Pharmacodynamic Effects of Low-dose Rivaroxaban With Antiplatelet Therapies

Recent studies indicate that anti-factor-Xa inhibition with low-dose rivaroxaban may have a
role in the reduction of ischemic recurrences in patients with atherosclerotic disease
manifestations.

However, although the introduction of newer antithrombotic strategies has been associated
with a reduction in ischemic recurrences in high-risk patients, these have been consistently
associated with an increase in bleeding complications. These have been observed particularly
with the combination of an oral anticoagulant agent, including low-dose rivaroxaban, with
standard DAPT, also known as "triple therapy". Observations from laboratory and clinical
studies suggest that in the presence of effective blockade of other pathways triggering
thrombotic complications aspirin may not offer added antithrombotic effects but contribute to
the increased bleeding. These observations have set the basis for a large number of clinical
outcomes studies evaluating whether dropping aspirin in the presence of more potent and
effective blockade of other pathways triggering thrombosis has a better safety profile
without a tradeoff in efficacy. Amongst these strategies, the use of low-dose rivaroxaban in
adjunct to a P2Y12 inhibitor, also known as dual therapy, has been proposed. This approach
may be of potential benefit to reduce atherothrombotic complications in high-risk patients
following an acute coronary event. On the other hand, regimens with more modest
antithrombotic effects compared with a combination of low-dose rivaroxaban and a P2Y12
receptor inhibitor such as low-dose rivaroxaban alone or in combination with aspirin may be
more suitable in more stabilized patients.

To date there is very little data, and not conducted in human subjects, on the interplay
between anti-Xa blockade with low-dose rivaroxaban and antiplatelet therapies, and in
particular how this affects profiles of platelet reactivity and thrombin generation. Given
the potential role for the use of low-dose rivaroxaban for the prevention of ischemic
recurrences in patients with atherothrombotic disease manifestations, including coronary
artery disease (CAD) and peripheral arterial disease (PAD), the study team proposes a
prospective pharmacodynamic (PD) investigation assessing the impact of low-dose rivaroxaban
when used in combination with antiplatelet treatment regimens commonly used in clinical
practice.

Inclusion criteria:

- Known CAD (defined as angiographic evidence of >50% coronary artery stenosis or prior
coronary revascularization) or PAD (defined as a positive ABI or prior
revascularization)

- on treatment with either aspirin (81mg/qd), aspirin (81mg/qd) plus clopidogrel
(75mg/qd), or aspirin (81mg/qd) plus ticagrelor (90mg/bid) for at least 3 months per
standard of care OR

- Atrial fibrillation (paroxysmal, persistent or permanent) on treatment with
rivaroxaban 20 mg qd (if CrCl >50 mL/min) or 15 mg qd (if CrCl 15 - 50 mL/min) per
standard of care. Patients with concomitant CAD or PAD who are also taking
antiplatelet medications are not eligible. However, if these are only on oral
anticoagulation with rivaroxaban (and no antiplatelet therapy) the person will be
eligible.

Exclusion criteria:

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

- CrCL <20mL/min

- Any clinical indication to be on triple antithrombotic therapy (DAPT plus an oral
anticoagulant)

- An acute coronary event in the past 90 days

- Prior hemorrhagic stroke or intracranial hemorrhage

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

- Chronic use of nonsteroidal anti-inflammatory drugs

- On treatment with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole,
itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) or
inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort).

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

- Prior hypersensitivity reaction to rivaroxaban

- On treatment with prasugrel in the past 10 days.

- Platelet count <80x106/mL

- Hemoglobin <10g/dL

- Hemodynamic instability

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