An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention.

Non-Valvular Atrial Fibrillation (AF) is a disease that causes the upper
chambers of the heart to quiver rather than contract normally. AF may cause
blood clots to form in the heart. When blood clots form in the blood vessels,
they can be dangerous because they can block the circulation. When blood clots
form in the arteries or heart, they stop the flow of blood. This can cause a
heart attack. If a blood clot clogs the blood vessels in the brain, this can
cause a stroke. A stroke is a condition where the brain can lose function,
cause serious disability, or cause death. In order to break down or prevent
clot formation in patients with AF, a blood thinner, such as Vitamin K
Antagonist (VKA) or other anticoagulant, such as apixaban, is commonly used.

The standard treatment to break down or prevent blood clots in patients with
ACS or a recent PCI is known as *Dual Antiplatelet Therapy* and is not
effective in breaking down clots related to AF.

The optimal treatment for patients with a current or history of AF and recent
ACS or PCI is not known at this time. Risk of bleeding is present with any
blood thinner. The combination of certain treatments can lead to increased risk
of bleeding. This study is being conducted to determine if apixaban is safer
than the blood thinner Warfarin in subjects with non-valvular AF and ACS or PCI
in relation to bleeding. In the Netherlands, Warfarin is not registered as
medication.

This study will also evaluate if treatment with apixaban or the oral VKA drug
called Warfarin and a P2Y12 inhibitor alone is safer than treatment of apixaban
or Warfarin with a combination of a P2Y12 inhibitor and Aspirin.

Dual Primary Objectives:
* To determine if apixaban is noninferior to VKA (INR target range 2.0-3.0) on
the combined endpoint of ISTH
major or clinically relevant non-major bleeding in patients with NVAF who
develop ACS or undergo PCI with
planned concomitant P2Y12 inhibitor therapy.
* To determine if anticoagulant plus single antiplatelet therapy with a P2Y12
inhibitor is superior to anticoagulant
plus dual antiplatelet therapy with a P2Y12 inhibitor and aspirin on the
combined outcome of ISTH major or
clinically relevant non-major bleeding in patients with NVAF who develop ACS or
undergo PCI with planned
concomitant P2Y12 inhibitor therapy.

Secondary Objectives:
To compare apixaban and VKA (with concomitant P2Y12 inhibitor therapy), in
patients with NVAF who develop
ACS or undergo PCI, with respect to:
Superiority on ISTH major or clinically relevant non-major (CRNM) bleeding
* The composite of all-cause death and all-cause rehospitalization.
* Death, stroke, myocardial infarction, stent thrombosis, or urgent coronary
revascularization
*

To compare aspirin and aspirin placebo (with concomitant P2Y12 inhibitor
therapy), in patients with NVAF who
develop ACS or undergo PCI with respect to:
The composite of all-cause death and all-cause rehospitalization.
* Death, stroke, myocardial infarction, stent thrombosis, or urgent coronary
revascularization
*

Patients with a recent ACS or undergoing PCI with NVAF and planned treatment
with P2Y12 inhibitor and oral
anticoagulation for at least 6 months will be evaluated for eligibility during
their ACS or post-PCI hospitalization.
Randomization can be performed up to 14 days after the ACS or PCI and should
take place as early as possible after
cessation of parenteral anticoagulant and when clinically stable. Both patients
with and without prior oral
anticoagulant treatment can be included in this trial. Patients who are on a
VKA prior to randomization will have
VKA discontinued and will not be dosed with apixaban for 4 days or until the
INR is less than 2.0. At the time of
enrollment, each patient who meets inclusion / exclusion criteria will be
randomized via IVRS using a 2 x 2 factorial
design to either apixaban or VKA and to either aspirin or aspirin placebo.
Randomization will be stratified by
indication at enrollment (ACS vs. PCI).
Overall, the trial will include approximately 1/3 of patients with a recent
ACS.

4 treatment groups:
Apixaban and aspirin
Warfarin and aspirin
Apixaban and aspirin placebo
Warfarin and aspirin placebo

please refer to protocol section 5.1 'Flow Chart/Time and Events Schedule' for
a complete overview of study procedures that will be done.

Apixaban:

Like all medicines, apixaban can cause side effects.
* Bleeding in the eye, under the skin, or from the nose and gums
* Bruising
* Vomiting of blood
* Blood in stool and urine

Uncommon Side Effects (between one in a hundred to one in a thousand might
experience the event)
* Sensitivity reaction (e.g. skin rash, difficulty breathing, swelling of the
face)
* Bleeding in the brain, in the lining of the stomach, from the mouth, and from
haemorrhoids (piles)
* Blood in sputum
* Abnormal bleeding from injection sites, sites of cuts or injuries, or vaginal
bleeding
Rare (between one in a thousand to one in ten-thousand)
* Bleeding in the respiratory tract (including the lungs)

VKA (including Warfarin, the drug that will be used in this trial)
Like all medicines, VKA Warfarin can cause side effects.
* Bleeding in the brain, under the skin, in the chest cavity, in or from
digestive tract, or from the nose
* Blood in the stool or urine
* Vomiting of blood
* Abnormal bleeding from injection sites, sites of cuts or injuries, or vaginal
bleeding
* Sensitivity reaction (e.g. skin rash, difficulty breathing, swelling of the
face)
* Fever, diarrhea, vomiting feeling and being sick
* Skin rashes
* Abdominal pain, bloating
* Liver enzyme changes
* Jaundice (yellowing of the skin and white of eyes)
The risk of bleeding or bruising while on a VKA Warfarin is related to the
intensity and duration of the blood thinning effect, and must be monitored
regularly with blood tests (INR monitoring).

Aspirin
Aspirin has many uses, but for the purpose of this study is being used as an
antiplatelet medication (helps to prevent blood*s clotting). Like all
medicines, Aspirin can cause side effects. Taking aspirin can increase risk of
bleeding.
* Gastrointestinal (stomach) bleeding/Ulcer
* Sensitivity reaction (e.g. skin rash, difficulty breathing/asthma, swelling
under your skin)
* Abdominal pain
* Heartburn
* Nausea
* Tinnitus or *ringing in the ears*

In addition VKAs and/or Aspirin can interact with numerous prescription and
over-the-counter medicines and herbal and botanical (natural) products, as well
as different foods.

Other Potential Risks
Assigned study treatment may not prevent blood clots from forming. It is
possible a blood clot can form and lead to a heart attack, stroke or even
death.

When study medications are taken alone or in combination with other
medications, there may be other risks that are unknown. All drugs have a
potential risk of an allergic reaction, which if not treated promptly, could
become life threatening.

When a sample of your blood is drawn, patient may experience some temporary
discomfort, faintness, inflammation of the vein, bruising, bleeding swelling
and/or, in rare circumstances, infection at the needle site.

Reproductive risks
Women: Study treatments may affect an unborn child or nursing infant.

Men: It is not known if the study treatment may affect sperm or an unborn
child.