Trial Information

Prevention of Recurrent Venous Thromboembolism in Patients With Low Circulating Levels of Antithrombin. Extended Anticoagulation vs 12-Month Oral Anticoagulation

Study population: subjects with a recent (<3 months) first VTE event will be enrolled for a
long-term follow-up. Clinical visits will be performed every 4-6 months (average).

In each case, objective diagnosis has to be achieved by compression ultrasonography, the
diagnosis being based on the lack of compressibility of one or more venous segments. PE has
to be documented by ventilation/perfusion lung scanning or by spiral computed tomography
(CT).

For each subject, information about pregnancy, active malignancy, recent (<3 mo) surgery or
trauma, fracture, immobilization, acute medical illness, use of oral contraceptives,
long-distance travel, personal or family history of arterial and/or venous thrombosis or
repeated birth losses will be collected. In the presence of at least one of the previous
risk factors, VTE will be defined as secondary otherwise idiopathic. Further information,
collected from the whole population by a trained staff, were the following: gender, age,
weight, height, body mass index (BMI), waist circumference, personal history of symptomatic
atherosclerosis (i.e. ischemic stroke, transient ischemic attack, acute myocardial
infarction, angina, intermittent claudication), arterial hypertension, use of
antihypertensive drugs, diabetes mellitus, use of antidiabetic drugs, hyperlipidemia, use of
statins, smoking habit (use of cigarettes/d), current use of heparin, use of oral
anticoagulant (how long) or of antiplatelet drugs (how long), chronic consumption of other
drugs.

All these information will be collected by a trained staff on admission and during follow-up
visits (every 4-6 months).

Exclusion criteria: missing data during the follow-up; contraindications to or lack of
compliance to oral anticoagulation (OAT), lack of informed consent; history of previous VTE
event; indication for continuous oral anticoagulation (e.g., an artificial heart valve or
chronic atrial fibrillation); events occurring during pregnancy, malignancy, puerperium,
oral contraceptive intake, hormone replacement therapy; deficiencies of Prot. C and Prot S
or combined inhibitor deficiencies.

Laboratory Studies All laboratory evaluations will be carried out at least 2 weeks after
cessation of the anticoagulant therapy or after a switching to low-molecular weight heparin
(LMWH) treatment. Antithrombin (AT) functional activity will be measured and VTE patients
will be stratified into 3 subgroups of AT% (1st: <70%, 2nd: 70-80, 3rd: >81%). AT
measurements will be confirmed in a second sample collected 3 months later. In case of
discrepancy between the results of the 2 tests, a third sample will be collected. Protein C
and S; antiphospholipid antibodies (IgG and IgM); homocysteine, and factor V Leiden and
prothrombin 20210A polymorphisms will be determined using commercially available kits by
technicians who had been unaware of the patients' treatment assignments and of the clinical
course.

Antithrombotic treatment The antithrombotic treatment will be decided according to the usual
practice of the enrolling Center. The duration of the initial treatment with parenteral
anticoagulation (Low Molecular Weight Heparin or Fondaparinux), the beginning of oral
anticoagulation (OAT) with Vit K inhibitors and the International Normalized Ratio (INR)
target will be recorded.

According to Center indications the OAT duration (6 months, 12 months or long-lasting) will
be recorded and population will be stratified accordingly. The length of therapy will be
counted from the date when a stable prothrombin time within the target INR range is
achieved.

The occurrence of surgery, trauma, prolonged immobilization (>7 days), pregnancy (VTE risk
periods) during the follow-up and the use of adequate anti-thrombotic prophylaxis will be
recorded.

Follow-up Subjects will be followed-up at 3, 6, and 12 months after enrollment and at least
every 6 months thereafter either by a visit to the Center or by telephone contact. INR
values will be reported by telephone twice monthly. At each visit the patients will be asked
about new symptoms of VTE and about bleeding manifestations. When appropriate, a clinical
assessment will be made and diagnostic tests will be performed.

Information on major and minor bleedings during oral anticoagulation will be collected in
the whole sample. Major bleedings will be defined as hemorrhages that were either
retroperitoneal or intracranial or associated with a decrease in hemoglobin of at least 2.0
g per deciliter or that had required either transfusion of at least 2 units of blood (or of
red cells) or an invasive procedure, including surgery, to stop them or if they warranted
permanent OAT withdrawing.

Study end points The incidence of objectively documented recurrent VTE (DVT and/or PE)
during the life-long follow-up is the primary outcome of this study. Contralateral DVT and
PE will be computed as a recurrence. Ipsilateral DVT will be adjudicated recurrent if the
results of the tests are worse than those obtained in a previous test or if the thrombus is
diagnosed in another venous district of the leg. DVT of the arm; CT or MRI-documented
occlusion of cerebral/abdominal veins; ultrasound-documented thrombosis of the great
saphenous vein of the leg not involved in the first appearance will be also defined as a
recurrence. The total (minor and major) bleeding occurrence during the life-long follow-up
represents the safety end-point of this study and will be analyzed according to the
thrombolysis in myocardial infarction (TIMI) bleeding score.

Sample size Assuming a 20:1:1 sample size ratio between AT% subgroups (AT%> 80%; AT%=70-80%;
and AT%<70%, respectively), to detect an increase in the incidence of recurrent events from
0.3 in the control population (AT% > 80%) to 0.6 in each of the other two subgroups
(AT%=70-80% and AT%<70%), a sample size of about 900 subjects is needed (power= 95%;
α=0.025, to allow for two independent comparisons).

Expected results Among individuals with a history of first VTE stratified according to AT%
levels, the risk/benefit analysis of this study will help identify group(s) of individuals
with a strong indication to long-term oral anticoagulation.