Open Access Rambam Maimonides Medical Journal Abbreviations: CTPA, computed tomographic pulmonary angiography; DVT, deep vein thrombosis; INR,… [630620]

Open Access Rambam Maimonides Medical Journal

Abbreviations: CTPA, computed tomographic pulmonary angiography; DVT, deep vein thrombosis; INR, international
normalized ratio; LMWH, low -molecular -weight heparin; NOAC, new (non -vitamin K -dependent) oral anticoagulant(s);
NT-proBNP, N -terminal propeptide of brain natriuretic peptide; PE, pulmonary embolism; (s)PESI, (simplified)
pulmonary embolism severity index; PPV, positive predictive value; rtPA, recombinant tissue plasm inogen activator ; RV,
right ventricle/right ventricular; VKA, vitamin K antagonists; VTE, venous thromboembolism.
Citation: Käberich A, Wärntges S, Konstantinides S . Risk -Adapted Management of Acute Pulmonary Embolism: Recent
Evidence, New Guidelines . Rambam Maimonides Med J 2014 ;5 (4):e0040 . doi:10.5041/RMMJ.10 174
Copyright: © 2014 Käberich et al . This is an open -access article. All its content, except where otherwise noted , is
distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/ 3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Conflict of interest: No potential conflict of interest relevant to this article was reported.
* To whom correspondence should be addressed. E-mail: stavros.konstantinides@unimedizin -mainz.de

Rambam Maimonides Med J | www.rmmj.org.il 1 October 2014  Volume 5  Issue 4  e0040
CURRENT CLINICAL PRA CTICE

Special Issue on Advances in Hematology
Guest Editor: Benjamin Brenner, M .D.
Risk-Adapted Management of Acute
Pulmonary Embolism: Recent Evidence,
New Guidelines
Anja Käberich, M.D.1, Simone Wärntges, M.D.1, and Stavros Konstantinides, M.D.1,2*
1Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany; and
2Department of Cardiology, Democr itus University of Thrace, Alexandroupolis, Greece

ABSTRACT
Venous thromboembolism (VTE), the third most frequent acute cardiovascular syndrome, may cause life –
threatening complications and imposes a substantial socio -economic burden. During the past years, several
landmark trials paved the way towards novel strate gies in acute and long -term management of patients with
acute pulmonary embolism (PE). Risk stratification is increasingly recognized as a cornerstone for an
adequate diagnostic and therapeutic management of the highly heterogeneous population of patients with
acute PE. Recently published European Guidelines emphasize the importance of clinical prediction rules in
combination with imaging procedures (assessment of right ventricular function) and laboratory biomarkers
(indicative of myocardial stress or inju ry) for identification of normotensive PE patients at intermediate risk
for an adverse short -term outcome. In this patient group, systemic full -dose thrombolysis was associated
with a significantly increased risk of intracranial bleeding, a complication wh ich discourages its clinical
application unless hemodynamic decompensation occurs. A large -scale clinical trial program evaluating
new oral anticoagulants in the initial and long -term treatment of venous thromboembolism showed at least

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 2 October 2014  Volume 5  Issue 4  e0040
comparable efficacy and presumably increased safety of these drugs compared to the current standard
treatment. Research is continuing on catheter -directed, ultrasound -assisted, local, low -dose thrombolysis in
the management of intermediate -risk PE.
KEY WORDS: Novel oral antic oagulants, pulmonary embolism, risk -adapted management, risk
stratification, thrombolysis

INTRODUCTION
Venous thromboembolism (VTE) is the third most
frequent acute cardiovascular syndrome in industri –
alized countries, accounting for approximately 100
to 200 new cases per 100,000 population per year.1,2
As the incidence of VTE increases in an exponential
manner with age, ongoing demographic changes will
result in a growing number of patients suffering
from the acute and long -term sequelae of VTE in the
future.3 Approximately one -third of all patients with
VTE present with acute pulmonary embolism (PE),
with or without clinically evident deep vein
thrombosis; acute PE accounts for the majority of
VTE -associated hospitalizations and deaths.2 The
broad spectrum of clinical presentation s of PE
ranges from clinically silent thromboembolic events
to sudden death due to fulminant right ventricular
failure. The non -specific signs and symptoms of
acute PE frequently hamper diagnosis, resulting in
an underestimation of the actual frequency of
disease. This is supported by data derived from
epidemiologic models suggesting that only 7% of
patients dying early in the course of acute PE are
diagnosed correctly during life.2 In unselected
patients, case fatality rates in the acute phase range
from 5 % to 15%, and it has been calculated that as
many as 370,000 deaths may be related to PE in
Europe each year.2
This review elaborates on the risk -adapted
diagnostic work -up and the acute -phase therapeutic
management of patients with PE, highlighting
recent ly published data and the revised guidelines
and recommendations issued by the European
Society of Cardiology (ESC) and endorsed by the
European Respiratory Society (ERS). Particular
focus is placed on the risk stratification of
normotensive patients, the emerging role of new
(non -vitamin K -dependent) oral anticoagulants for
the treatment and secondary prophylaxis of acute
PE, and the clinical benefits, risks, and indications
of thrombolysis and other modes of reperfusion
treatment. INITIAL RISK STRATIF ICAT ION
Rational use of diagnostic procedures to confirm (or
exclude) the presence of acute PE, and subsequent
treatment decisions, should be based upon a reliable
assessment of the patient’s risk of early mortality or
other major cardiovascular complications. The
presence and severity of right ventricular (RV)
dysfunction is known to be a crucial determinant of
outcome in the acute phase of PE.4,5 Functional
impairment of the right ventricle is due to thrombo –
embolic obstruction of the pulmonary arterial vascu –
lature causing an acute increase of RV afterload
which results in RV dilatation, increased wall
tension, and RV ischemia, which in turn perpetuate
hemodynamic worsening. Overall, less than 5% of
patients with acute PE present with hemodynamic
compromise ( shock or persistent arterial hyper –
tension) on admission due to clinically overt RV
failure.6 This condition is associated with an esti –
mated PE -related early mortality risk of at least 15%,
a fact which mandates emergency advanced medical
care.7 Thus, ini tial triage of patients with suspected
acute PE should be based upon the assessment of
the hemodynamic (clinical) stability allowing for a
simplified classification into a high -risk or a non –
high -risk group. This approach allows all
subsequent diagnostic a nd therapeutic strategies to
be adapted to the acuteness and severity of the
clinical situation, maximizing efficiency of resource
utilization and potentially saving lives.
RISK -ADAPTED DIAGNOSTIC
ALGORITHM
Based upon the initial stratification of patients into
those with (suspected) high -risk PE either with or
without shock or hypotension the ESC guidelines8
recommend two distinct algorithms (Figures 1 and
2, respectively) for diagnostic work -up. Clearly,
however, diagnostic approaches may vary among
hospi tals depending on local expertise and the
availability of individual imaging modalities.

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 3 October 2014  Volume 5  Issue 4  e0040
Suspected High -Risk PE with Shock or
Hypotension (Recommended Algorithm
Shown in Figure 1)
Suspected high -risk PE is an emergency situation.
Multidetector computed tomographic pulmonary
angiography (CTPA) is recommended, if
immediately available, for confirmation of the
diagnosis. Alternatively, transthoracic
echocar diography performed as a bedside
examination for detection of RV dysfunction
indirectly confirms acute “massive” PE.9 Apart from verifying RV dysfunction (indicated by RV
dilatation, paradoxical septal movement, abnormal
motion of the RV free wall (McConne ll sign),
disturbed RV ejection pattern, triscuspid valve
regurgitation, and dilatation and missing inspiratory
collapse of the inferior vena cava) and pulmonary
hypertension (increased tricuspid regurgitant jet
velocity and/or pulmonary arterial dilatatio n),8
transthoracic echocardiography may indicate the
presence of mobile thrombi in the right -sided heart
cavities.10–12 In unstable patients, signs of RV
dysfunction on echocardiography are sufficient for
Figure 1. Proposed Diagnostic Algorithm for Patients with Suspected High -Risk PE, i.e. Presenting with Shock or
Hypotension .
a Includes the cases in which the pa tient’s condition is so critical that it only allows bedside diagnostic tests.
b Apart from the diagnosis of RV dysfunction, bedside transthoracic echocardiography may, in some cases, directly
confirm PE by visualizing mobile thrombi in the right heart chambers .
c Thrombolysis; alternatively, surgical embolectomy or catheter -directed treatment .
CT, computed tomographic ( pulmonary angiography ); PE, pulmonary embolism; RV, right ventricle.

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 4 October 2014  Volume 5  Issue 4  e0040
prompt initiation of repe rfusion therapy (e.g.
systemic thrombolysis) without the necessity of
further testing. Moreover, echocardiography may
help to detect or exclude alternative causes of shock
such as aortic dissection, pericardial tamponade, or severe left ventricular failure . In patients primarily
admitted to the catheterization laboratory to
diagnose or exclude an acute coronary syndrome,
pulmonary angiography can be considered as an
alternative diagnostic approach.8
Figure 2. Proposed Diagnostic Algorithm for Patien ts with Suspected High -Risk PE in the Absence of Shock or
Hypotension .
a Two alternative classification schemes may be used for clinical probability assessment, i.e. a three -level scheme
(clinical probability defined as low, intermediate, or high) o r a two -level scheme (PE unlikely or PE likely). When
using a moderately sensitive assay, D -dimer measurement should be restricted to patients with low clinical
probability or a PE -unlikely classification, while highly sensitive assays may also be used in patients with
intermediate clinical probability of PE due to a higher sensitivity and negative predictive value .
b Treatment refers to anticoagulation treatment for PE.
c CT angiogram is considered diagnostic of PE if it shows PE at the segmental or more proximal level .
d In case of a negative CT angiogram in patients with high clinical probability, further investigation may be
considered before withholding PE -specific treatment.
CT, computed tomographic; PE , pulmonary embolism.

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 5 October 2014  Volume 5  Issue 4  e0040
Suspected High -Risk PE Without Shock or
Hypotension (Recom mended Algorithm
Shown in Figure 2)
Pulmonary embolism may escape prompt diagnosis
in hemodynamically stable patients, since clinical
signs and symptoms such as dyspnea, chest pain,
(pre -) syncope, or hemoptysis are frequently absent
or, if present, non -specific.13–17 In this group of
“stable” patients, diagnostic certainty is the
physician’s first priority in order to prevent VTE
recurrence but also to avoid unnecessary long -term
anticoagulation which may, by itself, cause
potentially life -threatening comp lications. The
diagnostic strategy should begin with assessment of
the clinical probability of PE using either validated
explicit clinical prediction rules or implicit clinical
judgment. In the past years, simplified versions of
the revised Geneva predicti on rule18 and the Wells
score,19 both assessing the pre -test probability of
acute PE, were developed and externally vali –
dated.20,21 Based on either the original or the
simplified versions of these prediction rules,20,22 –33
D-dimer testing is indicated as a second diagnostic
step before performing an imaging test in patients
with low or intermediate clinical probability of PE
(or PE -unlikely using a dichotomized score),
whereas in cases with high clinical probability (or
PE-likely), it is recommended to pro ceed to imaging
procedures without laboratory testing.8
Plasma concentrations of D -dimers are elevated
in acute thrombus formation due to simultaneous
stimulation of the fibrinolytic cascade and formation
of fibrin cleavage products. As the sensitivity and
negative predictive value of ELISA -based D -dimer
assays are high,34,35 PE can be safely ruled out in
patients with low or intermediate clinical probability
of the disease and a negative D -dimer test. These
patients can be left untreated (i.e. without anti –
coagulation), as proven in outcome studies and a
meta -analysis which indicated a 3 -month thrombo –
embolic risk below 1%.36–41 Notably, in hospitalized
patients, D -dimer measurement is of limited use. On
the other hand, it is well known that the specificity
of D -dimer testing (~30%42) is low and thus by no
means confirms the disease but only indicates that
further testing for PE is necessary. Several co –
morbidities or concomitant conditions, such as
active malignancy,43,44 hospitalization due to other
causes ,20,45 postoperative state,46 pregnancy,47,48 or
“simply” advanced age,42 can induce non -specific
increases in D -dimer plasma levels. As recently
shown, age -adjusted D -dimer cut -off levels (age × 10 µg/L for patients above 50 years) rather than the
establi shed fixed cut -off of 500 µg/L may help
increase the specificity of D -dimer measurements;49
in a multicenter management study, the proportion
of patients in whom acute PE could be excluded
without further testing increased to approximately
30% without elev ating the numbers of false -negative
findings.49
In all patients with a high clinical probability for
acute PE, and in those with a positive D -dimer test,
CTPA visualizing at least one clot at the segmental
or more proximal level of the pulmonary arteries
confirms PE with high sensitivity (83%) and
specificity (96%);50 alternatively, CTPA may help
establish an alternative diagnosis. Uncertainty
persists with regard to the clinical significance of
isolated subsegmental pulmonary emboli which
were confirmed in 4.7% of patients imaged by
single -detector CT and in 9.4% assessed with multi –
detector CTPA.51 Poor interobserver agreement and
the low positive predictive value of such findings
justify further testing (e.g. with compression
ultrasound) to confirm PE in this specific setting.8
Although CTPA has largely replaced other
imaging modalities in the diagnosis of acute PE, a
ventilation/perfusion lung scan remains a valuable,
radiation – and contrast medium -sparing diagnostic
option, especially for patients with c ontraindications
to CT imaging (including those with severe renal
insufficiency, hyperthyroidism, or contrast medium
allergy) or in order to avoid unnecessary radiation in
younger female patients as well as in pregnant or
breast -feeding women. Compression ultrasound
sonography visualizing proximal deep vein throm –
bosis also confirms PE without the need for further
imaging tests.
FURTHER RISK STRATIF ICATION OF
NORMOTENSIVE PATIENT S WITH PE
Prognostic assessment of confirmed acute PE is
based upon the patien t’s individual risk of early
mortality, taking into consideration the clinical
severity of PE as well as the patient’s cardio pul-
monary reserves and concomitant co -morbidities.
As already mentioned, high -risk PE is characterized
by overt hemodynamic compr omise (cardiogenic
shock or persistent arterial hypotension); this
emergency situation demands immediate confirma –
tion of the diagnosis and treatment to save the
patient’s life. In hemodynamically stable (non -high –
risk) patients with confirmed PE, advanced risk

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 6 October 2014  Volume 5  Issue 4  e0040
stratification intends to identify either patients at
low risk for early (usually 30 -day) mortality, who
may be suitable for early discharge and home
treatment, or patients at an intermediate risk who
may benefit from advanced medical care, monitor –
ing, and possibly early reperfusion therapy. Prog –
nostic assessment should use a validated clinical
prognostic score such as the Pulmonary Embolism
Severity Index (PESI)52 or its simplified version
(sPESI)53 (Tab le 1). Patients with a sPESI score of ≥1
point(s) or a PESI class of III –IV repre sent
approximately two -thirds of unselected PE patients and are characterized by a 30 -day mortality rate of
11%–25%.52,53 These patients are considered to have
intermediate -risk PE.8 In this subgroup, further risk
assessment consisting of cardiac bio marker levels
(such as, for myocardial injury, cardiac troponins I
or T; or, for cardiac failure, natriuretic peptides),
and the presence of RV dysfunction on CT or
echocardiography should be considered. This en –
ables patient classification into either intermediate –
low (RV dysfunction present or cardiac biomarker
levels ele vated or none of the two present) or
intermediate –high risk (presence of RV dysfunction
Table 1. Original and Simplified Pulmonary Embolism Severity Index.
Parameter Original Version52 Simplified Version53
Age Age in years 1 point
(if age >80 years)
Male sex +10 points –
Cancer +30 points 1 point
Chronic heart failure +10 points 1 point
Chronic pulmonary disease +10 points
Pulse rate ≥110 bpm +20 points 1 point
Systolic BP <100 mmHg +30 points 1 point
Respiratory rate >30 breaths per minute +20 points –
Temperature <36°C +20 points –
Altered mental status +60 points –
Arterial oxyhemoglobin saturation <90% +20 points 1 point
Risk strataa
Class I: ≤65 points —very low
30-day mortality risk (0 % to
1.6%)
Class II: 66–85 points —low
mortality risk (1.7 %–3.5%)
_____________
Class III: 86–105 points —
moderate mortality risk (3.2 %–
7.1%)
Class IV: 106–125 points —high
mortality risk (4.0 %–11.4%)
Class V: >125 points —very high
mortality risk (10.0 %–24.5%) 0 points —30-day
mortality risk 1.0%
(95% CI 0.0 %–
2.1%)

≥1 point(s) —30-
day mortality risk
10.9% (95% CI
8.5%–13.2%)
a Based on the sum of points .
bpm, beats per minute; PESI , pulmonary embolism severity index.

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 7 October 2014  Volume 5  Issue 4  e0040
plus elevated cardiac biomarker levels), which will
guide further treatment decisions.
In patients having a low risk of 30 -day mortality
according to the sPESI or the P ESI, additional
prognostic assessment using laboratory marker tests
of or the evaluation of RV function by imaging
modalities is not deemed necessary. However, if one
or both of these tests have already been performed
on admission, before (s)PESI calculati on, and
yielded abnormal findings (a sequence of events
which is quite likely in clinical routine), then
patients should probably also be classified into the
intermediate –low-risk category and treated as
explained below.
ACUTE -PHASE MANAGEMENT OF THE
PULMO NARY EMBOLISM
Anticoagulation
Anticoagulation prevents both early death and
recurrent symptomatic or fatal VTE. The standard
duration of anticoagulation should cover at least 3
months. Within this period, acute -phase treatment
consists of parenteral antico agulation
(unfractionated heparin, low -molecular -weight
heparin (LMWH), or fondaparinux) administration
over the first 5 –10 days. Parenteral heparin
administration should overlap with the initiation of
a vitamin K antagonist (VKA), or it can be followed
by one of the new oral anticoagulants dabigatran or
edoxaban (see below). If rivaroxaban or apixaban is
given instead (see below for studies), oral treatment
with one of these agents should be started directly or
after a 1 –2-day administration of unfractiona ted
heparin, LMWH, or fondaparinux. In this latter
case, acute -phase treatment consists of an increased
dose over the first 3 weeks (for rivaroxaban), or over
the first 7 days (for apixaban).
The non -vitamin K -dependent new oral
anticoagulants, i.e. the direct thrombin inhibitor
dabigatran and the direct factor Xa inhibitors
rivaroxaban, apixaban, and edoxaban, have been
tested in large phase 3 clinical trials. In RE -COVER I
and II , dabigatran was compared with warfarin for
the treatment of VTE. The primary outcome was the
6-month incidence of recurrent symptomatic or fatal
VTE. In the pooled analysis of the results of the
“twin” studies RECOVER I and II, including a total
of 5,109 patients ,54 dabigatran was non -inferior to
warfarin with regard to the primary efficacy end –
point (observed incidence 2.4% versus 2.2%; HR
1.09, 95% CI 0.76 –1.57). Major bleeding appeared to occur with lower frequency in the dabigatran group,
both during the period st arting at first intake of
study drug (which included the initial warfarin
loading together with heparin treatment in the
control arm as opposed to heparin alone until the
switch to the oral anticoagulant in the dabigatran
arm; HR 0.73 for dabigatran, 95% C I 0.48 –1.11) and
during the double -dummy phase (comparing
monotherapy of dabigatran versus warfarin; HR
0.60, 95% CI 0.36 –0.99).
In the EINSTEIN -DVT55 and EINSTEIN -PE56
trials, single oral drug treatment with the direct
factor Xa inhibitor rivaroxaban was tested in
patients with VTE using a randomized, open -label,
non-inferiority design. In the pooled analysis of the
results of both studies, including a total of 8,282
patients,57 rivaroxaban was non -inferior to standard
therapy for the primary efficacy outc ome (observed
incidence 2.1% versus 2.3%; HR 0.89, 95% CI 0.66 –
1.19). Major bleeding occurred with lower frequency
in the rivaroxaban group (HR 0.54, 95% CI 0.37 –
0.79).
The Apixaban for the Initial Management of
Pulmonary Embolism and Deep -Vein Thrombosis as
First -line Therapy (AMPLIFY) study compared
single oral drug treatment with apixaban with
standard therapy in 5,395 patients with acute VTE.58
Apixaban was non -inferior to conventional treat –
ment for the primary efficacy, and major bleeding
occurred les s frequently under apixaban compared
with standard therapy. A significant difference in
favor of apixaban was also observed for the com –
posite outcome of major or clinically relevant non –
major bleeding (observed incidence 4.3% versus
9.7%; RR 0.44, 95% CI 0.36 –0.55).
Finally, the Hokusai -VTE trial compared edoxa –
ban with conventional therapy in 8,240 patients
with VTE who had initially received heparin for at
least 5 days.59 Patients received edoxaban at a dose
of 60 mg once daily (reduced to 30 mg once dai ly in
the case of creatinine clearance of 30 –50 mL/min or
a body weight <60 kg), or warfarin. In contrast to
the fixed anticoagulation period(s) followed in
previous trials, the study drug was administered for
3–12 months based on the investigators’ judgme nt;
all patients were followed for 12 months. Edoxaban
was non -inferior to warfarin with respect to the
primary efficacy outcome of recurrent symptomatic
VTE. Major bleeding or clinically relevant non –
major bleeding was less frequently observed in the
edox aban group (HR 0.81, 95% CI 0.71 –0.94).

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 8 October 2014  Volume 5  Issue 4  e0040

Figure 3. Risk -Adjusted Management Strategies in Acute PE. Based on Konstantinides et al.8
a If echocardiography has already been performed during diagnostic work -up for PE and detected RV dysfunction, or
if the CT already performed for diagnostic work -up has shown RV enlargement (right/left ventricular ratio ≥0.9), a
cardiac troponin test should be performed except for cases in which primary reperfusion is not a therapeutic option
(e.g. due to severe co -morbidi ty or limited life expectancy of the patient) .
b Markers of myocardial injury (e.g. elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as
a result of (right) ventricular dysfunction (elevated natriuretic peptide concentrations in plasma). If a laboratory
test for a cardiac biomarker has already been performed during initial diagnostic work -up (e.g. in the chest pain
unit) and was positive, then an echocardiogram should be considered to assess RV function, or RV size should be
(re)assessed on CT.
c Patients in the PESI Class I –II, or with sPESI of 0, and elevated cardiac biomarkers or signs of RV dysfunction on
imaging tests are also to be classified into the intermediate -to-low-risk category. This might apply to situations in
which imaging or biomarker results become available before calculation of the clinical severity index. These
patients are probably not candidates for home treatment.
d Thrombolysis, if (and as soon as) clinical signs of hemodynamic decompensation appear; surg ical pulmonary
embolectomy or percutaneous catheter -directed treatment may be considered as alternative options to systemic
thrombolysis, particularly if the bleeding risk is high.
e Monitoring should be considered for patients with confirmed PE and a posi tive troponin test, even if there is no
evidence of RV dysfunction on echocardiography or CT.
f The simplified version of the PESI has not been validated in prospective home treatment trials; inclusion criteria
other than the PESI were used in two single -armed (non -randomized) management studies.
A/C, anticoagulation; CT, computed tomographic pulmo nary angiography; PE, pulmonary embolism; PESI, pulmonary
embolism severity index; RV, right ventricular; sPESI, simplified pulmonary embolism severity index.

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 9 October 2014  Volume 5  Issue 4  e0040
Taken together, the results of the trials using new
oral anticoagulants in the treatment of VT E indicate
that these agents are at least as effective and
probably safer (in terms of major bleeding) than the
standard heparin/VKA regimen. Experience with
the handling of these drugs in different clinical
scenarios, and with the management of their blee d-
ing complications, continues to accumulate, and
useful practical recommendations have recently
been published by the European Heart Rhythm
Association.60 Currently, rivaroxaban, dabigatran,
and apixaban are approved for treatment o f VTE in
Europe.
Thromb olytic, Interventional, or Surgical
Treatment
In unstable patients with high -risk PE, large -scale
epidemiological data support the notion that in –
hospital mortality can be lowered by thrombolytic
treatment.6 Therefore, thrombolysis is recommend –
ed as first -line therapy in this patient group.
Surgical and interventional treatments represent
alternative options, particularly if the bleeding risk
under thrombolysis is considered to be high and
provided that the necessary infrastructure, equip –
ment, and experti se are available on site.
In non -high -risk PE, the clinical benefits of
thrombolysis have remained controversial for many
years.61 Recently, a large multicenter, randomized
trial compared, in a double -blind manner, thrombo –
lysis with tenecteplase plus hep arin versus placebo
plus heparin in 1,006 patients with intermediate –
risk PE.62 Patients had RV dysfunction confirmed by
echocardiography or CT angiography, and myo –
cardial injury confirmed by a positive troponin I or T
test. The primary efficacy outcome, a composite of
all-cause death or hemodynamic decompensation/
collapse within 7 days of randomization, was
significantly reduced with tenecteplase (2.6% versus
5.6% in the placebo group; OR 0.44, 95% CI 0.23 –
0.88). The clinical benefit was driven mainly by a
significant reduction in the rate of hemodynamic
collapse (1.6% versus 5.0%, P = 0.002), while all –
cause mortality was low, both in the tenecteplase
and in the placebo group (1.2% versus 1.8%; P =
0.43).62 On the other hand, the safety data were not
favorable for thrombolysis, as the trial demonstrated
a 2% risk of hemorrhagic stroke after thrombolytic
treatment with tenecteplase; major non -intracranial
bleeding events were also increased in the
tenecteplase compared with the placebo group
(6.3% versus 1 .5%; P<0.001).62 These results indicate that routine primary thrombolysis is not
recommended for normotensive patients with acute
PE, unless they show clinical signs of hemodynamic
decompensation.
An alternative to systemic full -dose thrombolysis
may consist of local, catheter -delivered, ultrasound –
assisted thrombolysis using small doses of a throm –
bolytic agent, provided of course that the necessary
infrastructure, equipment, and expertise are all
available on site . In a phase 2 clinical trial, 59
patients with acute main – or lower -lobe PE and
echocardiographic right -to-left ventricular dimen –
sion ratio ≥1.0 were randomized to receive unfrac –
tionated heparin and an ultrasound -assisted throm –
bolytic regimen of 10 –20 mg recombinant tissue
plasminogen activator (rtPA) plus unfraction ated
heparin over 15 hours as opposed to unfractionated
heparin alone. Reduced -dose local thrombolysis
significantly reduced, compared to heparin alone,
the subannular right -to-left ventricu lar dimension
ratio from baselin e to 24 hours without an increase
in bleeding complications.63 The efficacy and safety
of local, “pharmacomechanical” thrombolysis is also
supported by the results of a recently presented
prospective, single -arm multi center trial which
enrolled 150 patien ts with submassive or massive
PE (Clinicaltrials.gov identifier: NCT01513759).
CONCLUSIONS
Venous thromboembolism has received relatively
little attention from the scientific and medical
community for decades. Recently , however,
advances in diagnostic imag ing, along with the
development of new antithrombotic agents and
strategies, increased awareness of the importance of
VTE and began to improve patient outcomes in the
acute phase and over the long term. The new
evidence that accumulated in all these areas has led
to clear -cut, clinical practice -relevant
recommendations which are included in the recently
updated ESC Guidelines on the management of
acute pulmonary embolism (Figure 3) .8
REFERENCES
1. Heit JA. The epidemiology of venous thrombo –
embolism in the com munity. Arterioscler Thromb
Vasc Biol 2008;28:370 –2. Full Text
2. Cohen AT, Agnelli G, Anderson FA, et al. Venous
thromboembolism (VTE) in Europe. The number of
VTE events and associated morbidity and mortality.
Thromb Haemost 2007;98:756 –64.

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 10 October 2014  Volume 5  Issue 4  e0040
3. Anderson FA Jr, Spencer FA. Risk factors for venous
thromboembolism. Circulation 2003;107(23 Suppl
1):I9 –I16.
4. Lualdi JC, Goldhaber SZ. Right ventricular dysfunc –
tion after acute pulmonary embolism: p athophysio –
logic factors, detection, and therapeutic implications.
Am Heart J 1995;130:1276 –82. Full Text
5. Konstantinides S. Pulmonary embolism: impact of
right ventricular dysfunction. Curr Opin Cardiol
2005;20:496 –501. Full Text
6. Stein PD, Matta F. Thrombolytic therapy in unstable
patients with acute pulmonary embolism: saves lives
but underused. Am J Med 2012;125:465 –70. Full
Text
7. Laporte S, Mismetti P, Decousus H, et al. Clinical
predictors for fatal pulmonary embolism in 15,520
patients with venous thromboembolism: findings
from the Registro Informatizado de la Enfermedad
TromboEmbolica venosa (RIETE) Registry.
Circulation 2008;117:1711 –16. Full Text
8. Konstantinides S, Torbicki A, Agnelli G, et al. 2014
ESC 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) Endorsed by the European Respiratory Society
(ERS). Eur Heart J 2014 Aug 29. [Epub ahead of
print]
9. Kucher N, Luder CM, Dornhofer T, Windecker S,
Meier B, Hess OM. Novel management strategy for
patients with suspected pulmonary embolism. Eur
Heart J 2003 ;24:366 –76. Full Text
10. Mansencal N, Attias D, Caille V, et al. Computed
tomography for the detection of free -floating thrombi
in the right heart in acute pulmonary embolism. Eur
Radiol 2011;21:240 –5. Full Text
11. Torbicki A, Galie N, Covezzoli A, Rossi E, De Rosa M,
Goldhaber SZ. Right heart thrombi in pulmonary
embolism: results from the International Cooperative
Pulmonary Embolism Registry. J Am Coll Cardiol
2003;41:2245 –51. Full Text
12. Casazza F, Bongarzoni A, Centonze F, Morpurgo M.
Prevalence and prognostic significance of right -sided
card iac mobile thrombi in acute massive pulmonary
embolism. Am J Cardiol 1997;79:1433 –5. Full Text
13. Miniati M, Prediletto R, Formichi B, et al. Accuracy of
clinical assessment in the di agnosis of pulmonary
embolism. Am J Respir Crit Care Med 1999;159:864 –
71. Full Text
14. Pollack CV, Schreiber D, Goldhaber SZ, et al. Clinical
characteristics, management, and outcomes of pa –
tients diagnosed with acute pulmonary embolism in the emergency department: initial report of
EMPEROR (Multicenter Emergency Medicine
Pulmonary Embolism in the Real World Registry). J
Am Coll Cardiol 2011;57:700 –6. Full Text
15. Wells PS, Ginsberg JS, Anderson DR, et al. Use of a
clinical model for safe management of patients with
suspected pulmonary embolism. Ann Intern Med
1998;129:997 –1005. Full Text
16. Thames MD, Alpert JS, Dalen JE. Syncope in patients
with pulmonary embolism. JAMA 1977;238:2509 –11.
Full Text
17. Stein PD, Henry JW. Clinical characteristics of
patients with acute pulmonary embolism stratified
according to their presenting syndromes. Chest 1997;
112:974 –9. Full Text
18. Klok FA, Mos IC, Nijkeut er M, et al. Simplification of
the revised Geneva score for assessing clinical
probability of pulmonary embolism. Arch Intern Med
2008;168:2131 –6. Full Text
19. Gibson NS, Sohne M, Krui p MJ, et al. Further
validation and simplification of the Wells clinical
decision rule in pulmonary embolism. Thromb
Haemost 2008;99:229 –34.
20. Douma RA, Mos IC, Erkens PM, et al. Performance of
4 clinical decision rules in the diagnostic manage –
ment of acute pulmonary embolism: a prospective
cohort study. Ann Intern Med 2011;154:709 –18. Full
Text
21. Douma RA, Gibson NS, Gerdes VE, et al. Validity and
clinical utility of the si mplified Wells rule for assess –
ing clinical probability for the exclusion of pulmonary
embolism. Thromb Haemost 2009;101:197 –200.
22. Le Gal G, Righini M, Roy PM, et al. Prediction of
pulmonary embolism in the emergency department:
the revised Geneva score. Ann Intern Med 2006;144:
165–71. Full Text
23. Ceriani E, Combescure C, Le Gal G, et al. Clinical
prediction rules for pulmonary embolism: a syste –
matic review and meta -analysis. J Thromb Haemost
2010;8:957 –70.
24. Lucassen W, Geersing GJ, Erkens PM, et al. Clinical
decision rules for excluding pulmonary embolism: a
meta -analysis. Ann Intern Med 2011;155:448 –60.
Full Text
25. Wells PS, Anderson DR, Rodger M, et al. Derivation
of a simple clinical model to categorize patients
probability of pulmonary embolism: increasing the
models utility with the SimpliRED D -dimer. Thromb
Haemost 2000;83:416 –20.
26. Anderson DR, Kovacs MJ, Dennie C, et al. Use of
spiral computed tomography contrast angiography
and ultrasonography to exclude the diagnosis of

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 11 October 2014  Volume 5  Issue 4  e0040
pulmonary embolism in the emergency department. J
Emerg Med 2005;29:399 –404. Full Text
27. Kearon C, Ginsberg JS, Douketis J, et al. An
evaluation of D -dimer in the diagnosis of pulmo nary
embolism: a randomized trial. Ann Intern Med
2006;144:812 –21. Full Text
28. Sohne M, Kamphuisen PW, van Mierlo PJ, Buller HR.
Diagnostic strategy using a modified clini cal decision
rule and D -dimer test to rule out pulmonary
embolism in elderly in – and outpatients. Thromb
Haemost 2005;94:206 –10.
29. van Belle A, Buller HR, Huisman MV, et al. Effective –
ness of managing suspected pulmonary embolism
using an algorithm combining clinical probability, D –
dimer testing, and computed tomography. JAMA
2006;295:172 –9. Full Text
30. Wells PS, Anderson DR, Rodger M, et al. Excluding
pulmonary embolism at the bedside without diag –
nostic imaging: management of patients with
suspected pulmonary embolism presenting to the
emergency department by using a simple clinical
model and d -dimer. Ann Intern Med 2001;135:98 –
107. Full Text
31. Rodger MA, Maser E, Stiell I, Howley HE, Wells PS.
The interobserver reliability of pretest probability
assessment in patients with suspected pulmonary
embolism. Thromb Res 2005;116:101 –7. Full Text
32. Runyon MS, Webb WB, Jones AE, Kline JA.
Comparison of the unstructured clinician estimate of
pretest probability for pulmonary embolism to the
Canadian score and the Charlotte rule: a prospective
obse rvational study. Acad Emerg Med 2005;12:587 –
93. Full Text
33. Wolf SJ, McCubbin TR, Feldhaus KM, Faragher JP,
Adcock DM. Prospective validation of Wells Criteria
in the evaluation of patients with suspected pul –
monary embolism. Ann Emerg Med 2004;44:503 –
10. Full Text
34. Di Nisio M, Squizzato A, Rutjes AW, Buller HR,
Zwinderman AH, Bossuyt PM. Diagnostic ac curacy of
D-dimer test for exclusion of venous thromboembol –
ism: a systematic review. J Thromb Haemost 2007;5:
296–304. Full Text
35. Stein PD, Hull RD, Patel KC, et al. D -dimer for the
exclusion of acute venous thrombosis and pulmonary
embolism: a systematic review. Ann Intern Med
2004;140:589 –602. Full Text
36. Perrier A, Roy PM, Aujesky D, et al. Dia gnosing
pulmonary embolism in outpatients with clinical
assessment, D -dimer measurement, venous ultra –
sound, and helical computed tomography: a multi –
center management study. Am J Med 2004;116:291 –
9. Full Text 37. Perrier A, Roy PM, Sanchez O, et al. Multidetector –
row computed tomography in suspected pulmonary
embolism. N Engl J Med 2005;352:1760 –8. Full Text
38. Perrier A, D esmarais S, Miron MJ, et al. Non -invasive
diagnosis of venous thromboembolism in outpatients.
Lancet 1999;353:190 –5. Full Text
39. Kruip MJ, Slob MJ, Schijen JH, van der Heul C,
Buller HR. Use of a clinical decision rule in combina –
tion with D -dimer concentration in diag nostic work –
up of patients with suspected pulmonary embolism: a
prospective management study. Arch Intern Med
2002;162:1631 –5. Full Text
40. Righini M, Le Gal G, Aujesky D, et al. Diagnosis of
pulmonary embolism by multidetector CT alone or
combined with venous ultrasonography of the leg: a
randomised non -inferio rity trial. Lancet 2008;371:
1343 –52. Full Text
41. Carrier M, Righini M, Djurabi RK, et al. VIDAS D –
dimer in combination with clinical pre -test proba –
bility to rule out pulmonary embo lism. A systematic
review of management outcome studies. Thromb
Haemost 2009;101:886 –92.
42. Righini M, Goehring C, Bounameaux H, Perrier A.
Effects of age on the performance of common diag –
nostic tests for pulmonary embolism. Am J Med
2000;109:357 –61. Full Text
43. Di Nisio M, Sohne M, Kamphuisen PW, Buller HR. D –
Dimer test in cancer patients with suspected acute
pulmonary embolism. J Thromb Haemost 2005;3:
1239 –42. Full Text
44. Righini M, Le Gal G, De Lucia S, et al. Clinical
usefulness of D -dimer testing in cancer patients with
suspected pulmonary embolism. Thromb Haemost
2006;95:715 –19.
45. Miron MJ, Perrier A, Bouna meaux H, et al. Contribu –
tion of noninvasive evaluation to the diagnosis of
pulmonary embolism in hospitalized patients. Eur
Respir J 1999;13:1365 –70. Full Text
46. Dindo D, Breitenstei n S, Hahnloser D, et al. Kinetics
of D -dimer after general surgery. Blood Coagul
Fibrinolysis 2009;20:347 –52. Full Text
47. Chabloz P, Reber G, Boehlen F, Hohlfeld P, de
Moerloose P. TAFI antigen and D -dimer levels during
normal pregnancy and at delivery. Br J Haematol
2001;115:150 –2. Full Text
48. Francalanci I, Comeglio P, Liotta AA, et al. D -dimer
concent rations during normal pregnancy, as
measured by ELISA. Thromb Res 1995;78:399 –405.
Full Text
49. Righini M, Van Es J, den Exter PL, et al. Age -adjusted
D-dimer cutoff levels to rule out pulmonary

Risk-Adapted Management of Pulmonary Embolism

Rambam Maimonides Medical Journal 12 October 2014  Volume 5  Issue 4  e0040
embolism: the ADJUST -PE study. JAMA 2014;311:
1117–24. Full Text
50. Stein PD, Fowler SE, Goodman LR, et al. Multi –
detector computed tomography for acute pulmonary
embolism. N Engl J Med 2006;354:2317 –27. Full
Text
51. Carrier M, Righini M, Wells PS, et al. Subsegmental
pulmonary embolism diagnosed by computed
tomography: incidence and clinical implications. A
systematic review and meta -analysis of the manage –
ment outcome studies. J Thromb Haemost 2010;8:
1716 –22. Full Text
52. Aujesky D, Obrosky DS, Stone RA, et al. Derivation
and validation of a prognostic model for pulmonary
embolism. Am J Respir Crit Care Med 2005;172:
1041 –6. Full Text
53. Jimenez D, Aujesky D, Moores L, et al. Simplification
of the pulmonary embolism severity index for prog –
nostication in patients with acute symptomatic pul –
monary embolism. Arch Intern Med 2010;170:1383 –
9. Full Text
54. Schulman S, Kakkar AK, Goldhaber SZ, et al.
Treatment of acute venous thromboembolism with
dabigatran or warfarin and pooled analysis.
Circulation 2014;129:764 –72. Full Text
55. Bauersachs R, Berkowitz SD, Brenne r B, et al. Oral
rivaroxaban for symptomatic venous thrombo embol –
ism. N Engl J Med 2010;363:2499 –510. Full Text
56. Buller HR, Prins MH, Lensin AW, et al. Oral rivar –
oxaban for the treatment of symptomatic pulmonary
embolism. N Engl J Med 2012;366:1287 –97. Full
Text 57. Prins MH, Lensing AW, Bauersachs R, et al. Oral
rivaroxaban versus standard therapy for the treat –
ment of sympt omatic venous thromboembolism: a
pooled analysis of the EINSTEIN -DVT and PE
randomized studies. Thromb J 2013;11:21. Full Text
58. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban
for the treatment of acute venous thromboembolism.
N Engl J Med 2013;369:799 –808. Full Text
59. Buller HR, Decousus H, Grosso MA, et al. Edoxaban
versus warfarin for the treatment of symptomatic
veno us thromboembolism. N Engl J Med 2013;369:
1406 –15. Full Text
60. Heidbuchel H, Verhamme P, Alings M, et al. EHRA
practical guide on the use of new oral anticoagulants
in patients with non -valvular atrial fibrillation:
executive summary. Eur Heart J 2013;34:2094 –106.
Full Text
61. Konstantinides S, Geibel A, Heusel G, Heinrich F,
Kasper W. Heparin plus alteplase compared with
heparin alone in patients with submassive pulmonary
embolism. N Engl J Med 2002;347:1143 –50. Full
Text
62. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for
patients with intermediate -risk pul monary embolism.
N Engl J Med 2014;370:1402 –11. Full Text
63. Kucher N, Boekstegers P, Muller OJ, et al. Random –
ized, controlled trial of ultrasound -assisted catheter –
directed thrombolysis for acute intermediate -risk
pulmonary embolism. Circulation 2014;129:479 –86.
Full Text