Clinical Question: Does ultrasound-facilitated, catheter-directed thrombolysis improve clinical outcomes in patients with acute pulmonary embolism (PE), right ventricular strain, and signs of cardiorespiratory distress?
Background: Clinical equipoise remains for this population, which sits between low-risk PE managed with anticoagulation alone and hemodynamically unstable PE where reperfusion is standard. Prior work (the PEITHO trial) showed that systemic thrombolysis with tenecteplase reduces hemodynamic collapse in these patients, but this comes at the cost of increased major extracranial bleeding (6.3% versus 1.2%) and hemorrhagic stroke (2.0% versus 0.2%), a trade-off that has limited its routine use.
Study Design: Multinational, open-label randomized controlled trial with blinded, independent outcome adjudication where 544 patients were randomized 1:1 to ultrasound-facilitated, catheter-directed thrombolysis (USCDT) plus anticoagulation, versus anticoagulation alone.
Synopsis: Patients had intermediate-risk PE (right ventricle to left ventricle ratio at least 1.0, with elevated troponin), and enrollment was enriched further by requiring at least two markers of cardiorespiratory distress (borderline hypotension, tachycardia, tachypnea, or hypoxemia) within six hours of randomization. This roughly corresponds to the European Society of Cardiology intermediate-high risk classification and the American Heart Association and American College of Cardiology classification (recently published) category C3, with a minority likely meeting D1. The trial met its primary endpoint, with a statistically significant reduction in the composite of PE-related death, decompensation or collapse, or symptomatic recurrence at seven days (4.0% versus 10.3%; relative risk, 0.39; 95% confidence interval [CI], 0.20 to 0.77). This was driven largely by the decompensation-collapse component (10 versus 28 patients), a substantial portion of which was captured by a National Early Warning Score of 9 or higher, a physiologic score calculated from vital signs, rather than by events such as cardiac arrest, shock, intubation, or ECMO. The National Early Warning Score threshold was intended to identify early physiologic deterioration before patients progressed to more overt cardiorespiratory collapse. The individual components of the composite did not differ meaningfully between groups, though these were not independently powered. In this open-label design, rescue therapy after randomization was used less often with USCDT than with anticoagulation alone (2.9% versus 9.2%). Major bleeding at 30 days was similar between arms (4.1% versus 3.0%), with no intracranial hemorrhage in either group.
Bottom Line: HI-PEITHO is the first large RCT to demonstrate clinical benefit from advanced therapy in this population. USCDT significantly reduced a composite outcome driven largely by early physiologic deterioration, with a reassuring bleeding profile.
Citation: Rosenfield K, et al. Ultrasound-facilitated, catheter-directed fibrinolysis for acute pulmonary embolism. N Engl J Med. 2026;394(20):1979-1990. https://doi.org/10.1056/NEJMoa2516567.
Dr. Smith
Dr. Smith is an academic hospitalist at Erlanger Hospital and division chief of general internal medicine and assistant professor of medicine at the University of Tennessee Health Science Center College of Medicine, both in Chattanooga, Tenn.