REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism.

• Status: Recruiting
• Trial end date: 2022-11-02
• Target enrollment: 0
• Participant gender: All

Summary

Patients with unprovoked venous thromboembolism (VTE) or VTE associated with persistent risk factors have a high risk of recurrence after stopping anticoagulation. In these patients, international guidelines recommend indefinite anticoagulation. However, prolonged use of warfarin or DOAC at therapeutic dose is associated with a significant risk of bleeding. Consequently, it has been hypothesized that extended anticoagulation at lower dosage might be as effective as and safer than full dose of anticoagulation. However, low-dose warfarin (INR 1.5-2) was less effective and not safer than conventional dose warfarin (INR 2-3).

Low dose of DOAC has the potential to validate this hypothesis. In a first randomized trial comparing full-dose or low-dose apixaban with a placebo during an additional one year of anticoagulation in patients where physicians were uncertain for prolonging anticoagulation ("Amplify-extension trial"), low-dose apixaban was more effective than placebo without any major concern regarding safety and possibly as effective as and safer than full-dose apixaban; in a second randomized trial comparing full-dose or low-dose rivaroxaban with aspirin, during an additional one year of anticoagulation in patients where physicians were uncertain for prolonging anticoagulation ("Einstein-Choice trial"), low-dose rivaroxaban was more effective than aspirin without any major concern regarding safety and possibly as effective as and safer than full-dose rivaroxaban. However, these two studies were not designed and powered to demonstrate non-inferiority on efficacy and superiority on safety of a reduced dose of DOAC versus a full dose DOAC and the selected population did not have strong indications for indefinite anticoagulation. Thus, there is currently no evidence to recommend a reduced dose rather than a full dose of DOAC for extended therapy in patients at high risk of recurrent VTE. Consequently, a randomized trial comparing low-dose DOAC with full-dose DOAC therapy in patients at high risk of recurrent VTE is needed and justified.

Main hypothesis:

After VTE at high risk of recurrence initially treated during 6 (-15 days) to 24 (+ 3 months) uninterrupted months, a reduced dose of DOAC will be non-inferior to a full dose of DOAC in terms of recurrent VTE during extended anticoagulation phase.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University Hospital, Brest
• Collaborator: University Hospital of Saint-Etienne
• Treatments: Anticoagulants; Apixaban; Rivaroxaban

Criteria

Inclusion Criteria:

• Patients >18 years

• Patients with indications for long-term anticoagulation after VTE (i.e.; symptomatic PE or proximal DVT) initially treated during 6 (-15 days) to 24 months (+ 3 months) :

• Patients with multiple episodes of VTE, or

• Patients with a first episode of unprovoked* VTE

• Patients with VTE associated with persistent risk factor**, or

• Patients for whom clinicians feel that indefinite anticoagulation is warranted

• Social security affiliation.

Exclusion Criteria:

• Known allergy to rivaroxaban and apixaban, allergy to any of the excipients

• Indication for therapeutic dose anticoagulant therapy

• Unable or refusal to give informed consent

• Isolated distal DVT

• HERDOO2 score ≤ 1

• Indication for anticoagulation other than DVT or PE (e.g.; atrial fibrillation, mechanic valves…)

• Treatment with investigational drug in the past 1 month except for patients benefiting from an anticoagulant at therapeutic doses for the initial pathology

• Interruption of anticoagulation for 14 days or more before the inclusion

• Chronic liver disease or chronic hepatitis

• Patient considered at high risk of bleeding (eg: previous gastro-intestinal tract bleeding in the past three months, uncontrolled hypertension, etc.)

• Renal insufficiency with creatinine <25 ml / min on Cockcroft and Gault formula

• Antiphospholipid syndrome

• Dual anti-platelet therapy or aspirin at dosage >100 mg per day

• Concomitant use of a strong inhibitor of cytochrome P-450 3A4 (CYP3A4) (e.g., a protease inhibitor for human immunodeficiency virus infection or azole-antimycotics agents ketoconazole, itraconazole, voriconazole, posaconazole) or a CYP3A4 inducer (e.g., rifampin, carbamazepine, or phenytoin),

• Active cancer of less than 6 months

• Active pregnancy or expected pregnancy

• No effective contraception in women of childbearing age

• Life expectancy <12 months