Defining Optimal Management of Patients With Intermediate-risk Pulmonary Emboli

Study Title: Ultrasound-facilitated, Catheter-directed, Thrombolysis in Intermediate-High Risk Pulmonary Embolism (HI-PEITHO)

ClinicalTrials.gov Identifier: NCT04790370

Participating Centers: Multicenter

Accrual Goal: 406 participants

Study Design: Phase IV randomized clinical trial

Rationale: Much debate and uncertainty exist surrounding the appropriate treatment for intermediate-risk pulmonary embolism (PE). Intermediate-risk or submassive PE refers to normotensive patients with evidence of right ventricular dysfunction and can be further refined into intermediate-high and intermediate-low risk by taking into account the PE severity index.¹  The need for and benefit of more aggressive thrombolytic therapies beyond anticoagulation alone have been studied,^2,3  with promising results; however, larger randomized studies demonstrated increased major bleeding and lacked convincing improvement of long-term outcomes.⁴  Numerous catheter-directed mechanical and thrombolytic therapies exist and deliver lower doses of fibrinolytic agents in close proximity to the emboli, and some have been shown to improve short-term hemodynamic parameters without increasing bleeding.⁵  Multiple therapeutic device options and variations in local expertise and procedural skills have fostered the development of PE response teams^6,7  at many institutions to help navigate the complexity and uncertainties of patient selection for more aggressive treatments.

Study Design: The HI-PEITHO trial is a multicenter randomized control trial evaluating the efficacy of ultrasound-facilitated, catheter-directed thrombolysis for patients with intermediate-risk PE. The study uses the EkoSonic™ Endovascular System in combination with continuous infusion of thrombolytics for seven hours. The ultrasound delivers high-frequency low-power waves hypothesized to increase thrombus permeability and improve efficiency of fibrinolytics. Planned enrollment is 406 participants, and eligible patients will be 18 to 80 years of age with objectively confirmed PE involving at least one main or proximal lobar pulmonary artery and having two other high-risk features such as tachycardia (≥100 beats per minute), systolic blood pressure 110 mm Hg or lower for at least 15 minutes, or respiratory rate higher than 20 per minute (or oxygen saturation <90%). Patients must also have a right-to-left ventricular diameter 1.0 or greater on computed tomography. A long list of exclusion criteria includes hemodynamic instability (massive PE), symptom duration longer than 14 days, active bleeding, pregnancy, thrombocytopenia, and use of low-molecular-weight heparin, therapeutic fondaparinux, apixaban, rivaroxaban, dabigatran, or edoxaban prior to randomization.

Study Outcomes: The primary outcome of interest will be determined by blinded adjudication and is a composite of PE-related mortality, PE recurrence, and cardiorespiratory decompensation or collapse within seven days. Hemodynamic decompensation is defined as cardiac arrest, new onset persistent arterial hypotension accompanied by end-organ hypoperfusion, placement on extracorporeal membrane oxygenation, intubation or initiation of noninvasive mechanical ventilation, or a National Early Warning Score of 9 or higher (confirmed on consecutive measurements taken 15 minutes apart). Secondary outcomes will include major bleeding, ischemic or hemorrhagic stroke, and all-cause mortality (at 7 and 30 days). Patients will be followed for 12 months with patient centered outcome assessments including a variety of general quality of life assessments and the post-venous thromboembolism functional status scale.

Comment: This study, which is currently enrolling, can help define the optimal care for patients with intermediate-risk PE. By providing both measurements of short-term safety and efficacy as well as more long-term patient centered outcomes, this randomized trial can hopefully settle some of the uncertainty surrounding management in this group of patients. If an ultrasound-facilitated catheter-directed thrombolytic strategy is proven superior over anticoagulation alone, the next most immediate question will be whether the EkoSonic™ system is truly required and offers additional benefits over catheter-directed thrombolytic therapy alone. In a small randomized trial of patients with acute iliofemoral deep vein thrombosis, ultrasound-facilitated catheter-directed thrombolysis did not improve percent of thrombus reduction compared to catheter-directed thrombolysis alone after 15 hours, as calculated by the length-adjusted thrombus score.⁸  Similarly, there was no difference in post-thrombotic scores at three months as measured by the Villalta score. However, much hope remains for this strategy as other novel therapies such as a thrombin activatable fibrinolysis inhibitor (DS-1040) did not appear to enhance endogenous fibrinolysis and reduce thrombus volume or right-to-left ventricular ratio in a phase two study of patients with intermediate-risk acute PE.⁹