Reduced-dosed rivaroxaban and standard-dosed rivaroxaban versus ASA in the long-term prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism
The Einstein Choice Study

Acute VTE, i.e. DVT or PE is a common disorder with an annual incidence rate of
approximately 1-2 per thousand. Based on the reported incidence rates for VTE,
the VITAE study described the extent of the health burden attributed to VTE in
France, Germany, Italy, Spain, Sweden and the UK as a total of 460,000 incident
and recurrent non-fatal DVT, 300,000 PE, and 370,000 VTE related deaths per
year. VTE is not only a burden for healthcare systems due to its high mortality
and considerable morbidity in terms of recurrent VTE, but also due to the
associated risk of long-term sequelae of post-thrombotic syndrome, and chronic
thromboembolic pulmonary hypertension. Treatment of DVT and PE has two aims: To
prevent the extension of the existing thrombus and to prevent recurrent VTE.
Treatment with vitamin K antagonists (VKAs) is challenging because of multiple
drug and food interactions and because it requires ongoing coagulation
monitoring leading to subsequent dose adaptations. The incidence rate of
recurrent VTE is around 5*10% in the year after discontinuation of VKA and is
around 30% after 8 years. The annual risk of major bleeding with VKAs is1-2%
after the first year of treatment. As a result of the very high risk for
recurrent VTE after the presentation of acute, symptomatic DVT and/or PE, there
is a wide consensus among physicians to treat patients with therapeutic-dosed
anticoagulants, despite the well documented high risk for major bleeding. After
the first months of treatment, the risk of recurrent VTE diminishes as does the
risk of major bleeding. During this period, the focus of physicians and
patients deviates from prevention of recurrent venous thromboembolism to
minimizing the risk of (anticoagulantinduced) bleeding, and the general burden
of monitored and adjusted dose anticoagulant treatment. The duration of
treatment with anticoagulants is recommended to be individualized for as long
as the balance between the risk for recurrent VTE, the associated bleeding
risk, and the burden of anticoagulation remains favorable. The current American
College of Chest Physicians (ACCP) guidelines recommend long-term treatment in
conjunction with periodic benefit-risk assessment in patients with first
unprovoked PE or proximal DVT, second unprovoked VTE or VTE in active cancer
and low-moderate bleeding risk.

1. The primary efficacy objective is to evaluate whether rivaroxaban, in doses
of 10 mg or 20 mg, is superior to ASA 100 mg in the prevention of the primary
efficacy outcome (i.e. fatal or non-fatal symptomatic recurrent venous
thromboembolism).

2. The secondary efficacy objective is to evaluate whether rivaroxaban 10 mg
and rivaroxaban 20 mg are superior to ASA 100 mg in the prevention of the
secondary efficacy outcome (i.e. fatal or non-fatal symptomatic recurrent
venous thromboembolism, myocardial infarction, ischemic stroke, systemic
non-CNS embolism).

3. The principal safety objective is to document the incidence of the principal
safety outcome (i.e. major bleeding).

4. The secondary safety objective is to document the incidence of the secondary
safety outcome (i.e. clinically relevant non-major bleeding).

5. Additional study objectives are to evaluate
a. the composite of non-fatal symptomatic venous thromboembolism and allcause
mortality
b. the composite of major bleeding and recurrent venous thromboembolism
c. the composite of major bleeding, recurrent venous thromboembolism,
myocardial infarction, ischemic stroke and systemic non-CNS embolism

This is a multicenter, randomized, double-blind, double-dummy,
active-comparator, eventdriven study. Patients with confirmed symptomatic DVT
and/or PE who completed 6 to 12 months (± 1 month) of anticoagulant treatment
and did not interrupt anticoagulation for longer than 1 week are eligible for
this study. Patients will be allocated by interactive voice/web response system
(IxRS) to a 12-month duration of either once-daily:
1. rivaroxaban 10 mg,
2. rivaroxaban 20 mg, or
3. ASA 100 mg.
Randomization will be stratified by country and by index event (i.e. DVT or
PE±DVT). All efficacy and safety analyses are based on time to first event. All
patients who prematurely stop study treatment need to be observed until the end
of the 12-month treatment period. All suspected recurrent VTEs, myocardial
infarctions, ischemic strokes, systemic non-CNS embolisms, deaths and all
episodes of bleeding will be evaluated by a central, blinded, independent
adjudication committee. Adjudication results will be the basis for the final
analyses. An independent data monitoring committee (DMC) will monitor the
patients* safety during the study and give recommendations to the steering
committee. The study is event-driven and requires at least 80 confirmed primary
efficacy outcomes. The expected number of patients required per group is 950.
The patients randomized last into the study will receive study medication for 6
months and will not receive a second supply at visit 4. A 24-hour emergency
telephone service will be available throughout the study. An observation visit
is planned for all patients 30 days after stopping study medication. Only SAEs
need to be reported with the exemption of all efficacy and safety outcomes.
Furthermore, all patients with Hb <10 g/dl (also if not related to overt
bleeding), white blood cells <3.0 x 109/l and /or neutrophils < 0.5 x 109/l,
platelets <50 x 109/l, and allergic skin
reactions, allergic systemic reactions, if possibly related to study drug (even
if not considered serious), need to be reported. These adverse events (AEs)
must be reported within 24 hours. Any pregnancy in a patient or in the
patient*s partner, and the outcome of the pregnancy need
to be reported.

NA

1. Risks and Discomforts Associated with Rivaroxaban
The most common side effect of rivaroxaban is bleeding from anywhere in your
body, which usually is not severe and stops when the medication is stopped.
Bleeding from rivaroxaban can rarely be fatal (less than 1 person per 1000).
Other side effects that may be seen with rivaroxaban are: nausea, abdominal and
stomach pains, increase of some of the liver enzymes or allergic reactions
including skin rash, hives (urticaria), itching and swelling of eyelids, face,
lips, mouth or throat.

2. Risks and Discomforts Associated with Aspirine

Bleeding, bruising, nausea, vomiting, pain or discomfort in stomach, ringing /
buzzing in the ears, allergic reactions including skin rash, hives (urticaria),
itching, swelling of eyelids, face, lips, mouth or tongue and difficulty in
breathing.

3. Risks and Discomforts Associated with study procedures

Taking of blood samples may cause discomfort at the injection site and
dizziness when having blood drawn.