Ultrasound-Facilitated, Catheter-Directed Fibrinolysis for Acute Pulmonary Embolism (HI-PEITHO)

Authors, Journal, Affiliations, Type, DOI

• Rosenfield K, Klok FA, Piazza G, Sharp ASP, Ní Áinle F, Jaff MR, Barco S, Goldhaber SZ, Kucher N, Lang IM, Schmidtmann I, Sterling KM, et al., for the HI-PEITHO Investigators
• The New England Journal of Medicine, published March 28, 2026
• Lead institutions: Massachusetts General Hospital (Boston), Leiden University Medical Center, Brigham and Women's Hospital/Harvard Medical School, University Medical Center Mainz (Center for Thrombosis and Hemostasis)
• Funded by Boston Scientific (sponsor); conducted in tripartite partnership with Boston Scientific, University Medical Center Mainz, and PERT Consortium (not-for-profit)
• Type: Multinational, adaptive-design, open-label randomized controlled trial with blinded outcome adjudication
• 59 sites across the United States and Europe; Aug 2021–Jul 2025
• DOI: 10.1056/NEJMoa2516567; ClinicalTrials.gov NCT04790370

Overview

HI-PEITHO is the first multicenter randomized controlled trial to demonstrate that ultrasound-facilitated, catheter-directed fibrinolysis (CDL) with alteplase plus anticoagulation is superior to anticoagulation alone in patients with acute intermediate-risk pulmonary embolism. In 544 randomized patients, the primary composite of PE-related death, cardiorespiratory decompensation/collapse, or symptomatic PE recurrence at 7 days occurred in 4.0% of the CDL group vs 10.3% of controls (RR 0.39; 95% CI 0.20–0.77; P=0.005). This benefit was achieved without a significant increase in major bleeding (4.1% vs 3.0% at 30 days; P=0.64) and with zero intracranial hemorrhage in either group — a safety profile markedly better than systemic thrombolysis. The trial fills the pivotal evidence gap identified in guidelines, where CDL lacked direct RCT evidence vs anticoagulation alone.

Keywords

Pulmonary embolism, intermediate-risk, catheter-directed fibrinolysis, ultrasound-facilitated thrombolysis, alteplase, EkoSonic, anticoagulation, right ventricular dysfunction, cardiorespiratory decompensation, HI-PEITHO

Key Takeaways

Background and Rationale

• Intermediate-risk PE (normotensive + RV dysfunction + elevated troponin) carries risk of cardiorespiratory collapse, but the optimal treatment beyond anticoagulation is uncertain
• Systemic fibrinolysis reduces hemodynamic collapse but increases ICH risk (~2.4% in PEITHO trial), limiting clinical adoption
• High-frequency low-power ultrasound potentiates fibrinolytic effect by altering fibrin fiber architecture, allowing lower alteplase doses with maintained efficacy
• Prior observational and single-arm studies (SEATTLE II, OPTALYSE PE, KNOCOUT PE) suggested CDL improves early RV recovery; no prior RCT vs anticoagulation alone existed

Study Design and Population

• Adaptive-design RCT: sample size increased from planned 406 to 544 after interim analysis per prespecified criteria
• Randomization 1:1 stratified by age (<75 vs ≥75) and RV/LV ratio (<1.5 vs ≥1.5); assignment and treatment required within 6 hours of PE confirmation
• Eligibility (intermediate-risk with additional distress): Adults 18–80 years; PE on CTPA in ≥1 main or proximal lobar PA; RV/LV end-diastolic ratio ≥1.0 on CTPA; elevated troponin; ≥2 of: SBP ≤110 mmHg, HR ≥100 bpm, RR >20 breaths/min or hypoxemia — within 6-hour window before randomization
• Exclusion: Persistent hemodynamic instability (AHA/ACC Category E equivalent); other standard thrombolysis contraindications
• Mean age 58.2±13.5 years; 42.6% women; 15.8% non-White; mean symptom duration 3.7±3.4 days; mean NEWS 6.0±1.9
• 4313 patients screened; 544 randomized (273 intervention, 271 control)

Intervention

• Device: EkoSonic endovascular system (Boston Scientific) delivering ultrasound energy concurrent with catheter-infused alteplase
• Alteplase dose: 8.85±0.67 mg (unilateral, n=20) or 16.92±3.47 mg (bilateral, n=251)
• Mean infusion duration: 7.16±0.52 hours
• CDL initiated ≤2 hours after randomization in 73.3% of intervention patients
• Anticoagulation: UFH most common in both groups (71.6% intervention, 55.7% control); LMWH in 50.6% and 53.9% respectively

Primary Efficacy Outcome (7-Day Composite)

• Primary composite (PE-related death + cardiorespiratory decompensation/collapse + symptomatic PE recurrence): 4.0% (11/273) vs 10.3% (28/271); RR 0.39 (95% CI 0.20–0.77); P=0.005
• Effect driven primarily by reduction in cardiorespiratory decompensation/collapse: 3.7% vs 10.3% (RR 0.4; 95% CI 0.2–0.7)
• High NEWS (≥9) persisting >24h post-randomization was the sole decompensation criterion in 15 patients (1 intervention vs 14 control)
• PE-related death RR 3.0 (95% CI 0.3–28.5) — numerically higher in intervention but CI crosses 1.0; one intervention patient died of inguinal hemorrhage after being enrolled in violation of exclusion criteria
• Symptomatic PE recurrence at 7 days: RR 1.0 (95% CI 0.1–15.8) — no difference
• Per-protocol and sensitivity analyses (stratification-adjusted logistic regression, OR 0.36; 95% CI 0.18–0.75) consistent with ITT

Secondary and Additional Outcomes

• Rescue therapy required: 2.9% (intervention) vs 9.2% (control); escalation required documented decompensation in 78.8%
• Mean hospital stay: 5.77±5.02 vs 6.48±4.88 days (mean difference −0.71 days; 95% CI −1.55 to 0.12)
• ICU admission: 71.1% vs 50.2% (higher in intervention due to procedural requirements)
• ICU duration: 2.19±3.02 vs 2.78±3.09 days (mean difference −0.59 days)
• 30-day all-cause mortality, recurrent symptomatic PE, and serious adverse events: no statistically significant difference between groups
• 9 total deaths through 30 days: 4 PE-related (3 intervention, 1 control)
• WHO functional class and Post-VTE Functional Status at 7 and 30 days: no substantial differences reported
• 6-minute walk at 30 days: 405 m (intervention) vs 393 m (control) — no significant difference
• RV/LV ratio improvement on echocardiography at 48±6 hours: detailed results in supplementary tables

Safety Outcomes

• Major bleeding (ISTH) at 72h: no significant difference
• Major bleeding (ISTH) at 7 days: no significant difference
• Major bleeding (ISTH) at 30 days: 4.1% vs 3.0% (RR 1.4; 95% CI 0.6–3.4; P=0.64)
• No intracranial hemorrhage in either group — key safety advantage over systemic thrombolysis
• GUSTO major bleeding at 7 days: no significant difference
• No substantial between-group differences in serious adverse events through 30 days

Limitations of the Document

• Open-label randomization; all primary and safety outcomes adjudicated by blinded clinical-events committee
• Low mortality in both arms despite intermediate-risk criteria; not powered to detect mortality difference
• Trial not powered to compare subgroups or draw firm conclusions about bleeding between groups
• Standardized differences >10% suggest possible baseline imbalance between groups on some variables
• Only 10.1% of patients were ≥75 years; moderate frailty index — elderly/frail populations may not be represented
• Not stratified by site; center-level effects cannot be excluded
• Does not test other catheter-based interventions (mechanical thrombectomy) or reduced-dose systemic fibrinolysis vs anticoagulation alone
• Industry-sponsored (Boston Scientific manufacturers EkoSonic device)
• 12-month follow-up ongoing; no long-term functional outcome or CTEPD data from this report
• Predominantly US/European sample; generalisability to more ethnically diverse populations uncertain

Key Concepts Mentioned

• concepts/Acute-PE-Clinical-Categories — trial population corresponds to Cat C3/D (intermediate-high risk with cardiorespiratory distress); results inform CDL recommendation upgrade
• concepts/Balloon-Pulmonary-Angioplasty — separate modality for CTEPH; not directly relevant but shares PE vascular context

Key Entities Mentioned

• entities/Pulmonary-Embolism — primary subject; CDL evidence now established by RCT
• entities/CTEPH — post-PE complication; 12-month data will assess CTEPD/CTEPH impact of CDL

Wiki Pages Updated

• wiki/sources/cdf-pe-hipeitho-nejm-2026.md — created
• wiki/entities/Pulmonary-Embolism.md — CDL section updated with HI-PEITHO RCT data; contradiction resolved; source_count updated
• wiki/concepts/Acute-PE-Clinical-Categories.md — CDL evidence updated; contradiction resolved; source_count updated
• wiki/sourceindex.md — new entry added
• wiki/wikiindex.md — Pulmonary-Embolism and Acute-PE-Clinical-Categories descriptions updated