Edoxaban in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy With Aspirin and Clopidogrel

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist is pivotal for
the treatment of patients with coronary artery disease (CAD) undergoing percutaneous coronary
intervention (PCI) and in patents following an acute coronary syndrome (ACS). Importantly, it
is not uncommon that patients requiring DAPT also need to be treated with oral anticoagulant
therapy, such as those with atrial fibrillation (AF). Warfarin and clopidogrel are still the
most widely utilized oral anticoagulant and P2Y12 receptor inhibitor, respectively. However,
this treatment regimen has shown to be associated with an increased risk of bleeding, as well
as ischemic complications. Over the past years, several non-vitamin K antagonist oral
anticoagulants (NOACs), including edoxaban, have been studied in the setting of AF showing
encouraging safety and efficacy profiles as compared with warfarin. In the phase III ENGAGE
AF-TIMI 48 trial, edoxaban (60mg or 30mg once/daily) was non-inferior to warfarin with
respect to the prevention of stroke or systemic embolism and was associated with
significantly lower rates of bleeding and death from cardiovascular causes, in patients with
AF. However, the effects of edoxaban in combination with DAPT in the setting of patients with
CAD are unexplored. This may indeed represent a limitation for the uptake of edoxaban in
modern day clinical practice where ~10% of patients with AF also have CAD requiring PCI and
thus may require triple antithrombotic therapy. Moreover, the role of edoxaban as part of a
dual antithrombotic treatment strategy, including clopidogrel and stopping aspirin,
represents another important area of clinical interest as it has the potential reduce the
risk of bleeding while preserving protection from ischemic events. This investigation is a
prospective, randomized, parallel-design, open label, pharmacodynamic study conducted in
patients with CAD on DAPT with aspirin and clopidogrel testing two different edoxaban dosing
regimens (60mg or 30mg once/daily) in addition to DAPT with aspirin and clopidogrel, as well
as in combination with clopidogrel only (after stopping aspirin).

Inclusion criteria:

1. Patients with angiographically documented CAD (previous PCI or ACS).

2. On DAPT with low-dose aspirin (81mg od) and clopidogrel for at least 30 days as per
standard-of-care.

3. Age above 18.

Exclusion criteria:

1. Active pathological bleeding, history of clinically significant bleeding events, or
deemed at increased risk of bleeding.

2. CrCL <15mL/min

3. Any clinical indication to be on anticoagulant therapy

4. Acute coronary events in the past 90 days

5. Prior hemorrhagic stroke or intracranial hemorrhage

6. Ischemic stroke/transient ischemic attack in the past 6 months

7. Chronic use of nonsteroidal anti-inflammatory drugs

8. On treatment with rifampin (induce or P-gp transporter)

9. Known moderate or severe hepatic impairment (Child-Pugh B and C).

10. On treatment with any antiplatelet agent other than aspirin and clopidogrel in the
past 30 days.

11. Platelet count <80x106/mL

12. Hemoglobin <10g/dL

13. Hemodynamic instability

14. Pregnant females [women of childbearing age must use reliable birth control (i.e. oral
contraceptives) while participating in the study].