Once-daily oral direct factor Xa rivaroxaban in the long-term prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep-vein thrombosis or pulmonary embolism. The Einstein-Extension study.

Patients with idiopathic PE or DVT and those with persistent risk factors
remain at risk for recurrent thromboembolic events.(5) This risk is most
pronounced in the first months after the acute episode and diminishes slowly
over subsequent years. The bleeding risk with VKA therapy is usually stable
over years with a tendency
to increase with advancing age and the occurrence of comorbid conditions.
Therefore, the decision to prolong VKA therapy is a challenge to the physician
who should balance the risk of disease progression or recurrence with that of
bleeding, against the background of the impact of this therapy on the patient*s
daily life.
Therefore there remains equipoise about the optimal duration of VKA therapy in
various categories of PE or DVT patients. This is reflected in a grade
2Arecommendation by the American College of Chest Physicians guidelines for
antithrombotic therapy, the *2* indicating that the risk/benefit of extended
treatment is not clear. Rather than restrict prolonged treatment to a
variably-defined selected group, it would be worthwhile to evaluate a broad
group of patients in whom treatment might be discontinued, and to study
prolonged treatment with a placebo comparator. In the decision to provide
extended anticoagulant treatment another aspect would be if it were safer than
warfarin and provided efficacy. A new therapeutic agent with an equal or
improved efficacy profile combined with a lower risk of bleeding could allow
for a longer treatment duration, especially if this can be achieved with easier
treatment logistics.
Rivaroxaban is a novel, direct oral factor Xa-inhibitor which plays its role at
the intersection of the extrinsic and the intrinsic pathways for thrombin
generation.
It requires no monitoring of its effect and has high benefit-risk ratio.
In the present study rivaroxaban will be compared to placebo. Placebo control
is needed because there remains equipoise about the optimal treatment duration
after the initial treamnet period (see above). If the present study shows that
this new treatment is effective without compromising patient's safety, extended
anticoagulant therapy with easy logistcs might be avialable for patients

The purpose of this study is to show that the incidence of new thrombotic
events during an additional 6 or 12 months of treatment with rivaroxaban is
lower when compared to placebo and that the likely advantage of an extended
effect is not offset by an increase of bleeding complications.

This is a multicenter, randomized, double-blind, placebo-controlled,
event-driven, superiority study for efficacy.
Patients with confirmed symptomatic DVT or PE who completed 6 to 14 months of
treatment with VKA (warfarin or acenocoumarol) outside the VTE treatment study
or who completed 6 or 12 months of treatment with VKA or rivaroxaban in the
11702 study, are eligible for this trial.
Therefore, patients who participated in the Einstein VTE program
(rivaroxaban/11702) and also patients treated outside
that program for 6 to 14 months with warfarin or acenocoumarol following the
initial diagnosis of PE or DVT and continued up to the moment of
randomization,are potential candidates. The treatment duration is 6 or 12
months and should be indicated prior torandomization. The last patient will be
treated for at least 3 months once the required number of events has been
reached.All patients will have a 30-day observational period after cessation of
studytreatment. Allocation to treatment will be done centrally by interactive
voice response system and will be stratified by 1) country, 2) previous
treatment
(rivaroxaban or VKA), and 3) intended treatment duration.
All suspected recurrent VTE, deaths and all episodes of bleeding and vascular
events will be evaluated by a central, blinded, independent adjudication
committee. Adjudication results will be the basis for the final analyses.
An independent data and safety monitoring board will monitor the patients*
safety during the study and give recommendations to the executive committee.
The study is event-driven and requires 30 confirmed recurrent thromboembolic
events. The expected number of patients required per group is 650.
A 24-hour emergency telephone service will be available throughout the study.

After randomization,patients allocated to rivaroxaban will receive rivaroxaban
20 mg once-daily, patients allocated to placebo will receive a matching placebo
tablet once-daily

In the present study there are 2 strata depending on the treatment duration
which is determined by the investigator prior to randomization
Depending on this treatment duration the number of visits is scheduled.
For the 6 month treatment period, 7 assessments are planned: 6 of these need to
be hospital visits and each time a blood sample will be taken (about 10-20 ml
per blood sample). The assessment at day 8 may be a telephone contact.
For the 12 month treatment period, 9 assessments are planned: 8 of these need
to be hospital visits and each time a blood sample will be taken (about 10-20
ml per blood sample). The assessment at day 8 may be a telephone contact.
If during the course of the study re-occurrence or worsening of deep-vein
thrombosis or pulmonary embolism is suspected, diagnostic testing will take
place. There is also an additional blood collection (about 10 ml). If suspected
pulmonary embolism or deep-vein thrombosis is confirmed, the study medication
will be discontinued and replaced by another therapy at the discretion of your
doctor. For this purpose, you will receive a booklet detailing what to do if
you develop symptoms suggestive for recurrent pulmonary embolism/ deep vein
thrombosis or bleeding. In case of any abnormal laboratory values, or clinical
signs and symptoms, an appropriately close monitoring will be performed until
complete normalisation. A blood sample (about 10 ml) will also be collected in
case of a bleeding complication.
Before treatment begins, your doctor will document your current health status
and you will have blood samples taken to check your kidney and liver function.
One of the blood tubes taken will be stored and evaluated only in case you will
develop unexpected complications or if requested by a health authority.
Female patients of childbearing potential will also have a urine pregnancy test
to exclude a pregnancy.
Hence, compared to standard treatment there will be more blood samples, and
out-patient visits . The risks associated with bloodsampling is low and the
extra effort required for out-patient visits is acceptable in view of the
trial.