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

Abstract

Intermediate high-risk pulmonary embolism (PE) is characterised by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent haemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of haemodynamic 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 Trial (PEITHO)-3 study (EudraCT 2018-000816-96) is a randomised, placebo-controlled, double-blind, multicentre, 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 fulfil at least one clinical criterion of severity: systolic blood pressure ≤ 110 mmHg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, haemodynamic decompensation or PE recurrence within 30 days of randomisation. 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, haemodynamic decompensation, or stroke within 30 days; dyspnoea, functional limitation or RV dysfunction at 6 months and 2 years; and utilisation of healthcare resources within 30 days and 2 years. The study is planned to enrol 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.

Chronic thromboembolic pulmonary hypertension and impairment after pulmonary embolism: the FOCUS study

“…Although a higher than expected proportion of our patients underwent systemic thrombolysis or other reperfusion procedures, their possible effect on the development of CTEPH after acute PE cannot be addressed by a study with an observational design and remains questionable, 39 awaiting the results of ongoing randomized controlled trials. 40 Finally, and although known pre-existing CTEPH was an exclusion criterion for FOCUS, we cannot exclude the possibility that some of the CTEPH cases diagnosed at follow-up may have already been present at baseline. Intensive research is ongoing in this field, and recent publications identified a number of radiological findings which, when sought and found in the computed tomography pulmonary angiography performed to diagnose acute PE, may increase the level of suspicion for pre-existing CTEPH and possibly help to modify the follow-up strategy.…”

Catheter-Based Therapies Decrease Mortality in Patients With Intermediate and High-Risk Pulmonary Embolism: Evidence From Meta-Analysis of 65,589 Patients

“…Future high-quality evidence from randomized controlled trials is required to provide clarity regarding the optimal PE management in specific subgroups of patients, including (i) the efficacy and safety of various CDT therapies among each other and relative to ST, (ii) the best therapy dependent on the patient’s risk of mortality (intermediate vs. high), and (iii) the effect of PERT implementation on clinical outcomes. For example, the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (NCT04430569) will investigate whether reduced-dose thrombolysis improves safety while maintaining reperfusion efficacy compared with standard heparin anticoagulation in 650 patients with intermediate-high-risk PE in a randomized, placebo-controlled, double-blind manner ( 44 ).…”

Pulmonary embolism response teams: Changing the paradigm in the care for acute pulmonary embolism

“…10 However, ST in patients with intermediate-high risk PE patients remains controversial and continues to be investigated. 13 The PEITHO-3 (NCT04430569) is an ongoing randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up to compare the efficacy and safety of a reduced-dose systemic IV alteplase regimen with standard heparin anticoagulation. The study will enroll 659 intermediate-high-risk PE patients.…”