A Multicentre, Randomised, Double-blind, Controlled, Phase IIIb Study to Assess the Efficacy and Safety of Rivaroxaban 10mg od Versus Enoxaparin 4000 UI for VTE PROphylaxis in NOn Major Orthopaedic Surgery
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 3,608
- 试验地点
- 38
- 主要终点
- Major VTE
研究概览
简要总结
PRONOMOS is an international multicentre, interventional, parallel, randomised, double-blind non-inferiority study comparing rivaroxaban 10mg od to an active comparator, enoxaparin 4000 UI od in 4040 valid subjects requiring orthopaedic surgery (except low risk such material removal foot surgery or hallux valgus without patient risk factor [6], and major orthopaedic surgeries for femoral neck and trochanteric fractures, THR, TKR)
Pre-randomization treatment with LMWH anticoagulant is allowed for a maximum duration of 24 hours. However, only a single pre-randomization dose of LMWH is allowed. After randomization, patients allocated to the rivaroxaban arm will receive rivaroxaban 10 mg once-daily started 6-10 hours provided haemostasis has been established after surgery or 24h hours after LMWH injection if needed for the intended treatment duration of 2 to 12 weeks based on medical judgment (according to immobilization). Patients allocated to the comparator arm will receive enoxaparin once daily for the same intended treatment duration. All patients will have a 30-day observational period after cessation of treatment.
详细描述
Major orthopedic surgery (hip, knee replacements and hip fracture) represents only a small part of all orthopaedic surgery procedures. Procedures for trauma patients and orthopaedic lower limb surgery without trauma are much more frequent (tibia osteotomy, arthrodesis, ligament repair....).
The incidence of trauma patients requiring surgery and prolonged immobilisation is rising, mainly because of the increasing popularity of recreational sports. However, the epidemiology and prevention of VTE after such injuries have been poorly studied. The combination of limb surgery with or without trauma in orthopaedic surgery is responsible for an increase in venous thromboembolism (VTE). Usually, surgery of lower limb is considered as moderate or high risk for DVT with different duration related to immobilisation. For instance tibia osteotomy is at very high risk during at least 6 weeks and knee arthroscopy for ligament repair is at moderate risk during 10 days. However LMWH is recommended in both surgeries. Non-major orthopaedic surgery represents a major additional risk factor by itself; therefore such patients undergoing surgery deserve to receive VTE prophylaxis.
Rivaroxaban is a new oral anticoagulant developing a potent anti-Xa activity. In major orthopaedic surgery, it has shown to be more effective and as safe as LMWH (Enoxaparin 4000 IU once daily) in THR and TKR patients (RECORD program). Up to now, pending the limited number of surgical settings in which it has been developed in orthopaedic surgery, it is only approved for the prevention of venous thromboembolism (VTE) in THR and TKR procedures, which represent only 20% of all orthopaedic interventions. Non-major elective lower limb surgery and traumatology population is younger as compared to prosthetic orthopaedic surgery patients. Fewer VTE and cardiovascular events are to be feared. These patients receive quite often injectable thromboprophylaxis for a total duration lying between approximately 6 weeks to 3 months. In the one hand, the risk of major bleeding is low in this younger population. On the other hand, compliance and cost should be in favour of Rivaroxaban, because no injection and no platelets counts are needed.
The results of Xamos descriptive sub-analysis in non-elective (fracture related) orthopaedic surgery are consistent with the overall results of Xamos and are in favour of further investigations in this area. In this small subset of patients (n=790), the incidence of symptomatic thromboembolic events observed was low in patients treated with Xarelto and the overall frequency of treatment emergent major bleedings was low in both groups and serious adverse events occurred less frequently in patients treated with Xarelto. Therefore, collection of clinical data in this population is needed and awaited by many orthopaedic surgeons and anaesthetists in charge of VTE prophylaxis.
The population with femoral neck and trochanteric fracture is a specific one with different characteristics, elderly, frail and with a higher bleeding risk. This population will be excluded.
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
- Triple (Participant, Investigator, 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
- •Signed and dated informed consent form,
- •Age ≥ 18 years,
- •Hospitalised for non-major orthopaedic surgery and requiring thromboprophylaxis according to the investigator's judgement on VTE risk such Achilles' repair, hip (except femoral neck and trochanteric fracture), knee, tibial plateau, femur (non femoral head), tibial and ankle fractures and tibial osteotomy, tibial transposition, arthrodesis of leg articulation, ligament repair of the knee or the ankle or any elective orthopaedic limb surgery requiring thromboprophylaxis).
排除标准
- •Major orthopaedic surgery Hip and Knee replacement, femoral neck and trochanteric fractures, spine surgery,
- •Low risk surgery without patient VTE risk: foot surgery (Hallux Valgus), material removal,
- •Delay between hospitalisation and randomisation greater than two days,
- •Women of childbearing potential not using a reliable contraceptive method throughout the study period (a list of reliable contraceptive methods is provided in the accompanying SPM),
- •Women pregnant or breast-feeding during the study period,
- •Body weight less than 50 kg (to avoid bleeding over risk) or over 120 kg,
- •Long term treatment with VKA therapy or NOAC,
- •Concomitant treatment with clopidogrel, prasugrel and ticagrelor,
- •Platelet count < 100 Giga/L,
- •Documented history of acquired or inherited bleeding disorder (e.g., von Willebrand's disease),
- •Severe renal failure with calculated creatinine clearance (Cockcroft Formula) < 30 mL/min,
- •Severe hepatic insufficiency with prothrombin time < 60% or liver impairment associated with coagulation disorders,
- •History of thrombocytopenia,
- •Any other current significant medical condition that might interfere with treatment evaluation according to the investigator's judgement,
- •Known hypersensitivity or other severe reaction to any component of the investigational medicinal product(s),
- •Participation in another clinical study involving an investigational medicinal product within 30 days prior to inclusion or concomitantly with this study,
- •Active bleeding or contraindication to anticoagulant therapy
- •Chronic alcoholic intoxication,
- •Anticipated poor compliance of subject with study procedures
研究组 & 干预措施
Group 1: Rivaroxaban treatment
Rivaroxaban active substance plus a placebo of enoxaparin
干预措施: Rivaroxaban (Drug)
Grouyp 2: Enoxaparine treatment
Enoxaparin active substance plus a placebo tablet of Rivaroxaban
干预措施: Enoxaparin (Drug)
结局指标
主要结局
Major VTE
时间窗: From date of randomization until the date of the end of the treatment period (up to 3 months maximum).
composite of proximal DVT (asymptomatic and symptomatic) assessed by ultrasonography, symptomatic events (distal and proximal DVT, PE) and VTE related deaths. The treatment period ranges from 15 days to 3 months depending on the type of surgery
次要结局
- Clinically relevant non-major bleeding(From date of randomization until the date of the end of the treatment period (up to 3 months maximum)..)
- Mortality(From date of randomization until the date of the end of the treatment period (up to 3 months maximum)..)
- Major bleeding(From date of randomization until the date of the end of the treatment period (up to 3 months maximum).)
- Overt thrombocytopenia(From date of randomization until the date of the end of the treatment period (up to 3 months maximum)..)