HI-PEITHO Trial: Ultrasound-facilitated, Catheter Directed Fibrinolysis for PE

Written by Mark Ramzy
REBEL Crit, REBEL EM
Medical Category: Resuscitation, Thoracic and Respiratory
catheter-directed thrombolysis, fibrinolysis, Fibrinolytics, HIPEITHO, intermediate-risk pulmonary embolism, PEITHO, Pulmonary, Pulmonary Embolism, pulmonary embolism intervention, subsegmental pulmonary Embolism

May 19, 2026

🗝️ Key Points

🏆 First of Its Kind: First RCT demonstrating that catheter-directed fibrinolysis plus anticoagulation reduces short-term hemodynamic decompensation versus anticoagulation alone in intermediate-high risk PE.
🎯 Highly Selected Population: Results apply only to the sickest subset of intermediate-risk PE, not broadly applicable to all intermediate-risk PE patients.
🚑 Identify Early, Anticoagulate First: Rapid identification of the intermediate-high risk PE phenotype with early PERT activation, if available, and immediate anticoagulation remains the foundation — advanced therapy decisions should follow from there.
💉 Is the Catheter Even Necessary?: Peripheral low-dose systemic thrombolysis appears equally effective as catheter-directed delivery — faster, cheaper, and accessible in many hospitals/units without specialized personnel or equipment

📝 Introduction

The debate regarding the most definitive therapy for patients with submassive PE has been ongoing for some time as new interventional therapies continue to emerge. While therapeutic anticoagulation remains the standard of care, fibrinolysis either systemically or via a catheter is constantly being explored. Catheter-based approaches aim to improve RV strain and clot burden while potentially reducing bleeding compared with systemic lysis. Prior studies have looked at large-bore mechanical thrombectomy but have not compared the method of administering fibrinolysis to anticoagulation alone. The authors of the HI-PEITHO trial performed an international RCT to answer the question of whether catheter directed fibrinolysis plus anticoagulation alone improved clinical outcomes compared to anticoagulation alone.

🧾 Paper

Rosenfield K,et al. HI-PEITHO Investigators. Ultrasound-Facilitated, Catheter-Directed Fibrinolysis for Acute Pulmonary Embolism. N Engl J Med. Mar 2026 PMID: 41910345

🔙PREVIOUSLY COVERED ON REBEL EM:

The Critical Pulmonary Embolism Patient

SubMassive PE: Full Dose, Half Dose, or No Dose?

SEATTLE II Trial: Catheter Directed Thrombolysis: The Magic Bullet for Submassive Pulmonary Embolism?

PEERLESS Trial: Large-Bore Mechanical Thrombectomy Versus Catheter-Directed Thrombolysis in Intermediate-Risk PE

⚙️ What They Did

📈 Results

CLINICAL QUESTION

In patients with intermediate-risk pulmonary embolism (PE), does ultrasound-facilitated, catheter-directed fibrinolysis (US-CDT) plus anticoagulation improve clinical outcomes compared to anticoagulation alone?

STUDY DESIGN

Adaptive-design, open-label randomized control trial with blinded adjudication for the primary composite outcome
Multi-national study that occurred at approximately 65 sites in Europe and the US
Conducted by tripartite partnership consisting of Boston Scientific (sponsor), University Medical Center of the Johannes Gutenberg University of Mainz and the Non-for-profit PERT Consortium
Following enrollment, patients were randomized and initiation of therapy followed as soon as possible but no more than six hours after confirmation of diagnosis
Performed additional follow up visits at 30 days, 6-months and 12-months post randomization

POPULATION

Inclusion Criteria:

Adult patients aged 18 to 80 years old
Confirmed acute PE on CT with a filling defect in at least one main or proximal lobar pulmonary artery
Elevated risk of early/death or hemodynamic collapse by at least TWO of the following clinical criteria
- HR > 100 on ECG not due to hypovolemia, arrhythmia or sepsis
- SBP < 110 for at least 15 minutes
- RR > 20/min OR SpO2 < 90% on room air
Right-toleft ventricular diameter ratio > 1.0 on CT Chest
Elevated serum troponin I or T levels above the upper limit of normal

Exclusion Criteria:

Hemodynamic instability defined by at least ONE of the following present:
- Cardiac arrest or need for CPR
- Need for ECMO or on circuit before randomization
- PE-related shock (ie. SBP < 90, vasopressors AND end-organ hypoperfusion)
- Isolated hypotension (ie. SBP < 90 or 40mmHg drop for at least 15 minutes not caused by new onset arrhythmia, hypovolemia or sepsis)
ICU admission for a reason other than index PE episode
Temperature above 39oC / 102.2oF
Active bleeding including intracranial
Major surgery in the last three weeks
Patients who already received some form of anticoagulation prior to randomization
Pregnant or lactating patients
Life expectancy less than 6 months
Additional criteria can be found in the supplemental information

INTERVENTION & COMPARATOR

Intervention:

Ultrasound-facilitated catheter-directed delivery of thrombolytic (specifically alteplase): 2mg bolus via catheter + 1mg/hr for 7 hours for total of 9 or 18mg) PLUS Low-molecular weight heparin (LMWH) or Unfractionated Heparin (UFH)

Comparator:

Anticoagulation via LMWH or UFH

OUTCOMES

Primary Outcome

Additional Outcomes

Primary: Composite at 7 days that consisted of the following three items:
- PE-related death
- Recurrent PE
- Cardiopulmonary decompensation/collapse (defined as the following)
  - Cardiac arrest or need for CPR again between randomization and day 7
  - New or persistent hypotension (SBP<90) over at least 15 minutes anytime between randomization and day 7
  - Need for vasopressors or end-organ hypoperfusion (AMS, anuria, elevated lactate)
  - Placement of ECMO
  - Intubation or initiation of non-invasive mechanical ventilation
  - National Early Warning Score (NEWS) of 9 or higher between 24 hours and day 7 after randomization

Major bleeding at 72 hours, 7 days, and 30 days after randomization
Ischemic stroke or acute intracranial hemorrhage within 7 days and 30 days
Recurrence of PE and occurrence of adverse events within 30 days
Death from any cause within 7 days and 30 days

RESULTS

💥 Critical Results

💪🏽 Strengths

First RCT Powered for this question: This is the first-large scale global RCT that asks and attempts to answer a clinically relevant question
Rigorous Patient Selection: The investigators looked specifically for patients who may actually benefit rather than all-comers with intermediate-risk PE
No Strings Attached: Registered the trial on clinicaltrials.gov to allow for fully transparency
International Design: Multi-center and multi-national study allows for greater generalizability and external validity
No Head Bleeds: No intracranial hemorrhage occurred in either group and major bleeding at 30 days was statistically similar
NEWS Score: This is the first PE study to include a standardized and validated physiologic monitoring framework that is used in clinical practice
Patient Follow-up: Performed thorough outpatient follow-up at different time periods (30 days, 6 months and 1 year)

⚠️ Limitations

Conflict of Interest: Financially funded by Boston Scientific that makers of the catheter device
Weighted Outcome: Primary outcome was a composite end-point which was largely driven by the component of cardiopulmonary collapse and deterioration which was powered by the NEWS score changes
Open-Label Design: Clinicians knew the patient’s treatment assignment which may have contributed to performance or detection bias
Not an Apples-to-Apples Comparison: Compared intervention to anticoagulation alone instead of different peripheral thrombolysis medications to the catheter plus anticoagulation
Highly Selected Patient Population: Had extremely strict exclusion criteria which may contribute to selection bias
Baseline Imbalances: Patients in the control arm had numerically more bilateral PE and more tachypnea at baseline when compared to the intervention which could have biased the results in favor of the catheter
Adaptive Design: Introduces complexity in interpretation and has the potential to inflate type I error risk

🗣️ Discussion

This is the first multicenter, multi-national RCT study we have looking specifically comparing ultrasound-facilitated catheter-directed fibrinolysis to anticoagulation alone in intermediate-high risk PE patients
These were HIGHLY selected patients and what this study emphasizes is the early identification of these intermediate-high risk patients who are on the sicker-end of the submassive PE spectrum.
Although PE Response Teams (PERT) wasn’t specifically mentioned in the paper, they should be triggered early for these patients and in the meantime consider the following:
- Anticoagulation remains the foundation of treatment for these patients and this trial should not be interpreted as a mandate for catheter based therapy in every PE patient
- In fact the decision to use advanced interventions like catheter directed fibrinolysis (if available) should be made in close communication with the specialists performing the procedure
- If your institution offers both large bore mechanical thrombectomy, the PEERLESS trial which we recently reviewed on REBEL, suggests that it may outperform ultrasound-facilitated catheter directed thrombolysis but again this is a conversation to be had with your PERT team and interventional radiology/cardiology
One important note before immediately jumping to catheter use is that data has shown that peripheral systemic thrombolysis is equally effective compared to catheter-directed thrombolysis 3,4. This is applicable to community hospitals without advanced catheter lab capabilities and/or PERT teams
In fact in those community hospital settings it may be more advantageous to use peripheral thrombolysis for several reasons:
- Less invasive than actually leaving a catheter across the tricuspid valve
- It can be administered anywhere in the hospital and does not require highly specialized personnel like interventional cardiology or radiology
- It’s more time and cost saving in that it can be started immediately plus the drug is less expensive than the catheter itself and that’s not including procedural and personnel costs

📘 Author's Conclusion

In patients with acute, intermediate-risk pulmonary embolism, ultrasound-facilitated, catheter-directed fibrinolysis plus anticoagulation led to a lower risk of the composite of pulmonary embolism–related death, cardiopulmonary decompensation or collapse, or symptomatic recurrence of pulmonary embolism within 7 days than anticoagulation alone

💬 Our Conclusion

The HI-PEITHO trial provides the strongest evidence that low-dose ultrasound-facilitated catheter directed fibrinolysis reduces short term hemodynamic collapse but in very carefully selected critically ill patients who are the sickest subset of those with intermediate-high risk PE. The bigger question is whether the expensive catheter is even necessary as the same benefits can be achieved quicker and cheaper with systemic thrombolysis, especially in a lower resource setting where PERT teams and advanced catheter labs may not always be immediately available.

🚨 Clinical Bottom Line

While the HI-PEITHO trial adds new evidence to the management of intermediate-high risk PE patients it emphasizes the need for early identification of these critically ill patients and anticoagulation remains the foundation of therapy. The decision to use catheter-directed fibrinolysis raises the question if it’s even needed since peripheral systemic fibrinolysis is faster, cheaper and equally effective.

📚 References

Rosenfield K,et al.
HI-PEITHO Investigators. Ultrasound-Facilitated, Catheter-Directed Fibrinolysis for Acute Pulmonary Embolism. N Engl J Med. Mar 2026
PMID: 41910345
Jaber, Wissam A et al.
Large-Bore Mechanical Thrombectomy Versus Catheter-Directed Thrombolysis in the Management of Intermediate-Risk Pulmonary Embolism: Primary Results of the PEERLESS Randomized Controlled Trial. Circulation vol. 151,5 (2025): 260-273.
PMID: 39470698
Kjærgaard J,et al.
A randomized trial of low-dose thrombolysis, ultrasound-assisted thrombolysis, or heparin for intermediate-high risk pulmonary embolism-the STRATIFY trial: design and statistical analysis plan. Trials. Dec 2024
PMID: 39732696
Avgerinos ED et al.
Randomized Trial Comparing Standard Versus Ultrasound-Assisted Thrombolysis for Submassive Pulmonary Embolism: The SUNSET sPE Trial. JACC Cardiovasc Interv. Oct 2021
PMID: 34167677

Post Peer Reviewed By: Anand Swaminathan, MD (X/IG: @EMSwami) and Marco Propersi DO, (X/IG: @Marco_Propersi)

👤 Meet the Author

Mark Ramzy, DO

Co-Editor-in-Chief

Emergency Medicine Attending Cardiothoracic Intensivist RWJBH/Rutgers Health, Newark, NJ

Meet The Team

Cite this article as: Mark Ramzy, "HI-PEITHO Trial: Ultrasound-facilitated, Catheter Directed Fibrinolysis for PE", REBEL EM blog, May 19, 2026. Available at: https://rebelem.com/hipeitho/.