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

Overview

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

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).

Interventions

• Drug Full-dose anticoagulant therapy (AC)
  Anticoagulant (AC) therapy: at the investigator's discretion in accordance with international recommendations for the management of DVT/PE
• Drug Antiplatelet therapy (AP)
  Aspirin (at a daily dose ≤100 mg) or Clopidogrel (at a daily dose ≤75mg)

Primary outcome measures

• Clinically relevant bleeding [Time frame: end of the full-dose treatment period, up to 12 months]

Secondary outcome measures (6)

• Net clinical benefit [Time frame: end of the full-dose AC treatment period, up to 12 months]
• Clinically relevant non-major bleeding [Time frame: end of the full-dose treatment period, up to 12 months]
• Major bleeding events [Time frame: end of the full-dose treatment period, up to 12 months]
• recurrent venous thromboembolism [Time frame: end of the full-dose treatment period, up to 12 months]
• arterial events [Time frame: end of the full-dose treatment period, up to 12 months]
• venous thromboembolism (VTE) sequels [Time frame: end of the full-dose treatment period, up to 12 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 28 centers

• CHU Amiens — Amiens
• CHU Angers — Angers
• CHU Besançon - Hôpital Jean Minjoz — Besançon
• CHRU Brest - Hôpital la Cavale Blanche — Brest
• Clinique du Parc - Castelnau-le -lez — Castelnau-le-Lez
• CHU Clermont-Ferrand - Hôpital Gabriel Montpied — Clermont-Ferrand
• CHU Dijon — Dijon
• CH le Corbusier - Firminy — Firminy
• … and 20 more centers

Identifiers

NCT: NCT05627375 · 20PH285

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗