Clinical Outcomes in Patients With Acute Pulmonary Embolism Undergoing Ultrasound‐Assisted Catheter‐Directed Thrombolysis

Abstract

Background

Ultrasound‐assisted catheter‐directed thrombolysis (USAT) for acute pulmonary embolism (PE) has garnered specific interest and is commonly employed in intermediate‐risk PE to prevent cardiac decompensation and death. However, evidence supporting the effectiveness and safety of USAT in routine clinical practice is limited. We therefore aimed to investigate the safety and effectiveness of USAT in a large patient population with PE.

Methods and Results

The ERASE PE (Bern Acute Pulmonary Embolism Registry) is a single‐center cohort study investigating the safety and effectiveness of PE treatment according to the decision of the local PE response team. The specified primary outcome was in‐hospital mortality. Between October 2017 and April 2023, 315 patients (mean age 64.3±14.2 years; 38% female) with intermediate‐high (n=257, 82%) and high risk (n=58, 18%) PE were treated with USAT. Patients presented with tachycardia (heart rate 104.3±20.4 bpm), hypoxemia (peripheral oxygen saturation 89.2%±7.5%), elevated mean pulmonary artery pressures (30.7±8.0 mm Hg), and reduced mixed venous saturation (venous oxygen saturation 58.5%±10.2%). Patients received USAT with a cumulative dose of 19.8±6.6mg rt‐PA over 14.4±2.2 hours. USAT was effective in reducing right ventricular overload and pulmonary artery pressure in 88% of patients with a mean reduction of right ventricular/left ventricular ratio of 0.37±0.29 and mean pulmonary artery pressure of 8.5±7.7 mm Hg, respectively. The primary end point was observed in 10 patients (3.2%). One patient had an embolic stroke (0.3%), 25 patients (7.9%) exhibited bleeding, including 3 patients with intracranial hemorrhage (1.0%), and 3 patients (1.0%) had recurrent PE.

Conclusions

Among patients with acute PE, USAT effectively reduces right ventricular overload and mean pulmonary artery pressure with low rates of in‐hospital mortality and bleeding.

Registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT04355975.

Nonstandard Abbreviations and Acronyms

rt‐PA

recombinant tissue‐type plasminogen activator

USAT

ultrasound‐assisted catheter‐directed thrombolysis

Clinical Perspective.

What Is New?

• Ultrasound‐assisted catheter‐directed thrombolysis (USAT) effectively reduces right ventricular overload in patients with intermediate‐high and high‐risk acute pulmonary embolism.

• USAT is associated with low rates of periprocedural bleeding, death, or other pulmonary embolism‐related complications.

• Patients with high‐risk pulmonary embolism had a 4‐fold increased risk of periprocedural death compared with patients with intermediate risk pulmonary embolism undergoing USAT.

What Are the Clinical Implications?

• This real‐world evidence supports the use of USAT in well‐selected patients with intermediate‐high and high risk acute pulmonary embolism.

• Randomized‐controlled trials are required to investigate differences in outcomes between USAT and systemic thrombolysis or anticoagulation alone as front‐line therapy. Furthermore, the role of large‐bore endovascular embolectomy and the differences in safety and efficacy when compared with USAT are currently unclear.

Among unstable patients with massive (high‐risk) acute pulmonary embolism (PE), immediate reperfusion is commonly achieved with thrombolytic therapy by intravenous injection of a plasminogen activator (eg, recombinant tissue‐type plasminogen activator [rt‐PA]). ¹ Systemic thrombolysis, however, is associated with a significant risk of bleeding in up to 20% of treated individuals, including rates of intracranial hemorrhage between 2% and 5%. ² Appropriate therapy is often withheld due to the anticipated risk of bleeding. ³ Submassive (intermediate risk) PE is characterized by right ventricular (RV) dysfunction or cardiac ischemia. Although early mortality rates are as high as 10.9% in this patient population, ⁴ clinical practice guidelines recommend anticoagulation rather than thrombolytic reperfusion therapy in stable patients due to the associated hazard of life‐threatening bleeding. ⁵

Catheter‐directed therapies for PE were mainly studied in hemodynamically stable patients and may avert the risk of RV overload in intermediate‐risk patients and minimize the risk of major bleeding. ⁶ , ⁷ , ⁸ Upon interventional techniques, catheter‐directed thrombolysis using ultrasound‐enhanced technology, the EkoSonic Endovascular System (EKOS) provides most of the evidence supporting an early treatment strategy for PE. ⁶ , ⁹ Although numerous single‐arm studies have evaluated the safety and effectiveness of this device, overall patient numbers are still low. ⁶ , ¹⁰ , ¹¹ , ¹²

Therefore, we aimed to investigate the benefits and risks of ultrasound‐assisted catheter‐directed thrombolysis (USAT) in a large patient population with PE and contribute to the understanding of safety and effectiveness of this catheter‐directed treatment in real‐world clinical practice.

METHODS

The ERASE PE (Bern Acute Pulmonary Embolism Registry) is a single‐center, prospective cohort study, with the aim to investigate the risks and benefits of treatment for acute PE. The cohort study was initiated in October 2017 and is conducted at Bern University Hospital. ERASE PE is registered at clinicaltrials.gov with NCT04355975.

Consecutive patients with PE referred for advanced PE care were considered for study inclusion. After arrival at the tertiary care center, patients were evaluated based on clinical presentation, hemodynamics, and imaging details by an experienced, interdisciplinary PE response team. Risk stratification, decision‐making, and the treatment of PE using advanced modalities is performed as 24 hours/day 7 days/week service at the Center for Pulmonary Embolism under the lead of the Department of Cardiology. For this analysis, consecutive patients undergoing USAT for PE were considered eligible. The study protocol was approved by the local ethics committee and all patients provided written informed consent for study participation. The investigation was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology cohort‐reporting guidelines. ¹³

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study Patients and Treatment

Patients were considered for USAT if they were diagnosed with acute PE within 14 days of symptom onset and had evidence of proximal central or segmental filling defects suggestive of pulmonary embolism on computed tomography angiography scan. Risk stratification was performed according to the 2019 European Society of Cardiology guidelines on the diagnosis and management of acute PE. ⁵ In brief, patients with PE were considered at high risk for early mortality in the presence of acute hemodynamic instability and overt obstructive shock. In patients without cardiogenic shock, right heart overload leading to cardiac ischemia was assessed by blood sampling of cardiac troponin and serum brain natriuretic peptide and by imaging proof of right heart dilation on computed tomography angiography and RV dysfunction on transthoracic echocardiography. Symptomatic patients with positive biomarkers or imaging signs of right heart overload were categorized as intermediate‐low risk, whereas patients with both parameters were categorized as intermediate‐high risk.

USAT was performed using a standardized protocol with the EKOS (Boston Scientific, Marlborough, MA). EKOS consists of a 5.4 Fr infusion catheter, which hosts a coaxial ultrasonic core to deliver low‐energy, noncavitational ultrasound supposed to unwind the fibrin fibrils of the embolus and thereby enhance lytic efficacy. ⁶ Ultrasound energy is provided by a control unit, which monitors the power of acoustic ultrasound and the temperature of the catheter. Per protocol, bilateral EKOS catheters were delivered through a single, double lumen 12 Fr femoral access after ultrasound guided femoral vein puncture. Before placement, patients received a full hemodynamic assessment by right heart catheterization and angiographic confirmation of clot location. In patients with reduced cardiac output as indicated by mixed venous oxygen saturation samples (<45%), a bolus therapy of rt‐PA was considered. During USAT treatment patients received a standard dose regimen of 10 mg rt‐PA/catheter for 15 hours, while monitored for hemodynamic or neurologic changes at an intermediate care unit. ¹⁰ In patients considered to be at increased risk for bleeding, the ERASE protocol allowed for a reduction to 7.5 mg rt‐PA/catheter (during 10 hours of treatment) or 5 mg rt‐PA/catheter for 5 hours and the adaption was performed according to the bleeding risk assessment based on clinical characteristics, medical history and comorbidities, and laboratory parameters. ¹⁴ After USAT treatment, pulmonary artery hemodynamics were transduced through the drug delivery catheter after the removal of the ultrasonic core catheter. The femoral sheath was removed 4 hours after termination of lytic drug infusion and the femoral access site was manually compressed until hemostasis was achieved. Full therapeutic anticoagulation using unfractionated heparin was continued through all treatment steps.

Data Collection and Study End Points

ERASE PE started in October 2017 as a local clinical quality assurance registry with consecutive patient registration, and patient data were prospectively collected and managed using Research Electronic Data Capture tools hosted at Bern University Hospital. ¹⁵ , ¹⁶ All data end points were collected by the research staff, were then reviewed and classified according to the end point definitions by a junior investigator, and were finally confirmed and adjudicated by an independent (not involved in the treatment of this particular patient) senior investigator of the study team.

The specified primary outcome measure was in‐hospital death. Secondary outcomes included periprocedural death (within 30 days) or other adverse events including cerebrovascular events, myocardial infarction, bleeding, kidney injury, and recurrent venous thromboembolic events (for end point definitions consult Data S1). Treatment success was characterized by the improvement in pulmonary hypertension, based on invasive assessment of the mean pulmonary artery pressure (PAP) at the time of catheter placement (before initiating USAT) and removal (after USAT).

Statistical Analysis

Descriptive information related to patients' characteristics, intervention, and discharge from index hospitalization were expressed as absolute counts and percentages or mean±SD as appropriate for categorical and normally distributed continuous variables, respectively; medians with interquartile ranges were reported for biomarkers. Differences in characteristics between patients remaining alive or not at 30 days of follow‐up and between those with high‐risk versus below high‐risk PE (including outcomes) were assessed by chi‐square or Fisher's test and ANOVA F‐test. Clinical events were reported as counts (percentages) of the first occurrence of each [sub]type up to 30 days follow‐up. All events are analyzed cross‐sectional using risk ratios from Mantel–Haenszel estimates with 95% CI. No imputation of missing data was performed. Analyses were performed using Stata 17 (StataCorp LCC, College Station, TX). All P values were considered significant at the nominal level of <0.05.

RESULTS

Among 315 patients enrolled into the prospective ERASE PE study, 58 (18%) and 257 patients (82%) had high‐ and intermediate‐risk PE, respectively. PE severity index was 110.3±38.5 and 167 patients (53.0%) were considered at high or very high risk for early mortality (PE severity index >105) (Figure 1).

Figure 1. Pulmonary embolism risk assessment according to the left panel: ESC risk stratification, right panel: Pulmonary Embolism Severity Index.

ESC indicates European Society of Cardiology.

Baseline clinical characteristics and details on clinical presentation are summarized in Table 1. Overall, 196 patients (62%) were male, with a mean age of 64.3±14.2 years, and 39% of patients had obesity. On average, patients were normotensive, yet tachycardic (heart rate 104.3±20.4 beats per minute), presented with tachypnea (respiratory rate 23.2±6.4 breaths per minute), and oxygen desaturation (89.2±7.5%). Patients were symptomatic (mean duration 4.4±5.4 days) with severe dyspnea (88% in New York Heart Association functional class ≥III), chest pain (42%), and syncope (n=63, 20%) being the most common presentations. Overall, 14 patients (4%) were resuscitated in the prehospital setting. For 32 patients (10%) cardiac decompensation during the hospital stay was the indication for USAT treatment.

Table 1.

Baseline Demographics and Clinical Presentation

	Overall
	No.=315
Age, y	64.3±14.2
Sex, male	196 (62%)
Body mass index, kg/m2	29.2±5.8
COVID associated	17 (6%)
Hypertension	143 (45%)
Diabetes	50 (16%)
Glomerular filtration rate, mL/min per 1.73 m2	73.9±22.7
Dyslipidemia	62 (20%)
D‐dimer (μg/L)	8089.5 (4261.5; 13922.8)
hs‐cTnT (ng/L)	97.5 (52.0; 178.3)
hs‐cTnT >99th percentile URL	279 (98%)
N‐terminal pro‐B‐type natriuretic peptide (pg/mL)	1700.0 (341.0; 4441.0)
PESI	110.3±38.5
High‐ and very‐high‐risk PE (PESI >105)	167 (53.0%)
Right ventricular/left ventricular ratio	1.41±0.27
Clinical presentation
Duration of symptoms, d	4.4±5.4
Heart rate (per minute)	104.3±20.4
Respiratory rate (per minute)	23.2±6.4
Peripheral oxygen saturation (%)	89.2±7.5
Systolic blood pressure, mm Hg	131.4±29.0
Diastolic blood pressure, mm Hg	85.2±19.1
Chest pain	129 (42%)
Dyspnea New York Heart Association III/IV	278 (88%)
Cough	61 (20%)
Fever	13 (4%)
Hemoptysis	2 (1%)
Syncope	63 (20%)
Unilateral lower limb pain	55 (18%)
Unilateral extremity swelling	49 (16%)
Altered mental status	19 (6%)
Neurological symptoms	11 (4%)
S/p resuscitation	14 (4%)
Hemodynamic decompensation during the hospitalization	32 (10%)

Depicted are counts (%) or means±SD and medians (25%; 75% quartiles). hs‐cTnT indicates high‐sensitivity cardiac troponin T; S/p, Status post or history of; and PESI, pulmonary embolism severity index.

The prevalence of well‐established risk factors for venous thromboembolism in the study cohort is provided in Table 2. The most frequent risk factors were obesity (n=124; 39%), previous venous thromboembolism (n=78; 25%), active infection (n=43; 14%), chronic pulmonary disease (n=37; 12%), recent orthopedic surgery (n=39; 12%), and immobility due to sitting (n=32; 10%).

Table 2.

Risk Factors for Venous Thromboembolism

	Overall
	No.=315
Fracture of the lower limb	5 (2%)
Hospitalization for heart failure or atrial fibrillation/atrial flutter <3 mo	1 (0%)
Hip or knee replacement	23 (8%)
Major trauma	3 (1%)
Myocardial infarction <3 mo	2 (1%)
Previous venous thromboembolism	78 (25%)
Previous pulmonary embolism	41 (53%)
Spinal cord injury	4 (1%)
Arthroscopic knee surgery	4 (1%)
Autoimmune disease	20 (6%)
Blood transfusion	4 (1%)
Central venous lines	1 (0%)
Chemotherapy	7 (2%)
Congestive heart failure	14 (4%)
Chronic pulmonary disease (any)	37 (12%)
Erythropoiesis‐stimulating agents	0 (0%)
Hormone replacement therapy	8 (3%)
In vitro fertilization	3 (1%)
Infection	43 (14%)
Inflammatory bowel disease	6 (2%)
Oral contraceptive therapy	8 (3%)
Disabling stroke (history)	3 (1%)
Postpartum period	4 (1%)
Superficial vein thrombosis	10 (3%)
Thrombophilia	11 (3%)
Bed rest >3 d	29 (9%)
Immobility due to sitting (eg, prolonged car or air travel)	32 (10%)
Increasing age≥40 y	292 (93%)
Laparoscopic surgery within 4 weeks	4 (1%)
Obesity	124 (39%)
Active pregnancy	0 (0%)
Splenectomy (history)	1 (0%)

Depicted are counts (%).

Procedural information is depicted in Table 3. The majority of patients received bilateral catheter‐directed thrombolysis (n=282; 90%) mainly by using the right femoral vein access (n=299; 95%). Pulmonary artery hemodynamics revealed an increased PAP (mean PAP 30.7±8.0 mm Hg) and reduced mixed venous saturation (58.5±10.2%). Although 31 patients (10%) required immediate thrombolytic bolus therapy due to reduced cardiac output, the mean total dose of rtPA was 19.8±6.6 mg. After 14.4±2.2 hours of USAT treatment, an improvement in mean PAP was observed in 88% of patients with a mean reduction of 8.5±7.7 mm Hg. RV/left ventricular dimension ratio decreased from 1.41±0.27 at baseline to 1.03±0.18 at discharge (mean reduction, 0.37 [95% CI, 0.34–0.41], P<0.001) (Figure 2, Figure S1). After a mean hospital duration of 3.1±3.2 days, 50% and 37% of patients were discharged home and back to the referring hospital, respectively (Table 3).

Table 3.

Procedural Characteristics and Discharge Information

	Overall
	No.=315
Amount of contrast, mL	17.4±21.3
Amount of radiation, cGy·cm2	2651.6±2239.0
Pulmonary hemodynamics at baseline
PAPs (mmHg)	53.4±14.8
PAPd (mmHg)	17.6±6.0
PAPm (mmHg)	30.7±8.0
Mixed venous saturation, %	58.5±10.2
RAm (mmHg)	8.8±5.5
Details of catheter‐directed therapy
Access location (femoral)	315 (100%)
Access location (femoral right)	299 (95%)
Thrombolytic bolus therapy	31 (10%)
Duration of ultrasound‐assisted catheter‐directed thrombolysis, h	14.4±2.2
Cumulative dose of recombinant tissue‐type plasminogen activator, mg	19.8±6.6
Extracorporeal membrane oxygenation use	1 (0%)
Bailout/conversion to other pulmonary embolism treatment modality	0 (0%)
Hemodynamic assessment (before discharge)
PAPs (mmHg)	37.3±12.6
PAPd (mmHg)	15.2±6.0
PAPm (mmHg)	22.5±7.2
RAm (mmHg)	8.6±8.0
Discharge to
Home	158 (50%)
Referring hospital	117 (37%)
Rehabilitation clinic	10 (3%)
Nursing home	3 (1%)
Other	27 (9%)
Days between intervention and discharge	3.1±3.2
Intensive care unit, d	0.5±2.0
Intermediate care, d	1.7±0.9
General ward, d	2.0±2.6

Depicted are counts (%) or mean±SD. PAPd indicates diastolic pulmonary artery pressure; PAPm, mean pulmonary artery pressure; PAPs, systolic pulmonary artery pressure; and RAm, mean right atrial pressure.

Figure 2. Change in RV/LV ratio and mean pulmonary artery pressure: baseline minus postprocedure.

RV/LV indicates right ventricular/left ventricular.

Complete follow‐up for relevant clinical outcomes up to 30 days was achieved in 100% of patients. The primary end point, in‐hospital death, occurred in 10 patients (3.2%) and 2 additional patients died in the periprocedural phase up to 30 days after the intervention (3.8%) (Table 4). Bleeding was observed in 25 patients (7.9%)—most frequently at the vascular access site (n=10; 3.2%). Three patients (1.0%) developed intracranial hemorrhage; detailed information on clinical presentation and procedural characteristics for patients with intracranial hemorrhage is provided in Table S1. Recurrent PE was observed in 3 patients (1.0%) during the first 30 days.

Table 4.

Clinical Outcomes

	Overall
	No.=315
In‐hospital outcomes
Death	10 (3.2%)
Stroke (any)	1 (0.3%)
Embolic stroke	1 (0.3%)
Myocardial infarction	0 (0.0%)
Bleeding (any)	25 (7.9%)
Bleeding location
Intracranial bleeding	3 (1.0%)
Retroperitoneal bleeding	2 (0.6%)
Vascular access site bleeding	10 (3.2%)
Gastrointestinal bleeding	0 (0.0%)
Genitourinary bleeding	1 (0.3%)
Other source of bleeding	5 (1.6%)
Bleeding severity
BARC 2	10 (3.2%)
BARC 3	16 (5.1%)
BARC 3a	7 (2.2%)
BARC 3b	7 (2.2%)
BARC 3c	3 (1.0%)
BARC 4	0 (0.0%)
BARC 5	0 (0.0%)
Recurrent pulmonary embolism (any)	3 (1.0)
Clinical outcomes at 30 d
Death	12 (3.8%)
Stroke (any)	2 (0.6%)
Embolic stroke	2 (0.6%)
Myocardial infarction	0 (0.0%)
Bleeding (any)	25 (7.9%)
Bleeding severity
BARC 2	10 (3.2%)
BARC 3	16 (5.1%)
BARC 3a	7 (2.2%)
BARC 3b	7 (2.2%)
BARC 3c	3 (1.0%)
BARC 4	0 (0.0%)
BARC 5	0 (0.0%)
Recurrent pulmonary embolism (any)	3 (1.0%)

Depicted are counts (%)—only considering the first occurrence per event (sub)type. BARC indicates Bleeding Academic Research Consortium.

Survivors Versus Nonsurvivors

Baseline demographics and details on clinical presentation of deceased patients during the index hospitalization of PE are presented in Table S2. When compared with survivors, nonsurvivors presented with higher PE severity index (176.0±61.1 versus 108.2±35.7, P<0.001) and lower systolic (101.1±33.1 versus 132.1±28.6, P=0.005) and diastolic (61.1±21.9 versus 85.7±18.7, P=0.001) blood pressures. Nonsurvivors more frequently arrived with neurological symptoms (42% versus 2%; P<0.001) or altered mental status (50% versus 5%, P<0.001), had hemodynamic decompensation during the hospitalization (90% versus 8%, P<0.001), or were resuscitated in the preclinical setting (40% versus 3%, P<0.001). Risk factors for venous thromboembolism were comparable between nonsurvivors and survivors (Table S3).

Procedural details of survivors and nonsurvivors during the index hospitalization are presented in Table S4. During the procedure nonsurvivors had a higher average heart rate (113.0±21.5 versus 96.4±18.6 bpm; P=0.006), higher diastolic PAP (22.0±5.3 versus 17.4±6.0 mm Hg; P=0.017), and lower mixed venous saturation (46.6±14.0 versus 58.9±9.8%; P<0.001) when compared with survivors. Nonsurvivors received an increased overall dose of rt‐PA (24.0±23.0 versus 19.6±5.4 mg; P=0.040) over shorter USAT treatment duration (10.2±5.0 versus 14.5±1.9 hours; P<0.001).

Outcomes According to PE Risk Category

Baseline demographics and details on clinical presentation of intermediate‐risk and high‐risk patients are presented in Table S5. Patients with high‐risk PE had higher PE severity index (150.3±50.1 versus 101.3±28.6, P<0.001), larger RV/left ventricular ratio (1.55±0.29 versus 1.39±0.26; P<0.001), and more frequently presented with higher heart (110.0±26.3 versus 103.2±18.8; P=0.027) and respiratory rate (25.8±7.7 versus 22.7±6.0; P=0.005) and lower peripheral oxygen saturation (87.0±8.0 versus 89.7±7.3; P=0.019) and blood pressure (P _syst. 100.5±30.1 versus 137.6±24.5; P<0.001). High‐risk patients more frequently were in New York Heart Association functional class III or IV (71% versus 47%, P=0.001), more frequently had syncope (38% versus 16%, P<0.001) or a history of resuscitation (22% versus 0%) related to PE in the preclinical setting, and presented with neurological symptoms or altered mental status.

Risk factors for venous thromboembolism according to PE risk category are detailed in Table S6. Patients with high‐risk PE more frequently had a previous history of myocardial infarction within 3 months preceding the index PE (3% versus 0%; P=0.33); they had blood transfusions (5% versus 0%; P=0.021) and chemotherapy in their immediate medical history (7% versus 1%; P=0.024) and more frequently reported bed rest >3 days (19% versus 7%; P=0.010).

Procedural characteristics according to PE risk are shown in Table S7. During the procedure high‐risk patients had a higher average heart rate (106.7±20.5 versus 94.8±17.8 bpm; P<0.001), higher PAP (mean PAP34.1±9.2 versus 29.9±7.6 mm Hg; P<0.001) and lower mixed venous saturation (49.9±12.3 versus 60.5±8.5%; P<0.001) when compared with intermediate‐risk patients. Patients with high‐risk PE more frequently received a bolus therapy of rt‐PA (41% versus 3%; P<0.001) resulting in an increased overall dose of rt‐PA (22.1±11.2 versus 19.3±4.9 mg; P=0.003) and had longer in‐hospital stay (4.4±5.9 versus 2.8±2.0 days; P=0.001) when compared with patients with intermediate‐risk PE.

Rates of in‐hospital death were significantly higher in high‐risk patients (12.1% versus 1.2%, risk ratio [RR], 4.19 [95% CI, 2.60–6.74]), whereas overall rates of bleeding, stroke, myocardial infarction, and recurrent PE were comparable between risk groups (Table S8). Only bleeding events were found to be significantly more severe in high‐risk patients, which was related to an increase in Bleeding Academic Research Consortium 3 bleeding complications (10.3% versus 3.9%; RR, 2.16 [95% CI, 1.09–4.25]). At 30 days, rates of death remained increased in high‐risk patients (RR, 4.04 [95% CI, 2.52–6.49]), whereas serious adverse events and clinical outcomes remained nonsignificant and comparable between PE risk groups.

DISCUSSION

This single‐center analysis of a large, prospective, and real‐world patient cohort with intermediate‐ and high‐risk acute PE investigating the safety and effectiveness of USAT can be summarized as follows:

• In symptomatic patients with acute PE, USAT is safe with low rates of procedural complications and is effective in the majority of patients by reducing RV overload as assessed by the periprocedural decrease in RV/left ventricular ratio and PAP.

• Patients with high‐risk PE had a 4‐fold increased risk of periprocedural death compared with patients with intermediate‐risk PE undergoing USAT, whereas rates of bleeding, stroke, and myocardial infarction were low and comparable between risk groups.

• Despite appropriate patient selection and evaluation of the individual patient risk for bleeding by an experienced and multidisciplinary PE response team, intracranial hemorrhage was observed during USAT with low‐dose rt‐PA.

• There is significant variation in the treatment response and the change in mean PAP after successful USAT treatment.

Although there is still ongoing discussion on how to select the optimal reperfusion strategy for patients with acute pulmonary embolism, ERASE PE adds real‐world evidence supporting the use of USAT in well‐selected patients with intermediate‐high and high‐risk acute PE. Indeed, a standardized USAT protocol with low‐dose rt‐PA was effectively able to reduce RV overload as assessed with mean PAP in the majority of patients and had low rates of periprocedural complications. Rates of all‐cause mortality were 3.2% and 3.8% during the in‐hospital course and at 30 days, respectively and were comparable to the literature and previous studies investigating the effectiveness and the safety of USAT for acute PE. In fact, the SEATTLE II (Submassive and Massive Pulmonary Embolism Treatment With Ultrasound Accelerated Thrombolysis Therapy) Study had rates of in‐hospital and 30‐day mortality of 2.0% and 2.7%, ¹¹ whereas OPTALYSE (Study of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in the Treatment of Acute Submassive Pulmonary Embolism) presented in‐hospital mortality rates as low as 1%. ¹² The small difference in mortality might be explained by the risk difference between the studied patient population (ERASE‐PE—high risk 18%, intermediate‐high 79%; SEATTLE II—high risk 20.7%, intermediate‐high 79.3%; OPTALYSE—intermediate‐high 79% intermediate‐low 21%) and obvious differences in the treatment protocol. Whereas ERASE‐PE followed the treatment protocol of the ULTIMA (Ultrasound Accelerated Thrombolysis of PE) randomized clinical trial (20 mg rt‐PA over 15 hours USAT), ¹⁰ SEATTLE II (24 mg rt‐PA during 24‐hour USAT) and OPTALYSE (dose‐finding study with 8–12 mg rt‐PA during 2–6 hours of USAT) had different dose strategies. Recent data from the KNOCOUT PE (Ekosonic Registry of the Treatment and Clinical Outcomes of Patients With Pulmonary Embolism) registry showed that contemporary clinical practice is slowly moving toward lower‐dose and even shorter duration treatment protocols, ¹⁷ which is supported by the results of OPTALYSE, showing that USAT treatment protocols with very low doses of rt‐PA were highly efficient in reverting the RV pressure overload. Although higher doses of rt‐PA were associated with greater clot dissolution, this came at an increased risk of bleeding. A summary table including a direct comparison of relevant periprocedural outcomes in ERASE‐PE and previously published major studies is provided in Table S9.

As expected, nonsurvivors and patients with high‐risk PE had higher risk profiles according to the European Society of Cardiology classification and were more likely to exhibit unstable hemodynamics. This is consistent with the European Society of Cardiology 30‐day mortality prediction model, considering a 30‐day mortality rate of 22% in high‐risk patients, of 7.7% in intermediate‐high risk patients, 6.0% in intermediate‐low risk patients and only 0.5% in low‐risk patients, when accordingly treated with anticoagulation or thrombolysis, respectively. ⁴ Unsurprisingly, symptoms, such as an altered mental state, neurological symptoms, and hemodynamic decompensation during the hospitalization, were more common in nonsurvivors, who also had lower venous oxygen saturation at presentation, all being consistent with a worse clinical condition at presentation.

To date, evidence of a long‐term benefit of USAT over anticoagulation with heparin alone remains scarce, with ULTIMA being the only trial to directly compare these 2 treatment strategies so far. ¹⁰ For the moment, the HI‐PEITHO (Higher‐Risk Pulmonary Embolism Thrombolysis) study (ClinicalTrials.gov Identifier: NCT04790370) is enrolling up to 544 patients with intermediate‐high risk PE and will assess whether USAT in combination with anticoagulation is associated with a significant reduction in adverse events compared with anticoagulation alone within 7 days of randomization. ¹⁸ A recent meta‐analysis concluded that catheter‐directed thrombolysis was indeed associated with lower mortality but an increased bleeding risk, ¹⁹ confirming the conclusions of previous meta‐analyses investigating the effects of systemic thrombolysis. ²

Moreover, the added value of the noncavitational ultrasound technology of USAT on top of catheter‐directed infusion of the thrombolytic agent alone remains unclear. The SUNSET‐sPE (Standard vs Ultrasound‐Assisted Catheter Thrombolysis for Submassive Pulmonary Embolism) trial tried to address this issue in 81 patients with acute PE and failed to show superiority of USAT over standard catheter‐directed thrombolysis for the primary outcome pulmonary obstruction index reduction. ⁷ The authors of this study, however, also acknowledge the need for larger trials and the necessity to evaluate also shorter treatment protocols to conclusively address this question.

The search for reperfusion strategies in acute PE without the use of thrombolytic drug infusion has driven interest toward large‐bore, catheter‐directed, endovascular embolectomy with the FlowTriever (Inari Medical, Irvine, CA), which is currently evaluated in randomized clinical trials. Indeed, PEERLESS just completed the enrolment of 550 randomized patients with intermediate‐risk PE to FlowTriever versus USAT (ClinicalTrials.gov Identifier: NCT05111613), ²⁰ and PEERLESS II will compare the outcomes of up to 1200 patients with intermediate‐risk PE treated with the FlowTriever system versus anticoagulation alone (ClinicalTrials.gov Identifier: NCT06055920). The results of these randomized clinical trials will further contribute high‐quality clinical evidence to inform the discussion on the optimal treatment strategy for patients with acute PE.

Limitations

The results of the present study should be interpreted in light of the following limitations: First, the results of the present study reflect the experience of a single high‐volume center with an established PE response team and may not be generalizable to other institutions with different patient characteristics or different treatment algorithms for intermediate‐ and high‐risk PE. Second, ERASE PE is performed at a tertiary care center specialized in catheter‐directed interventions and as patients with PE may have been monitored at the diagnosing external institution for symptom or hemodynamic worsening and were referred only after clinical deterioration, a certain selection bias cannot be excluded. Third, despite best efforts, our registry is not exempt from the inherit limitations of registries related to the granularity of the data, especially during a longer follow‐up period. In addition, the lack of an independent and interdisciplinary clinical event adjudication team for this observational registry might be considered a sufficient cause for reporting bias to occur. Fourth, it remains unclear how the individual endogenous fibrinolytic potential adds to the local catheter‐directed therapy in patients with acute PE and dedicated laboratory values and clinical parameters to estimate the preexisting potential to further adjust the lytic dose regimen on an individual basis were not investigated. Finally, due to the absence of a direct comparator, the outcome information including mortality and bleeding can be used only for hypothesis generating. No definitive conclusion can be drawn about a safety and efficacy superiority over alternative treatment strategies. Notably, although our study focuses on in‐hospital outcomes with a follow‐up to 30 days, future investigations may need to allow longer follow‐up periods to confirm a lasting effect of USAT.

CONCLUSIONS

This first ERASE PE analysis confirms the effectiveness USAT with the EKOS system in reducing RV overload and PAP as well as safety with low rates of bleeding complications in a consecutively enrolled, real‐world patient cohort. Future trials will need to identify treatment strategies to further improve therapeutic response and reduce bleeding rates for an optimal benefit–risk ratio for individual patients.

Sources of Funding

ERASE PE is sponsored by intramural study grants provided by the Swiss Cardiovascular Center Bern.

Disclosures

Stephan Windecker reports research, travel, or educational grants to the institution from Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow TherPEutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen‐Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi‐Aventis, Servier, Sinomed, Terumo, Vifor, and V‐Wave. Stephan Windecker serves as advisory board member or member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V‐Wave, and Xeltis with payments to the institution but no personal payments. He is also member of the steering/executive committee group of several investigator‐initiated trials that receive funding by industry without impact on his personal remuneration. Stefan Stortecky reports research grants to the institution from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott, as well as personal fees from Boston Scientific, Teleflex, and BTG. Thomas Pilgrim reports research, travel, or educational grants to the institution without personal remuneration from Biotronik, Boston Scientific, Edwards Lifesciences, and ATSens; speaker fees and consultancy fees from Biotronik, Boston Scientific, Edwards Lifesciences, Abbott, Medtronic, Biosensors, and Highlife. Jonas Lanz reports speaker fees from Edwards Lifesciences and Abbott to the institution. Lorenz Räber received research grants to the institution by Abbott, Biotronik, BostonScientific, Sanofi, Regeneron, Infraredx, Heartflow, and Swiss National Science Foundation and speaker/consultation fees from Abbott, Amgen, Novo Nordisk, Medtronic, Occlutech, and Sanofi. Stephan Dobner accepted a research grant on behalf of the institution (Inselspital Bern) from Pfizer and reports speaker fees and travel grants from Boehringer Ingelheim, Alnylam, and Pfizer, all outside of the submitted work. The remaining authors have no disclosures to report.

Supporting information

Data S1

Tables S1–S9

Figure S1