A recently published multinational randomized trial provides new evidence supporting the use of ultrasound-facilitated catheter-directed thrombolysis (USCDT) in selected patients with intermediate-risk pulmonary embolism (PE).1 The study suggests that the interventional approach, when added to anticoagulation, reduces early clinical deterioration without a clear increase in major bleeding.
USCDT emerged as a promising therapy by delivering low-dose alteplase directly into the pulmonary arteries while employing ultrasonic energy to enhance thrombus penetration. Prior observational studies suggested favorable hemodynamic effects, but randomized outcomes data have been lacking.
“This study confirmed earlier studies that selected intermediate-high risk patients who may benefit from upfront reperfusion,” said investigator Frederikus A. Klok, MD, PhD, of Leiden University Medical Center, Leiden, Netherlands. “It is the best study [with regard to quality] published to date and probably to be published in the coming years on this topic. It shows us a clear definition of who to select for treatment.”
The HI-PEITHO trial enrolled 544 patients across 59 sites in North America and Europe between August 2021 and July 2025. Eligible participants had acute intermediate-risk PE, defined by right ventricular dysfunction (RV/LV ratio ≥1.0), elevated troponin, and at least two markers of cardiorespiratory stress, including relative hypotension, tachycardia, or tachypnea.
Patients were randomized to receive either USCDT plus anticoagulation or standard anticoagulation alone. The primary end point was a composite of PE-related death, cardiorespiratory decompensation or collapse, or recurrent symptomatic PE within seven days.
The trial met its primary end point, demonstrating a reduction in early adverse outcomes in the interventional group. A primary outcome event occurred in 4.0% of patients receiving USCDT compared with 10.3% in those treated with anticoagulation alone (RR, .39; 95% CI, 0.20-0.77).
Importantly, the benefit was driven primarily by a reduction in cardiorespiratory decompensation or collapse rather than by differences in mortality, Dr. Klok said. Rates of PE-related death remained low overall in both groups. The need for rescue therapy also favored the intervention arm (2.9% vs 9.2%), suggesting a clinically meaningful effect on disease progression in the early phase.
Of course, concerns regarding bleeding remain central to any thrombolytic strategy, he said.
In this trial, major bleeding at seven days occurred in 4.1% of patients in the USCDT group vs 2.2% with anticoagulation alone (RR 1.8; 95% CI, 0.8-7.9). At 30 days, major bleeding rates remained comparable (4.1% vs 3.0%). Notably, no intracranial hemorrhages were reported in either group—a finding that contrasts with historical data on systemic thrombolysis, according to the investigators. Other adverse events, including mortality and recurrent PE at 30 days, were comparable between groups.
The interventional protocol involved relatively low doses of alteplase (mean ~17 mg for bilateral catheter placement) administered over about seven hours, reflecting a standardized regimen designed to minimize exposure while maintaining efficacy, Dr. Klok said.
For clinicians, the findings offer compelling support for a more proactive approach in carefully selected intermediate-risk patients, Dr. Klok said. By reducing short-term clinical deterioration—particularly progression to shock or respiratory failure—USCDT may help bridge the gap between conservative anticoagulation and high-risk systemic thrombolysis.
However, caveats remain. The trial was not designed to detect differences in mortality, and the overall mortality rate was relatively low. In addition, long-term outcomes, including the development of chronic thromboembolic pulmonary hypertension, remain under investigation.
As further data emerge—particularly on long-term outcomes and comparative effectiveness vs other catheter-based approaches—USCDT may become a component of modern PE care pathways.
“We live in an era of accumulating evidence,” Dr. Klok said. “Within a year, three or more large randomized controlled trials on reperfusion with several techniques in different definitions of intermediate-risk PE patients will be published. Together with HI-PEITHO, this evidence will shape future guidelines and clinical practice.”
References
1. Rosenfield K, Klok FA, Piazza G, et al. Ultrasound-facilitated, catheter-directed fibrinolysis for acute pulmonary embolism. N Engl J Med. 2026;394(20):1979-1990. doi:10.1056/NEJMoa2516567
