Research progress in interventional therapy for acute intermediate-high-risk and high-risk pulmonary embolism

Introduction

Background

Pulmonary embolism (PE) is frequently caused by lower extremity deep vein thrombosis (1) and is established as the third most prevalent cause of cardiovascular mortality (2,3). As the population ages, the incidence of PE continues to increase. The annual incidence rate of PE is approximately 60–120 per 100,000 people, although the incidence may have increased as a result of diagnostic model development, which has facilitated the identification of low- and intermediate-risk PE cases (4).

Currently, PE is associated with high mortality rates. In the United States, approximately 60,000–100,000 patients die of PE annually. Persistent hypotension and right heart overload often lead to PE mortality (5). Thus, diagnosing patients with PE as soon as possible and assessing their risk are essential to choose the best treatment and minimize complications (6). The severity of acute PE (APE) is evaluated according to the patient’s clinical symptoms, comorbidities, biological indicators, right ventricular dysfunction (RVD) imaging, and other comprehensive factors. Moreover, several risk scores can identify patients at higher risk and estimate the 30-day mortality of APE (7).

Rationale and knowledge gap

The 2019 European Society of Cardiology (ESC) guidelines for PE are most widely used in clinical practice (8,9). Parenteral or oral anticoagulants are commonly administered for low- and intermediate-low-risk PE because of its fatality rate of <0.6%. In contrast, systemic thrombolysis (ST) is advised as the initial course of treatment for high-risk PE because of its fatality fate of approximately 19% (10). However, owing to increased bleeding risks, interventional therapy is considered an alternative reperfusion therapy for intermediate-high- and high-risk APE; this treatment can rapidly reduce thrombus burden, improve right heart function, and reduce bleeding risk. As new devices are being created and existing technologies are more frequently employed in clinics, large-scale randomized trials are being conducted to analyze the effectiveness and safety of interventional therapies. Consequently, interventional therapy is in an era of accelerated innovation and evidence production (11).

Objective

In this review, we first summarize different interventional catheter treatment methods, compare their advantages and disadvantages, and introduce their clinical applications and related clinical studies and trial results. We hope that these findings will provide clinical evidence of catheter-directed therapy for APE and ideas for the selection of interventional treatment for intermediate- and high-risk patients with APE (Figure 1).

Figure 1 Trials related to interventional therapy for pulmonary embolism. CDT, catheter-directed thrombolysis; USAT, ultrasound-assisted thrombolysis; PM-CDT, pharmacomechanical catheter-directed thrombolysis; PE, pulmonary embolism; sPE, submassive pulmonary embolism; MT, mechanical thrombectomy; FIH, first-in-human; RCT, randomized controlled trial.

Risk stratification

APE can cause a range of clinical symptoms, including dyspnea, chest pain, and chest tightness. More severe conditions can result in obstructive shock. Accurate risk assessment of right heart function and hemodynamic damage is essential to guide patient management (12).

Definition of risk stratification of PE

American Heart Association (AHA) and ESC guidelines define the risk stratification for PE quite differently (Table 1).

High-risk

The 2019 ESC guidelines for PE define patients with hemodynamic instability as high-risk, which can be characterized by persistent hypotension, obstructive shock, and cardiac arrest (13). For high-risk PE, consensus recommendations include ST. However, a study conducted in the United States found that owing to contraindications and the possibility of cerebral hemorrhage, 60.3% of high-risk patients at the hospital were not treated with systemic thrombolytic therapy. Therefore, percutaneous interventional therapy should be studied for high-risk patients with PE who do not respond to or have contraindications for thrombolysis (14).

Intermediate-risk

Intermediate-risk PE refers to hemodynamic stability and RVD, which can be diagnosed using imaging or cardiac biomarkers. Enlargement of the right heart on echocardiography or pulmonary angiography or a right ventricular/left ventricular (RV/LV) ratio of ≥0.9 was suggestive of RVD. Increased brain natriuretic peptide (BNP) and troponin levels suggest cardiac failure and/or volume overload. Intermediate-high-risk (double positive imaging and biological markers) and intermediate-low-risk (single positive imaging and biological markers) were the two segments of intermediate-risk PE that were further separated according to ESC guidelines. A total of 35–55% of hospitalized patients with PE belong to the intermediate-risk stratification of PE (15). Considering the high incidence of intracranial hemorrhage, the acceptance of ST in these patients is low. According to the clinical practice guidelines, individuals with intermediate-risk APE should not undergo full-dose systemic fibrinolysis unless they have the lowest risk of bleeding (16). Based on the safety of therapeutic strategies, catheter-directed interventional therapies have gradually attracted attention (17).

Low-risk

Patients who did not exhibit hemodynamic instability or RVD were classified as having low-risk PE. They account for 40–65% of all patients with PE, and their 30-day mortality rate is approximately 1%. When treating patients with low-risk PE, outpatient therapy with conventional anticoagulation (AC) is recommended (18).

Indicators of risk in PE

The risk of PE cannot be determined with high specificity by a single metric; instead, a combination of factors, including clinical history, comorbidities, physical examination, laboratory biomarkers, and imaging results must be considered (19). Shortness of breath, chest tightness, low arterial oxygen saturation (SaO₂), low systolic blood pressure (SBP), and other clinical signs and symptoms are common in certain patients with PE and indicate a poor prognosis. In a study of 436 patients with APE, tachycardia (49.8%) and tachypnea (45%) were often used to quickly identify patients at higher risk (20).

PE imaging primarily relies on computed tomography pulmonary angiography (CTPA) and echocardiography. McConnell’s sign, ventricular septal contradictory motion, RV diameter enlargement (21), RV/LV ratio of ≥0.9, and weakened RV free wall shown on echocardiographic imaging can indicate RVD and increase short-term mortality in patients (22). An elevated RV/LV diameter ratio on CTPA also suggests a high mortality rate for PE. Additional studies have reported that combining artificial intelligence algorithms with CTPA can improve the sensitivity and specificity of detecting PE (23-25) (Figure 2).

Figure 2 A man was admitted to the hospital with deep venous thrombosis in the lower limb as well as chest distress. Echocardiography and CTPA examination revealed straddle thrombosis in the pulmonary artery. CTPA, computed tomography pulmonary angiography.

According to the latest guidelines, PE risk stratification incorporates troponin and BNP biomarkers. A prospective cohort study showed that combined elevated plasma lactate levels and RVD imaging can predict poor PE prognosis (26). Sławek-Szmyt et al. recently reported a study about enrolled 110 PE patients. This study’s findings showed that 48 hours after catheter-directed mechanical aspiration thrombectomy (CDMT), there was a significant shift in surrogate indicators of RVD, including as tachycardia, troponin, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and lactate levels (27). There are not enough data available from randomized controlled trials on how interventional strategies affect biomarkers associated with APE. This will guide the course of future research.

Scores to identify patients with higher risk

Pulmonary Embolism Severity Index (PESI) and simplified PESI (sPESI) scores have a wide range of clinical applications worldwide. The ability of the PESI to predict 30-day mortality was almost identical in modeling, internal verification, and external verification groups, suggesting good evaluation accuracy. For computational simplicity, Jimenez et al. removed variables unrelated to death from the PESI to establish the sPESI (28). A meta-analysis of 50,021 patients showed that the sPESI was comparable to the PESI in predicting risk. The sPESI and Hestia rules are equally safe and effective in classifying patients with PE who have normal blood pressure for home treatment (29).

The Bova score, which was developed based on outpatient data, divides patients into three levels of increasing risk and is suitable for identifying patients with APE with stable hemodynamics and no comorbidities. A systematic review of 8,342 patients concluded that the Bova score effectively distinguished the short-term prognosis of stable PE (30). The Functional Assessment Staging Test (FAST) score is another predictive method for stratifying normotensive PE at varying risk levels and is composed of three variables: heart rate of ≥100 bpm, syncope, and increased cardiac troponin (31).

The Calgary Acute Pulmonary Embolism (CAPE) score was recently proposed to predict adverse hospitalization and secondary outcomes of 30-day all-cause mortality (32). The Pulmonary Embolism Mortality Score (PEMS) was also recently developed as a more sensitive predictor of 30-day mortality in PE (33). Current clinical risk scores are generally simple and linear. El-Bouri et al. developed a machine-learning-based score that analyzed a wide range of information from patient health records and nonlinear connections among patient variables to predict long-term mortality in patients with PE (34) (Table 2).

Interventional therapies

Catheter-directed thrombolysis (CDT) and mechanical thrombectomy (MT) are the two primary methods used in catheter-based therapy. When determining a suitable treatment for PE, various factors must be considered, such as the position and burden of the blood clot, patient risk stratification, experience of the medical team, and equipment availability at the medical center (Table 3).

CDT

CDT is a precise and local thrombolysis technique that delivers a thrombolytic agent through a catheter to the pulmonary artery thromboembolic site with the main purpose of reducing thrombolytic drugs and diminishing the bleeding rate (11). In addition, some studies have suggested that CDT may overcome the theoretical limitations of thrombolysis in the transperipheral venous system; thus, blood may flow to an open pulmonary artery segment rather than to a thrombotic pulmonary artery segment (9,35,36).

Standard CDT (SCDT)

Uni-fuse catheters (AngioDynamics Inc., Latham, NY, USA) and Craig-McNamara catheters (ev3 Inc., Plymouth, MN, USA) are two commonly used SCDT catheters with multiple side holes. In early clinical practice, surgeons typically used 4F–5F catheters for PE.

Although many clinical trials are linked to CDT, additional evidence is needed to determine whether patients at intermediate and high risk can benefit from CDT. Hennemeyer et al. retrospectively analyzed 105 cases of intermediate- to high-risk PE that occurred continuously over a 2-year period and showed that CDT therapy significantly improved the RV/LV ratio within 24–48 h after surgery and reduced the rate of rehospitalization, compared with AC alone, suggesting that CDT therapy may be more beneficial for patients with RV enlargement. The long-term mortality and bleeding risks were similar in both groups (37). The CANARY randomized trial compared the outcomes of AC therapy with those of SCDT therapy for intermediate-high-risk PE. A Cragg-McNamara infusion catheter served as the CDT device. The findings demonstrated that, compared with that of the AC alone group, the proportion of individuals with RV/LV ratios of >0.9 measured on CTPA at the 3-month follow-up was lower in the CDT group. Additionally, fewer incidents of major bleeding were associated with CDT. These findings are optimistic for research on PE interventional therapy (38). An ongoing randomized, controlled, multicenter PE-TRACT study (NCT05591118) will evaluate the long-term results of CDT combined with AC versus AC alone at the 1-year follow-up. Peak oxygen uptake at 3 months and New York Heart Association (NYHA) grade at twelve months were assessed. Regardless of the outcome, the PE-TRACT will create a Level 1 guideline recommendation for the interventional treatment of PE.

In a previous meta-analysis, CDT was found to be more beneficial than ST in reducing mortality and bleeding. However, compared with AC, CDT has a lower risk of death but a comparable risk of bleeding (39). The author believes that most research results are observational with an insufficient level of evidence. Zhang et al. assessed the outcomes of ST, CDT, and AC alone. Many crucial findings emerged from their meta-analysis. First, when the study was limited to intermediate-risk PE, CDT was observed to have a lower all-cause mortality than AC and ST alone. Second, compared with AC alone, CDT carried a slightly higher risk of major bleeding; nevertheless, the risk was not as high as that of ST. Finally, CDT was the most beneficial treatment in terms of efficacy, and AC is lacking in safety, compared with alternative options (40).

Ultrasound-assisted thrombolysis (USAT)

The theory behind the EKOS or EkoSonic endovascular system (EKOS; Boston Scientific Corp., Bothell, WA, USA) is that local thrombolytic drugs can more effectively penetrate blood clots and break down uncrosslinked fibrin fibers when they are exposed to high-frequency, low-energy ultrasound. The main clinical benefits of USAT include minimization of thrombolytic agents and treatment time. The EKOS system, which is commonly used in clinical practice, was formally approved by the United States Food and Drug Administration (FDA) for the treatment of PE.

The clinical outcomes of USAT using the EKOS endovascular system were assessed in the SEATTLE II trial. A total of 150 patients participated in the study. After 48 h following surgery, the average RV/LV ratio, mean pulmonary artery SBP, and modified Miller index scores declined significantly. No cases of intracranial hemorrhage were observed. Further research is required to determine whether USAT is superior to AC alone or full- or half-dose ST (16). A randomized, controlled ULTIMA study by Kucher et al. examined whether USAT was superior to AC therapy alone for treating intermediate-risk patients. According to data analysis, the RV/LV ratio in the USAT group decreased by an average of 0.30±0.20 from baseline to 24 h, whereas the heparin group experienced an average decline of 0.03±0.16 (P<0.001). No major bleeding occurred in either group after 90 days of treatment. This study demonstrated that a standardized USAT regimen was more beneficial than heparin AC alone in treating intermediate-risk patients with PE, improving RVD within 24 h without increasing bleeding risk (41). Another retrospective study on patients with acute submassive PE (sPE) was designed by Kline et al. to assess the safety of USAT, compared with that of AC alone. Research findings indicated that the rates of severe or potentially fatal GUSTO (Global Use of Streptokinase and t-PA for Occluded Coronary Arteries) bleeding were similar between the two groups (42).

The SUNSET sPE randomized trial compared the results of USAT with standard therapy in patients with sPE. The EKOS^® USAT group was administered the EKOS^® USAT catheter, whereas the control group was administered either the Uni-Fuse or Cragg-McNamara multilateral porous catheter. In this trial, both technical protocols significantly improved RV function with good safety. However, no improvement was observed in the reduction of the pulmonary thrombosis score in patients with sPE treated with USAT, compared with that in patients treated with standard multi-hole catheter thrombolysis. Available research has not yet shown that SCDT with traditional catheters and multiple lateral holes is inferior to USAT with EKOS catheters, and larger trials are needed in the future (43). The REAL-PE study was a retrospective trial of patients who underwent USAT or MT over a 14-year period. The safety and bleeding rates of the two treatments were evaluated using laboratory analyses and blood transfusion management. Multiple analyses showed that USAT resulted in a lower rate of intracranial hemorrhage than MT seven days after surgery. All other safety events observed in this study tended to favor EKOS for the treatment of higher-risk PE.

Few large-scale controlled trials have compared USAT with ST. Güner et al. claimed that because pulmonary vessels are the convergence center of venous reflux, the venous access site for tissue plasminogen activator (t-PA) injection was irrelevant. All t-PA molecules eventually enter pulmonary circulation. They did not deny the clinically beneficial results of USAT for PE but suggested that similar findings may be obtained in low-dose thrombolytic therapy through peripheral venous circulation (44-46).

Pharmacomechanical CDT (PM-CDT)

The Bashir endovascular catheter (Thrombolex Inc., New Britain, PA, USA) is a novel PM-CDT device that can stretch and contract with an infusion basket that measures 3 mm when closed and 45 mm when completely unfolded. This device provides pulsed injection of thrombolytic drugs via six branches of an elongated infusion basket. The unique feature of the catheter is that blood flow forms at the thrombus site as soon as the infusion basket is inserted, facilitating quicker reperfusion, increasing the exposure of the thrombus to endogenous and exogenous thrombolytic agents, accelerating thrombolysis, and saving time. In patients with intermediate-risk APE, the Bashir endovascular catheter demonstrated preliminary safety and feasibility in a first-in-human (FIH) study. However, larger trials are required to assess its efficacy (47).

With Investigational Device Exemption (IDE) approval from the United States FDA, the RESCUE trial assessed the effects of Bashir catheters for intermediate-risk PE. The data showed that the RV/LV ratio improved by 33.3% within 48 h after surgery, which is superior to that of ST and most contemporary catheter-guided therapies. A noteworthy outcome of this trial was a 35.9% decline in pulmonary artery obstruction, the first minimization of pulmonary artery obstruction to this extent in catheter therapy using a small dosage of t-PA. The exceptionally low incidence of major bleeding (0.9%), which was lower than that in any multicenter EKOS CDT experiment (between 4% and 10%), is another valuable result. This slight bleeding rate also appears to be superior to that of modern percutaneous MT devices, which cause suction-related programmed blood loss. Moreover, the median hospital stay in this trial was shorter than that in any prior CDT or percutaneous MT trial. Subsequent controlled trials should assess the outcomes of PM-CDT versus alternative therapies (48) (Table 4).

MT

MT refers to the mechanical removal of a thrombus by percutaneous puncture and placement of special thrombus ablation catheters into the vascular lumen. These catheters are complex automatic mechanical devices that can impregnate, chop, remove, dissolve, or liquefy thrombi.

Indigo aspiration system

The Indigo thrombus extraction system (Penumbra Inc., Alameda, CA, USA) consists of a CAT thrombus catheter, separator, vacuum pump, and other accessories. CATs are of multiple sizes and accommodate different vascular diameters and thrombus sites. The Lightning 12 system is a next-generation aspiration system that combines intelligent lightning aspiration with a CAT 12 thrombus catheter. This allows doctors to enhance clot removal and minimize blood loss by utilizing the unique clot detection mechanism of the device. The FDA has approved this system for the treatment of PE and removal of blood clots in peripheral veins and arteries.

The EXTRACT-PE trial assessed the outcomes of the Indigo aspiration device in patients with acute sPE. In total, 119 patients were recruited from 22 sites in the United States. The average 48-h RV/LV reduction in the EXTRACT-PE study was comparable to that in the SEATTLE II and FLARE studies. However, the major bleeding rate in the EXTRACT-PE trial was 1.7%, which was lower than that reported in the thrombolytic therapy study. Thrombolytic drugs were not required in 98.3% of cases. In 2019, the FDA approved the Indigo Aspiration System for the treatment of PE in the United States.

This study had some limitations owing to the absence of randomization, comparison groups, and long-term results. Furthermore, because the subjects in the EXTRACT-PE study had sPE, the findings cannot be applied to high-risk patients with PE. Further research is needed to explore whether Indigo is more beneficial than ST for high-risk individuals. Grabka et al. from Poland reported a case study of a patient with a history of venous thromboembolism (VTE) who developed APE and obstructive shock in early pregnancy. Considering thrombolysis complications and high surgical mortality, percutaneous pulmonary thrombectomy was performed to remove large pulmonary thrombus with Indigo device and quickly restore pulmonary blood perfusion. During the postoperative follow-up, the patient’s heart function improved significantly without right heart enlargement. There are many patients in the clinic who develop APE in early pregnancy, and interventional pulmonary embolectomy will be considered as the preferred practice option when they are assessed as having intermediate-risk or high-risk PE (49).

To assess the long-term outcomes of the Indigo system for PE, a prospective multicenter STRIKE-PE research is planned (50). The STORM-PE (NCT05684796) trial will focus on determining whether treating patients with intermediate-to-high-risk PE with the Indigo system can relieve right heart tension more effectively than AC alone, without raising the possibility of adverse events. In addition, this study will evaluate the quality of life and functional statuses of the patients over a 90-day follow-up period. The findings of this trial will help clinicians fully understand MT therapy and inform future guidelines for PE.

FlowTriever aspiration system

The FlowTriever system (Inari Medical Inc., CA, USA) is a large-diameter, catheter-type MT device that mechanically binds to the thrombus through a self-expanding nitinol disc. During aspiration, the nitinol disc retracts into the catheter and entrains the thrombus. The FlowTriever system quickly removes emboli without the use of thrombolytic agents, relieves pressure on the right ventricle, and improves clinical symptoms. It received United States FDA 510(k) approval for PE indication in May 2018 (51).

The FLARE trial evaluated the clinical efficacy of the FlowTriever system for acute intermediate-risk PE. The mean RV/LV ratio improvement 48 h after surgery was 0.38, or 25.1% (P<0.0001). The main bleeding rate was 0.9%, and no cerebral hemorrhage was noted, indicating excellent safety. The main defects of the trial were its small scale, lack of a control group, and lack of assessment of the effects on high-risk PE (52). The FLAME trial is the largest trial for high-risk patients with PE, who are difficult to enroll in traditional trials owing to hemodynamic instability. The primary outcomes were a combination of major bleeding, clinical exacerbation, thrombus removal approach, and in-hospital all-cause mortality. Compared with the existing literature, a decreased correlation with in-hospital adverse results was observed in patients who opted to undergo MT using the FlowTriever system. The FLAME trial provides evidence that MT is safe for high-risk PE (53).

The PEERLESS II trial (NCT06055920) compared the FlowTriever system with conventional AC alone, whereas the PEERLESS study (NCT05111613) compared the FlowTriever system with CDT. Two randomized controlled trials were conducted on patients with intermediate-risk PE. Both trials aimed to generate credible evidence to advance the PE field and influence PE treatment guidelines regarding the FlowTriever as the preferred choice for intermediate-risk PE (54,55).

Viper Catheter System (Hēlo)

The Viper Catheter System, or Hēlo (Endovascular Engineering [E2] Inc., Monroe Park, CA, USA), is a uniquely designed, easy-to-use MT system that combines large-caliber suction function with mechanical resection. A high-speed stirring shaft is placed inside the catheter, which can break the thrombus inhaled into the funnel, so the thrombus can be easily sucked out, avoiding the thrombus blocking the catheter. Fresh and fibrotic thrombi can be removed. The catheter profile is only 16 Fr, and the distal end has a self-expanding lamination design with a suction funnel that can expand to 24 Fr, which allows it to travel through both simple and complex anatomies without affecting the lumen size.

The ENGULF study (NCT05597891) is currently assessing the clinical effectiveness of the Viper Catheter System (Hēlo). According to preliminary trial results, emboli were successfully removed using the device in all patients. Within 48 h following surgery, the mean RV/LV ratio decreased significantly, comparable with other FDA-approved devices, and no major adverse events occurred. Furthermore, no deaths occurred within a 30-day period. In the future, Endovascular Engineering should conduct more clinical studies to confirm the clinical value of the Viper Catheter System (Hēlo).

AlphaVac F1885 system

The AlphaVac F1885 system (AngioDynamics Inc., Latham, NY, USA) includes an obturator, waste bag, 18-F casing, and handle. This novel system has been approved by the United States FDA as an emergent first-line device for PE. The application of the AlphaVac F1885 system to the field of MT represents an important breakthrough in the interventional therapy of patients with PE.

The purpose of the Acute Pulmonary Embolism Extraction Trial (APEX-AV) (NCT05318092) was to evaluate the safety and efficacy of the AlphaVac F1885 system for the treatment of PE. In December 2023, the recruitment of 122 individuals with acute intermediate-risk PE from 25 hospitals across the United States ended. The follow-up period was 30 d. The results revealed that the mean decrease in the RV/LV ratio was 0.45, the thrombus burden was reduced by an average of 35.5%, and the rate of major adverse events was 4.1% from baseline to 48 h postoperatively. The findings of this study add to the evidence of the efficacy of MT for the treatment of PE.

Penumbra CAT 12 Lightning Flash 2.0 CAVT system

The Lightning Flash intelligent thrombus suction system (Penumbra Inc., Alameda, CA, USA) consists of three key components: an ENGINE suction pump, a Lightning control unit, and a CAT 12 catheter. The ENGINE suction pump can produce a negative pressure of 29 in of mercury (Hg), which nears vacuum suction. The Lightning control unit can automatically alter the suction mode and identify blood clots and blood flow using algorithms based on flow and pressure data. The CAT 12 catheter has two lengths, 100 and 115 cm, and an interior diameter of 0.131 in (0.333 cm). Catheters that use MaxID hypotube technology have a large size and high torque and can remove a significant volume of blood clots from the body, particularly those in the deep veins or pulmonary arteries.

The United States FDA has approved Lightning Flash 2.0 equipment for the treatment of PE. However, this is an updated version of the Lightning Flash, as Advanced Lightning Flash algorithms were used in the development of Lightning Flash 2.0. Together with Penumbra’s existing catheter technology, the Lightning Flash 2.0 system helps operators enhance thrombus clearance while minimizing blood loss by limiting suction time. Currently, some clinical cases demonstrate that the Lightning Flash system is a safe and effective device for PE, but large-scale experimental research is needed to verify these findings.

eTrieve catheter

The Magneto eTrieve catheter (Magneto Inc., Or Yehuda, Israel) eliminates blood clots based on its electrical properties. When a voltage is applied to the catheter, the negatively charged clot attracts the catheter’s positively charged electrodes, forming an intense grip force that safely removes blood clots without injuring the surface inside the vascular lumen, thereby minimizing the risk of distal embolism.

FIH research revealed the preliminary safety and performance of eTrieve in individuals with APE, including a significant reduction in the RV/LV ratio at 48 h, no device-related complications, and successful removal of blood clots of all types and sizes from areas that previous methods could not easily reach. Given the outcomes of the FIH trial, Magneto acquired IDE approval for the eTrieve catheter, and a pivotal multicenter study (eTrieve II) (NCT05821426) will commence immediately.

Akura Thrombectomy Catheter System

The Akura Thrombectomy Catheter System (Akura Medical, Campbell, CA, USA) combines rheology, dynamic aspiration, and accurate orientation. Akura integrated suction and softening by incorporating a high-speed cross-jet into a 12 F catheter. The soft, spinning cut head is intended to improve thrombosoftening by increasing the surface area touching the thrombus. Using a sensor at the tip of the sheath, the operator can monitor variations in pressure both before and after a clot is cleared. Angiography without catheter replacement can help doctors identify the position of the catheter in relation to the clot before starting suction and confirm vascular patency after treatment.

In 2023, a prospective, single-arm FIH trial was initiated in Peru for the treatment of PE using the Akura Thrombectomy Catheter System. Only five patients, with saddle thrombi visible on CTPA, were included. A reduction in the RV/LV ratio within 48 h was the main efficacy point, whereas the comprehensive rate of major adverse events was the primary safety outcome. All patients successfully completed surgery with an average operative time of 117±50 min. The blood loss was 247±80 mL on average. The RV/LV diameter ratio decreased by 27% after 48 h. During the 7-day timeframe, no deaths or device-related adverse events occurred. Furthermore, in patients with APEs, the ATC system designed by Akura Medical can rapidly rebuild pulmonary blood flow by manually eliminating thrombi. An interventional trial (NCT06152341) will be conducted to assess the safety and efficacy of the Akura Thrombectomy Catheter System in patients with APE.

Chinese pulmonary thrombus removal system

With widespread clinical interest in interventional therapy for APE, numerous PE thrombus removal devices have been developed. Chinese medical technology companies have also contributed to this effort by making devices such as the JETi (Abbott) thrombectomy device, SIRIUS TWIFLOW^® pulmonary artery thrombectomy system, ForTriever^® thrombectomy stent system, TideFlow^® thrombectomy system, Tendvia™ pulmonary artery thrombectomy system, and FuseVive™ pulmonary thrombus removal system.

In the Chinese Clinical Trial Registry, we retrieved a single-arm trial to evaluate the effects of the MT system (Tendvia™ pulmonary artery thrombectomy system) developed and manufactured by Shanghai Tendfo Medical Technology Co., Ltd. (Shanghai, China), for APE (registration number: ChiCTR2300070564).

Other devices under study

The Symphony Thrombectomy System (Imperative Care Inc., Campbell, CA, USA) removes pulmonary thrombus/embolus/clots using aspiration and MT, thereby improving blood perfusion and oxygen uptake for transport throughout the body and reducing hypoxic symptoms. Approximately 150 patients from various United States sites will participate in crucial a study entitled the SYMPHONY-PE study (NCT06062329), which aims to assess the clinical outcomes of the Symphony Thrombectomy System in treating APE.

The Cleaner™ Pro Thrombectomy System (Argon Medical, Frisco, USA) includes a handle, dilator, aspiration catheter, and container to make up a catheter-based aspiration thrombectomy system. The CLEAN-PE trial (NCT06189313), with 125 subjects from the United States, investigated the safety and efficacy of the Cleaner™ Pro Thrombolectomy System (Argon Medical) for treating PE. Future data from this study will be used to discuss interventional therapies for PE (Tables 5,6).

Long-term outcomes of PE

While research is currently being conducted on treatment methods for intermediate- to high-risk APE, the long-term consequences after APE have not received adequate attention. We summarized the clinical effects of interventional treatment of PE from three aspects: long-term mortality, post-pulmonary embolism syndrome (PPES), and quality of life.

Long-term mortality

The majority of current studies have selected 30-day mortality as short-term mortality for PE. There are few studies on the impact of long-term mortality over 30 days. Gupta et al. conducted a retrospective observational study on patients who underwent CDT for intermediate-risk PE. In this study cohort, 5-year all-cause mortality was 18.7%, with 9.2% of deaths related to cardiovascular causes (56). Semaan et al. retrospectively compared the long-term effects of AC therapy and CDT in patients with sPE. The findings demonstrated that CDT was positively correlated with a decreased risk of death at one, three, and five years, compared with AC (57). And one meta-analysis concluded that CDT combined with systematic AC significantly reduced the in-hospital, 30-day, 90-day, and 1-year mortality rates of patients with intermediate-risk PE, compared with systematic AC alone (58). But Harvey et al. identified one small trial showing no clear differences between ultrasound-augmented CDT with alteplase plus systemic heparinisation versus systemic heparinisation alone in all-cause mortality by 90 days (11).

Based on a real-world analysis, the results of ST and CDT for the treatment of PE were compared by Geller et al. Compared with that of the ST group, the CDT group’s mortality rate was lower after 1 year. Unfortunately, patients with a lower risk of mortality could not benefit from the findings of the analysis, as the findings were based on patients with PE who had a higher risk of mortality (59). Lin et al. revealed that among patients initially diagnosed with PE and in need of reperfusion therapy, CDT and pulmonary endarterectomy (PEA) yielded similar long-term all-cause mortality rates (60). Also, Ishisaka et al. found that no statistically significant difference was observed in the long-term mortality rates of CDT, ST, and surgical embolectomy (SE) in patients with intermediate- and high-risk PE (61). Further studies are required to provide reliable evidence that CDT is an acceptable and efficient method for treating intermediate-risk PE (Table 7).

PPES

PPES is a condition in which patients with APE develop clinical syndromes characterized by persistent dyspnea, limited movement or functional states, and decreased quality of life that cannot be explained by other diseases in the resting or active state after ≥3 months of adequate AC therapy (63). At present, the main area of research on PPES is chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is commonly regarded as a long-term life-threatening consequence of APE. Skilled teams can perform thorough evaluations of patient history, clinical symptoms, laboratory data, and imaging features to identify chronic thromboembolic pulmonary disease (CTEPD) and offer timely and appropriate therapies. Patients with a definitive diagnosis of CTEPD should undergo lifetime AC treatment and follow-up (64).

Following an updated systematic review, Luijten et al. reported a cumulative CTEPH-weighted incidence of 2.7% after PE. A link between persistent RVD and an increased risk of CTEPH has been determined in patients with PE (65). Another meta-analysis found that patients treated with thrombolysis had lower prevalence of RVD (1-year 0.17 and 0.07 in ST and CDT, respectively) than those treated with AC therapy alone (1-year 0.24). Regarding the FLASH registry project for the FlowTriever system used for PE, the data showed 6-month prevalences of 1% for CTEPH and 1.9% for CTEPD (66).

Quality of life

If patients with APE do not receive timely standardized treatment, they can gradually develop chronic diseases that may affect their quality of life and cause physical and mental burdens. Substantial evidence is lacking on whether interventional therapy can improve patients’ long-term quality of life, compared with traditional treatment. A secondary analysis of the SUNSET sPE study was conducted by Andraska et al. In patients with acute sPE, the long-term effects of CDT were compared with those of AC alone. The study found that after three months of therapy, the levels of CTEPH biomarkers, 6-minute walk test results, and quality of life assessments were comparable between the two groups (67). FLASH registration showed that patients’ 6-month quality of life greatly improved after treatment with the Indigo MT system (66). Clinical studies of other devices related to MT have not yet reported definitive long-term results.

The OPTALYSE-PE study analyzed the long-term outcomes of patients who underwent CDT or USAT for acute sPE. The results showed that functional performance scores and quality of life improved, and many patients in this trial reported no dyspnea or fatigue during the 6-minute walk test between 1 month and 1 year after the start of treatment (68). In another retrospective study, Rao et al. compared the quality of life of patients receiving CDT with those receiving USAT for >3 years. The average follow-up period was 17.9±11.4 months for the USAT group and 16.6±7.1 months for the CDT group. The findings indicated that in comparison with SCDT, USAT did not seem to offer any extra quality-of-life advantages for patients with intermediate-high-risk PE (69). CDT is helpful for improving the long-term quality of life in patients with PE; however, which type of CDT is more effective remains unclear.

Strengths and limitations of the review

The strength of this review is its updated discussion of interventional therapy for acute intermediate-high-risk and high-risk PE with the use of international guidelines and expert consensus, landmark clinical trials, and latest systematic reviews. The limitations include the certain bias of the review, which mean that the conclusion needs to be further verified.

Conclusions

Owing to the lack of specificity in clinical presentation, clinicians face challenges assessing the severity of APE based on symptoms or signs alone, and early risk stratification is a key step in guiding treatment strategies for APE. At present, several commonly used scoring scales have been established according to patients’ clinical symptoms, signs, laboratory indicators, and imaging parameters; however, these scales are limited to short-term prognosis and cannot effectively evaluate long-term results. Incorporating potential prognostic biomarkers into the old score to improve its efficacy or exploring new scores for specific populations may be the next step in risk stratification assessment tools.

Updated guidelines recommend percutaneous interventional therapy with an intensity limited to IIa and IIb for intermediate- or high-risk PE. Most relevant studies are single-arm, single-center, retrospective observational studies showing good clinical benefits at 48 h and 30 days after surgery. The long-term outcomes of PE include post-PE syndrome, quality of life score, and long-term mortality. Whether interventional catheter therapy affects the long-term prognosis of patients with APE remains unknown. In the future, more large-scale, prospective, randomized controlled studies with long-term follow-ups are required to yield more objective evidence for the interventional treatment of PE.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1049/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1049/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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