Deep Vein Thrombosis of the Lower Extremities Clinical Trial
Official title:
Limited Versus Extended Ultrasonography for the Diagnosis of Clinically Symptomatic Deep Vein Thrombosis of the Lower Extremities. A Randomized Study
Currently, patients with suspected deep vein thrombosis (DVT) of the lower extremities receive the ultrasound investigation of their deep vein system, either by limited ultrasonography (ultrasonography confined to the proximal veins, repeating the test after one week in patients with positive D-dimer) or by extended ultrasonography (ultrasonography extented to the entire deep vein system of the legs). No study has directly compared the two strategies to assess their accuracy and safety. We plan to compare the accuracy and safety of the two strategies in a prospective randomized study addressing more than 2000 consecutive outpatients presenting with the clinical suspicion of DVT.
All consecutive outpatients referred to the study center with clinically suspected deep vein
thrombosis are potentially eligible for inclusion. Patients are excluded if they have a
history of previous venous thromboembolism, have clinical suspicion of pulmonary embolism,
have a life expectancy shorter than 3 months, have used therapeutic doses of unfractionated
heparin, low molecular weight heparin or oral anticoagulants for more than 48 hours, have
another indication for anticoagulant treatment, are pregnant, are aged less than 18 years,
are inaccessible to follow-up, or refuse participation in the study.
Randomization Before randomization, patients are interviewed using a standardized
questionnaire in order to collect information on risk factors for venous thrombosis, and the
presence of several clinical signs and symptoms. Subsequently, they are randomized to the
limited or the extended ultrasound strategy through computer generated lists, each of 100
patients arranged in balanced blocks of 10, specific for each center. The list is accessible
only for a study nurse who informed the study physicians about group allocation once
patients had provided informed consent.
Initial diagnostic workup Patients randomized to limited ultrasonography undergo compression
ultrasonography, confining the investigation to the common femoral and the popliteal vein
down to its trifurcation. In patients with normal findings D-dimer testing is performed, and
they are subsequently managed according to its results: patients with normal D-dimer levels
do not receive further investigation, while those with abnormal test are scheduled for
repeat compression ultrasonography within one week.
Patients randomized to the extended ultrasonography receive first the evaluation of the
proximal vein system, including the common femoral, the superficial femoral and the
popliteal vein down its trifurcation. Then patients with compressible proximal veins undergo
the extensive evaluation of the calf vein system, including the anterior tibial, posterior
tibial and peroneal veins, and, if the deep veins were normal, also of the muscular
(gastrocnemial and soleal) veins.
Limited ultrasonography and D-dimer The common femoral at the groin, and the popliteal vein
down to its branching into the calf deep veins at the popliteal fossa, are examined in the
transverse plane only, with a 7.5 MHz linear probe. The test results are categorized as
normal (compressible veins) or abnormal (non compressible veins).
We use a rapid whole blood bedside D-dimer assay (SimpliRED® D-Dimer assay, AGEN Biomedical
Ltd., Brisbane Australia). This assay is based on autologous red cell agglutination, using a
chemical conjugate of a monoclonal antibody specific to human D-dimer (DD-3B6/22) linked to
a monoclonal antibody which binds to the surface of human red blood cells (RAT-1C3/86) as
active agent. The test can be performed either on capillary or on citrated venous blood.
Agglutination occurs at D-dimer concentrations above 0.2 mg/L. The SimpliRED® results are
categorized as normal, abnormal or non interpretable. The latter finding is categorized as
abnormal.
Extended ultrasonography All veins are imaged along their length with a 7.5 MHz linear
transducer. The proximal venous system is examined starting from the (common and
superficial) femoral veins, which are scanned down to the distal part of the thigh, with the
patient lying supine. Then, with the patient in the prone position the popliteal vein down
to its trifurcation is evaluated. The calf veins are evaluated with the patient sitting with
his/her legs hanging over the edge of the bed. Starting from the most proximal venous
segments downwards, the anterior, posterior tibial and peroneal veins are visualized along
their length, employing augmentation maneuvers (manual squeezing of the distal calf or of
the foot) to enhance vessel visualization. The same approach is used to image the muscular
veins. The only criterion to adjudicate a thrombosis involving the proximal system and the
tibial and peroneal veins is the finding of a non compressible venous segment. As for the
muscular veins, criteria for abnormal testing are incompressibility or the lack of
spontaneous intraluminal color filling or reverse-flow color filling after augmentation
maneuvers. All tests are performed by highly skilled physicians.
Follow-up All patients with an initial normal workup are discouraged from receiving
antithrombotic drugs, and are scheduled for a clinical evaluation at three months. They are
instructed to immediately contact the study centers should symptoms of venous
thromboembolism become manifest in the meantime. In this case they undergo instrumental
testing to confirm or refute the presence of the disease. Patients failing to attend the
scheduled visit are contacted by telephone to assess their status, and invited to attend a
clinical evaluation at the study centre.
Outcomes The primary outcomes of the study are: (1) the prevalence and location of venous
thrombosis as shown by the initial diagnostic workup; (2) the rate of symptomatic venous
thromboembolic events (including proximal vein thrombosis, isolated thrombosis of the tibial
or peroneal veins in either leg, and pulmonary embolism) during three months of follow up in
patients with an initially normal diagnostic workup. All suspected events are to be
objectively evaluated as follows: ipsilateral or contralateral deep vein thrombosis is ruled
in by abnormal compression ultrasonography or by the finding of an intraluminal filling
defect on ascending venography, visible on two different projections; suspected pulmonary
embolism is confirmed by an abnormal spiral computed tomography of the lung, by a high
probability ventilation-perfusion lung scan, or by an abnormal pulmonary angiography. Fatal
pulmonary embolism is adjudicated on the findings of autopsy, in case of sudden and
otherwise inexplicable death, or on clinical grounds according to the opinion of an
independent physician.
An independent and blind committee adjudicates all suspected thromboembolic events and all
deaths occurring during the follow up based on all relevant documents and footage.
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Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic