Treatment of portal, mesenteric, and splenic vein thrombosis with rivaroxaban.
A pilot, prospective cohort study

Splanchnic vein thrombosis (SVT) is an unusual site manifestation of venous
thromboembolism (VTE). It includes the Budd-Chiari syndrome (BCS), portal vein
thrombosis (PVT), mesenteric vein thrombosis (MVT) and splenic vein thrombosis
(spVT). PVT is the most frequent manifestation of SVT, followed by MVT.
Although accurate epidemiologic data are scant, the diagnosis of SVT is likely
increasing also due to the larger use of abdominal ultrasound or computed
tomography in at risk populations, such as patients with liver cirrhosis or
solid abdominal cancer. In a recent retrospective review of all abdominal CT
scans performed at a single institution, we reported 1.74% prevalence of
incidentally detected abdominal vein thrombosis, mainly in the splanchnic
venous system [1].

SVT is a potentially life-threatening disease, with a broad range of clinical
presentations including abdominal infarction or gastrointestinal bleeding.
Acute MVT is associated with intestinal infarction in almost one-third of
patients and has a mortality rate of 20% at 30 days [2]; gastrointestinal
bleeding and ascites can be found in up to one-fourth of patients with PVT and
BCS, and are triggered by portal hypertension [3].

The complex balance between the increased bleeding risk associated with
esophageal varices and thrombocytopenia and the thrombotic predisposition
associated with cirrhosis and malignancy, among others, make the treatment of
SVT a clinical challenge. Unfortunately, no randomized controlled trials are
available and current recommendations are derived from observational studies
with high risk of selection bias.

In the absence of major contraindications, anticoagulant therapy is generally
recommended for all patients presenting with acute symptomatic SVT, starting
with either low-molecular weight heparin (LMWH) or unfractionated heparin and
continuing with the vitamin K antagonists in most patients [4]. Treatment of
incidentally detected SVT is suggested only for patients with evidences of
acute thrombosis, thrombus extension or concomitant risk factors for recurrence
(e.g. concomitant cancer). As for usual site VTE, it is generally recommended
that anticoagulant treatment should be continued for at least 3 months, or
indefinitely if underlying persistent prothrombotic factors are identified [4].
Very few data are actually available on the short- and long-term rates of
recurrent SVT and bleeding and only very few studies have a sufficiently large
sample size to provide some meaningful information. The only prospective study
was a European multicenter study assessing the outcome of early anticoagulation
after acute PVT [5]. Anticoagulant treatment successfully prevented thrombus
extension and was associated with a favorable 1-year recanalization rate (38%
for portal vein, 54% for splenic vein and 61% for superior mesenteric vein),
two patients developed mesenteric infarction [5]. Bleeding was reported in nine
of the 95 treated patients, but neither definition of the severity of this
outcome nor the timing of the events was provided in the study. In a
retrospective cohort of PVT patients, of whom nearly two thirds were treated
with anticoagulant drugs, the incidence rate of thrombotic events was 5.5/100
patient-years and the absence of anticoagulant therapy was an independent
predictor for thrombosis [6]. Gastrointestinal bleeding occurred with an
incidence rate of 12.5/100 patients-year, but again no standardized definition
of bleeding severity was used in this study [6].

We previously assessed the long-term safety and efficacy of anticoagulant
treatment in a multicenter, retrospective cohort study on patients with MVT
receiving secondary prevention with vitamin K antagonists (VKA) [7]. The
overall recurrence rate was 2.34/100 patient-years and increased to 4.59/100
patient-years after discontinuation of treatment. The incidence of hemorrhagic
complications was low, with only 2.6% of patients experiencing a major bleeding
event [7].

In a recent prospective multicenter, international registry on more than 600
SVT patients, we observed that the majority of patients were initially treated
with LMWH, and that more than a third of them were continued on long-term
parenteral treatment [8].

Rivaroxaban has been approved by the European Medical Agency for the acute
phase treatment and the long-term secondary prevention of deep vein thrombosis
of the lower limbs and pulmonary embolism. In the Einstein studies, rivaroxaban
was administered at the dosage of 15 mg twice a day for the first 3 weeks
followed by 20 mg once daily in patients with acute DVT and was compared to the
standard therapy with LMWH and VKA [9,10]. The primary outcome measure of
symptomatic recurrent VTE was similar between the two groups as well as the
incidence of bleeding events.

Patients with splanchnic vein thrombosis are at increased risk of recurrent VTE
and bleeding. Routine anticoagulation with unfractionated heparin or low
molecular weight heparin followed by warfarin is recommended in this setting,
but limited data is available to support this recommendation and more than 20%
of these patients do not receive antithrombotic treatment due the fear for
bleeding complications.

The pharmacokinetic and pharmacodynamic characteristics of rivaroxaban make
this drug an ideal alternative therapeutic strategy for the treatment of
patients with SVT. Thanks to the oral route of administration, the short
half-life, the high bioavailability, the predictable dose-response and the lack
of effects on platelet activity, rivaroxaban could result as an important
alternative to both LMWH and warfarin in the acute and long-term treatment of
SVT patients. A few anedoctal experiences with rivaroxaban in this setting have
recently been published [11].

Furthermore, in the pooled analysis of the EINSTEIN studies, the incidence of
major bleeding was significantly reduced from 1.7% in the standard therapy
group to 1.0% in the rivaroxaban group (hazard ratio 0.54; 95% CI, 0.37-0.79)
[12], and this observed benefit in the safety profile of rivaroxaban would be
extremely relevant in the treatment of patients with SVT, given their potential
higher risk of bleeding as compared to patients with deep vein thrombosis in
the lower limbs.

In this prospective cohort study, patients presenting with acute SVT will
receive rivaroxaban 15 mg bid for 3 weeks followed by rivaroxaban 20 mg once
daily for a total of 3 months. The primary safety and efficacy outcomes will be
measured at 3 months.

This a Phase 3, Single Group Assignment, Open Label, prospective cohort study
aiming to treat Portal, Mesenteric, and Splenic Vein Thrombosis With
Rivaroxaban.

Rivaroxaban 15 mg bid for three weeks followed by rivaroxaban 20 mg once daily
for a total of 3 months. After the end of the study period the decision to
continue anticoagulant treatment with any of the available drugs will be left
to the discretion of the attending physician.

Rivaroxaban, like other anticoagulants, should be used with caution in patients
with
an increased bleeding risk. Bleeding can occur at any site during therapy with
rivaroxaban. The possibility of a hemorrhage should be considered in evaluating
the condition of any
anticoagulated patient. Any unexplained fall in hemoglobin or blood pressure
should lead to a search for a bleeding site. Certain medications may increase
the bleeding risk. Please refer to the concomitant medications section for
further details (section 3.3).

Should severe bleeding occur, treatment with rivaroxaban must be discontinued
and the
source of bleeding investigated promptly. Close clinical surveillance (looking
for signs of bleeding or anemia) is recommended throughout the treatment
period, especially in the presence of multiple risk factors for bleeding (see
Table 1 below).

Table 1 - Factors Which Increase Hemorrhagic Risk