Target Trial Emulation Analysis for the Management of High-Risk Acute Pulmonary Embolism

Background Introduction

Acute pulmonary embolism (PE) is a life-threatening cardiovascular disease affecting more than 35 people per 100,000 annually. Approximately 5% of PE patients present with persistent hypotension, cardiogenic shock, or cardiac arrest, often associated with acute right ventricular (RV) failure. These patients are classified as high-risk PE cases and exhibit extremely high mortality rates. For high-risk PE patients, key objectives in emergency care include hemodynamic stabilization and rapid restoration of pulmonary perfusion. However, evidence regarding the efficacy of advanced circulatory support and pulmonary recanalization strategies remains limited.

Although veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is currently the first-line mechanical circulatory support device for refractory circulatory failure or cardiac arrest, its efficacy as a bridge to recovery or reperfusion has not been fully established. Additionally, optimal selection among advanced recanalization strategies such as systemic thrombolysis (Sys), surgical thrombectomy (ST), and percutaneous catheter-directed treatment (PCDT) lacks sufficient evidence. Therefore, this study aimed to evaluate the impact of different advanced treatment strategies on in-hospital all-cause mortality in high-risk acute PE patients using target trial emulation.

Study Source

This study was conducted by Andrea Stadlbauer, Tom Verbelen, Leonhard Binzenhöfer, and other scholars from multiple European academic institutions, involving 34 European clinical centers. The data were collected from high-risk acute PE patients treated between January 2012 and August 2022. The paper was published in Intensive Care Medicine in 2025, titled “Management of high-risk acute pulmonary embolism: an emulated target trial analysis.”

Study Design and Methods

Study Design

This study employed a retrospective observational design and analyzed data through target trial emulation. A total of 1060 high-risk acute PE patients were included, with 991 patients analyzed in the target trial emulation. Patients were divided into four groups:
1. VA-ECMO alone (n=126);
2. Intrahospital systemic thrombolysis (Sys) (n=643);
3. Surgical thrombectomy (ST) (n=49);
4. Percutaneous catheter-directed treatment (PCDT) (n=173).

VA-ECMO was allowed as a bridge to recanalization strategies to stabilize patients’ hemodynamics. The primary outcome was in-hospital all-cause mortality, while secondary outcomes included 3-month and 1-year mortality, cerebral performance category (CPC) score at discharge, length of ICU stay, total hospital stay, and bleeding complications.

Data Analysis

The study used the G-formula as the primary analytical method, estimating marginal causal contrasts via logistic regression models. Sensitivity analyses included:
1. Targeted maximum likelihood estimation (TMLE) with machine learning;
2. Inverse probability of treatment weighting (IPTW);
3. Multiple imputation for missing values;
4. Complete target trial emulation (excluding the VA-ECMO alone group).

Study Results

Key Findings

1. In-Hospital Mortality:

   • Estimated in-hospital mortality for VA-ECMO alone was 57% (95% CI 47%-67%);
     
   • Mortality for the systemic thrombolysis group was 48% (95% CI 44%-53%);
     
   • Mortality for the surgical thrombectomy group was 34% (95% CI 18%-50%);
     
   • Mortality for the percutaneous catheter-directed treatment group was 43% (95% CI 35%-51%).
     

2. Risk Ratios:

   • Risk ratios for systemic thrombolysis, surgical thrombectomy, and percutaneous catheter-directed treatment were all superior to VA-ECMO alone;
     
   • Surgical thrombectomy showed the most significant reduction in mortality.
     

3. Neurological Outcomes:

   • Patients surviving to discharge in all groups exhibited high rates of favorable neurological outcomes, particularly in the percutaneous catheter-directed treatment group (91% of patients had CPC 1).
     

Sensitivity Analyses

All sensitivity analyses supported the robustness of the main results. TMLE and IPTW analyses showed that any recanalization strategy was superior to VA-ECMO alone. Additionally, complete target trial emulation (excluding the VA-ECMO alone group) yielded consistent results with the primary analysis.

Discussion and Conclusion

The findings indicate that systemic thrombolysis, surgical thrombectomy, and percutaneous catheter-directed treatment significantly reduce in-hospital mortality compared to VA-ECMO alone in high-risk acute PE patients. Among these, surgical thrombectomy demonstrated the greatest survival benefit. However, due to the retrospective nature of the study, these results require further validation in prospective randomized controlled trials.

Furthermore, the study suggests that the role of surgical thrombectomy in clinical practice may be underestimated, while percutaneous catheter-directed treatment showed lower bleeding complications and higher neurological recovery rates. These findings provide new insights into treatment strategies for high-risk PE and highlight the importance of multidisciplinary teams and tertiary centers in managing complex cases.

Study Highlights

1. Large-Scale Data: This study is one of the largest cohort studies of high-risk acute PE patients to date, covering data from 34 European clinical centers.
   
2. Target Trial Emulation: By employing target trial emulation, the study overcame limitations of retrospective data, providing strong support for causal inference.
   
3. Multi-Strategy Comparison: Direct comparisons among systemic thrombolysis, surgical thrombectomy, and percutaneous catheter-directed treatment offer critical guidance for clinical decision-making.
   
4. Potential of Surgical Thrombectomy: The study suggests that the role of surgical thrombectomy in managing high-risk PE may be underestimated and warrants further research and promotion.
   

Application Value and Future Directions

This study provides important evidence-based insights into the emergency management of high-risk acute PE, highlighting the positive role of recanalization strategies in improving short-term survival. Future research should focus on optimizing complex treatment pathways, exploring risk prediction models, and evaluating the efficacy of specific treatment approaches to improve long-term patient outcomes. Additionally, the establishment and promotion of multidisciplinary PE response teams will become a key direction in future clinical practice.

Other Valuable Information

1. Bleeding Complications: The percutaneous catheter-directed treatment group had the lowest rate of bleeding complications (15.0%), while the VA-ECMO alone group had the highest rate (47.6%).
   
2. ICU Stay Duration: The surgical thrombectomy group had the longest ICU stay (median 9 days), while the percutaneous catheter-directed treatment group had the shortest (median 3 days).
   
3. Treatment Switching Time: 85% of patients switched to recanalization strategies within 5 hours after VA-ECMO initiation.
   

The findings of this study provide new perspectives on the emergency management of high-risk PE and lay the foundation for further prospective research.