynamic response and pharmacokinetic parameters, allowing for fixed oral dosing with no need for laboratory monitoring. For patients with AF, dabigatran is already approved for the prevention of stroke and systemic embolism, rivaroxaban appears to be an effective alternative to warfarin in high-risk patients, and apixaban may also be an effective alternative to aspirin in patients unable to take warfarin. Otamixaban shows promise as an intravenous alternative for patients with ACS in the acute care setting. Likewise, rivaroxaban, dabigatran, and darexaban with or without dual antiplatelet therapy may be beneficial for secondary prevention of ischemic events in patients with ACS.

Introduction

Thrombosis is an underlying cause of many cardiovascular disorders, and generation of thrombi in the arterial circulation can lead to unstable angina, acute myocardial infarction, or ischemic stroke. Antithrombotic therapy is widely used, with proven benefit for the prevention of ischemic stroke or thromboembolic events in patients with atrial fibrillation (AF) and for the prevention of further ischemic cardiac complications in patients with acute coronary syndrome (ACS).[1–5] Antithrombotic therapy encompasses anticoagulant agents that target procoagulation factors in the clotting cascade and antiplatelet agents that inhibit platelet aggregation. Traditional anticoagulants—such as unfractionated heparin (UFH), low-molecularweight heparin ([LMWH] enoxaparin or dalteparin), and warfarin—and antiplatelet agents—such as aspirin, clopidogrel, or prasugrel—are typically used in patients with AF or ACS; however, there are limitations to their use.

Aspirin and warfarin have long been the only oral antithrombotic agents used for the prevention of ischemic stroke or thromboembolism in patients with AF. In practice, aspirin alone is recommended for individuals with AF at low-to-moderate risk for stroke and can reduce risk of stroke by 20%.[1] Aspirin is associated with hyporesponsiveness in some individuals, hypersensitivity reactions, gastrointestinal adverse effects, and bleeding. However, in patients with AF who have moderate-to-severe risk for stroke, warfarin is superior to aspirin and reduces the risk of stroke by 60–70%.[6–8] Limitations of warfarin include a narrow therapeutic window and significant risk of major bleeding; delayed onset of action; regular laboratory monitoring to detect subtherapeutic, supratherapeutic, and therapeutic doses; bleeding; and numerous drug interactions. Recently, clopidogrel has been recommended as an alternative in combination with aspirin for patients with AF who are unsuitable for warfarin therapy.[2] However, its limitations also include bleeding, drug interactions, unpredictable inhibition of platelet aggregation in certain individuals, leading to resistance, and prolonged duration of action requiring early cessation before surgical procedures.

Typical anticoagulants used for patients undergoing urgent revascularization or medical management in ACS include UFH, LMWH, fondaparinux, and bivalirudin. In addition, patients may require bridging therapy to oral anticoagulants by using UFH, LMWH, or fondaparinux. Limitations to UFH include its variable pharmacokinetic and pharmacodynamic profile, inability to inhibit fibrin-bound thrombin, sensitivity to platelet factor 4 with risk of heparin-induced thrombocytopenia, and marked interindividual variability in therapeutic response requiring substantial laboratory monitoring and dosage titration.[9] The LMWHs have some similar limitations as those of UFH, and both agents require parenteral administration making them inconvenient for long-term use. However, LMWHs have a more consistent pharmacokinetic and pharmacodynamic profile over UFH and do not typically require laboratory monitoring.

Fondaparinux is selective for factor Xa inhibition, unlike UFH and LMWHs; however, like these agents, it does not directly inhibit factor Xa or platelet-bound factor Xa. Fondaparinux has a long half-life of 17–21 hours, has no direct reversal agent, and may require additional heparin boluses and frequent flushes during percutaneous coronary intervention (PCI) to prevent coronary-guided catheter thrombus formation.[5] Bivalirudin is currently the only parenteral direct thrombin inhibitor (DTI) approved by the United States Food and Drug Administration (FDA) specifically for use in PCI in patients with heparin-induced thrombocytopenia. It requires reconstitution for administration, has a half-life of 20–30 minutes, and requires dosage adjustments in patients with renal dysfunction.[10]

Available antiplatelet therapy for secondary prevention of cardiovascular events in patients with ACS consists of aspirin and an adenosine diphosphate platelet inhibitor, clopidogrel or prasugrel. Limitations of these antiplatelet agents in these patients are similar to those described for AF; however, early termination may be associated with increased risk of thrombosis in patients with ACS who recently received cardiac stents.

To overcome some of the limitations of traditional parenteral and oral antithrombotics, there has been continual movement toward the development of new agents that are highly selective for specific coagulation factors blocking the synthesis of thrombin. The impetus has been to develop anticoagulant drugs with the ability to bind clot-bound coagulation factors, have predictable pharmacologic profiles that allow for oral dosing and negate the need for frequent monitoring, have fixed and convenient dosing regimens, and have rapid onset of action, with the potential to have high efficacy and low bleeding risk compared with standard therapies.

Clinicians must have an understanding of new anticoagulants to aid in the selection of appropriate therapies for patients. In this review, we describe the most relevant phase II and phase III clinical trials that evaluated several new and emerging anticoagulant drugs and their use in patients with AF or ACS.

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