🧭 REBEL Rundown
🗝️ Key Points
- 🫁⚖️ In intermediate-risk PE patients already selected for catheter-based therapy, LBMT (FlowTriever) beat CDT on the 5-component win ratio (driven largely by ICU utilization).
- 🧮🏥 When ICU admission/ICU LOS were removed (4-component win ratio), the difference was no longer statistically significant, suggesting the primary result is heavily influenced by system-level practices.
- 🩸🧠⚰️ Mortality, intracranial hemorrhage, and major bleeding were not statistically different between LBMT and CDT.
📝 Introduction
The optimal treatment strategy for intermediate-risk (submassive) pulmonary embolism (PE) remains controversial. These patients are not in shock, but they have right ventricular (RV) dysfunction and myocardial injury, which are associated with higher risk for clinical decompensation and adverse outcomes.1-3
The standard of care for intermediate-risk PE is therapeutic anticoagulation, though select patients may be considered for escalation to thrombolysis or catheter-based therapies.4 Systemic fibrinolysis can reduce hemodynamic decompensation but carries substantial bleeding risk. In PEITHO, fibrinolysis reduced decompensation but increased major hemorrhage and stroke.1 The MOPETT trial explored “safe-dose” systemic thrombolysis and demonstrated improvements in pulmonary pressures without a clear mortality benefit.5
Catheter-based approaches aim to improve RV strain and clot burden while potentially reducing bleeding compared with systemic lysis. CDT has demonstrated physiologic improvements and low intracranial hemorrhage rates in selected populations (e.g., SEATTLE II).6 Ongoing trials (HI-PEITHO and PE-TRACT) will further define whether catheter-based strategies improve outcomes compared with anticoagulation alone.7,8
Before PEERLESS, there were no high-quality randomized trials directly comparing CDT to large-bore mechanical thrombectomy (LBMT) in intermediate-risk PE.
🧾 Paper
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
⚙️ What They Did
📈 Results
Enrollment & sites
- 599 patients randomized; 550 ultimately enrolled and treated
- Treatment arms: LBMT n=274 vs CDT n=276
- Conducted at 57 sites in 3 countries from Feb 2022–Feb 2024
Post-randomization exclusions
- 49 post-randomization exclusions total
- 35/49 (71.4%) due to the prespecified systolic pulmonary artery pressure requirement
Parallel registry
142 patients with contraindications to thrombolytics enrolled in a nonrandomized registry (Table S1)
Baseline characteristics
- Mean age: 63.7 (LBMT) vs 61.2 (CDT) years
- Male sex: 54.4% (LBMT) vs 51.4% (CDT)
- Elevated troponin: 94.7% (consistent with intermediate-high-risk PE per ESC)
- VTE-BLEED ≥2: 26.4% of patients
- Relative thrombolytic contraindications: 4.2% of randomized population
Anticoagulation at baseline
- On parenteral anticoagulation: 95.3% (LBMT) vs 96.7% (CDT)
- Majority received unfractionated heparin: 80.7% (LBMT) vs 85.5% (CDT)
Timing to procedure
Time from presentation to catheter insertion: 22.3 ± 17.7 h (LBMT) vs 24.9 ± 19.7 h (CDT); P=0.08
Procedural access
- LBMT: 100% via common femoral/femoral vein access
- CDT: 35.1% via jugular vein access
CDT technical details
- Bilateral catheters: 92.0%
- Total tPA dose (median): 16.0 mg (IQR 12.0–24.0)
- tPA infusion duration (median): 12.0 h per lung (IQR 6.0–15.6)
- Infusion rate: 0.5–1.0 mg/h per lung in 95.9%
- Infusion duration: 6–24 h in 90.8%
Types of CDT used
- Ultrasound-facilitated CDT: 59.8%
- Standard side-hole CDT: 23.2%
- Standard side-slit CDT: 8.7%
💥 Critical Results
- Primary endpoint: 5-component hierarchical win ratio favored LBMT vs CDT: 5.01 (95% CI 3.68–6.97; P<0.001).
- Only 2 of 5 primary components differed (drivers of the win):
- Clinical deterioration/bailout therapy: 1.8% (LBMT) vs 5.4% (CDT); P=0.04
- ICU admission: 41.6% vs 98.6%
- ICU stay >24h: 19.3% vs 64.5%
- Post-procedural ICU utilization (major driver): P<0.001
- Hard safety outcomes were similar:
- All-cause mortality (in-hospital): 0.0% vs 0.4%; P=1.00
- Intracranial hemorrhage (ICH): 0.7% vs 0.4%; P=0.62
- Major bleeding: 6.9% vs 6.9%; P=1.00
- Key interpretive result: the 4-component win ratio (excluding ICU outcomes) was not significant: 1.34 (95% CI 0.78–2.35; P=0.30.
💪🏽 Strengths
Design & execution
- Prospective, multicenter randomized controlled trial
- Automated randomization with stratification by VTE-BLEED score, reducing selection bias
- Intention-to-treat analysis preserved the benefits of randomization
- External statistical oversight (BAIM Institute) strengthens credibility for an industry-sponsored trial
Generalizability
Broad mix of specialties and practice settings across 60 international sites, improving external validity
Outcome rigor
- Several key endpoints were objective and less bias-prone (death, ICH, major bleeding, ICU admission)
- Imaging (echo/CTPA) reviewed by a single independent, blinded physician
- Independent clinical events committee adjudicated safety outcomes
- Included patient-centered outcomes (dyspnea and quality-of-life measures)
Baseline balance
- While the CDT arm appeared modestly higher risk (VTE-BLEED/sPESI, troponin, clot burden, dyspnea), between-group differences were not large
⚠️ Limitations
Comparators & applicability
- Does not compare either strategy to anticoagulation alone (current standard of care for most intermediate-risk PE)
- Patients enrolled only after being deemed “appropriate for intervention,” introducing indication/spectrum bias
- Manuscript does not report how many intermediate-risk PE patients were screened but not enrolled (limits assessment of selection bias)
Bias & confounding risk
- Open-label design increases risk of performance/ascertainment bias, especially for:
- Clinical deterioration/escalation to bailout therapy
- ICU admission and ICU LOS
- Readmissions
- ICU outcomes are particularly vulnerable to protocol confounding, since many centers routinely admit CDT patients to ICU for monitoring
- Baseline differences suggest CDT patients may have been slightly sicker, which could influence deterioration/escalation outcomes
Intervention heterogeneity
- CDT was delivered per local practice (variable catheters and thrombolytic dosing), which may:
- Dilute real differences between CDT strategies
- Increase between-site variability not fully captured
Endpoint construction & follow-up
- Primary endpoint assessed at discharge or 7 days, which may reflect institutional practice patterns (especially ICU use)
- Composite includes non-equivalent components (e.g., ICU admission/LOS vs death)
- “30-day” follow-up allowed up to +15 days, increasing outcome window variability
- 30 days may be insufficient to detect longer-term differences
Post-randomization exclusions & transparency
- 49 patients excluded post-randomization due to intraprocedural systolic PA pressure ≥70 mmHg, introducing potential post-randomization bias
- Trial sponsor (Inari Medical) helped design the study (conflict risk)
- Data not shared for external verification, limiting reproducibility
🗣️ Discussion
In Summary
PEERLESS is the first large, international randomized trial to directly compare large-bore mechanical thrombectomy (LBMT) using the FlowTriever system versus catheter-directed thrombolysis (CDT) in intermediate-risk pulmonary embolism (PE) patients who were already deemed appropriate for catheter-based intervention. The trial’s headline result favored LBMT on the 5-component win ratio composite. Importantly, the 4-component win ratio (excluding ICU outcomes) was not significant, suggesting the primary result may be driven by ICU practice patterns.
Understanding the Win Ratio
The win ratio is a prioritized composite endpoint that compares paired patients across treatment arms, starting with the most important outcome (e.g., death). If there is a tie, the comparison moves down the hierarchy (e.g., ICH, major bleeding, then clinical deterioration, then ICU metrics). The advantage of this approach is that it can increase statistical power and reflect clinical priorities better than an unweighted composite. The tradeoff is that results can become heavily influenced when large between-group differences occur in lower-tier, protocol-sensitive outcomes—particularly in an open-label trial.
Inside the Numbers
One major limitation includes that while the LBMT arm was standardized with use of the FlowTrevier System, the CDT arm was not standardized, with variations between local standards when selecting device and thrombolytic dosing. Many institutions require ICU-level care for post-procedure monitoring of CDT, causing potential confounding bias when comparing ICU utilization. This may have ultimately influenced the win ratio when assessing the primary endpoint. Additionally, ICU admission and length of stay are not patient-oriented outcomes.
Clinical deterioration could have been influenced by small differences in patient group differences. Patients in the CDT group may have been overall sicker compared to the LBMT group, with higher VTE-BLEED and sPESI scores, more elevated troponin levels, more saddle embolus and main artery PE, higher heart rate and dyspnea scores. This may have led to higher rates of clinical deterioration in the CDT group and influence of the win ratio.
What This Does and Does Not Answer
PEERLESS compares outcomes for two interventions in patients in which further intervention beyond anticoagulation was considered to be clinically indicated. However, it does not compare either intervention to anticoagulation, which is the current standard of care. Further, it does not assist in the decision to initiate further intervention in patients with intermediate-risk PE. Additional research is needed to establish optimal practice patterns for patients with intermediate-risk PE.
📘 Author's Conclusion
“PEERLESS met its primary end point in favor of LBMT compared with CDT in treatment of intermediate-risk pulmonary embolism. LBMT had lower rates of clinical deterioration and/or bailout and postprocedural intensive care unit use compared with CDT, with no difference in mortality or bleeding.”
💬 Our Conclusion
The PEERLESS trial is the first randomized study to compare LBMT with CDT in intermediate-risk PE patients already judged to need intervention beyond anticoagulation. Although the composite primary endpoint favored LBMT, that advantage appears largely driven by clinician- and system-sensitive outcomes—clinical deterioration/escalation, ICU utilization, and readmissions—which are particularly vulnerable to bias in an open-label design. Importantly, there was no statistically significant difference in all-cause mortality between LBMT and CDT. Additional randomized trials are needed to determine whether these findings justify broad adoption of LBMT for intermediate-risk PE and to clarify how either strategy compares with anticoagulation alone.
❓ FAQ
What is the PEERLESS trial?
A randomized trial comparing LBMT (FlowTriever) vs CDT in intermediate-risk PE patients selected for catheter intervention.Did PEERLESS show a mortality benefit?
No—mortality was low and not statistically different between groups.What drove the primary endpoint?
Differences in ICU admission/ICU LOS and clinical deterioration/bailout.What is the “4-component win ratio” and why does it matter?
It excludes ICU outcomes; it was not significant, suggesting ICU practice patterns may drive the primary result.Does this prove intervention is better than anticoagulation alone?
No—PEERLESS compares two interventions and does not include an anticoagulation-only arm.
🚨 Clinical Bottom Line
This study is the first RCT to compare interventional techniques for intermediate-risk PE, though does not clearly demonstrate superiority of LBMT compared to CDT due to concern for bias as the major driver of statistical differences in the primary outcome. It remains to be seen if intervention is superior to anticoagulation alone.
📚 References
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- Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs JSR, Huisman MV, Humbert M, Kucher N, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)Endorsed by the European Respiratory Society (ERS). European Heart Journal. 2014;35:3033-3080. PMID: 25173341
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- Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Anticoagulation SoCo. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13:2119-2126. PMID: 26764429
Post Peer Reviewed By: Mark Ramzy, DO (X: @MRamzyDO), and Marco Propersi, DO (X: @Marco_Propersi)
👤 Guest Authors
Maren Leibowitz MD
