REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism. The RENOVE Open-label, Randomized, Controlled Trial.
REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism. The RENOVE Open-label, Randomized, Controlled Trial.
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.
Patients with unprovoked venous thromboembolism (VTE) or VTE associated with persistent risk factors have a high risk of recurrence after stopping anticoagulation. In the "PADIS-PE" trial comparing an additional 18 months of warfarin (target international normalized ratio (INR) from 2 to 3) versus placebo in 371 patients who have completed 6 months of anticoagulation for a first unprovoked pulmonary embolism, the PADIS-PE trial confirmed that prolonged warfarin therapy was highly effective for preventing recurrent VTE but that benefit was lost after stopping anticoagulation. In another trial, similar findings had been reported using direct oral anticoagulants (DOAC) at therapeutic dose. These results reinforce international recommendation for indefinite anticoagulation in patients at high risk of recurrent VTE (unprovoked VTE, recurrent VTE or persistent risk factors).
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. First, DOACs have been shown to be as effective as and safer than warfarin (INR 2-3) during the first 6 months of anticoagulation after an acute VTE. Second, 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.
Design
The "RENOVE" trial is designed as an academic, multicenter, open, with blind evaluation (PROBE), randomized, parallel arm, controlled, trial sponsored by the Brest University Hospital Center. Patients meeting the inclusion criteria will be randomized at visit 1 (day 0) and allocated to receive:
The study is powered to demonstrate the following hypotheses using a three steps hierarchical analysis:
Randomization will be centralized and stratified on:
At visit 1, patients will have a therapeutic education and they will be instructed to call research team in case of any medical event during the study treatment period. Follow-up visits will be planned at 3, 6, 12 months and every 6 months until study end (i.e.; after the last included patient has achieved 12-month of study treatment period).
All critical events will be adjudicated by an independent adjudication committee blinded from the treatment allocation. A data safety board will be constituted and will meet on a regular basis. Duration of each patient's participation will be on average 36 months (12 months for the last included patient) and a total duration of the study is expected for 65 months.
Objectives:
Main Objective
• To demonstrate that a reduced dose of DOAC is non-inferior to a full dose of DOAC for the risk of recurrent VTE during the during a mean study treatment period of 36 months in patients with VTE that warrants indefinite anticoagulation and who have been initially treated for 6 (-15 days) to 24 (+3 months) uninterrupted months.
Secondary Objectives
• Key secondary objectives: if the main objective is verified, key secondary objectives are to demonstrate the superiority of a reduced dose of DOAC over a full dose of DOAC during a mean study treatment period of 36 months :
on the risk of major or CRNMB and, if confirmed,
on the composite of recurrent VTE, major bleeding or CRNMB.
• Other secondary objectives:
To evaluate the benefit of a reduced dose of DOAC on the risk of major bleeding during a mean study treatment period of 36 months
To evaluate the benefit of a reduced dose of DOAC on the composite outcome of recurrent VTE and major bleeding during a mean study treatment period of 36 months
To determine the impact of a reduced dose of DOAC on deaths of all causes and deaths related to recurrent VTE or major bleeding during a mean study treatment period of 36 months
To evaluate dyspnea and post-thrombotic syndrome (villalta score)(65).
To evaluate compliance treatment using the Girerd auto-questionnaire
To analyse the treatment effect on recurrent VTE and major bleeding and CRNM among predefined sub-groups (screening for heterogeneity among predefined strata).
Sample size justification
A- Initial hypothesis before starting enrolment in the RENOVE study:
The study is powered to demonstrate the following hypotheses using a three steps hierarchical analysis:
Taking in account 5% of loss to follow-up, a total of 2200 patients are required in order to be able to confirm these three conditional hypotheses.
All estimates were calculated based on major randomized trials on extended anticoagulation in VTE patients.
B- New hypothesis based on observed primary endpoint at 2147 included patients:
On February, 12th 2021, 27 recurrent VTE, all adjudicated, occurred on 2147 included patients, during a mean follow-up of 12 months.
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) :
Social security affiliation.
Exclusion Criteria: