CardiologyClinical Features

Intermediate-high risk pulmonary embolism: addressing a knowledge gap through multinational collaboration

Case Study: A 78-year-old male with a background medical history of hypertension presented to the emergency department with pleuritic chest pain and a 30-second episode of collapse. Further investigations revealed elevated d-dimer (>20 µg/mL), troponin (232 ng/L), and BNP (2644 ng/L) levels. A CT pulmonary angiogram (CTPA) showed extensive bilateral pulmonary emboli in the main pulmonary arteries, extending into the lobar and segmental pulmonary branches. The CTPA also revealed evidence of heart strain with a RV/LV ratio >1.0. On the basis of clinical and imaging parameters, the patient was categorised as having an intermediate-high risk pulmonary embolism.


Venous thromboembolism, comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of death in developed countries.1 PE can be lethal through a spiral of events culminating in right ventricular strain, right ventricular failure, systemic hypotension and cardiac failure.2 Assessment of PE severity is crucial when determining appropriate treatment options. High risk pulmonary embolism is defined by current European Society of Cardiology (ESC) guidelines by cardiac arrest or haemodynamic instability/ shock and is associated with very high mortality.2, 3 Patients with intermediate risk pulmonary embolism do not fulfil criteria for high-risk PE but may be very unwell, with right ventricular strain, elevated biomarkers of myocardial injury and a high “PE severity index”, which predicts early mortality.2

In particular, patients with severe (intermediate-high risk) pulmonary embolism according to ESC criteria may deteriorate rapidly. This situation is a clinical emergency. Optimal management of these patients remains an urgent knowledge gap and is now being addressed in a landmark randomized controlled trial (RCT) comparing ultrasoundfacilitated, catheter-directed thrombolysis to anticoagulation for acute intermediate-high risk pulmonary embolism.4 This trial, the “higher-risk pulmonary embolism thrombolysis (HiPEITHO) study” (ClinicalTrials. gov Identifier: NCT04790370) has been designed to address this important gap in clinical evidence by comparing the clinical benefits of the ultrasound-facilitated local delivery of a thrombolytic agent and anticoagulation with those of anticoagulation alone in patients with intermediate high-risk PE at a higher estimated risk of early decompensation based on clinical parameters at presentation. The EkoSonicTM Endovascular device (Boston Scientific) will be utilized in the HI PEITHO RCT, employing ultrasound energy intended for the ultrasound-facilitated, controlled, and selective infusion of physicianspecified fluids, including thrombolytics, into the vasculature for the treatment of PE.

The primary objective of the study is to assess whether ultrasoundfacilitated, catheter directed, thrombolysis and anticoagulation are associated with a significant reduction in the composite outcome of PE-related mortality, cardiorespiratory decompensation or collapse, or non-fatal symptomatic and objectively confirmed recurrence of PE compared to anticoagulation alone within seven days of randomization. Additional objectives are to contribute further evidence to the existing data on the treatment and outcomes of acute, intermediatehigh risk PE and to provide controlled data comparing a catheter-based intervention to the standard of care that is currently recommended in the guidelines.

Study Design

The trial is a post-market, randomized, controlled, adaptive, open-label, multicentre parallel group trial with blinded adjudication of the primary composite outcome. Subjects will be randomized 1:1 to treatment with ultrasound-facilitated catheter-directed thrombolysis (USCDT) and anticoagulation or anticoagulation alone. The study is unblinded to Investigators and subjects, but adjudication of the outcome measure and other safety outcomes will be completed by a blinded Clinical Events Committee.

Initially, 406 subjects are planned to be enrolled at up to 65 sites in the US and Europe. There will be a planned interim analysis after 50% are enrolled, with the potential to enrol up to 544 subjects. The follow up period for each subject is 12 months.

Treatment Groups

Test Arm: Assignment to the USCDT will include both treatment with the USCDT procedure and treatment with anticoagulation. The USCDT procedure will entail delivery of alteplase using the EkoSonicTM Endovascular System. Treatment must be initiated as soon as practical but no more than 6 hours after confirmation of diagnosis of intermediate-high risk PE. It is strongly recommended that it begins within 2 hours of randomization. Assignment to the experimental USCDT arm will also include initiation or continuation of anticoagulation therapy i.e. low- molecular weight heparin (LMWH) or unfractionated heparin (UFH).

Control Arm: Assignment to the anticoagulation-only control arm will include either initiation or continuation of anticoagulation therapy i.e., low-molecular weight heparin (LMWH) or unfractionated heparin (UFH). Therapeutic anticoagulation is the current standard of care in the treatment of acute intermediate-high risk PE.

The Irish Network for VTE Research is privileged to participate in this potentially practice-defining study and two sites have been selected in Ireland: The Mater Misericordiae University Hospital (under the leadership of Dr Umer Salati,

National Principal Investigator) and Galway University Hospital (under the leadership of Dr Gerry O’Sullivan). The Hi-PEITHO study will, for the first time, address a crucial knowledge gap that has been deemed to be of extremely high priority by the patients that we serve. With clinically important endpoints, the highquality study design, led by global leaders in the field of PE care and intervention, will be delivered by teams of multidisciplinary partners in both hospitals. The data will shape future clinical guidelines by providing high-quality data to guide the management of some of our sickest PE patients.


1. Barco, S., et al., Trends in mortality related to pulmonary embolism in the European Region, 2000-15: analysis of vital registration data from the WHO Mortality Database. Lancet Respir Med, 2020. 8(3): p. 277-287.

2. Konstantinides, S.V., et al., 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J, 2019.

3. Barco, S., et al., Prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in patients with low-risk pulmonary embolism: a systematic review and metaanalysis. Eur Heart J, 2019. 40(11): p. 902-910.

4. Klok, F.A., et al., Ultrasoundfacilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediatehigh-risk pulmonary embolism: Rationale and design of the HI-PEITHO study. Am Heart J, 2022. 251: p. 43-53.

Read HPN April 2023 here

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