In the treatment of patients with acute, intermediate-risk pulmonary embolism (PE), administering ultrasound-facilitated, catheter-directed thrombolysis (USCDT) on top of anticoagulation results in better short-term outcomes compared with anticoagulation alone, as shown in the multinational, adaptive-design, open-label HI-PEITHO trial.
The primary outcome of a composite of pulmonary embolism–related death, cardiorespiratory decompensation or collapse, or symptomatic recurrence of PE within 7 days occurred in 4 percent of patients who underwent USCDT vs 10.3 percent of those who received anticoagulation alone (relative risk [RR], 0.39, 95 percent confidence interval [CI], 0.20–0.77; p=0.005). [N Engl J Med 2026;doi:10.1056/NEJMoa2516567]
The difference in the composite outcome was driven by a lower incidence of cardiorespiratory decompensation or collapse in the UFCDT arm than in the anticoagulation arm (3.7 percent vs 10.3 percent; RR, 0.4, 95 percent CI, 0.2–0.7), according to senior investigator Dr Stavros Konstantinides from the University Medical Center of the Johannes Gutenberg University, Mainz, Germany, who presented the results at the annual ACC meeting.
Meanwhile, PE-related mortality and PE recurrence were low and infrequent in both treatment arms, Konstantinides added.
Safety results were similar between the USCDT and anticoagulation arms, with no significant difference observed in the incidences of ISTH-defined major bleeding at 7 days (4.1 percent vs 2.2 percent; p=0.32) and at 30 days (4.1 percent vs 3 percent; p=0.64) and moderate-to-severe bleeding according to GUSTO criteria at 7 days (3.3 percent vs 1.5 percent; p=0.26). There were no cases of intracranial haemorrhage documented in either treatment arm.
Konstantinides pointed out that USCDT allows low doses of alteplase to be infused locally, with the aim of maintaining efficacy while reducing the risk of major bleeding.
“HI-PEITHO shows that a catheter intervention can indeed be effective and improve the prognosis for patients with severe PE and elevated risk of early death or life-threatening complications. If the right patients are selected for this procedure, it can prevent patients from deteriorating, and it can do so at an acceptably low risk of bleeding complications,” he said.
Great leap forward
In an editorial accompanying the paper, Dr Alex Spyropoulos from Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, US, and Dr Suresh Vedantham from Washington University School of Medicine, St Louis, Missouri, US, described HI-PEITHO as a challenging and important trial. [N Engl J Med 2026;doi:10.1056/NEJMe2603115]
“The finding that USCDT plus anticoagulation was associated with a lower risk of acute clinical deterioration than anticoagulation alone in a multicentre, randomized controlled trial of this scale represents a major advance in the foundation of evidence for thrombolytic approaches,” since the original PEITHO trial that came out more than a decade ago, Spyropoulos and Vedantham added.
PEITHO, which evaluated systemic fibrinolysis in patients with intermediate-risk PE, showed that tenecteplase plus heparin was associated with a reduced incidence of death or haemodynamic decompensation or collapse within 7 days compared with placebo plus heparin (2.6 percent vs 5.6 percent; odds ratio, 0.44, 95 percent CI, 0.23–0.87; p=0.02). However, this benefit came at the cost of a high rate of stroke (2.4 percent vs 0.2 percent), particularly haemorrhagic stroke. [N Engl J Med 2014;370:1402-1411]
“The lower incidence of major bleeding associated with USCDT in the current trial than with systemic fibrinolysis in the PEITHO trial should increase comfort with the use of this approach,” Spyropoulos and Vedantham said.
Intermediate-risk PE population
HI-PEITHO included 544 patients (The mean age 58.2 years, 42.6 percent female, 15.8 non-White) with intermediate-risk PE. This population was defined according to the following criteria: a ratio of right ventricular end-diastolic diameter to left ventricular end-diastolic diameter of ≥1.0, elevated serum troponin level, and at least two indicators of cardiorespiratory distress (ie, systolic BP of ≤110 mm Hg, tachycardia with a heart rate of ≥100 bpm, or tachypnea or hypoxemia with a respiratory rate of >20 breaths per min). Patients with haemodynamic instability were excluded.
“The aim of these specific criteria was to place more focus on patients who would be sick enough to really need some sort of advanced treatment,” Konstantinides pointed out.
Spyropoulos and Vedantham noted that before HI-PEITHO, it was unclear whether advanced thrombolytic therapies provided “a benefit at an acceptable cost for the large group of patients … whose condition appears to be haemodynamically stable but who have evidence of right ventricular dysfunction and clinical or laboratory signs that suggest a risk of cardiorespiratory decompensation.”
The findings of HI-PEITHO support a lower threshold for the use of UFCDT in this population, they added. “The wisdom of applying this approach to patients with less severe intermediate-risk PE remains unclear and will benefit from additional studies, including those assessing long-term functional outcomes, applying mechanical thrombectomy, and potentially using safer background anticoagulants, such as factor XI or factor Xia inhibitors.”
HI-PEITHO details
Patients were randomly assigned to undergo USCDT with alteplase, delivered using the EKOS+ endovascular device, plus anticoagulation (n=273) or receive anticoagulation alone (n=271).
USCDT was initiated within 2 h after randomization in 73.3 percent of the cases, with the mean total dose of alteplase being 8.85 mg for the 20 patients who had catheter placement on one side only and 16.92 mg for the 251 patients who had catheter placement into both the right and left pulmonary arteries. The mean total infusion duration was 7.16 h.
Unfractionated heparin was the most common anticoagulant used in both the USCDT and anticoagulation arms (71.6 percent and 55.7 percent, respectively), followed by low-molecular-weight heparin (50.6 percent and 53.9 percent, respectively).
At 30 days, all-cause mortality was 1.8 percent in the USCDT arm vs 1.1 percent in the anticoagulation arm. Symptomatic recurrence was low, occurring in 0.4 percent and 0.7 percent of patients in the respective treatment arms.
The incidence of serious adverse events over 30 days was also similar in the USCDT and anticoagulation arms, at 14.8 percent and 16.2 percent (p=0.64), respectively.
Rescue therapy was allowed in patients with documented cardiorespiratory decompensation. The percentage of patients who received rescue treatment was 2.9 percent in the USCDT arm vs 9.2 percent in the anticoagulation arm.
Cardiorespiratory decompensation, according to Konstantinides, required the fulfilment of at least one of the following criteria: cardiac arrest or indication for cardiopulmonary resuscitation, signs of shock, extracorporeal membrane oxygenation, intubation or noninvasive mechanical ventilation, or a National Early Warning Score (NEWS) that rose to or persisted at 9 or higher (between 24 h and 7 days, on two consecutive measurements 15 min apart).
“NEWS is a practical, easy-to-use score for quantifying the patient’s vital status based on the vital parameters. The more a vital parameter is abnormal, the more points are attributed to it. A NEWS of at least 7 already means that the patient may need intensive care, while a NEWS of at least 9 indicates a medical emergency,” he explained.
Spyropoulos and Vedantham noted, however, that while the use of NEWS at a threshold of 9 to indicate decompensation “enhanced the reproducibility of the trial results and reduced expectation bias in an open-label trial design,” the score is not widely used in North America. “Whether it represents a clinically relevant surrogate for decompensation, as well as whether it was applied similarly in both treatment groups, is uncertain.”
Study discussant Dr Joshua Beckman from UT Southwestern Medical Center, Dallas, Texas, US, congratulated Konstantinides and colleagues for “starting a new day in understanding the management of PE … [and] bringing [it] into the future.
“[USCDT plus anticoagulation] does not have an excess of statistically significant bleeding, and the composite outcome is improved. How it’s placed in routine therapy still needs to be discussed among the community, and I’m really interested to see the physiologic outcomes as they come in the next several months,” Beckman said.