Definitions for the class of recommendations (I, II, IIa, IIb, III) and level of evidence (A, B, C) are provided at the end of the "Major Recommendations."
Note from European Society of Cardiology: Throughout these guidelines and for the purpose of clinical management, 'confirmed pulmonary embolism (PE)' is understood as a probability of PE high enough to indicate the need for PE-specific treatment and 'excluded PE' as a probability of PE low enough to justify withholding specific PE-treatment with an acceptably low risk despite a clinical suspicion of PE. These terms are not meant to indicate absolute certainty regarding the presence or absence of emboli in the pulmonary arterial bed.
Diagnosis
Clinical Presentation
Clinical signs, symptoms and routine laboratory tests do not allow the exclusion or confirmation of acute PE but increase the index of its suspicion.
Assessment of Clinical Probability
Clinical evaluation makes it possible to classify patients into probability categories corresponding to an increasing prevalence of PE, whether assessed by implicit clinical judgment or by a validated prediction rule.
D-Dimer
A negative D-dimer result in a highly sensitive assay safely excludes PE in patients with a low or moderate clinical probability, while a moderately sensitive assay excludes PE only in patients with a low clinical probability. When using a recently introduced two-level clinical probability assessment scheme, a negative D-dimer result excludes PE safely in PE-unlikely patients either by a highly sensitive or moderately sensitive assay.
Compression Ultrasonography (CUS) and Computed Tomographic Venography
Searching for a proximal deep vein thrombosis (DVT) in patients with PE by compression venous ultrasonography (CUS) yields a positive result in around 20% of patients. CUS can be used either as a backup procedure to reduce the overall false-negative rate when using single-detector computed tomography (CT) (see "Diagnostic Strategies" below and in the original guideline document) or it can be performed to avoid CT when positive in patients with contraindications to contrast dye and/or irradiation. Combining CT venography with CT angiography adds a significant amount of radiation and is not useful when using multidetector computed tomography (MDCT).
Ventilation-Perfusion Scintigraphy (V/Q Scan)
A normal perfusion scan is very safe for excluding PE. Although less well validated, the combination of a non-diagnostic V/Q scan in a patient with low clinical probability of PE is an acceptable criterion for excluding PE. A high-probability ventilation-perfusion scan establishes the diagnosis of PE with a high degree of probability, but further tests may be considered in selected patients with a low clinical probability due to the lower positive predictive value (PPV) of a high-probability V/Q scan result in such patient. In all other combinations of V/Q scan result and clinical probability, further tests should be performed.
Computed Tomography
A single-detector computed tomography (SDCT) or MDCT showing a thrombus up to the segmental level can be taken as adequate evidence of PE in most instances, whereas the necessity to treat isolated subsegmental thrombi in a patient without a DVT is unclear. In patients with a non-high clinical probability, a negative SDCT must be combined with negative CUS to safely exclude PE, whereas MDCT may be used as a stand-alone test. Whether further testing is mandatory in the rare patients who have a negative MDCT despite a high clinical probability is not settled.
Pulmonary Angiography
Pulmonary angiography is a reliable but invasive test and is currently useful when the results of non-invasive imaging are equivocal. Whenever angiography is performed, direct haemodynamic measurements should be performed.
Echocardiography
In a patient with suspected PE who is in a critical condition, bedside echocardiography is particularly helpful in emergency management decisions. In a patient with shock or hypotension, the absence of echocardiographic signs of right ventricular (RV) overload or dysfunction practically excludes PE as a cause of haemodynamic compromise. The main role of echocardiography in non-high-risk PE is further prognostic stratification to the intermediate low-risk category.
Diagnostic Strategies
Suspected high-risk and non-high-risk PE are two distinct situations that must be distinguished because the diagnostic strategies differ.
It should be recognized that the approach to suspected PE may legitimately vary according to the local availability of tests in specific clinical settings. The most straightforward diagnostic algorithms for suspected PE are presented in Figures 1 and 2 in the original guideline document. In contrast, Table 10 in the original guideline provides the information needed to create alternative evidence-based algorithms whenever necessary.
The recommendations for diagnosis of PE are summarized in the table below.
Recommendations: Diagnosis |
Classa |
Levelb |
Suspected high-risk PE |
- In high-risk PE, as indicated by the presence of shock or hypotension, emergency CT or bedside echocardiography (depending on availability and clinical circumstances) is recommended for diagnostic purposes
|
I |
C |
Suspected non-high-risk PE |
- In non-high-risk PE, basing the diagnostic strategy on clinical probability assessed either implicitly or using a validated prediction rule is recommended
|
I |
A |
- Plasma D-dimer measurement is recommended in emergency department patients to reduce the need for unnecessary imaging and irradiation, preferably using a highly sensitive assay
|
I |
A |
- Lower limb CUS in search of DVT may be considered in selected patients with suspected PE to obviate the need for further imaging tests if the result is positive
|
IIb |
B |
- Systematic use of echocardiography for diagnosis in haemodynamically stable, normotensive patients is not recommended
|
III |
C |
- Pulmonary angiography should be considered when there is discrepancy between clinical evaluation and results of non-invasive imaging tests
|
IIa |
C |
- The use of validated criteria for diagnosing PE is recommended. Validated criteria according to clinical probability of PE (low, intermediate or high) are detailed below (see also Table 10 in the original guideline document)
|
I |
B |
Suspected non-high-risk PE |
Low clinical probability |
- Normal D-dimer tenet using either a highly or moderately sensitive assay excludes PE
|
I |
A |
- Normal perfusion lung scintigraphy excludes PE
|
I |
A |
- Non-diagnostic (low or intermediate probability) V/Q scan may exclude PE particularly when combined with negative proximal CUS
|
IIa
I
|
B
A
|
- Negative MDCT safely excludes PE
|
I |
A |
- Negative SDCT only excludes PE when combined with negative proximal CUS
|
I |
A |
|
IIa
IIb
|
B
B
|
- CUS showing a proximal DVT confirms PE
|
l |
B |
- If CUS shows only a distal DVT, further testing should be considered to confirm PE
|
IIa |
B |
- SDCT or MDCT showing a segmental or more proximal thrombus confirms PE
|
I |
A |
- Further testing should be considered to confirm PE if SDCT or MDCT shows only subsegmental clots
|
IIa |
B |
Suspected non-high-risk PE |
Intermediate clinical probability |
- Normal D-dimer level using a highly sensitive assay excludes PE
|
I |
A |
- Further testing should be considered if D-dimer level is normal when using a less sensitive assay
|
IIa |
B |
- Normal perfusion lung scintigraphy excludes PE
|
I |
A |
- In case of a non-diagnostic V/Q scan, further testing is recommended to exclude or confirm PE
|
I |
B |
- Negative MDCT excludes PE
|
I |
A |
- Negative SDCT only excludes PE when combined with negative proximal CUS
|
I |
A |
- High-probability ventilation-perfusion lung scintigraphy confirms PE
|
I |
A |
- CUS showing a proximal DVT confirms PE
|
I |
B |
- If CUS shows only a distal DVT, further testing should be considered
|
IIa |
B |
- SDCT or MDCT showing a segmental or more proximal thrombus confirms PE
|
I |
A |
- Further testing may be considered in case of subsegmental clots to confirm PE
|
IIb |
B |
Suspected non-high-risk PE |
High clinical probability |
- D-dimer measurement is not recommended in high clinical probability patients as a normal result does not safely exclude PE even when using a highly sensitive assay
|
III |
C |
- In patients with a negative CT, further tests should be considered in selected patients to exclude PE
|
IIa |
B |
- High-probability ventilation-perfusion lung scintigraphy confirms PE
|
I |
A |
- CUS showing a proximal DVT confirms PE
|
I |
B |
- If CUS shows only a distal DVT, further testing should be considered
|
IIb |
B |
- SDCT or MDCT showing a segmental or more proximal thrombus confirms PE
|
I |
A |
- Further testing may be considered where there are subsegmental clots, to confirm PE
|
IIb |
B |
a Class of recommendation
b Level of evidence
Prognostic Assessment
Clinical Assessment of Haemodynamic Status
Hypotension and Shock
Shock and hypotension are principal markers of high risk of early death in acute PE.
Markers of Right Ventricular Dysfunction (RVD)
RV dysfunction is related to intermediate risk of short-term mortality in acute PE. Prognostic assessment based on signs of RVD is limited by the lack of universally accepted criteria, which in some trials included isolated signs of pulmonary hypertension.
Markers of Myocardial Injury
Myocardial injury in patients with PE can be detected by troponin T or I testing. Positive results are related to an intermediate risk of short-term mortality in acute PE. Prognostic assessment based on signs of myocardial injury is limited by the lack of universally accepted criteria. New markers of injury and the concomitant assessment of markers of RVD may help improve the substratification of patients with acute PE.
Additional Risk Markers
Multiple variables provided by clinical evaluation and routine laboratory tests are related to the prognosis in acute PE. Consideration of pre-existing patient-related factors may be useful in final risk stratification.
Strategy of Prognostic Assessment
Evaluation of haemodynamic status, signs of RVD and myocardial injury and the assessment of additional patient-related factors are useful for optimal risk stratification.
The recommendations for prognostic assessment of PE are summarized in the table below.
Recommendations: Prognostic Assessment |
Classa |
Levelb |
- Initial risk stratification of suspected and/or confirmed PE based on the presence of shock and hypotension is recommended to distinguish between patients with high and non-high-risk of PE-related early mortality.
|
I |
B |
- In non-high-risk PE patients, further stratification to an intermediate- or low-risk PE subgroup based on the presence of imaging or biochemical markers of RVD and myocardial injury should be considered.
|
IIa |
B |
a Class of recommendation
b Level of evidence
Treatment
Haemodynamic and Respiratory Support
Haemodynamic and respiratory support is necessary in patients with suspected or confirmed PE presenting with shock or hypotension.
Thrombolysis
Thrombolytic therapy is the first-line treatment in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension, with very few absolute contraindications. Routine use of thrombolysis in non-high risk patients is not recommended, but may be considered in selected patients with intermediate-risk PE and after thorough consideration of conditions increasing the risk of bleeding. Thrombolytic therapy should be not used in patients with low-risk PE.
Surgical Pulmonary Embolectomy
With current surgical techniques pulmonary embolectomy is a valuable therapeutic option in patients with high-risk PE in whom thrombolysis is absolutely contraindicated or has failed.
Percutaneous Catheter Embolectomy and Fragmentation
Catheter embolectomy or fragmentation of proximal pulmonary arterial clots may be considered as an alternative to surgical treatment in high-risk PE patients when thrombolysis is absolutely contraindicated or has failed.
Initial Anticoagulation
Anticoagulation with unfractionated heparin, low-molecular-weight heparin (LMWH) or fondaparinux should be initiated without delay in patients with confirmed PE and those with a high or intermediate clinical probability of PE while the diagnostic workup is still ongoing. Except for patients at high risk of bleeding and those with severe renal dysfunction, subcutaneous LMWH or fondaparinux rather than intravenous unfractionated heparin should be considered for initial treatment.
Therapeutic Strategies
The recommendations for acute treatment of PE are summarized in the table below.
Recommendations: Acute Treatment |
Classa |
Levelb |
High-risk pulmonary embolism |
- Anticoagulation with unfractionated heparin should be initiated without delay in patients with high-risk PE
|
I |
A |
- Systematic hypotension should be corrected to prevent progression of RV failure and death due to PE
|
I |
C |
- Vasopressive drugs are recommended for hypotensive patients with PE
|
I |
C |
- Dobutamine and dopamine may be used in patients with PE, low cardiac output and normal blood pressure
|
IIa |
B |
- Aggressive fluid challenge is not recommended
|
III |
B |
- Oxygen should be administered in patients with hypoxaemia
|
I |
C |
- Thrombolytic therapy should be used in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension
|
I |
A |
- Surgical pulmonary embolectomy is a recommended therapeutic alternative in patients with high-risk PE in whom thrombolysis is absolutely contraindicated or has failed
|
I |
C |
- Catheter embolectomy or fragmentation of proximal pulmonary arterial clots may be considered as an alternative to surgical treatment in high-risk patients when thrombolysis is absolutely contraindicated or has failed
|
IIb |
C |
Non-high-risk pulmonary embolism |
- Anticoagulation should be initiated without delay in patients with high or intermediate clinical probability of PE while diagnostic workup is still ongoing
|
I |
C |
- Use of LMWH or fondaparinux is the recommended form of initial treatment for most patients with non-high-risk PE
|
I |
A |
- In patients at high risk of bleeding and in those with severe renal dysfunction, unfractionated heparin with an activated partial thromboplastin time (aPTT) target range of 1.52.5 times normal is a recommended form of initial treatment
|
I |
C |
|
I
I
|
A
C
|
- Routine use of thrombolysis in non-high-risk PE patients is not recommended, but it may be considered in selected patients with intermediate-risk PE
|
IIb |
B |
- Thrombolytic therapy should be not used in patients with low-risk PE
|
III |
B |
a Class of recommendation
b Level of evidence
Long-Term Anticoagulation and Secondary Prophylaxis
Recommendations for long-term anticoagulation are provided in the table below.
Recommendations : Long-Term Treatment |
Classa |
Levelb |
- For patients with PE secondary to a transient (reversible) risk factor, treatment with a vitamin K antagonist (VKA) is recommended for 3 months
|
I |
A |
- For patients with unprovoked PE, treatment with a VKA is recommended for at least 3 months
|
I |
A |
- Patients with a first episode of unprovoked PE and low risk of bleeding, and in whom stable anticoagulation can be achieved, may be considered for long-term oral anticoagulation
|
IIb |
B |
- For patients with a second episode of unprovoked PE, long-term treatment is recommended
|
I |
A |
- In patients who receive long-term anticoagulant treatment, the risk/benefit ratio of continuing such treatment should be reassessed at regular intervals
|
I |
C |
|
IIa
I
|
B
C
|
- In patients with PE, the dose of VKA should be adjusted to maintain a target INR of 2.5 (range 2.0-3.0) regardless of treatment duration
|
I |
A |
a Class of recommendation
b Level of evidence
Venous Filters
Recommendations: Venous Filters |
Classa |
Levelb |
- Inferior vena cava (IVC) filters may be used when there are absolute contraindications to anticoagulation and a high risk of venous thromboembolism (VTE) recurrence
|
IIb |
B |
- The routine use of IVC filters in patients with PE is not recommended
|
III |
B |
a Class of recommendation
b Level of evidence
Specific Problems
Pregnancy
In pregnant women with a clinical suspicion of PE an accurate diagnosis is necessary, because a prolonged course of heparin is required. All diagnostic modalities, including CT scanning, may be used without significant risk to the fetus. Low molecular weight heparins are recommended in confirmed PE; VKAs are not recommended during the first and third trimester and may be considered with caution in the second trimester of pregnancy.
Anticoagulant treatment should be administered for at least 3 months after delivery.
Malignancy
Malignancy is a major predisposing factor for the development and recurrence of VTE. However, routine extensive screening for cancer in patients with a first episode of non-provoked PE is not recommended. In cancer patients with confirmed PE, LMWH should be considered for the first 3-6 months of treatment and anticoagulant treatment should be continued indefinitely or until definitive cure of the cancer.
Right Heart Thrombi
Right heart thrombi, particularly when mobile (i.e., in transit from the systemic veins) are associated with a significantly increased risk of early mortality in patients with acute PE. Immediate therapy is necessary, but optimal treatment is controversial in the absence of controlled trials. Thrombolysis and embolectomy are probably both effective whereas anticoagulation alone appears less effective.
Heparin-Induced Thrombocytopenia (HIT)
HIT is a life-threatening immunological complication of heparin therapy. Monitoring of platelet counts in patients treated with heparin is important for the early detection of HIT. Treatment consists of discontinuation of heparin and alternative anticoagulant treatment, if still required.
Chronic Thromboembolic Pulmonary Hypertension
Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe though rare consequence of PE. Pulmonary endarterectomy provides excellent results and should be considered as first-line treatment whenever possible. Drugs targeting the pulmonary circulation in patients in whom surgery is not feasible or has failed are currently being tested in clinical trials.
Non-thrombotic Pulmonary Embolism
Non-thrombotic PE does not represent a distinct clinical syndrome. It may be due to a variety of embolic materials and result in a wide spectrum of clinical presentations, making the diagnosis difficult. With the exception of severe air and fat embolism, the haemodynamic consequences of non-thrombotic emboli are usually mild. Treatment is mostly supportive but may differ according to the type of embolic material and clinical severity.
Definitions:
Classes of Recommendations
Class I: Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.
Class II: Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure.
Class IIa: Weight of evidence/opinion is in favour of usefulness/efficacy.
Class IIb: Usefulness/efficacy is less well established by evidence/opinion.
Class III: Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful.
Levels of Evidence
Level of evidence A: Data derived from multiple randomized clinical trialsa or meta-analysis.
Level of evidence B: Data derived from a single randomized clinical triala or large non-randomized studies.
Level of evidence C: Consensus of opinion of the experts and/or small studies, retrospective studies, registries.
a Or large accuracy or outcome trial(s) in the case of diagnostic tests or strategies.