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REVIEW
Clinical update
Pulmonary embolism: risk assessment
and management
Stavros Konstantinides1,2* and Samuel Z. Goldhaber3
1Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Building 403, Langenbeckstrasse 1, 55131 Mainz, Germany; 2Department of Cardiology,
University General Hospital, Democritus University of Thrace, Alexandroupolis, Greece; and 3Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA, USA
Received 20 May 2012; revised 24 July 2012; accepted 27 July 2012
Acute pulmonary embolism (PE) poses a significant burden on health and survival. Its severity ranges from asymptomatic, incidentally dis-
covered subsegmental thrombi to massive, pressor-dependent PE complicated by cardiogenic shock and multisystem organ failure. Rapid
and accurate risk stratification is therefore of paramount importance to ensure the highest quality of care. This article critically reviews cur-
rently available and emerging tools for risk-stratifying acute PE, and particularly for distinguishing between elevated (intermediate) and low
risk among normotensive patients. We focus on the potential value of risk assessment strategies for optimizing severity-adjusted manage-
ment. Apart from reviewing the current evidence on advanced early therapy of acute PE (thrombolysis, surgery, catheter interventions, vena
cava filters), we discuss recent advances in oral anticoagulation with vitamin K antagonists, and with new direct inhibitors of factor Xa and throm-
bin, which may contribute to profound changes in the treatment and secondary prophylaxis of venous thrombo-embolism in the near future.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Pulmonary embolism † Prognosis † Risk assessment † Imaging † Biomarkers † Prediction rules †
Anticoagulants † Thrombolysis † Embolectomy † Intervention
Clinical cases in pulmonaryembolism
Case 1A 75-year-old man who underwent left nephrectomy for renal cell
carcinoma 6 months ago is admitted to the emergency department
with acute severe dyspnoea and cyanosis. His blood pressure is
100 over 60 mmHg; his heart rate, 120 b.p.m. Arterial oxygen sat-
uration is 75% while breathing room air and fails to rise under supple-
mental oxygen. The patient undergoes endotracheal intubation and is
mechanically ventilated with 100% oxygen, which results in further
drop of the arterial saturation to 65% despite correct positioning of
the tube. Chest X-ray shows clear lungs without infiltrates. Transthor-
acic echocardiography reveals a large right ventricle with a hypoki-
netic free wall. What are the next diagnostic and therapeutic steps?
Case 2A 50-year-old woman is re-admitted to the hospital with
mild-to-moderate dyspnoea 10 days after surgical cholecystectomy.
Physical examination reveals a swollen right calf and no further
pathological findings. Acute pulmonary embolism (PE) and deep vein
thrombosis are confirmed by computed tomography (CT) and ultra-
sonography, respectively. The patient strongly desires to be discharged
immediately and receive treatment at home. Is this acceptable?
Case 3A 60-year-old woman presents for clinical follow-up 6 months after
acute PE. The event was unprovoked, i.e. no reversible predisposing
factors were found, but thrombophilia screening revealed heterozy-
gous factor V Leiden mutation; the patient is obese (body mass
index, 34 kg/m2). She had an uneventful in-hospital course and
was treated with vitamin K antagonists over the past 6 months
without recurrence; there were a few minor bleeding episodes
under warfarin. Can anticoagulation be safely discontinued now,
or is the patient a candidate for indefinite secondary prophylaxis?
Is regular echocardiographic follow-up necessary for early detection
of chronic thrombo-embolic pulmonary hypertension (CTEPH)?
Introduction
Pulmonary embolism spans a broad spectrum of illness, ranging
from asymptomatic, incidentally discovered subsegmental
*Corresponding author. Tel: +49 6131 176255, Fax: +49 6131 173456, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected]
European Heart Journal
doi:10.1093/eurheartj/ehs258
European Heart Journal Advance Access published September 13, 2012
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thrombus detected on chest CT scan1 to pressor-dependent PE
complicated by cardiogenic shock and multisystem organ
failure.2,3 Between these two extremes are patients with symptom-
atic low-risk or intermediate-risk disease.4,5
As clinicians specializing in cardiovascular medicine, we are likely
to be consulted on patients at the sicker end of the risk continuum.
Our toolbox of options is rapidly expanding. For the patient
without haemodynamic compromise, we can offer conventional
unfractionated heparin, low-molecular-weight heparin (LMWH),
or fondaparinux as a ‘bridge’ to vitamin K antagonists. More re-
cently, oral monotherapy anticoagulation (without any injectable
or intravenous anticoagulant) was reported to be safe and effect-
ive.6 On the other hand, some normotensive and most unstable
patients will require specific advanced therapy, in addition to par-
enteral anticoagulation. Options for advanced therapy include
placement of an inferior vena cava filter, systemic thrombolysis,
open surgical embolectomy, or pharmacomechanical therapy.5,7
This article critically reviews currently available and emerging
tools for risk-stratifying acute PE as well as severity-adjusted man-
agement strategies. We also discuss the recent advances in oral
anticoagulation with vitamin K antagonists, and with new direct
inhibitors of factor Xa and thrombin which are being introduced
into the market and may contribute to profound changes in the
treatment strategy for acute venous thrombo-embolism in the
near future.
Risk assessment in pulmonaryembolism
Initial risk stratificationThe key to an effective treatment of PE in the acute phase lies in
the assessment of the patient’s early death risk. A crucial determin-
ant is the presence and severity of right ventricular (RV) dysfunc-
tion resulting from acute pressure overload.8,9 The definition of
high-risk (European classsification5) or massive (North American
classification7) PE is usually straightforward and relies on the pres-
ence of clinically overt RV failure which results in haemodynamic
compromise. This condition, which is encountered in ,5% of all
patients presenting with acute PE,10,11 constitutes a medical emer-
gency, since it is associated with at least a 15% risk of in-hospital
death, particularly during the first hours after admission.12–14
Advanced risk stratification: clinicalscoresThe absence of haemodynamic collapse or persistent hypotension
at presentation is generally thought to predict a favourable early
outcome, provided that the disease is diagnosed correctly and
anticoagulation is started without delay.3,12,15 However, some of
the (initially) normotensive patients with acute PE may have an ele-
vated risk of death or major complications (intermediate-risk PE in
Europe; submassive PE in North America) which warrants further
risk stratification and possibly specific advanced therapy.
Prediction rules based on clinical findings at diagnosis can help
with the prognostic assessment of patients with acute PE.16,17
These scores account both for the clinical severity of the acute
event and the patient’s comorbidity. The Pulmonary Embolism Se-
verity Index (PESI) is the most extensively validated prognostic
clinical score to date.17–20 Its major strength lies in excluding
(ruling out) an adverse outcome as indicated by the high negative
predictive value (NPV) of the lowest PESI classes I and II.21,22 In
fact, a recently published randomized trial successfully employed
a low PESI score as the main inclusion criterion for home treat-
ment of acute PE.23 The main limitation of the index is that it
requires numerous variables and is relatively complex to calculate,
which may reduce its practicability in high-volume centres. Reliable
prognostic information can also be obtained with a simplified
version of the score (sPESI) which focuses on six equally weighted
variables: age .80 years; history of cancer; history of heart failure
or chronic lung disease; systolic blood pressure ,100 mmHg;
pulse rate .110 b.p.m.; and arterial oxyhaemoglobin saturation
,90%.24 In an external validation study, the sPESI was at least as
accurate as imaging and biomarker criteria for excluding an ele-
vated risk.25 The implications of this latter score for patient man-
agement remain to be shown.26
Advanced risk stratification: imagingfindingsImaging of the right ventricle with echocardiography detects the
changes occurring in the morphology and function of the right ven-
tricle as a result of acute pressure overload in PE.9,27 Registries and
cohort studies demonstrate an association between echocardio-
graphic parameters of RV dysfunction and a poor in-hospital
outcome.3,15,28,29 Nevertheless, the prognostic value of cardiac
ultrasound in haemodynamically stable patients appears moderate
at best,30 mostly due to the poor standardization of echocardio-
graphic criteria.30,31 In a prospective randomized trial, normoten-
sive patients with intermediate-risk PE (mostly) defined by
echocardiography appeared to have a low early mortality risk, re-
gardless of whether they received thrombolysis plus heparin or
heparin alone.32 It thus appears that an abnormal echocardiogram
needs to be accompanied by clinical signs indicating severe PE, or
by a positive biomarker test indicating the presence of heart failure
or myocardial injury (as explained below), to justify advanced
therapy in normotensive patients with acute PE.
Four-chamber views of the heart on multidetector-row CT may,
besides visualizing the thrombi in the pulmonary vasculature
(Figure 1A and B), also detect RV enlargement and (indirectly) dys-
function (Figure 1C).30 The prognostic value of an enlarged right
ventricle on CT was recently confirmed by an international pro-
spective cohort study,33 but data from therapeutic trials are
needed before it can be safely concluded that this modality can
replace the echocardiogram in guiding risk-adjusted management
of acute PE.
Advanced risk stratification: laboratorymarkersCirculating biochemical markers have been proposed as an alterna-
tive (or additional) tool for risk stratification of normotensive
patients with PE. Among these, circulating natriuretic peptides are
highly sensitive indicators of neurohormonal activation due to
acute and chronic heart failure. A meta-analysis of 13 studies found
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that 51% of 1132 patients with acute PE had elevated brain natriuret-
ic peptide (BNP) orN-terminal (NT)-proBNP concentrations; these
were associated with an increased risk of early death and a compli-
cated in-hospital course.34 Nevertheless, their positive predictive
value for an elevated risk has been consistently low.35
Elevated cardiac troponin I or T levels are also found in up to
50% of the patients with acute PE.36 A meta-analysis of studies
published between 1998 and 2007, with a total of 1985 patients,
showed that cardiac troponin elevation was associated with an
increased risk of death and major adverse events in the acute
phase.37 However, another meta-analysis which excluded hypoten-
sive patients did not confirm the prognostic value of circulating
troponin levels.38 Recently developed high-sensitivity assays may
improve the prognostic performance of this biomarker, at least
at the low-risk end of the severity spectrum. More specifically, a
derivation study showed that high-sensitivity troponin T (hsTnT)
was useful for excluding an adverse outcome in the acute phase
of PE.39 In a multicentre, multinational cohort of 526 normotensive
patients with acute PE, hsTnT exhibited a high NPV (98%) which
was comparable with that of the sPESI (99%).40
Heart-type fatty acid-binding protein (H-FABP) is a small cyto-
plasmic protein which diffuses rapidly into the circulation following
myocardial cell damage.41 It may provide relevant prognostic
information in non-high-risk PE.42 Cardiac expression of growth-
differentiation factor-15 (GDF-15), a distant member of the
transforming growth factor-b cytokine family, also increases
sharply after pressure overload or myocardial ischaemia.43,44
Growth-differentiation factor-15 might be capable of integrating in-
formation on RV dysfunction, myocardial injury, and possibly co-
morbidity in patients with acute PE.45 Both biomarkers appear
promising and deserve further evaluation in external patient cohorts.
Emerging concepts: combinedparameters and scoresA critical overview of currently available and emerging prognostic
tools for patients with acute PE is shown in Table 1. For the time
being, no individual laboratory marker or imaging parameter has
been shown to justify advanced therapy in haemodynamically
stable patients with PE. Therefore, attention is shifting to prognos-
tic models combining clinical, imaging, and biochemical parameters.
Some registries and cohort studies did suggest that biomarkers
may possess prognostic value additive to that of clinical parameters
and echocardiography,45–49 and various combinations of the three
modalities were reported to possess satisfactory predictive per-
formance.50,51 An external validation of these scores has not yet
been undertaken. At present, one large randomized trial is
testing the possible implications of a combination prognostic
model for the management of intermediate-risk or submassive
PE. The Pulmonary Embolism Thrombolysis Study (PEITHO) is
randomizing 1000 normotensive patients with acute PE, an echo-
cardiogram (or CT scan) indicating RV dysfunction, and a positive
cardiac troponin test, to receive thrombolysis with tenecteplase as
opposed to heparin alone.52 Recruitment is completed, and the
results will be available in 2013.
Initial treatment of pulmonaryembolism
Heparin anticoagulationAnticoagulant treatment should be administered to all patients
with high or intermediate clinical probability of acute PE, without
awaiting definitive confirmation by imaging procedures.5,53 Intra-
venous unfractionated heparin is the preferred mode of initial
anticoagulation for patients with severe renal impairment (creatin-
ine clearance ,20–30 mL/min); for those at high risk of bleeding;
for high-risk, hypotensive patients; and, as a rule, for extremely
overweight, underweight, or old patients. With the exception of
these circumstances, LMWH or fondaparinux is given subcutane-
ously at weight-adjusted doses53 (Figure 2); routine anticoagulation
monitoring, i.e. measurement of anti-factor Xa levels, is not neces-
sary. Though controversial, obtaining these levels may be
Figure 1 The extent of thrombotic load on computed tomography does not always correlate with the clinical severity of acute pulmonary
embolism or its impact on right ventricular function. (A) A straightforward case in which massive thrombi are present in both the right and the
left pulmonary artery of a patient presenting with haemodynamic instability (persistent tachycardia, systolic blood pressure between 90 and
100 mmHg). (B) However, a patient presenting with similar clinical findings had an apparently much smaller thrombotic load on computed tom-
ography; in this latter patient, the size of thrombi was also in discordance with the impressive enlargement (as a surrogate for dysfunction) of
the right ventricle (C).
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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 1 Risk assessment tools in acute pulmonary embolism
Strengths Weaknesses
Clinical prediction rules
PESI Assessment of clinical severity, comorbidity Prognostic value for intermediate-risk PE unknown
Geneva risk score PESI strong for defining low-risk PE, successfully
employed in a randomized trial
Clinical scores do not account for RV function, a key
prognostic determinant in the early phase
Imaging tests
Echocardiography Real-time, bedside assessment of RV size and function,
PA systolic pressure
Moderate positive and NPV
Poorly standardized parameters and criteria
Ultrasound failed to identify candidates for thrombolysis
in a randomized trial
CT Diagnosis of PE and assessment of RV size in one test Implications of an enlarged RV on CT for the
management of intermediate-risk PE unclearFindings correlated with PE prognosis
Laboratory markers
Cardiac troponin I, T Troponin elevation correlated with PE prognosis Non-specific test, positive predictive value low
(positive test does not justify advanced therapy)Sensitive test, high NPV
Widely used test
Natriuretic peptides
(BNP, NT-proBNP)
BNP/NT-proBNP elevation correlated with PE prognosis Non-specific test, positive predictive value very low
(positive test does not justify advanced therapy)
High NPV Appropriate cut-off value(s) unclear
Widely used test
H-FABP Early marker of adverse outcome Not available for routine use at present
GDF-15 ‘Global’ marker of myocardial injury, heart failure,
comorbidity
Not available for routine use at present
PESI, Pulmonary Embolism Severity Index; CT, computed tomography; PE, pulmonary embolism; BNP, brain natriuretic peptide; GDF-15, growth differentiation factor-15;
H-FABP, heart-type fatty acid-binding protein; NT-proBNP, N-terminal pro-brain natriuretic peptide; PA, pulmonary artery; RV, right ventricular; NPV, negative predictive value.
Figure 2 Current and evolving anticoagulation regimens for acute pulmonary embolism. b.i.d., twice daily; Fonda, fondaparinux; LMWH,
low-molecular-weight heparin; o.d., once daily; s.c., subcutaneously; VKA, vitamin K antagonist. *Unfractionated heparin (continuous intraven-
ous infusion) can be given as an alternative to LMWH; †see text and reference 90 for details of dosing regimen; ‡see text and references 6 and
85 for details of dosing regimen.
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considered in patients with (moderate) impairment of renal func-
tion, and intermittently during pregnancy. In these cases, anti-Xa
levels should be determined 4 h after the morning injection; the
proposed target range is 0.6–1.0 IU/mL for twice-daily and 1.0–
2.0 IU/mL once-daily administration. The anti-Xa assay must be
calibrated separately by the laboratory for each anticoagulant
that is assayed.
Anticoagulation with unfractionated heparin or LMWH/fonda-
parinux should be continued for at least 5 days. Oral anticoagulants
(vitamin K antagonists) should be initiated as soon as possible in
haemodynamically stable patients, preferably on the same day as
heparin (Figure 2). Parenteral anticoagulation can be stopped as
soon as the international normalized ratio (INR) has been in the
therapeutic range (between 2.0 and 3.0) on 2 consecutive days.
ThrombolysisRandomized trials have consistently shown that thrombolytic
therapy of PE effectively resolves thrombo-embolic obstruction
and promptly reduces pulmonary artery pressure and resistance
with a concomitant increase in cardiac output.54 One trial also
demonstrated a significant improvement in RV function as assessed
by echocardiography.29 In the only randomized thrombolysis trial
with clinical endpoints, early thrombolytic treatment given to
normotensive patients with evidence of RV dysfunction significantly
reduced the need for emergency escalation of therapy during the
hospital stay.32
Currently approved thrombolytic regimens for PE, and the con-
traindications to thrombolysis, are shown in Table 2. Overall,
.90% of patients with PE appear to respond favourably to
thrombolysis as indicated by clinical and echocardiographic im-
provement within the first 36 h.55 The greatest benefit is observed
when treatment is initiated within 48 h of symptom onset, but
thrombolysis can still be useful in patients who have had symptoms
for 6–14 days.56
Two recent epidemiological reports, derived from the Nation-
wide Inpatient Sample (representing ≏20% of non-federal, short-
term hospitals in the USA) and including more than 2 000 000
patients discharged between 1998 and 2008 with the diagnosis
of PE, support the efficacy and safety of thrombolysis in haemo-
dynamically unstable patients with acute PE. In the first report,10
case fatality rates attributable to PE were drastically lower
among unstable patients who received (compared with those
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 2 Thrombolysis for pulmonary embolism
Agents and regimens Contraindications
Streptokinasea Absolute
History of haemorrhagic stroke or stroke of unknown origin
Ischaemic stroke in previous 6 months
Central nervous system neoplasms
Major trauma, surgery, or head injury in previous 3 weeks
Relative
Transient ischaemic attack in previous 6 months
Oral anticoagulation
Pregnancy or first postpartum week
Non-compressible puncture sites
Traumatic resuscitation
Refractory hypertension (systolic blood pressure .180 mmHg)
Advanced liver disease
Infective endocarditis
Active peptic ulcer
250 000 U as a loading dose over 30 min, followed by
100 000 U/h over 12–24 h
Accelerated regimen: 1.5 million IU over 2 hb
Urokinasea,c
4400 U per kg of body weight as a loading dose over
10 min, followed by 4400 U/kg/h over 12–24 h
Accelerated regimen: 3 million U over 2 hb
Alteplasea
100 mg over 2 hd
Accelerated regimen: 0.6 mg/kg for 15 min
Reteplasea,e
Two bolus injections of 10 U 30 min apart
Tenecteplasef
30–50 mg bolus for 5–10 s adjusted for body weight
,60 kg 30 mg
≥60 to ,70 kg 35 mg
≥70 to ,80 kg 40 mg
≥80 to ,90 kg 45 mg
≥90 kg 50 mg
Adapted and modified from references 5 and 111.aUnfractionated heparin should not be infused together with streptokinase or urokinase; it can be given during alteplase or reteplase administration. Low-molecular-weight
heparins have not been tested in combination with thrombolysis in patients with pulmonary embolism.bShort (2 h) infusion periods are generally recommended.53
cUrokinase is not available in the USA.dFDA-approved regimen.eOff-label use of reteplase.fOff-label use of tenecteplase; this is the regimen recommended for acute myocardial infarction. A randomized pilot trial112 found it to be safe and effective in non-high-risk
pulmonary embolism.
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who did not receive) thrombolytic treatment [relative risk, 0.20;
95% confidence interval (CI), 0.19–0.22]. Unfortunately, only
21 390 out of 72 230 unstable (30%) patients received
thrombolytic agents as recommended. In the second report,57
the overall prevalence of intracerebral haemorrhage after
thrombolytic therapy was low (0.9%), although it did appear to
increase in the elderly and in patients with kidney disease.
Surgical or interventional treatmentPulmonary embolectomy is a recommended therapeutic option in
patients with high-risk PE in whom there are absolute contraindi-
cations to thrombolysis, or if thrombolysis has failed.5,53 Recent
technical advances in transportable extracorporeal assist systems,
and particularly the timely early involvement of the cardiac
surgeon as part of an interdisciplinary approach to high-risk PE
before haemodynamic collapse, have contributed to improved
postoperative outcomes and case fatality rates as low as 23%.58
As an alternative to surgical procedures, catheter-based reperfu-
sion is an option for patients with high-risk PE, and possibly also for
selected patients with intermediate-risk PE. In case of absolute
contraindications to thrombolysis, thrombus fragmentation, rheo-
lytic thrombectomy, suction thrombectomy, or rotational thromb-
ectomy have been performed. If no absolute contraindications are
present, conventional catheter-directed thrombolysis and, more
recently, pharmacomechanical thrombolysis have become
available. The methods and techniques of catheter-based interven-
tions were reviewed recently.59 Although the evidence is thus far
mostly based on uncontrolled data and single-centre experience,
a review of 29 retrospective and 6 prospective series yielded
promising success rates.60 Two multicentre clinical trials, a
randomized study in Europe and a single-arm study in the
USA (NCT01166997 and NCT01513759, respectively), are
currently underway to determine the efficacy and safety of
ultrasound-enhanced low-dose catheter-delivered thrombolysis in
intermediate-risk PE.
Inferior vena cava filtersCaval filters may be used as a means of primary or secondary PE
prevention. However, the data on their safety and efficacy
remain inconclusive. Moreover, therapeutic anticoagulation is gen-
erally very effective in preventing recurrent thrombo-embolism.61
In a meta-analysis, fatal PE occurred in 0.3–1.3% of patients
during the first 3 months of treatment with heparin or warfarin.62
On the other hand, recent epidemiological data suggest that the
combination of thrombolytic therapy with the placement of a
vena cava filter may be particularly effective in lowering case fatality
rates in unstable patients.10,63 At present, retrievable inferior vena
cava filters have a place mostly when anticoagulation is absolutely
contraindicated, or in cases of recurrence despite therapeutic
dosing of anticoagulants.53 Their widespread use in clinical practice,
as recently recorded in the USA,64 may not be justified.
Risk-adjusted management strategyIn view of the high early mortality and complication risk associated
with high-risk PE, patients who present with persistent arterial
hypotension or shock are in need of immediate pharmaco-
logical or mechanical recanalization of the occluded pulmonary
arteries.5,7,53 Patients with suspected high-risk PE should immedi-
ately receive a weight-adjusted bolus of unfractionated heparin; if
PE is confirmed, thrombolysis should be administered without
delay. If thrombolysis is contraindicated or has failed, surgical em-
bolectomy or catheter-based reperfusion treatment are valuable
alternatives.
Low-molecular-weight heparin or fondaparinux is considered ad-
equate initial treatment for most normotensive patients. Thrombo-
lysis may be considered in selected cases,5 such as in patients with
evidence of RV dysfunction or myocardial injury, particularly if
they also present with acute respiratory failure and/or are at high
risk of death (due, for example, to diminished cardiopulmonary
reserves and severe comorbidity), provided they have no contraindi-
cations to thrombolytic agents. A recently presented small pilot
study in patients with ‘moderate’ PE suggested that a lower dose
of a thrombolytic (half the standard dose of alteplase) might
reduce the rate of PE recurrence and persistent pulmonary hyper-
tension without causing excess bleeding (ACC 2012 Late-Breaking
Trials; session 308). These results may be hypothesis-generating,
but do not justify a change in our practice regarding the management
of the intermediate-risk group or the dosing of alteplase.
A large multinational randomized trial has set out to determine
whether normotensive patients with RV dysfunction, detected by
echocardiography or CT, plus evidence of myocardial injury indi-
cated by a positive troponin test, may benefit from early thrombo-
lytic treatment.52 The primary efficacy endpoint is a clinical
composite endpoint of all-cause mortality or haemodynamic col-
lapse within the first 7 days. Six-month and 2-year follow-up is
also being conducted.
Normotensive patients without serious comorbidity or signs of
(right) heart failure belong to a low-risk group which could be
treated out of hospital.65–67 Recently, a randomized study
reported that low-risk patients as defined by the PE severity
index can safely be discharged within 24 h and treated as outpati-
ents.23 Early discharge of patients with low-risk PE is mentioned as
an option in updated guidelines,53 but the appropriate criteria for
identifying the patients to benefit from such treatment remain to
be defined.
Established and new oralanticoagulants in treatment andsecondary prophylaxis
Vitamin K antagonistsWorldwide, vitamin K antagonists such as warfarin, acenocou-
marol, or phenprocoumon remain the predominant anticoagulant
prescribed for PE. In 2010, for example, more than 25 million pre-
scriptions were written for warfarin in the USA.68 Nevertheless,
this is a difficult medication to utilize properly, being responsible
for one-third of emergency hospitalizations due to adverse drug
events in patients 65 years of age or older.69 Not surprisingly, in
view of its actual and perceived bleeding risks, warfarin continues
to be largely underused in clinical practice.70
Although warfarin is an ‘old drug’, several developments have
improved its profile and the quality of anticoagulation. Centralized
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anticoagulation services appear to reduce the risks of warfarin
compared with usual care.71 Certain ‘tricks of the trade’ have
emerged. If the INR is out of range, it is preferable to make
small and subtle changes in warfarin dosing rather than large
dosing adjustments. And, counterintuitively, vitamin K supplemen-
tation can improve the stability of anticoagulation for patients with
unexplained variability in response to warfarin.72 Some patients
may have stable INRs from month to month, and thus their INR
testing can be reduced in frequency to once every 12 weeks.73
Trials of self-testing INR at home with ‘point of care’ devices
have generally been favourable, but the results are not conclusive.
A recent meta-analysis of 11 trials with 6417 participants and
12 800 person-years of follow-up demonstrated a halving of
thrombo-embolic events in the self-monitoring group, but no dif-
ference in major bleeding.74
Rapid turnaround pharmacogenetic testing may increase the
precision of warfarin dosing.75,76 In particular, variations in two
genes may account for more than one-third of the dosing variabil-
ity of warfarin. One gene determines the activity of cytochrome
CYP2C9, the hepatic isoenzyme that metabolizes the S-enantiomer
of warfarin into its inactive form, whereas the other determines the
activity of vitamin K epoxide reductase (VKORC1), the enzyme that
produces the active form of vitamin K.77 Pharmacogenetic algo-
rithms, such as the one available at www.warfarindosing.org, incorp-
orate genotype and clinical information and recommend warfarin
doses according to the integration of these data. A randomized
trial undertook a clinical effectiveness comparison of pharmacoge-
netic vs. standard care warfarin dosing in 1866 patients who were
starting warfarin therapy.78 The pharmacogenetic cohort had a
10% absolute reduction in out-of-range INRs at 1 month, primarily
due to fewer INR values ,1.5, which coincided with a 66% lower
rate of deep vein thrombosis. The pharmacogenetic cohort also
had higher times in therapeutic ranges than the usual care group:
69 vs. 58% at 1 month, and 71 vs. 59% at 3 months. There are at
least four ongoing large randomized, controlled trials testing phar-
macogenetic testing to guide warfarin dosing: two in the USA, one
in Europe, and one in Asia.68
New oral anticoagulantsNew oral anticoagulants are characterized by a rapid onset of
action, a predictable anticoagulant effect, a specific coagulation
enzyme target, and a low potential for drug or food interactions.
They can be prescribed in fixed doses because of predictable
pharmacokinetics, and routine laboratory coagulation monitoring
is not required.79–82 Of the drugs that have completed phase 3
trials in venous thrombo-embolism, rivaroxaban competitively
binds activated factor X, whereas dabigatran is a direct inhibitor
of thrombin. To date, neither drug has a specific antidote. In a ran-
domized crossover study performed in 12 male healthy volunteers,
prothrombin complex concentrate rapidly reversed the effect of
rivaroxaban on the prothrombin time, although it could not
reverse the prolongation of coagulation parameters (activated
partial thromboplastin time, ecarin clotting time, and thrombin
time) caused by dabigatran.83 Of note, however, this study did
not address clinical endpoints such as the reversibility of
drug-related bleeding. If emergent bleeding must be reversed,
dialysis appears to be an option for dabigatran84 but not for rivar-
oxaban, which is 95% protein bound.
The ‘Oral Rivaroxaban for Symptomatic Venous Thrombo-
embolism’ (EINSTEIN) programme tested the efficacy and safety
of oral monotherapy (replacing both parenteral anticoagulation
and warfarin) with rivaroxaban to treat venous thrombo-
embolism. EINSTEIN comprised three trials: (i) the Acute Deep
Vein Thrombosis (DVT) Study85; (ii) the Continued Treatment
Study of DVT85; and (iii) the Acute PE Study.6 In both the acute
DVT and PE studies, the dosing regimen of rivaroxaban was
15 mg twice daily for the first 3 weeks, followed by 20 mg once
daily thereafter. A higher dose was administered for 3 weeks
because PE and DVT patients are considered especially hypercoa-
gulable during this period, when the highest rate of treatment fail-
ures occur.86–88 Patients with a creatinine clearance ,30 mL/min
were excluded from the EINSTEIN programme. This approach dif-
fered from the dosing regimen of rivaroxaban in the atrial fibrilla-
tion trial, in which patients with a creatinine clearance between 30
and 49 mL/min received a reduced dose (15 mg rather than 20 mg
once daily).89
In the EINSTEIN-PE study,6 4832 patients were enrolled. Recur-
rent venous thrombo-embolism occurred in 2.1% of patients re-
ceiving rivaroxaban compared with 1.8% of those on standard
enoxaparin/warfarin therapy. Rivaroxaban was non-inferior to
standard therapy (P ¼ 0.003). Major or clinically relevant non-
major bleeding occurred in 10.3% of rivaroxaban patients com-
pared with 11.4% standard therapy patients (P ¼ 0.32); however,
major bleeding was observed in only 1.1% of patients taking rivar-
oxaban compared with 2.2% of those on enoxaparin/warfarin (P ¼
0.003). In particular, intracranial bleeding occurred in one rivarox-
aban patient compared with 10 patients receiving standard therapy.
Thus, the results of the EINSTEIN trial support the use of rivarox-
aban as monotherapy for the management of acute PE. The single
oral drug approach is also being evaluated in an ongoing trial testing
the factor Xa inhibitor, apixaban (AMPLIFY; NCT00643201). In this
latter trial, the dosing regimen of apixaban is 10 mg twice daily for
the first week, followed by 5 mg twice daily thereafter (Figure 2).
Dabigatran also showed non-inferiority for the prevention of re-
current venous thrombo-embolism in patients presenting with
acute PE or DVT. In the RE-COVER trial, dabigatran 150 mg
twice daily was compared with warfarin for the treatment of
acute venous thrombo-embolism.90 Patients with a creatinine
clearance ,30 mL/min were excluded. All patients, regardless of
randomization assignment, received at least 5 days of parenteral
anticoagulation, usually enoxaparin. The primary outcome was
the 6-month incidence of recurrent symptomatic and objectively
confirmed venous thrombo-embolism. Overall, 2564 patients
were enrolled, 21% with PE only and the rest with DVT with/
without PE. Parenteral anticoagulation was administered for a
mean of 10 days in both groups. For the efficacy endpoint, dabiga-
tran was non-inferior to warfarin (2.4 vs. 2.1%, respectively). The
rates of major bleeding in the two groups were similar: 1.6% for
dabigatran and 1.9% for warfarin. There were no intracranial
bleeds with dabigatran compared with three intracranial bleeds
with warfarin. There were also fewer episodes of any bleeding
with dabigatran (16%) compared with warfarin (22%). The
RE-COVER trial supports the use of dabigatran as a fixed dose
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oral treatment for acute DVT and PE, after an initial period of par-
enteral anticoagulation. The switch to a new oral anticoagulant
(compared with warfarin) following at least 5 days of parenteral
anticoagulation is also being evaluated in an ongoing trial testing
the factor Xa inhibitor edoxaban (Hokusai, NCT00986154)
(Figure 2).
Risk of recurrence and optimal durationof anticoagulationOne of the most common dilemmas when managing patients with
PE is to decide upon the optimal duration of anticoagulation. The
recurrence rate of venous thrombo-embolism after discontinuing
anticoagulation is surprisingly high. For example, in a cohort of
1626 patients with proximal DVT or PE, the cumulative incidence
of recurrence was 11% after 1 year, 20% after 3 years, 29% after 5
years, and 40% after 10 years; the strongest risk factor predisposing
to recurrent thrombosis was an initial ‘idiopathic’, unprovoked
event.91 Another study evaluated the long-term clinical benefit of
extending a 3-month course of oral anticoagulant therapy to 6
months (PE associated with temporary risk factors) or to 1 year
(idiopathic PE); patients with PE had a substantial risk for recur-
rence after discontinuation of oral anticoagulation, regardless of
treatment duration.92 It thus appears that physicians should try
to identify patients who are at high risk for recurrence and there-
fore potential candidates for indefinite oral anticoagulant therapy.
This recommendation is supported by data showing that patients
who receive extended anticoagulation are effectively protected
from recurrent thrombo-embolism while on therapy.85,93
What determines recurrence risk after acute PE? In a cohort of
929 patients, 19% of whom had recurrent venous thrombo-
embolism after a median of 43 months following discontinuation
of anticoagulation, the most important risk factors for recurrence
were idiopathic, rather than provoked, PE; male gender; location of
the thrombotic event (proximal DVT. calf DVT and PE. prox-
imal DVT); and elevated D-dimer levels.94 Other reported risk
factors include excess body weight95 and persistent RV dysfunction
at hospital discharge after acute PE.96 An association has also been
reported with immobilization, cancer, chronic obstructive pulmon-
ary disease, low high-density lipoprotein cholesterol, and a positive
family history.97
A literature review found that .50% of patients with PE had re-
sidual thrombi on CT imaging 11 months after the initial event98;
this rate was lower, ≏30%, when lung scan was used for follow-
up.99 However, the clinical relevance of these findings remains
unclear and certainly does not support basing the duration of
anticoagulation therapy on serial imaging tests. Moreover, and
perhaps counterintuitively, most thrombophilias do not appear
to be associated with an elevated risk of recurrent venous
thrombo-embolism.100
Current guidelines recommend 3 months of anticoagulation in
patients with PE provoked by surgery or by a non-surgical transient
risk factor.5,53 Patients with an unprovoked PE will need evaluation
for the risk–benefit ratio of extended anticoagulation therapy after
the first 3 months of treatment. Nevertheless, many patients reside
in a ‘grey zone’ where personalized assessment is required to
decide on the optimal duration of anticoagulation.97
In a recent investigator-initiated, double-blind study, patients
who had completed 6–18 months of oral anticoagulation after a
first episode of unprovoked venous thrombo-embolism were ran-
domly assigned to aspirin, 100 mg daily, or placebo for 2 years.101
Recurrence occurred in 28 of the 205 patients (6.6% per year) on
aspirin vs. 43 of 197 (11.2% per year) on placebo (hazards ratio,
0.58; 95% CI, 0.36–0.93). Although the relative proportion of pla-
telets in venous thrombi is low, they participate by releasing poly-
phosphates, microparticles, and proinflammatory mediators, and
by interacting with neutrophils to generate DNA–histone–
granule constituent complexes.102 Clearly, any protection offered
by aspirin is inferior to that provided by vitamin K antagonists
and new oral anticoagulants; however, if these results are con-
firmed by larger trials, aspirin might find a place in long-term sec-
ondary prophylaxis for selected patients with high bleeding risk.
Early discharge and outpatienttreatment
The traditional approach to venous thrombo-embolism manage-
ment has been to treat most DVT patients as outpatients and to
treat virtually all PE patients initially in the hospital. With the devel-
opment of more precise tools for accurate and rapid risk stratifica-
tion, and with the availability of new oral anticoagulants and
simplified regimens, the decisions about whether to hospitalize
and the optimal duration of hospital stay may soon warrant
re-examination.
It is usually straightforward to identify the patients who are not
candidates for outpatient treatment. Clearly, patients with severe
comorbidity and a predicted high potential for adverse outcomes
should be hospitalized. These patients have consistently been
excluded from prospective management (cohort) studies focusing
on home treatment66,67 (exclusion criteria reviewed in Lankeit and
Konstantinides26). Many will require supplemental oxygen, paren-
teral analgesics or antibiotics, or specific treatment for concomi-
tant disease, and they may be considered for advanced therapy
such as systemic thrombolysis, pharmacomechanical catheter-
directed therapy, surgical embolectomy, or a vena cava filter.
Another crucial factor besides the patient’s medical prognosis is
the presence of an adequate social safety net to ensure strict ad-
herence to the prescribed anticoagulation regimen.
A randomized trial of 344 patients with low-risk PE (PESI risk
class I or II) was undertaken to determine the safety and effective-
ness of outpatient treatment.23 After randomization to outpatient
treatment, patients were contacted by the study staff daily for 7
days, and then on days 14, 30, 60, and 90. Outcomes were excel-
lent in both groups. Only one patient in the outpatient group and
none in the inpatient group had recurrent venous thrombo-
embolism within 90 days. Only two outpatients and no inpatients
had major bleeding. With this model of assiduous outpatient
care, which may be feasible in the Netherlands66,67 and a few
other European countries, it appears that low-risk patients with
PE can be safely and effectively treated without (or with very
short) hospitalization. Whether the home treatment concept is
likely to carry over to other, larger parts of the ‘real world’ in
the future remains to be determined.
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Conclusions and outlook
Although case fatality rates appear to have dropped over the past
two decades,11,103 acute PE continues to pose a serious burden on
health and survival.104 Rapid and accurate risk stratification is of
paramount importance to ensure the highest quality of care.
We must first classify patients as ‘stable’ or ‘unstable’, i.e. distin-
guish between high-risk and non-high-risk PE. This dichotomy
will help us to optimize patient management. High-risk PE clearly
warrants immediate thrombolytic, surgical, or interventional reper-
fusion therapy. However, the intensive search continues for an
intermediate-risk group among normotensive patients who will
benefit from advanced therapy in addition to anticoagulation.
The large European randomized trial, PEITHO, may yield some
answers shortly. Significant progress has been made in the field
of anticoagulation with the optimization of treatment with
vitamin K antagonists and the encouraging results of trials using
new oral anticoagulants. Emerging management strategies may sim-
plify secondary prevention in the future and help to resolve the
persistent controversy over the optimal duration of anticoagula-
tion after acute PE.
Resolution of cases
In Case 1, we are dealing with a patient who most likely has high-
risk (massive) PE, even if he does not fulfil all formal criteria of
haemodynamic instability or cardiogenic shock. This is an emer-
gency situation. The patient’s persistent respiratory insufficiency
and ‘paradoxical’ further aggravation of hypoxaemia after endo-
tracheal intubation is a particular reason for concern. We strongly
recommend bedside contrast echocardiography, as the most prob-
able explanation is the presence of a patent foramen ovale, which
is now wide open due to the increased right atrial pressure and
leads to severe right-to-left shunting.105 In view of the patient’s
persistent tachycardia, marginally low blood pressure, and intract-
able hypoxaemia, we would not demand further confirmation of
the diagnosis by CT; instead, we would immediately proceed to
systemic thrombolysis with 100 mg of alteplase administered
over 2 h.
In Case 2, we need to make clear to the patient that immediate
discharge and out-of-hospital anticoagulation is not (yet) a widely
accepted treatment option for PE. Even if the calculation of the
(simplified) PESI yields a low risk, the patient may still have a re-
sidual risk for early complications which needs to be further clari-
fied by future management trials; besides, most studies on home
treatment have thus far excluded obese patients.26 New oral antic-
oagulants may facilitate home treatment of PE in the future, but
they are not yet approved for this indication. Therefore, we
would recommend a brief (4–6 days) hospitalization to ensure
that parenteral anticoagulants are administered properly and that
overlapping administration of a vitamin K antagonist results in a
therapeutic INR (2.0–3.0) for 2 consecutive days.
In Case 3, the patient has completed the minimal duration of
anticoagulation after a first episode of unprovoked PE. Unequivocal
indications for indefinite anticoagulation, such as active cancer or
the antiphospholipid antibody syndrome, are not present in this
case. The patient is obese and has heterozygous thrombophilia;
these conditions increase the risk of recurrence moderately94,106
and may not mandate lifelong treatment according to current
guidelines.5,53 As the patient also reported repeated episodes of
minor bleeding during the past 6 months, we would recommend
optimization of anticoagulation, perhaps at a lower than standard
intensity such as targeting an INR range of 2.0 to 2.5. We
would also strongly encourage lifestyle modification and physical
activity with weight loss. An alternative approach would be to
interrupt treatment for 1 month and then resume anticoagulation
(only) if the D-dimer test is positive.107 Finally, although one study
indicated that CTEPH may develop in as many as 3.8% of patients 2
years after acute PE,108 the true incidence of the disease is prob-
ably lower,109 and the recent data from a large population with
idiopathic PE did not provide support for routine echocardio-
graphic follow-up in search of developing CTEPH.110 We would
recommend 6-month echocardiographic follow-up of a patient
with elevated pulmonary artery pressure at discharge, but acknow-
ledge that the issue remains unsettled. The randomized PEITHO
trial52 will include a 2-year prospective follow-up to determine
whether thrombolysis of intermediate-risk PE may, among
others, prevent the development of CTEPH over the long term.
Conflict of interest: S. K. received research grants from Bayer
HealthCare, Boehringer Ingelheim and Consultancy and lecture
fees from Bayer HealthCare, Boehringer Ingelheim, Bristol Myers
Squibb, GlaxoSmithKline, LEO Pharma. S. Z. G received research
grants from Daiichi Sankyo, Eisai, EKOS, Johnson and Johnson,
and Sanofi Aventis. Consultancy fees from Baxter, Boehringer
Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Merck,
Pfizer, Portola, and Sanofi Aventis.
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