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Catheter-Directed Thrombolysis of Pulmonary Embolism

Editor: Nagendra Gupta Updated: 5/2/2024 2:41:28 AM

Introduction

An estimated 10 million individuals worldwide experience venous thromboembolism (VTE) annually, leading to over 500,000 fatalities in Europe and a range of 100,000 to 300,000 deaths in the US.[1][2] Pulmonary embolisms (PE) can manifest with varying degrees of severity, ranging from asymptomatic to sudden death. This broad spectrum highlights the importance of accurately assessing PE severity from the outset.

Given this diversity, it is critical to stratify patients based on their PE-related risk to tailor treatment approaches effectively. While anticoagulation therapy generally suffices for patients at low risk of complications, the benefits of active thrombus removal, such as catheter-directed thrombolysis (CDT), become increasingly evident with the severity of PE.[3]

CDT has emerged as a nuanced treatment option, particularly for patients with intermediate to high-risk PE. This intervention aims to reduce the thrombus burden in the pulmonary arteries, potentially improving right ventricular (RV) function and patient outcomes[4]. However, the application of CDT is not without risks, as the potential for bleeding and other complications must be weighed against the therapeutic benefits.[5]

The landscape of interventional therapies for PE is evolving, with new devices and techniques being developed and approved for clinical use. This dynamic field necessitates a clear understanding of the current state of endovascular interventions and the development of evidence to guide their application in various clinical scenarios.

Anatomy and Physiology

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Anatomy and Physiology

PE usually originate from the deep veins of the lower extremities or pelvis. Dislodgement of a deep vein thrombosis (DVT) can cause the blood clot to travel up the venous system through the right heart and become lodged in the pulmonary vasculature. Common locations for a PE to lodge include the pulmonary trunk, main pulmonary artery, and segmental or subsegmental branches.

Once lodged in the pulmonary vasculature, the blockage may result in hemodynamic heart strain and a decrease in blood supply to the downstream pulmonary parenchyma, depending on the size and location of the PE. This obstruction can lead to RV failure due to acute pressure overload, which is a significant cause of mortality in severe PE cases.

Obstruction of over 30% to 50% of the pulmonary arterial bed's cross-sectional area leads to increased pulmonary artery pressure (PAP).[6] PE-induced vasoconstriction, mediated by thromboxane A2 and serotonin release, increases pulmonary vascular resistance (PVR) and decreases arterial compliance.[7] 

The resultant RV dilation alters the myocardium's contractile properties, increasing wall tension and myocyte stretch, prolonging RV contraction time, and triggering compensatory neurohumoral activation for inotropic and chronotropic stimulation. However, the RV's limited capacity to sustain high PAP can lead to hemodynamic instability. Excessive neurohumoral activation, potentially causing myocarditis, and the imbalance between oxygen supply and demand can further damage the RV myocardium.[8]

Respiratory failure in PE primarily arises from hemodynamic disturbances leading to ventilation/perfusion mismatch. Additionally, there is the potential for right-to-left shunting through a patent foramen ovale, which exacerbates hypoxemia and increases the risk of paradoxical embolization and stroke.[9]

Indications

Meticulous patient selection remains the cornerstone of endovascular strategies in PE management. 3 critical considerations guide the decision to proceed with CDT:

Disease severity and acuity:

  • Massive PE: Systemic thrombolysis is the primary choice, offering lower all-cause mortality.[10] In cases where systemic thrombolysis fails, endovascular approaches, including CDT, become potential options within a PE response team (PERT) approach, considering extracorporeal membrane oxygenation (ECMO) and surgical embolectomy for life-saving situations.[11][12]
  • Submassive PE: Systemic thrombolysis provides a mortality benefit but raises major bleeding risk, especially intracranial hemorrhage.[10][13]. American College of Cardiology (ACC) and American Heart Association (AHA) guidelines consider CDT for deterioration or when adverse prognosis indicators are present. The European Society of Cardiology (ESC) advocates 2-step risk stratification with validated tools like the PE Severity Index followed by imaging and biomarker assessment.[3][14] If both clinical and objective assessments indicate high risk and impending cardiopulmonary deterioration is likely, CDT may be considered. This reflects the ongoing need for robust randomized trials. Existing data on ultrasound-assisted CDT (UA-CDT) shows promise, exceeding heparin alone in improving RV size within 24 hours without major bleeding or recurrent VTE.[15]
  • Low-risk PE: Endovascular interventions are generally contraindicated due to low morbidity and mortality. The exception might be large saddle emboli without hemodynamic or RV issues. Ongoing trials on optimal dosing and duration are underway.[16]

Major adverse bleeding risk: 

Balancing potential CDT benefits with individual bleeding risks is crucial. Comorbidities and bleeding history require careful evaluation.

Patient-specific considerations: 

Shared decision-making, incorporating patient values, preferences, and goals, is paramount. It ensures that treatment aligns with individual circumstances and desires.

Contraindications

Though thrombolysis is administered locally during CDT, there is a risk of systemic effects associated with thrombolysis therapy. Systemic thrombolytic therapy is implicated in many severe CDT complications, such as severe bleeding. Hence, practitioners must thoroughly review the patient's medical history before considering thrombolytic therapy (see Table. Contraindication for Thrombolytic Therapy). 

Table 1. Contraindication for Thrombolytic Therapy[17]

Absolute Contraindications

  • Structural intracranial disease
  • Intracranial hemorrhage
  • Ischemic stroke within 3 months
  • Active bleeding
  • Recent brain/spinal surgery
  • Recent head trauma with fracture/brain injury
  • Bleeding diathesis

Relative Contraindications

  • Systolic BP >180 mm Hg
  • Diastolic BP >110 mm Hg
  • Recent non-intracranial bleeding
  • Recent surgery/invasive procedure
  • Ischemic stroke >3 months
  • Anticoagulation
  • Traumatic CPR
  • Pericarditis/pericardial fluid
  • Diabetic retinopathy
  • Pregnancy
  • Age >65
  • Low body weight
  • Female
  • Black race

Equipment

Systemic thrombolysis, the traditional approach for acute PE treatment, faces limitations. The risk of major bleeding, particularly in high-risk patients, can be significant. Additionally, systemic delivery may not adequately reach and break down the clot, potentially limiting its effectiveness.

CDT emerges as a promising alternative. This targeted approach delivers clot-busting medication (thrombolytics) directly to the PE through a catheter, potentially enhancing efficacy while reducing bleeding risk compared to systemic administration. However, the optimal CDT approach remains nuanced, varying based on individual characteristics and PE severity.

Evidence Landscape

While the evidence base for CDT is evolving, it shows promise. Ongoing clinical trials like PE-Thrombus Removal with Catheter-Directed Therapy (PE-TRACT) and Higher Risk Pulmonary Embolism Thrombolysis (HI-PEITHO) are investigating its effectiveness in specific patient populations. However, further research is needed to solidify its role and define optimal treatment strategies.

Table 2. Catheter-Directed Thrombolysis (CDT) Trials 

 

Catheter Name

Delivery Method

Thrombolytic Dose

Thrombolytic Duration

Key Findings from Trials

Cragg-McNamara

Multi-sidehole infusion

Lower than systemic (12-24 mg)

24 hours 

CANARY Trial:[18] 

  • Prematurely stopped due to COVID-19 pandemic
  • Improvement in RV/LV ratio at 3 months with CDT compared to AC (0.7 vs 0.8 p-value 0.01).

EKOSonic (Ultrasound-assisted Thrombolysis)

Multi-sidehole infusion with ultrasound

Lower than systemic

  • ULTIMA: dosing 10-20 mg
  • OPTALYSE 4-12 mg, SEATTLE II 24mg )

ULTIMA: 12 to 15 hours

OPTALYSE 2 to 6 hours

SEATTLE II 12 to 24 hrs

  • ULTIMA Trial:[19] USAT was superior to AC in reversing RV dilatation at 24 hours (0.30±0.20 versus 0.03±0.16 (P<0.001)
  • OPTALYSE PE[20]: USAT using a shorter delivery duration and lower-dose tPA was associated with improved right ventricular function and reduced clot burden compared with baseline
  • SEATTLE II[15] Decrease in Mean RV/LV ratio decreased from baseline to 48 hours post-procedure (1.55 vs. 1.13; P < 0.0001)
  • HI-PEITHO(Ongoing)

 

Bashir Endovascular Catheter

Pharmacomechanical

Lower than systemic (7-14 mg)

 5 hours 

RESCUE Trial:[21] RV/LV diameter ratio decreased by 0.56 (33.3%; P < 0.0001) at 48 hours

AC = Anticoagulation, tPA = Tissue plasminogen activator, USAT = Ultrasound assisted thrombolysis

CDT in Practice

Several CDT devices are available, each with unique mechanisms. Two such mechanisms are the established EKOS Intelligent Drug Delivery System (IDDC) and the recently approved Bashir Endovascular Catheter (BEC-CDT), each equipped with distinctive instruments to combat PE clots.

EKOS-CDT

  • Central conductor: The EKOS-IDDC serves as the central conduit for intervention. This multi-lumen catheter allows simultaneous delivery of a thrombolytic agent (eg, rt-PA) and saline coolant directly to the target thrombus.
  • Sonic disruption module: The MicroSonic Device (MSD) nested within the IDDC harbors multiple ultrasound transducers that emit targeted low-frequency sonic waves to facilitate clot fragmentation and enhance drug penetration.
  • Hemodynamic monitoring: Continuous monitoring of hemodynamic parameters (eg, pulmonary artery pressure and cardiac output) and electrocardiogram (ECG) is essential for ensuring patient safety throughout the procedure and guiding therapeutic adjustments.[22]

BEC-CDT

  • Expandable catheter: The central role in this system is occupied by the 7-F BEC-CDT. Its unique feature is an expandable "basket" equipped with 48 orifices, allowing for strategic deployment and maximizing drug-thrombus contact within the clot.
  • Pulse spray delivery: A dedicated syringe administers controlled "pulse sprays" of the thrombolytic agent, creating initial fissures within the clot. Subsequently, a continuous infusion pump ensures sustained thrombolysis.
  • Fluoroscopic visualization: Real-time fluoroscopy offers visual guidance for catheter placement, ensuring optimal positioning of the expanding basket within the target thrombus.[21]

Shared Instrumental Landscape

  • Venous access establishment: Both procedures require initial venous access, typically achieved using a micropuncture needle and introducer sheath, contingent upon individual patient anatomy and institutional protocols.
  • Guidewire navigation: A guidewire serves as the forerunner, facilitating the navigation of the catheters to the target thrombus within the pulmonary artery.
  • Anticoagulation support: Anticoagulant therapy plays a crucial role in both paradigms, preventing further clot formation and maintaining vascular patency throughout the procedure.

Personnel

The new guidelines recommend a PERT approach at healthcare facilities.[23] The PERT is a multidisciplinary team specialized in diagnosing and managing acute PE. It brings together experts from various specialties to collaborate on optimal patient care. PERTs usually focus on submassive and massive PE cases but can also benefit low-risk patients with major contraindications to standard anticoagulation, such as intracranial hemorrhage. Critical considerations for PERT activation include the following:

  • Initiation of anticoagulation remains crucial and should not be delayed unless contraindicated.
  • PERT activation should occur concurrently with implementing treatment recommendations.
  • PERT structure varies by institution but may involve specialties like critical care, pulmonology, cardiology, interventional radiology, and more.
  • Each member plays a specific role in patient care, from diagnosis and risk stratification to procedures and medication management.

The PERT algorithm provides a general framework and may require adaptation based on specific institutional protocols and patient needs.[24] The following steps encompass the PERT approach to the management of PE:

1. Patient identification: Identify patients with suspected or confirmed acute PE, especially submassive or massive cases. Consider low-risk PE with significant contraindications to anticoagulation.

2. PERT activation: Trigger activation based on predefined criteria (eg, PE severity and comorbidities). Ensure a precise mechanism for team notification and assembly.

3. Initial assessment: The emergency medicine or admitting team performs initial patient evaluation and diagnosis. They gather relevant data such as clinical presentation, risk factors, vital signs, laboratory findings, and imaging studies.

4. Multidisciplinary consultation: PERT convenes to discuss the case and treatment options. Consider the potential roles of each specialty:

  • Critical care: Hemodynamic management, respiratory support
  • Pulmonology: Diagnosis, risk stratification, follow-up
  • Cardiology: Medical management, thrombolysis consideration
  • Radiology: Advanced imaging, procedures (eg, catheter embolectomy)
  • Vascular surgery: Surgical thrombectomy if needed
  • Hematology: Anticoagulation selection, thrombophilia evaluation
  • Pharmacy: Medication dosing and monitoring

5. Treatment decision: PERT collaboratively determines the most appropriate treatment approach based on patient factors and available resources. Options may include:

  • Anticoagulation alone
  • Thrombolysis (systemic or catheter-directed)
  • Mechanical thrombectomy (catheter or surgical)
  • Combination therapies

6. Ongoing management: PERT remains involved in monitoring and follow-up care, adjusting treatment as needed. Patients receive necessary interventions such as oxygen and hemodynamic support. Regular reassessment and monitoring for complications are conducted to ensure optimal patient outcomes.

 PERT is a new team approach to improving coordinated care in acute PE. It brings together specialists for rapid consultations and shared decision-making, improving communication and streamlining treatment. Studies indicate the feasibility of creating PERT teams [25], and the PERT consortium, a collaborative effort, is gathering data to assess its impact.[24] This data will provide valuable insights into PERT's effectiveness in enhancing patient outcomes, care practices, cost-efficiency, and overall PE treatment knowledge.

Preparation

Before initiating the procedure, the practitioner should inspect the thrombolysis catheter delivery system to ensure all components are present. This procedure necessitates a fully operating catheterization laboratory. Healthcare professionals must adhere to proper sterile techniques, including drapes, gloves, and gowns.

Technique or Treatment

The EKOS system employs low-frequency ultrasound delivered through a specialized catheter to disaggregate fibrin strands within the clot.[22] This disaggregation increases the clot's permeability, enabling deeper penetration and enhanced efficacy of co-administered thrombolytic agents like rt-PA. Additionally, the ultrasound energy generates microstreaming effects, further facilitating drug transport within the clot.[26] It is essential to take a step-by-step approach to USAT.

Patient Selection and Preparation

Meticulous patient selection based on risk stratification and established inclusion/exclusion criteria is paramount for successful US-CDT. Informed consent and pre-procedural imaging, such as echocardiography, are mandatory steps.

Catheter Placement

Venous access is typically obtained via the common femoral vein. A guidewire and angiographic catheter navigate to the embolic occlusion in the pulmonary artery. The EKOS-IDDC replaces the angiographic catheter, allowing a precise positioning of the MSD-containing ultrasound transducers within the IDDC.[22] 

Treatment Delivery

Simultaneous rt-PA infusion and saline coolant administration commence through the IDDC at precisely determined rates. Adjustments based on patient factors, such as weight and comorbidities, may be made to optimize treatment efficacy and minimize complications. Concomitant ultrasound delivery begins, utilizing specific protocols based on institutional guidelines and patient characteristics. Hemodynamic monitoring and continuous ECG are essential throughout the procedure to ensure patient safety and treatment efficacy.

The initial treatment duration varies depending on institutional protocols and individual patient factors, typically 12 to 24 hours. Rt-PA dose and ultrasound delivery adjustments are tailored to the patient's clinical response and potential complications.

Close monitoring for bleeding, compartment syndrome, and other potential complications is crucial throughout the procedure. Upon treatment completion, the EKOS devices are meticulously removed. Post-procedural imaging, such as a CT scan, evaluates treatment efficacy and identifies residual thrombus. Patients receive ongoing anticoagulation and clinical monitoring as per standard protocols.

The Bashir Endovascular Catheter [21]

The BEC, a 7-F catheter with a unique expandable "basket" featuring 48 orifices, offers a novel pharmaco-mechanical approach for treating acute PE. This design facilitates clot breakdown by establishing a wide passage for blood flow within the blockage, enhancing the effectiveness of pharmacological agents.

Procedural Steps

Like other CDT approaches, venous access is typically obtained via the femoral or internal jugular vein. The BEC is advanced over a guidewire and positioned within the thrombus in the pulmonary artery. The pulse spray system delivers an initial burst of thrombolytics followed by a continuous infusion over several hours, maximizing drug delivery and penetration within the clot. Close hemodynamic and clinical monitoring throughout the procedure ensure patient safety. Upon completion, the BEC is removed at the bedside under careful supervision.

Complications

There are several possible complications from CDT for PE, with most being secondary to the increased risk of bleeding. The risk of major bleeding is significantly lower than with systemic lytic therapy. Systemic lytic therapy for acute PE is associated with a major bleeding risk of up to 20%.[27] In contrast, the risk of bleeding in patients undergoing CDT is 1.4% in intermediate-risk PE and 6.7% in high-risk PE.[28] 

One of the most common and most feared complications is a hemorrhagic stroke, potentially leading to a devastating outcome for the patient. Other common complications include vascular access-related injuries such as hematoma, pulmonary hemorrhage, retroperitoneal hemorrhage, cardiogenic shock, perforation or dissection of the pulmonary artery, arrhythmias, right-sided valvular regurgitation, pericardial tamponade, and contrast-induced nephropathy.[29]

Clinical Significance

Systemic thrombolysis remains the standard for high-risk acute PE patients, but its bleeding risk, particularly in older individuals, raises concerns. However, the optimal strategy remains unclear for those with intermediate-high-risk PE and RVD. Full-dose systemic thrombolysis offers minimal mortality benefits while exposing patients to potential bleeding complications.

CDT emerges as a potential game-changer. This precise approach delivers clot-busting medication directly to the blockage, offering the possibility of reduced bleeding by lowering the thrombolytic dose. This makes it particularly attractive for high-risk PE patients with contraindications to systemic thrombolysis. Early data, though primarily observational, paints a promising picture. CDT reduces right ventricular dysfunction, a key predictor of mortality in patients with PE, and shows promise in improving short-term functional limitations and hemodynamic measures.[30] However, definitive recommendations await more robust evidence from ongoing randomized controlled trials like PE-TRACT and HI-PEITHO, which compare CDT to standard anticoagulation in intermediate-high-risk PE patients.

Until then, expert interventional cardiologists must rely on individualized assessments and collaborative decision-making within PE response teams.[25] These teams, empowered by local protocols and resources, can tailor therapy to each patient's needs. Implementing PE response teams and encouraging participation in clinical trials are key to unlocking CDT's full potential and improving outcomes for this vulnerable population.

Enhancing Healthcare Team Outcomes

CDT offers improved clinical outcomes in patients with severe, hemodynamically unstable, massive, or submassive PEs. Without CDT, these patients are at a higher risk of morbidity and mortality. The current guidelines recommend all healthcare facilities treating PEs should establish a PERT.[31]

The PERT team is an interprofessional team comprising specialists from various clinical fields, including emergency medicine, critical care, cardiology, internal medicine, radiology, and specialty-trained nurses from critical care, radiology, and emergency care. Clinical pharmacists, especially those trained in critical care, cardiac care, and anticoagulation, are also essential members of this team. Working collaboratively, they can efficiently and effectively deliver CDT to improve patient care.

Once CDT is chosen as a management course, the team should counsel the patient and family regarding the procedure's risks and benefits. A trained clinical provider knowledgeable in the risks and benefits should have this discussion with the nurses to ensure informed consent has been obtained.

An anesthesiologist or nurse anesthetist should then evaluate the patient to determine the need, mode, and safety of anesthetic delivery. An imaging specialist or structuralist may then be consulted for further recommendations on the size and burden of the pulmonary embolism.

The emergency care and critical care nurses must assist in monitoring the patient during the procedure and subsequent infusion therapy for hemodynamic or neurologic complications. The clinical pharmacists assist the interventional team by providing appropriate medication and dosing for the procedure. The critical care pharmacist must help the team adjust other concurrent medications to minimize adverse side effects.

Multiple studies have shown that the institution of a PERT can reduce adverse events in PE care [32]. Swift and early diagnosis followed by early treatment is the key to the successful thrombolysis of pulmonary embolism.

Nursing, Allied Health, and Interprofessional Team Monitoring

Due to the risk of complications during CDT, close monitoring during thrombolytic infusion is required. Most hospitals require intensive care unit-level monitoring during infusion. The patient should receive neurologic checks every hour and regular vascular access site checks to monitor for early signs of possible complications. It is also recommended that the patient be monitored for 24 to 48 hours after infusion for potential complications in the same manner. If any complications (eg, signs of bleeding or an acute neurologic event) are observed or abnormalities are seen in laboratory data, a clinician should be notified immediately.

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