ENRICH-AF

To assess whether edoxaban (60/30 mg daily) compared to non-anticoagulant medical therapy (either no antithrombotic therapy or antiplatelet monotherapy) reduces the risk of stroke (composite of ischemic, hemorrhagic and unspecified stroke) in high-risk atrial fibrillation (CHA2DS2-VASc score ≥2) patients with previous intracranial hemorrhage.

Primary efficacy outcome: All Stroke (ischemic, hemorrhagic and unspecified stroke)

Secondary outcome: Ischemic stroke; cardiovascular death; hemorrhagic stroke; disabling/fatal stroke; composite of all stroke, myocardial infarction, systemic thromboembolism or all-cause death; net clinical
benefit (composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ) mRS at 12 months.

Safety outcomes: Major hemorrhage (ISTH criteria); all intracranial hemorrhage (Intracerebral Hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage); fatal intracranial hemorrhage; subdural hemorrhage; hospitalization for any cause.

Anticoagulation of atrial fibrillation (AF) patients after intracranial hemorrhage poses a challenging clinical
dilemma that requires balancing the benefit of reducing thromboembolism against the risk of recurrent
intracranial bleeding.

Physician surveys demonstrate significant clinical equipoise with broad variations of practice both globally
and amongst institutions within the same region. This variability in practice exposes patients to undue harm
from either anticoagulation in patients at high risk for recurrent intracranial hemorrhage or under-treatment of
individuals who would receive significant therapeutic benefit and mandates a randomized trial.

Non-vitamin K antagonist oral anticoagulants (NOACs) are a promising treatment option in this patient
population. Factor Xa inhibitors in particular have been reported to provide equivalent therapeutic benefit in
the prevention of ischemic stroke and systemic embolism resulting from AF in comparison with warfarin, but
with an intracranial hemorrhage risk (the most feared complication of anticoagulation) that is comparable to
aspirin.

In previous randomized trials in high-risk patients with atrial fibrillation, edoxaban has demonstrated low rates
of intracranial hemorrhage. Based on the available data on incident intracranial hemorrhage, we hypothesize
that treatment with edoxaban will provide superior stroke prevention (composite of ischemic, hemorrhagic
stroke and unspecified stroke) in patients with high-risk (CHA2DS2-VASc score ≥2) AF with previous
intracranial hemorrhage compared to non-anticoagulant medical therapy.

Hypotheses:
Efficacy: Treatment with edoxaban will reduce the risk of stroke (composite of ischemic, hemorrhagic and
unspecified stroke) compared with non-anticoagulant medical therapy.

Safety: Treatment with edoxaban (60/30 mg daily) has a comparable risk of major hemorrhage as compared
to non-anticoagulant medical therapy (either no antithrombotic therapy or antiplatelet monotherapy).

The EdoxabaN foR IntraCranial Hemorrhage survivors with Atrial Fibrillation (ENRICH-AF) study is a prospective, randomized open-label, blinded end-point (PROBE), investigator-initiated, phase III study that will define the efficacy and safety of edoxaban compared with non-anticoagulant medical therapy (no antithrombotic therapy or antiplatelet monotherapy) for stroke prevention in high-risk AF patients and previous intracranial hemorrhage.

Intracranial hemorrhage includes intracerebral hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage and subdural hematoma.

Recruitment will occur at 250-300 stroke research centres in North and South America, Europe and Asia over 24 months.
Number of participants: 1200 adult participants with high-risk AF (CHA2DS2-VASc score ≥2) and previous spontaneous or traumatic intracranial hemorrhage (while on or off antithrombotic therapy).

Patients will be randomized to receive either edoxaban or to non-anticoagulant medical therapy. These treatment arms are as follows:
Edoxaban (60/30 mg daily; lower dose depending on clinical criteria)
Non-anticoagulant medical therapy: no antithrombotic therapy or antiplatelet monotherapy (at discretion local investigator)
Participants will be followed every 6 months until the common study end date. This trial is event driven to accrue 123 primary events, anticipated one year after the end of the recruitment. Average of 24 months of follow-up per participant (range 1 to 3 years).