Pulmonary embolism

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Omar Elshafei, MD[2] Cafer Zorkun, M.D., Ph.D. [3]; Rim Halaby, M.D. [4]

Synonyms and keywords: PE; lung blood clot; blood clot-lung; embolism-pulmonary

Overview

Pulmonary embolism (PE) is an obstruction of blood flow in the pulmonary arterial circulation, most commonly by a thrombus that has embolized from the deep veins of the lower limbs. Together with deep vein thrombosis (DVT), PE forms the spectrum of venous thromboembolism (VTE). PE is the third leading cause of cardiovascular mortality, and its presentation ranges from an incidental, asymptomatic finding on imaging to cardiogenic shock and cardiac arrest. Death in acute PE results mainly from acute pressure overload and failure of the right ventricle (RV).

The incidence of PE is approximately 60 to 120 per 100,000 people per year. Major risk factors include surgery, trauma, hospitalization, active cancer, pregnancy and the postpartum period, estrogen-containing therapy, previous VTE, and thrombophilia, although many VTE events have no identifiable provoking factor. Mortality from PE has declined in Europe and in large registries, but the decline in the United States slowed or reversed after the late 2000s.

In hemodynamically stable patients, PE is diagnosed with a sequential strategy: assessment of clinical (pretest) probability by clinical gestalt or a validated rule such as the Wells score or the revised Geneva score, the pulmonary embolism rule-out criteria (PERC) in low-risk emergency department patients, D-dimer testing with fixed, age-adjusted, or probability-adapted thresholds (such as the YEARS and PEGeD strategies), and computed tomography pulmonary angiography (CTPA), with ventilation/perfusion (V/Q) scanning when CTPA is contraindicated or unavailable. In patients with hemodynamic instability, bedside echocardiography showing acute RV dysfunction can justify emergency treatment when CTPA cannot be performed safely.

Severity assessment determines the site of care and the intensity of treatment. The 2026 AHA/ACC multisociety guideline replaced the terms massive, submassive, and low-risk PE with the Acute PE Clinical Categories A to E, which combine symptoms, a clinical severity score (PESI, sPESI, or Hestia), RV imaging, cardiac biomarkers, markers of hypoperfusion, and a respiratory modifier. The 2019 ESC/ERS guideline, which remains the current European guideline, classifies patients as being at high, intermediate-high, intermediate-low, or low risk of early death.

Anticoagulation is the cornerstone of treatment. Direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for most patients, low molecular weight heparin is preferred over unfractionated heparin for parenteral therapy unless reperfusion is anticipated, and carefully selected patients with low-severity PE can be treated at home. Systemic thrombolysis is indicated for PE with cardiopulmonary failure, and surgical embolectomy or catheter-directed therapy is used when thrombolysis is contraindicated or has failed. Randomized trials published in 2026 showed that catheter-directed thrombolysis reduces early hemodynamic decompensation in normotensive patients with RV dysfunction and elevated cardiac biomarkers (intermediate-risk or intermediate-high-risk PE), without a demonstrated reduction in mortality. Inferior vena cava filters are considered mainly when anticoagulation is contraindicated or PE recurs despite therapeutic anticoagulation. All patients receive at least 3 months of anticoagulation, and extended treatment is considered after unprovoked PE or PE associated with a persistent risk factor. Survivors should be asked about persistent dyspnea and functional limitation, which can signal chronic thromboembolic pulmonary hypertension (CTEPH) or the broader post-PE syndrome.

Historical Perspective

• In the 19th century, Rudolf Virchow described the embolization of venous thrombi to the pulmonary arteries and introduced the term embolism. The combination of venous stasis, endothelial injury, and hypercoagulability that bears his name (Virchow's triad) remains the conceptual framework of VTE pathogenesis.
• In 1971, McIntyre and Sasahara described the hemodynamic response to PE in patients without prior cardiopulmonary disease, which underpins the observation that pulmonary artery pressure rises once more than 30% to 50% of the cross-sectional area of the pulmonary arterial bed is occluded.
• In 1990, the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) defined the accuracy of V/Q scanning. Of patients with a high-probability scan and a definitive angiogram, 88% had PE, but a high-probability scan had a sensitivity of only 41% (specificity 97%), whereas any abnormal scan had a sensitivity of 98% and a specificity of 10%.
• In 1997 and 1999, the MAPPET and ICOPER registries established the prognostic weight of hemodynamic status. In-hospital mortality ranged from 8.1% in stable patients to 25% in patients with cardiogenic shock and 65% in those who needed cardiopulmonary resuscitation, and crude 3-month mortality was 17.4% among 2454 consecutive patients.
• In 1998, the PREPIC trial showed that permanent vena cava filters reduced early PE (1.1% vs 4.8% by day 12) at the cost of more recurrent DVT at 2 years (20.8% vs 11.6%), with no difference in mortality.
• In 2000 and 2001, Wells and colleagues derived a simple clinical probability model and showed that a low pretest probability combined with a negative D-dimer could exclude PE without imaging, with a negative predictive value of 99.5%.
• In 2003, the CLOT trial established low molecular weight heparin (LMWH) as treatment for cancer-associated VTE, with a 6-month probability of recurrence of 9% vs 17% with a coumarin.
• In 2004 and 2005, the pulmonary embolism rule-out criteria (PERC) and the Pulmonary Embolism Severity Index (PESI) were derived.
• In 2006, PIOPED II established multidetector CTPA as the main diagnostic test (sensitivity 83%, specificity 96%), the revised Geneva score was published, and the Christopher study validated a diagnostic algorithm combining clinical probability, D-dimer, and computed tomography.
• Between 2009 and 2013, the RE-COVER, EINSTEIN-DVT, EINSTEIN-PE, AMPLIFY, and Hokusai-VTE trials established direct oral anticoagulants as alternatives to LMWH followed by a vitamin K antagonist.
• In 2011, an AHA scientific statement defined massive, submassive, and low-risk PE, and a US analysis linked the introduction of CTPA to an 81% rise in PE incidence with only a 3% fall in mortality, suggesting overdiagnosis.
• In 2014, the PEITHO trial showed that systemic fibrinolysis in intermediate-risk PE prevented hemodynamic decompensation but increased major bleeding and stroke, and the ADJUST-PE study validated the age-adjusted D-dimer cutoff.
• Between 2017 and 2019, the YEARS and PEGeD studies validated D-dimer thresholds adapted to clinical probability, pregnancy-specific diagnostic algorithms were validated, and the ESC and ERS published their 2019 guideline with a four-tier risk classification.
• In 2025, the PEERLESS trial compared large-bore mechanical thrombectomy with catheter-directed thrombolysis in 550 patients with intermediate-risk PE, and the API-CAT, RENOVE, and HI-PRO trials refined the use of reduced-dose and extended anticoagulation.
• In 2026, the first AHA/ACC multisociety guideline on acute PE in adults introduced the Acute PE Clinical Categories A to E. In the same year, the HI-PEITHO and PRAGUE-26 trials showed that catheter-directed thrombolysis reduced early decompensation in normotensive patients with RV dysfunction and elevated cardiac biomarkers, and the COBRRA trial showed less clinically relevant bleeding with apixaban than with rivaroxaban.

Classification

PE can be classified by clinical severity and risk of early death, by the presence and type of provoking risk factors, by the anatomic level of the most proximal embolus, and by its time course.

AHA/ACC 2026 Acute Pulmonary Embolism Clinical Categories

The 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN guideline replaced the massive, submassive, and low-risk terminology with five clinical categories (A to E) and subcategories that integrate symptoms, a clinical severity score, cardiopulmonary dysfunction, hemodynamic status, and end-organ perfusion.

Category	Definition	Subcategories and examples	Disposition emphasized by the guideline
A	Subclinical, incidental, or asymptomatic PE	A1: asymptomatic PE found incidentally, for example a subsegmental PE on a cancer-staging computed tomography scan	Discharge from the emergency department; outpatient treatment is reasonable for selected patients
B	Symptomatic PE with a low clinical severity score (for example, PESI class I to II, sPESI of 0, or Hestia of 0)	B1: single or multiple subsegmental PE B2: segmental or more proximal PE	Early discharge; outpatient treatment is reasonable for selected patients
C	Symptomatic PE with an elevated clinical severity score (for example, PESI class III to V, sPESI of 1 or more, or Hestia of 1 or more)	C1 to C3 are assigned according to evidence of cardiopulmonary dysfunction on cardiac biomarkers (troponin, natriuretic peptide) and RV size and function on echocardiography or computed tomography; for example, bilateral lobar PE without RV enlargement or troponin elevation is classified as C1, whereas RV dysfunction with a positive troponin corresponds to C3	Hospitalization
D	Incipient cardiopulmonary failure (for example, normotensive shock)	D1: transient or recurrent hypotension (including hypotension relative to baseline) that is short-lived or responsive to volume, without hypoperfusion or end-organ dysfunction D2: transient hypotension with a marker of decreased perfusion or end-organ dysfunction (for example, acute kidney injury or persistently elevated lactate)	Hospitalization; advanced therapies can be considered in D1 to D2
E	Cardiopulmonary failure	E1: recurrent or persistent hypotension (hemodynamic collapse) with cardiogenic shock (SCAI stage C) E2: refractory cardiogenic shock (SCAI stage D to E) or cardiac arrest	Hospitalization; advanced therapies are reasonable in E1

• The suffix R (for example, C3R or D2R) denotes prominent respiratory abnormalities, such as hypoxemia, tachypnea, or a supplemental oxygen requirement, with escalating oxygen or ventilatory support in the higher categories.
• Markers of hypoperfusion or end-organ dysfunction cited by the guideline include lactate >2 mmol/L, acute kidney injury, urine output <0.5 mL/kg/h, altered mental status, cardiac index <2.2 L/min/m², mean arterial pressure <60 mm Hg, and an increased shock score or stage.
• Thrombus burden (for example, a saddle or central embolus) should not be used for risk stratification in categories A to C (Class 3: No Benefit, Level B-NR).
• Early single-center validations suggest better prognostic discrimination than the ESC 2019 model. In 2251 hospitalized patients, the 30-day mortality AUC was 0.885 for the AHA/ACC categories vs 0.763 for the ESC model, and 75.7% of 37 patients in categories D to E who were classified as ESC intermediate risk died within 30 days. In 1050 inpatients, the AUC for in-hospital death was 0.716 vs 0.610; 77.1% of ESC intermediate-low patients were reclassified to C2 or higher and 34.3% to D2 or D2R (in-hospital mortality 8.1%), but the advantage was concentrated in patients with active cancer and may partly reflect comorbidity, so prospective multicenter validation is needed.

ESC 2019 Classification of PE Severity and Risk of Early Death

The 2019 ESC/ERS guideline first identifies hemodynamic instability (high risk) and then stratifies hemodynamically stable patients using a clinical severity score, RV imaging, and cardiac troponin.

Early mortality risk	Hemodynamic instability	PESI class III to V or sPESI ≥1	RV dysfunction on TTE or CTPA	Elevated cardiac troponin
High	Present	Not required for classification	Present	Not required for classification
Intermediate-high	Absent	Present	Present	Present
Intermediate-low	Absent	Present	One or none present
Low	Absent	Absent	Assessment optional; if assessed, both absent

• Hemodynamic instability is defined as cardiac arrest requiring cardiopulmonary resuscitation; obstructive shock (systolic blood pressure <90 mm Hg, or vasopressors required to achieve a blood pressure ≥90 mm Hg despite adequate filling status, together with end-organ hypoperfusion such as altered mental status, cold and clammy skin, oliguria or anuria, or increased serum lactate); or persistent hypotension (systolic blood pressure <90 mm Hg or a systolic blood pressure drop ≥40 mm Hg, lasting longer than 15 minutes and not caused by new-onset arrhythmia, hypovolemia, or sepsis).
• Hemodynamic instability combined with PE confirmed by CTPA or RV dysfunction on transthoracic echocardiography is sufficient for high-risk classification without calculating PESI or measuring troponin.
• Patients with RV dysfunction or elevated cardiac biomarkers despite PESI class I to II or sPESI of 0 are classified as intermediate risk.
• In a pooled analysis of 906 patients classified with the 2014 ESC model, which uses the same categories, 30-day mortality was 22% in high-risk, 7.7% in intermediate-high-risk, 6.0% in intermediate-low-risk, and 0.5% in low-risk patients (negative predictive value 99.5%).

Legacy AHA 2011 Terminology

The 2011 AHA scientific statement definitions remain in wide use, and several trials enrolled patients with submassive PE.

• Massive PE: acute PE with sustained hypotension (systolic blood pressure <90 mm Hg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE such as arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction), pulselessness, or persistent profound bradycardia (heart rate <40 beats/min with signs or symptoms of shock).
• Submassive PE: acute PE without systemic hypotension (systolic blood pressure ≥90 mm Hg) but with either RV dysfunction or myocardial necrosis.
  • RV dysfunction: RV dilation (apical four-chamber RV diameter divided by left ventricular diameter >0.9) or RV systolic dysfunction on echocardiography; RV dilation (four-chamber RV diameter divided by left ventricular diameter >0.9) on computed tomography; elevation of BNP (>90 pg/mL) or NT-proBNP (>500 pg/mL); or electrocardiographic changes (new complete or incomplete right bundle branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion).
  • Myocardial necrosis: troponin I >0.4 ng/mL or troponin T >0.1 ng/mL.
• Low-risk PE: acute PE without the clinical markers of adverse prognosis that define massive or submassive PE.

The three classification systems use different variables and thresholds, so the correspondence between them is approximate. Most randomized reperfusion trials published through 2026 enrolled patients defined by ESC (intermediate-risk or intermediate-high-risk) or AHA 2011 (submassive) criteria.

AHA/ACC 2026 category	Closest ESC 2019 class	Closest AHA 2011 term
A: incidental or asymptomatic PE	No dedicated class	No dedicated term
B: symptomatic PE, low clinical severity score	Low risk; intermediate-low risk if RV dysfunction or elevated troponin is present	Low-risk PE; submassive PE if RV dysfunction or myocardial necrosis is present
C: symptomatic PE, elevated clinical severity score, without hypotension	Intermediate-low or intermediate-high risk, depending on RV imaging and troponin	Low-risk or submassive PE, depending on RV dysfunction and myocardial necrosis
D: incipient cardiopulmonary failure	Intermediate or high risk, depending on the duration of hypotension and the presence of end-organ hypoperfusion	Usually submassive PE; massive PE if hypotension lasts at least 15 minutes or requires inotropic support
E: cardiopulmonary failure	High risk	Massive PE

Classification by Provoking Risk Factors

• Guidance from the ISTH Scientific and Standardization Committee categorizes VTE according to whether it is associated with a major transient, minor transient, or persistent risk factor, or has no identifiable risk factor (unprovoked), because these categories predict the risk of recurrence after anticoagulation is stopped.
• The ESC 2019 guideline no longer uses the binary terms provoked and unprovoked and instead groups risk factors by the estimated long-term risk of recurrence (low <3% per year, intermediate 3% to 8% per year, and high >8% per year); the full table appears under Assessment of Probability of Subsequent VTE in the Diagnosis section.

Anatomic Classification

• PE is described by the most proximal level of the embolus: saddle (straddling the bifurcation of the main pulmonary artery), main pulmonary artery, lobar, segmental, or subsegmental.
• Clinical features vary with embolus location; in PIOPED II, dyspnea or tachypnea occurred in 92% of patients with emboli in the main or lobar pulmonary arteries but in only 65% when the largest embolus was segmental.
• In the AHA/ACC system, anatomic level separates B1 (subsegmental) from B2 (segmental or more proximal) PE, but thrombus burden is not used for risk stratification in categories A to C.
• Isolated subsegmental PE is detected more frequently with modern CTPA. In a prospective cohort of 266 patients with isolated subsegmental PE and no proximal DVT on serial ultrasonography who were managed without anticoagulation, the 90-day cumulative incidence of recurrent VTE was 3.1% (2.1% for single and 5.7% for multiple subsegmental PE).

Temporal Classification

• Acute PE: the presentation addressed by the AHA/ACC and ESC acute PE classifications.
• Chronic thromboembolic pulmonary disease (CTEPD): symptomatic patients with mismatched perfusion defects and evidence of chronic, organized thromboembolic obstruction after at least 3 months of therapeutic anticoagulation, with or without pulmonary hypertension; CTEPD with pulmonary hypertension corresponds to CTEPH.

Pathophysiology

Pathogenesis

• PE is characterized by occlusion of blood flow in a pulmonary artery, typically by a thrombus that travels from a vein in a lower limb.
• VTE is considered a consequence of the interaction between patient-related, usually permanent, risk factors and setting-related, usually temporary, risk factors. These factors act through one or more components of Virchow's triad: venous stasis, endothelial injury, and hypercoagulability.

Hemodynamic Consequences

• Acute PE interferes with both the circulation and gas exchange. Acute right-sided heart failure is the primary cause of death in patients presenting with massive PE.
• Pulmonary artery pressure increases when more than 30% to 50% of the total cross-sectional area of the pulmonary arterial bed is occluded by thromboemboli.
• Pulmonary vasoconstriction mediated by platelet-derived thromboxane A2 and serotonin contributes to the initial rise in pulmonary vascular resistance and helps explain why hemodynamic compromise can be out of proportion to the degree of mechanical obstruction.
• The abrupt rise in pulmonary vascular resistance dilates the RV and increases wall tension and myocyte stretch. Neurohumoral activation and systemic vasoconstriction initially maintain systemic blood pressure, but a non-preconditioned, thin-walled RV is unable to generate a mean pulmonary artery pressure >40 mm Hg.
• Prolongation of RV contraction into early left ventricular diastole causes leftward bowing of the interventricular septum. This ventricular interdependence impairs left ventricular filling, lowers stroke volume, and can lead to low cardiac output and cardiogenic shock.
• An imbalance between RV oxygen supply and demand, aggravated by systemic hypotension that lowers coronary driving pressure, causes RV ischemia and myocardial injury, reflected by elevated circulating troponin. Myocardial inflammation may contribute to the secondary hemodynamic destabilization that sometimes occurs 24 to 48 hours after acute PE.

Gas Exchange Abnormalities

• Respiratory failure in PE is predominantly a consequence of hemodynamic disturbances. Low cardiac output desaturates mixed venous blood, and zones of reduced flow in obstructed arteries combined with overflow in the capillary bed served by nonobstructed vessels produce ventilation/perfusion mismatch and hypoxemia.
• In about one-third of patients, right-to-left shunting through a patent foramen ovale can be detected by echocardiography; it can cause severe hypoxemia and increases the risk of paradoxical embolization and stroke.
• Small distal emboli can create areas of alveolar hemorrhage that present with hemoptysis, pleuritis, and a usually mild pleural effusion, a picture known as pulmonary infarction.

Chronic Thromboembolic Sequelae

• In a minority of survivors, emboli are transformed into fibrotic intravascular material that occludes the proximal pulmonary arteries. Combined with a secondary microvasculopathy of vessels <500 µm, this increases pulmonary vascular resistance and leads to progressive right heart failure (CTEPH).
• The mechanism responsible for the transformation of red clots into fibrotic material has not been elucidated.

Genetics

• Hereditary and acquired thrombophilia are risk factors for VTE. Inherited thrombophilias include factor V Leiden, the prothrombin G20210A variant, and deficiencies of antithrombin, protein C, and protein S; antiphospholipid syndrome is the main acquired thrombophilia.
• Whether thrombophilia testing helps guide management is controversial, and ASH 2023 issued 23 recommendations on when testing may change management.

Causes

Thrombotic Pulmonary Embolism

• Most pulmonary emboli are thrombi that originate in the deep veins of the lower limbs; compression ultrasonography shows DVT in 30% to 50% of patients with PE.
• Central venous lines, intravenous catheters, and leads are moderate risk factors for VTE.
• The patient-related and setting-related factors that provoke thrombosis are described under Risk Factors and Triggers.

Non-thrombotic Pulmonary Embolism

• Non-thrombotic emboli include fat (for example, after long-bone fracture), air, amniotic fluid, tumor cells, septic emboli, and foreign material. Their presentation can resemble thrombotic PE, but management is directed at the underlying cause.
• Amniotic fluid embolism should be considered in a pregnant or postpartum woman with unexplained hemodynamic instability or respiratory deterioration and disseminated intravascular coagulation (ESC 2019, Class IIa, Level C).

Differentiating Pulmonary Embolism from other Diseases

PE should be considered in patients presenting with acute chest pain, shortness of breath, or syncope. Its clinical features overlap with those of many cardiopulmonary disorders. Several tests that are abnormal in PE, including D-dimer, troponin, and natriuretic peptides, are not specific for it, and RV dilation can result from other causes of RV pressure overload or RV failure. Acute aortic dissection is a critical alternative diagnosis, because anticoagulation and thrombolysis can be harmful if dissection is present.

Disease	Distinguishing clinical features	Electrocardiogram	Imaging and laboratory findings	Comments
Pulmonary embolism	Sudden dyspnea, pleuritic or anginal chest pain, presyncope or syncope, hemoptysis; tachycardia, tachypnea, hypoxemia; signs of DVT	Sinus tachycardia; T-wave inversion in V1 to V4, QR pattern in V1, S1Q3T3 pattern, incomplete or complete right bundle branch block in more severe cases; atrial fibrillation	Filling defect on CTPA; mismatched perfusion defects on V/Q scan; RV dilation or dysfunction on echocardiography; elevated D-dimer, troponin, or natriuretic peptides	Diagnosis follows a probability-based strategy
Acute coronary syndrome	Pressure-like retrosternal chest pain radiating to the arm, neck, or jaw; diaphoresis; atherosclerotic risk factors	ST-segment elevation or depression or T-wave inversion in a coronary distribution	Rise and fall of cardiac troponin; regional wall motion abnormality on echocardiography; culprit lesion on coronary angiography	Central PE can cause anginal pain from RV ischemia, troponin elevation, and anterior T-wave inversion
Acute aortic dissection	Abrupt, severe, tearing chest or back pain; pulse or blood pressure differential; new aortic regurgitation murmur; neurologic deficit	Often nonspecific; ischemic changes if a coronary ostium is involved	Widened mediastinum on chest radiograph; intimal flap on CT angiography of the aorta or transesophageal echocardiography	Anticoagulation and thrombolysis can be harmful if dissection is missed
Pneumothorax	Sudden pleuritic chest pain and dyspnea; reduced breath sounds and hyperresonance on the affected side; hypotension and tracheal deviation in tension pneumothorax	Usually normal or sinus tachycardia	Visceral pleural line on chest radiograph; absent lung sliding on ultrasonography; CT in uncertain cases	Tension pneumothorax is a cause of obstructive shock
Pneumonia	Fever, productive cough, pleuritic chest pain, focal crackles or bronchial breath sounds	Usually sinus tachycardia	Consolidation on chest radiograph; leukocytosis	Pulmonary infarction can cause fever, pleuritic pain, and peripheral opacities that mimic pneumonia
Acute pericarditis and cardiac tamponade	Sharp, positional chest pain relieved by sitting forward; pericardial friction rub; tamponade: hypotension, elevated jugular venous pressure, pulsus paradoxus	Widespread ST elevation with PR depression; low voltage or electrical alternans with a large effusion	Pericardial effusion on echocardiography; right atrial and RV diastolic collapse in tamponade, in contrast to the dilated RV of PE	Both PE and tamponade can cause obstructive shock
Acute RV failure of other causes (RV infarction, decompensated pulmonary hypertension)	Known pulmonary hypertension or inferior myocardial infarction; jugular venous distension; clear lung fields	Inferior ST elevation with ST elevation in right precordial leads in RV infarction	RV dilation without intraluminal filling defects on CTPA; RV wall hypertrophy suggests chronic pressure overload	RV dilation and dysfunction also occur with RV infarction, acute decompensation of chronic pulmonary hypertension, and acute respiratory distress syndrome
Chronic obstructive pulmonary disease or asthma exacerbation	Wheeze, prolonged expiration, change in sputum, known obstructive airway disease	Sinus tachycardia; features of chronic lung disease	Hyperinflation on chest radiograph; no filling defect on CTPA	PE was confirmed within 48 hours in 5.9% of patients hospitalized with acutely worsening COPD
Acute decompensated heart failure	Orthopnea, paroxysmal nocturnal dyspnea, bilateral crackles, peripheral edema, third heart sound	Left ventricular hypertrophy, prior myocardial infarction, or arrhythmia	Pulmonary congestion on chest radiograph; left ventricular dysfunction on echocardiography; natriuretic peptides elevated in both conditions	Natriuretic peptides do not discriminate between the two conditions
Syncope of other causes	Vasovagal prodrome, orthostatic symptoms, or palpitations	Arrhythmia or conduction disease in arrhythmic syncope	No filling defect on CTPA when performed	PE was found in 17.3% of patients hospitalized for a first syncope with systematic work-up, but in only 0.06% to 0.55% of all patients with syncope in administrative databases
Musculoskeletal chest pain	Pain reproduced by palpation or movement; normal vital signs and oxygen saturation	Normal	Normal	A diagnosis of exclusion

Epidemiology and Demographics

Incidence

• VTE occurs in approximately 1 to 2 individuals per 1000 each year, corresponding to approximately 300,000 to 600,000 events in the United States annually; VTE is responsible for the hospitalization of more than 250,000 Americans each year.
• VTE affects nearly 10 million people every year worldwide. Studies from Western Europe, North America, Australia, and southern Latin America report annual VTE incidences of 0.75 to 2.69 per 1000 individuals, increasing to 2 to 7 per 1000 among those aged 70 years or older. Global VTE incidence has been estimated at 115 to 269 per 100,000, with mortality of 9.4 to 32.3 per 100,000.
• The incidence of PE is approximately 60 to 120 per 100,000 people per year, and PE affects approximately 370,000 patients per year in the United States.
• In Germany (885,806 patients, 2005 to 2015), the incidence of acute PE was 99 per 100,000 population per year, rising from 85 per 100,000 in 2005 to 109 per 100,000 in 2015.
• In the United States, the introduction of CTPA was followed by an 81% increase in PE incidence (from 62.1 to 112.3 per 100,000), whereas mortality fell by only 3% (from 12.3 to 11.9 per 100,000) and case fatality fell by 36% (from 12.1% to 7.8%), consistent with overdiagnosis.
• In the Netherlands, PE incidence declined from 2015 to 2019 but rose by 23%, 52%, and 7% in 2020, 2021, and 2022 compared with 2019, during the COVID-19 pandemic.
• Public awareness of PE (54%) and DVT (44%) is lower than awareness of heart attack (88%) and stroke (85%).

Prevalence among Patients Evaluated for PE

• PE is confirmed in a minority of patients evaluated for it in contemporary emergency department cohorts, for example 7.4% in the PEGeD study and 7.1% in the MODS trial.
• Regardless of the prediction rule used, PE is expected in about 10% of patients with low, 30% with intermediate, and 65% with high clinical probability (three-level classification), and in about 12% of patients classified as PE-unlikely (two-level classification).

Mortality

• PE represents the third leading cause of cardiovascular mortality, and approximately 60,000 to 100,000 patients die from PE each year in the United States.
• In 41 member states of the WHO European Region, age-standardized PE-related mortality fell from 12.8 to 6.5 deaths per 100,000 population between 2000 and 2015, with an average of 38,929 PE-related deaths per year in 2013 to 2015.
• In the United States, age-standardized PE mortality fell from 6.0 per 100,000 in 2000 to 4.4 per 100,000 in 2006; thereafter it decreased to 4.1 per 100,000 in women and plateaued at 4.5 per 100,000 in men by 2017, and the median age at death from PE decreased from 73 to 68 years (2000 to 2018). A separate analysis found that the decline reversed after a 2008 inflection point (average annual percent change -4.4% before vs +0.6% after).
• In Germany, in-hospital case fatality fell from 20.4% to 13.9% between 2005 and 2015. In the RIETE registry (23,858 patients, 2001 to 2013), risk-adjusted 30-day all-cause mortality fell from 6.6% to 4.9%, and PE-related mortality fell from 3.3% to 1.8%.
• In a Danish nationwide cohort of 60,614 patients (2000 to 2020), 30-day mortality fell from 19.1% to 7.3% in patients without recent cancer and from 32.2% to 14.1% in those with recent cancer, whereas 31-day to 365-day mortality in patients with recent cancer remained stable (39.4% to 38.3%).
• In the Netherlands, 1-year mortality after PE increased by 10% in 2020 and by 9% in 2021 compared with 2019.

Age

• VTE incidence increases steeply with age, reaching 2 to 7 per 1000 per year at 70 years or older.
• In the United States, PE mortality increased after 2006 among adults aged 25 to 64 years, and between 1999 and 2018 age-adjusted mortality in this age group increased by an average of 2.1% per year while remaining stable in adults older than 65 years.
• In a nationwide analysis of 5733 children and adolescents aged 0 to 19 years admitted with acute PE in the United States (2016 and 2019), the annual incidence was 3.5 per 100,000, with peaks in infants younger than 1 year and adolescents aged 15 to 19 years, and in-hospital case fatality was 4.5%.

Sex

• Of the 5733 children and adolescents with acute PE in the US nationwide analysis, 58.5% were female.
• During 2020 to 2022 in the Netherlands, changes in PE incidence and mortality were generally greater in males.
• Pregnancy, the postpartum period, and estrogen-containing contraception or hormone therapy are sex-specific risk factors (see Risk Factors).

Race

• In the United States, PE mortality has been consistently higher, by up to 50%, in Black than in White individuals, and another analysis found approximately 2-fold higher age-adjusted mortality in Black men and women than in White men and women.

Pregnancy and the Postpartum Period

• VTE complicates approximately 1.2 of every 1000 deliveries.
• Women who are pregnant or postpartum have a 4-fold to 5-fold increased risk of thromboembolism compared with nonpregnant women; approximately 80% of thromboembolic events in pregnancy are venous, with a prevalence of 0.5 to 2.0 per 1000 pregnant women, and VTE accounts for 9.3% of all maternal deaths in the United States.
• In a 30-year population-based study, the relative risk of VTE in pregnant or postpartum women was 4.29, the overall incidence was 199.7 per 100,000 woman-years, and PE was far more common postpartum than during pregnancy (159.7 vs 10.6 per 100,000).

Cancer

• In a Danish population-based cohort of 499,092 patients with cancer, the 12-month cumulative incidence of VTE was 2.3% vs 0.35% in matched comparison individuals (HR 8.5), and it rose from 1.0% in 1997 to 3.4% in 2017.

Risk Factors

VTE results from the interaction between patient-related, usually permanent, risk factors and setting-related, usually temporary, risk factors. Between one quarter and one half of all clinically recognized symptomatic VTE events occur in people who are neither hospitalized nor recovering from a major illness. Strong provoking risk factors include major surgery and active cancer, but most VTE events are unprovoked.

The ESC 2019 guideline classifies predisposing factors by the strength of their association with VTE (data modified from Rogers and colleagues and from Anderson and Spencer).

Strong risk factors (odds ratio >10)	Moderate risk factors (odds ratio 2 to 9)	Weak risk factors (odds ratio <2)
Fracture of the lower limb Hospitalization for heart failure or atrial fibrillation or flutter within the previous 3 months Hip or knee replacement Major trauma Myocardial infarction within the previous 3 months Previous VTE Spinal cord injury	Arthroscopic knee surgery Autoimmune diseases Blood transfusion Central venous lines Intravenous catheters and leads Chemotherapy Congestive heart failure or respiratory failure Erythropoiesis-stimulating agents Hormone replacement therapy (depending on the formulation) In vitro fertilization Oral contraceptive therapy Postpartum period Infection (specifically pneumonia, urinary tract infection, and HIV) Inflammatory bowel disease Cancer (highest risk in metastatic disease) Paralytic stroke Superficial vein thrombosis Thrombophilia	Bed rest for more than 3 days Diabetes mellitus Arterial hypertension Immobility due to sitting (for example, prolonged car or air travel) Increasing age Laparoscopic surgery (for example, cholecystectomy) Obesity Pregnancy Varicose veins

Selected Risk Factors

• In a population-based case-control study (625 patients with a first VTE and 625 controls), independent risk factors included surgery (OR 21.7), trauma (OR 12.7), hospital or nursing home confinement (OR 8.0), malignant neoplasm with chemotherapy (OR 6.5) or without chemotherapy (OR 4.1), a central venous catheter or pacemaker (OR 5.6), superficial vein thrombosis (OR 4.3), and neurologic disease with extremity paresis (OR 3.0). The risk associated with varicose veins diminished with age (OR 4.2 at 45 years, 1.9 at 60 years, and 0.9 at 75 years).
• Combined oral contraceptives increase the risk of venous thrombosis (relative risk 3.5), and pills containing 30 to 35 µg of ethinylestradiol with gestodene, desogestrel, cyproterone acetate, or drospirenone carry an approximately 50% to 80% higher risk than pills containing levonorgestrel.
• In ambulatory patients starting chemotherapy, the Khorana score assigns 2 points for a very high-risk cancer site (stomach or pancreas) and 1 point each for a high-risk site (lung, lymphoma, gynecologic, bladder, or testicular), a prechemotherapy platelet count ≥350 × 10⁹/L, hemoglobin <10 g/dL or use of erythropoiesis-stimulating agents, a prechemotherapy leukocyte count >11 × 10⁹/L, and a body mass index ≥35 kg/m². VTE rates in the derivation and validation cohorts were 0.8% and 0.3% with a score of 0, 1.8% and 2% with a score of 1 to 2, and 7.1% and 6.7% with a score of 3 or more.
• Hereditary and acquired thrombophilia are risk factors for VTE. Antiphospholipid syndrome places patients in the high (>8% per year) category for long-term recurrence.
• One or more previous episodes of VTE in the absence of a major transient or reversible risk factor, and active cancer, also confer a high long-term risk of recurrence.

Triggers

• In a case-crossover study of 16,781 participants of the Health and Retirement Study linked to Medicare data (399 VTE hospitalizations), infection was the most common trigger, present in 52.4% of risk periods before hospitalization (adjusted incidence rate ratio 2.90). Erythropoiesis-stimulating agents (incidence rate ratio 9.33) and blood transfusion (incidence rate ratio 2.57) were also associated with VTE hospitalization, as were fractures (2.81), immobility (4.23), and chemotherapy (5.70).
• Surgery, trauma, and hospital or nursing home confinement are potent short-term triggers.
• Immobility due to prolonged sitting, such as long car or air travel (economy class syndrome), is a weak risk factor (odds ratio <2). ASH conditionally recommends graduated compression stockings or LMWH for long-distance travelers only if they are at high risk for VTE.
• Hospitalization for heart failure or atrial fibrillation or flutter, and myocardial infarction, within the previous 3 months are strong risk factors.

Screening

VTE Risk Assessment and Prophylaxis

• Screening asymptomatic individuals for PE is not part of routine practice. Prevention instead relies on assessing VTE risk in hospitalized medical and surgical patients and in ambulatory patients with cancer, and on giving thromboprophylaxis when the expected benefit outweighs the bleeding risk.
• In ambulatory patients receiving chemotherapy, the Khorana score identifies patients at high risk of VTE who may benefit from primary thromboprophylaxis; ASH 2021 strongly recommends against thromboprophylaxis in ambulatory patients at low risk of VTE.

Occult Cancer Screening after Unprovoked VTE

• In the SOME trial (854 patients with a first unprovoked VTE), occult cancer was newly diagnosed in 3.9% within 1 year (3.2% with limited screening vs 4.5% with limited screening plus CT of the abdomen and pelvis; P=0.28), and the proportion of occult cancers missed by screening, the primary outcome, did not differ (29% vs 26%; P=1.0).
• In the MVTEP trial (399 randomized patients), limited screening plus FDG PET/CT detected cancer in 5.6% vs 2.0% with limited screening alone after the initial screen (P=0.07).
• In an individual-patient data meta-analysis of 10 prospective studies (2316 patients), the 12-month period prevalence of cancer was 5.2%. Extensive screening detected more cancers than limited screening initially (OR 2.0) but not at 12 months (OR 1.4), and prevalence was higher at age 50 years or older (OR 7.1).

Thrombophilia Testing

• ASH 2023 strongly recommends against testing the general population for thrombophilia before starting combined oral contraceptives, conditionally recommends testing in selected scenarios (for example, VTE associated with nonsurgical major transient or hormonal risk factors), and conditionally recommends against testing in other scenarios.
• NICE NG158 also provides recommendations on thrombophilia testing in people with VTE.

Screening for Chronic Thromboembolic Pulmonary Hypertension

• In the InShape II management study (424 patients), a screening algorithm started 3 months after acute PE used a CTEPH prediction score and symptoms, followed by CTEPH rule-out criteria (ECG reading and NT-proBNP), to select patients for echocardiography. Echocardiography was deemed unnecessary in 81% of patients, the algorithm failure rate was 0.29%, and CTEPH was diagnosed in 3.1%, 10 of 13 within 4 months of the PE.
• The ESC 2019 guideline recommends routine clinical evaluation 3 to 6 months after acute PE (Class I, Level B); further diagnostic evaluation should be considered in patients with persistent or new-onset dyspnea or exercise limitation (Class IIa, Level C) and may be considered in asymptomatic patients with risk factors for CTEPH (Class IIb, Level C).
• The 2026 AHA/ACC guideline recommends asking about symptoms and functional limitation at every visit for at least 1 year after PE.

Natural History, Complications and Prognosis

Natural History

• Acute PE can progress rapidly to RV failure and death. Early mortality is highest in patients who present with shock, and secondary hemodynamic destabilization can occur 24 to 48 hours after presentation.
• In a multicenter registry of 1001 patients with major PE, in-hospital mortality was 8.1% in hemodynamically stable patients, 25% in those with cardiogenic shock, and 65% in those who needed cardiopulmonary resuscitation.
• In a population-based cohort of 1719 patients with a first VTE, the cumulative incidence of recurrence was 1.6% at 7 days, 5.2% at 30 days, 10.1% at 180 days, 12.9% at 1 year, and 30.4% at 10 years.
• After anticoagulation is stopped following a first unprovoked VTE, recurrent VTE occurs at a rate of 10.3 events per 100 person-years in the first year, with a cumulative incidence of 16% at 2 years, 25% at 5 years, and 36% at 10 years and a case fatality rate of 4% for recurrent VTE.
• In a cohort of 308 patients with unprovoked PE, 558 with provoked PE, and 334 controls in whom PE was ruled out, only 70% of patients with PE were free of adverse events after 1 year, fewer than 60% after 2 years, and fewer than 50% after 4 years, compared with 84% of controls at 4 years.

Complications

• Death from acute RV failure, mainly in patients with hemodynamic instability.
• Recurrent VTE, with the highest risk early after diagnosis and after anticoagulation is stopped.
• Bleeding from anticoagulant or thrombolytic therapy (see Treatment).
• Chronic thromboembolic pulmonary hypertension: the pooled incidence after acute PE is 0.56% in all comers, 3.2% in survivors, and 2.8% in survivors without major comorbidities. In the prospective FOCUS study (1017 patients), CTEPH was diagnosed in 1.6%, with an estimated 2-year cumulative incidence of 2.3%.
• Post-PE syndrome and impairment: CTEPH is the most severe form of the post-PE syndrome, and many more survivors have reduced quality of life and functional capacity. The 2-year cumulative incidence of post-PE impairment was 16.0% in FOCUS, and in the ELOPE cohort 46.5% of patients had a peak oxygen uptake <80% of predicted on cardiopulmonary exercise testing 1 year after a first PE.
• Paradoxical embolism and stroke through a patent foramen ovale.
• Pulmonary infarction, presenting with pleuritic chest pain, hemoptysis, and pleural effusion.
• Arrhythmias, particularly atrial fibrillation.

Prognosis

• In the International Cooperative Pulmonary Embolism Registry (2454 patients), crude 3-month mortality was 17.4%, and systolic arterial hypotension (HR 2.9) and RV hypokinesis on echocardiography (HR 2.0) were among the significant prognostic factors.
• In the EMPEROR emergency department registry (1880 patients), mortality directly attributed to PE was 1% and 30-day all-cause mortality was 5.4%.
• Contemporary prognostic assessment combines hemodynamic status, a clinical severity score (PESI, sPESI, or Hestia), RV imaging, cardiac biomarkers, and lactate, as described under Risk Stratification in the Diagnosis section.
• Patients with cancer have worse outcomes: in a Danish nationwide cohort, 30-day mortality in patients with recent cancer fell to 14.1% by 2018 to 2020, whereas 31-day to 365-day mortality remained stable (39.4% to 38.3%).
• With multimodal therapy, patients with CTEPH can achieve 3-year survival above 90%. In a worldwide registry of 1009 patients, 3-year survival was 94% after pulmonary endarterectomy, 92% after balloon pulmonary angioplasty, and 71% without mechanical intervention.

Diagnosis

Diagnostic Approach | Assessment of Clinical Probability and Risk Scores | Assessment of Probability of Subsequent VTE and Risk Scores | History and Symptoms | Physical Examination | Laboratory Findings | Arterial Blood Gas Analysis | D-dimer | Biomarkers | Electrocardiogram | Chest X Ray | Ventilation/Perfusion Scan | Echocardiography | Compression Ultrasonography | CT | MRI

Diagnostic Approach

• The diagnostic strategy depends on hemodynamic status. In suspected high-risk PE, bedside transthoracic echocardiography or emergency CTPA, depending on availability and clinical circumstances, is recommended for diagnosis (ESC 2019, Class I, Level C), and intravenous unfractionated heparin (UFH), including a weight-adjusted bolus, should be started without delay (Class I, Level C).
• In patients with a systolic blood pressure of at least 90 mm Hg, evaluation proceeds in 3 steps: assessment of clinical probability, D-dimer testing if indicated, and chest imaging if indicated. Anticoagulation should be started without delay in patients with high or intermediate clinical probability while the diagnostic workup is in progress (ESC 2019, Class I, Level C).
• For patients at low (unlikely) VTE risk, using D-dimer as the initial test reduces the need for diagnostic imaging; for patients at high (likely) risk, imaging is warranted, and V/Q scanning and CTPA are the most validated tests for PE.
• The American College of Physicians best practice advice states that clinicians should:
  • Use validated clinical prediction rules to estimate pretest probability.
  • Not obtain D-dimer measurements or imaging studies in patients with a low pretest probability who meet all PERC criteria.
  • Obtain a high-sensitivity D-dimer as the initial test in patients with intermediate pretest probability, or with low pretest probability who do not meet all PERC criteria, and not use imaging as the initial test in these patients.
  • Use age-adjusted D-dimer thresholds (age × 10 ng/mL rather than a generic 500 ng/mL) in patients older than 50 years, and not obtain imaging when the D-dimer level is below the age-adjusted cutoff.
  • Obtain CTPA in patients with high pretest probability, reserve V/Q scanning for patients with a contraindication to CTPA or when CTPA is unavailable, and not obtain a D-dimer measurement in patients with high pretest probability.
• Emergency medicine and radiology societies have published complementary guidance on the evaluation of suspected PE in the emergency department and on the selection of imaging tests.

The following algorithm summarizes the diagnostic approach to suspected PE without hemodynamic instability, based on the 2019 ESC/ERS guideline, the ASH 2018 diagnostic guideline, and the 2015 ACP best practice advice.

Suspected PE without hemodynamic instability

Assess clinical (pretest) probability Clinical gestalt or a validated rule (Wells, revised Geneva, YEARS items, or 4PEPS)

Low or intermediate probability, or PE unlikely

High probability, or PE likely

Low gestalt probability in the emergency department: apply PERC; if all 8 criteria are met, no further testing Otherwise: D-dimer with a fixed, age-adjusted, or probability-adapted threshold

Start anticoagulation without delay CTPA (V/Q scan if CTPA is contraindicated or unavailable) No D-dimer testing

D-dimer below threshold: PE excluded, no anticoagulation

D-dimer above threshold: CTPA (or V/Q scan); start anticoagulation while awaiting imaging if probability is intermediate

CTPA negative: PE excluded

CTPA positive: PE confirmed; continue anticoagulation and assess severity (clinical category or risk class)

CTPA positive: treat as PE CTPA negative: PE excluded

The following algorithm summarizes the diagnostic approach to suspected PE with hemodynamic instability, adapted from the 2019 ESC/ERS guideline.

Suspected PE with hemodynamic instability (ESC high risk; AHA/ACC category E)

Start UFH with a weight-adjusted bolus and hemodynamic support Bedside transthoracic echocardiography

Acute RV dysfunction?

Yes

No: search for other causes of shock or hemodynamic instability

Is CTPA immediately available, and can the patient be transferred safely?

Yes: CTPA PE confirmed: PE-specific treatment, including primary reperfusion No PE: search for other causes

No: treat as high-risk PE, including primary reperfusion Bedside compression ultrasonography or transesophageal echocardiography may support the diagnosis

Assessment of Clinical Probability and Risk Scores

Clinical probability can be assessed using clinical gestalt or a structured score. In a meta-analysis of 52 studies (55,268 patients), pooled sensitivity and specificity were 0.85 and 0.51 for gestalt, 0.84 and 0.58 for a Wells score <2, 0.60 and 0.80 for a Wells score ≤4, 0.84 and 0.50 for the Geneva score, and 0.91 and 0.37 for the revised Geneva score.

Wells Score

Item	Original version	Simplified version
Clinical signs and symptoms of DVT	3	1
Alternative diagnosis less likely than PE	3	1
Heart rate >100 beats/min	1.5	1
Immobilization or surgery in the previous 4 weeks	1.5	1
Previous DVT or PE	1.5	1
Hemoptysis	1	1
Malignancy (on treatment, treated within the previous 6 months, or palliative)	1	1
Clinical probability	Three levels: low <2, intermediate 2 to 6, high >6 Two levels: PE unlikely ≤4, PE likely >4	Two levels: PE unlikely 0 to 1, PE likely ≥2

• In the derivation study, 7.8% of patients with a score ≤4 had PE, but only 2.2% (derivation) and 1.7% (validation) of those with a score ≤4 and a negative D-dimer had PE, a combination present in 46% of patients.
• In a management study of 930 emergency department patients, PE occurred in 1.3%, 16.2%, and 37.5% of patients with low, moderate, and high pretest probability, and the negative predictive value of a low pretest probability with a negative D-dimer was 99.5%.
• In the Christopher study (3306 patients), a PE-unlikely score with a normal D-dimer occurred in 32.0% of patients, and nonfatal VTE developed in 0.5% of those left untreated; the 3-month VTE incidence after a negative CT in untreated patients was 1.3%.

Revised Geneva Score

Item	Original version	Simplified version
Previous PE or DVT	3	1
Heart rate 75 to 94 beats/min	3	1
Heart rate ≥95 beats/min	5	2
Surgery or fracture within the past month	2	1
Hemoptysis	2	1
Active cancer	2	1
Unilateral lower-limb pain	3	1
Pain on lower-limb deep venous palpation and unilateral edema	4	1
Age >65 years	1	1
Clinical probability	Three levels: low 0 to 3, intermediate 4 to 10, high ≥11 Two levels: PE unlikely 0 to 5, PE likely ≥6	Three levels: low 0 to 1, intermediate 2 to 4, high ≥5 Two levels: PE unlikely 0 to 2, PE likely ≥3

• In the validation set of the revised Geneva score, PE prevalence was 8% in the low-probability, 28% in the intermediate-probability, and 74% in the high-probability category.
• In 1049 patients, the area under the curve was 0.75 for the revised and 0.74 for the simplified score, and no patient with a low, intermediate, or PE-unlikely simplified score and a normal D-dimer had VTE at 3 months.
• Table adapted from the 2019 ESC/ERS guideline.

Pulmonary Embolism Rule-out Criteria

In patients with a clinical probability of PE below 15%, the presence of all 8 PERC criteria identifies patients at very low risk in whom no further testing is needed.

PERC criterion (all must be present)
Age <50 years
Heart rate <100 beats/min
Oxygen saturation >94%
No recent surgery or trauma
No prior VTE
No hemoptysis
No unilateral leg swelling
No estrogen use

• In the derivation study, the rule had sensitivities of 96% and 100% and specificities of 27% and 15% in low-risk and very low-risk groups, and PE prevalence among patients meeting all criteria was 1.4% and 0%.
• In a prospective multicenter evaluation of 8138 outpatients, low gestalt suspicion plus a negative PERC applied to 20% of patients, with a false-negative rate of 1.0%, sensitivity of 97.4%, and specificity of 21.9%.
• A meta-analysis identified 12 cohorts (13,885 patients), and pooled data from 10 included studies gave a sensitivity of 0.97 and a specificity of 0.23.
• In the PROPER cluster-randomized noninferiority trial (1916 patients in 14 French emergency departments), PE was diagnosed during 3-month follow-up in 0.1% of patients in the PERC group vs none in the control group, and CTPA use was 13% vs 23%.

D-dimer Thresholds and Clinical Decision Strategies

Strategy	Rule for excluding PE without imaging	Key evidence
Fixed threshold	Low or intermediate clinical probability (or PE unlikely) and D-dimer <500 ng/mL	Posttest probability of PE less than 1.85% with a D-dimer <500 ng/mL in patients with low or intermediate clinical probability
Age-adjusted threshold	Age × 10 ng/mL in patients older than 50 years	ADJUST-PE (3346 patients): 3-month failure rate 0.3% with a D-dimer above 500 ng/mL but below the age-adjusted cutoff; in patients aged 75 years or older, PE was excluded by D-dimer in 29.7% vs 6.4% with the fixed cutoff
YEARS	Three items (clinical signs of DVT, hemoptysis, PE as the most likely diagnosis): D-dimer <1000 ng/mL with no items, or <500 ng/mL with 1 or more items	YEARS study (3465 patients): 3-month VTE 0.61% in patients in whom PE was ruled out; CTPA not indicated in 48% vs 34% with the Wells score and a fixed threshold
PEGeD	Low clinical pretest probability and D-dimer <1000 ng/mL, or moderate clinical pretest probability and D-dimer <500 ng/mL	2017 outpatients: no VTE among 1325 patients with a negative test; chest imaging in 34.3% vs 51.9% with a 500 ng/mL threshold
4PEPS	13 clinical variables scored from -2 to 5: score <0, no testing; 0 to 5, D-dimer <1.0 µg/mL; 6 to 12, D-dimer below the age-adjusted cutoff; >12, imaging without D-dimer	External validation: false-negative testing rates 0.71% and 0.89%, absolute reductions in imaging of 22% and 19%; not yet tested in an outcome study
YEARS with PERC and age-adjusted threshold (MODS)	No YEARS items and D-dimer <1000 ng/mL, or 1 or more items and D-dimer below the age-adjusted threshold	Cluster-randomized trial (1414 patients): 3-month VTE 0.15% vs 0.80%; chest imaging 30.4% vs 40.0%
Single question	D-dimer threshold based on whether PE is the most likely diagnosis: 1000 ng/mL if PE is not the most likely diagnosis, otherwise the age-adjusted threshold (applied to all patients, including those at high clinical probability)	Single-arm study (1221 patients): diagnostic failure 0.00% (0.12% after multiple imputation); chest imaging 32%, an absolute reduction of 19% vs a fixed 500 ng/mL strategy

• As an alternative to the fixed cutoff, an age-adjusted cutoff (Class IIa, Level B) or a D-dimer threshold adapted to clinical probability (Class IIa, Level B) should be considered to exclude PE in patients with low or intermediate clinical probability or who are PE-unlikely; D-dimer measurement is not recommended in patients with high clinical probability (Class III, Level A).
• In an individual-patient data meta-analysis of 16 studies (20,553 patients), the efficiency of rule-out strategies was highest in patients younger than 40 years (47% to 68%) and lowest in those aged 80 years or older (6.0% to 23%) or with cancer (9.6% to 26%).
• A prediction model developed from individual-patient data of 28,305 patients achieved a pooled c-statistic of 0.87, compared with 0.73 for the Wells score with an age-adjusted D-dimer.

Assessment of Probability of Subsequent VTE and Risk Scores

The risk of recurrence after anticoagulation is stopped depends mainly on the presence and type of provoking risk factors at the time of the index event.

Estimated long-term risk of recurrence	Risk factor category for the index PE	Examples
Low (<3% per year)	Major transient or reversible factors associated with a more than 10-fold increased risk for the index VTE event	Surgery with general anesthesia for more than 30 minutes; confinement to bed in hospital (only "bathroom privileges") for at least 3 days because of an acute illness or acute exacerbation of a chronic illness; trauma with fractures
Intermediate (3% to 8% per year)	Transient or reversible factors associated with an up to 10-fold increased risk for the index VTE event	Minor surgery (general anesthesia for less than 30 minutes); admission to hospital for less than 3 days with an acute illness; estrogen therapy or contraception; pregnancy or the puerperium; confinement to bed out of hospital for at least 3 days with an acute illness; leg injury without fracture associated with reduced mobility for at least 3 days; long-haul flight
	Nonmalignant persistent risk factors	Inflammatory bowel disease; active autoimmune disease
	No identifiable risk factor	None identified (unprovoked PE)
High (>8% per year)	Active cancer; one or more previous episodes of VTE in the absence of a major transient or reversible factor; antiphospholipid antibody syndrome

• Table adapted from the 2019 ESC/ERS guideline.
• HERDOO2 rule: the rule comprises Hyperpigmentation, Edema, or Redness in either leg; a D-dimer level ≥250 µg/L; Obesity with a body mass index ≥30; and Older age (≥65 years), and women with none or one criterion are classified as low risk. In a multinational management study of 2785 patients with a first unprovoked VTE, low-risk women who stopped anticoagulation had recurrent VTE at 3.0% per patient-year, compared with 8.1% in high-risk women and men who stopped and 1.6% in high-risk women and men who continued anticoagulation.
• After a first unprovoked VTE, the cumulative incidence of recurrence after stopping anticoagulation is 16% at 2 years, 25% at 5 years, and 36% at 10 years.

History and Symptoms

• PE should be considered in patients presenting with acute chest pain, shortness of breath, or syncope.
• Typical symptoms are dyspnea, chest pain, presyncope or syncope, and hemoptysis. Chest pain is usually caused by pleural irritation from distal emboli causing pulmonary infarction, whereas in central PE it may have an anginal character, possibly reflecting RV ischemia.
• PE may also be asymptomatic and discovered incidentally on imaging performed for other reasons.
• In PIOPED II, dyspnea or tachypnea occurred in 92% of patients with PE in the main or lobar pulmonary arteries and in 65% of those whose largest embolus was segmental.
• Among 560 patients hospitalized for a first episode of syncope who underwent systematic work-up, PE was found in 17.3%, including 12.7% of those with an alternative explanation and 25.4% of those without. In administrative databases from 4 countries, PE prevalence was 0.06% to 0.55% in all patients with syncope and 0.15% to 2.10% in hospitalized patients.
• Symptoms of DVT (unilateral leg pain or swelling) and risk factors such as recent surgery, immobilization, cancer, pregnancy or the postpartum period, estrogen use, and previous VTE should be sought.

Physical Examination

• Tachypnea is common: in PIOPED II, dyspnea or tachypnea occurred in 92% of patients with emboli in the main or lobar pulmonary arteries, whereas symptoms and signs may be mild or absent, particularly when PE is limited to the segmental branches. Sinus tachycardia is present in 40% of patients and may be the only electrocardiographic abnormality in milder PE, and up to 40% of patients have a normal arterial oxygen saturation.
• Signs of DVT include unilateral leg swelling and pain on deep venous palpation, which are components of the Wells and revised Geneva scores.
• Signs of acute RV pressure overload include elevated jugular venous pressure, a parasternal heave, a loud pulmonic component of the second heart sound, and a murmur of tricuspid regurgitation.
• Hypotension, signs of hypoperfusion (altered mental status, cold and clammy skin, oliguria), or cardiac arrest indicate hemodynamic instability and high-risk PE.

Laboratory Findings

Arterial Blood Gas Analysis

• Hypoxemia is frequent, but up to 40% of patients with PE have a normal arterial oxygen saturation; hypocapnia is also often present.

D-dimer

• D-dimer testing has a high negative predictive value, and a normal level makes acute PE or DVT unlikely; the positive predictive value of an elevated level is low, so D-dimer cannot confirm PE.
• D-dimer is more frequently elevated in patients with cancer, in hospitalized patients, in severe infection or inflammatory disease, and during pregnancy.
• Specificity declines with age: with the conventional cutoff, specificity fell from 57.6% at 51 to 60 years to 14.7% above 80 years, whereas age-adjusted cutoffs yielded specificities of 62.3%, 49.5%, 44.2%, and 35.2% across 4 age bands, with sensitivity above 97% in all.

Cardiac Biomarkers and Lactate

• Elevated troponin is associated with short-term mortality (OR 5.24), PE-related death (OR 9.44), adverse outcomes (OR 7.03), and mortality in hemodynamically stable patients (OR 5.90).
• Elevated BNP or NT-proBNP is associated with a complicated in-hospital course (OR 6.8) and 30-day mortality (OR 7.6).
• Among 496 normotensive patients, plasma lactate ≥2 mmol/L (27.2% of patients) was associated with PE-related complications (10.4%; adjusted OR 5.3), with a negative predictive value of 98.3%.
• The 2026 AHA/ACC guideline recommends measuring lactate in categories C to E (Class 1, Level B-NR) and troponin or BNP in category C (Class 1, Level B-NR).
• NT-proBNP ≥600 ng/L, heart-type fatty acid-binding protein ≥6 ng/mL, or copeptin ≥24 pmol/L may provide additional prognostic information but have not been used to guide treatment in randomized trials.

Other Laboratory Tests

• Baseline complete blood count with platelet count, renal function (creatinine clearance), liver function, and coagulation tests help select the anticoagulant and dose; severe renal impairment and pregnancy affect the choice of agent.

Electrocardiogram

• Electrocardiographic signs of RV strain, such as T-wave inversion in leads V1 to V4, a QR pattern in V1, an S1Q3T3 pattern, and incomplete or complete right bundle branch block, are usually found in more severe PE; in milder cases, the only abnormality may be sinus tachycardia, present in 40% of patients. Atrial arrhythmias, most frequently atrial fibrillation, may be associated with acute PE.
• In a meta-analysis, 6 findings predicted hemodynamic collapse and 30-day mortality: heart rate >100 beats/min, S1Q3T3, complete right bundle branch block, inverted T waves in V1 to V4, ST elevation in aVR, and atrial fibrillation.

Chest X Ray

• The chest X-ray is frequently abnormal in PE, but its findings are usually nonspecific; it is useful for excluding other causes of dyspnea or chest pain.
• In pregnancy, chest radiography is recommended as the first radiation-associated procedure (strong recommendation).

Ventilation/Perfusion Scan

• In PIOPED, a high-probability scan had a sensitivity of 41% and a specificity of 97%, whereas any abnormal scan had a sensitivity of 98% and a specificity of 10%.
• A normal perfusion scan excludes PE (ESC 2019, Class I, Level A); a high-probability V/Q scan supports accepting the diagnosis (Class IIa, Level B); and a nondiagnostic V/Q scan combined with a negative proximal compression ultrasonography should be considered to exclude PE in patients with low clinical probability or a PE-unlikely status (Class IIa, Level B).
• V/Q single-photon emission computed tomography (SPECT) may be considered for PE diagnosis (ESC 2019, Class IIb, Level B).
• In a randomized trial of 1417 patients, VTE occurred after PE was excluded in 0.4% of patients evaluated with CTPA vs 1.0% with V/Q scanning, while PE was diagnosed in 19.2% vs 14.2%.
• In pregnant women with a normal chest radiograph, lung scintigraphy is the preferred test (strong recommendation). In other patients, the ACP advises reserving V/Q scanning for those with a contraindication to CTPA or when CTPA is unavailable.
• In patients with pulmonary hypertension, CTEPH is suspected when a V/Q scan shows mismatched perfusion defects.

Echocardiography

• Echocardiography cannot rule out PE: the most common sign, right heart strain, had a sensitivity of 53% and a specificity of 83% for diagnosing PE.
• Signs of RV pressure overload include an RV-to-left ventricular basal diameter ratio >1.0, the McConnell sign, flattening of the interventricular septum, a distended inferior vena cava with diminished inspiratory collapsibility, the 60/60 sign, right heart mobile thrombi, reduced tricuspid annular plane systolic excursion, and reduced tricuspid annular systolic velocity.
• In suspected high-risk PE, the absence of RV dysfunction on bedside echocardiography practically excludes PE as the cause of hemodynamic instability.
• Echocardiographic RV dysfunction is associated with short-term mortality in PE without hemodynamic compromise (OR 2.36). The 2026 AHA/ACC guideline recommends RV imaging in categories C to D (Class 1, Level A) and states that echocardiography is preferred over CT for short-term risk stratification in categories C to D (Class 2a, Level B-NR).
• Point-of-care multiorgan ultrasonography (lung, heart, and leg veins) had a sensitivity of 90% and a specificity of 86.2% for PE, compared with 60.9% and 95.9% for lung, 32.7% and 90.9% for heart, and 52.7% and 97.6% for vein ultrasonography alone.

Compression Ultrasonography

• Compression ultrasonography shows DVT in 30% to 50% of patients with PE. Accepting the diagnosis of VTE (and PE) is recommended if compression ultrasonography shows a proximal DVT in a patient with clinical suspicion of PE (ESC 2019, Class I, Level A); if only a distal DVT is found, further testing to confirm PE should be considered (Class IIa, Level B); and if a positive proximal compression ultrasonography is used to confirm PE, assessment of PE severity should be considered to permit risk-adjusted management (Class IIa, Level C).
• In the pregnancy-adapted YEARS algorithm, compression ultrasonography was performed in women with symptoms of DVT, and CTPA was not performed if a clot was present.

CT

• Multidetector CTPA is the main imaging test for PE. In PIOPED II, CTPA had a sensitivity of 83% and a specificity of 96%, and combined CT angiography and CT venography had a sensitivity of 90% and a specificity of 95%.
• A normal CTPA excludes PE in patients with low or intermediate clinical probability or who are PE-unlikely (ESC 2019, Class I, Level A); a segmental or more proximal filling defect confirms PE in patients with intermediate or high clinical probability (Class I, Level B); rejecting PE without further testing should be considered if CTPA is normal in a patient with high clinical probability (Class IIa, Level B); further imaging may be considered for isolated subsegmental filling defects (Class IIb, Level C); and CT venography is not recommended as an adjunct to CTPA (Class III, Level B).
• An increased RV-to-left ventricular diameter ratio on CT is associated with all-cause mortality (OR 2.5), adverse outcome (OR 2.3), and PE-related mortality (OR 5.0).
• The wider use of CTPA has increased the detection of small emboli and has been associated with overdiagnosis.

MRI

• Magnetic resonance angiography is not recommended for ruling out PE (ESC 2019, Class III, Level A) because of its low sensitivity, the high proportion of inconclusive scans, and its low availability in emergency settings.

Other Imaging

• Invasive pulmonary angiography is now rarely needed for diagnosis; in pregnant women with a nondiagnostic V/Q result, CTPA is recommended rather than digital subtraction angiography (strong recommendation).

Risk Stratification

• Initial risk stratification of suspected or confirmed PE based on the presence of shock or persistent hypotension is recommended to identify patients at high risk of early mortality (ESC 2019, Class I, Level B). In patients without high-risk PE, further stratification into intermediate-risk and low-risk categories is recommended (Class I, Level B), validated clinical scores, preferably PESI or sPESI, should be considered (Class IIa, Level B), and assessment of the RV by imaging or laboratory biomarkers should be considered even with a low PESI or a negative sPESI (Class IIa, Level B).
• In the 2026 AHA/ACC framework, the clinical severity score separates category B from category C, and RV imaging, troponin or BNP, and lactate refine risk within categories C to E.

Pulmonary Embolism Severity Index

Parameter	Original PESI (points)	Simplified PESI (points)
Age	Age in years	1 if age >80 years
Male sex	+10	Not included
Cancer	+30	1
Chronic heart failure	+10	1 (chronic heart failure or chronic pulmonary disease)
Chronic pulmonary disease	+10
Pulse rate ≥110 beats/min	+20	1
Systolic blood pressure <100 mm Hg	+30	1
Respiratory rate >30 breaths/min	+20	Not included
Temperature <36 °C	+20	Not included
Altered mental status	+60	Not included
Arterial oxyhemoglobin saturation <90%	+20	1
Risk strata (30-day mortality)	Class I (≤65 points): 0% to 1.6% Class II (66 to 85): 1.7% to 3.5% Class III (86 to 105): 3.2% to 7.1% Class IV (106 to 125): 4.0% to 11.4% Class V (>125): 10.0% to 24.5%	0 points: 1.0% 1 or more points: 10.9%

• PESI was derived and validated in 15,531 inpatient discharges, and 30-day mortality across classes is shown for the derivation and validation samples.
• sPESI was derived in 995 outpatients (30-day mortality 1.0% low risk vs 10.9% high risk) and validated in 7106 RIETE outpatients (1.1% vs 8.9%).
• Table adapted from the 2019 ESC/ERS guideline.

Hestia Criteria

The Hestia rule identifies patients suitable for outpatient treatment; a "yes" to any criterion means the patient should not be treated at home.

Hestia criterion
Hemodynamically unstable (systolic blood pressure <100 mm Hg with heart rate >100 beats/min, or condition requiring admission to an intensive care unit)
Thrombolysis or embolectomy necessary
Active bleeding or high risk of bleeding (gastrointestinal bleeding in the preceding 14 days, stroke within 4 weeks, operation within 2 weeks, bleeding disorder or platelet count <75 × 109/L, or uncontrolled hypertension with systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg)
Oxygen supply needed for more than 24 hours to maintain oxygen saturation >90%
PE diagnosed during anticoagulant treatment
Severe pain needing intravenous pain medication for more than 24 hours
Medical or social reason for treatment in hospital for more than 24 hours (for example, infection, malignancy, or no support system)
Creatinine clearance <30 mL/min (Cockcroft-Gault formula)
Severe liver impairment (at the physician's discretion)
Pregnancy
Documented history of heparin-induced thrombocytopenia

• In the Hestia study (297 outpatients), 2.0% had recurrent VTE and 1.0% died at 3 months, none of fatal PE.
• In the HOME-PE randomized trial (1975 patients), triage by Hestia was noninferior to triage by sPESI (30-day composite outcome 3.82% vs 3.57%), and 38.4% vs 36.6% of patients were treated at home.

Bova Score

Variable	Points
Systolic blood pressure 90 to 100 mm Hg	2
Elevated cardiac troponin	2
RV dysfunction (echocardiography or CT)	2
Heart rate ≥110 beats/min	1
Stages	Stage I (0 to 2 points), stage II (3 to 4 points), stage III (more than 4 points)

• In pooled data from 2874 normotensive patients, 30-day PE-related complications occurred in 4.2%, 10.8%, and 29.2% of patients in stages I, II, and III.

Other Prognostic Tools

• A multimarker calculator based on the sPESI variables, natriuretic peptide, troponin, and concomitant DVT improved the C-statistic for 30-day mortality to 0.79 vs 0.56 for the ESC model in 60,042 stable RIETE patients; at an estimated risk >10%, its positive predictive value for mortality was 15.7% vs 5.0%.
• RV dysfunction on echocardiography (OR 2.36) and elevated BNP (OR 7.7) predicted short-term mortality in patients without hemodynamic compromise, whereas RV dilation on CT did not reach significance (OR 1.54) in one meta-analysis.

Special Diagnostic Considerations

Pregnancy

• Formal diagnostic assessment with validated methods is recommended when PE is suspected during pregnancy or the postpartum period (ESC 2019, Class I, Level B); D-dimer measurement and clinical prediction rules should be considered to rule out PE (Class IIa, Level B); venous compression ultrasonography should be considered, particularly with symptoms of DVT (Class IIa, Level B); and perfusion scintigraphy or low-radiation-dose CTPA should be considered, with CTPA as the first-line option if the chest radiograph is abnormal (Class IIa, Level C).
• The ATS/STR guideline made strong recommendations for chest radiography as the first radiation-associated procedure, lung scintigraphy when the chest radiograph is normal, and CTPA rather than digital subtraction angiography after a nondiagnostic V/Q result.
• In the CT-PE-Pregnancy study (395 women), PE was diagnosed in 7.1%, and the 3-month VTE rate among untreated women after PE was excluded was 0.0%.
• In the Artemis study of the pregnancy-adapted YEARS algorithm (498 women), PE was diagnosed in 4.0% at baseline, 1 patient (0.21%) had a popliteal DVT during follow-up and none had PE, and CTPA was avoided in 39% (65% in the first trimester and 32% in the third trimester).
• The 2025 ESC guideline on cardiovascular disease and pregnancy is the most recent ESC guidance addressing VTE in pregnancy.

Cancer

• In the Hydra randomized trial (698 patients with active cancer), the YEARS algorithm was noninferior to CTPA alone (primary outcome 1.8% vs 5.5% in the per-protocol population), and CTPA was avoided in 22% of patients.
• The efficiency of D-dimer-based rule-out strategies is low in cancer (9.6% to 26%).

Children

• In the BEEPER study of 4011 children aged 4 to 17 years in 21 US pediatric emergency departments (prevalence of PE or proximal DVT 6.3%), the PERC-Peds rule had a sensitivity of 99.6%, a specificity of 19.6%, and a false-negative rate of 0.1%; sequential PERC-Peds and D-dimer testing ruled out PE or proximal DVT in 54.3% with a false-negative rate of 0.9%.

Older Adults

• Age-adjusted D-dimer thresholds increase the proportion of older patients in whom PE can be excluded without imaging, from 6.4% to 29.7% in patients aged 75 years or older in ADJUST-PE.

Exacerbation of Chronic Obstructive Pulmonary Disease

• In 740 patients hospitalized with acutely worsening COPD, PE was confirmed within 48 hours of admission in 5.9%, and PE occurred during follow-up in 0.7% of 670 untreated patients without VTE at admission, including 3 PE-related deaths.

Treatment

Treatment Approach | Medical Therapy | IVC Filter | Pulmonary Thrombectomy | Pulmonary Thromboendarterectomy | Discharge Care and Long Term Treatment | Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Initial Management

General Principles

• Treatment intensity and site of care are matched to the clinical category or risk class.
• Anticoagulation should be started without delay in patients with high or intermediate clinical probability of PE while the diagnostic workup is in progress (ESC 2019, Class I, Level C).
• If anticoagulation is started parenterally, LMWH or fondaparinux is recommended over UFH for most patients (ESC 2019, Class I, Level A), and the 2026 AHA/ACC guideline recommends LMWH over UFH for initial parenteral anticoagulation, including in hospitalized patients in categories C to E1 (Class 1), and notes that LMWH can also be used in patients undergoing catheter-based therapy or thrombolysis. The ESC 2019 guideline prefers UFH in patients in whom primary reperfusion is being considered, and in patients with serious renal impairment (creatinine clearance ≤30 mL/min) or severe obesity.
• In a Cochrane review of 29 randomized trials (10,390 participants), fixed-dose LMWH reduced recurrent VTE (Peto OR 0.69) and major hemorrhage (Peto OR 0.69) compared with adjusted-dose UFH, without a significant difference in mortality (Peto OR 0.84).

Pulmonary Embolism Response Teams

• The 2026 AHA/ACC guideline recommends PERT evaluation for patients in categories C to E (Class 1). The ESC 2019 guideline states that a multidisciplinary team and program for the management of high-risk and, in selected cases, intermediate-risk PE should be considered (Class IIa, Level C).
• The PERT Consortium has published consensus practice for the diagnosis, treatment, and follow-up of acute PE.

Site of Care

• The 2026 AHA/ACC guideline emphasizes discharge from the emergency department for category A, early discharge for category B, and hospitalization for categories C to E; outpatient treatment of selected patients in categories A and B (Class 2a, Level B-R) and the use of a validated decision tool to select them (Class 2a, Level B-R) are reasonable.
• Carefully selected patients with low-risk PE should be considered for early discharge and home treatment if proper outpatient care and anticoagulant treatment can be provided (ESC 2019, Class IIa, Level A). ASH 2020 suggests home treatment over hospital-based treatment for uncomplicated PE at low risk of complications (conditional recommendation), and the British Thoracic Society has issued a dedicated guideline on outpatient management.
• Evidence for outpatient treatment:
  • In a randomized noninferiority trial of patients in PESI class I or II, recurrent VTE within 90 days occurred in 0.6% of 171 outpatients vs none of 168 inpatients, and major bleeding in 1.8% vs none.
  • In the single-arm HoT-PE trial (525 patients treated with rivaroxaban after early discharge), symptomatic nonfatal VTE recurrence occurred in 0.6% and major bleeding in 1.2%.
  • In the HOME-PE trial (1975 patients), triage by Hestia was noninferior to triage by sPESI (30-day composite 3.82% vs 3.57%), with 38.4% vs 36.6% of patients treated at home.
  • In an individual-patient data meta-analysis of 2694 patients treated at home after triage, mortality was 0.11% at 14 days and 0.30% at 30 days, 30-day adverse events occurred in 1.2%, and cancer was associated with higher 30-day mortality (RR 4.9).
• Patients receiving systemic or catheter-directed thrombolysis should be cared for in a monitored unit (AHA/ACC 2026, Class 1, Level C-EO).

Hemodynamic and Respiratory Support

• Supplemental oxygen is indicated in patients with an oxygen saturation <90%; high-flow nasal oxygen and noninvasive or invasive ventilation should be considered in extreme instability, recognizing that hypoxemia cannot be corrected without pulmonary reperfusion.
• If mechanical ventilation is needed, positive intrathoracic pressure can reduce venous return and worsen RV failure; positive end-expiratory pressure should be applied with caution, tidal volumes of approximately 6 mL/kg lean body weight should be used to keep the end-inspiratory plateau pressure <30 cm H₂O, and anesthetic drugs prone to cause hypotension should be avoided during induction.
• Management of acute RV failure relies on treating the underlying cause, judicious fluid management, inotropes and vasopressors, mechanical assist devices, and an RV-protective ventilation strategy.

Strategy	Properties and use in high-risk PE
Volume optimization	Cautious volume loading (saline or Ringer's lactate, ≤500 mL over 15 to 30 minutes) in patients with normal to low central venous pressure; volume loading can overdistend the RV, worsen ventricular interdependence, and reduce cardiac output
Norepinephrine (0.2 to 1.0 µg/kg/min)	Increases RV inotropy and systemic blood pressure, promotes positive ventricular interactions, and restores the coronary perfusion gradient; excessive vasoconstriction may worsen tissue perfusion
Dobutamine (2 to 20 µg/kg/min)	Increases RV inotropy and lowers filling pressures; may aggravate arterial hypotension if used alone without a vasopressor, and may trigger or aggravate arrhythmias
Venoarterial extracorporeal membrane oxygenation	Rapid short-term circulatory support combined with an oxygenator; complications, including bleeding and infection, increase with use beyond 5 to 10 days; requires an experienced team

• Table adapted from the 2019 ESC/ERS guideline; norepinephrine and/or dobutamine should be considered in patients with high-risk PE (Class IIa, Level C).

Management Algorithm

The following algorithm summarizes the initial management of confirmed acute PE according to the AHA/ACC Acute PE Clinical Categories, integrating the 2026 AHA/ACC and 2019 ESC/ERS recommendations.

Confirmed acute PE Assess symptoms, hemodynamic status, end-organ perfusion, clinical severity score (PESI, sPESI, or Hestia), RV imaging, cardiac biomarkers, and lactate

Category A or B Incidental or asymptomatic PE (A), or symptomatic PE with a low clinical severity score (B)

Category C Symptomatic PE with an elevated clinical severity score; C1 to C3 by RV imaging and cardiac biomarkers

Category D Incipient cardiopulmonary failure (normotensive shock): transient or volume-responsive hypotension (D1), or with hypoperfusion or end-organ dysfunction (D2)

Category E Cardiopulmonary failure: persistent hypotension with cardiogenic shock (E1), or refractory shock or cardiac arrest (E2)

Anticoagulation, preferably with a DOAC Discharge from the emergency department (A) or early discharge (B) for selected patients using a validated decision tool such as Hestia or sPESI

Hospitalize; anticoagulation (LMWH preferred if parenteral) Troponin or natriuretic peptide, lactate, and RV imaging (echocardiography preferred) PERT evaluation; no routine primary systemic thrombolysis; rescue reperfusion if hemodynamic deterioration

Hospitalize with close monitoring; PERT evaluation Parenteral anticoagulation: LMWH preferred by AHA/ACC; ESC 2019 favors UFH if reperfusion is likely Advanced therapy can be considered: systemic thrombolysis, catheter-directed therapy, or surgical embolectomy

Intensive care; parenteral anticoagulation (LMWH preferred in E1 by AHA/ACC; ESC 2019 favors UFH with a weight-adjusted bolus); cautious fluids; norepinephrine and/or dobutamine; caution with intubation PERT activation; advanced therapy is reasonable in E1: systemic thrombolysis, or surgical embolectomy or catheter-directed therapy if thrombolysis is contraindicated or has failed VA-ECMO may be considered for refractory circulatory collapse or cardiac arrest

Medical Therapy

Anticoagulation

• Anticoagulation is the cornerstone of treatment. Therapeutic anticoagulation for at least 3 months is recommended for all patients with PE (ESC 2019, Class I, Level A).
• DOACs are recommended over vitamin K antagonists (VKAs) unless contraindicated (AHA/ACC 2026, Class 1, Level B-R; ESC 2019, Class I, Level A), and ASH 2020 suggests DOACs over VKAs for primary treatment of VTE (conditional recommendation).
• Compared with heparin followed by a VKA, DOACs are noninferior for treating PE and have a 0.6% lower rate of bleeding. In a meta-analysis of 6 phase 3 trials (27,023 patients), recurrent VTE occurred in 2.0% of DOAC recipients vs 2.2% of VKA recipients (RR 0.90), and DOACs reduced major bleeding (RR 0.61).

Agent	Regimen in phase 3 trials	Pivotal trial	Recurrent VTE (DOAC vs comparator)	Bleeding (DOAC vs comparator)
Apixaban	10 mg twice daily for 7 days, then 5 mg twice daily; no parenteral lead-in	AMPLIFY: 5395 patients with acute VTE; comparator enoxaparin followed by warfarin	2.3% vs 2.7% (recurrent VTE or VTE-related death)	Major bleeding 0.6% vs 1.8% (RR 0.31); major or clinically relevant nonmajor bleeding 4.3% vs 9.7%
Rivaroxaban	15 mg twice daily for 3 weeks, then 20 mg once daily; no parenteral lead-in	EINSTEIN-PE: 4832 patients with PE; comparator enoxaparin followed by a VKA	2.1% vs 1.8%	Major bleeding 1.1% vs 2.2% (HR 0.49); major or clinically relevant nonmajor bleeding 10.3% vs 11.4%
Edoxaban	After initial heparin, 60 mg once daily, or 30 mg once daily (for example, with creatinine clearance of 30 to 50 mL/min or body weight below 60 kg)	Hokusai-VTE: 4921 patients with DVT and 3319 with PE; comparator warfarin	3.2% vs 3.5%; 3.3% vs 6.2% in 938 patients with RV dysfunction assessed by NT-proBNP	Major or clinically relevant nonmajor bleeding 8.5% vs 10.3%
Dabigatran	150 mg twice daily after initial parenteral anticoagulation (median 9 days in RE-COVER)	RE-COVER and RE-COVER II; comparator warfarin	2.4% vs 2.1% (RE-COVER); 2.3% vs 2.2% (RE-COVER II)	Major bleeding 1.6% vs 1.9% (RE-COVER); 1.2% vs 1.7% (RE-COVER II)

• In the COBRRA trial (2760 patients with acute PE or proximal DVT), published after all current guidelines, clinically relevant bleeding during 3 months of treatment occurred in 3.3% with apixaban vs 7.1% with rivaroxaban (RR 0.46), and death from any cause in 0.1% vs 0.3%.
• NOACs are not recommended in patients with severe renal impairment, during pregnancy and lactation, or in patients with antiphospholipid antibody syndrome (ESC 2019, Class III, Level C).
• In patients with a body mass index >40 kg/m² or weight >120 kg, standard-dose rivaroxaban or apixaban are among the appropriate options for VTE treatment, whereas dabigatran, edoxaban, and betrixaban are not suggested; parenteral anticoagulation is suggested over a DOAC in the acute phase after bariatric surgery.

Vitamin K Antagonists

• When a VKA such as warfarin is used, overlap with parenteral anticoagulation is recommended until an INR of 2.5 (range 2.0 to 3.0) is reached (ESC 2019, Class I, Level A). ASH 2020 strongly recommends an INR range of 2.0 to 3.0 over a lower INR range for patients who use a VKA for secondary prevention.
• A VKA is preferred over a DOAC for indefinite treatment of patients with antiphospholipid antibody syndrome (see Special Populations).

Systemic Thrombolysis

• Indications:
  • Systemic thrombolytic therapy is recommended for high-risk PE (ESC 2019, Class I, Level B), and rescue thrombolytic therapy is recommended for patients who deteriorate hemodynamically on anticoagulation (Class I, Level B); routine primary systemic thrombolysis is not recommended in intermediate-risk or low-risk PE (Class III, Level B).
  • ASH 2020 strongly recommends thrombolytic therapy for patients with PE and hemodynamic compromise.
  • The 2026 AHA/ACC guideline considers advanced therapies, including systemic thrombolysis, reasonable in category E1 and an option that can be considered in categories D1 to D2.
• Evidence in intermediate-risk (submassive) PE:
  • In PEITHO (1005 normotensive patients with RV dysfunction and a positive troponin), tenecteplase plus heparin reduced death or hemodynamic decompensation within 7 days (2.6% vs 5.6%; OR 0.44), but 7-day mortality did not differ (1.2% vs 1.8%), extracranial bleeding increased (6.3% vs 1.2%), and stroke occurred in 2.4% vs 0.2% (hemorrhagic in 10 of 12 patients with tenecteplase). At long-term follow-up (709 patients, median 37.8 months), mortality (20.3% vs 18.0%), persistent dyspnea or functional limitation (36.0% vs 30.1%), and confirmed CTEPH (2.1% vs 3.2%) did not differ significantly.
  • In MAPPET-3 (256 patients), alteplase plus heparin reduced treatment escalation (10.2% vs 24.6%), with mortality of 3.4% vs 2.2%.
  • In TOPCOAT (83 patients, terminated early), at least one adverse outcome occurred in 15% with tenecteplase vs 37% with placebo, and one patient treated with tenecteplase had a fatal intracranial hemorrhage.
  • In MOPETT (121 patients), reduced-dose alteplase plus anticoagulation was associated with less pulmonary hypertension at 28 months (16% vs 57%), with no bleeding in either group.
• Meta-analyses:
  • In 16 randomized trials (2115 patients), thrombolysis was associated with lower all-cause mortality (2.17% vs 3.89%; OR 0.53; number needed to treat 59) but more major bleeding (9.24% vs 3.42%; OR 2.73; number needed to harm 18) and intracranial hemorrhage (1.46% vs 0.19%; OR 4.63; number needed to harm 78).
  • In 15 randomized trials (2057 patients), the mortality reduction (OR 0.59) was no longer significant after excluding studies of high-risk PE (OR 0.64), whereas major hemorrhage (OR 2.91) and fatal or intracranial bleeding (OR 3.18) increased.
  • In a Cochrane review of 21 trials (2401 participants), thrombolytics plus heparin probably reduced death (OR 0.58) but increased major hemorrhage (OR 2.84) and hemorrhagic stroke (OR 7.59).
• Reduced-dose regimens: in a randomized trial of 118 patients with hemodynamic instability or massive obstruction, alteplase 50 mg over 2 hours had efficacy similar to 100 mg over 2 hours, with bleeding in 3% vs 10% (14.8% vs 41.2% in patients weighing less than 65 kg). The placebo-controlled PEITHO-3 trial is evaluating reduced-dose alteplase in intermediate-high-risk PE.

Thrombolytic agent	Regimen
Alteplase (recombinant tissue plasminogen activator)	100 mg over 2 hours; or 0.6 mg/kg over 15 minutes (maximum dose 50 mg), an accelerated regimen that is not officially approved but is sometimes used in extreme hemodynamic instability such as cardiac arrest
Streptokinase	250,000 IU as a loading dose over 30 minutes, followed by 100,000 IU/h over 12 to 24 hours; accelerated regimen: 1.5 million IU over 2 hours
Urokinase	4400 IU/kg as a loading dose over 10 minutes, followed by 4400 IU/kg/h over 12 to 24 hours; accelerated regimen: 3 million IU over 2 hours

• UFH should not be infused concurrently with streptokinase or urokinase, but it can be continued during alteplase infusion. Table adapted from the 2019 ESC/ERS guideline.

Absolute contraindications to fibrinolysis	Relative contraindications to fibrinolysis
History of hemorrhagic stroke or stroke of unknown origin Ischemic stroke in the previous 6 months Central nervous system neoplasm Major trauma, surgery, or head injury in the previous 3 weeks Bleeding diathesis Active bleeding	Transient ischemic attack in the previous 6 months Oral anticoagulation Pregnancy or first postpartum week Noncompressible puncture sites Traumatic resuscitation Refractory hypertension (systolic blood pressure >180 mm Hg) Advanced liver disease Infective endocarditis Active peptic ulcer

• Table adapted from the 2019 ESC/ERS guideline.

Reversal of Anticoagulation

• In ANNEXA-4 (352 patients with acute major bleeding within 18 hours of a factor Xa inhibitor), andexanet alfa reduced median anti-factor Xa activity by 92% with apixaban and rivaroxaban, hemostatic efficacy was excellent or good in 82% of evaluable patients, and within 30 days 14% died and 10% had a thrombotic event.
• In REVERSE-AD (503 patients), idarucizumab 5 g achieved a median maximum reversal of dabigatran of 100%, the median time to cessation of bleeding was 2.5 hours, and at 90 days thrombotic events had occurred in 6.3% and 7.4% and mortality was 18.8% and 18.9% in the bleeding and urgent-procedure groups.

Procedural / Surgical Therapy

• Surgical pulmonary embolectomy is recommended for patients with high-risk PE in whom thrombolysis is contraindicated or has failed (ESC 2019, Class I, Level C), percutaneous catheter-directed treatment should be considered in the same setting (Class IIa, Level C), and either should be considered as an alternative to rescue thrombolysis in patients who deteriorate on anticoagulation (Class IIa, Level C).
• The 2026 AHA/ACC guideline considers advanced therapies (systemic thrombolysis, catheter-directed thrombolysis, mechanical thrombectomy, and surgical embolectomy) reasonable in category E1 and an option that can be considered in categories D1 to D2. Members of its writing committee have described catheter-based therapy as a field in transition. The guideline's literature search covered February to October 2024, with key studies added through April 2025, so several randomized trials of catheter-based therapy postdate it.
• AHA and ESC scientific statements summarize the available catheter-based techniques, periprocedural anticoagulation, and remaining evidence gaps.

Catheter-Directed Thrombolysis

• Catheter-directed thrombolysis delivers a low dose of fibrinolytic drug into the pulmonary arteries, with or without ultrasound facilitation.
• Early studies (surrogate end points):
  • ULTIMA (59 patients): ultrasound-assisted catheter-directed thrombolysis (10 to 20 mg alteplase over 15 hours) plus UFH reduced the RV-to-left ventricular diameter ratio from baseline to 24 hours by 0.30 vs 0.03 with UFH alone, with no major bleeding at 90 days.
  • SEATTLE II (150 patients, single arm, 24 mg alteplase): the RV-to-left ventricular diameter ratio fell from 1.55 to 1.13 at 48 hours; severe or moderate bleeding occurred in 10%, and there was no intracranial hemorrhage.
  • OPTALYSE PE (101 patients): regimens of 4 to 12 mg alteplase per lung over 2 to 6 hours all reduced the RV-to-left ventricular diameter ratio; major bleeding occurred in 4%, with 2 intracranial hemorrhages.
  • SUNSET sPE (81 patients): ultrasound-assisted thrombolysis did not reduce thrombus burden more than standard catheter-directed thrombolysis, and the RV-to-left ventricular diameter ratio fell by 0.37 with ultrasound-assisted vs 0.59 with standard catheter-directed thrombolysis.
  • CANARY (94 patients, stopped early): conventional catheter-directed thrombolysis reduced the proportion of patients with an RV-to-left ventricular diameter ratio >0.9 at 72 hours (27.0% vs 52.1%), but not significantly at 3 months (4.3% vs 12.8%).
• Clinical outcome trials (2026):
  • HI-PEITHO (544 patients with intermediate-risk PE, an RV-to-left ventricular diameter ratio ≥1.0, an elevated troponin, and at least 2 of systolic blood pressure ≤110 mm Hg, heart rate ≥100 beats/min, or respiratory rate >20 breaths/min): ultrasound-facilitated catheter-directed fibrinolysis with alteplase plus anticoagulation reduced the 7-day composite of PE-related death, cardiorespiratory decompensation or collapse, or symptomatic recurrence (4.0% vs 10.3%; RR 0.39), driven mainly by less cardiorespiratory decompensation. Major bleeding occurred in 4.1% vs 2.2% at 7 days and 4.1% vs 3.0% at 30 days, and there was no intracranial hemorrhage.
  • PRAGUE-26 (558 patients with intermediate-high-risk PE, defined by an sPESI ≥1 and RV dysfunction plus an elevated troponin or natriuretic peptide): catheter-directed thrombolysis with alteplase plus anticoagulation reduced the 7-day composite of death from any cause, recurrent PE, or cardiorespiratory decompensation or collapse (0.7% vs 6.8%; RR 0.10). Clinically relevant bleeding (4.6% vs 5.0%) and major bleeding (1.4% vs 2.2%) were similar, and intracranial hemorrhage occurred in 2 patients (0.7%) vs none; 1 patient in the thrombolysis group died within 30 days, and 4 patients in the standard-care group died within 7 days.
  • In both trials, the benefit was driven mainly by fewer episodes of cardiorespiratory decompensation or collapse rather than by a demonstrated reduction in mortality, and both were published after the evidence review of the 2026 AHA/ACC guideline.
• Low-dose regimens: in STRATIFY (210 patients with intermediate-high-risk PE), low-dose alteplase (20 mg over 6 hours) reduced the refined modified Miller score by 3.6 points compared with heparin alone, with no difference between ultrasound-assisted and intravenous delivery; bleeding complications were numerically, but not significantly, more frequent with low-dose thrombolysis, no differences in other outcomes were reported, and the authors' conclusion noted increased rates of death and bleeding with low-dose thrombolysis. In BETULA (60 patients), catheter-directed thrombolysis with 4 mg alteplase per catheter over 2 hours changed the RV-to-left ventricular diameter ratio by -0.17 vs +0.02 with UFH alone at 24 hours, without major bleeding.
• In a network meta-analysis of 45 studies (81,705 patients), catheter-directed thrombolysis was associated with lower mortality (OR 0.55) but more major bleeding (OR 1.84) than anticoagulation alone, whereas systemic thrombolysis was not associated with lower mortality and increased major bleeding (OR 2.16) and intracranial hemorrhage (OR 2.26).

Mechanical Thrombectomy

• Single-arm studies and registries:
  • FLARE (106 patients, large-bore aspiration thrombectomy): the RV-to-left ventricular diameter ratio fell by 0.38 (25.1%) at 48 hours, and major bleeding occurred in 1.0%.
  • EXTRACT-PE (119 patients, continuous aspiration): the ratio fell by 0.43 at 48 hours, major adverse events occurred in 1.7%, and intraprocedural thrombolytics were avoided in 98.3%.
  • FLASH (800 US patients): major adverse events occurred in 1.8%, all-cause mortality was 0.3% at 48 hours and 0.8% at 30 days, and the ratio fell from 1.23 to 0.98.
  • FLAME (114 patients with high-risk PE, nonrandomized): the in-hospital composite end point occurred in 17.0% with mechanical thrombectomy vs 63.9% in the context arm, and in-hospital mortality was 1.9% vs 29.5%.
  • STRIKE-PE (interim analysis of 300 patients, computer-assisted vacuum thrombectomy): the ratio fell from 1.40 to 0.99 at 48 hours (26.8% reduction), and the 48-hour major adverse event rate was 2.0%.
• Randomized trials:
  • PEERLESS (550 patients with intermediate-risk PE): large-bore mechanical thrombectomy was superior to catheter-directed thrombolysis on a hierarchical end point (win ratio 5.01), driven by less clinical deterioration or bailout (1.8% vs 5.4%) and fewer intensive care unit admissions (41.6% vs 98.6%), with no differences in mortality, intracranial hemorrhage, or major bleeding (30-day mortality 0.4% vs 0.8%).
  • STORM-PE (100 patients with intermediate-high-risk PE): computer-assisted vacuum thrombectomy plus anticoagulation reduced the RV-to-left ventricular diameter ratio at 48 hours more than anticoagulation alone (0.52 vs 0.24); 7-day major adverse events occurred in 4.3% vs 7.5%, including 2 PE-related deaths in the thrombectomy group. At 90 days, the 6-minute walk distance was 478.7 vs 368.0 m and NYHA class I was reported by 97.4% vs 75.6%, with no differences in mortality or symptomatic PE recurrence.

Trial	Population	Comparison	Main findings
ULTIMA (2014)	59, intermediate risk	Ultrasound-assisted catheter-directed thrombolysis plus UFH vs UFH	RV-to-left ventricular ratio reduction at 24 hours 0.30 vs 0.03
SUNSET sPE (2021)	81, submassive	Ultrasound-assisted vs standard catheter-directed thrombolysis	No difference in thrombus reduction
CANARY (2022)	94, intermediate-high risk	Catheter-directed thrombolysis vs anticoagulation	RV-to-left ventricular ratio >0.9 at 3 months 4.3% vs 12.8% (not significant)
PEERLESS (2025)	550, intermediate risk	Large-bore mechanical thrombectomy vs catheter-directed thrombolysis	Win ratio 5.01; less deterioration or bailout and fewer intensive care admissions
STORM-PE (2026)	100, intermediate-high risk	Computer-assisted vacuum thrombectomy plus anticoagulation vs anticoagulation	RV-to-left ventricular ratio reduction 0.52 vs 0.24 at 48 hours
HI-PEITHO (2026)	544, intermediate risk with markers of cardiorespiratory distress	Ultrasound-facilitated catheter-directed fibrinolysis plus anticoagulation vs anticoagulation	7-day composite 4.0% vs 10.3% (RR 0.39); no intracranial hemorrhage
PRAGUE-26 (2026)	558, intermediate-high risk	Catheter-directed thrombolysis plus anticoagulation vs anticoagulation	7-day composite 0.7% vs 6.8% (RR 0.10); intracranial hemorrhage 0.7% vs 0
STRATIFY (2026)	210, intermediate-high risk	Low-dose alteplase (ultrasound-assisted or intravenous) vs heparin	Greater reduction in thrombus burden; no difference between delivery routes; bleeding numerically more frequent with thrombolysis
BETULA (2026)	60, intermediate-high risk	Low-dose, short-duration catheter-directed thrombolysis plus UFH vs UFH	RV-to-left ventricular ratio change -0.17 vs +0.02 at 24 hours

Surgical Pulmonary Embolectomy

• In a meta-analysis of 56 studies (1579 patients), pooled in-hospital mortality after surgical embolectomy was 26.3%, and surgical site complications occurred in 7.0% of operations.
• In the US National Inpatient Sample (2010 to 2014; 58,974 patients), in-hospital mortality was 20% after surgical embolectomy, 16% after systemic thrombolysis, and 7% after catheter-directed therapy; these observational comparisons are subject to selection bias.
• In a Japanese nationwide database of 2813 patients with high-risk PE, surgical embolectomy was associated with lower in-hospital mortality than thrombolysis (22.2% vs 30.1%) and more favorable neurologic outcomes at discharge (72.5% vs 66.7%).

Extracorporeal Membrane Oxygenation

• ECMO may be considered, in combination with surgical embolectomy or catheter-directed treatment, in patients with PE and refractory circulatory collapse or cardiac arrest (ESC 2019, Class IIb, Level C).
• In the ELSO registry (821 patients, 833 ECMO runs), in-hospital mortality was 68.1% with extracorporeal cardiopulmonary resuscitation, 42.7% with venoarterial ECMO, and 28.2% with venovenous ECMO.
• In a meta-analysis of 17 studies (327 patients on ECMO), mortality was 22.6% with mechanical reperfusion vs 42.8% with other strategies (OR 0.439), and the OR for surgical embolectomy vs thrombolysis was 0.368.
• In US hospitalizations for high-risk PE (122,735 patients; ECMO in 2.3%), ECMO plus thrombolysis was associated with lower in-hospital mortality than neither reperfusion nor ECMO (aOR 0.61), ECMO plus mechanical reperfusion showed no difference (aOR 1.03), and ECMO alone was associated with higher mortality (aOR 1.60).
• In an international cohort of 492 patients on venoarterial ECMO for high-risk PE (69% with cardiac arrest), early mechanical reperfusion within 48 hours was not associated with significantly lower 90-day mortality than ECMO alone after propensity matching (32% vs 39%; HR 0.68; P=.07), and bleeding occurred in 50% of patients.

Inferior Vena Cava Filters

• IVC filters should be considered in patients with acute PE and absolute contraindications to anticoagulation (ESC 2019, Class IIa, Level C) and in cases of PE recurrence despite therapeutic anticoagulation (Class IIa, Level C); routine use of IVC filters is not recommended (Class III, Level A).
• The Society of Interventional Radiology guideline provides 18 recommendations on filter use in patients with or at substantial risk of VTE, and ASH 2019 conditionally recommends against IVC filters for VTE prevention in patients undergoing major surgery.
• In PREPIC (400 patients with proximal DVT), permanent filters reduced PE by day 12 (1.1% vs 4.8%) but increased recurrent DVT at 2 years (20.8% vs 11.6%), with no difference in mortality. At 8 years, symptomatic PE occurred in 6.2% vs 15.1% and DVT in 35.7% vs 27.5%, with no effect on survival.
• In PREPIC2 (399 hospitalized patients with severe PE and lower-limb DVT), a retrievable filter plus anticoagulation did not reduce recurrent PE at 3 months compared with anticoagulation alone (3.0% vs 1.5%; RR 2.00).

Pulmonary Endarterectomy and Balloon Pulmonary Angioplasty

• In patients with CTEPH, treatment modalities include lifelong anticoagulation plus surgery (pulmonary endarterectomy), balloon pulmonary angioplasty, and medical therapy, selected according to the location and characteristics of the lesions; patients should be assessed by a multidisciplinary CTEPH team.
• In a worldwide registry of 1009 patients, 3-year survival was 94% after pulmonary endarterectomy, 92% after balloon pulmonary angioplasty, and 71% without mechanical intervention.
• In the RACE trial (105 patients with inoperable CTEPH), balloon pulmonary angioplasty reduced pulmonary vascular resistance to 39.9% of baseline vs 66.7% with riociguat at 26 weeks, but treatment-related serious adverse events occurred in 42% vs 9%. In MR BPA (61 patients), mean pulmonary artery pressure improved by -16.3 vs -7.0 mm Hg at 12 months.

Long-Term Management

Duration of Anticoagulation

• Therapeutic anticoagulation for at least 3 months is recommended for all patients with PE (ESC 2019, Class I, Level A).
• For a first PE secondary to a major transient or reversible risk factor, discontinuation after 3 months is recommended (Class I, Level B).
• Indefinite oral anticoagulation is recommended for recurrent VTE not related to a major transient or reversible risk factor (Class I, Level B), and indefinite treatment with a VKA is recommended for antiphospholipid antibody syndrome (Class I, Level B). ASH 2020 strongly recommends indefinite anticoagulation for recurrent unprovoked VTE.
• Extended oral anticoagulation of indefinite duration should be considered after a first PE with no identifiable risk factor (Class IIa, Level A), with a persistent risk factor other than antiphospholipid antibody syndrome (Class IIa, Level C), or with a minor transient or reversible risk factor (Class IIa, Level C).
• The 2026 AHA/ACC guideline recommends an extended phase of anticoagulation beyond the initial 3 to 6 months after a first PE that was not provoked by a major reversible risk factor or that is associated with a persistent risk factor.
• Patients whose long-term risk of recurrence outweighs the long-term risk of major bleeding, such as those with active cancer or men with unprovoked VTE, should receive indefinite anticoagulation. The CHEST 2021 update provides 29 guidance statements, 13 of them strong recommendations, from initial management through secondary prevention.
• In PADIS-PE (371 patients with a first unprovoked PE treated for 6 months), 18 additional months of warfarin reduced recurrent VTE or major bleeding during treatment (3.3% vs 13.5%; HR 0.22), but the benefit was not maintained after warfarin was stopped (20.8% vs 24.0% at 42 months).
• In patients receiving extended anticoagulation, drug tolerance and adherence, hepatic and renal function, and bleeding risk should be reassessed at regular intervals (ESC 2019, Class I, Level C).
• The HERDOO2 rule identifies women with a first unprovoked VTE who have a low risk of recurrence after stopping anticoagulation (see Assessment of Probability of Subsequent VTE).

Extended-Phase Therapy

• If extended anticoagulation is chosen for a patient without cancer, a reduced dose of apixaban (2.5 mg twice daily) or rivaroxaban (10 mg once daily) should be considered after 6 months of therapeutic anticoagulation (ESC 2019, Class IIa, Level A); aspirin or sulodexide may be considered in patients who refuse or cannot tolerate any oral anticoagulant (Class IIb, Level B).

Trial	Comparison	Main results
EINSTEIN-Extension	Rivaroxaban vs placebo	Recurrent VTE 1.3% vs 7.1% (HR 0.18); nonfatal major bleeding 0.7% vs 0%
AMPLIFY-EXT	Apixaban 2.5 mg or 5 mg twice daily vs placebo for 12 months	Recurrent VTE or VTE-related death 1.7% and 1.7% vs 8.8%; major bleeding 0.2% and 0.1% vs 0.5%
RE-MEDY and RE-SONATE	Dabigatran 150 mg twice daily vs warfarin (RE-MEDY) and vs placebo (RE-SONATE)	Recurrent VTE 1.8% vs 1.3% with warfarin (noninferior) and 0.4% vs 5.6% with placebo (HR 0.08)
EINSTEIN CHOICE	Rivaroxaban 20 mg or 10 mg once daily vs aspirin 100 mg	Recurrent VTE 1.5% and 1.2% vs 4.4%; major bleeding 0.5% and 0.4% vs 0.3%
WARFASA	Aspirin 100 mg vs placebo after 6 to 18 months of anticoagulation for a first unprovoked VTE	Recurrent VTE 6.6% vs 11.2% per year (HR 0.58); one major bleed in each group
ASPIRE	Aspirin 100 mg vs placebo after initial anticoagulation for a first unprovoked VTE	Recurrent VTE 4.8% vs 6.5% per year (HR 0.74; P=0.09); composite of VTE, myocardial infarction, stroke, or cardiovascular death reduced (HR 0.66)
RENOVE	Reduced-dose (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) vs full-dose DOAC in patients at high risk of recurrence	5-year cumulative incidence of recurrent VTE 2.2% vs 1.8% (adjusted HR 1.32), so noninferiority was not shown; major or clinically relevant bleeding 9.9% vs 15.2% (adjusted HR 0.61)
HI-PRO	Apixaban 2.5 mg twice daily vs placebo for 12 months in provoked VTE with at least one enduring risk factor	Recurrent VTE 1.3% vs 10.0% (HR 0.13); major bleeding in 1 vs 0 patients; clinically relevant nonmajor bleeding 4.8% vs 1.7%

• After anticoagulation is stopped following a first unprovoked VTE, recurrence occurs at 10.3 events per 100 person-years in the first year.

Follow-Up

Support group

• Routine clinical evaluation of patients 3 to 6 months after acute PE is recommended (ESC 2019, Class I, Level B), as is an integrated model of care involving hospital specialists, appropriately qualified nurses, and primary care physicians (Class I, Level C).
• Further diagnostic evaluation should be considered in patients with persistent or new-onset dyspnea or exercise limitation (Class IIa, Level C), and symptomatic patients with mismatched perfusion defects persisting on V/Q scan more than 3 months after acute PE should be referred to a pulmonary hypertension or CTEPH expert center (Class I, Level C).
• The 2026 AHA/ACC guideline recommends asking about symptoms and functional limitation at every visit for at least 1 year.
• Persistent symptoms are common: in FOCUS, the 2-year cumulative incidence of post-PE impairment was 16.0%, and in ELOPE, 46.5% of patients had reduced exercise capacity at 1 year.
• Rehabilitation: a physiotherapist-guided home exercise program after acute PE (140 patients) produced no significant between-group differences, whereas in 211 patients with persistent dyspnea 6 to 72 months after PE, an 8-week exercise program improved the incremental shuttle walk test by 53.0 m and PE-specific quality of life, without adverse events.

Chronic Thromboembolic Pulmonary Disease

• CTEPH is suspected when a V/Q scan shows mismatched perfusion defects in a patient with pulmonary hypertension, and it is confirmed by right heart catheterization and vascular imaging. Pulmonary hypertension is defined hemodynamically by a mean pulmonary arterial pressure >20 mm Hg, and precapillary pulmonary hypertension additionally by a pulmonary arterial wedge pressure ≤15 mm Hg and pulmonary vascular resistance >2 Wood units.
• In CHEST-1 (261 patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after endarterectomy), riociguat increased the 6-minute walk distance by 39 m vs a decrease of 6 m with placebo (difference 46 m) and reduced pulmonary vascular resistance (difference -246 dyn·s·cm^-5) at 16 weeks.
• With multimodal therapies, 3-year survival exceeds 90%. Procedural options are described under Procedural / Surgical Therapy.

Special Populations

Special Scenarios: Pregnancy | Cancer

Cancer

• Guidelines: ASH 2021 strongly recommends LMWH for initial treatment of VTE in patients with cancer and conditionally recommends LMWH or a DOAC for initial treatment, a DOAC for short-term treatment, and LMWH or a DOAC for long-term treatment. ASCO 2023 added apixaban as an option for the treatment of cancer-associated VTE (strong recommendation). ITAC 2022 recommends LMWH or a DOAC for at least 6 months, with DOACs reserved for patients who are not at high risk of gastrointestinal or genitourinary bleeding and who have no strong drug-drug interactions or impaired gastrointestinal absorption.
• The ESC 2019 guideline states that weight-adjusted subcutaneous LMWH should be considered for the first 6 months over VKAs (Class IIa, Level A); edoxaban (Class IIa, Level B) or rivaroxaban (Class IIa, Level C) should be considered as alternatives in patients without gastrointestinal cancer; and extended anticoagulation beyond 6 months should be considered for an indefinite period or until the cancer is cured (Class IIa, Level B).
• Trials of initial and long-term treatment:
  • CLOT (672 patients): dalteparin reduced recurrent VTE compared with a coumarin (6-month probability 9% vs 17%; HR 0.48), with no significant difference in major bleeding.
  • Hokusai VTE Cancer (1046 patients): edoxaban was noninferior to dalteparin for recurrent VTE or major bleeding (12.8% vs 13.5%), with recurrent VTE in 7.9% vs 11.3% and major bleeding in 6.9% vs 4.0%.
  • SELECT-D (406 patients): 6-month recurrence was 4% with rivaroxaban vs 11% with dalteparin, with major bleeding in 6% vs 4% and clinically relevant nonmajor bleeding in 13% vs 4%.
  • Caravaggio (1155 patients): apixaban was noninferior to dalteparin (recurrent VTE 5.6% vs 7.9%), with major bleeding in 3.8% vs 4.0%.
  • ADAM VTE (287 patients analyzed): major bleeding occurred in 0% with apixaban vs 1.4% with dalteparin, and recurrent VTE in 0.7% vs 6.3%.
  • CANVAS (671 patients): recurrent VTE at 6 months was 6.1% with DOACs vs 8.8% with LMWH (noninferior), whereas major bleeding (5.2% vs 5.6%) did not meet the noninferiority criterion.
• Extended treatment:
  • API-CAT (1766 patients after at least 6 months of anticoagulation): apixaban 2.5 mg twice daily was noninferior to 5 mg twice daily for recurrent VTE (2.1% vs 2.8%) and reduced clinically relevant bleeding (12.1% vs 15.6%).
  • EVE (360 patients): major plus clinically relevant nonmajor bleeding occurred in 8.9% with apixaban 2.5 mg vs 12.2% with 5 mg twice daily, a nonsignificant difference.
  • ONCO PE (178 patients with cancer and an sPESI of 1): 18 months of rivaroxaban reduced recurrent VTE compared with 6 months (5.6% vs 19.1%), with major bleeding in 7.8% vs 5.6%.
• Incidental PE: therapeutic anticoagulation for at least 6 months, preferably with LMWH, is recommended for incidental PE of the main, lobar, segmental, or multiple subsegmental pulmonary arteries and for isolated subsegmental PE with proximal DVT, whereas treatment of isolated subsegmental PE with distal or no DVT is decided case by case. Incidental PE should be managed in the same manner as symptomatic PE if it involves segmental or more proximal branches, multiple subsegmental vessels, or a single subsegmental vessel with proven DVT (ESC 2019, Class IIa, Level B).

Pregnancy and the Postpartum Period

• A therapeutic, fixed dose of LMWH based on early pregnancy body weight is the recommended therapy for PE in most pregnant women without hemodynamic instability (ESC 2019, Class I, Level B), and ASH 2018 strongly recommends LMWH over UFH for acute VTE in pregnancy.
• ASH 2018 conditionally recommends either once-daily or twice-daily LMWH dosing, initial outpatient therapy over hospital admission for low-risk acute VTE, and no routine anti-factor Xa monitoring to guide LMWH dosing.
• NOACs are not recommended during pregnancy or lactation (ESC 2019, Class III, Level C). Insertion of a spinal or epidural needle is not recommended unless more than 24 hours have passed since the last therapeutic dose of LMWH, and LMWH should not be given within 4 hours of removal of an epidural catheter (Class III, Level C).
• Thrombolysis or surgical embolectomy should be considered for pregnant women with high-risk PE (ESC 2019, Class IIa, Level C). In a systematic review of 127 cases of severe PE in pregnancy or within 6 weeks of delivery, survival after thrombolysis was 94%, with major bleeding in 17.5% during pregnancy vs 58.3% postpartum; after surgical thrombectomy, maternal survival was 86.1% and major bleeding occurred in 20.0%.
• For prevention in women with a history of VTE, the Highlow trial (1110 pregnant women) found no significant difference in VTE between weight-adjusted intermediate-dose and fixed low-dose LMWH (2% vs 3%), with major bleeding in 4% of both groups. ASH 2018 strongly recommends antepartum prophylaxis for women with a history of unprovoked or hormonally associated VTE.
• The ACOG Practice Bulletin and the 2025 ESC guideline on cardiovascular disease and pregnancy provide additional guidance on peripartum anticoagulation.

Children

• The ASH/ISTH 2024 guideline update provides 20 recommendations for pediatric VTE, including the role of DOACs.
• In EINSTEIN-Jr (500 children), recurrent VTE occurred in 1% with rivaroxaban vs 3% with standard anticoagulants, and major or clinically relevant nonmajor bleeding in 3% vs 2%.
• In DIVERSITY (267 children randomized), dabigatran was noninferior to standard care for a composite efficacy end point (46% vs 42%), with major bleeding in 2% of both groups.
• In Kids-DOTT (417 patients younger than 21 years with provoked VTE), 6 weeks of anticoagulation was noninferior to 3 months (1-year recurrent VTE 0.66% vs 0.70%; clinically relevant bleeding 0.65% vs 0.70%).
• In a pediatric cohort of 170 patients with acute PE, 22% had massive and 7% had submassive PE, and PESI predicted 30-day mortality with an area under the curve of 0.76.

Antiphospholipid Syndrome

• In TRAPS (120 patients with triple-positive antiphospholipid syndrome), events occurred in 19% with rivaroxaban vs 3% with warfarin, including thromboembolic events in 12% vs none.
• In a noninferiority trial of 190 patients, recurrent thrombosis occurred in 11.6% with rivaroxaban vs 6.3% with a VKA, and stroke in 9 vs 0 patients. In ASTRO-APS, stroke occurred in 6 of 23 patients randomized to apixaban vs 0 of 25 randomized to warfarin.
• In a meta-analysis of 4 randomized trials (472 patients), DOACs were associated with more arterial thrombotic events than VKAs (OR 5.43) but not with more VTE or major bleeding. A VKA is therefore preferred, and indefinite VKA treatment is recommended (ESC 2019, Class I, Level B).

Subsegmental PE

• In a prospective cohort of 266 patients with isolated subsegmental PE and no proximal DVT on serial ultrasonography who were managed without anticoagulation, the 90-day cumulative incidence of recurrent VTE was 3.1% (2.1% for single and 5.7% for multiple subsegmental PE), with no fatal recurrent PE.
• The randomized, placebo-controlled SAFE-SSPE trial is comparing clinical surveillance with rivaroxaban in low-risk patients with isolated subsegmental PE.

COVID-19

• In noncritically ill patients hospitalized with COVID-19 (2219 patients), therapeutic-dose heparin increased organ support-free days compared with usual-care thromboprophylaxis (adjusted OR 1.27), with an adjusted absolute gain of 4.0 percentage points in survival to discharge without organ support, and major bleeding in 1.9% vs 0.9%.
• In critically ill patients (1098 patients), therapeutic-dose heparin did not improve organ support-free days (adjusted OR 0.83; trial stopped for futility); survival to discharge was 62.7% vs 64.5%, and major bleeding occurred in 3.8% vs 2.3%.
• ITAC 2022 includes guidance for patients with cancer and COVID-19.

Prevention

• Hospitalized medical patients: ASH 2018 strongly recommends pharmacologic VTE prophylaxis in acutely or critically ill inpatients at acceptable bleeding risk and mechanical prophylaxis when bleeding risk is unacceptable, and recommends against DOACs during hospitalization and against extending pharmacologic prophylaxis after discharge.
• Surgical patients: ASH 2019 issued 30 recommendations, including conditional recommendations for mechanical prophylaxis over no prophylaxis, pneumatic compression over graduated compression stockings, and against IVC filters in major surgery, and for either aspirin or anticoagulants (with a DOAC preferred over LMWH) after total hip or knee arthroplasty.
• Ambulatory patients with cancer:
  • In CASSINI (841 patients with a Khorana score ≥2), rivaroxaban 10 mg daily did not significantly reduce the primary end point up to day 180 (6.0% vs 8.8%; HR 0.66; P=0.10) but reduced events during the intervention period (2.6% vs 6.4%; HR 0.40), with major bleeding in 2.0% vs 1.0%.
  • In AVERT (563 patients with a Khorana score ≥2 starting chemotherapy), apixaban 2.5 mg twice daily reduced VTE (4.2% vs 10.2%; HR 0.41) but increased major bleeding (3.5% vs 1.8%).
  • ASH 2021 conditionally recommends LMWH or a DOAC for ambulatory patients receiving systemic therapy at high risk of VTE, and ITAC 2022 recommends primary prophylaxis with LMWH or a DOAC (rivaroxaban or apixaban) in ambulatory patients with locally advanced or metastatic pancreatic cancer treated with anticancer therapy and at low bleeding risk.
  • ASCO 2023 added apixaban and rivaroxaban as options for extended thromboprophylaxis after cancer surgery (weak recommendation), and ITAC 2022 recommends 4 weeks of extended LMWH prophylaxis after major abdominopelvic surgery in patients not at high risk of bleeding.
• Long-distance travel: graduated compression stockings or LMWH are conditionally recommended only for travelers at high risk of VTE.
• Secondary prevention: see Long-Term Management.

Future or Investigational Therapies

• PEITHO-3: a randomized, placebo-controlled, double-blind trial of reduced-dose intravenous alteplase on top of heparin in intermediate-high-risk PE (650 patients planned), with a primary outcome of death, hemodynamic decompensation, or PE recurrence within 30 days.
• PEERLESS II: a randomized trial of large-bore mechanical thrombectomy plus anticoagulation vs anticoagulation alone in up to 1200 patients with intermediate-risk PE, using a hierarchical win-ratio end point.
• SAFE-SSPE: a placebo-controlled noninferiority trial of clinical surveillance vs anticoagulation for low-risk isolated subsegmental PE, with symptomatic recurrent VTE at 90 days as the primary outcome.
• HI-PEITHO was designed as an adaptive trial comparing ultrasound-facilitated catheter-directed thrombolysis with anticoagulation alone, and its results were published in 2026 (see Procedural / Surgical Therapy).

Trials

Landmark Trials

Area	Trial (year)	Design and population	Key finding
Diagnosis	PIOPED (1990)	Prospective diagnostic study of V/Q scanning against pulmonary angiography	High-probability scan: sensitivity 41%, specificity 97%
	PIOPED II (2006)	Prospective diagnostic accuracy study of multidetector CT (824 patients)	CTPA sensitivity 83%, specificity 96%
	Christopher (2006)	Management study of Wells score, D-dimer, and CT (3306 patients)	PE unlikely with normal D-dimer in 32.0%; 3-month VTE 0.5% without treatment
	ADJUST-PE (2014)	Management study of the age-adjusted D-dimer cutoff (3346 patients)	Failure rate 0.3% below the age-adjusted cutoff
	YEARS (2017)	Management study (3465 patients)	3-month VTE 0.61%; CTPA not indicated in 48% vs 34%
	PROPER (2018)	Cluster-randomized noninferiority trial of PERC (1916 patients)	Missed PE 0.1% vs 0%; CTPA 13% vs 23%
	PEGeD (2019)	Management study of D-dimer adjusted to clinical probability (2017 patients)	No VTE among 1325 patients with a negative test; imaging 34.3% vs 51.9%
	Artemis (2019)	Pregnancy-adapted YEARS algorithm (498 pregnant women)	3-month VTE 0.21%; CTPA avoided in 39%
	Hydra (2026)	Randomized noninferiority trial of YEARS vs CTPA alone in active cancer (698 patients)	Primary outcome 1.8% vs 5.5%; CTPA avoided in 22%
Anticoagulation	CLOT (2003)	Dalteparin vs coumarin in cancer-associated VTE (672 patients)	Recurrence 9% vs 17% at 6 months
	EINSTEIN-PE (2012)	Rivaroxaban vs enoxaparin and VKA (4832 patients with PE)	Recurrence 2.1% vs 1.8%; major bleeding 1.1% vs 2.2%
	AMPLIFY (2013)	Apixaban vs enoxaparin and warfarin (5395 patients)	Recurrence 2.3% vs 2.7%; major bleeding 0.6% vs 1.8%
	Hokusai-VTE (2013)	Edoxaban vs warfarin after heparin (8240 patients)	Recurrence 3.2% vs 3.5%; 3.3% vs 6.2% with RV dysfunction
	Caravaggio (2020)	Apixaban vs dalteparin in cancer-associated VTE (1155 patients)	Recurrence 5.6% vs 7.9%; major bleeding 3.8% vs 4.0%
	COBRRA (2026)	Apixaban vs rivaroxaban (2760 patients)	Clinically relevant bleeding 3.3% vs 7.1%
Site of care	OTPE (2011)	Outpatient vs inpatient treatment, PESI class I to II	Recurrence 0.6% vs 0%
	HOME-PE (2021)	Hestia vs sPESI triage (1975 patients)	Composite 3.82% vs 3.57% (noninferior)
Reperfusion	PEITHO (2014)	Tenecteplase vs placebo, intermediate-risk PE (1005 patients)	Death or decompensation 2.6% vs 5.6%; stroke 2.4% vs 0.2%
	PEERLESS (2025)	Mechanical thrombectomy vs catheter-directed thrombolysis (550 patients)	Win ratio 5.01
	STORM-PE (2026)	Computer-assisted vacuum thrombectomy vs anticoagulation (100 patients)	RV-to-left ventricular ratio reduction 0.52 vs 0.24
	HI-PEITHO (2026)	Ultrasound-facilitated catheter-directed fibrinolysis vs anticoagulation (544 patients)	7-day composite 4.0% vs 10.3%
	PRAGUE-26 (2026)	Catheter-directed thrombolysis vs anticoagulation (558 patients)	7-day composite 0.7% vs 6.8%
Vena cava filters	PREPIC (1998)	Permanent filter vs no filter in proximal DVT (400 patients)	Early PE 1.1% vs 4.8%; 2-year DVT 20.8% vs 11.6%
	PREPIC2 (2015)	Retrievable filter plus anticoagulation vs anticoagulation (399 patients)	Recurrent PE 3.0% vs 1.5%
Extended treatment	AMPLIFY-EXT (2013)	Apixaban 2.5 mg or 5 mg vs placebo	Recurrence 1.7% and 1.7% vs 8.8%
	EINSTEIN CHOICE (2017)	Rivaroxaban 20 mg or 10 mg vs aspirin	Recurrence 1.5% and 1.2% vs 4.4%
	RENOVE (2025)	Reduced-dose vs full-dose DOAC (2768 patients)	Recurrence 2.2% vs 1.8%; bleeding 9.9% vs 15.2%
	API-CAT (2025)	Apixaban 2.5 mg vs 5 mg in cancer-associated VTE (1766 patients)	Recurrence 2.1% vs 2.8%; clinically relevant bleeding 12.1% vs 15.6%
	HI-PRO (2025)	Apixaban 2.5 mg vs placebo in provoked VTE with enduring risk factors (600 patients)	Recurrence 1.3% vs 10.0%
CTEPH	CHEST-1 (2013)	Riociguat vs placebo (261 patients)	6-minute walk distance difference 46 m
	RACE (2022)	Balloon pulmonary angioplasty vs riociguat (105 patients)	Pulmonary vascular resistance 39.9% vs 66.7% of baseline

Case Studies

Case #1

Related Chapters

• Venous thromboembolism
• Deep venous thrombosis
• Chronic thromboembolic pulmonary hypertension