Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial.

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.

Sanchez O ，Charles-Nelson A ，Ageno W ，Barco S ，Binder H ，Chatellier G ，Duerschmied D ，Empen K ，Ferreira M ，Girard P ，Huisman MV ，Jiménez D ，Katsahian S ，Kozak M ，Lankeit M ，Meneveau N ，Pruszczyk P ，Petris A ，Righini M ，Rosenkranz S ，Schellong S ，Stefanovic B ，Verhamme P ，de Wit K ，Vicaut E ，Zirlik A ，Konstantinides SV ，Meyer G ，PEITHO-3 Investigators ... -  《-》

Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: Rationale and design of the HI-PEITHO study.

Due to the bleeding risk of full-dose systemic thrombolysis and the lack of major trials focusing on the clinical benefits of catheter-directed treatment, heparin antiocoagulation remains the standard of care for patients with intermediate-high-risk pulmonary embolism (PE). The Higher-Risk Pulmonary Embolism Thrombolysis (HI-PEITHO) study (ClinicalTrials.gov Identifier: NCT04790370) is a multinational multicenter randomized controlled parallel-group comparison trial. Patients with: (1) confirmed acute PE; (2) evidence of right ventricular (RV) dysfunction on imaging; (3) a positive cardiac troponin test; and (4) clinical criteria indicating an elevated risk of early death or imminent hemodynamic collapse, will be randomized 1:1 to treatment with a standardized protocol of ultrasound-facilitated catheter-directed thrombolysis plus anticoagulation, vs anticoagulation alone. The primary outcome is a composite of PE-related mortality, cardiorespiratory decompensation or collapse, or non-fatal symptomatic and objectively confirmed PE recurrence, within 7 days of randomization. Further assessments cover, apart from bleeding complications, a broad spectrum of functional and patient-reported outcomes including quality of life indicators, functional status and the utilization of health care resources over a 12-month follow-up period. The trial plans to include 406 patients, but the adaptive design permits a sample size increase depending on the results of the predefined interim analysis. As of May 11, 2022, 27 subjects have been enrolled. The trial is funded by Boston Scientific Corporation and through collaborative research agreements with University of Mainz and The PERT Consortium. Regardless of the outcome, HI-PEITHO will establish the first-line treatment in intermediate-high risk PE patients with imminent hemodynamic collapse. The trial is expected to inform international guidelines and set the standard for evaluation of catheter-directed reperfusion options in the future.

Klok FA ，Piazza G ，Sharp ASP ，Ní 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 ... -  《-》

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 Thrombolysi

In acute pulmonary embolism (PE), overt right ventricular (RV) failure with cardiogenic shock indicates a poor prognosis. However, normotensive patients with acute RV dysfunction on echocardiography or computed tomography and with myocardial troponin elevation may also have an adverse outcome. Thrombolysis rapidly reverses RV pressure overload in PE, but it remains unclear whether it may improve the early and long-term clinical outcome of selected normotensive patients. The Pulmonary EmbolIsm THrOmbolysis (PEITHO) trial is a prospective, multicenter, international, randomized (1:1), double-blind comparison of thrombolysis with tenecteplase vs placebo in normotensive patients with confirmed PE, an abnormal right ventricle on echocardiography or computed tomography, and a positive troponin I or T test result. Both treatment groups receive standard anticoagulation. The primary efficacy outcome is the composite of death from any cause or hemodynamic collapse within 7 days of randomization. Safety outcomes include ischemic/hemorrhagic strokes and other major bleeding episodes. In addition, 180-day clinical and echocardiographic follow-up will be performed. The study is expected to enroll approximately 1,000 patients. By determining the benefits vs risks of thrombolysis in submassive or intermediate-risk PE, this trial is expected to answer a long-standing query on the management of this patient population.

Steering Committee 《-》

Advancing the management of acute intermediate-high-risk pulmonary embolism: The enduring legacy of Professor Guy Meyer.

Konstantinides SV ，Sanchez O ，Goldhaber SZ ，Meneveau N ... -  《-》

Fibrinolysis for patients with intermediate-risk pulmonary embolism.

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 ，Galiè 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 ... -  《-》