New pharmacotherapeutic options for oral anticoagulant treatment in atrial fibrillation patients aged 65 and older: factor XIa inhibitors and beyond

ABSTRACT

Introduction

Although much progress has been made using anticoagulation for stroke prevention in patients with non-valvular atrial fibrillation, bleeding is still a major concern.

Areas covered

This article reviews current pharmacotherapeutic options in this setting. Particular emphasis is placed on the ability of the new molecules to minimize the bleeding risk in elderly patients. A systematic search of PubMed, Web of Science, and the Cochrane Library up to March 2023 was carried out.

Expert opinion

Contact phase of coagulation is a possible new target for anticoagulant therapy. Indeed, congenital or acquired deficiency of contact phase factors is associated with reduced thrombotic burden and limited risk of spontaneous bleeding. These new drugs seem particularly suitable for stroke prevention in elderly patients with non-valvular atrial fibrillation in whom the hemorrhagic risk is high. Most of anti Factor XI (FXI) drugs are for parenteral use only. A group of small molecules are for oral use and therefore are candidates to substitute direct oral anticoagulants (DOACs) for stroke prevention in elderly patients with atrial fibrillation. Doubts remain on the possibility of impaired hemostasis. Indeed, a fine calibration of inhibition of contact phase factors is crucial for an effective and safe treatment.

KEYWORDS:

• Atrial Fibrillation
• blood coagulation factors
• factor XI
• stroke
• hemorrhage
• aged

Article highlights

• Oral anticoagulants (Vitamin K Antagonists-VKA and Direct Oral Anticoagulants-DOAC) ensure prevention of thromboembolic stroke in patients with atrial fibrillation, but bleeding complications limit their clinical use especially in elderly patients.

• Inhibition of the contact pathway of coagulation is being investigated as a promising new strategy to achieve antithrombotic efficacy, while limiting the incidence of bleeding.

• Several oral (small molecules) and parenteral inhibitors (monoclonal antibodies and antisense oligonucleotides) of the contact pathway factor FXI have been developed and are progressing through clinical trials including the setting of atrial fibrillation.

• Additional agents undergoing preclinical evaluation include synthetic, single stranded oligonucleotides (aptamers), and naturally occurring peptides.

• If the promise of efficacious anticoagulation with minor hemorrhagic risk holds true, contact pathway inhibitions will be especially valuable in elderly patients at high risk of bleeding.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.