A Multicentre, Randomized Trial of Catheter-directed Thrombolysis in Intermediate-high Risk Acute Pulmonary Embolism (PRAGUE-26)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 558
- 试验地点
- 2
- 主要终点
- Primary endpoint
研究概览
简要总结
Background: Intermediate-high risk acute pulmonary embolism (PE) remains associated with substantial mortality despite standard anticoagulation therapy. Previous efforts to decrease mortality in these patients via administration of systemic thrombolysis have failed due to an increased rate of major bleeding complications. Catheter-directed thrombolysis (CDT) has already shown some promising results in terms of efficacy and safety, including the results of our randomized pilot study. However, large randomized trials with clinical endpoints comparing catheter-directed local thrombolysis versus standard anticoagulation therapy are still lacking, thus the treatment of intermediate-high risk acute PE patients has not changed for decades. Hypothesis: Catheter-directed local thrombolysis is superior to standard anticoagulation therapy in the treatment of intermediate-high risk acute pulmonary embolism, with no additional safety concerns. Statistical considerations: Estimated incidence of the primary endpoint of 1.5% in the CDT group and 6.0% in the standard anticoagulation group, 80% power for each arm with a 2-sided alpha of 0.05. Five hundred fifty-eight should provide the requisite number of events. Statistical Analysis - Intention to Treat. Methods and Results: A Multicentre, Randomized Trial of Catheter-directed thrombolysis in intermediate-high risk acute pulmonary embolism (PRAGUE-26) is a noncommercial, multicentre, randomized, controlled parallel-group comparison trial. The trial plans to include 558 patients with intermediate-high risk acute PE. Patients will be randomized in a 1:1 ratio to CDT or to standard anticoagulation therapy. The primary outcome of the study is a clinical composite of all-cause mortality, PE recurrence or cardiorespiratory decompensation, within 7 days of randomization. Secondary objectives cover all bleeding complications, functional and patient-reported outcomes over a follow-up period of 24 months and cost-effectiveness analysis.
详细描述
- Introduction Intermediate-high risk acute pulmonary embolism (PE) remains associated with substantial mortality despite standard anticoagulation therapy [1]. Previous efforts to decrease mortality in these patients via administration of systemic thrombolysis have failed; such treatments were associated with major bleeding complications [2,3]. Catheter-directed thrombolysis (CDT) has already shown some promising results; effectively reducing right ventricle (RV) overload, decreasing systolic pulmonary artery pressure (sPAP), and reducing pulmonary thrombotic burden while remaining safe for the patient (i.e., not increasing the rate of intra-cranial or life-threatening bleeding complications) [4-7]. There are currently two main treatment options - ultrasound-assisted local thrombolysis (USAT) or simple catheter-directed local thrombolysis (i.e., without ultrasound facilitation). The USAT has yielded promising results, but is expensive and thus infrequently used. Simple CDT has shown similar efficacy compared to USAT [8] and represents a low-cost alternative. Unfortunately, randomized trials with clinical endpoints are still lacking [9].
Investigators have performed a first randomized pilot trial of catheter-directed thrombolysis or standard anticoagulation therapy in patients with intermediate-high acute pulmonary embolism [10]. In this randomized trial, a safe and simple method of CDT was introduced. Efficacy in terms of RV function improvement (RV/LV ratio reduction) and systolic pulmonary artery pressure reduction compared to standard anticoagulation therapy was demonstrated, with no safety concerns.
Recently, enrolment in HI-PEITHO Trial (sponsored by Boston Scientific Corporation) has begun investigating the clinical outcomes of intermediate-high risk acute PE patients undergoing USAT (EKOS system) plus anticoagulation therapy compared to anticoagulation therapy alone (NCT04790370) [11].
However, there is currently no randomized trial investigating the clinical outcomes in patients undergoing simple CDT plus anticoagulation compared to anticoagulation therapy alone. 2. Study objectives The purpose of this study is to investigate clinical outcomes in patients with intermediate-high risk acute PE undergoing catheter-directed (local) thrombolysis compared to standard anticoagulation therapy. 3. Study design Prospective, multicentre, randomized, active-controlled, unblinded, parallel-group study to evaluate clinical outcomes in patients with intermediate-high risk acute PE undergoing CDT in comparison to standard anticoagulation therapy.
3.1 Randomization A web-based randomization software will be used for the randomization with a ratio of 1:1. Randomization into treatment groups will be stratified by the following criteria: age, gender, uni- or bilateral acute PE*, time from the diagnosis of acute PE (diagnostic CT angiography), direct admission to tertiary care cardio centre.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age > 18 years and not over 80 years.
- •Computed tomography angiography (CTA)-verified proximal* PE AND symptom onset < 14 days prior.
- •Intermediate-high risk PE with a SPESI score ≥ 1 AND RV dysfunction** AND an elevated biomarker *** (hs-troponin or NT-proBNP) level.
- •Signed informed consent.
排除标准
- •Active clinically significant bleeding.
- •Any haemorrhagic stroke OR a recent (< 6 months) ischaemic stroke/transient ischaemic attack.
- •Recent (< 3 months) cranial trauma OR another active intracranial/intraspinal process.
- •Major surgery within 7 days prior.
- •Active malignancy OR other severe illness with expected survival < 2 years.
- •Haemoglobin level < 80 g/L; international normalised ratio > 2.0, platelet count ≤ 100 x 109; creatinine level > 200 µmol/L.
- •Pregnant or breastfeeding, fertility without previous exclusion of gravidity.
- •Allergic to thrombolytics or heparin or low-molecular-weight heparin (LMWH), contrast allergy, a history of heparin-induced thrombocytopenia.
- •Floating thrombi in transit through a patent foramen ovale.
- •Participation in another clinical trial.
- •A perfusion defect in at least one main or one lobar pulmonary artery is evident on CTA.
- •RV/LV ratio ≥ 0.9 on transthoracic echocardiography or CTA. *** hs-troponin I (TnI) > 53 ng/L (men) or > 34 ng/L (women), hs-troponin T (hs cTnT) > 14 ng/L; NT-proBNP level > 600 pg/mL, BNP > 100 pg/mL.
- •SPESI - Simplified Pulmonary Embolism Severity Index.
研究组 & 干预措施
Catheter-Directed Thrombolysis
Venous access should be obtained under ultrasound guidance (via the common femoral vein). The use of a double-lumen 8-Fr introducer (single access site) or two 4-Fr introducers (two ipsilateral access sites) is at the discretion of the operator.
After each thrombolytic catheter placement into left and/or right pulmonary artery, a subsequent bolus of 1mg of Alteplase (Actilyse, Boehringer Ingelheim)/catheter is administered, followed by continuous infusion at 1 mg/h/catheter for 9 h (total dose 10mg for unilateral and 20mg for bilateral PE).
Intravenous unfractionated heparin is continued to a target activated partial thromboplastin time (aPTT) of 50-60 s. After the end of local thrombolysis, the catheters are removed and anticoagulation with unfractionated heparin continues.
干预措施: Thrombolytic (Drug)
Standard Anticoagulation
Before randomization, all patients are treated with intravenous unfractionated heparin (to a target aPTT of 70-90 s) or subcutaneous LMWH (the full therapeutic dose). For patients in the CDT group, the anticoagulation treatment was is described above; among CDT patients who received LMWH, the procedure should be postponed for 8 h after the last dose of LMWH. Patients in the standard care group continue therapeutic anticoagulation with either unfractionated heparin or LMWH. Subsequent change for oral anticoagulation is at the discretion of the treating physician (not earlier than 24 hours post-randomization).
干预措施: Standard anticoagulation (Drug)
结局指标
主要结局
Primary endpoint
时间窗: 7 days
Combined; clinical composite of any of the following parameters within 7 days of randomization 1. All-cause mortality 2. PE recurrence (non-fatal symptomatic and objectively confirmed recurrence of PE by repeated CTA) 3. Cardiorespiratory decompensation or collapse\* \* Defined as at least one of following criteria: 1. cardiac arrest or need for CPR at any time between randomization and day 7; 2. signs of shock; 3. placement on extracorporeal membrane oxygenation (ECMO); 4. intubation, or initiation of non-invasive mechanical ventilation at any time between randomization and day 7; 5. National Early Warning Score (NEWS) of 9 or higher, between 24 hours and 7 days after randomization, confirmed on consecutive measurements taken twice, 15 minutes apart.
次要结局
- Secondary endpoints(24 months)
研究者
Viktor Kocka
Chief Interventional cardiologist
Faculty Hospital Kralovske Vinohrady