Unresolved issues in the use of direct acting oral anticoagulants

ABSTRACT

Introduction

Currently approved direct oral anticoagulants (DOACs) target thrombin or coagulation factor Xa. Administered in fixed doses without routine laboratory monitoring, DOACs have simplified the approach to oral anticoagulation, when previously the choice was limited to vitamin K antagonists (VKAs).

Area covered

We discuss a) unresolved issues related to optimal use of DOACs and b) new developments including the potential for FXIa inhibitors to be effective and safer anticoagulants.

Expert opinion

By simplifying oral anticoagulation, DOACs have facilitated the uptake of anticoagulation. The DOACs are approved for stroke prevention in atrial fibrillation and for the prevention and treatment of venous thromboembolism, and their indications are expanding to include the prevention of atherothrombosis. DOACs have now replaced vitamin K antagonists (VKAs) for most indications, but not all. DOACs are inferior to VKAs for patients with mechanical heart valves, left ventricular assist device, rheumatic atrial fibrillation, and those with antiphospholipid syndrome, and their safety and efficacy are uncertain in some populations (e.g. advanced renal and liver disease). Impediments to use include concerns for bleeding and cost. The newly developed FXIa and FXIIa inhibitors have the potential to be safer than current anticoagulants, but phase 3 trials are needed to confirm their clinical efficacy and safety.

KEYWORDS:

• Direct oral anticoagulants
• vitamin K antagonists
• factor XIa inhibitors
• mechanical heart valve
• antiphospholipid syndrome
• valvular atrial fibrillation
• DOAC drug level

Article highlights

• Direct oral anticoagulants have now replaced vitamin K antagonists for most but not all indications.

• There have been no head-to-head comparisons among DOACs in RCTs. Thus, the decision to choose one DOAC over another is based on the results of systematic reviews of indirect comparisons of RCTs and observational studies as well as other considerations.

• Up to 25% of patients with atrial fibrillation were being treated ‘off label’ with lower than recommended doses of DOAC. Such ‘off label’ use has been criticized by some, but its use may be reasonable in selected high-risk patients whose characteristics excluded them from clinical trials because they had a high risk of bleeding.

• Most patients treated with DOACs do not need laboratory monitoring, but there are clinical circumstances in which knowledge of drug levels might be useful. These circumstances include patients who experience bleeding or thrombotic events as well as some who were ineligible for inclusion in the randomized trials.

• Vitamin K antagonists remain the anticoagulants of choice for patients with mechanical heart valves or left ventricular assist devices or with valvular atrial fibrillation and in those with antiphospholipid syndrome because of the relative ineffectiveness of DOACs for these indications.

• FXII and FXI inhibitors are new anticoagulants under clinical development. To date, phase 2 clinical trials have focused on the evaluation of FXIa inhibitors and have consistently shown less bleeding compared with LMWH for VTE prevention and apixaban for stroke prevention in AF, respectively. Phase 3 trials are required to confirm their efficacy and safety.

• By inhibiting the contact pathway, the newly developed FXIIa and FXIa inhibitors also have the potential to be effective in the prevention of medical device thrombosis (e.g. mechanical heart valves).

Declaration of interest

N Chan has received speaker fees from Boehringer Ingelheim and Stago. N Chan is supported by a Heart and Stroke of Canada New Investigator Award.

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

A peer reviewer on this manuscript is a consultant for Alveron and Astra Zeneca, which manufacture reversal agents. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.