Deep Vein Thrombosis Clinical Trial
Official title:
Residual Vein Thrombosis (RVT) Establishes the Optimal Duration of Oral Anticoagulants After a First Episode of Deep Vein Thrombosis of the Lower Limbs
ABSTRACT Background The optimal duration of oral anticoagulant treatment in patients with
idiopathic venous thromboembolism is still uncertain . The present study addressed the
possible role of the Residual Vein Thrombosis in assessing the need for a prolonged
anticoagulation.
Methods Patients with a first episode of symptomatic unprovoked or provoked proximal Vein
Thrombosis (VT) were given Oral Anticoagulant Treatment (OAT) for 3 months. Residual Vein
Thrombosis (RVT), ultrasonographically-detected, will be then assessed. Patients without RVT
did not continue OAT, whereas those with RVT will be randomized to either stop or continue
OAT for 9 more months. Patients were followed-up prospectively focusing on the study
outcomes: occurrence of recurrent venous thromboembolism and major bleeding over a period of
at least 12 months after OAT discontinuation.
INTRODUCTION Long-term anticoagulant treatment with adjusted doses of vitamin K antagonists
is highly effective in preventing recurrent events after a first episode of unprovoked
Venous ThromboEmbolism (VTE), even if the optimal duration of this therapy is still
uncertain. Since the risk of recurrency is greatest in the first year after the initial
thrombotic episode and gradually diminishes thereafter, the benefit of an extended course of
anticoagulant treatment may be offset over time by the persisting risk of clinically
important bleeding.
A potential clinically relevant approach for establishing the optimal duration of Oral
AntCoagulant Therapy (OAT) is that of predicting the individual risk for thrombotic
recurrency after the index Deep Vein Thrombosis (DVT). Although the current scheme for
establishing the duration of OAT is based on the nature of index DVT (idiopathic or
provoked), some new data starting to select other parameters to optimize this decision.
Recently, the use of D-dimer has been proven to be effective for selecting OAC duration;
however, this investigation evaluated only patients with idiopathic DVT and, moreover, the
use of D-dimer can not be easily handle by most of Institutions.
In earlier prospective studies conducted in patients with symptomatic DVT, the presence of a
residual thrombus was associated with an increased risk of thrombotic recurrencies either in
idiopathic or provoked venous thrombosis. Interestingly, recurrent events occurred not only
in the previously affected veins but also in other sites, thus suggesting that Residual Vein
Thrombosis (RVT) may express a pro-thrombotic status. Based on these findings, the detection
of RVT may be, therefore, of help in establishing the duration of anticoagulation.
To test this hypothesis, we planned a randomized, prospective, follow-up study in patients
with a first episode of symptomatic DVT treated with OAT for 3 months. Patients without RVT
will not continue anticoagulation, whereas those with RVT will be randomized to either stop
or resume anticoagulation.
METHODS Study patients. Patients with a first episode of documented unprovoked and provoked
proximal DVT will be eligible for the study if they had completed at least three months of
OAT (target INR 2.5, range 2.0-3.0). 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 healthy individuals. Patients with
active cancer, limited life expectancy, antiphospholipid antibody syndrome, or an other
known thrombophilic status (such as antithrombin deficiency), serious liver disease, renal
insufficiency (serum creatinine > 2 mg/dL), those who lived too far from the center will be
excluded from the study. The study has been 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 patients with a first episode of
symptomatic (either provoked or idiopathic) proximal DVT detected by Compression
UltraSonography (C-US) and receiving OAT [warfarin (Coumadin, Bristol Myers Squibb) for 3
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 OAT
(INR 2.0-3.0) for additional 9 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 OAT 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 ultrasonography 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 was 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,
compression ultrasonography 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 has been 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. Baseline differences between groups will be assessed by the chi-square
test (Yates’ correction) for categorical variables and t-test or Mann-Withney U test for
continuous variables, as appropriate. Data will be analyzed on intention-to-treat basis.
Kaplan-Meier survival curves are plotted to estimate the cumulative incidence of symptomatic
recurrent venous thromboembolism and major bleeding. Patients who during the study will
develop clinical conditions interfering with the study outcomes (such as ischemic heart
disease, cancer, stroke, superficial vein thrombosis, etc) and left the assigned group will
be regularly followed-up and included in analysis. Hazard ratios and their 95 percent
confidence intervals will be calculated using the Cox’s proportional hazards model. The data
will be analyzed using the Prism statistical software package (Version 3.0, GraphPad
Software Incorporated, San Diego, CA) and the SPSS statistical package (Version 14.0, SPSS
Inc., Chicago, IL).
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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