Role of catheter-based interventions in treating pulmonary embolism

Abstract

Pulmonary embolism (PE) ranks as the third leading cause of cardiovascular-related deaths in Western nations. Patients classified as high-risk (HR)-those exhibiting hemodynamic instability-require immediate interventions to restore blood flow. While intermediate–HR (IHR) individuals remain hemodynamically stable, they face a significant chance of clinical decline and thus need close and continuous observation. Effective risk assessment, mortality prediction, and therapeutic decision-making in these patients rely on a combination of clinical evaluation and imaging studies. Catheter-directed therapy (CDT) has emerged as a promising option, offering the ability to alleviate clot burden and reduce strain on the right ventricle, all while posing a lower risk of major bleeding compared to systemic thrombolysis. The growing adoption of CDT reflects its increasing relevance in PE treatment, especially when managed by specialized PE response teams that ensure individualized, multidisciplinary care. As clinical practices evolve, further studies and robust clinical trials are necessary to clearly define CDT’s role in lowering the risks of complications and death among IHR PE patients. This article explores the current understanding and future direction of managing PE, focusing in the role of catheter-based interventions.

Key Words: Pulmonary embolism; Catheter directed therapy; Mechanical thrombectomy; Risk stratification; Intermediate-high-risk

Core Tip: Pulmonary embolism (PE) ranks as the third leading cause of cardiovascular-related deaths in Western nations. Patients classified as high-risk-those exhibiting hemodynamic instability-require immediate interventions to restore blood flow. Catheter-directed therapy has emerged as a promising option, offering the ability to alleviate clot burden and reduce strain on the right ventricle, all while posing a lower risk of major bleeding compared to systemic thrombolysis. This article explores the current understanding and future direction of managing PE, focusing in the role of catheter-based interventions.

INTRODUCTION

Venous thromboembolism (VTE)-which encompasses both deep vein thrombosis (DVT) and pulmonary embolism (PE)-poses a significant worldwide health overload, with frequency estimates around 1.7 cases per 1000 individuals per year[1]. Some main contributors to VTE development are hospitalization or surgical operation, malignancy, prolonged immobility, and certain inherited thrombophilia disorders[2]. Incidence rates rise notably with advancing age, likely due to the increased prevalence of comorbid conditions and other associated risk factors in older populations[1]. Consequently, as the global population continues to age, VTE has become an increasingly prominent public health issue[2]. In terms of mortality, VTE is the most common cause of death among hospitalized patients and ranks third after myocardial infarction and stroke among cardiovascular-related fatalities[3].

This mini-review examines key challenges in assessing and treating patients with PE, highlighting the expanding role of catheter-directed therapies. It aims to synthesize current evidence and discuss future directions for more effective and individualized care.

DIAGNOSIS AND ASSESSMENT OF PE

Barco et al[4] reported that PE accounts for 86930 deaths-representing 0.46% of nearly 18.7 million total deaths-across a global dataset of 213 countries. The wide variability in PE-related mortality is likely influenced by differences in national healthcare systems, socioeconomic status, risk factor prevalence, and clinical management[4,5]. Effective management, thus, depends on precise risk stratification to identify those in need of rapid escalation in treatment[5,6].

High-risk (HR) PE is characterized by circulatory instability and carries a short-term (30-day) mortality rate of approximately 30%[5]. This subgroup represents about 5% of hospitalized PE patients. According to the most recent guidelines from the European Society of Cardiology (ESC), immediate systemic thrombolysis is the recommended treatment approach for these cases[6]. Intermediate–HR (IHR) PE, by contrast, is defined by imaging evidence of right ventricular dysfunction (RVD) [via echocardiography or computed tomography (CT)] and elevated cardiac biomarkers, but without signs of shock[6]. Anticoagulation is the cornerstone of treatment, and the associated 30-day mortality rate ranges from 6.6% to 12.6%[7]. However, around 5% of patients in this category may suffer sudden hemodynamic decline shortly after hospital presentation[8]. Although systemic thrombolysis may be beneficial in such situations, it carries a considerable risk of serious bleeding events, including intracranial hemorrhage[8,9]. As a result, many unstable patients-potentially over half-may not receive thrombolytic therapy due to concerns about bleeding complications[10].

Over the past several years, catheter-directed therapy (CDT)-which includes techniques like localized thrombolysis and mechanical thrombectomy-has emerged as a promising treatment modality for PE. It has attracted increasing attention as both an alternative and adjunctive approach. Current ESC guidelines from 2019 recommend CDT for patients with HR PE who either cannot undergo systemic thrombolysis or who do not respond to it. Additionally, in IHR PE cases showing signs of clinical deterioration, CDT, along with rescue thrombolysis or surgical embolectomy, may be warranted[6]. A recent ESC position paper emphasized a preventative approach to managing IHR PE, arguing that intervention should occur before hemodynamic collapse, not after[10]. Relying solely on anticoagulants may be inadequate in patients showing early signs of decompensation[8]. CDT presents a potentially safer option, capable of decreasing thrombus load while minimizing the risk of major bleeding events[3].

Beyond the immediate threat, PE has long-term consequences, including a sustained increase in mortality compared to the general population and the risk of chronic conditions[6,7,11]. Whether early use of reperfusion strategies-including thrombolysis and catheter-based interventions-can reduce long-term complications such as persistent pulmonary hypertension, functional decline, or symptom burden remains uncertain[5,6,12,13].

Risk stratification

The classification system most commonly used to assess the severity of acute PE is outlined in the 2019 guidelines from the ESC (Table 1). This system introduces a three-tiered risk model-high, intermediate, and low-based on clinical status, hemodynamic findings, RVD, and cardiac biomarker levels such as troponin. Each category corresponds with a distinct short-term mortality risk, typically measured during hospitalization or within 30 days[6]. This approach differs slightly from the earlier American Heart Association (AHA) classification, which organized PE into massive, submassive, and low-risk types[14]. A later AHA statement examined these differences more closely[5]. For practical purposes, it has been suggested that the ESC’s HR and low-risk groups align with the AHA’s massive and low-risk classifications, respectively, while the ESC’s intermediate-risk (IR) group broadly matches the AHA’s former submassive category[5].

Table 1 Simplified risk stratification for acute pulmonary embolism adapted from the 2019 European Society of Cardiology guidelines.

Risk level	Key features	Prevalence in pulmonary embolism cases	Estimated 30-day mortality
HR	Indicators of severe circulatory compromise: Cardiac arrest; obstructive shock (systolic BP < 90 mmHg with organ damage); sustained low BP (< 90 mmHg or drop ≥ 40 mmHg for > 15 minutes) not due to arrhythmia/sepsis; high lactate levels (≥ 2 mmol/L)	5%–10%	30%–55%
Intermediate-high	Signs of RV strain and cardiac injury: RV/LV diameter ratio ≥ 1; TAPSE ≤ 16 mm; PESI class III–V or sPESI ≥ 1; elevated troponin or BNP	15%–20%	10%–15%
Intermediate-low	Presence of either: RV dysfunction (RV/LV ratio ≥ 1, TAPSE ≤ 16 mm, PESI III–V or sPESI ≥ 1); elevated cardiac biomarkers (troponin, BNP)	30%–40%	5%–15%
Low risk	Does not meet any of the above intermediate or HR criteria	30%–40%	< 3%

BNP: B-type Natriuretic Peptide; BP: Blood pressure; HR: High-risk; PESI: Pulmonary Embolism Severity Index; RV: Right ventricular; RV/LV: Right ventricular-to-left ventricle; TAPSE: Tricuspid Annular Plane Systolic Excursion; SPESI: Simplified Pulmonary Embolism Severity Index.

HR PE is identified by hemodynamic compromise, typically indicated by a systolic blood pressure below 90 mmHg[6]. Because of the urgency, waiting for laboratory results or CT pulmonary angiography (CTPA) is not necessary if these are not immediately accessible[6]. In contrast, bedside transthoracic echocardiography plays a crucial role in ruling out other causes of shock. A lack of right ventricular (RV) overload or dysfunction on echocardiography virtually excludes PE as the underlying cause of the patient’s unstable condition[6]. Conversely, if RV strain is evident and PE is clinically suspected, this alone may justify immediate fibrinolytic therapy when imaging cannot be promptly obtained[6]. Once hemodynamic instability has been ruled out, further assessment should include clinical scoring systems, laboratory tests, imaging, and a review of the patient's medical history and comorbidities. Patients who are hemodynamically stable but exhibit signs of RV dysfunction and/or elevated troponin, along with a Pulmonary Embolism Severity Index (PESI) score of class III–V or a simplified PESI (sPESI) score of 1 or higher, fall into the IR category. This group can be further subdivided: Those with both RVD and positive troponin levels are classified as IHR, while those with only one-or neither-are categorized as intermediate–low risk[6]. Importantly, the presence of RVD or raised troponin levels qualifies a patient as IR, even if their PESI score is class I–II or their sPESI is zero[6].

Risk assessment and therapeutic considerations in IHR PE

Patients in the IHR category represent the most critical subset among those who are hemodynamically stable but still face significant clinical danger. This group carries a notable short-term mortality risk-ranging from 6.6% to 12.6%-and remains particularly vulnerable to sudden hemodynamic decline[7,8]. A subsequent non-randomized study, PEITHO-2, reported a lower incidence of such outcomes (1%)[15].

Given these concerns, the ESC recommends continuous observation of IHR patients for at least the first 48–72 hours post-diagnosis[6]. During this critical window, clinicians should reassess the patient’s risk profile frequently and look for warning signs indicative of potential decompensation.

Clinical indicators of severity

The PESI is the most thoroughly validated tool for assessing mortality and morbidity risk in patients with acute PE[16,17]. This scoring system integrates 11 clinical variables-including demographics, comorbidities, and vital signs-without requiring blood tests or imaging. It classifies patients into five risk groups, ranging from less than 1% mortality in class I to up to 24.5% in class V. A streamlined alternative, the sPESI, includes six variables and was validated in 2010. It has shown comparable accuracy in predicting clinical outcomes[16,17].

While PESI and sPESI offer strong sensitivity, their specificity is limited, with a predictive accuracy of 0.78. Consequently, roughly one in five patients may be misclassified using these tools[16,17]. These scoring systems are particularly effective in identifying low-risk patients who might be considered for early discharge or outpatient treatment, as supported by later research[18,19]. In contrast, the risk stratification frameworks used by the AHA and ESC focus more directly on identifying patients at higher risk of death specifically from PE. These guidelines emphasize early mortality and are aimed at guiding decisions around intensive therapy and monitoring[5]. Importantly, PESI does not account for biomarkers such as elevated troponin or signs of RVD-both of which are independently linked to early mortality[20].

Beyond PESI-based assessments, other clinical markers can help identify at-risk patients who remain hemodynamically stable[10]. Factors such as a heart rate above 100 beats per minute, systolic blood pressure between 90 mmHg and 100 mmHg, a respiratory rate exceeding 20 breaths per minute, oxygen saturation below 90%, chronic heart failure, and active malignancy have all been associated with an increased likelihood of early deterioration and PE-related death[8]. Evaluating these variables in the initial assessment can assist clinicians in tailoring the management strategy for IHR patients. However, it is worth noting that no clinical trials to date have demonstrated a clear survival or clinical benefit from administering reperfusion therapy preemptively based on any specific combination of these risk factors[10].

RVD in PE

In severe PE, the primary mechanism leading to death is acute RV failure caused by sudden pressure overload[6]. Consequently, detecting RV dysfunction through imaging-either echocardiography or CTPA-is essential for both confirming a PE diagnosis and guiding risk assessment. Due to the RV’s complex and non-uniform shape, echocardiographic definitions of dysfunction differ across studies, and no single measurement can reliably capture its function[21]. Commonly evaluated indicators include reduced RV contractility (hypokinesis), McConnell’s sign, RV end-diastolic diameter, tricuspid annular plane systolic excursion (TAPSE), pulmonary artery pressure (PAP), and the RV-to-left ventricle (RV/LV) diameter ratio[21-24]. However, published data often show varying conclusions.

In a trial involving 1416 patients, an RV/LV diameter ratio ≥ 0.9 measured via echocardiography was found to independently predict in-hospital mortality[22]. Another prospective study assessing 411 patients with intermediate-risk or low-risk PE revealed that TAPSE was a strong predictor of 30-day mortality or the need for rescue thrombolysis following hemodynamic worsening[24]. Another article further demonstrated that in hemodynamically stable patients, each unit increase in the RV/LV ratio more than doubled the risk of death from all causes[23]. Current data reinforced these findings, showing a significant correlation between increased RV/LV ratios and abnormal TAPSE with short-term mortality in PE patients[21]. However, sensitivity analyses involving only stable patients did not confirm a consistent link between these parameters and death. In the same study, RV hypokinesis was significantly associated with a higher risk of short-term complications[21].

In cases where PE is suspected, it is also crucial to investigate for a thrombus in transit and the presence of a patent foramen ovale, as both conditions are linked to increased mortality[6]. No dedicated guideline recommendations currently exist for its management, though improved survival has been observed in patients treated with thrombolytics or surgical removal of the clot[25]. CTPA is widely available and often serves as the initial imaging test in patients with suspected PE, particularly when they are hemodynamically stable[6].

In a multicenter prospective study with 457 participants, an RV/LV diameter ratio ≥ 0.9 on axial (non-ECG-gated) CT images emerged as an independent predictor of in-hospital complications. This was true both for the overall PE cohort and for normotensive patients[26,27].

Reflecting these data, contemporary instructions recommend using an RV/LV diameter ratio of ≥ 1.0 as the threshold most strongly associated with worse prognosis[6]. A newer study analyzing 609 consecutive PE patients proposed that an axial RV/LV ratio ≥ 1.5 combined with inferior vena cava contrast reflux may serve as an optimal indicator of RV dysfunction. This combination showed superior prognostic performance for identifying complications in both the general PE population and among stable patients[28].

In summary, assessing RV function-whether through echocardiography or CT-is critical for effective risk stratification in PE. Nonetheless, the most reliable evaluation relies on a comprehensive, multiparametric approach that includes imaging, lab tests, clinical findings, and patient history.

Serum biomarkers in the risk stratification of PE

Cardiac troponins (cTns) T and I, commonly used to detect myocardial damage and diagnose myocardial infarction, are also frequently elevated in patients with acute PE. These markers are rapidly accessible in emergency settings[6]. In the context of PE, increased levels of troponin-whether type I or T-is associated with increased immediate mortality and a greater likelihood of PE-related complications. This prognostic relationship is consistent even in patients who are hemodynamically stable and applies to both standard cTn and high-sensitivity troponin assays (hsTn)[29-31]. One investigation demonstrated that using a hsTn assay with a threshold of 14 pg/mL provided better sensitivity and negative predictive value than conventional assays, and was the only method associated with long-term survival prediction[31]. However, another study involving 834 stable PE patients reported that hsTn detected more cases of elevated troponin but did not outperform cTn in predicting 30-day adverse outcomes, suggesting that hsTn may overstate risk in otherwise stable patients[32].

ESC guidelines define elevated cTn levels as those exceeding the assay-specific reference range[6,33]. In hemodynamically stable PE, troponin testing is valuable for its high negative predictive value. When combined with clinical severity scores and imaging-based evidence of RV dysfunction, it helps to identify patients at low risk for early complications[34,35].

Natriuretic peptides (B-type natriuretic peptide and N-terminal fragmen-pro B-type natriuretic peptide)

B-type natriuretic peptide (BNP) originates as an inactive precursor, pro-BNP, which is cleaved into biologically active BNP and the inactive N-terminal fragment (NT-proBNP). These peptides are released in response to myocardial stretch, making them indirect indicators of RV pressure overload[36,37].

Several meta-analyses have confirmed that elevated BNP or NT-proBNP levels are associated with increased early mortality and higher rates of PE-related complications[36,37]. Although these biomarkers lack strong specificity and have limited positive predictive value in predicting death among normotensive PE patients, their low values are clinically useful. When BNP or NT-proBNP levels are low, the probability of an adverse early event is significantly reduced, indicating a strong negative predictive capacity[6]. Another investigation proposed that interpreting BNP levels as a multiple of the upper normal limit (UNL)-specifically, 3.5 times the UNL-may be more effective in identifying patients at higher risk of death, accounting for variations between laboratory assays[38].

Although BNP is not part of the primary stratification criteria in current PE guidelines, it plays a pivotal role in certain treatment decisions, especially in IHR patients. For instance, BNP is incorporated into the Composite Pulmonary Embolism Shock (CPES) score, which helps detect occult shock in normotensive patients-an important predictor of early mortality[39,40].

Lactate as a prognostic marker

Lactate levels in the bloodstream serve as a marker of inadequate oxygen delivery to tissues. An arterial lactate concentration of ≥ 2 mmol/L has been shown to predict prognosis in both unselected and hemodynamically stable PE patients[41-44]. Elevated lactate correlates independently with increased risks of in-hospital death, PE-specific mortality, and combined endpoints such as death and clinical deterioration-regardless of blood pressure status or presence of RV dysfunction at the time of diagnosis[43-45]. In normotensive individuals specifically, data from a large, multicenter, prospective study revealed that elevated lactate levels alone were predictive of PE-related death or clinical deterioration[41].

Normotensive shock in IHR PE

The current ESC risk classification does not fully capture the likelihood of deterioration in patients with IHR PE, many of whom may progress to hemodynamic instability and cardiogenic shock due to worsening RV failure[46,47]. The FLASH registry, an observational study focusing on catheter-based mechanical thrombectomy using the FlowTriever system (Inari), offers insight into this issue[48]. Normotensive shock is characterized by a cardiac index ≤ 2.2 L/minute/m² despite a systolic blood pressure ≥ 90 mmHg. Interestingly, in this group, 17.4% of individuals had a sPESI score of zero, indicating the limitations of conventional risk scoring in detecting underlying instability[48].

To better identify patients at risk, the authors of the FLASH study developed the CPES Score, a six-point tool incorporating elevated troponin, raised natriuretic peptides, RV dysfunction, saddle PE, concomitant DVT, and tachycardia. A perfect score of 6 significantly increased the odds of normotensive shock, with a clear trend showing that higher CPES scores correlated with increased prevalence of normotensive shock-from 0% at a score of 0 to 58.3% at a score of 6[48]. Further retrospective analysis confirmed the CPES score’s utility in predicting clinical outcomes[49].

Alternative study supported refining CPES score’s positive threshold from ≥ 3 points to ≥ 4 points. Although this stricter threshold flagged fewer patients, it provided stronger predictive accuracy for identifying a severe course, including death, circulatory collapse, or recurrent PE. Similar results were found within the subgroup of IHR patients[50]. These findings are particularly relevant for IHR PE, as individuals in a state of normotensive shock may stand to benefit most from advanced interventions like thrombolytic therapy or catheter-directed reperfusion. However, no large randomized controlled trials to date have demonstrated definitive clinical outcome benefits of CDT over anticoagulation alone in this population. The CPES score, while promising, still requires validation in larger cohorts.

To address limitations in existing models, the RISA-PE classification was developed, adapting the Society for Cardiovascular Angiography and Interventions (SCAI) five-stage shock framework to specifically reflect RV failure due to PE: (1) Stage A: RV dysfunction plus elevated troponin; (2) Stage B: Criteria from stage A plus serum lactate > 2 mmol/L or shock index ≥ 1; (3) Stage C: Persistent hypotension; (4) Stage D: Obstructive shock; and (5) Stage E: Cardiac arrest.

This system was applied to a group of 334 IHR and HR PE individuals. It demonstrated a clear association between advancing stages and rising in-hospital mortality: (1) 1.2%; (2) 6.4%; (3) 19.0%; (4) 25.6%; and (5) 57.7% for stages A through stages E, respectively (P < 0.001). This trend held independently of other known mortality risk factors such as bilateral central emboli and respiratory failure[51]. Compared to the existing ESC classification, the RISA-PE model showed superior predictive accuracy for in-hospital death. Despite these encouraging results, broader validation across diverse clinical settings is needed before the model can be widely implemented in practice.

CATHETER-DIRECTED THERAPIES IN PE

When to consider catheter-directed therapies in PE

Currently, CDT is not regarded as a first-line intervention for patients with HR or IR PE. According to the 2019 ESC guidelines, CDT is advised for select scenarios: Specifically, for HR patients who cannot undergo or have not responded to systemic thrombolysis, and for IHR individuals who show clinical signs of hemodynamic decline despite being on therapeutic anticoagulation[6]. In a subsequent position paper, the ESC further clarified what constitutes a failure of both anticoagulation and thrombolytic therapy, and presented an algorithm to assist with clinical decision-making[10].

At the heart of this treatment framework is the Pulmonary Embolism Response Team (PERT)-a multidisciplinary team typically comprising specialists in cardiology, pulmonology, hematology, vascular medicine, intensive care, radiology, and cardiothoracic surgery. This collaborative model ensures timely, individualized management decisions and allows for more nuanced assessment of clinical severity and treatment options. Given the complexity of PE management, the ESC supports widespread adoption of PERT structures to promote consistent care and improve clinical outcomes[6,45,48,52]. Such reports stress the value of a team-based strategy for evaluating patients for advanced reperfusion strategies-particularly in cases where conventional therapy is contraindicated or ineffective. They advocate for the development of regional PERT networks and coordinated hospital protocols to ensure equitable access to cutting-edge interventions and standardized patient care. Furthermore, the authors call for large-scale randomized trials to compare CDT with traditional treatment approaches, emphasizing the need for data-driven guidelines, ongoing clinical education, and enhanced research in this evolving field[45,49]. CDT is increasingly recognized as a vital tool in bridging the gap between evolving best practices and the realities of current clinical workflows.

As per ESC recommendations, any initially stable patient who subsequently experiences clear signs of cardiorespiratory compromise while on anticoagulants should be considered to have experienced treatment failure-prompting an urgent escalation of care, including systemic thrombolysis if not contraindicated[10]. However, deterioration isn’t always dramatic. In such scenarios, PERT consultation is crucial to evaluate the potential need for rescue reperfusion strategies[6,10]. Moreover, treatment failure may also be defined by a lack of any significant clinical, imaging, or laboratory improvement after 24-48 hours of anticoagulation. If the patient continues to meet IHR criteria-such as a TAPSE < 16 mm and an RV/LV ratio ≥ 1-despite initial therapy, escalation to reperfusion treatment ought to be taken into account, even without overt cardiovascular compromise[10].

Furthermore, a collaborative, multidisciplinary evaluation is essential, and PERT involvement is recommended for all patients being considered for advanced intervention[10]. An additional factor in selecting appropriate candidates for CDT is understanding the nature of the thrombus. Determining whether a clot is fresh and fibrin-rich or more chronic and fibrotic can help in choosing both the appropriate therapeutic approach and the specific device to maximize procedural success. Recognizing complex cases-such as acute PE superimposed on chronic thromboembolic disease or pulmonary hypertension-is also vital for selecting the most effective and safe management strategy.

Technologies in CDT for PE

CDT approaches are generally divided into three main categories based on their method of thrombus removal (Table 2): (1) Catheter-directed thrombolysis; (2) Mechanical thrombectomy; and (3) Pharmaco-mechanical thrombectomy. These interventions aim to restore perfusion by reducing the clot burden in the pulmonary arteries, easing RV strain, and ultimately improving RV function. The effectiveness of CDT is judged not by complete thrombus clearance, but by measurable clinical improvements-such as stabilization of blood pressure, improved oxygenation, normalization of heart and respiratory rates-as well as reductions in PAPs and RV dysfunction[10].

Table 2 Catheter-based interventions for pulmonary embolism.

Therapy type	Key devices	Mechanism of action	Evidence and trials	Benefits	Complications/risks
CDT	Standard/perforated infusion catheters (Uni-Fuse, Cragg-McNamara)	Local thrombolytic drug infusion into thrombus	Supported by ULTIMA, SEATTLE II, OPTALYSE PE	Lower bleeding risk than systemic thrombolysis	Requires prolonged infusion, potential bleeding
Ultrasound-assisted thrombolysis	EKOS (EkoSonic)	Ultrasound energy enhances thrombolytic penetration	Same trials as CDT, plus KNOCOUT PE, SUNSET sPE	Effective RV-to-left ventricle ratio reduction, low bleeding	Variable efficacy vs standard catheter-directed thrombolysis, longer duration
Mechanical thrombectomy-FlowTriever	FlowTriever (Inari)	Aspiration with large-bore catheters and clot disruption tip	FLARE, FLASH registry	Immediate hemodynamic improvement, low mortality	Blood loss, procedural complexity
Mechanical thrombectomy-Indigo	Indigo system (Penumbra)	Automated aspiration using suction pump and separator wire	EXTRACT-PE, STRIKE-PE	Rapid improvement in RV strain, symptom relief	Device-related events (rare), training required
Pharmaco-mechanical thrombectomy	Combined use of thrombolytics and mechanical devices	Dual action: Clot lysis and mechanical removal	PEERLESS Trial	Improved outcomes over thrombolysis in some studies	Need for precise patient selection, limited long-term data

CDT: Catheter-directed therapy; RV: Right ventricular.

Catheter-directed thrombolysis (CDT and ultrasound-assisted thrombolysis)

Local thrombolytic delivery is achieved via multi-perforated standard catheters (e.g., pigtail), dedicated infusion catheters (e.g., Uni-Fuse by AngioDynamics or Cragg-McNamara by Medtronic), or ultrasound-assisted devices like the EKOS system (EkoSonic, Boston Scientific).

Ultrasound-assisted thrombolysis (USAT) enhances the penetration of thrombolytic agents into the clot by disrupting fibrin strands with ultrasonic energy, making the thrombus more susceptible to drug action. Among CDT techniques, USAT using the EKOS system has the most robust body of supporting clinical data. Trials such as ULTIMA, SEATTLE II, and OPTALYSE PE, along with the KNOCOUT PE registry, have all shown its effectiveness in lowering RV/LV ratios with a low rate of major bleeding events (approximately 1.6%)[48,52-54]. The SUNSET sPE trial compared standard catheter-directed thrombolysis (SCDT) with USAT in IR individuals, showing similar efficacy in clot reduction[55]. By comparison, the PEITHO trial reported an 11.5% major bleeding rate with systemic thrombolysis[8,56,57].

One key advantage of USAT and SCDT over systemic thrombolysis is the use of significantly lower thrombolytic doses, thereby potentially reducing bleeding complications. Treatment protocols vary by center, but infusion durations can extend up to 24 hours. These therapies are most appropriate for hemodynamically stable patients without contraindications to thrombolytics or anticoagulation[10].

Mechanical thrombectomy

Mechanical approaches rely on aspiration to extract thrombi. This is achieved manually or via suction catheters[10].

The FlowTriever system features three nested aspiration catheters [16 French (Fr), 20 Fr, and 24 Fr], a large-volume aspiration syringe (60 mL), and a catheter with a mechanical clot-disruption tip. The new FlowSaver accessory allows aspirated blood to be returned to the patient, reducing blood loss. In the FLARE trial, a prospective multicenter study of 104 IHR PE patients, FlowTriever use led to a mean RV/LV ratio drop of 0.38 and a 2.0 mmHg reduction in PAP within 48 hours. Major bleeding occurred in 0.9% of patients, with no device-related deaths[58]. FLASH, a registry evaluating second-generation FlowTriever devices, showed similar positive results in over 800 patients (mostly IHR PE). Improvements included significant reductions in RV/LV ratio and pulmonary pressures, along with a 0.3 L/minute/m² average increase in cardiac index among those with baseline impairment. Major adverse events occurred in 1.8% of patients, again with no device-related deaths[59].

The Indigo system (Penumbra) offers aspiration catheters in 7 Fr, 12 Fr, and 16 Fr sizes. These are powered by a suction pump and feature a separator wire (in 7 Fr and 12 Fr models) to assist in clot extraction. Newer Indigo systems are equipped with automated, blood-sparing features. The earlier EXTRACT-PE trial used the 8 Fr Indigo system in 119 IR patients, achieving a mean RV/LV ratio reduction of 0.43 and a major adverse event percentage of 1.7%[60].

Next-generation Indigo systems are currently assessed in the STRIKE-PE trial. Early outcomes from 150 individuals showed a 25.7% decrease in RV/LV ratio and significant reductions in both systolic and median PAPs. Four patients (2.7%) experienced major adverse events (e.g., bleeding, vascular or cardiac injury), but none of these were fatal or device-related[61]. By 90 days, patients reported improved symptoms (Borg scores), better quality of life, and functional status returning to pre-PE levels.

Furthermore, recently one study from our center was published regarding our experience. This prospective single-center study evaluated the effectiveness and safety of percutaneous mechanical thrombectomy (PMT) using the FlowTriever system in 25 patients with IHR acute PE over an 18-month period in a Greek tertiary cardiology center. Patients, with a mean age of 62 years, were selected by a PERT and underwent large-bore catheter thrombectomy based on evidence of significant RV dysfunction and thrombotic burden. The study demonstrated a rapid and statistically significant improvement in key hemodynamic parameters: (1) Systolic PAP dropped from 64 ± 10 mmHg to 38 ± 9 mmHg (P = 0.006); (2) Cardiac index rose from 2.1 L/minute/m² to 3.1 L/minute/m² at 48 hours (P = 0.007); and (3) RV/LV ratio decreased by 17.5% (P < 0.001). Clinically, most patients showed marked dyspnea relief immediately after aspiration, and respiratory indices such as the arterial oxygen tension/inspiratory oxygen fraction ratio improved significantly from 268 ± 64 to 397 ± 95 within 48 hours. Importantly, there were no in-hospital deaths or major adverse events, and only one minor access site complication was reported.

At six-month follow-up, all patients were alive, with 92% reporting New York Heart Association class I functional status and no recurrent PE or DVT. The majority remained on anticoagulation therapy, and no cases of chronic thromboembolic pulmonary hypertension (CTEPH) were observed. The study aligns with findings from larger registries and prior trials like FLARE and FLASH, supporting the utility of PMT in IHR PE. A key takeaway was the importance of recognizing "normotensive shock", characterized by normal blood pressure but reduced cardiac output and tissue perfusion-present in nearly half the cohort. The authors underscored that a hemodynamically informed selection protocol involving cardiac index and lactate levels may help identify ideal candidates for early intervention. While limited by its small sample size and lack of a control group, this study added real-world evidence suggesting that timely PMT guided by PERT protocols can yield significant clinical benefit with a favorable safety profile[62].

Device comparisons and recent evidence

A recent meta-analysis compared FlowTriever and Indigo thrombectomy devices with EKOS thrombolysis. Technical success was nearly identical (99.6% vs 99.4%), but thrombectomy offered shorter intensive care unit (ICU) and hospital stays, lower blood loss, and longer procedure times. EKOS achieved greater clot burden reduction (Miller Index) and pulmonary pressure drop[63]. In contrast, the REAL-PE observational study found higher bleeding risk with FlowTriever compared to EKOS, although mortality, readmission, and length of stay were similar. This analysis did not incorporate ESC-based risk stratification or account for concurrent thrombolytic therapy[64]. The PEERLESS trial, a multicenter randomized controlled trial, compared large-bore mechanical thrombectomy (LBMT) with catheter-directed thrombolysis in 550 IR PE patients. Conducted across 57 centers in the United States and Europe, it evaluated a composite endpoint including mortality, bleeding, clinical deterioration, need for ICU care, and more. LBMT significantly outperformed thrombolysis, mainly due to fewer bailout therapies and reduced ICU admissions and prolonged stays. Mortality and major bleeding rates were similar between groups[65]. Additional benefits of LBMT included lower respiratory rates at 24 hours, fewer severe dyspnea cases, shorter hospital stays (4.5 nights vs 5.3 nights), and fewer 30-day readmissions (3.2% vs 7.9%). No significant difference in 30-day mortality was observed (0.4% vs 0.8%).

Clinical implications

Although both CDT techniques show promise, further randomized trials are necessary to identify the optimal technology for specific patient profiles. Currently, device selection should be tailored to individual clinical status, underlying comorbidities, and institutional capabilities. Mechanical thrombectomy is often preferred when thrombolysis is contraindicated, systemic lysis has failed, or rapid hemodynamic decline is anticipated, due to its capacity for immediate clot removal without using thrombolytics. In contrast, USAT remains a safe and relatively straightforward procedure with proven efficacy, although it typically requires longer infusion durations (Figure 1).

Figure 1  Comparison of thrombus aspiration systems and catheter-directed thrombolysis for interventional decision-making.

Anticipated advantages of catheter-directed therapies

CDTs offer the unique advantage of delivering treatment directly at the site of thrombus formation. This facilitates mechanical clot removal, localized thrombolytic administration, or a combination of both (pharmaco-mechanical intervention), depending on the selected technique. From a technical standpoint, effective local thrombolysis requires precise catheter positioning-ideally as distally as possible within the pulmonary artery-to ensure optimal dispersion of the thrombolytic agent throughout the thrombus. In contrast, aspiration-based techniques tend to be more technically demanding but offer distinct benefits.

One major benefit of aspiration thrombectomy is the immediate restoration of pulmonary blood flow, which results in rapid hemodynamic stabilization. While there is no universally accepted definition of procedural success, previous studies suggest that a reduction of more than 7 mmHg in mean PAP, along with improvements in blood pressure, oxygen saturation, and heart rate, may be indicative of a favorable response. These physiological changes are generally associated with reduced RV strain and significantly lower short-term mortality-reported at under 1% in observational studies[60]. Many patients also experience quick relief from symptoms, including dyspnea and chest discomfort.

Evidence is also emerging to support the longer-term benefits of CDT. Observational data indicate improved long-term survival, better exercise tolerance, and enhanced quality of life following treatment. Because CDT aims to reduce thrombus burden effectively, it may help prevent post-PE syndrome, a condition marked by persistent breathlessness, decreased physical performance, and chronic functional impairment[66]. Furthermore, timely and targeted removal of the embolus may lower the risk of CTEPH and reduce the clinical burden of recurrent PE-the leading cause of mortality within the first month after an acute episode[11]. That said, despite these promising findings, further well-designed studies are essential to validate CDT’s clinical benefits in routine practice.

LIMITATIONS

This article is a narrative review and is therefore subject to several inherent limitations. Unlike systematic reviews or meta-analyses, it does not employ a formal methodology for literature selection or data synthesis, which may introduce selection bias. The studies discussed vary widely in design, population characteristics, inclusion criteria, outcome definitions, and procedural protocols, limiting direct comparability. Additionally, many of the available data come from observational studies or single-arm trials, with a relative paucity of large, randomized controlled trials comparing catheter-directed therapies head-to-head. As such, while this review summarizes current knowledge and highlights evolving clinical trends, definitive conclusions about device superiority, long-term outcomes, and optimal patient selection remain premature. Future high-quality randomized studies are necessary to establish the most effective and safest interventional strategies for managing IHR PE.

CONCLUSION

Acute PE presents considerable clinical challenges, particularly in patients at IHR, who face a substantial chance of hemodynamic decline. These cases demand early and accurate risk assessment, followed by timely therapeutic decisions. The ESC recommends a stratified risk approach-categorizing patients into high, intermediate, and low-risk groups-each associated with differing prognoses and management protocols. Prompt identification of IHR patients is essential to initiate the most appropriate treatment, potentially preventing progression to cardiovascular collapse. Risk prediction tools like the PESI and sPESI provide initial guidance, while additional markers such as cTns and RVD refine stratification further. Innovative therapies, including USAT and mechanical thrombectomy, are increasingly recognized as valuable options for patients who are either unsuitable for anticoagulation or unresponsive to it. However, broader adoption of these therapies depends on further validation through large-scale randomized studies. Multidisciplinary coordination through PERTs is crucial. These teams facilitate integrated care by combining diagnostic expertise and therapeutic planning-ensuring that complex PE cases are managed with tailored, evidence-based strategies. As a result, PERTs are playing an ever more central role in optimizing outcomes for patients with life-threatening PE.