Trial Information

Residual Vein Thrombosis Establishes the Optimal Duration of Low Molecular Weight Heparins in Cancer Patients With Deep Vein Thrombosis of the Lower Limbs

BACKGROUND. Currently there is no consensus on the optimal duration of antithrombotic
therapy in cancer patients experiencing a first episode of deep vein thrombosis (DVT) of
lower limbs. Recent guidelines suggest that patients with active cancer suffering of DVT of
the lower limbs should be treated for at least six months with low molecular weight heparin
(LMWH). However, although the current scheme for establishing the duration of LMWH and/or
Oral Anticoagulants (OA) is based on the nature of index DVT (idiopathic or provoked), some
new data starting to select other parameters to individualise this decision. The use of
D-dimer has been proven to be effective for selecting OA duration but this information is
valid only for non cancer patients with idiopathic DVT. Moreover, D-dimer does not seem
reliable in patients with chronic condition (such as cancer).

Recently, the presence of a Residual Vein Thrombosis (RVT) has been found to be associated
with an increased risk for recurrency (even in the contralateral leg or other venous sites)
and it can establishes the optimal duration of anticoagulant. However, such information is
not present in cancer patients, a population considered at high risk for recurrent
thrombosis. To test this hypothesis, we planned a randomized study in cancer patients with a
first episode of symptomatic idiopathic or provoked DVT treated with LMWH for 6 months.
Patients without RVT will not continue anticoagulation (group B), whereas those with RVT
will be randomized to either stop (group A2) or continue heparin (group A1).

METHODS Study patients. Cancer patients with a first episode of documented unprovoked and
provoked proximal DVT will be eligible for the study if they had completed 6 months of LMWH
(at therapeutic dosage for the first month, then dose reduced by 25% for the remaining 5
months). Provoked DVTs are defined as thrombotic episodes associated with pregnancy or
puerperium, recent (i.e. within three months) fracture or plaster casting of a leg,
immobilization with confinement to bed for three consecutive days and surgery with general
anesthesia lasting longer than 30 minutes. Unprovoked DVTs are defined as thrombotic
episodes occurred in apparently absence of risk factor other than cancer. Patients with
known thrombophilia, serious liver disease, renal insufficiency (creatinine clearance < 30
ml/min.) or those who lived too far from the center will be excluded from the study. The
study has to be approved by the institutional review boards of all participating centers.
All enrolled patients will provide written informed consent.

STUDY DESIGN. This is a multicenter prospective study in cancer patients with a first
episode of symptomatic (either provoked or idiopathic) proximal DVT detected by Compression
UltraSonography (C-US) and receiving LMWH for 6 months. At this time, subjects who agreed to
participate in the study have a physical examination to assess baseline clinical conditions
and to exclude contraindications. C-US of the proximal deep vein system in both legs will be
performed, measuring the diameters of any detectable thrombus in the Common Femoral Vein
(CFV) and Popliteal Veins (PV). Images will be obtained in transverse section only. Lumen
compressibility will be then evaluated on CFV and PV by gentle pressure of the probe, as
previously described. Briefly, the major and the minor diameters of the vein segment are
measured and recorded before and after compression. C-US findings are scored as "absence of
RVT" when residual thrombus occupied, at maximum compressibility, less than 40% of the vein
area. Patients without RVT will not continue anticoagulation, whereas those with RVT will be
randomized to either stop or continue LMWH for additional 6 months. A different
randomization sequence for each different study site is computer generated and encapsulated
in a randomization computer program. The sequences are balanced by blocks of ten.

STUDY OUTCOMES AND FOLLOW-UP. From the assignment visit, patients will be followed up for at
least one year after LMWH discontinuation; during the follow-up period, patients will be
contacted by the clinical centers every 3 months. C-US will be performed only when recurrent
symptomatic DVT is suspected. The study outcome is the composite of confirmed recurrent
venous thromboembolism (including DVT and/or fatal or non-fatal pulmonary embolism) and
major bleeding events from the index DVT to the last day of follow-up. In cases of suspected
DVT recurrence the results of C-US will be compared with the previous examination. A
diagnosis of recurrent venous thrombosis is made if a previously fully compressible segment
(contralateral or ipsilateral) became incompressible. In absence of a previous normal C-US,
DVT recurrence is diagnosed if a previously non-occlusive thrombus shifted to occlusive
thrombus, provided the vein area before compression had increased by more than 50%); in
undetermined cases, contrast venography will be performed. In patients with suspected
pulmonary embolism, diagnosis of recurrence is based on objective algorithms using clinical
probability, ventilation-perfusion lung scanning/helical computed tomography, C-US and/or
D-dimer if indicated. The diagnosis of clinically relevant haemorrhage will be made in case
of decrease of haemoglobin levels > 2.0 gr/dl, retroperitoneal, intracranial or
life-threatening. Patients will be instructed to contact the clinical center immediately if
symptoms developed suggestive of venous thromboembolism or bleeding. All suspected outcome
events and all deaths will be evaluated by a central adjudication committee whose members
were unaware of the name of the subject, the enrolling center, the C-US findings and the
assigned group.

STATISTICAL ANALYSIS. The sample size has been calculated by considering, for the group with
worst prognosis (being it A1, or A2 or B) an incidence of recurrent venous thromboembolism
of 20%, and a percentage of complications of 5% in the group with the best prognosis. An
overall sample size of 300 patients (100 for each study group) has been calculated to reach
a power of 80% to document a difference of at least 15% in at least one of the different
head-to-head comparisons, by using Bonferroni method to distribute type I error (0.05) among
multiple comparisons. An interim analysis is planned after the inclusion of 200 patients.
The chi square test and 95% confidence intervals will be used to evaluate the difference in
recurrence of VTE or bleeding between groups. A multivariable analysis with logistic
regression model will be performed to identify risk factors predictive for recurrence of
VTE. The model of logistic regression will be applied for both possible categories of
patients, those with idiopathic or post-operative DVT. The planned duration of the
enrollment phase is 3 years.