Current and emerging pharmacotherapy for ischemic stroke prevention in patients with atrial fibrillation

ABSTRACT

Introduction

Atrial fibrillation (AF) is associated with high morbidity and mortality rates due to thromboembolic complications, and anticoagulation is central to the management of this common arrhythmia to prevent acute thromboembolic events. The traditional anticoagulants: heparin, fondaparinux, and vitamin K antagonists (VKA, e.g. warfarin, acenocoumarol or phenprocoumin) have long served as pharmacotherapy for ischemic stroke prophylaxis.

Areas covered

In this review article, the authors provide an overview on current and emerging pharmacotherapy for ischemic stroke prevention. Furthermore, they review the data from novel therapeutic targets in the coagulation cascade, and investigational anticoagulant drugs currently assessed in preclinical and clinical studies.

Expert opinion

The introduction of nonvitamin K antagonist oral anticoagulants (NOACs) was an important milestone, as these drugs show relative efficacy, safety, and convenience compared to the VKAs. Nevertheless, their clinical use still has some limitations with, for example, patients with severe renal impairment and those with mechanical heart valves, high bleeding risks, lack of standard laboratory monitoring and (some) reversal agents. To overcome some of these limitations, various attempts are now underway to discover new strategies and targets via the hemostatic pathway in order to develop new coagulation inhibiting drugs.

KEYWORDS:

• Atrial fibrillation
• cardiovascular disease
• pharmacotherapy
• ischemic stroke
• coagulation cascade
• stroke prevention
• anticoagulation

Declaration of interest

GYH Lip receives consultancy fees from Bayer Healthcare, Janssen Pharmaceuticals, Bristol-Myers Squibb, Pfizer Inc, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi Sankyo as well as speaker’s fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer Inc, Medtronic, Boehringer Ingelheim, and Daiichi Sankyo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• Anticoagulation is central to the management of atrial fibrillation to prevent acute thromboembolic events

• Nonvitamin K oral anticoagulants have become the cornerstone of treatment, as these drugs show relative efficacy, safety and convenience compared to the VKAs

• Betrixaban, a novel oral direct factor Xa inhibitor, has a primary hepatobiliary elimination route, which may confer a significant benefit for safer use in patients with impaired renal function

• Tecarfarin (ATI-5923) is a novel VKA under development with a unique CYP-independent metabolic pathway

• Antisense oligonucleotides and monoclonal antibodies targeting Factor XI and XII are widely investigated in experimental models with proved thromboprophylactic effect. IONIS-416,858 is undergoing a phase II clinical trial in patient with end-stage renal disease on hemodialysis.

• Ichorcumab is a recombinant fully human IgG4 antibody against thrombin, specifically binding to exosite I of the molecule with huge potential in anticoagulation

This box summarizes key points contained in the article.

Additional information

Funding

This manuscript was not funded.