'Thrombectomy in High-Risk Pulmonary Embolism - Device Versus Thrombolysis Netherlands': TORPEDO-NL

Обзор

TORPEDO-NL will be an investigator-initiated, academically sponsored, multicentre, open-label, randomized controlled trial (RCT). Patients with high-risk pulmonary embolism (PE) require immediate reperfusion therapy on top of anticoagulation. The standard reperfusion treatment in these patients is full-dose systemic thrombolysis. This carries a significant risk of major bleeding (10-25%) and intracranial haemorrhage (ICH, 3%). Catheter-directed thrombectomy (CDT) is a promising alternative to systemic thrombolysis with a more direct effect on reducing pulmonary artery clot burden and very likely a better safety profile. Randomized trials evaluating the safety and efficacy of CDT in high-risk patients are currently unavailable. The investigators hypothesize that in high-risk PE patients, CDT is superior to the current standard of systemic thrombolysis in terms of mortality and adverse events, i.e., is associated with a lower composite incidence of all-cause mortality, treatment failure, major bleeding and all-cause stroke. The investigators also hypothesize that CDT will lead to a shorter length of stay (LOS) at the intensive care unit (ICU) and in-hospital, faster recovery, and better long-term quality of life (QoL). Objective: To determine whether CDT in high-risk PE relative to systemic thrombolysis is: * more effective and safer in terms of a reduction of the composite endpoint on all-cause mortality and adverse events defined as treatment failure, major bleeding and all-cause stroke at day 30 (primary outcome) * leads to a better Desirability of Outcome Ranking (DOOR) at day 7 * associated with a lower level of oxygen supplementation at 48 hours * associated with shorter length of stay (LOS) at the intensive care unit (ICU) and in the hospital * associated with better functional recovery as well as better patient-reported outcomes such as QoL at one year * cost-effective after a time horizon of one year

Вмешательства

• Устройство Catheter-directed thrombectomy (CDT)
  The intervention consists of immediate thrombectomy (thrombectomy with any approved device) without systemic/locally administered thrombolysis. Thrombectomy is performed via jugular or femoral venous access according to the instructions for use for the particular device. The catheter is advanced over a preplaced guidewire across the right heart into the pulmonary arteries to the location of proximal thrombus. Procedural therapeutic anticoagulation with heparin is administered. After removal of t
• Препарат thrombolysis therapy
  Standard reperfusion treatment for high-risk PE patients is thrombolytic therapy, typically consisting of Alteplase, Urokinase, or Tenecteplase, with the idea of accelerated fragmentation of the thrombus by lytic medication given systemically.

Первичные конечные точки

• The composite incidence of the binary endpoints of all-cause mortality, treatment failure, major bleeding and all-cause stroke at day 30. [Срок оценки: Day 30]

Вторичные конечные точки (12)

• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a better survival. [Срок оценки: Day 7 and day 30]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of treatment failure. [Срок оценки: Day 7 and day 30]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of all-cause mortality. [Срок оценки: Day 7, day 30 and day 90]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of all-cause stroke. [Срок оценки: Day 7 and day 30]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower composite incidence of the binary endpoints of the primary outcome at day 7. [Срок оценки: Day 7]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a better Desirability of Outcome Ranking (DOOR). [Срок оценки: Day 7]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of BARC3b and BARC3c bleeding. [Срок оценки: Day 7 and day 30]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of ISTH major and non-major clinically relevant bleeding. [Срок оценки: Day 7 and day 30]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower level of oxygen supplementation. [Срок оценки: 48 hours]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with shorter length of stay (days) at the ICU (Intensive Care Unit) and in hospital. [Срок оценки: Up to 1 year]
• To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with better patient-relevant outcomes such as Quality of life (QoL), functional recovery and symptom burden. [Срок оценки: Day 7 and after 3, 6, 9 and 12 months]
• Cost-effectiveness analysis after a time horizon of one year and budget impact analysis [Срок оценки: 1 Year]

Критерии участия

Критерии включения

• Adult patients with confirmed acute PE, i.e. contrast filling defect in a lobar or more proximal pulmonary artery on computed tomography pulmonary angiography (CTPA), and/or obstructive shock with echocardiographic confirmed dilatation of the right ventricle and a congested vena cava inferior, both with/without echocardiographic signs of clot in transit or deep vein thrombosis of the leg.
• High risk for mortality, i.e.

• post cardiac arrest (after temporary need for cardiopulmonary resuscitation), OR
• obstructive shock (systolic blood pressure <90 mmHg and signs of end-organ hypoperfusion (e.g. elevated lactate levels >2 mmol/l) or the need for vasopressors (adrenalin or noradrenalin) to maintain an adequate blood pressure), OR
• persistent hypotension (systolic blood pressure <90 mmHg or systolic blood pressure drop ≥40 mmHg for at least 15 minutes) not caused by new onset arrhythmia, hypovolemia, or sepsis, OR
• abnormal RV function on transthoracic echocardiography or CTPA AND elevated cardiac troponin levels AND respiratory failure defined as hypoxemia (SaO2 <90%) refractory to O2 supplementation by nasal cannula or Venturi mask, requiring full face mask O2 supplementation (100% FiO2), high-flow nasal O2, or (non-)invasive mechanical ventilation.
• CDT available and technically feasible so as to allow for a randomization-to-needle time of 60 minutes or less.

Критерии исключения

• "Catastrophic PE", i.e. ongoing cardiac arrest and/or need for extracorporeal cardiopulmonary resuscitation (ECPR) and/or immediate indication for venoarterial extracorporeal membrane oxygenation (VA-ECMO) as judged by the responsible physician(s)
• Glascow Coma Scale <8 following resuscitation for cardiac arrest
• Alternative diagnosis than acute PE contributing largely to the acute hemodynamic and/or respiratory failure, e.g. sepsis, COPD GOLD 3 or 4, or known heart failure with NYHA Functional Classification of 4, as judged by the treating physician.
• A known "do not admit to the ICU" or "do not resuscitate" directive
• An absolute contraindication to systemic thrombolysis, i.e.

• History of hemorrhagic stroke
• Ischemic stroke in past 6 months
• Central nervous system neoplasm
• Major trauma, major surgery or major head injury in past 3 weeks (note: mild external laceration of the head after, e.g. syncope, does not count as major head injury, especially when a CT scan of the head shows no hematoma)
• Active bleeding, life-threatening or into a critically organ/area; OR known severe bleeding diathesis with previous bleeding fulfilling these criteria
• Reperfusion therapy (systemic thrombolysis, surgical thrombectomy or CDT/other catheter directed therapy), or placement of a non-retrieved inferior vena cava filter for acute pulmonary embolism in the past 3 months
• Thrombus in transit through a patent foramen ovale.
• Known chronic thromboembolic pulmonary hypertension (CTEPH), or strong suspicion of CTEPH based on pre-existing clinical findings and combinations of signs of PE chronicity on echocardiography and/or CTPA.
• Known hypersensitivity to systemic thrombolysis, heparin, or to any of the excipients
• If, in the Investigator's opinion, or after consultation with the local PERT-team or EC-members, the patient is not appropriate for thrombectomy
• Chronic use of full-dose oral or parenteral anticoagulation before presentation.
• Pregnancy
• Current participation in another study that would interfere with participation in this study
• Previous enrolment in this study
• Refusal of deferred consent by the next of kin or by the patient himself to use the data. Deferred consent will not be asked to relatives of patients who die in scene, but are included in the study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Нидерланды · 1 центр

• Leiden University Medical Centre — Leiden

Публикации

• Arora S, Vallabhajosyula S, Aggarwal V, Basir MB, Kelly B, Atreya AR. Novel Risk Stratification and Hemodynamic Profiling in Acute Pulmonary Embolism: A Proposed Classification Inspired by Society for Cardiovascular Angiography and Intervention Shock Staging. Interv Cardiol Clin. 2023 Jul;12(3S):e1-e20. doi: 10.1016/j.iccl.2024.04.002. Epub 2024 May 25. PMID 38964819
• Kapur NK, Kanwar M, Sinha SS, Thayer KL, Garan AR, Hernandez-Montfort J, Zhang Y, Li B, Baca P, Dieng F, Harwani NM, Abraham J, Hickey G, Nathan S, Wencker D, Hall S, Schwartzman A, Khalife W, Li S, Mahr C, Kim JH, Vorovich E, Whitehead EH, Blumer V, Burkhoff D. Criteria for Defining Stages of Cardiogenic Shock Severity. J Am Coll Cardiol. 2022 Jul 19;80(3):185-198. doi: 10.1016/j.jacc.2022.04.049 PMID 35835491
• Gwozdz AM, de Jong CMM, Fialho LS, Likitabhorn T, Sossi F, Jaber PB, Hojen AA, Arcelus JI, Auger WR, Ay C, Barco S, Gazzana MB, Bayley J, Bertoletti L, Cate-Hoek AT, Cohen AT, Connors JM, Galanaud JP, Labropoulos N, Langlois N, Meissner MH, Noble S, Nossent EJ, de Leon Lovaton PP, Robert-Ebadi H, Rosovsky RP, Smolenaars N, Toshner M, Tromeur C, Wang KL, Westerlund E, de Wit K, Black SA, Klok FA. D PMID 36055334
• Evans SR, Rubin D, Follmann D, Pennello G, Huskins WC, Powers JH, Schoenfeld D, Chuang-Stein C, Cosgrove SE, Fowler VG Jr, Lautenbach E, Chambers HF. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR). Clin Infect Dis. 2015 Sep 1;61(5):800-6. doi: 10.1093/cid/civ495. Epub 2015 Jun 25. PMID 26113652
• Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 1 PMID 21670242
• Ende-Verhaar YM, Meijboom LJ, Kroft LJM, Beenen LFM, Boon GJAM, Middeldorp S, Nossent EJ, Symersky P, Huisman MV, Bogaard HJ, Vonk Noordegraaf A, Klok FA. Usefulness of standard computed tomography pulmonary angiography performed for acute pulmonary embolism for identification of chronic thromboembolic pulmonary hypertension: results of the InShape III study. J Heart Lung Transplant. 2019 Jul;38(7 PMID 30962147
• Kabrhel C, Okechukwu I, Hariharan P, Takayesu JK, MacMahon P, Haddad F, Chang Y. Factors associated with clinical deterioration shortly after PE. Thorax. 2014 Sep;69(9):835-42. doi: 10.1136/thoraxjnl-2013-204762. Epub 2014 May 20. PMID 24846902
• Pancani R, Villari L, Aquilini F, Palla A, Carrozzi L, Celi A. Prognostic role of respiratory failure in acute pulmonary embolism: a prospective multicenter study. Thromb Res. 2022 Sep;217:33-35. doi: 10.1016/j.thromres.2022.07.002. Epub 2022 Jul 9. No abstract available. PMID 35849919

Идентификаторы

NCT: NCT06833827 · NL87503.058.24

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗