Introduction and Scope of the Problem

The incidence of venous thromboembolism (VTE), including pulmonary embolism (PE) and deep venous thromboembolism (DVT), in the United States is unclear because there is no national surveillance system. However, PE is considered to be the third most common cause of cardiovascular death, with 60,000-100,000 deaths per year.^1-3 This is likely an underestimation because PE can result in unexplained sudden cardiac death. Treatment varies depending on the severity of the disease and the center's expertise and resources. A consensus document was recently issued by the Pulmonary Embolism Response Team (PERT) Consortium, which endorses a PERT approach to high- and intermediate-risk cases by a multidisciplinary team. This team includes, but is not limited to, cardiac surgery, cardiology, hematology, critical care, vascular medicine, vascular surgery, and radiology specialists who discuss complex cases and expedite treatment decisions.⁴

Diagnosis and Risk Stratification

PE presenting symptoms are variable, thus making the diagnosis challenging (Table 1). Once PE is suspected, a determination of pretest probability using either the Wells or Geneva scores may be used.^5,6 In cases of low and intermediate pretest probability, testing D-dimer is helpful because a negative result may be used to rule out PE. The PE rule-out criteria can also be used in cases of low pretest probability. Using this rule, PE can be ruled out without further imaging if there is absence of any of the following:⁷

• Age ≥50
• Heart rate ≥100
• Saturation on room air <95%
• Leg swelling
• Hemoptysis
• Recent trauma or surgery
• History of PE or DVT
• Hormonal therapy

For patients with intermediate or high pretest probability or a positive D-dimer, a contrast-enhanced chest computed tomography (CT) angiography is indicated.

Table 1: Signs and Symptoms Associated With PE

Symptoms

Dyspnea Chest pain Palpitations Dizziness Syncope Flank tenderness (pulmonary infarction)

Signs on Physical Exam

Tachycardia Tachypnea Right ventricular (RV) strain Jugular vein distension Loud S2 Pulsatile liver Parasternal heave

Electrocardiographic Findings

Sinus tachycardia Anterior precordial T Wave inversion S1Q3T3 Precordial ST-segment elevation

Echocardiographic Findings

Right heart dilation Septal shift McConnell's sign: RV free wall akinesis sparing the apex

Imaging Findings

Hampton hump: wedge opacity in the setting of pulmonary infarct Westermark sign: Prominent pulmonary artery with decreased peripheral vasculature DVT per ultrasound

Once a PE is diagnosed, the patient should be risk stratified (Table 2). Short-term mortality in PE is driven by hemodynamic derangements and RV failure. Patients with low-risk PE are generally treated with anticoagulation and may not merit admission to the hospital. Further, patients with a single sub-segmental PE but no DVT, active cancer, or symptoms may not require anticoagulation.⁸ Patients with massive (high-risk) PE require immediate intervention including thrombolytics and thrombectomy, with or without mechanical hemodynamic support. Normotensive patients are further risk stratified using clinical scores such as the Pulmonary Embolism Severity Index (PESI)⁹ and its simplified version, sPESI,¹⁰ biomarkers, and imaging modalities that detect RV strain. The presence of RV strain by both biomarkers and imaging indicates a high-risk, submassive PE and portends worse prognosis, which may merit more aggressive treatment.¹¹

Table 2: Risk Stratification and Treatment of PE

	Low Risk	Intermediate Risk (Submassive)	High Risk (Massive)
Presentation	Normotensive Low risk per PESI and sPESI Normal biomarkers	PESI class III-IV sPESI ≥1 Echo or CT evidence of RV strain Positive troponin Elevated B-type natriuretic peptide or N-terminal B-type natriuretic peptide	Hypotension (systolic blood pressure <90 mmHg for ≥15 min, drop in systolic blood pressure of ≥40 mmHg or vasopressor) Thrombus in transit Syncope Cardiac arrest
Treatment	Anticoagulation: Direct oral anticoagulants are preferred Candidates for early discharge	Anticoagulation: Consider unfractionated heparin over others if any of the therapies below are possible Systemic thrombolytic (100 mg over 2 h) High risk of bleeding: Half-dose thrombolytic (50 mg over 2 h) Catheter-directed therapy Surgical embolectomy High-risk PE and cardiogenic shock: Mechanical support to allow stability for thrombolysis, catheter-directed therapy, or surgical embolectomy

Treatment

Anticoagulation should be initiated as soon as the diagnosis of PE is suspected.⁸ Unfractionated heparin may be preferred in patients who are candidates for further advanced therapies such as thrombolysis, catheter-directed thrombolytics or embolectomy, or surgical embolectomy because it provides more flexibility for procedures.⁴ Direct oral anticoagulants are first-line therapy for low-risk patients and intermediate- and high-risk patients once they have achieved hemodynamic stability.^8,12 Systemic thrombolytic therapy should be considered in massive PE due to observed reduction in mortality and recurrence.¹³ Systemic thrombolytic therapy may be considered in high-risk submassive PE in the absence of contraindications because it has been shown to improve hemodynamics, reverse RV dilatation, and prevent hemodynamic decompensation, though no significant short-term mortality reduction has been observed.^8,14 Unfortunately, systemic thrombolytic therapy is associated with significant bleeding, including a 6% risk of major bleeding and up to 3% of intracranial hemorrhage (ICH).^14,15 In patients with relative contraindications to systemic thrombolytic therapy, half-dose thrombolytic can be used because it provides similar improvements in RV strain and pulmonary artery pressures.¹⁶

Catheter-Directed Therapy

Given the significant risks of systemic thrombolytic therapy including ICH, catheter-directed approaches have been developed to reduce the dose of thrombolytics used or avoid thrombolytics altogether (Table 3). This technology has been tested in randomized controlled trials using the endpoint of improvement in RV/left ventricular (LV) ratio because this predicts mortality and adverse outcomes.¹⁷ Safety endpoints include major bleeding, mortality, and recurrent PE. Two primary approaches are currently used. The first, catheter-directed thrombolytics, involves local delivery of lytic therapy to the pulmonary arteries. This may be performed using a standard pigtail catheter or pulmonary artery catheter to deliver the lytics locally. Alternatively, the lytics may be delivered using the EKOS EkoSonic (BTG PLC; London, UK) catheter for ultrasound-assisted catheter-directed thrombolysis. This catheter uses locally delivered ultrasound to separate fibrin strands in the thrombus, potentially enhancing penetration of the thrombolytic. The second catheter-directed approach includes mechanical thrombectomy, which may be used in isolation or in combination with lytic therapy based on the clinical scenario. The catheter systems currently approved for this indication include the Penumbra Indigo (Penumbra, Inc.; Alameda, CA) and FlowTriever (Inari Medical, Inc.; Irvine, CA) catheters. Other systems are currently under development or investigation for this indication. There are no published head-to-head trials comparing the various systems or comparing catheter-directed therapy to systemic thrombolysis. Therefore, the choice of modality should be based on local expertise and availability. Overall, the risk associated with catheter-directed therapies is low, with a 0.35% risk of ICH and 4.6% risk of major complications.¹⁸ Therefore, guidelines recommend use of catheter-directed lytics in intermediate-high-risk PE with relative contraindications to thrombolytic and use of catheter-directed thrombectomy in patients with absolute contraindications to thrombolytics or failed thrombolytic therapy.⁴

Table 3: Catheter-Directed Therapy

Device	Sheath	Technique	TrialREF and Indications
Ultrasound-Assisted Thrombolysis
EkoSonic	5.2 Fr	High-frequency, low-power ultrasound waves aim to disrupt the clot allowing lytic to penetrate clot with a lower dose requirement	ULTIMA (Ultrasound Accelerated Thrombolysis of Pulmonary Embolism)19 20 mg tPA 0.3 difference in RV/LV ratio 0% major bleeding SEATTLE II (Submassive and Massive Pulmonary Embolism Treatment With Ultrasound Accelerated Thrombolysis Therapy)20 24 mg of tPA 0.42 difference in RV/LV ratio 10% major bleeding, no ICH OPTALYSE-PE (Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism)21 4-12 mg of tPA for 2-6 hrs 0.3-0.4 difference in RV/LV ratio 1 episode of ICH in the arm of 12 mg over 6 h Overall risk of bleeding of 4%
Suction Thrombectomy
Indigo	4, 6, 8 Fr	High-velocity vacuum suction catheter	EXTRACT PE (Evaluating the Safety and Efficacy of the Indigo® Aspiration System in Acute Pulmonary Embolism) 0.43 reduction (in the RV/LV ratio after 48 hours Small caliber
FlowTriever	20 Fr	Large aspiration guide catheter, device has 3 self-expanding nitinol disks unsheathed to disrupt and aspirate clot	FLARE (FlowTriever Pulmonary Embolectomy Clinical Study)22 No tPA required Major bleeding rate 0.9%

Surgical Embolectomy

Surgical embolectomy is recommended in patients with high-risk or intermediate-high-risk PE with absolute contraindications to thrombolytic therapy, failed thrombolytic therapy, or cardiogenic shock that may cause death prior to thrombolytic therapy. Surgical embolectomy is often considered as first-line therapy for patients with thrombus in the right heart or across a patent foramen ovale (clot-in-transit). The risk of the procedure depends on the patient's baseline hemodynamic status and comorbidities, but it has been reported to be ≤11%.^23,24

Mechanical Circulatory Support

In patients with high-risk PE and cardiogenic shock, cardiac arrest, or impending hemodynamic collapse, further mechanical support should be considered. Venoarterial extracorporeal membrane oxygenation (VA ECMO) is effective when used in combination with any of the above treatments with good survival rates and low complication risks.^25,26 VA ECMO provides complete hemodynamic support with up to 5-6 L of output in conjunction with an oxygenator, which provides oxygenation and ventilation support. Importantly, as it bypasses the pulmonary circulation, it reduces the RV pre-load and reduces RV distention while having no effect on the pulmonary artery pressure. RV support with heart pumps has also been described in case reports in the setting of PE. These devices deliver blood directly into the pulmonary artery. Studies have not compared these modalities to VA ECMO in the setting of PE.

Supportive Care and Follow-Up

In patients with PE who cannot tolerate anticoagulation, current guidelines recommend the use of inferior vena cava filters.⁸ The addition of inferior vena cava filters to anticoagulation has not been demonstrated to be beneficial in prospective trials but may be considered in patients with large, mobile, or proximal DVT.^4,27,28 Retrievable filters should be removed as soon as possible. Finally, patients should be followed in the outpatient setting to assess for recurrent PE, guide further anticoagulation, complete a comprehensive coagulopathy evaluation, and assess for possible persistent RV dysfunction and chronic thromboembolic disease.⁴

Conclusions

PE is a common clinical problem with varied manifestations ranging from benign to fatal. Given the complexities of diagnostic, stabilization, and treatment modalities, a rapidly assembled and collaborative multi-disciplinary approach is helpful. Further development of treatment options and randomized clinical trials are needed to delineate optimal approaches for these patients. The consensus document published by the PERT consortium provides a foundation for the decision-making required for these patients.

References

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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, SCD/Ventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Nuclear Imaging

Keywords: Venous Thromboembolism, Pulmonary Embolism, Anticoagulants, Angiography, Coronary Angiography, Heparin, Hemoptysis, Heart Rate, Consensus, Dilatation, Pulmonary Artery, Specialization, Embolectomy, Thrombolytic Therapy, Fibrinolytic Agents, Thrombectomy, Intracranial Hemorrhages, Hematology, Cardiac Surgical Procedures, Death, Sudden, Cardiac, Critical Care, Neoplasms, Prognosis, Risk Assessment, Patient Care Team

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