Guidelines on the diagnosis and management
of acute pulmonary embolism
The Task Force for the Diagnosis and Management of Acute
Pulmonary Embolism of the European Society of Cardiology (ESC)
Authors/Task Force Members: Adam Torbicki, Chairperson (Poland)*,
Arnaud Perrier (Switzerland), Stavros Konstantinides (Germany),
Giancarlo Agnelli (Italy), Nazzareno Galie ` (Italy), Piotr Pruszczyk (Poland),
Frank Bengel (USA), Adrian J.B. Brady (UK), Daniel Ferreira (Portugal),
Uwe Janssens (Germany), Walter Klepetko (Austria), Eckhard Mayer (Germany),
Martine Remy-Jardin (France), and Jean-Pierre Bassand (France)
Full author affiliations can be found on the page dedicated to these guidelines on the ESC Web Site
ESC Committee for Practice Guidelines (CPG): Alec Vahanian, Chairperson (France), John Camm (UK),
Raffaele De Caterina (Italy), Veronica Dean (France), Kenneth Dickstein (Norway), Gerasimos Filippatos (Greece),
Christian Funck-Brentano (France), Irene Hellemans (Netherlands), Steen Dalby Kristensen (Denmark),
Keith McGregor (France), Udo Sechtem (Germany), Sigmund Silber (Germany), Michal Tendera (Poland),
Petr Widimsky (Czech Republic), and Jose Luis Zamorano (Spain)
Document Reviewers: Jose-Luis Zamorano, (CPG Review Coordinator) (Spain), Felicita Andreotti (Italy),
Michael Ascherman (Czech Republic), George Athanassopoulos (Greece), Johan De Sutter (Belgium),
David Fitzmaurice (UK), Tamas Forster (Hungary), Magda Heras (Spain), Guillaume Jondeau (France),
Keld Kjeldsen (Denmark), Juhani Knuuti (Finland), Irene Lang (Austria), Mattie Lenzen (The Netherlands),
Jose Lopez-Sendon (Spain), Petros Nihoyannopoulos (UK), Leopoldo Perez Isla (Spain), Udo Schwehr (Germany),
Lucia Torraca (Italy), and Jean-Luc Vachiery (Belgium)
Pulmonary embolism † Venous thrombosis † Shock † Hypotension † Chest pain † Dyspnoea
† Heart failure † Diagnosis † Prognosis † Treatment † Guidelines
* Corresponding author. Department of Chest Medicine, Institute for Tuberculosis and Lung Diseases, ul. Plocka 26, 01–138 Warsaw, Poland. Tel: þ48 22 431 2114,
Fax: þ48 22 431 2414; Email: firstname.lastname@example.org
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the
ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.
Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health
professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of health
professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient’s
guardian or carer. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.
& The European Society of Cardiology 2008. All rights reserved. For permissions please email: email@example.com
European Heart Journal (2008) 29, 2276–2315
Table of contents
List of acronyms and abbreviations . . . . . . . . . . . . . . . . . . 2277
Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2277
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2278
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2279
Predisposing factors . . . . . . . . . . . . . . . . . . . . . . . . . 2279
Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2279
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2280
Severity of pulmonary embolism . . . . . . . . . . . . . . . . . 2281
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2282
Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . 2282
Assessment of clinical probability . . . . . . . . . . . . . . . . 2282
D-dimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2283
Compression ultrasonography and computed
tomographic venography . . . . . . . . . . . . . . . . . . . . . . 2284
Ventilation–perfusion scintigraphy . . . . . . . . . . . . . . . . 2284
Computed tomography . . . . . . . . . . . . . . . . . . . . . . . 2285
Pulmonary angiography . . . . . . . . . . . . . . . . . . . . . . . 2286
Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . 2287
Diagnostic strategies . . . . . . . . . . . . . . . . . . . . . . . . . 2288
Suspected high-risk pulmonary embolism . . . . . . . . . 2288
Suspected non-high-risk pulmonary embolism . . . . . . 2289
Prognostic assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . 2292
Clinical assessment of haemodynamic status . . . . . . . . . 2292
Markers of right ventricular dysfunction . . . . . . . . . . . . 2292
Markers of myocardial injury . . . . . . . . . . . . . . . . . . . 2293
Additional risk markers . . . . . . . . . . . . . . . . . . . . . . . 2294
Strategy of prognostic assessment . . . . . . . . . . . . . . . . 2294
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2295
Haemodynamic and respiratory support . . . . . . . . . . . . 2295
Thrombolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2296
Surgical pulmonary embolectomy . . . . . . . . . . . . . . . . 2297
Percutaneous catheter embolectomy and fragmentation . 2297
Initial anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . 2298
Therapeutic strategies . . . . . . . . . . . . . . . . . . . . . . . . 2299
High-risk pulmonary embolism . . . . . . . . . . . . . . . . 2299
Non-high-risk pulmonary embolism . . . . . . . . . . . . . 2300
Long-term anticoagulation and secondary prophylaxis . . . 2301
Venous filters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2302
Specific problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2303
Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2303
Malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2304
Right heart thrombi . . . . . . . . . . . . . . . . . . . . . . . . . 2304
Heparin-induced thrombocytopenia . . . . . . . . . . . . . . . 2305
Chronic thromboembolic pulmonary hypertension . . . . . 2305
Non-thrombotic pulmonary embolism . . . . . . . . . . . . . 2306
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2307
List of acronyms and abbreviations
activated partial thromboplastin time
anti-factor Xa activity
brain natriuretic peptide
chronic thromboembolic pulmonary hypertension
compression venous ultrasonography
deep vein thrombosis
enzyme-linked immunoabsorbent assay
international normalized ratio
inferior vena cava
low molecular weight heparin
multidetector computed tomography
negative predictive value
NT-proBNP N-terminal proBNP
arterial oxygen pressure
PE pulmonary embolism
PIOPED Prospective Investigation On Pulmonary Embolism
PPVpositive predictive value
rtPArecombinant tissue plasminogen activator
RV right ventricle
RVDright ventricular dysfunction
SBPsystolic blood pressure
SDCTsingle-detector computed tomography
VKAvitamin K antagonist
V/Q scanventilation–perfusion scintigraphy
Guidelines and Expert Consensus Documents summarize and
evaluate all currently available evidence on a particular issue with
the aim of assisting physicians in selecting the best management
strategies for a typical patient, suffering from a given condition,
taking into account the impact on outcome, as well as the risk/
benefit ratio of particular diagnostic or therapeutic means. Guide-
lines are no substitutes for textbooks. The legal implications of
medical guidelines have been discussed previously.
A great number of Guidelines and Expert Consensus Docu-
ments have been issued in recent years by the European Society
of Cardiology (ESC) as well as by other societies and organizations.
Because of the impact on clinical practice, quality criteria for the
development of guidelines have been established in order to
make all decisions transparent to the user. The recommendations
for formulating and issuing ESC Guidelines and Expert Consensus
Documents can be found on the ESC Web Site (http:\\www.
In brief, experts in the field are selected and undertake a com-
prehensive review of the published evidence for management
and/or prevention of a given condition. A critical evaluation of
diagnostic and therapeutic procedures is performed, including
assessment of the risk–benefit ratio. Estimates of expected
health outcomes for larger societies are included, where
data exist. The level of evidence and the strength of recommen-
dation of particular treatment options are weighed and graded
according to predefined scales, as outlined in Tables 1 and 2.
The experts of the writing panels have provided disclosure
statements of all relationships they may have which might be per-
ceived as real or potential sources of conflicts of interest. These
disclosure forms are kept on file at the European Heart House,
headquarters of the ESC. Any changes in conflict of interest that
arise during the writing period must be notified to the ESC.
The Task Force report was entirely supported financially by the
European Society of Cardiology and was developed without any
involvement of the industry.
The ESC Committee for Practice Guidelines (CPG) supervises
and coordinates the preparation of new Guidelines and Expert
Consensus Documents produced by Task Forces, expert groups
or consensus panels. The Committee is also responsible for the
endorsement process of these Guidelines and Expert Consensus
Documents or statements. Once the document has been finalized
and approved by all the experts involved in the Task Force, it is
submitted to outside specialists for review. The document is
revised, and finally approved by the CPG and subsequently
After publication, dissemination of the message is of paramount
importance. Pocket-sized versions and personal digital assistant
(PDA)-downloadable versions are useful at the point of care.
Some surveys have shown that the intended end-users are some-
times not aware of the existence of guidelines, or simply do not
translate themintopractice; this is why implementation
programmes for new guidelines form an important component
of the dissemination of knowledge. Meetings are organized by
the ESC and are directed towards its member national societies
and key opinion leaders in Europe. Implementation meetings can
also be undertaken at national level, once the guidelines have
been endorsed by the ESC member societies and translated into
the national language. Implementation programmes are needed
because it has been shown that the outcome of disease may be
favourably influenced by the thorough application of clinical
Thus, the task of writing Guidelines or Expert Consensus Docu-
ments covers not only the integration of the most recent research,
but also the creation of educational tools and implementation
programmes for the recommendations. The loop between clinical
research, the writing of guidelines, and implementing them into
clinical practice can then only be completed if surveys and regis-
tries are performed to verify that real-life daily practice is in
keeping with what is recommended in the guidelines. Such
surveys and registries also make it possible to evaluate the
impact of implementation of the guidelines on patient outcomes.
Guidelines and recommendations should help physicians to make
decisions in their daily practice; however, the ultimate judgement
regarding the care of an individual patient must be made by the
physician in charge of that patient’s care.
Pulmonary embolism (PE) is a relatively common cardiovascular
emergency. By occluding the pulmonary arterial bed it may lead
to acute life-threatening but potentially reversible right ventricular
failure. PE is a difficult diagnosis that may be missed because of
non-specific clinical presentation. However, early diagnosis is fun-
damental, since immediate treatment is highly effective. Depending
on the clinical presentation, initial therapy is primarily aimed either
at life-saving restoration of flow through occluded pulmonary
arteries (PA) or at the prevention of potentially fatal early recur-
rences. Both initial treatment and the long-term anticoagulation
that is required for secondary prevention must be justified in
each patient by the results of an appropriately validated diagnostic
Epidemiology, predisposing factors, natural history, and the
pathophysiology of PE have been described more extensively else-
where.2–5This document focuses on currently available and vali-
dated methods of diagnosis, prognostic evaluation and therapy of
PE. In contrast to previous guidelines, we decided to grade also
the level of evidence of diagnostic procedures. The most robust
data come from large-scale accuracy or outcome studies. Accuracy
studies are designed to establish the characteristics of a diagnostic
test (sensitivity and specificity) by comparing test results with a
reference diagnostic criterion (the so-called gold standard).
Outcome studies evaluate patient outcomes when a given
diagnostic test or strategy is used for clinical decision-making. In
the field of PE, the outcome measurement is the rate
of thromboembolic events [deep vein thrombosis (DVT) or PE]
during a 3-month follow-up period in patients left untreated by
anticoagulants. The reference for comparison is the rate of DVT
or PE in patients left untreated after a negative conventional
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
Class IIb Usefulness/efficacy is less well established by
Class III Evidence or general agreement that the given
treatment or procedure is not useful/
effective, and in some cases may be
Table 1 Classes of recommendations
Class IEvidence and/or general agreement that a
given treatment or procedure is beneficial,
useful, and effective
Table 2 Levels of evidence
Level of evidence A Data derived from multiple randomized clinical
Data derived from a single randomized clinical
trialaor large non-randomized studies
Consensus of opinion of the experts and/or
small studies, retrospective studies, registries
Level of evidence B
Level of evidence C
aOr large accuracy or outcome trial(s) in the case of diagnostic tests or strategies.
pulmonary angiogram, which is around 1–2%, with an upper limit
of the 95% confidence interval (CI) of 3% during a 3-month
follow-up.6The advantage of outcome studies is that they are
easily carried out under normal clinical circumstances and their
results are therefore generalizable. However, they do not yield
any information on false positives and potential overtreatment.
We used the following criteria for grading levels of evidence
from diagnostic studies:
† Data derived from multiple comparisons or outcome studies or
meta-analyses are considered level of evidence A.
† Data from a single large comparison or outcome study are con-
sidered level of evidence B.
† Expert consensus and/or data derived from small comparison or
outcome studies are considered level of evidence C.
The first edition of the ESC Clinical Practice Guidelines on PE,
published in 2000, was among the documents most often down-
loaded from the Eur Heart J Web Site.7We dedicate the
current Guidelines to Prof. Henri Denolin, former President of
the ESC, Prof. Mireille Brochier, former President of the French
Cardiac Society, Prof. Jiri Widimsky, former President of the Cze-
choslovak Cardiac Society, and Prof. Mario Morpurgo, former
Chairman of the ESC Working Group on Pulmonary Circulation,
and to other eminent cardiologists who paved the path towards
the more effective diagnosis and clinical management of acute pul-
PE and DVT are two clinical presentations of venous thromboem-
bolism (VTE) and share the same predisposing factors. In most
cases PE is a consequence of DVT. Among patients with proximal
DVT, about 50% have an associated, usually clinically asymptomatic
PE at lung scan.8In about 70% of patients with PE, DVT can be
found in the lower limbs if sensitive diagnostic methods are used.5,9
The epidemiology of VTE has recently been reviewed.4Although
DVT and PE are manifestations of a single disease, namely VTE, PE
has features that are distinct from DVT. The risk of death related
to the initial acute episode or to recurrent PE is greater in patients
who present with PE than in those who present with DVT.10
According to prospective cohort studies, the acute case fatality
rate for PE ranges from 7 to 11%.11Also, recurrent episodes are
about three times more likely to be PE after an initial PE than
after an initial DVT (about 60% after PE vs. 20% after DVT).11
The prevalence of PE among hospitalized patients in the United
States, according to data collected between 1979 and 1999, was
0.4%.12Though only 40–53 per 100 000 persons were diagnosed
with PE per year, the annual incidence in the United States was
estimated at 600 000 cases.13The corresponding figures for
Europe are unavailable. Among regional registries, an analysis of
2356 autopsies performed in 1987 on 79% of all deceased inhabi-
tants from the city of Malmo, Sweden, with a population of
230000, revealed VTE in 595 (25%), while PE was found in 431
(18.3%) of all cases.14In 308 autopsies (13.1%), PE was considered
to be the main cause or a contributory cause of death. The inci-
dence of PE, as diagnosed by lung scintigraphy, within the same
period and population was only 48 (2%) cases in the whole
Malmo region. From autopsy, phlebography and lung scintigraphy
results, the authors estimated the incidence of VTE in the city of
Malmo at 42.5/10000 inhabitants/year. However, recalculation
of their data indicates that the incidence of PE was 20.8/10000
inhabitants/year.14In a more recent community-based study
involving 342 000 inhabitants in Brittany, France, the incidences
of VTE and PE were 18.3 and 6.0/10000/year respectively.
However, autopsy data were not available.15The true incidence
of PE is therefore difficult to assess in view of its non-specific
Although PE can occur in patients without any identifiable predis-
posing factors, one or more of these factors are usually identified
(secondary PE). The proportion of patients with idiopathic or
unprovoked PE was about 20% in the International Cooperative
Pulmonary Embolism Registry (ICOPER).17
VTE is currently regarded as the result of the interaction
between patient-related and setting-related risk factors.18,19
whereas setting-related predisposing factors are more often
temporary (Table 3).
Patient-related predisposing factors include age, history of pre-
vious VTE, active cancer, neurological disease with extremity
paresis, medical disorders causing prolonged bed rest, such as
heart or acute respiratory failure, and congenital or acquired
thrombophilia, hormone replacement therapy and oral contracep-
The incidence of VTE increases exponentially with age and this
is the case for both idiopathic and secondary PE.14,15The mean age
of patients with acute PE is 62 years; about 65% of patients are
aged 60 years or older. Eight-fold higher rates are observed in
patients over 80 compared with those younger than 50.20Identifi-
cation of the presence and estimation of the relative significance of
predisposing factors2may be helpful both in the assessment of
clinical probability for diagnostic purposes and for decisions
regarding primary prevention. However, according to a recent
survey performed in 358 hospitals across 32 countries, only 58.5
and 39.5% patients at risk of VTE due to medical or surgical
causes, respectively, received adequate prophylaxis.21
An association between idiopathic PE and cardiovascular events,
including myocardial infarction and stroke, has recently been
reported.22,23Reports of a high risk of PE among obese people,
smokers and patients affected by systemic hypertension or meta-
bolic syndrome have renewed interest in the link between arterial
thromboembolism and VTE.
are usually permanent,
Since PE in most cases is a consequence of DVT, the natural
history of VTE should be considered as a whole instead of
looking at DVT and PE separately.
The initial studies on the natural history of VTE were carried
out in the setting of orthopaedic surgery during the 1960s.24A
landmark report showed that VTE started during surgery with
DVT of the calf in about 30% of patients. DVT resolved spon-
taneously after a few days in about one-third and did not extend
in about 40%, but in 25% it developed into proximal DVT
and PE. Since this initial report, knowledge about natural history
of VTE has improved.5,20,23,25–31The evidence suggests that DVT
develops less frequently in general than in orthopaedic surgery.
The risk of VTE after surgery is highest during the first 2 weeks
after surgery but remains elevated for 2–3 months. Antithrombo-
tic prophylaxis significantly reduces the risk of perioperative VTE.
The longer the duration of antithrombotic prophylaxis, the
lower the incidence of VTE.5,9
Most patients with symptomatic DVT have proximal clots, and
in 40–50% of cases this condition is complicated by PE, often
without clinical manifestations. Asymptomatic PE is common in
the postoperative phase, particularly in patients with asymptomatic
DVT who are not given any thromboprophylaxis.5,9
PE occurs 3–7 days after the onset of DVT, and may be fatal
within 1 h after the onset of symptoms in 10% of cases, the diag-
nosis going clinically unrecognized in most fatal cases. PE presents
with shock or hypotension in 5–10% of cases, and in up to 50% of
cases without shock but with laboratory signs of right ventricular
dysfunction (RVD) and/or injury, which indicates a poorer progno-
sis.32,33After PE, complete resolution of perfusion defects occurs
in about two-thirds of all patients.34Most deaths (.90%) seem to
occur in untreated patients, because of unrecognized PE.35Fewer
than 10% of all deaths were thought to occur in treated
patients.5,9,13Chronic thromboembolic pulmonary hypertension
(CTEPH) was found in 0.5–5% of patients with treated PE.5,9,36,37
The frequency of VTE recurrence is identical whatever the
initial clinical manifestation of VTE (DVT or PE). It is, however,
higher in patients with idiopathic VTE. The risk of fatal PE is
higher after a previous episode of isolated DVT, because of the
tendency to repeat the initial presentation type in case of sub-
sequent recurrences.10,38Without anticoagulation about 50% of
patients with symptomatic proximal DVT or PE have a recurrence
of thrombosis within 3 months.5,9In patients with previous
VTE who had finished their course of at least 3–12 months of
anticoagulation treatment, the risk of fatal PE was 0.19–0.49
events per 100 patient-years, depending on the applied diagnostic
The consequences of acute PE are primarily haemodynamic and
become apparent when .30–50% of the pulmonary arterial bed
is occluded by thromboemboli.39The contribution of reflex or
humoral pulmonary vasoconstriction, documented in experimental
PE, is less important in humans.40–43
Non-thrombotic pulmonary emboli are rare and have different
pathophysiological consequences and clinical characteristics (see
Non-thrombotic pulmonary embolism).
The key consequences of a pulmonary thromboembolic episode
are haemodynamic.32Large and/or multiple emboli might abruptly
increase pulmonary vascular resistance to a level of afterload which
cannot be matched by the right ventricle (RV). Sudden death may
occur, usually in the form of electromechanical dissociation.44
Alternatively, the patient presents with syncope and/or systemic
hypotension, which might progress to shock and death due to
acute RV failure. Rightward bulging of the interventricular
septum may further compromise systemic cardiac output as a
result of diastolic left ventricle (LV) dysfunction.45
In patients surviving the acute embolic episode despite RV
failure, systemic sensors activate the sympathetic system. Inotropic
and chronotropic stimulation and the Frank–Starling mechanism
result in increased pulmonary arterial pressure, which helps to
restore resting pulmonary flow, left ventricular filling and output.
Together with systemic vasoconstriction, these compensatory
mechanisms may stabilize systemic blood pressure.46This is par-
ticularly important because decreased aortic pressure may affect
RV coronary perfusion and the function of the RV. However, a
non-preconditioned, thin-walled RV is not expected to generate
mean pulmonary pressures exceeding 40 mmHg.39
Secondary haemodynamic destabilization may occur, usually
within first 24–48 h, as a result of recurrent emboli and/or
deterioration of RV function. This may be caused by early recur-
rences, which are common in undiagnosed or inadequately
Strong predisposing factors (odds ratio .10)
Fracture (hip or leg)
Hip or knee replacement
Major general surgery
Spinal cord injury
Moderate predisposing factors (odds ratio 2–9)
Arthroscopic knee surgery
Central venous lines
Chronic heart or
Weak predisposing factors (odds ratio ,2)
Bed rest .3 days
Immobility due to sitting
Table 3 Predisposing factors for venous
Predisposing factor Patient-relatedSetting-related
Data are modified from reference 2. This article was published in Circulation,
Vol. 107, Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism,
I-9–I-16. & (2003) American Heart Association, Inc.
chronotropic stimulation may not suffice to maintain RV function
in the long term even in the absence of new embolic episodes.
This might be attributable to a potentially detrimental combination
of increased RV myocardial oxygen demand and decreased RV
coronary perfusion gradient. Both elements contribute to RV
ischaemia and dysfunction, and may initiate a vicious circle
leading to a fatal outcome.48Pre-existing cardiovascular disease
may influence the efficacy of compensatory mechanisms and
consequently affect the prognosis.17
Respiratory insufficiency in PE is predominantly a consequence
of haemodynamic disturbances. Several factors may contribute to
hypoxia occurring during an episode of PE.49Low cardiac output
results in the desaturation of mixed venous blood entering the pul-
monary circulation. Zones of reduced flow and zones of overflow
of the capillary bed served by non-obstructed vessels result in
ventilation–perfusion mismatch contributing to hypoxaemia. In
about one-third of patients, right-to-left shunt through a patent
foramen ovale induced by an inverted pressure gradient between
the right and left atrium may lead to severe hypoxaemia and an
increased risk of paradoxical embolization and stroke.50
Smaller and distal emboli, even though not affecting haemo-
dynamics, may cause areas of alveolar pulmonary haemorrhage,
resulting in haemoptysis, pleuritis and usually mild pleural effusion.
This clinical presentation is known as ‘pulmonary infarction’.
Its effect on gas exchange is usually mild, except in patients with
pre-existing cardiorespiratory disease.
Severity of pulmonary embolism
The severity of PE should be understood as an individual estimate
of PE-related early mortality risk rather than the anatomical burden
and the shape and distribution of intrapulmonary emboli. There-
fore, current guidelines suggest replacing potentially misleading
terms such as ‘massive’, ‘submassive’ and ‘non-massive’ with the
estimated level of the risk of PE-related early death.
PE can be stratified into several levels of risk of early death (under-
stood as in-hospital or 30-day mortality) based on the presence of
risk markers. For practical purposes, risk markers useful for risk stra-
tification in PE can be classified into three groups (Table 4).
Immediate bedside clinical assessment for the presence or
absence of clinical markers allows stratification into high-risk and
non-high-risk PE (Table 5). This classification should also be
applied to patients with suspected PE, as it helps in the choice of
the optimal diagnostic strategy and initial management.
Markers of RV
dysfunction overload on echocardiography
RV dilatation on spiral computed tomography
BNP or NT-proBNP elevation
Elevated right heart pressure at RHC
Table 4 Principal markers useful for risk stratification
in acute pulmonary embolism
RV dilatation, hypokinesis or pressure
Cardiac troponin T or I positiveb
BNP ¼ brain natriuretic peptide; NT-proBNP ¼ N-terminal proBNP;
RHC ¼ right heart catheterization; RV ¼ right ventricle.
aDefined as a systolic blood pressure ,90 mmHg or a pressure drop of
?40 mmHg for .15 min if not caused by new-onset arrhythmia, hypovolaemia
bHeart-type fatty acid binding protein (H-FABP) is an emerging marker in this
category, but still requires confirmation.
Table 5 Risk stratification according to expected pulmonary embolism-related early
aIn the presence of shock or hypotension it is not necessary to confirm RV dysfunction/injury to classify as high risk of PE-related
PE ¼ pulmonary embolism; RV ¼ right ventricle.
High-risk PE is a life-threatening emergency requiring specific
Non-high-risk PE can be further stratified according to the
presence of markers of RVD and/or myocardial injury into
intermediate- and low-risk PE. Intermediate-risk PE is diagnosed if at
least one RVD or one myocardial injury marker is positive. Low-risk
PE is diagnosed when all checked RVD and myocardial injury
markers are found negative (short-term PE-related mortality ,1%)
data and on the page dedicated to these guidelines on the ESC web
site (www.escardio.org/guidelines). These data show the cutoff
values for the key markers of RVD and myocardial injury used in rel-
evant clinical trials which assessed the prognosis of patients with PE].
Throughout these guidelines and for the purpose of clinical man-
agement, ‘confirmed 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 withhold-
ing 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.
Evaluating the likelihood of PE in an individual patient according to
the clinical presentation is of utmost importance in the interpret-
ation of diagnostic test results and selection of an appropriate diag-
nostic strategy. In 90% of cases, suspicion of PE is raised by clinical
symptoms such as dyspnoea, chest pain and syncope, either singly
or in combination. In several series, dyspnoea, tachypnoea, or chest
pain were present in more than 90% of patients with PE.52,53
Syncope is a rare but important presentation of PE since it may
indicate a severely reduced haemodynamic reserve. In the most
severe cases, shock and arterial hypotension may be present.
Pleuritic chest pain, whether or not combined with dyspnoea, is
one of the most frequent presentations of PE (Table 6). The pain
is usually caused by pleural irritation due to distal emboli causing
a so-called pulmonary infarction, an alveolar haemorrhage, some-
times accompanied by haemoptysis (54). Isolated dyspnoea of
rapid onset is usually due to more central PE causing more promi-
nent haemodynamic consequences than the pulmonary infarction
syndrome. It may be associated with retrosternal angina-like
chest pain, which may reflect right ventricular ischaemia. Occasion-
ally, the onset of dyspnoea may be very progressive over several
weeks, and the diagnosis of PE is evoked by the absence of
other classic causes of progressive dyspnoea. In patients with pre-
existing heart failure or pulmonary disease, worsening dyspnoea
may be the only symptom indicative of PE.
Knowledge of which predisposing factors for VTE are present is
essential in the evaluation of the likelihood of PE, which increases
with the number of predisposing factors present. However, in
around 30% of cases PE occurs in the absence of any predisposing
factors (unprovoked or idiopathic PE). Individual clinical signs and
symptoms are not very helpful, as they are neither sensitive nor
specific (Table 6). The chest X-ray is usually abnormal, and the
most frequently encountered findings (plate-like atelectasis,
pleural effusion or elevation of a hemidiaphragm) are non-
specific.56However, the chest X-ray is very useful in excluding
other causes of dyspnoea and chest pain. PE is generally associated
with hypoxaemia, but up to 20% of patients with PE have a normal
arterial oxygen pressure (PaO2) and a normal alveolar-arterial
oxygen gradient [D(A-a)O2].57Electrocardiographic (ECG) signs
of RV strain, such as inversion of T waves in leads V1–V4, a QR
pattern in lead V1, the classic S1Q3T3 type and incomplete or
complete right bundle-branch block, may be helpful, particularly
when of new onset.58,59Nevertheless, such changes are generally
associated with the more severe forms of PE and may be found in
right ventricular strain of any cause.
In summary, 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
Despite the limited sensitivity and specificity of individual symp-
toms, signs and common tests, the combination of these variables,
either implicitly by the clinician60–63or by the use of a prediction
rule,64–66makes it possible to discriminate suspected PE patients
in categories of clinical or pretest probability corresponding to
an increasing prevalence of PE. This has become a key step in all
diagnostic algorithms for PE. Indeed, the post-test probability of
PE depends not only on the characteristics of the test used but
also on pretest probability. Practical implications will be dealt
with in further sections.
The value of implicit clinical judgement has been shown in
several large series,60–63one of which was the Prospective Inves-
tigation On Pulmonary Embolism Diagnosis (PIOPED).60There
were three main findings of this study: (i) classifying patients into
Chest pain (pleuritic)52%
Chest pain (substernal)12%
Tachycardia (.100/min) 26%
Signs of DVT15%
Table 6 Prevalence of symptoms and signs in patients
with suspected PE according to final diagnosis
(n 5 219)
(n 5 546)
Data are form references 53 and 55.
DVT ¼ deep vein thrombosis.
three categories of clinical likelihood of PE is fairly accurate, the
prevalence of PE increasing with increasing clinical probability
(low, 9%; moderate, 30%; high, 68%); (ii) 90% of patients have a
low or moderate (i.e. non-high) clinical probability; and (iii) for
an identical result of ventilation–perfusion lung scintigraphy (V/Q
scan), the prevalence of PE varies considerably according to the
pretest or clinical probability.60
The main limitations of implicit judgement are lack of standard-
ization and the impossibility of teaching it. Therefore, several expli-
cit clinical prediction rules have been developed in the last few
years. The most frequently used clinical prediction rule is the
Canadian rule, by Wells et al.65(Table 7). This rule has been vali-
dated extensively using both a three-category (low, moderate or
high clinical probability) and a two-category scheme (PE likely or
unlikely).67–71It is simple and based on easily collected infor-
mation. However, the interobserver reproducibility was found to
be variable72–74due to the weight of one subjective item in the
rule (alternative diagnosis less likely than PE). The revised
Geneva rule is also used in Europe.64It is simple, based entirely
on clinical variables, and standardized. It has also been validated
internally and externally,64although less extensively than the
Wells rule. Whichever rule is used, the proportion of patients
with PE is around 10% in the low probability category, 30% in
the moderate probability category and 65% in the high clinical
In summary, clinical evaluation makes it possible to classify
patients into probability categories corresponding to an increasing
prevalence of PE, whether assessed by implicit clinical judgement
or by a validated prediction rule.
Plasma D-dimer, a degradation product of crosslinked fibrin, has
been investigated extensively in recent years.75,76D-dimer levels
are elevated in plasma in the presence of an acute clot because
of simultaneous activation of coagulation and fibrinolysis. Hence,
a normal D-dimer level renders acute PE or DVT unlikely, i.e.
the negative predictive value (NPV) of D-dimer is high. On the
other hand, although D-dimer is very specific for fibrin, the
specificity of fibrin for VTE is poor because fibrin is produced
in a wide variety of conditions, such as cancer, inflammation,
infection, necrosis, dissection of the aorta, and the positive pre-
dictive value (PPV) of D-dimer is low. Therefore, D-dimer is not
useful for confirming PE. There are a number of available assays
with different characteristics.75,76The quantitative enzyme-linked
immunoabsorbent assay (ELISA) and ELISA-derived assays have a
sensitivity of .95% and a specificity around 40%. They can there-
fore be used to exclude PE in patients with either a low or a mod-
erate probability of PE. In the emergency department, a negative
ELISA D-dimer test can exclude PE without further testing in
approximately 30% of patients.63,68,77,78Outcome studies using
Age .65 years
Previous DVT or PE
Surgery or fracture within 1 month
Unilateral lower limb pain
Pain on lower limb deep vein at
palpation and unilateral oedema
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Table 7 Clinical prediction rules for PE: the Wells score and the revised Geneva score
Revised Geneva score64
Previous DVT or PE
Recent surgery or immobilization
þ4 Clinical signs of DVT
Alternative diagnosis less likely than PE
Clinical probability (3 levels)
Clinical probability (2 levels)
the Vidas D-dimer assay showed that the 3-month thromboem-
bolic risk in patients was below 1% in patients left untreated on
the basis of a negative test result63,77–79(Table 8). Quantitative
latex-derived assays and a whole-blood agglutination assay have
lower sensitivity, in the range of 85–90%, and are often referred
to as moderately sensitive assays.75,76The most extensively
studied to date in outcome studies are the Tinaquant and the
SimpliRED assays, which yield a 3-month thromboembolic risk of
,1% in patients with a low clinical probability who are left
untreated. However, their safety for ruling out PE has not been
established in the moderate clinical probability category when
using a three-level probability scheme. When using the dichoto-
mous Wells rule, which classifies patients as ‘PE unlikely’ and ‘PE
likely’, moderately sensitive assays are safe for the exclusion of
PE in patients categorized as PE unlikely, i.e. those with a score
of ?4 points.
The diagnostic yield of D-dimer relies on its specificity, which
varies according to patient characteristics. The specificity of
D-dimer in suspected PE decreases steadily with age and may
reach ?10% in patients above 80 years.81D-dimer is also more
frequently elevated in patients with cancer,82,83in hospitalized
patients84and during pregnancy.85,86Therefore, the number of
patients with suspected PE in whom D-dimer must be measured
to exclude one PE (also referred to as the number needed to
test) varies between 3 in the emergency department and 10 or
above in the specific situations listed above. Deciding whether
measuring D-dimer is worthwhile in a given situation remains a
matter of clinical judgement.
In summary, 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 and
computed tomographic venography
In 90% of patients, PE originates from DVT in a lower limb.87In a
classic study using venography, DVT was found in 70% of patients
with proven PE.88Nowadays, lower limb compression venous
ultrasonography (CUS) has largely replaced venography for diag-
nosing DVT. CUS has a sensitivity over 90% for proximal DVT
and a specificity of about 95%.89,90CUS shows a DVT in
30–50% of patients with PE,89,90and finding a proximal DVT in
patients suspected of PE is sufficient to warrant anticoagulant treat-
ment without further testing.91In the setting of suspected PE, CUS
can be limited to a simple four-point examination (groin and popli-
teal fossa). The only validated diagnostic criterion for DVT is
incomplete compressibility of the vein, which indicates the pre-
sence of a clot, whereas flow criteria are unreliable. The diagnostic
yield of CUS in suspected PE might be raised by performing com-
plete ultrasonography, including the distal veins. In a recent study,
the proportion of patients with PE in whom a DVT could be
detected increased from 22% when performing proximal CUS
only to 43% using complete CUS, but the specificity decreased
accordingly from 96–84%.92The high specificity of a positive prox-
imal CUS result for PE is confirmed by data from a large prospec-
tive outcome study in which 524 patients underwent both
multidetector computed tomography (MDCT) and CUS. The sen-
sitivity of CUS for the presence of PE on MSCT was 39% and its
specificity was 99%.91The probability of a positive proximal CUS
in suspected PE is higher in patients with leg signs and symptoms
than in asymptomatic patients.89,90
More recently, computed tomography (CT) venography has
been advocated as a simple way to diagnose DVT in patients
with suspected PE as it can be combined with chest CT angiogra-
phy as a single procedure using only one intravenous injection of
contrast dye. In the recent PIOPED II study, combining CT veno-
graphy with CT angiography increased sensitivity for PE from 83
to 90% and had a similar specificity (around 95%).93,94However,
the corresponding increase in NPV was not clinically significant.
Therefore, CT venography increases the overall detection rate
only marginally in patients with suspected PE and adds a significant
amount of irradiation, which may be a concern, especially in
In summary, searching for a proximal DVT in patients with
PE by 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 CT (see
Diagnostic strategies) 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 angiogra-
phy adds a significant amount of radiation and is not useful when
Ventilation–perfusion scintigraphy (V/Q scan) is a robust and well-
established diagnostic test for suspected PE. The test has been
proved extremely safe to apply and few allergic reactions have
been described. The basic principle of the test is based on an
Low or moderatea
Table 8 Diagnostic yield of various D-dimer assays in excluding acute PE according to outcome studies
Series Clinical probabilityPatients
D-dimer <500 mg/L
3-month thromboembolic risk
[% (95% CI)]
aPE unlikely in reference 67.
CI ¼ confidence interval.
intravenous injection of technetium (Tc)-99 m labelled macro-
aggregated albumin particles, which block a small fraction of pul-
monary capillaries and thereby enable scintigraphic assessment of
lung perfusion at the tissue level. Where there is occlusion of pul-
monary arterial branches, the peripheral capillary bed will not
receive particles, rendering the area ‘cold’ on subsequent images.
Perfusion scans are combined with ventilation studies, for which
multiple tracers, such as xenon (Xe)-133 gas, Tc-99 m labelled
aerosols or Tc-99 m-labelled carbon microparticles (Technegas),
can be used. The purpose of the additional ventilation scan is to
increase specificity by the identification of hypoventilation as a
non-embolic cause of hypoperfusion due to reactive vasoconstric-
tion (perfusion–ventilation match). On the contrary, in the case of
PE, ventilation is expected to be normal in hypoperfused segments
(perfusion–ventilation mismatch).96,97Traditionally, planar per-
fusion and ventilation images in at least six projections are
acquired. Tc-99 m-labelled ventilation tracers, which (in contrast
to the situation in the United States) are approved for clinical
use in Europe, are considered preferable to radioactive gases for
ventilation imaging because they are deposited in the bronchoal-
veolar system with little washout, and thus allow the acquisition
of multiple projections and more accurate regional matching of per-
fusion and ventilation.98,99The radiation exposure from a lung scan
with 100 MBq of Tc-99 m macroaggregated albumin particles is
1.1 mSv for an average sized adult according to the International
Commission on Radiological Protection (ICRP), and thus signifi-
cantly lower than that of a spiral CT (2–6 mSv).100In comparison,
a plain chest X-ray delivers a dose of approximately 0.05 mSv.
Lung scan results are frequently classified according to criteria
established in the North American PIOPED trial60into four cat-
egories: normal or near-normal, low, intermediate (non-diagnostic)
and high probability of PE. The criteria for classification have been
a matter of debate and revision.101,102Nevertheless, the validity of
a normal perfusion lung scan has been evaluated in several pros-
pective clinical outcome studies, which observed low event
rates,103,104suggesting that it is a safe practice to withhold anti-
coagulant therapy in patients with a normal perfusion scan. This
has been confirmed recently in a randomized trial comparing the
V/Q scan and CT.105In this large series, 247 patients (35.0%) had
normal scan results. Of these, only two patients (0.8%) had proximal
DVT on ultrasonography and were treated with anticoagulants.
None of the remaining 245 patients had a thromboembolic event
during follow-up. Some radiologists accept a single mismatched seg-
mental perfusion defect as indicating a high-probability of PE. Indeed,
in a total of 350 patients with at least one segmental perfusion
defect and focally normal ventilation, the PPV was 88% (95% CI,
84–91%).60,106–112This PPV constitutes sufficient proof of the pre-
sence of PE to warrant the institution of long-term anticoagulant
therapy in most patients. The more stringent PIOPED criteria for
a high-probability pattern (two or more mismatched segmental per-
fusion defects) have a higher PPV for PE and such a result is usually
accepted as a confirmation of PE. An analysis from the recent
PIOPED II study confirmed the performance of the high-probability
V/Q scan for diagnosing PE and of the normal perfusion scan for
ruling it out.113Some centres perform only a perfusion phase and
use the chest X-ray as a surrogate for the ventilation study. This
is not a preferred strategy when the perfusion scan is not normal,
but is acceptable in patients with a normal chest X-ray; any perfusion
defect in this situation will be considered a mismatch.114
The high frequency of non-diagnostic intermediate probability
scans has been a source of criticism because they indicate the
necessity of further diagnostic testing. Multiple strategies to at
least partially overcome this problem have been proposed,
notably the incorporation of clinical probability,115–117and data
acquisition in tomographic mode.118–120More recent studies
have strongly suggested that data acquisition in tomographic
mode as single photon emission computed tomography (SPECT)
increases diagnostic accuracy and reduces the frequency of non-
diagnostic scans.118–120SPECT imaging may even allow the use
of automated detection algorithms for PE.121
In summary, 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 a 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 PPV of a high-probability V/Q scan result in such patients.
In all other combinations of V/Q scan result and clinical probability,
further tests should be performed.
The value of CT angiography for decision-making in suspected
PE has changed with recent improvements in the technology
available. Two systematic overviews on the performance of single-
detector spiral CT in suspected PE reported wide variations
regarding both the sensitivity (53–100%) and specificity (73–
100%) of CT.122,123Two large and methodologically robust clinical
studies reported a sensitivity around 70% and a specificity of 90%
for single-detector CT (SDCT).124,125The rate of technically
inadequate CT angiograms because of motion artefacts or insuffi-
cient opacification of the pulmonary vessels was 5–8%. Therefore,
a negative SDCT test is not safe for ruling out PE, while the com-
bination of a negative SDCT and the absence of a proximal DVT
on lower limb venous ultrasonography in non-high clinical prob-
ability patients was associated with a 3-month thromboembolic
risk of approximately 1% in two large-scale outcome studies.61,78
Since the introduction of MDCT with high spatial and temporal
resolution and quality of arterial opacification, CT angiography
has become the method of choice for imaging the pulmonary
vasculature for suspected PE in routine clinical practice. It allows
adequate visualization of the pulmonary arteries up to at least
the segmental level.126–128Although a sensitivity and specificity
for PE above 90% have been reported in an early series,129the
large recent PIOPED II series observed a sensitivity of 83% and a
specificity of 96% for MDCT (mainly four-detector).94Although
the choice of the reference diagnostic criteria for PE in the
PIOPED II has been criticized, it highlighted the influence of clinical
probability on the predictive value of MDCT. In patients with a low
or intermediate clinical probability of PE as assessed by the Wells
score, a negative CT had a high NPV for PE (96 and 89%, respect-
ively), whereas it was only 60% in those with a high pretest prob-
ability. Conversely, the PPV of a positive CT was high (92–96%) in
patients with an intermediate or high clinical probability but
much lower (58%) in patients with a low pretest likelihood of PE.
Therefore, clinicians should be wary in the infrequent situation of
discordance between clinical judgement and MDCT result. Four
recent studies provide evidence in favour of CT as a stand-alone
test to exclude PE. In a prospective management study including
756 consecutive patients referred to the emergency department
with a clinical suspicion of PE, all patients with either a high clinical
probability or a non-high clinical probability and a positive ELISA
D-dimer test underwent both lower limb ultrasonography and
MDCT.77The proportion of patients in whom a proximal DVT
was found on ultrasound despite a negative MDCT was only
3/324 (0.9%, 95% CI, 0.3–2.7%).67In the Christopher Study, all
patients classified as PE likely by the dichotomized Wells score
and those with a positive D-dimer test underwent a chest MDCT.
The 3-month thromboembolic risk in the 1505 patients left
untreated because of a negative CT was low (1.1%; 95% CI, 0.6–
1.9%).67Two randomized controlled trials reached similar con-
clusions. In a Canadian trial comparing V/Q scan and CT (mostly
MDCT), only seven of the 531 patients with a negative CT had a
DVT and one had a thromboembolic event during follow-up.
Hence, the 3-month thromboembolic risk would have been 1.5%
(95% CI, 0.8–2.9%) if only CT had been used.105A European
study compared two diagnostic strategies based on D-dimer
and MDCT, one with and the other without lower limb CUS.130
In the D-dimer–CT arm, the 3-month thromboembolic risk was
0.3% (95% CI, 0.1–1.2%) among the 627 patients left untreated
based on a negative D-dimer or MDCT.
Taken together, these data suggest that a negative MDCT is an
adequate criterion for excluding PE in patients with a non-high
clinical probability of PE. Whether patients with a negative CT
and a high clinical probability should be further investigated by
CUS and/or V/Q scintigraphy or pulmonary angiography is
controversial. Also, a MDCT showing PE at the segmental or
more proximal level is adequate proof of PE in patients with a
non-low clinical probability. Since the PPV of MDCT is lower in
patients with a low clinical probability of PE (58% in the PIOPED
II study),94further testing should be considered in at least some
such patients. As the specificity and PPV of MDCT depend not
only on clinical probability but also on the most proximal clot
level,94further testing should be discussed in patients with a low
clinical probability and a segmental clot, while treatment could
be warranted based on an MDCT showing a thrombus in the
lobar or main pulmonary artery.
There has been controversy about the role of CT venography
performed in addition to chest CT angiography for diagnosing PE.
In the PIOPED II study, the sensitivity of chest CT angiography
combined with CT venography was 90% compared with 83% for
CT angiography alone.67However, the absolute gain due to CT
venography was modest (detection of 14 additional patients with
PE among the 824 patients with a reference diagnosis), reflected
by a mere 2% increase in the NPV (97% compared with 95%). CT
venography combined with clinical assessment did not yield
significantly different predictive values compared with chest CT
alone. The lack of clinical usefulness of additional CT venography
is compounded by the results of the outcome studies discussed
above.67,77Also, CT venography substantially increases the overall
examination radiation, particularly at the pelvic level. Estimates of
pelvic radiation vary considerably according to the specific CT veno-
graphy protocol used. In a study using SDCT, the calculated radiation
dose was approximately 2.2 mSv for the chest and 2.5 mSv for the
pelvis,131i.e. twice the radiation dose of a V/Q scan. The gonadal
dose for CT venography was two orders of magnitude above that
for CT arteriography alone. Interestingly, the analysis of a subgroup
of 711 patients from the PIOPED II study who had both venous
ultrasonography and CT venography showed a 95.5% concordance
between the results of these tests.93Also, patients with signs or
symptoms of DVT were eight times more likely to have DVT and
patients with a history of DVT were twice as likely to have positive
findings. Therefore, ultrasonography should be used instead of CT
venography if indicated (see Diagnostic strategies).
Another controversial area is the clinical significance of isolated
subsegmental PE, i.e. the presence of a single subsegmental clot on
MDCT, which is found in 1–5% of patients with suspected PE
undergoing MDCT.77,132,133Indeed, the PPV of such a finding is
low, and results of outcome studies suggest that such patients
left untreated by anticoagulants may have an uneventful course.
There may be a role for CUS in this situation in order to ensure
that the patient does not have a DVT that would require treatment
to assist in decision-making. In a patient without a DVT and with an
isolated subsegmental PE, no definitive recommendation can be
made because of lack of evidence.
In summary, a 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 was refined and was standard practice
from the late 1960s onwards.134The era of digital subtraction
angiography has improved image quality. The diagnostic criteria
for acute PE in direct angiography were defined almost 40 years
ago and consist of direct evidence of a thrombus, either a filling
defect or amputation of a pulmonary arterial branch. With direct
angiography, thrombi as small as 1 or 2 mm within the subsegmen-
tal arteries can be visualized.135However, there is substantial
interobserver variability at the subsegmental level.60Other indirect
signs of PE include the presence of a slow flow of contrast, regional
hypoperfusion and delayed or diminished pulmonary venous flow,
but these are not validated and hence not diagnostic.
The Miller score in Europe134and the Walsh score in the United
States136were used to quantify the extent of luminal obstruction.
However, with the development and refinement of CT pulmonary
angiography, direct pulmonary angiography with contrast injection
into the pulmonary arteries is now rarely performed as an isolated
Pulmonary angiography is invasive and not devoid of hazards.
The mortality due to pulmonary angiography was 0.2% (95% CI,
0–0.3%) in a pooled analysis of five series with a total of 5696
patients.137However, the rare deaths attributable to pulmonary
angiography occurred in very sick patients with haemodynamic
compromise or acute respiratory failure. Although pulmonary
angiography has been the gold standard for the diagnosis or
exclusion of PE, the technique is now rarely employed because
non-invasive CT angiography offers similar or better information.
Right ventriculography is difficult to interpret and is now an obso-
lete technique in the daily practical diagnosis of RVD from acute
PE, having been superseded by echocardiography and biomarkers.
Moreover, the risk of local bleeding complications is markedly
increased if thrombolysis is attempted in patients with PE diag-
nosed by standard pulmonary angiography.138,139However, if
angiography is done, haemodynamic measurements of pulmonary
artery pressure should be recorded.
In summary, 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.
Right ventricular dilatation is found in at least 25% of patients
with PE, and its detection, either by echocardiography or CT, is
useful in risk stratification. Echocardiographic criteria used for the
diagnosis of PE were different across trials, though usually based
on tricuspid insufficiency jet velocity and right ventricular dimen-
sions. Because of the reported sensitivity of around 60–70%, a nega-
tive result cannot exclude PE.116,140–145On the other hand, signs of
RV overload or dysfunction may also be due to concomitant cardiac
or respiratory disease, in the absence of acute PE.146Data suggesting
that some echocardiographic signs may be more specific are
limited.147,148Three different sets of echocardiographic criteria
potentially useful for diagnosing acute PE were compared in a
series in which 100 symptomatic patients were enrolled, of whom
62% were referred from the intensive care unit. The criteria
which were based either on disturbed RV ejection pattern (the
60–60 sign) or on depressed contractility of the RV free wall com-
pared with its apex (the McConnell sign) seemed to have a higher
PPV despite pre-existing cardiorespiratory diseases (Table 9).148
However, concomitant echocardiographic signs of pressure over-
load are required to prevent the false diagnosis of acute PE in
patients with RV free-wall hypo/akinesis due to RV infarction,
which may mimic the McConnell sign.149Tissue Doppler imaging
was used to obtain various indices of myocardial performance,
which were reported to have a sensitivity of 85–92% and a speci-
ficity of 78–92% for PE, but the data are still limited.150
Hence, echocardiographic examination is not recommended as
an element of elective diagnostic strategy in haemodynamically
stable, normotensive patients with suspected PE.116
In patients with suspected high-risk PE presenting with shock or
hypotension, the absence of echocardiographic signs of RV over-
load or dysfunction practically excludes PE as a cause of haemo-
dynamic instability. Furthermore, echocardiography may help in
the differential diagnosis of the cause of shock, by detecting
cardiac tamponade, acute valvular dysfunction, acute myocardial
infarction or hypovolaemia. Conversely, unequivocal signs of RV
pressure overload and dysfunction in a haemodynamically compro-
mised patient with suspected PE are highly evocative and may
justify aggressive treatment for PE if bedside diagnostic tools
must suffice because of the patient’s critical condition. In one
series, such treatment was introduced in the joint presence of
high clinical probability, a shock index ?1 (defined as heart rate
divided by systolic blood pressure) and RVD on echocardiography,
and resulted in an acceptable 30-day outcome.151
Concomitant exploration of proximal veins in search of venous
clots with compression ultrasound152and searching for emboli in
main pulmonary arteries by transoesophageal echocardiography
may be considered in specific clinical situations.153,154Indeed,
because of the high prevalence of bilateral central pulmonary
thromboemboli in patients with haemodynamically significant PE,
transoesophageal echocardiography may confirm the diagnosis in
most cases.155Also, right heart thrombi, which can be found
with transthoracic echocardiography in 4–18% patients with
acute PE, justify treatment.156–159
dition, bedside echocardiography is particularly helpful in emergency
RV overload criteria60/60 sign
RV overload criteria60/60 sign
Specificity (%)78100 100
Sensitivity (%) 8125 19
PPV (%) 90 100 100
NPV (%)64 3735
Table 9 Diagnostic value of three sets of echocardiographic signs suggesting the presence of acute PE in subgroups with
and without known previous cardiorespiratory diseases
Patients without known previous
cardiorespiratory diseases (n 5 46)
Patients with known previous
cardiorespiratory diseases (n 5 54)
McConnell sign McConnell sign
Dataarefromreference 148. This articlewaspublished inthe American Journal of Cardiology,Vol.90, KurzynaM, TorbickiA, Pruszczyk P,BurakowskaB, Fijalkowska A, Kober J et al.,
Disturbed right ventricular ejection pattern as a new Doppler echocardiographic sign of acute pulmonary embolism, 507–511. & Elsevier 2002.
RV overload criteria (140): the presence of ?1 of four signs: (i) right-sided cardiac thrombus; (ii) RV diastolic dimension (parasternal view) .30 mm or a RV/LV ratio .1;
(iii) systolic flattening of the interventricular septum; and (iv) acceleration time ,90 ms or tricuspid insufficiency pressure gradient .30 mmHg in absence of RV hypertrophy.
The 60/60 sign148is acceleration time of RV ejection ,60 ms in the presence of tricuspid insufficiency pressure gradient ? 60 mmHg.
The McConnell sign147is normokinesia and/or hyperkinesia of the apical segment of the RV freewall despite hypokinesia and/or akinesia of the remaining parts of the RV free wall.
Concomitant echocardiographic signs of pressure overload are required to prevent false diagnosis of acute PE in patients with RV free wall hypo/akinesis due to RV infarction.149
PPV ¼ positive predictive value; NPV ¼ negative predictive value.
management decisions. In a patient with shock or hypotension, the
absence of echocardiographic signs of RV overload or dysfunction
practically excludes PE as a cause of haemodynamic compromise.
nostic stratification to the intermediate or low-risk category.
Suspected high-risk and non-high-risk PE are two distinct situations
that must be distinguished because the diagnostic strategies differ.
Overall, with adequate clinical awareness the prevalence of PE in
patients in whom the disease is suspected is low (10–35% in
recent large series).67,68,71,77,160Pulmonary angiography, the defini-
tive standard criterion, is invasive, costly and sometimes difficult to
interpret.6,161Hence, non-invasive diagnostic approaches are
warranted, and various combinations of clinical evaluation,
plasma D-dimer measurement, lower limb CUS, V/Q lung scinti-
graphy and, more recently, CT have been evaluated to obviate
the requirement for pulmonary angiography. These strategies
were applied to patients presenting with suspected PE in the emer-
gency ward,63,68,77,160during a hospital stay,162or both.61,67,71In a
recent survey, failure to comply with evidence-based diagnostic
strategies when withholding anticoagulation despite the clinical
suspicion of PE was related to a significant increase in the
number of VTE episodes and in sudden death in the 3 months
of follow-up.1It should be recognized that the approach to sus-
pected 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 contrast, Table 10 provides the information needed
to createalternative evidence-based
Suspected high-risk pulmonary embolism
Although the greatest body of evidence concerns suspected
haemodynamically stable, non-high-risk PE, we have chosen to
deal with suspected high-risk PE first because it is an immediately
life-threatening situation and patients presenting with shock or
hypotension present a distinct clinical problem. The clinical
probability is usually high and the differential diagnosis includes
cardiogenic shock, acute valvular dysfunction, tamponade and
aortic dissection. Hence, the most useful initial test in this situation
is echocardiography, which will usually show indirect signs of acute
pulmonary hypertension and right ventricular overload if acute PE is
the cause of the haemodynamic consequences. Right heart thrombi
in transit can be sometimes found on transthoracic echocardiogra-
phy.156–159When available, transoesophageal echocardiography
may allow direct visualization of a thrombus in the pulmonary
artery.153,155,163However, in a highly unstable patient, or if other
tests are not available, the diagnosis of PE may be accepted on
the basis of compatible indirect echocardiographic findings alone
(Figure 1). If the patient is stabilized by supportive treatment, a defi-
nite diagnosis should be sought. Because of the high thrombus load
in the pulmonary circulation, CT is usually able to confirm the diag-
nosis. Conventional pulmonary angiography should be avoided
Figure 1 Proposed diagnostic algorithm for patients with suspected high-risk PE, i.e. presenting with shock or hypotension. *CT is considered
not immediately available also if the critical condition of a patient allows only bedside diagnostic tests.#Transoesophageal echocardiography
may detect thrombi in the pulmonary arteries in a significant proportion of patients with RV overload and PE that is ultimately confirmed
by spiral CT; confirmation of DVT with bedside CUS might also help in decision-making.
because it carries a risk of mortality in unstable patients161and
increases the risk of bleeding due to thrombolysis.138,139
Suspected non-high-risk pulmonary embolism
Strategy based on computed tomographic angiography
CT angiography has become the main thoracic imaging test for
investigating suspected PE.164,165V/Q scintigraphy remains a
validated option but it is less frequently performed because of a
high proportion of inconclusive results.60However, since most
patients with suspected PE do not have the disease, CT should not
be the first-line test. In patients admitted to the emergency depart-
ment, plasma D-dimer measurement combined with clinical prob-
ability assessment is the logical first step and allows PE to be ruled
out in around 30% of patients, with a 3-month thromboembolic
risk in patients left untreated below 1% (Table 8).63,67,68,77–80
D-dimer should not be measured in patients with a high clinical
probability because of a low NPV in this population.166It is also
less useful in hospitalized patients because the number needed to
treat to obtain a clinically relevant negative result is high. In most
centres, MDCT is the second-line test in patients with an elevated
D-dimer level and the first-line test in patients with a high clinical
probability (Figure 2). SDCT or MDCT are considered diagnostic
of PE when they show a clot at least at the segmental level of the
pulmonary arterial tree. A negative MDCT has been shown to
exclude PE safely in several large-scale outcome studies.67,77,167,168
sonography to safely exclude PE.61,78False-negative results of
SDCT61,78and MDCT94have been reported in patients with a
high clinical probability of PE. However, this situation is infrequent
and the 3-month thromboembolic risk is low in such patients.67
Therefore, both the necessity of performing further tests and the
nature of these tests in such patients is controversial.
Role of lower limb compression ultrasonography
The role of lower limb CUS is still debated. CUS is mandatory
when using SDCT because of its low sensitivity;124,125indeed,
CUS shows a clear DVT in a number of patients with a negative
SDCT.61.78However, most centres are now equipped with
MDCT and several large-scale outcome studies have shown that
a negative MDCT safely excludes PE, at least in patients with a
non-high clinical probability.67,77Nevertheless, CUS could still be
useful when using MDCT. CUS shows a DVT in 30–50% of
patients with PE89,90and finding a proximal DVT in a patients sus-
pected of PE is sufficient to warrant anticoagulant treatment
without further testing.91Hence, performing CUS before CT
might be sensible in patients with relative contraindications for
CT (renal failure, allergy to contrast dye), so that it can be
avoided in patients with a proximal DVT (the specificity for PE
of finding a distal DVT is markedly lower).92CUS might play a
role in risk stratification as it has been shown that the presence
Figure 2 Proposed diagnostic algorithm for patients with suspected non-high-risk PE (i.e. without shock and hypotension). Two alternative
classification schemes may be used to assess clinical probability: a three-level scheme (clinical probability low, intermediate or high) or a two-
level scheme (PE unlikely or PE likely). When using a moderately sensitive assay, D-dimer measurement should be restricted to patients with a
low clinical probability or a ‘PE unlikely’ classification, while highly sensitive assays may be used in patients with a low or intermediate clinical
probability of PE. Plasma D-dimer measurement is of limited use in suspected PE occurring in hospitalized patients. *Anticoagulant treatment for
PE.†CT is considered diagnostic of PE if the most proximal thrombus is at least segmental.‡If single-detector CT is negative, a negative proximal
lower limb venous ultrasonography is required in order to safely exclude PE.#If multidetector CT is negative in patients with high clinical prob-
ability, further investigation may be considered before withholding PE-specific treatment (see text). PE, pulmonary embolism.
of a proximal DVT increases the risk of recurrent VTE in patients
Role of V/Q scintigraphy
In centres where V/Q scintigraphy is readily available, it remains a
valid option for patients with an elevated D-dimer and a contraindi-
cation to CT, such as allergy to iodine contrast dye or renal failure.
V/Q lung scintigraphy is diagnostic (with either normal or high
probability) in approximately 30–50% of emergency ward patients
with suspected PE.52,60,62,107The number of patients with a non-
conclusive result may be further reduced by taking clinical prob-
ability into account.60Indeed, patients with a low-probability lung
scan and a low clinical probability of PE have a very low prevalence
of PE.60,62,116The NPV of this combination is further reduced
by the absence of a DVT on lower limb CUS. In one trial, PE
could be excluded by this combination in an additional 24% of
patients63and the 3-month thromboembolic risk of those patients
who were left untreated was only 1.7%.62In an outcome study
combining D-dimer, CUS, lung scanning and clinical evaluation, PE
could be definitely established or excluded in 89% of the study
patients.63In a recent randomized trial comparing two diagnostic
strategies, 99% of patients could be safely managed without
pulmonary angiography or CT by a combination of V/Q scan, clinical
probability and CUS (initial CUS in all patients and repeat CUS at 1
week in selected patients).105Only 6 of 611 patients (1.0%, 95% CI,
0.5–2.1%) in whom PE was excluded developed VTE during
follow-up. The yield of repeat CUS was very low (one DVT out
of 78 examinations).105
Table 10 Validated diagnostic criteria for diagnosing PE in patients without shock and
hypotension (non-high-risk PE) according to clinical probability
Valid criterion (no further testing required), 1, green; invalid criterion (further testing necessary), –, red; controversial criterion
(further testing to be considered), +++++, yellow.
aNon-diagnostic lung scan: low or intermediate probability lung scan according to the PIOPED classification.
CUS ¼ compression venous ultrasonography; DVT ¼ deep venous thrombosis; PE ¼ pulmonary embolism;
V/Q scan ¼ ventilation–perfusion scintigraphy.
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
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
† 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
† 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
† Systematic use of echocardiography for diagnosis in haemodynamically stable, normotensive patients is not recommended
† Pulmonary angiography should be considered when there is discrepancy between clinical evaluation and results of non-invasive
† 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)
Suspected non-high-risk PE
Low clinical probability
† Normal D-dimer level using either a highly or moderately sensitive assay excludes PE
† Normal perfusion lung scintigraphy excludes PE
† Non-diagnostic (low or intermediate probability) V/Q scan may exclude PE
particularly when combined with negative proximal CUS
† Negative MDCT safely excludes PE
† Negative SDCT only excludes PE when combined with negative proximal CUS
† High-probability V/Q scan may confirm PE but ...
further testing may be considered in selected patients to confirm PE
† CUS showing a proximal DVT confirms PE
† If CUS shows only a distal DVT, further testing should be considered to confirm PE
† SDCT or MDCT showing a segmental or more proximal thrombus confirms PE
† Further testing should be considered to confirm PE if SDCT or MDCT shows only subsegmental clots
Suspected non-high-risk PE
Intermediate clinical probability
† Normal D-dimer level using a highly sensitive assay excludes PE
† Further testing should be considered if D-dimer level is normal when using a less sensitive assay
† Normal perfusion lung scintigraphy excludes PE
† In case of a non-diagnostic V/Q scan, further testing is recommended to exclude or confirm PE
† Negative MDCT excludes PE
† Negative SDCT only excludes PE when combined with negative proximal CUS
† High-probability ventilation–perfusion lung scintigraphy confirms PE
† CUS showing a proximal DVT confirms PE
† If CUS shows only a distal DVT, further testing should be considered
† SDCT or MDCT showing a segmental or more proximal thrombus confirms PE
† Further testing may be considered in case of subsegmental clots to confirm PE
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
† In patients with a negative CT, further tests should be considered in selected patients to exclude PE
† High-probability ventilation–perfusion lung scintigraphy confirms PE
† CUS showing a proximal DVT confirms PE
† If CUS shows only a distal DVT, further testing should be considered
† SDCT or MDCT showing a segmental or more proximal thrombus confirms PE
† Further testing may be considered where there are subsegmental clots, to confirm PE
aClass of recommendation.
bLevel of evidence.
CUS ¼ compression venous ultrasonography.
Role of echocardiography
Echocardiography does not play a major part in detecting sus-
pected non-high-risk PE. Indeed, it has a limited sensitivity
(around 60–70%)116,143–145and a negative echocardiogram does
not allow the exclusion of PE. Its specificity is around 90% and
an echocardiogram showing signs of right ventricular dysfunction
in a patient with a moderate or high clinical probability of PE
would theoretically yield a post-test probability of PE high
enough to consider the diagnosis confirmed.116,143–145However,
most clinicians would probably require more direct evidence of
a clot, either in the lower limbs or in the pulmonary arteries, to
confirm the diagnosis before deciding on several months of
anticoagulant treatment. Therefore, the main role for echocardio-
graphy in non-high-risk PE is prognostic stratification to the inter-
mediate or low risk category.
Areas of uncertainty
Despite considerable progress in PE diagnosis, several areas of
uncertainty persist. The diagnostic value and clinical significance
of a single subsegmental defect on MDCT are still debated.170
Therefore, deciding between further investigations, treatment or
abstention should be made on an individual basis. Likewise,
although false-negative MDCT examinations are reported in
patients with a high clinical probability,94it is unclear whether
they should be submitted to further tests. In particular, pulmonary
angiography is no longer unanimously considered as the gold
standard for PE. The role and cost-effectiveness of CUS in
suspected PE should be further clarified.
Clinical assessment of haemodynamic
Hypotension and shock
The existing evidence regarding the prognostic significance of
shock and hypotension in acute PE has been reviewed recently.33
It is mostly derived from observational studies such as the
ICOPER and Management and Prognosis in Pulmonary Embolism
Trial (MAPPET) registry.17,51In a post hoc analysis of ICOPER
data, the 90-day all-cause mortality rate was 52.4% (95% CI,
43.3–62.1%) in patients with systolic blood pressure (SBP)
,90 mmHg compared with 14.7% (95% CI, 13.3–16.2%) in
normotensive patients.171According to data from MAPPET,
systemic hypotension, defined as SBP ,90 mmHg or a reduction
of at least 40 mmHg for at least 15 min, seems to carry a
slightly lower risk compared with shock (in-hospital all-cause
mortality, 15.2 vs. 24.5%, respectively).51However, the expected
mortality is still very high and justifies classification of a patient
in the high-risk PE category, requiring immediate aggressive
Syncope and cardiac arrest may occur in a patient with PE. In
most cases, such an episode is related to persistent systemic hypo-
tension and/or shock, which are markers of high risk. In the few
patients who immediately regain consciousness and a stable
blood pressure, risk assessment should be made on a case-by-case
basis. It should take into account the severity of right ventricular
dysfunction and the presence of impending embolism due to a
floating right heart or proximal venous thrombi.
In summary, shock and hypotension are principal markers of
high risk of early death in acute PE.
Markers of right ventricular dysfunction
Echocardiographic findings suggesting RVD have been reported to
occur in at least 25% of PE patients.173A meta-analysis found more
than a two-fold increased risk of PE-related mortality in patients
with echocardiographic signs of right ventricular dysfunction.174
Two out of the seven studies included an estimation of risk in
normotensive patients with PE.140,175In such patients RVD had
sensitivity of 56–61% and was related to the absolute increase in
the early PE-related mortality of 4–5%.174Importantly, patients
outcome, with in hospital PE-related mortality ,1% in most of
the reported series.140–142(Table 11).
Unfortunately, echocardiographic criteria of RVD differ among
published studies and include RV dilatation, hypokinesis, increased
RV/LV diameter ratio and increased velocity of the jet of tricuspid
regurgitation.173,176(Table 11). Thus, since a universal definition of
RVD on echocardiography is lacking, only a completely normal
result should be considered as defining low-risk PE. This is par-
ticularly important because in some of the trials echocardio-
graphic signs of RV pressure overload alone (such as increased
tricuspid insufficiency peak gradient and decreased acceleration
time of right ventricular ejection) were considered sufficient to
classify a patient to the RVD group.140In addition to RVD,
echocardiography can also identify two specific markers, each
indicating doubled mortality risk in PE: right-to-left shunt
through a patent foramen ovale and the presence of right heart
Contrast-enhanced non-ECG-gated spiral CT used for pulmonary
angiography allows assessment of the right-to-left ventricular
dimension ratio but provides no direct information regarding
RV function. With SDCT, identification of the longest minor
axis of the RV and LV requires inspection of relevant transverse
thoracic planes. An RV/LV ratio .1.0 was found in 58% of 120
initially stable patients with confirmed PE, and it had a PPV
of 10% with regard to 30-day PE-related mortality (95% CI,
2.9–17.4%). The combination of RV/LV .1.0 and a CT-derived
vascular obstruction index
.40% increased the PPV for
3-month PE-related mortality to 18.8%. The predictive value of
an RV/LV ratio ?1.0 for an uneventful outcome was 100%
(95% CI, 94.3–100%).178
Two studies by the same group reported experience with
16-detector CT. A pilot study found an RV/LV ratio .0.9,
measured in the four-chamber view from reformatted, non-ECG-
triggered images of the heart, to be slightly superior to measure-
ments from axial views in identifying patients with PE and worse
prognosis.179In a follow-up study including 431 patients, RV/LV
.0.9 was present in 64% of patients with PE, and its NPV and
PPV for 30-day mortality were 92.3% and 15.6%, respectively
(Web Site Table A). The hazard ratio of RV/LV .0.9 for predicting
30-day death was 5.17 (95% CI, 1.63–16.35; P ¼ 0.005) after
adjusting for other risk factors such as pneumonia, cancer,
chronic obstructive pulmonary disease and age.180
When reports on smaller patient populations are also taken
into consideration, most studies do suggest that CT scanning
contributes to the risk stratification of patients with confirmed
PE.181Its greatest value appears to be the identification of
low-risk patients based on the lack of RV dilatation (Web Site
Table A). Other CT-derived indices, such as interventricular
septum shape, or pulmonary artery dimensions, have not been
found to be of prognostic relevance, while evidence regarding a
more complex CT-derived vascular obstruction index is non-
Brain natriuretic peptide
Ventricular dysfunction is associated with increased myocardial
stretch which leads to the release of brain natriuretic peptide
(BNP). There is growing evidence that in acute PE levels of
BNP or N-terminal proBNP (NT-proBNP) reflect the severity of
RVD and haemodynamic compromise.185–188Recent reports
suggest that BNP or NT-proBNP as markers of RVD provide
Although elevated BNP or NT-proBNP concentrations are
related to worse outcome, their PPV is low (12–26%) (Web Site
Table B). On the other hand, low levels of BNP or NT-proBNP
can be reliably used for identification of patients with a good
prognosis regarding short-term mortality or a complicated clinical
outcome (NPV 94–100%).186,190–194
Other markers of RV dysfunction
Jugular vein distension, if not caused by cardiac tamponade or med-
iastinal tumours, may be a reliable sign of RVD in patients with PE.
Other clinical signs, such as tricuspid regurgitation murmur and RV
gallop, are more subjective and thus potentially misleading. New
appearance of ECG signs of RV strain such as inversion of T
waves in leads V1–V4, QR pattern in V1 lead, the classic
S1Q3T3 pattern and incomplete or complete right bundle-branch
block, are useful but of limited sensitivity.59,195–197Right heart
catheterization allows direct assessment of RV filling pressures
and cardiac output, but its routine use for risk stratification in
acute PE is not recommended.
In summary, 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
Markers of myocardial injury
Transmural RV infarction despite patent coronary arteries has
been found in autopsies of patients who died of massive
PE.198,199Several observational studies reported elevated cardiac
troponin levels in PE.189,193,200–207While RV myocardium might
not necessarily be its only source, elevated plasma troponin
levels have been repeatedly reported as associated with worse
prognosis in patients with PE208(Web Site Table C).
In an early study, the prevalence of a positive troponin T test,
defined as .0.1 ng/mL, was reported in 0–35% and 50% of
patients with non-massive, submassive and clinically massive PE,
respectively.202Positive troponin T was related to an in-hospital
mortality of 44%, compared with 3% for negative troponin T
[odds ratio (OR, 15.2; 95% CI, 1.2–190.4]. In another study,
levels of troponins I and T correlated both with in-hospital mor-
tality and a complicated clinical course.204Increased in-hospital
mortality has also been reported in normotensive patients with
PE using cutoff values for troponin T as low as 0.01 ng/mL (OR,
21.0; 95% CI, 1.2–389.0)].206Repeated blood sampling 6–12 h
after admission should be considered, because initially negative
results may convert to positive, with prognostic implications.206
A further study derived from a large therapeutic trial analysed
the data of 458 consecutive patients with submassive PE
and found that 13.5% of them had cardiac troponin I levels
.0.5 ng/mL measured within 24 h of clinical presentation.
Goldhaber et al.175
Ribeiro et al.141
126Normotensive and hypotensive
Kasper et al.142
317 Normotensive and hypotensive
Grifoni et al.140
162BP ?100 mmHg
Table 11 Major trials reporting definitions and prognostic significance of RV dysfunction assessed by echocardiography
in acute pulmonary embolism
Patient characteristics Echocardiographic criteriaEarly mortality
RVD(1) vs. RVD(–)
RV hypokinesis and dilatation
RV .30 mm or TI .2.8 m/s
At least one of the following:
RV .30 mm or RV/LV .1
Paradox septal systolic motion
AcT ,90 ms or TIPG .30 mmHg
4.3 vs. 0%
12.8 vs. 0%
13 vs. 0.9%
4.6 vs. 0%
Kucher et al.176
1035BP ?90 mmHg 16.3 vs. 9.4%a
All data refer to in-hospital PE-related mortality, excepta30 day all-cause mortality.
RVD(þ) ¼ patients with RV dysfunction; RVD(–) ¼ patients with normal RV function.
RV ¼ right ventricle; BP ¼ blood pressure; TI ¼ tricuspid insufficiency; LV ¼ left ventricle; AcT ¼ acceleration time of right ventricular ejection; TIPG ¼ tricuspid insufficiency
Cardiac troponin elevation was associated with a 3.5-fold higher
risk of all-cause death at three-month follow-up (95% CI,
1.0–11.9) (201). The prevalence of cTnI . 2.3 mg/L, correspond-
ing to the levels indicating acute myocardial infarction, was 3.5%
(95% CI, 2.0–5.6). Most trials reported PPV and NPV of elevated
troponin for PE-related early mortality in the range of 12–44%,
with very high NPV (99–100%), irrespective of various methods
and cutoff values applied. A recent meta-analysis confirmed that
elevated troponin levels were associated with increased mortality
in the subgroup of haemodynamically stable patients (OR, 5.9;
95% CI, 2.7–12.9).208
New markers of myocardial injury
Few reports exist on the prognostic value of other biomarkers
of myocardial injury in acute PE (Web Site Table C). Recently, heart-
type fatty acid binding protein (H-FABP), an early marker of
myocardial injury, was reported to be superior to troponin or
myoglobin measurements for risk stratification of PE on admission.
H-FABP .6 ng/mL had a PPV and NPV for early PE-related
mortality of 23–37% and 96–100%, respectively.209,210
Combination of markers of myocardial injury
and RV dysfunction
Simultaneous measurements of troponin and NT-proBNP were
found to stratify normotensive patients with PE more accurately
(Web Site Table D). PE-related 40-day mortality in the group with
high levels of both cardiac troponin T and NT-proBNP exceeded
30%. Patients with an isolated elevation of NT-proBNP had an
intermediate mortality rate (3.7%), while low levels of both
biomarkers indicated a good short-term prognosis.189
An alternative approach consists of troponin testing combined
with echocardiography. In one trial a combination of cardiac tropo-
nin I .0.1 ng/L and RV/LV .0.9 on echocardiography identified a
subgroup with all-cause 30-day mortality of 38%.211Preserved RV
function without biochemical signs of myocardial injury identified
patients with an excellent prognosis (Web Site Table E).193,211,212
The currently available data do not allow the proposal of specific
cutoff levels of markers that could be used for therapeutic
decision-making in patients with non-high-risk PE. An ongoing mul-
ticentre randomized trial is evaluating the potential benefit of
thrombolysis in normotensive patients with echocardiographic
signs of RVD and abnormal troponin levels.
In summary, 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
Clinical and routine laboratory tests
Several variables collected during routine clinical and laboratory
evaluation have prognostic significance in PE. Many of them are
related to the pre-existing condition and the comorbidities of
the individual patient rather than to the severity of the index PE
episode. For example, in the ICOPER registry, age .70 years,
cancer, congestive heart failure and chronic obstructive pulmonary
disease were identified as prognostic factors.17Several other
clinical and laboratory features have been studied and risk scores
for prognostic stratification have been proposed169,213
validated.214,215These risk scores use clinical variables and/or
laboratory markers of prognosis. Some of them are intended to
identify low-risk patients,169,214–216who are potential candidates
for early discharge and outpatient treatment, while other models
seek to detect high-risk patients,193,206who could benefit from
more intensive management.
The Geneva prognostic score uses an eight-point scoring system
and defines six predictors of adverse outcome: cancer and hypo-
tension (,100 mmHg), 2 points each; heart failure, prior DVT,
arterial hypoxaemia (PaO2,8 kPa), and ultrasound-proven DVT,
1 point each.169Male sex, tachycardia, hypothermia, altered
mental status and low arterial oxygen saturation have also been
identified as clinical prognostic markers and used in a clinical
model of risk evaluation.213In this risk score, 11 clinical variables
are used to generate a score that divides patients into five risk
classes for 30-day all-cause mortality, ranging from very low to
very high risk (Table 12).
Elevated serum creatinine levels have also been reported as
having significant prognostic relevance in acute PE patients.17,189
Another study found D-dimer levels below 1500 mg/L to have a
99% NPV in predicting all-cause 3-month mortality.217
In summary, 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
Concurrently with the diagnosis of PE, prognostic assessment is
required for risk stratification and therapeutic decision-making.
Chronic lung disease
Heart rate .110/min
Systolic blood pressure ,100 mmHg
Respiratory rate ?30/min
Body temperature ,368C
Disorientation, lethargy, stupor, coma
Table 12 Routinely available clinical predictors of
30-day all-cause mortality in patients with acute PE
Data are from reference 214.
Risk categories (30-day all-cause mortality,%): class I, ,65 points (0%);
class II, 66–85 points (1%); class III, 86–105 points (3.1%); class IV,106–125 points
(10.4%); class, V .125 points (24.4%). Low risk ¼ classes I and II (0–1%).
† 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
† 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
Risk stratification of PE is performed in stages: it starts with clinical
assessment of the haemodynamic status and continues with the
help of laboratory tests (see Tables 4 and 5 in the subsection
Severity of pulmonary embolism).
High-risk PE is diagnosed in the presence of shock or persistent
arterial hypotension (defined as a systolic blood pressure
,90 mmHg or a pressure drop of ?40 mmHg for .15 min if
not caused by new-onset arrhythmia, hypovolaemia or sepsis),
and represents an immediately life-threatening emergency requir-
ing specific management.33,171
In the remaining normotensive patients with non-high-risk PE,
the presence of markers of RVD173and/or myocardial injury208
identify intermediate-risk PE. It is likely that patients with inter-
mediate-risk PE in whom markers of dysfunction and injury are
both positive have a greater risk than patients with discordant
results. Although short-term mortality above 30% has been
reported, evidence is still insufficient to make a definitive
Haemodynamically stable patients without evidence of RVD or
myocardial injury have low-risk PE. A patient with non-high-risk
PE can be classified into the low-risk PE category if at least one
of the myocardial dysfunction markers and at least one of the
myocardial injury markers are assessed.
Routinely collected clinical and laboratory data may also have
prognostic implications in acute PE when integrated into a
weighted score (Table 12). Such a score, accounting also for the
pre-existing condition and comorbidities of the patient, can be of
help when considering early discharge and ambulatory treatment
of patients with otherwise low-risk PE.
The anatomical distribution and burden of embolic occlusion
of the pulmonary arterial bed can be assessed by means of
angiography (Millerand Walsh
anatomical assessment seems less relevant for risk stratification
than assessment based on functional (haemodynamic) conse-
quences of PE, and is currently not recommended for prognostic
In summary, evaluation of haemodynamic status, signs
of RVD and myocardialinjury
additional patient-related factors are useful for optimal risk
Recommendations: prognostic assessment Classa
aClass of recommendation.
bLevel of evidence.
Haemodynamic and respiratory support
Acute RV failure with resulting low systemic output is the leading
cause of death in patients with high-risk PE. Therefore, supportive
treatment is of vital importance in patients with PE and RV failure.
Experimental studies indicate that aggressive volume expansion
may worsen RV function by causing mechanical overstretch and/or
by reflex mechanisms that depress contractility.219On the other
hand, a small clinical study observed an increase in cardiac index
from 1.6 to 2.0 L/min/m2after a 500 ml dextran infusion in normo-
tensive patients with acute PE and low cardiac index.220It appears
that a modest fluid challenge may help increase cardiac index in
patients with PE, low cardiac index and normal blood pressure.
Isoproterenol is an inotropic drug which also induces pulmonary
vasodilatation, but these favourable effects are often outweighed
by peripheral vasodilatation. The resulting hypotension may lead
to decreased RV perfusion and ischaemia.221Norepinephrine
appears to improve RV function via a direct positive inotropic
effect while also improving RV coronary perfusion by peripheral
vascular alpha receptor stimulation and the increase in systemic
blood pressure. No clinical data are available on the effects of nor-
epinephrine in PE, and its use should probably be limited to hypo-
tensive patients.222In a small series of patients requiring admission
to an intensive care unit for PE, dobutamine raised cardiac output
and improved oxygen transport and tissue oxygenation at a con-
stant arterial PO2.223In another study of 10 patients with PE,
low cardiac index and normal blood pressure, a 35% increase in
cardiac index was observed under intravenous dobutamine infu-
sion at a moderate dosage without significant change in heart
rate, systemic arterial pressure or mean pulmonary arterial
pressure.224Accordingly, the use of dobutamine and/or dopamine
can be considered for patients with PE, low cardiac index and
normal blood pressure. However, raising the cardiac index above
physiological values may aggravate the ventilation–perfusion mis-
match by further redistributing flow from (partly) obstructed to
non-obstructed vessels.221,223Epinephrine combines the beneficial
properties of norepinephrine and dobutamine without the sys-
temic vasodilatory effects of the latter drug.221In patients with
PE and shock, epinephrine may exert beneficial effects.225
Vasodilators decrease pulmonary arterial pressure and pulmon-
ary vascular resistance in animals and, to a lesser extent, in patients
with PE.40,42The main concern is the lack of specificity of these
drugs for the pulmonary vasculature after systemic (intravenous)
administration. To overcome this limitation, vasodilators may be
administered by inhalation.226According to data from small clinical
studies, inhalation of nitric oxide may improve the haemodynamic
status and gas exchange in patients with PE.227–229There are few
data with respect to inhaled aerosolized prostacyclin in the treat-
ment of pulmonary hypertension secondary to PE.226,230,231
Preliminary experimental data suggest that levosimendan may
restore right ventricular–pulmonary arterial coupling in acute PE
as a result of combined pulmonary vasodilation and increased RV
There is increasing interest in the use of endothelin antagonists
and phosphodiesterase-5 inhibitors in PE. In experimental studies,
antagonism of endothelin receptors attenuated the severity of
pulmonary hypertension caused by massive PE.233,234Sildenafil
infusion also attenuated the increase in pulmonary artery pressure
in experimental PE.235,236
Hypoxaemia and hypocapnia are frequently encountered in
patients with PE, although they are of moderate severity in most
cases. A patent foramen ovale may aggravate hypoxaemia due to
shunting when the right atrial pressure exceeds the left atrial
pressure.177,237Hypoxaemia is usually reversed with nasal oxygen,
and mechanical ventilation is rarely necessary. Oxygen consumption
should be minimized with measures to reduce fever and agitation,
and by instituting mechanical ventilation if the work of breathing
is excessive. When mechanical ventilation is required, care should
be taken to limit its adverse haemodynamic effects. In particular,
positive intrathoracic pressure induced by mechanical ventilation
may reduce venous return and worsen RV failure in patients
with massive PE. Therefore, positive end-expiratory pressure
should be applied with caution. Low tidal volumes (approximately
6 ml/kg lean body weight) should be used in an attempt to keep
the end-inspiratory plateau pressure below 30 cm H2O.238
In summary, haemodynamic and respiratory support is necess-
ary in patients with suspected or confirmed PE presenting with
shock or hypotension.
Randomized trials175,218,239–244have consistently shown that
thrombolytic therapy rapidly resolves thromboembolic obstruc-
tion and exerts beneficial effects on haemodynamic parameters.
In an early small trial, an 80% increase in cardiac index and a
40% decrease in pulmonary arterial pressure was observed after
72 h of streptokinase treatment.245In the Plasminogen Activator
Italian Multicenter Study 2, serial angiograms revealed that
100 mg of recombinant tissue plasminogen activator (rtPA)
induced a 12% decrease in vascular obstruction at the end of the
2 h infusion period, whereas no change was observed in patients
receiving heparin.239The effect of rtPA was associated with a
30% reduction in mean pulmonary arterial pressure and a 15%
increase in cardiac index. One of the largest thrombolysis trials
demonstrated a significant reduction in mean RV end-diastolic
area on echocardiography 3 h after treatment with rtPA.175
With regard to the comparison of different thrombolytic agents,
the Urokinase–Streptokinase Pulmonary Embolism Trial (USPET)
documented equal efficacy of urokinase and streptokinase
infused over a period of 12–24 h.246In more recent randomized
trials,247,248100 mg rtPA infused over 2 h led to faster angiographic
and haemodynamic improvement compared with urokinase
infused over 12 or 24 h at the rate of 4400 IU/kg/h, although the
results no longer differed at the end of the urokinase infusion. Simi-
larly, the 2 h infusion of rtPA appeared to be superior to a 12h
streptokinase infusion (at 100000 IU/h), but no difference was
observed when the same streptokinase dose was given over
2 h.249,250Furthermore, two trials that compared the 2 h, 100 mg
rtPA regimen with a short infusion (over 15 min) of 0.6 mg/kg
rtPA reported non-significant trends for both slightly faster
improvements and slightly higher bleeding rates with the 2 h
regimen.251,252Direct local infusion of rtPA via a catheter in the
pulmonary artery (at a reduced dosage) was not found to offer
any advantages over systemic intravenous thrombolysis.253This
approach should generally be avoided, as it also carries an
increased risk of bleeding at the puncture site.
The approved thrombolytic regimens of streptokinase, urokinase
and rtPA are shown in Table 13. Satisfactory haemodynamic results
also have been obtained with double-bolus reteplase, two injections
(10 U) 30 min apart.254Preliminary uncontrolled data appear to
support the efficacy and safety of tenecteplase in acute PE.255
Heparin should not be infused concurrently with streptokinase or
urokinase, but it can be given during alteplase administration.
Overall, approximately 92% of patients can be classified as
responders to thrombolysis based on clinical and echocardio-
graphic improvement within the first 36 h.256The greatest
benefit is observed when treatment is initiated within 48 h of
symptom onset,243but thrombolysis can still be useful in patients
who have had symptoms for 6–14 days.257
Although of rapid onset, the haemodynamic benefits of thrombo-
lysis over heparin appear to be confined to the first few days. One
tion218,239and the reversal of RVD258were no longer different
between thrombolysis-treated and heparin-treated patients.
Thrombolytic therapy carries a significant risk of bleeding,
marized data from randomized trials218,239,241,247,248,252,253,259–261
reveal a 13% cumulative rate of major bleeding and a 1.8% rate of
intracranial/fatal haemorrhage. In the most recent of these
trials,175,259life-threatening haemorrhage has been less common.
This appears to be in line with the observation that thrombolysis-
related bleeding rates are lower when non-invasive imaging
methods are used to confirm PE,262a strategy that has been
adopted increasingly over the past 10 years.
The overall effects of thrombolysis on the clinical outcome of
patients with PE are difficult to assess. With one exception,259
thrombolysis trials have not been designed to address clinical end-
points. In weighing the risk of bleeding against the possible clinical
benefits of thrombolysis, it is important to keep in mind the natural
history and prognosis of high-risk, intermediate-risk and low-risk
PE. Hence, contraindications to thrombolysis that are considered
absolute in acute myocardial infarction, e.g. surgery within the pre-
ceding 3 weeks or gastrointestinal bleeding within the last month
(Table 14) might become relative in a patient with immediately life-
threatening, high-risk PE.
Table 13 Approved thrombolytic regimens
for pulmonary embolism
Streptokinase 250 000 IU as a loadingdose over 30 min, followed by
100 000 IU/h over 12–24 h
Accelerated regimen: 1.5 million IU over 2 h
4400 IU/kg as a loading dose over 10 min, followed by
4400 IU/kg/h over 12–24 h
Accelerated regimen: 3 million IU over 2 h
100 mg over 2 h
or 0.6 mg/kg over 15 min (maximum dose 50 mg)
rtPA ¼ recombinant tissue plasminogen activator.
In summary, 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 contrain-
dications. 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
Several decades before the introduction of medical treatment for
PE, the first successful surgical pulmonary embolectomy was per-
formed in 1924.264For a long time, pulmonary embolectomy
remained a rare rescue operation and there were few data on
its efficacy and safety. Recently however, interdisciplinary thera-
peutic approaches to PE involving the cardiac surgeon have
begun to emerge in several centres.265,266
Traditionally, pulmonary embolectomy has been reserved for
patients with PE who may necessitate cardiopulmonary resuscita-
tion. It is also performed in patients with contraindications or
inadequate response to thrombolysis, and in those with patent
foramen ovale and intracardiac thrombi.256,265Transportable
extracorporeal assist systems with percutaneous femoral cannula-
tion can be helpful in critical situations, providing circulation and
oxygenation and thus time for definitive diagnosis.267–269In one
series, pulmonary embolectomy was also performed in patients
with PE and RVD without persistent hypotension or shock.270
In centres with routine cardiac surgery programmes, pulmonary
embolectomy is a simple operation. Following rapid induction of
anaesthesia and median sternotomy, normothermic cardiopulmon-
ary bypass is instituted. Unless intracardiac thrombi or a patent
foramen ovale are present, aortic crossclamping and cardioplegic
cardiac arrest should be avoided.266,270With an incision of the
PA trunk and usually an additional arteriotomy of the right pulmn-
ary artery, clots can be removed from both pulmonary arteries
using blunt grasping instruments under direct vision. Prolonged
periods of postoperative cardiopulmonary bypass and weaning
may be necessary until the recovery of RV function. Bleeding
may be a problem in patients with preoperative thrombolysis,
although previous thrombolysis is not a contraindication to surgical
embolectomy.270The routine perioperative placement of an
inferior vena caval filter remains controversial.
In the past, the results of pulmonary embolectomy were con-
sidered poor as early mortality rates were high.271–273With a
broader spectrum of indications for embolectomy in patients
with RVD but in the absence of severe shock, early mortality
rates of 6–8% have been reported.256,266,270
Patients presenting with an episode of acute PE superimposed
on a history of long-lasting dyspnoea and severe pulmonary
hypertension are likely to suffer from chronic thromboembolic
pulmonary hypertension. These patients are not candidates for
embolectomy as they need specific pulmonary endarterectomy,
which should be performed in specialized centres.274
In summary, 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
Percutaneous catheter embolectomy
Percutanous techniques to open a partially occluded pulmonary
trunk or major pulmonary arteries may be life-saving in some criti-
cal situations of high-risk PE.275,276Although the available evidence
is limited to case reports or series, such procedures can be per-
formed as an alternative to thrombolysis when there are absolute
contraindications, as adjunctive therapy when thrombolysis has
failed to improve haemodynamics, or as an alternative to surgery
if immediate access to cardiopulmonary bypass is unavailable.
The Greenfield suction embolectomy catheter was introduced in
1969277and it remains the only device with FDA approval. Fragmen-
tation and dispersion using conventional cardiac catheters275or
specially designed pulmonary catheters with rotational or other
macerating devices278has evolved technically since the late 1980s.
Variably good results are described with currently used devices,
but these have never been rigorously evaluated in clinical trials.
Deployment of some of the devices (which can be introduced
via catheter sheaths ranging from 6 to 11 F) within the pulmonary
arteries may require dexterity, particularly if the right main pul-
monary artery is occluded. Catheter techniques should only be
used in the main arteries since fragmentation within the smaller
branches is unlikely to be of benefit and may damage the more
delicate structures, with risk of perforation.279
Haemodynamic improvement can be dramatic following suc-
cessful thrombus fragmentation. Crucially, the procedure should
be terminated as soon as haemodynamics improve, regardless of
the angiographic result. Substantial improvement in pulmonary
blood flow may result from what appears to be only modest
† Transient ischaemic attack in preceding 6 months
† Oral anticoagulant therapy
† Pregnancy or within 1 week post partum
† Non-compressible punctures
† Traumatic resuscitation
† Refractory hypertension (systolic blood pressure .180 mmHg)
† Advanced liver disease
† Infective endocarditis
† Active peptic ulcer
Table 14 Contraindications to fibrinolytic therapy
† Haemorrhagic stroke or stroke of unknown origin at any time
† Ischaemic stroke in preceding 6 months
† Central nervous system damage or neoplasms
† Recent major trauma/surgery/head injury (within preceding
† Gastrointestinal bleeding within the last month
† Known bleeding
From reference 263.
aContraindications to thrombolysis that are considered absolute, e.g. in acute
myocardial infarction, might become relative in a patient with immediately
life-threatening high-risk PE.
Complications of percutaneous procedures include local
damage to the puncture site, usually the femoral vein, perforation
of cardiac structures, tamponade and contrast reactions. Iliac and
caval flow can be assessed angiographically, but obstruction by
remaining thrombus is rarely a problem.
In summary, 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.
Anticoagulant treatment plays a pivotal role in the management
of patients with PE. The need for immediate anticoagulation
in patients with PE is based on a landmark study which was
performed in the 1960s and demonstrated the benefits of
unfractionated heparin in comparison with no treatment.280The
objectives of the initial anticoagulant treatment of PE are to
prevent death and recurrent events with an acceptable rate of
Rapid anticoagulation can only be achieved with parenteral
anticoagulants, such as intravenous unfractionated heparin, subcu-
taneous low-molecular-weight heparin (LMWH) or subcutaneous
fondaparinux.281Considering the high mortality rate in untreated
patients, anticoagulant treatment should be considered in patients
with suspected PE while awaiting definitive diagnostic confirmation.
Treatment with parenteral anticoagulants is usually followed
by the administration of oral vitamin K antagonists (VKAs). The
requirement for an initial course of heparin in addition to VKAs,
compared with starting treatment with VKA therapy alone, was
established in a randomized controlled study that reported a three-
fold higher rate of recurrent VTE in patients who received VKAs
only.282If intravenous unfractionated heparin is given, a weight-
adjusted regimen of 80 U/kg as a bolus injection followed by infusion
at the rate of 18 U/kg/h should be preferred to fixed dosages of
heparin.283Subsequent doses of unfractionated heparin should be
adjusted using an activated partial thromboplastin time (aPTT)-based
nomogram to rapidly reach and maintain aPTT prolongation
(between 1.5 and 2.5 times control) corresponding to therapeutic
heparin levels (Table 15). The aPTT should be measured 4–6 h
after the bolus injection and then 3 h after each dose adjustment,
or once daily when the target therapeutic dose has been reached.
It should be noted that aPTT is not a perfect marker of the
intensity of the anticoagulant effect of heparin. Therefore, it
is not necessary to increase the infusion rate above 1667 U/h
(corresponding to 40 000 U/day) provided the anti-factor Xa
heparin level is at least 0.35 IU/mL, even if the aPTT ratio is
below the therapeutic range.284
Low molecular weight heparins should be given with care in
patients with renal failure and their dose adjusted according to
anti-Xa level. Intravenous unfractionated heparin should be the pre-
ferred mode of initial anticoagulation for patients with severe renal
impairment (creatinine clearance ,30 ml/min), as it is not elimi-
nated by the kidneys, and for those at high risk of bleeding, as its
anticoagulant effect can be rapidly reversed. For all other cases of
acute PE, unfractionated heparin can be replaced by LMWH given
subcutaneously at weight-adjusted doses without monitoring.
Several trials compared the efficacy and safety of subcutaneous
LMWH with those of unfractionated heparin. Major studies285–293
with a total of 1951 patients with non-high-risk symptomatic PE or
with asymptomatic PE in association with symptomatic DVT were
included in a meta-analysis294At the end of the study treatment
(5–14 days), LMWH was at least as efficacious as unfractionated
heparin regarding the rate of recurrent VTE (OR, 0.63; 95% CI,
0.33–1.18) and at least as safe regarding major bleeding (OR,
0.67; 95% CI, 0.36–1.27). All-cause mortality was similar in the
two groups (OR, 1.20; 95% CI, 0.59–2.45).
Table 16 lists the low molecular weight heparins that are cur-
rently approved for the treatment of acute PE. Other LMWH,
approved for the treatment of DVT, are sometimes also used in
PE. LMWH cannot be recommended for high-risk PE with haemo-
dynamic instability, as such patients were excluded from random-
ized trials testing the efficacy and safety of these drugs in PE.
Anti-factor Xa activity (anti-Xa) levels need not be measured
,35 s (,1.2 times control)
Table 15 Adjustment of intravenous unfractionated
heparin dosage based on the activated partial
Change of dosage
80 U/kg bolus; increase infusion
rate by 4 U/kg/h
40 U/kg bolus; increase infusion
rate by 2 U/kg/h
Reduce infusion rate by 2 U/kg/h
Stop infusion for 1 h, then reduce
infusion rate by 3 U/kg/h
35–45 s (1.2–1.5 times control)
46–70 s (1.5–2.3 times control)
71–90 s (2.3–3.0 times control)
.90 s (.3.0 times control)
Data are from reference 283. This article was published in Arch Intern Med, Vol.
156, Raschke RA, Gollihare B, Peirce JC. The effectiveness of implementing the
weight-based heparin nomogram as a practice guideline, 1645–1649. Copyright&
(1996) American Medical Association. All Rights reserved.
Enoxaparin 1.0 mg/kg
or 1.5 mg/kga
Tinzaparin 175 U/kg
Fondaparinux5 mg (body weight ,50 kg)
7.5 mg (body weight 50–100 kg)
10 mg (body weight .100 kg)
Table 16 Subcutaneous regimens of low molecular-
weight heparins and fondaparinux approved for the
treatment of pulmonary embolism
Every 12 h
In patients with cancer, Dalteparin is approved for extended treatment of
symptomatic VTE (proximal DVT and/or PE), at an initial dose of 200 U/kg s.c.
once daily (see drug labelling for details).
aOnce-daily injection of enoxaparin at the dose of 1.5 mg/kg is approved for
inpatient (hospital) treatment of PE in the United States and in some, but not all,
routinely in a patient receiving LMWH, but they should be con-
sidered in patients with severe renal failure as well as during preg-
nancy.295The usual time to take samples for the anti-Xa assay is
4 h after the morning injection, when anti-Xa levels are highest.
A target range of 0.6–1.0 IU/mL is suggested for twice-daily admin-
istration, and a target range of 1.0–2.0 IU/mL is suggested for
once-daily administration, although neither recommendation is
Because of the risk of heparin-induced thrombocytopenia (HIT),
monitoring of the platelet count is necessary during treatment with
unfractionated or low-molecular-weight heparin (see Specific
The selective factor Xa inhibitor fondaparinux given sub-
cutaneously at weight-adjusted doses without monitoring is a valu-
able alternative to LMWH. Because of its half-life of 15–20 h,
fondaparinux allows once-a-day subcutaneous administration
(Table 16). An open-label trial which enrolled 2213 patients with
acute PE and no indication for thrombolytic therapy found that
weight-adjusted, fixed-dose, fondaparinux was associated with
rates of recurrent VTE (3.8 vs. 5.0% at 3 months) and major bleed-
ing (1.3 vs. 1.1%) similar to those obtained with intravenous unfrac-
tionated heparin.296As no proven HIT case has ever been
observed with fondaparinux, platelet count monitoring is not
needed with this compound. Fondaparinux is contraindicated in
severe renal failure with creatinine clearance ,20 ml/min.
Anticoagulation with unfractionated heparin, LMWH or fonda-
parinux should be continued for at least 5 days. Two randomized
clinical trials in patients with proximal DVT reported that unfrac-
tionated heparin given for 5–7 days is as effective as unfractionated
heparin given for 10–14 days, provided that it is followed by ade-
quate long-term anticoagulant therapy.297,298VKAs should be
initiated as soon as possible and preferably on the same day as
the initial anticoagulant. Parenteral anticoagulants should be
stopped when the international normalized ratio (INR) lies
between 2.0 and 3.0 for at least 2 consecutive days. If warfarin is
used, a starting dose of 5 or 7.5 mg is preferred over higher
doses. Two trials performed in hospitalized patients showed that
starting warfarin at a dose of 5 mg was associated with less exces-
sive anticoagulation compared with 10 mg. Taken together, these
data suggest that warfarin can usually be started at a dose of
10 mg in younger (e.g. ,60 years), otherwise healthy outpatients,
and at a dose of 5 mg in older patients and in those who are
hospitalized. Subsequent doses should be adjusted to maintain
the INR at a target of 2.5 (range 2.0–3.0).
There is no evidence concerning the benefit of immobilization
for the clinical outcome of patients with pulmonary embolism.
Indeed, most of the data are related to patients with DVT.
In these patients, recent studies have shown a similar incidence
of new PE on routine repeat lung scanning with early ambulation
and leg compression compared with immobilization.299–301
A recent Cochrane review that combined the findings of the
most recent studies estimated that wearing stockings markedly
reduced the cumulative incidence of post-thrombotic syndrome
in patients with proximal DVT 2 years after the index event
(OR, 0.3; 95% CI, 0.2–0.5).302
Recent studies have explored the possibility of outpatient
(home) treatment for patients with PE, but none of them specifi-
cally randomized patients with acute PE to be treated either in
hospital or at home. It is conceivable that this approach could be
reserved for selected patients with low-risk PE.
Rapid-acting oral anticoagulants could replace parenteral agents
for the initial VTE treatment. A number of new oral anticoagulants,
particularly Xa and IIa inhibitors not requiring monitoring, are
currently under clinical evaluation.
In summary, anticoagulation with unfractionated 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 fondapar-
inux rather then intravenous unfractionated heparin should be
considered for initial treatment.
High-risk pulmonary embolism
Patients with PE presenting with shock or hypotension (previously
considered ‘clinically massive’ PE) are at high risk of in-hospital
death, particularly during the first few hours after admission.303
Intravenous unfractionated heparin should be the preferred
mode of initial anticoagulation in these patients, as LMWH and fon-
daparinux have not been tested in the setting of hypotension and
shock. To date, only one small randomized trial has specifically
addressed the benefits of thrombolysis (streptokinase) vs.
heparin in high-risk PE.199Pooled data from five trials that included
Recurrent PE or death12/128 (9.4%) 24/126 (19.0%)0.45 (0.22–0.92)
Recurrent PE 5/128 (3.9%)9/126 (7.1%) 0.61 (0.23–1.62)
Death8/128 (6.2%) 16/126 (12.7%) 0.47 (0.20–1.10)
Major bleeding28/128 (21.9%) 15/126 (11.9%) 1.98 (1.00–3.92)
Table 17 Meta-analysis of thrombolysis trials in patients with pulmonary embolism
OutcomeTrials that included patients with massive PE Trials that excluded patients with massive PE
Heparin Odds ratio
Heparin Odds ratio
Adapted from reference 139. This article was published in Circulation, Vol. 110, Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial
treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials, 744–749. & (2004) American Heart Association, Inc.
n ¼ number of patients with study endpoint; N ¼ total number of patients; OR ¼ odds ratio.
High-risk pulmonary embolism
† Anticoagulation with unfractionated heparin should be initiated without delay in patients with high-risk PE
† Systemic hypotension should be corrected to prevent progression of RV failure and death due to PE
† Vasopressive drugs are recommended for hypotensive patients with PE
† Dobutamine and dopamine may be used in patients with PE, low cardiac output and normal blood pressure
† Aggressive fluid challenge is not recommended
† Oxygen should be administered in patients with hypoxaemia
† Thrombolytic therapy should be used in patients with high-risk PE presenting with cardiogenic shock and/or persistent
† Surgical pulmonary embolectomy is a recommended therapeutic alternative in patients with high-risk PE in whom thrombolysis
is absolutely contraindicated or has failed
† 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
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
† Use of LMWH or fondaparinux is the recommended form of initial treatment for most patients with non-high-risk PE
† In patients at high risk of bleeding and in those with severe renal dysfunction, unfractionated heparin with an aPTT target range
of 1.5–2.5 times normal is a recommended form of initial treatment
† Initial treatment with unfractionated heparin, LMWH or fondaparinux should be continued for at least 5 days and
may be replaced by vitamin K antagonists only after achieving target INR levels for at least 2 consecutive days
† 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
† Thrombolytic therapy should be not used in patients with low-risk PE
aClass of recommendation.
bLevel of evidence.
patients with high-risk PE appear to suggest a significant reduction
in death or PE recurrence after thrombolysis (Table 17).139There-
fore, thrombolysis should be undertaken in patients with high-risk
PE unless there are absolute contraindications to its use. Uncon-
trolled data also suggest that thrombolysis may be a safe and effec-
tive alternative to surgery in patients with PE and free-floating
thrombi in the right heart.304,305
In patients with absolute contraindications to thrombolysis and
in those in whom thrombolysis has failed to improve haemo-
dynamic status, surgical embolectomy is the preferred therapy. If
this is not immediately available, catheter embolectomy or throm-
bus fragmentation may be considered, though the safety and effi-
cacy of such interventions has not been adequately documented.
Non-high-risk pulmonary embolism
Normotensive patients with non-high-risk PE generally have a
favourable short-term prognosis. For most cases of acute
non-high-risk PE without severe renal dysfunction, LMWH or fon-
daparinux, given subcutaneously at weight-adjusted doses without
monitoring, is the treatment of choice. Pooled data from six trials
revealed no clinical benefits from thrombolytic therapy in this
group (Table 17).139
Intermediate-risk pulmonary embolism defines patients who appear
haemodynamically stable on admission but have evidence of RVD
and/or myocardial injury. A recent trial randomized 256 patients
with intermediate-risk PE and no relative contraindications to
thrombolysis (Table 14) to heparin vs. rtPA treatment.259The
primary combined endpoint, in-hospital death or clinical deterio-
ration requiring escalation of treatment, was significantly reduced
in the thrombolysis group compared with the heparin group.
The difference was due to a more frequent need for secondary
(emergency) thrombolysis in the heparin group during the hospital
stay, while the overall mortality rate was not affected by thrombo-
lysis. Thus, it appears that the risk/benefit ratio of thrombolysis
may be favourable in selected patients with intermediate-risk PE,
particularly in those without an elevated risk of bleeding
(Table 14). A large multinational European trial has been initiated
and will attempt to resolve the controversy still surrounding the
appropriate treatment of this patient group.
Low-risk pulmonary embolism defines patients without principal
PE-related risk factors, who can be considered for early discharge,
if proper outpatient care and anticoagulant treatment can be pro-
vided. Pre-existing, non-specific patient-related risk factors, as well
as the risk of bleeding, should always be considered.
Recommendations: acute treatmentClassa
and secondary prophylaxis
The long-term anticoagulant treatment of patients with PE is
aimed at preventing fatal and non-fatal recurrent VTE events.
VKAs are used in the vast majority of patients, while LMWH
may be an effective and safe alternative to VKAs in cancer
patients.306,307VKAs should be given at doses adjusted to
maintain a target INR of 2.5 (range 2.0–3.0).
Most of the studies focusing on long-term anticoagulation for
VTE included patients with DVT, and only one study specifically
focused on patients with PE.308However, the implications for
treatment of proximal DVT or PE are very similar, the main
difference being that recurrent episodes are about three
times more likely to be PE after an initial PE than after an
The need for long-term anticoagulant treatment of VTE is
supported by three lines of evidence, all from randomized
trials. One of these studies showed a 20% rate of symptomatic
extension and/or recurrence within 3 months in patients with
anticoagulant treatment.309Another study proved the lack of
efficacy of low-dose unfractionated heparin as an alternative to
VKAs after proximal DVT.310In further studies, reducing the dur-
ation of treatment to 4 or 6 weeks resulted in an increased
recurrence rate compared with the conventional duration of
Clinical trials that have evaluated different durations of anticoa-
gulant therapy can be divided into three categories according to
the duration of therapy compared: (i) short vs. intermediate dur-
ation; (ii) different intermediate durations of therapy; and (iii)
indefinite vs. intermediate duration. The main findings from
these studies are: (i) the duration of anticoagulant therapy
should not be limited to 4–6 weeks in patients with unprovoked
VTE; (ii) a similar risk of recurrence is expected if anticoagulants
are stopped after 6 or 12 months compared with 3 months; (iii)
indefinite treatment reduces the risk of recurrent VTE by about
90%, but this advantage is partially offset by the risk of major
bleeding.38,311,313,314In general, VKAs are highly effective in
preventing recurrent VTE during treatment, but they do not elim-
inate the risk of subsequent recurrence after treatment discon-
tinuation.38,314Thus, the duration of anticoagulant treatment in
a particular patient represents a balance between the estimated
risk of recurrence after treatment discontinuation and the risk
of bleeding complications while on treatment. An additional
factor may be the inconvenience of treatment with VKAs in
patients with INR 2–3, including the need for regular laboratory
Active cancer is a major risk factor for recurrence of VTE, the
rate of recurrence being about 20% during the first 12 months
after the index event.315,316As a risk factor for recurrence,
cancer outweighs all other patient-related risks. Therefore,
cancer patients are candidates for indefinite anticoagulant treat-
ment after a first episode of PE. In a randomized study of patients
with DVT and cancer, the LMWH dalteparin, given at the dose of
200 U/kg once daily for 4–6 weeks followed by 75% of the
not receiving long-term
initial dose given once daily for up to 6 months, was more effective
than warfarin in preventing recurrent VTE.317Accordingly, at least
6 months of treatment with LMWH are recommended for
patients with VTE and cancer, followed by treatment with
LMWH or VKAs as long as the disease is considered active.306
With the exception of cancer patients, the risk of recurrent
VTE after treatment discontinuation is related to the features
of the index VTE event. A study that followed patients with a
first episode of acute PE found that the recurrence rate after
treatment discontinuation was approximately 2.5% per year
after PE associated with reversible risk factors compared with
4.5% per year after idiopathic (unprovoked) PE.308Similar obser-
vations were made in other prospective studies on patients with
DVT.311Reversible risk factors for VTE include surgery, trauma,
medical illness, oestrogen therapy and pregnancy. For patients
with PE secondary to a transient (reversible) risk factor, treat-
ment with a VKA for 3 months should be preferred over
shorter periods, with the possible exception of patients with
distal DVT associated with a reversible risk factor. Treatment
for longer than 3 months is generally not recommended,
provided that the causative transient risk factor has been
Risk stratification of patients with unprovoked PE is more
complex and remains an unresolved issue. The following risk
factors may help identify patients at higher long-term risk (relative
risk 1.5–2.0) of VTE recurrence: (i) one or more previous
episodes of VTE; (ii) antiphospholipid antibody syndrome; (iii)
hereditary thrombophilia; (iv) male vs. female sex; and (v) residual
thrombosis in the proximal veins. An additional risk factor for VTE
recurrence in patients with PE appears to be persistence of RVD at
hospital discharge as assessed by echocardiography.318On the
other hand, a negative D-dimer test 1 month after withdrawal
of the VKA seems to be a protective factor for VTE recurrence
(relative risk 0.4).319
Among carriers of molecular thrombophilia, patients with lupus
anticoagulant, those with confirmed deficit of protein C or protein
S, and patients homozygous for factor V Leiden or homozygous
for PTG20210A may be candidates for indefinite anticoagulant
treatment after a first unprovoked VTE. No evidence of a clinical
benefit of extended anticoagulant treatment is currently available
for heterozygous carriers of factor V Leiden or the prothrombin
In addition to the risk of recurrence, the risk of bleeding needs
to be considered in determining the duration of treatment.
Among the risk factors for major bleeding during anticoagulant
therapy, the following appear to be of clinical relevance: (i) old
age, particularly above 75 years; (ii) previous gastrointestinal
bleeding, particularly if not associated with a reversible cause;
(iii) previous non-cardioembolic stroke; chronic renal or hepatic
disease; (iv) concomitant antiplatelet therapy (to be avoided if
possible); (v) other serious acute or chronic illness; (vi) poor
anticoagulant control; and (vii) suboptimal monitoring of anticoa-
Based on the above considerations, patients with unprovoked
PE should be treated with VKA for at least 3 months. All patients
† For patients with PE secondary to a transient
(reversible) risk factor, treatment with a VKA
is recommended for 3 months
† For patients with unprovoked PE, treatment
with a VKA is recommended for at least
† 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
† For patients with a second episode of
unprovoked PE, long-term treatment is
† In patients who receive long-term anticoagulant
treatment, the risk/benefit ratio of continuing
such treatment should be reassessed at regular
† For patients with PE and cancer, LMWH should
be considered for the first 3–6 months ...
after this period, anticoagulant therapy with VKA
or LMWH should be continued indefinitely or
until the cancer is considered cured
† 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
should then be evaluated for the risks vs. benefits of indefinite
therapy. Indefinite anticoagulant therapy is recommended for
patients with a first unprovoked proximal DVT or PE and a low
risk of bleeding, when this is consistent with the patient’s prefer-
ence. Indefinite treatment is recommended for most patients
with a second unprovoked DVT or PE.
Reduced VKA doses for extended treatment in patients with
idiopathic VTE were shown to be effective and safe when com-
pared with placebo,320but they were less effective and not safer
when compared with conventional intensity anticoagulation.321
This approach should not be generalized, but reserved for selected
The efficacies of different durations of chronic anticoagulant
treatment in preventing the development of chronic thrombo-
embolic pulmonary hypertension are unknown.
An oral anticoagulant with no need for laboratory monitoring
and dose adjustment is currently needed for the long-term treat-
ment of PE. At least two types of oral agents, the selective throm-
bin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban
and apixaban, are currently under investigation for the long-term
treatment of PE.
Recommendations: long-term treatmentClassa
aClass of recommendation.
bLevel of evidence.
Interruption of the inferior vena cava as a method or preventing
PE was first suggested by Trousseau in 1868. Venous filters
became available in the late 1960s and percutaneous deployment
was made possible almost 30 years ago.322Filters are usually
placed in the infrarenal portion of the inferior vena cava (IVC). If
thrombus is identified in the IVC below the renal veins, more
superior placement may be indicated.
Permanent IVC filters may provide lifelong protection against
PE; however, they are associated with complications and late
sequelae, including recurrent DVT episodes and development of
the post-thrombotic syndrome.
Complications of permanent IVC filters are common, although
they are infrequently fatal.323Early complications, including inser-
tion site thrombosis, occur in 10% of patients. Late complications
are much more frequent and include recurrent DVT in approxi-
mately 20% and the post-thrombotic syndrome in 40% of
patients. Overall, occlusion of the vena cava affects approximately
22% of patients at 5 years and 33% at 9 years, regardless of the use
and duration of anticoagulation.324–326Other IVC filters are
designed to be retrieved after their period of required usage has
passed. It is recommended that retrievable devices should be
removed within 2 weeks of implantation. However, available data
indicate that temporary devices are often left in situ for longer
periods of time, with a late complication rate of up to 10%, includ-
ing migration and device thrombosis.327The exact risk/benefit
ratio of IVC filters is difficult to determine because follow-up has
been incomplete in most series and reported recurrence did not
require objective tests for PE. In the only randomized study to
date, 400 patients with DVT (with or without PE) were treated
either with an anticoagulant (unfractionated vs. low molecular
weight heparin plus an oral anticoagulant) alone, or with an
anticoagulant combined with the insertion of a vena cava filter.
During the first 12 days, the PE rate was 1.1% with the filter in
place vs. 4.8% with anticoagulant alone (P ¼ 0.03). However,
during the 2-year follow-up, the difference became non-significant.
Although there was no difference in total mortality at 12 days
(2.5% in each group), four of five deaths in the non-filter group
were due to PE vs. none of five deaths in the filter group.291
Overall, this trial, now with 8 years of follow-up data available,324
shows a reduced risk of recurrent PE at the cost of an increased
risk of recurrent DVT with no overall effect on survival in patients
undergoing permanent IVC filter insertion.
At present, the systematic use of venous filters is not rec-
ommended in the general population with VTE. On the other
hand, venous filters may be used when there are absolute contra-
indications to anticoagulation and a high risk of VTE recurrence,
including, for example, the period immediately after neurosurgery
or other major surgery. They may also be considered in pregnant
women who develop extensive thrombosis in the weeks before
delivery. As soon as it is safe to use anticoagulants, retrievable
filters should be removed; however, there are no data from
prospective randomized trials to dictate optimal duration of
IVC filter use.
There are no data to support the routine use of venous filters in
patients with free-floating proximal deep venous thrombosis. In
one series, the PE recurrence rate among such patients who
received adequate anticoagulant treatment alone was low
(3.3%).328Similarly, planned thrombolysis is not an indication for
prophylactic filter insertion.
† IVC filters may be used when there are absolute contraindications to anticoagulation and a high risk of VTE recurrence
† The routine use of IVC filters in patients with PE is not recommended
aClass of recommendation.
bLevel of evidence.
IVC, inferior vena cava; VTE, venous thromboembolism.
Recommendations: venous filtersClassa
The incidence of PE during pregnancy ranges between 0.3 and 1
per 1000 deliveries.329PE is the leading cause of pregnancy-related
maternal death in developed countries.330The risk of PE is higher
in the post-partum period, particularly after a Caesarean section.
The clinical features of PE are no different in pregnancy compared
with the non-pregnant state.331However, pregnant women often
present with breathlessness, and this symptom should be inter-
preted with caution, especially when isolated and neither severe
nor of acute onset. PaO2is normal during pregnancy. However,
arterial blood should be drawn in the upright position as the
PaO2 may be lower in the supine position during the third
Diagnosis of pulmonary embolism in pregnancy
Exposure of the fetus to ionizing radiation is a concern when
investigating suspected PE during pregnancy. However, this
concern is largely overcome by the hazards of missing a potentially
fatal diagnosis. Moreover, erroneously assigning a diagnosis of PE
to a pregnant woman is also fraught with risk since it unnecessarily
exposes the fetus and mother to the risk of anticoagulant treat-
ment. Therefore, investigations should aim for diagnostic certainty.
Plasma D-dimer levels increase physiologically throughout
pregnancy. In a prospective study, however, around 50% of women
had a normal D-dimer level at the 20th week of pregnancy.85
A normal D-dimer value has the same exclusion value for PE in
pregnant women as in other patients with suspected PE. Therefore,
it should be measured even though the probability of a negative
result is lower than in other patients with suspected PE, in order to
avoid unnecessary exposure of the fetus to X-rays. An elevated
unnecessary. If ultrasonography is negative, however, the diagnosis
should be pursued.
The amount of radiation absorbed by the fetus in different diag-
nostic tests is shown in Table 18. The upper limit with regard to
the danger of injury to the fetus is considered to be 50 mSv
(50 000 mGy)333and all radiological tests fall well below this
limit. Recent data on chest CT suggest that the radiation dose
delivered to the fetus is lower than that of perfusion lung scintigra-
phy in the first or second trimester334and that it can therefore be
performed safely. However, perfusion lung scintigraphy is also a
reasonable option; its diagnostic yield is high in pregnant women
(75%) and a retrospective series reported excellent outcomes
in pregnant women left untreated based on a normal perfusion
scan.331Perfusion scanning compares favourably with CT as far
as exposure of breast tissue to radiation is concerned.
Ventilation phase does not appear to add enough information to
warrant the additional radiation. In women left undiagnosed by
perfusion lung scintigraphy, however, CT should be preferred
over pulmonary angiography, which carries a significantly higher
X-ray exposure for the fetus (2.2–3.7 mSv).333
Treatment of pulmonary embolism in pregnancy
The treatment of PE in pregnancy is based mainly on heparin—
either unfractionated heparin or LWMH, neither of which
crosses the placenta or is found in breast milk in any significant
amount. Increasing experience suggests that LMWH is safe in
pregnancy335,336and its use is endorsed by several reports.337,338
As there are no specific data in the setting of pregnancy, treatment
should consist of a weight-adjusted dose of LMWH. Adaptation
according to anti-Xa monitoring may be considered in women at
extremes of body weight or with renal disease, or whenever felt
necessary. The heparin treatment should be given throughout
the entire pregnancy. As there are no data in pregnancy, fondapar-
inux cannot be used in this situation. VKA antagonists cross the
placenta and are associated with a well-defined embryopathy
during the first trimester.339Administration of VKA antagonists
in the third trimester can result in fetal and neonatal haemorrhage
as well as in placental abruption. Warfarin may be associated with
central nervous system anomalies in any trimester in pregnancy.
Perfusion lung scan with technetium
99m-labelled albumin (1–2 mCi)
Ventilation lung scan
Pulmonary angiography by femoral
Pulmonary angiography by brachial
Table 18 Estimated radiation absorbed by fetus in
procedures for diagnosing pulmonary embolism
Test Estimated radiation
Data are from references 333 and 334.
Although some experts recommend the cautious use of warfarin
during the second trimester of pregnancy by analogy with a fre-
quently used regimen in pregnant women with mechanical heart
valves,340this therapeutic approach should be avoided whenever
possible. The management of labour and delivery require particular
attention. Epidural analgesia cannot be used unless LMWH is dis-
continued at least 12 h before an epidural approach. Treatment
can be resumed 12–24 h after withdrawal of the epidural catheter.
In any case, close collaboration between obstetrician, anaesthetist
and attending physician is recommended.
After delivery, heparin treatment may be replaced by anticoagu-
lation with VKA. Anticoagulant treatment should be administered
for at least 3 months after delivery. VKAs can be given even to
There is published information on 36 women treated with
thrombolytic agents in pregnancy, massive PE being the indication
in about one-third of them.341Streptokinase was the agent most
frequently used. Streptokinase (and probably other thrombolytic
drugs) does not cross the placenta. However in mothers the
overall incidence of bleeding is about 8%, usually from the genital
tract. This risk does not seem unreasonable compared with the
death rate seen in patients with massive PE treated with heparin
alone. At the time of delivery, thrombolytic treatment should
not be used except in extremely severe cases and if surgical embo-
lectomy is not immediately available. Indications for cava filters in
pregnant women are similar to those in other patients with PE.
In summary, 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 trime-
sters and may be considered with caution in the second trimester
Anticoagulant treatment should be administered for at least
3 months after delivery.
The association of PE and cancer is well documented. Cohort
studies and clinical trials both suggest that patients presenting
with an idiopathic or unprovoked PE subsequently develop a
cancer in about 10% of the cases over a 5–10 year follow-up
The risk of thrombosis among cancer patients is about four
times higher than in the general population and the risk increases
to about 6.7-fold in patients receiving chemotherapy.345A number
of anticancer agents, as well as of drugs used in supportive cancer
therapy, have been associated with an increased risk of venous
thromboembolic events. The combination of hormonal and che-
motherapy seems to play a synergistic role in the development
of thrombosis in patients with cancer.346The use of antiangiogenic
agents such as thalidomide is also frequently complicated by
Cancer patients with VTE are more likely to develop recurrent
thromboembolic complications and major bleeding during anti-
coagulant treatment than those without malignancy.315,316These
risks correlate with the extent of cancer.
The use of more or less sophisticated imaging techniques, such
as ultrasound, endoscopic gastrointestinal examinations, CT scan-
ning, magnetic resonance imaging and nuclear medicine examin-
ations for routine screening of cancer in patients with so-called
idiopathic PE, is still controversial despite extensive investi-
Most authors suggest that an extensive
workup should be performed only if there is a strong suspicion
of cancer after a careful clinical history and physical examination,
routine blood tests and chest X-ray.351–353
The association between cancer and activation of blood coagu-
lation has been known since Trousseau’s time. The hypercoagul-
able state often encountered in cancer patients not only acts as
an important risk factor for thrombosis, but may also play a role
in tumour progression and metastasis. Heparins and other anti-
coagulants have been reported as having some anticancer
effects.354,355The results of a randomized trial307pointing to posi-
tive effects of LMWH in tumour biology gave further encourage-
ment to this concept, which is still under active investigation.
Several papers have been published regarding the efficacy advan-
tages of LMWH relative to coumarin derivatives. In the CLOT
(Randomized Comparison of Low-Molecular-Weight Heparin
Versus Oral Anticoagulant Therapy for the Prevention of Recur-
rent VTE in Patients With Cancer) trial,306the use of dalteparin
relative to oral anticoagulants was associated with improved survi-
val in patients with solid tumours who did not have metastatic
disease at the time of an acute venous thromboembolic event. In
the FAMOUS (Fragmin Advanced Malignancy Outcome Study)
trial,307this benefit in survival was found only in a subgroup of
patients with a better prognosis but not in patients with advanced
cancer. All studies seem to indicate that there is a good safety
profile for the administration of LMWH to cancer patients, result-
ing in the suggestion that these agents seem to be safer than VKAs
in this context. For patients with PE and cancer, LMWH should be
considered for the first 3–6 months. After this period, anticoagu-
lant therapy with VKAs or LMWH should be continued indefi-
nitely, or until the cancer is considered cured.
In summary, 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
In patients with PE, it is not uncommon to see right heart thrombi
at echocardiography. Patients with right heart thrombi have lower
systemic blood pressure, higher prevalence of hypotension, higher
heart rate, and more frequently RV hypokinesis at echocardio-
graphy in comparison with other patients with PE.157,159This
unfavourable association explains the relatively high prevalence
of right heart thrombi (7–18%) in PE patients admitted to inten-
sive care units.156,305,356The prevalence of right heart thrombi in
unselected patients with PE is below 4% and probably would
not warrant routine echocardiography screening in clinically
In patients with PE, the presence of right heart thrombi,
especially those that are mobile, probably in transit from the
peripheral veins to the lungs, is associated with increased early
mortality.159,304,305,357Whether right heart thrombi are an inde-
pendent risk factor for mortality is unclear. However, the available
data indicate that the presence of mobile right heart thrombi
should be considered as a potentially life-threatening condition
associated with a high risk of recurrent PE. In patients with
mobile right heart thrombi, the death rate has been reported to
be as high as 80–100% when left untreated.304,358In these patients,
the treatment of choice is controversial. In the ICOPER registry,
thrombolytic treatment was the preferred option but the 14-day
mortality was above 20%.159In contrast, excellent results of such
treatment were reported in a recent series of 16 patients, in
which 50, 75 and 100% of clots disappeared from the right heart
within first 2, 12 and 24 h after administration of thrombolysis,
respectively.157All patients survived 30 days even though the
disappearance of thrombi seemed to have resulted from their
embolization to pulmonary circulation rather than to in situ lysis.
However, publication bias should also be considered, and
current evidence does not allow us assess survival rates with
thrombolytic treatment compared with surgery in individual
Heparin used alone seems to be insufficient even in patients
whose clinical condition otherwise would appear benign.159,304,357
Surgical or catheter embolectomy remain as alternatives, but data
are scarce. Surgical embolectomy seems a treatment of choice in
cases of right heart thrombi straddling the interatrial septum
through the foramen ovale,359though good outcomes with
medical treatment have also been reported.359,360
Whichever therapy is selected, it should be implemented
without delay: in the presence of unequivocal echocardiographic
visualization of a mobile right heart thrombus no further diagnostic
tests are needed.
In summary, 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. Immedi-
ate 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.
This is a potentially serious complication of heparin therapy. The
immune-mediated type of HIT is referred to as type II to distinguish
it from other non-immune-mediated and more benign forms. It is
caused by immunoglobulin G directed against the platelet factor
4–heparin complex.361,362HIT type II usually occurs between 5
and 14 days after exposure to heparin, or earlier in cases of
re-exposure. Paradoxically, despite a moderate to severe fall in
the platelet count, patients with HIT are at high risk of venous
and arterial thromboembolic events.
Several factors may influence the frequency of HIT: heparin type
(unfractionated heparin . LMWH . fondaparinux); patient type
(surgical . medical); and sex (female . male). The incidence of
HIT ranges from 1 to 3% in patients exposed to unfractionated
heparin and is about 1% in patients receiving LMWH. However,
a recent meta-analysis did not confirm a lower prevalence of
HIT among patients with VTE treated with LMWH compared
with unfractionated heparin.363HIT type II occurs in about 2% of
patients undergoing heart or thoracic surgery requiring cardio-
HIT type II should be suspected in all patients with a
previous normal platelet count who present a fall to less than
100 000/mm3or to less than 50% of the basal value. The diagnosis
of HIT type II should always be confirmed by excluding
other causes of thrombocytopenia and by performing specific
If there is a clinical suspicion of HIT type II, heparin should be
discontinued and the patient should be switched to an alternative
agent, if anticoagulation is still required, until the platelet count
returns above 100 000/mm3. Direct thrombin inhibitors, such as
lepirudin and argatroban, are effective agents in treating compli-
cations of HIT.365Isolated oral anticoagulation is contraindicated
in the acute phase of this disorder but can be considered as a
long-term treatment of the thromboembolic events.
No formally proven case of HIT has been reported with fonda-
parinux,366which has been anecdotally reported as being used in
the management of HIT type II.
In summary, HIT is a life-threatening immunological compli-
cation 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
CTEPH is a relatively rare complication of PE.367In patients with
CTEPH, the original embolic material is replaced over a period
of months to years with fibrous tissue that is incorporated into
the intima and media of the pulmonary arteries. This material
may extend to the segmental and subsegmental branches of the
pulmonary arteries. Partial recanalization or total occlusion of
the involved pulmonary artery vasculature may occur.
The chronic obstruction of the pulmonary vascular bed is
followed by progressive elevation of pulmonary artery resistance,
ultimately leading to right heart failure.274The initial phase of the
disease is often asymptomatic, but is followed by progressive dys-
pnoea and hypoxaemia. In the late phase of the disease, patients
may have all the signs of advanced right heart failure. CTEPH
should be suspected in every patient with pulmonary hyper-
tension.368The diagnostic strategy is based on echocardiography,
perfusion scintigraphy, CT, right heart catheterization and pulmon-
ary angiography.369Medical therapy aims to treat right heart
failure and to lower pulmonary artery resistance. Preliminary data
suggest some haemodynamic and/or functional improvement with
phosphodiesterase-5 inhibitors. However, the efficacy of any
medical therapy is limited by the morphological substrate of pul-
monary artery obstruction. Therefore, potential future candidates
for chronic medical treatment in CTEPH include non-operable
patients and patients in whom surgical intervention has failed to
restore near-normal haemodynamics.
Pulmonary thromboendarterectomy (endarterectomy) was first
introduced in 1957 and has since then evolved to become a rela-
tively common treatment for CTEPH. Selection criteria for
pulmonary thromboendarterectomy have been defined by the
guidelines of the American College of Chest Physicians370and
include: (i) New York Heart Association (NYHA) functional class
III or IV symptoms; (ii) preoperative pulmonary vascular resistance
greater than 300 dyn s cm25; (iii) surgically accessible thrombi in
the main, lobar or segmental pulmonary arteries; and (iv)
absence of severe comorbidity.
Surgical removal of the obstructing material requires a true
endarterectomy as opposed to a simple embolectomy.371For
this reason the operation is performed on cardiopulmonary
bypass, with deep hypothermia and complete circulatory arrest
in order to provide adequate visibility. The main pulmonary
arteries are incised and the right endarterectomy level within the
wall is defined. Thereafter, the plane is followed circumferentially
down to the segmental and sometimes subsegmental branches of
each lobar artery, a procedure which is performed with the help
of special suction dissectors.372
As there is currently no preoperative classification system for
CTEPH, patients with CTEPH can be postoperatively classified
into four categories according to the location and type of the
lesions found during operation.373Type 1 is characterized by a
fresh thrombus in the main lobar pulmonary arteries; type 2 by
thickening and fibrosis of the intima proximally to the segmental
arteries; type 3 by the involvement of distal segmental arteries
only; and type 4 by distal arteriolar involvement without visible
Perioperative mortality is related to the severity of the disease,
with a mortality rate of 4% in patients with a preoperative pulmon-
ary vascular resistance less than 900 dyn s cm25and 20% in those
with pulmonary vascular resistance above 1200 dyn s cm25. The
functional results of a successful pulmonary thromboendarterect-
omy are excellent and generally sustained over time,374,375with
a 3-year survival rate of about 80%.376Although recent data
have demonstrated a 2-year cumulative incidence of 3.8% for
CTEPH after a symptomatic PE,377no recommendations can be
made yet regarding screening for CTEPH in PE survivors.
In summary, CTEPH is a severe though rare consequence of
PE. Pulmonary endarterectomy provides excellent results and
should be considered as a 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
Non-thrombotic pulmonary embolism
Septic embolism to the pulmonary circulation is a relatively rare
clinical event. Septic pulmonary emboli are most commonly asso-
ciated with tricuspid valve endocarditis, mainly occurring in drug
addicts378but also in patients with infected indwelling catheters
and pacemaker wires,379and in patients with peripheral septic
thrombophlebitis or organ transplants.380
present with fever, cough and haemoptysis. Antibiotic treatment
is generally successful; however, occasionally the source of
emboli must be removed surgically.381
Intravascular foreign bodies
Several types of intravascular foreign bodies can embolize to the
pulmonary arteries. They include broken catheters, guidewires
and vena cava filters382–384and, more recently, coils for emboli-
zation and endovascular stent components. Most intravascular
foreign bodies are found in the pulmonary arteries, and the remain-
der in the right heart or the vena cava.385Intravascular retrieval
using snares is frequently successful.386,387
The fat embolism syndrome is a combination of respiratory,
haematological, neurological and cutaneous symptoms and signs
associated with trauma and several other surgical and medical con-
ditions. The incidence of the clinical syndrome is low (,1%), while
the embolization of marrow fat appears to be an almost inevitable
consequence of long bone fractures.388The presentation may be
fulminating with pulmonary and systemic embolization of fat,
right ventricular failure and cardiovascular collapse.389More
usually, the onset is gradual, with hypoxaemia, neurological symp-
toms, fever and a petechial rash, typically 12–36 h after injury.390
Fat embolism is reported in many other conditions,388such as lipo-
suction,391lipid and propofol infusions,392and in patients with
hepatic necrosis and fatty liver.393
The pathogenesis of fat embolism syndrome is not completely
understood.394Treatment is non-specific and supportive.388
Venous air embolism
Vascular air embolism is the entrainment of air (or exogenously
delivered gas) from the operative field or other communication
with the environment into the venous or arterial vasculature,
producing systemic effects.395The morbidity and mortality rates
of vascular air embolism are directly related to the volume of air
entrainment and rate of accumulation. From case reports of acci-
dental intravascular delivery of air, the adult lethal volume has
been described as between 200 and 300 ml, or 3–5 ml/kg396
injected at a rate of 100 ml/s.397
The major effect of venous air embolism is the obstruction of
the right ventricular pulmonary outflow tract or obstruction of
the pulmonary arterioles by a mixture of air bubbles and fibrin
clots formed in the heart. The result in either situation is cardio-
vascular dysfunction and failure. Principal goals of management
include prevention of further air entry, a reduction in the volume
of air entrained, if possible, and haemodynamic support.395
Patients with suspected venous air embolism should be placed in
the left lateral decubitus head-down position. Occasionally, intra-
operative needle aspiration is performed to relieve large air
There have been numerous case reports and case series
illustrating the potential benefits of hyperbaric oxygen therapy,
especially in the presence of cerebral arterial gas embolism.395
Amniotic fluid embolism
Amniotic fluid embolism is a rare but catastrophic complication
unique to pregnancy. Amniotic emboli occur in 1/8000–1/80 000
pregnancies; however, the emboli result in high maternal and
fetal mortality rates (80 and 40%, respectively). It is a complex
phenomenon, ranging from mild degree of organ dysfunction to
coagulopathy, cardiovascular collapse and death.
This condition occurs when amniotic fluid is forced into the
bloodstream through small tears in the uterine veins during
normal labour. Dyspnoea, cyanosis and shock that are abrupt in
onset classically progress rapidly to cardiopulmonary collapse
and severe pulmonary oedema. The pathophysiology of amniotic
fluid embolism is multifactorial and poorly understood. The diag-
nosis is one of exclusion and management is supportive.398
Many substances, such as magnesium trisilicate (talc), starch and
cellulose, are used as fillers in drug manufacturing. Some of
these drugs (prepared as oral medications), such as amphetamines,
methylphenidate, hydromorphone and dextropropoxyphene, are
ground by drug users, mixed in liquid, and injected intravenously.
These filler particles are mainly entrapped within the pulmonary
vasculature and can cause thrombosis and the formation of
Pulmonary intravascular tumour emboli are seen in up to 26% of
autopsies but are much less frequently identified before death.399
Pulmonary tumour embolism radiologically mimics pneumonia,
tuberculosis or interstitial lung disease. Intracardiac source of pul-
monary tumour emboli may be diagnosed by imaging methods. In a
review of microscopic pulmonary tumour emboli associated with
dyspnoea, Kane et al. found that carcinomas of the prostate
gland and breast were the most common causes, followed by
hepatoma, then carcinomas of the stomach and pancreas.400Treat-
ment for this entity has not been studied extensively, since the
diagnosis is usually not made until the post mortem. However
there are reports of limited success with chemotherapy.
There are several reports describing rare causes of non-
thrombotic PE: cotton embolism, hydatid embolism, iodinated oil
embolism, metallic mercury embolism and cement (polymethyl-
methacrylate) embolism may account for more or less severe PE
with great variability of symptoms.
In summary, 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 embo-
lism, 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.
Supplementary material is available at European Heart Journal online
and on the page dedicated to these guidelines on the ESC Web
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are available at the web sites of the European Heart Journal (http://cme.oxfordjournals.org/cgi/hierarchy/oupcme_node;ehj) and the European Society of Cardiology (http://www.
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