Best Antithrombotic Therapy in Patients With Acute Venous ThromboEmbolism While Taking Antiplatelets

Study Overview
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Brief Summary
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Venous thromboembolism (VTE) and atherosclerotic cardiovascular disease share common risk factors and frequently coexist in the same patients. Their management requires use of antithrombotic agents: anticoagulant therapy (AC) for secondary prevention of VTE recurrence, antiplatelet (AP) for secondary prevention of major adverse ischemic cardiovascular and cerebrovascular event (MACCE) in patients with atherosclerotic cardiovascular disease (coronary artery disease, atherosclerotic cerebrovascular disease, lower extremity peripheral arterial disease). Side effects of antithrombotic drugs are the 1st cause of emergency admission and hospitalization for an adverse drug reaction (mainly bleeding), and the combination of AC with AP strongly increases this risk.

Detailed Description
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Up to one third of VTE patients receive concomitant AP therapy, with conflicting results on patient outcomes. Concomitant therapy (AC+AP) has been associated with a higher risk of bleeding (up to 3-fold) when aspirin was associated with vitamin-K antagonist (VKA) in a multicenter cohort study, or with direct oral anticoagulants (DOACs) for acute VTE in a post-hoc subgroup analysis. Conversely, patients with acute VTE in whom clinicians decided to maintain AC+AP were found to have an increased risk of MACCE without any higher risk of bleeding, in a multicenter registry. However, in most cases, the type (aspirin or another) and indication (primary versus secondary prevention) of AP was unknown, as was the duration of the combination AC+AP, and therefore these observational results may be confounded. Therefore, there is persistent equipoise regarding the benefit/risk of combining an antiplatelet therapy with anticoagulation in patients undergoing treatment for VTE, when there is a prior history of atherosclerotic cardiovascular disease. This may explain why clinical practice varies widely. Considering the conflicting data about the risk of bleeding in patients on AP therapy for secondary prevention, who need to start full-dose anticoagulant therapy for acute VTE, a randomized trial comparing the two strategies, in patients with acute VTE and with history of stable atherosclerotic cardiovascular disease is needed and justified. The investigators hypothesize that a strategy based on the prescription of a full-dose AC therapy alone will decrease the risk of bleeding, when compared to the the strategy of combined AP and full-dose AC therapies, and that this strategy will translate in a positive net clinical benefit (a composite of clinically relevant bleeding, recurrent venous thromboembolism, and major adverse ischemic cardiovascular and cerebrovascular events).

Official Title
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Best Antithrombotic Therapy in Patients With Acute Venous ThromboEmbolism While Taking Antiplatelets

Conditions
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Venous Thromboembolic Disease

Intervention / Treatment
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* Drug: Full-dose anticoagulant therapy (AC)
* Drug: Antiplatelet therapy (AP)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Signed informed consent Patients with acute objectively confirmed symptomatic proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE) (with or without deep-vein thrombosis). Proximal deep-vein thrombosis is defined as thrombosis involving at least the popliteal vein or a more proximal vein of the lower limb. Indication of full-dose anticoagulant therapy for at least 3 months. Prescription of antiplatelet therapy for secondary prevention of atherosclerotic cardiovascular diseases, at the time of VTE diagnosis Life expectancy more than 3 months Social security affiliation Exclusion Criteria: Unable to give informed consent Active bleeding or a high risk of bleeding contraindicating anticoagulant treatment; a systolic blood pressure of more than 180 mm Hg or a diastolic blood pressure of more than 110 mm Hg Anticoagulation for more than 5 days prior to randomization Active pregnancy or expected pregnancy or no effective contraception Isolated distal deep vein thrombosis Antiplatelet therapy prescribed for primary prevention of cardiovascular disease Indication to maintain a dual-antiplatelet therapy. Triple positive antiphospholipid syndrome, with arterial thrombosis Major cardiovascular and cerebrovascular event in the past 12 months for acute coronary syndrome, and in the past 6 months for cerebrovascular diseases and peripheral arterial diseases

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: strategy of full-dose anticoagulant therapy alone (AC)<br>The experimental group receiving full-dose anticoagulant therapy alone (AC). Anticoagulant (AC) therapy :at the investigator's discretion in accordance with international recommendations for the management of DVT/PE Antiplatelet therapy will be stopped. | Drug: Full-dose anticoagulant therapy (AC)<br>* Anticoagulant (AC) therapy: at the investigator's discretion in accordance with international recommendations for the management of DVT/PE<br>|
| Active Comparator: strategy of combined full-dose anticoagulant and antiplatelet therapies (AC+AP)<br>The control group receiving the standard of care: Antiplatelet therapy will be combined to full-dose anticoagulant therapy. Anticoagulant (AC) therapy :at the investigator's discretion in accordance with international recommendations for the management of DVT/PE Antiplatelet (AP) therapy : Aspirin or Clopidogrel | Drug: Full-dose anticoagulant therapy (AC)<br>* Anticoagulant (AC) therapy: at the investigator's discretion in accordance with international recommendations for the management of DVT/PE<br>Drug: Antiplatelet therapy (AP)<br>* Aspirin (at a daily dose ≤100 mg) or Clopidogrel (at a daily dose ≤75mg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically relevant bleeding | Clinically relevant bleeding is composite of major bleeding events and clinically relevant non-major bleeding events). | end of the full-dose treatment period, up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Net clinical benefit | Net clinical benefit is defined by the composite of clinically relevant bleeding, recurrent venous thromboembolism, and major adverse ischemic cardiovascular and cerebrovascular events | end of the full-dose AC treatment period, up to 12 months | 
| Clinically relevant non-major bleeding |  | end of the full-dose treatment period, up to 12 months | 
| Major bleeding events |  | end of the full-dose treatment period, up to 12 months | 
| recurrent venous thromboembolism | proximal deep venous thromboembolism and/or pulmonary embolism symptomatic or incidental, and including fatal-PE | end of the full-dose treatment period, up to 12 months | 
| arterial events | major adverse cardiovascular and cerebrovascular events (nonfatal ischemic stroke, nonfatal myocardial infarction, acute lower limb ischemia, lower limb amputation or revascularization for vascular causes, cardiovascular deaths), | end of the full-dose treatment period, up to 12 months | 
| venous thromboembolism (VTE) sequels | post-thrombotic syndrome (defined as a Villalta score up to 4) and post-PE syndrome (defined as the combination of a persistant dyspnea with a NYHA (New York Heart Association) scale more than I with residual vascular obstruction on lung scan | end of the full-dose treatment period, up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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deep venous thrombosis, pulmonary embolism, anticoagulant, antiplatelet, Venous Thromboembolism, Direct oral anticoagulants, major adverse ischemic cardiovascular and cerebrovascular event, secondary prevention