Catheter-directed Thrombolysis in Intermediate-high Risk Acute Pulmonary Embolism

NCT05493163 | Recruiting Phase 4 DMC

• 2 other identifiers: PRAGUE-262022-002218-18
• Study Type: interventional
• Target: 558
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pulmonary Embolism

Keywords

Acute Pulmonary Embolism; Local Thrombolysis; Catheter-Directed Thrombolysis; Intermediate-High Risk

Outcome Measures

Primary Outcomes (1)

• Primary endpoint

  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.

  7 days

Secondary Outcomes (20)

• Secondary endpoints

  7 days to 24 months

• Secondary endpoints

  7 days to 24 months

• Secondary endpoints

  7 days

• Secondary endpoints

  30 days

• Secondary endpoints

  7 and 30 days

Study Arms (2)

Catheter-Directed Thrombolysis

EXPERIMENTAL

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.

Drug: Thrombolytic

Standard Anticoagulation

ACTIVE COMPARATOR

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).

Drug: Standard anticoagulation

Interventions

Thrombolytic DRUG

Local, catheter-directed thrombolysis with a total dose of 10mg per affected lung administered over 9 hours.

Catheter-Directed Thrombolysis

Standard anticoagulation DRUG

Standard anticoagulation therapy of acute pulmonary embolism.

Standard Anticoagulation

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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); NT-proBNP level \> 600 pg/mL.
• SPESI - Simplified Pulmonary Embolism Severity Index.

Sponsors & Collaborators

• Faculty Hospital Kralovske Vinohrady: lead
• Charles University, Czech Republic: collaborator
• University Hospital Ostrava: collaborator
• University Hospital Olomouc: collaborator
• University Hospital Brno: collaborator
• St. Anne´s University Hospital Brno: collaborator
• General University Hospital, Prague: collaborator
• University Hospital Pilsen: collaborator
• Pardubice Hospital: collaborator

Study Sites (1)

University Hospital Kralovske Vinohrady

Prague, 100 34, Czechia

RECRUITING

Related Publications (13)

• Becattini C, Agnelli G, Lankeit M, Masotti L, Pruszczyk P, Casazza F, Vanni S, Nitti C, Kamphuisen P, Vedovati MC, De Natale MG, Konstantinides S. Acute pulmonary embolism: mortality prediction by the 2014 European Society of Cardiology risk stratification model. Eur Respir J. 2016 Sep;48(3):780-6. doi: 10.1183/13993003.00024-2016. Epub 2016 May 12.

  PMID: 27174887 BACKGROUND

• Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Am Heart J. 2012 Jan;163(1):33-38.e1. doi: 10.1016/j.ahj.2011.10.003.

  PMID: 22172434 BACKGROUND

• Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz B, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097.

  PMID: 24716681 BACKGROUND

• Kuo WT, Banerjee A, Kim PS, DeMarco FJ Jr, Levy JR, Facchini FR, Unver K, Bertini MJ, Sista AK, Hall MJ, Rosenberg JK, De Gregorio MA. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. Chest. 2015 Sep;148(3):667-673. doi: 10.1378/chest.15-0119.

  PMID: 25856269 BACKGROUND

• Piazza G, Hohlfelder B, Jaff MR, Ouriel K, Engelhardt TC, Sterling KM, Jones NJ, Gurley JC, Bhatheja R, Kennedy RJ, Goswami N, Natarajan K, Rundback J, Sadiq IR, Liu SK, Bhalla N, Raja ML, Weinstock BS, Cynamon J, Elmasri FF, Garcia MJ, Kumar M, Ayerdi J, Soukas P, Kuo W, Liu PY, Goldhaber SZ; SEATTLE II Investigators. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015 Aug 24;8(10):1382-1392. doi: 10.1016/j.jcin.2015.04.020.

  PMID: 26315743 BACKGROUND

• Kucher N, Boekstegers P, Muller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Muller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Hartel D, Grunwald H, Empen K, Baumgartner I. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28;129(4):479-86. doi: 10.1161/CIRCULATIONAHA.113.005544. Epub 2013 Nov 13.

  PMID: 24226805 BACKGROUND

• Tapson VF, Sterling K, Jones N, Elder M, Tripathy U, Brower J, Maholic RL, Ross CB, Natarajan K, Fong P, Greenspon L, Tamaddon H, Piracha AR, Engelhardt T, Katopodis J, Marques V, Sharp ASP, Piazza G, Goldhaber SZ. A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: The OPTALYSE PE Trial. JACC Cardiovasc Interv. 2018 Jul 23;11(14):1401-1410. doi: 10.1016/j.jcin.2018.04.008.

  PMID: 30025734 BACKGROUND

• Avgerinos ED, Jaber W, Lacomis J, Markel K, McDaniel M, Rivera-Lebron BN, Ross CB, Sechrist J, Toma C, Chaer R; SUNSET sPE Collaborators. Randomized Trial Comparing Standard Versus Ultrasound-Assisted Thrombolysis for Submassive Pulmonary Embolism: The SUNSET sPE Trial. JACC Cardiovasc Interv. 2021 Jun 28;14(12):1364-1373. doi: 10.1016/j.jcin.2021.04.049.

  PMID: 34167677 BACKGROUND

• Klein AJ, Shishehbor MH. Ultrasound-assisted catheter directed therapy (CDT) for pulmonary embolism versus standard CDT: Sounds of a cry for data! Vasc Med. 2019 Jun;24(3):248-250. doi: 10.1177/1358863X19838346. Epub 2019 Mar 27. No abstract available.

  PMID: 30915915 BACKGROUND

• Kroupa J, Buk M, Weichet J, Malikova H, Bartova L, Linkova H, Ionita O, Kozel M, Motovska Z, Kocka V. A pilot randomised trial of catheter-directed thrombolysis or standard anticoagulation for patients with intermediate-high risk acute pulmonary embolism. EuroIntervention. 2022 Oct 7;18(8):e639-e646. doi: 10.4244/EIJ-D-21-01080.

  PMID: 35620984 BACKGROUND

• Klok FA, Piazza G, Sharp ASP, Ni Ainle F, Jaff MR, Chauhan N, Patel B, Barco S, Goldhaber SZ, Kucher N, Lang IM, Schmidtmann I, Sterling KM, Becker D, Martin N, Rosenfield K, Konstantinides SV. Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: Rationale and design of the HI-PEITHO study. Am Heart J. 2022 Sep;251:43-53. doi: 10.1016/j.ahj.2022.05.011. Epub 2022 May 16.

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MeSH Terms

Conditions

Pulmonary Embolism

Interventions

Fibrinolytic Agents

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Embolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Cardiovascular Agents; Therapeutic Uses; Hematologic Agents

Study Officials

• Viktor Kocka, MD, PhD

  Deputy Head of Department of Cardiology

  PRINCIPAL INVESTIGATOR

• Josef Kroupa, MD, PhD

  Interventional Cardiologist

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jitka Havlikova

CONTACT

+420 267 16 3742; jitka.havlikova@fnkv.cz

Erika Eksteinova, Ing.

CONTACT

+420 267 16 2621; erika.eksteinova@fnkv.cz

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Interventional cardiologist

Model Details: 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.

Study Record Dates

• First Submitted: July 30, 2022
• First Posted: August 9, 2022
• Study Start: October 19, 2022
• Primary Completion: January 1, 2026
• Study Completion (Estimated): January 1, 2028
• Last Updated: November 8, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF

Locations

CZ (1)