Introduction

Several developments in risk assessment, diagnosis, and management of pulmonary thromboembolic disease have taken place since the last European Society of Cardiology (ESC) guidelines in 2016 and the last update of American College of Chest Physicians guidelines in 2016. Over the past 16 years, the annual incidence rate of acute pulmonary embolism (PE) diagnosis has increased throughout the world. This is evidenced by a reported prevalence of 50% per diagnostic study in North America, with current confirmation rates as low as 5%. However, the case fatality has decreased, likely due to increased incidence through the diagnosis of subsegmental PE. Here we summarize the 2019 ESC guidelines for the diagnosis and management of acute PE, which were developed in collaboration with the European Respiratory Society.¹

Risk Assessment

1. Pretest probability scores include the revised Geneva Score and the Wells rule. Expected rates of PE confirmation based on pre-test probability are 10% in low, 30% in moderate, and 65% in high pretest probability. The Pulmonary Embolism Rule-out Criteria (PERC) score is intended for patients in the emergency department who have such low pretest probability that diagnostic testing should not be initiated. The PERC score includes 8 parameters significantly associated with an absence of PE: age <50 years, pulse <100 beats per minute, oxygen saturation >94%, no unilateral leg swelling, no hemoptysis, no recent trauma or surgery, no history of venous thromboembolism (VTE), and no oral hormone use.
2. D-dimer
   1. Point-of-care D-dimers should be used only in patients with a low pretest probability because there is a reduced sensitivity (88%) compared with the standard laboratory-based assay (95%).
   2. In patients with low to intermediate clinical probability of PE, D-dimer should be the initial test. If negative, no treatment is indicated. If positive, computed tomographic pulmonary angiography (CTPA) should be performed for definitive diagnosis.
   3. Age-adjusted D-dimer (age x 10 mcg/L) for patients older than 50 years should be considered to identify low-risk patients (Class IIa).
3. Hemodynamic instability is clearly defined as follows:
   1. Cardiac arrest
   2. Obstructive shock (systolic blood pressure [BP] <90 mmHg or need for vasopressors to achieve BP ≥90 mmHg and end organ hypoperfusion
   3. Persistent hypotension (systolic BP <90 mmHg or systolic BP drop ≥40 mmHg lasting longer than 15 minutes and not due to another identifiable cause
4. In patients with high clinical probability of PE, CTPA should be performed as the initial test.

Imaging

1. The diagnosis of VTE and PE should be accepted if compressive ultrasonography shows a proximal deep venous thrombosis (DVT) in a patient with clinical suspicion for PE.
2. Echocardiography alone cannot be used to rule out PE. It is useful in suspected high-risk PE, in which the absence of echocardiographic signs of right ventricular (RV) overload or dysfunction essentially rules out PE as the reason for hemodynamic instability.
3. Many imaging studies are available for the diagnosis of acute PE:
   1. CTPA is the most accessible, provides excellent specificity (96%), and may provide an alternative diagnosis. However, the effective radiation dose is 3-10 mSv, which should be of concern especially in young women for radiation exposure to the breast tissue. Additionally, renal dysfunction should be taken into consideration due to the use of iodinated contrast.
   2. Planar ventilation/perfusion (V/Q) scan is inexpensive with few contraindications and relatively low radiation exposure (2 mSv). However, it is often unable to provide an alternative diagnosis and is inconclusive in 50% of cases.
   3. V/Q single-photon emission computed tomography provides the lowest rate of non-diagnostic tests (<3%), has few contraindications, and provides a binary result with low radiation (2 mSv). However, it will not provide an alternative diagnosis and has no validated outcome data.
   4. Pulmonary angiography is the gold standard, but it is an invasive procedure with the highest radiation dose (10-20 mSv).

Prognosis

1. Initial risk stratification (Class I) should be performed in all patients with suspected or confirmed PE. Prognostic assessment should include clinical parameters (simplified Pulmonary Embolism Severity Index [PESI] score, RV function, hemodynamics, and elevated biomarkers).
2. Unfavorable short-term prognosis in acute PE is predicted by tachycardia, low systolic BP, respiratory insufficiency, or syncope.
3. Echocardiographic findings associated with a poor prognosis are an RV/left ventricular diameter ratio ≥1.0 and tricuspid annular plane systolic excursion <16 mm.
4. An RV/left ventricular diameter ratio ≥1.0 on computed tomography is associated with a 2.5-fold increased risk of all-cause mortality and 5-fold increased PE-related mortality.
5. High-sensitivity troponin has a 98% negative predictive value when <14 pg/mL for excluding an adverse in-hospital clinical outcome.
6. B-type natriuretic peptide, N-terminal pro-B-type natriuretic peptide, and troponin have low specificity and positive predictive value for early mortality for normotensive patients with PE.
7. Elevated lactate, high serum creatinine, and hyponatremia are some of the other laboratory markers of adverse prognosis.
8. Of the clinical scores integrating PE severity and comorbidity, the PESI score, which includes 11 weighted variables, has been extensively validated. Simplified PESI score has been shown to be equally useful. Simplified PESI is a weighted score that uses 7 variables including age, cancer, chronic cardiopulmonary disease, heart rate, systolic BP, and oxyhemoglobin saturation levels.
9. Prognostic assessment strategy is recommended for patients without hemodynamic instability
   1. Low risk (PESI Class I-II, simplified PESI of 0)
   2. Intermediate low risk (elevated PESI score with or without RV dysfunction or elevated troponin)
   3. Intermediate high risk (elevated PESI score with both RV dysfunction and elevated troponin)
   4. High risk (hemodynamic instability)

Treatment

1. Initial anticoagulation should be initiated in high or intermediate probability PE while awaiting results of diagnostic testing (Class I).
   1. Low molecular weight heparin (LMWH) and fondaparinux are preferred over unfractionated heparin (UFH) because there are lower risks of major bleeding or heparin-induced thrombocytopenia (Class I).
   2. UFH should be reserved for hemodynamically unstable patients or patients awaiting reperfusion therapy.
2. Oral anticoagulants
   1. Direct-acting oral anticoagulants (DOACs) have been shown to be noninferior to LMWH and vitamin K antagonist (VKA), though there have been significantly lower rates of major bleeding, and are recommended over VKA in eligible patients (Class I).
   2. Studied dosing regimens follow:
      1. Dabigatran parenteral anticoagulation for ≥5 days followed by dabigatran 150 mg BID
      2. Rivaroxaban 15 mg BID for 3 weeks followed by 20 mg QD
      3. Apixaban 10 mg BID for 7 days followed by 5 mg BID
      4. Edoxaban UFH or LMWH for ≥5 days followed by 60 mg daily or 30 mg daily if creatinine clearance = 30-50 mL/min or body weight <60kg
   3. If VKA is given, UFH, LMWH, or fondaparinux should be continued ≥5 days and until international normalized ratio is 2.5 (range 2.0-3.0) (Class I).
   4. Initial starting dose of warfarin may be 10 mg when <60 years in healthy patients, though 5 mg starting dose is suggested for all others.
   5. Novel oral anticoagulants are contraindicated in severe renal impairment, during pregnancy and lactation, or with anti-phospholipid syndrome (Class III).
3. Systemic thrombolytic therapy should be reserved for high-risk, hemodynamically unstable patients (Class I). If these patients fail thrombolytic therapy or are not candidates, then surgical embolectomy is recommended (Class I). Catheter-directed thrombolysis should be reserved for high-risk patients in whom thrombolysis has failed or is contraindicated (Class IIa).
4. Routine use of inferior vena cava filters is still not routinely recommended (Class III), though it could be considered if absolute contraindications to anticoagulation (Class IIa) or in cases of recurrent PE despite therapeutic anticoagulation (Class IIa).
5. Early discharge with continuation of home anticoagulation therapy should be considered in the following cases:
   1. The Hestia exclusion criteria integrate aspects of PE severity, comorbidity, and the feasibility of home treatment by means of a checklist of 12 questions that can be answered at bedside.
   2. The risk of early PE-related death or serious complication is low (Hestia criteria all negative).
   3. No serious comorbidity or aggravating conditions warranting hospitalization.
   4. Infrastructure for proper outpatient care and follow-up are provided.

Duration of Anticoagulation

1. All patients should receive 3 months of therapy (Class I).
2. Discontinuation is recommended after 3 months if index PE/DVT due to major transient or reversible risk factor (Class I).
3. The risk of recurrence is similar when therapy is withdrawn at 3-6 months versus 12-24 months.
4. Extended duration of anticoagulation increases bleeding risk but decreases recurrence risk by ≤90%.
5. Indefinite anticoagulation for recurrent VTE not related to a major transient or reversible risk factor (Class I).
6. Indefinite anticoagulation with VKA is recommended for patients with antiphospholipid syndrome (Class I).

Groups at Increased Risk of Recurrence (high at >8%/year)

1. A strong (major) attributable transient or reversible risk factor, such as major surgery or trauma
2. Persistence of a weak (minor) transient or reversible risk factor or a non-malignant risk factor for thrombosis
3. Index episode that occurred in the absence of any identifiable risk factor
4. One or more previous episodes of VTE and those with a major persistent prothrombotic condition
5.  Active cancer

Cancer Population

1. LMWH reduces VTE recurrence by up to 40% compared to VKAs, though overall remains high at 7-9% compared to non-cancer patients and should be considered over VKA for the first 6 months of treatment (Class IIa).
2. All patients should be treated for ≥3-6 months with acute PE, especially with gastrointestinal cancers. Extended therapy for an indefinite period could be considered for patients who have not been "cured" of their cancer (Class IIa).
3. Rivaroxaban or edoxaban could be considered for patients with low risk of bleeding and without gastrointestinal cancer (Class IIa).
4. If PE is detected in patients without cancer, investigation into an underlying malignancy should be limited to history, exam, basic laboratory studies, and a chest X-ray if a CTPA was not performed.
5. Asymptomatic PE should be treated the same way as symptomatic PE (Class IIa).

Pregnancy

1. Risk factors include in vitro fertilization, prior VTE, obesity, medical comorbidities, stillbirth, pre-eclampsia, post-partum, hemorrhage, and caesarean section.
2. LMWH is the treatment of choice for PE and VTE during pregnancy (Class I). DOACs are contraindicated in pregnancy (Class III). The last dose of LMWH should be ≥24 hours prior to epidural anesthesia (Class III).
3. If pre-test probability is high, or low/intermediate with positive D-dimer, anticoagulation should be initiated with LMWH. A chest X-ray and/or compressive proximal duplex ultrasound should be performed following initial assessment.
4. CTPA radiation is well below the fetal risk level and is considered as the initial imaging test of choice for diagnosis with an abnormal chest X-ray (Class IIa). V/Q scans also expose low levels of radiation and may be considered as an alternative to CTPA in patients with a normal chest X-ray.
5. In high-risk patients (recent PE), LMWH should be converted to UFH ≥36 hours prior to delivery, and the infusion should be stopped 4-6 hours prior to delivery.
6. Reinitiation of anticoagulation should be decided by a multidisciplinary team and should occur no earlier than 4 hours after removal of an epidural catheter (Class III).
7. Treatment should continue for ≥6 weeks after delivery, with a minimum total treatment duration of 3 months.
8. LMWH and warfarin can be given to breastfeeding mothers; DOACs (Class III) are contraindicated.

Follow-Up

1. Perform 3-6 months after diagnosis of acute PE (Class I), with dyspnea assessed by either the Medical Research Council scale or World Health Organization functional scale.
2. A transthoracic echocardiogram should be ordered if patient has persistent dyspnea at 3-6 months (Class IIa).
3. A V/Q scan should be considered at 3-6 months should there be concern for pulmonary hypertension (PH) to assess for chronic thromboembolic PH (Class IIa), with referral to a PH or chronic thromboembolic PH specialist if abnormal (Class I).

References

1. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism Developed in Collaboration With the European Respiratory Society (ERS): The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Respir J 2019;54:1901647.

Clinical Topics: Anticoagulation Management, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Pulmonary Hypertension, Hypertension

Keywords: Hypertension, Pulmonary, Venous Thromboembolism, Warfarin, Risk Factors, Heparin, Low-Molecular-Weight, Heparin, Antiphospholipid Syndrome, Antiphospholipid Syndrome, Cesarean Section, Pre-Eclampsia, Follow-Up Studies, Breast Feeding, Mothers, X-Rays, Pregnancy, Factor Xa Inhibitors, Creatinine, International Normalized Ratio, Vena Cava Filters, Oxyhemoglobins, Heart Rate

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