REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism. The RENOVE Open-label, Randomized, Controlled Trial.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 2,774
- 试验地点
- 38
- 主要终点
- Recurrent VTE
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Reduced dose of DOAC
A reduced dose of DOAC (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) during a mean follow-up period of 36 months (12 to 65 months)
干预措施: Reduced dose of DOAC (Drug)
Full dose of DOAC
A full dose of DOAC (Apixaban 5 mg twice daily or Rivaroxaban 20 mg once daily) during a mean follow-up period of 36 months (12 to 65 months).
干预措施: Full dose of DOAC (Drug)
结局指标
主要结局
Recurrent VTE
时间窗: during a mean study treatment period of 36 months
Adjudicated symptomatic objectively confirmed recurrent VTE (non fatal or fatal VTE) during the study treatment period.
次要结局
- Major and clinically relevant non major bleeding(during a mean study treatment period of 36 months)
- Arterial cardio-vascular events(during a mean study treatment period of 36 months)
- The composite of recurrent VTE or major bleeding or non major clinically relevant bleeding(during a mean study treatment period of 36 months)
- Mortality(during a mean study treatment period of 36 months)
- Compliance(during a mean study treatment period of 36 months)
- Treatment effect(during a mean study treatment period of 36 months)