Archives of Cardiovascular Disease (2014) 107, 406—414

Available online at

ScienceDirect
www.sciencedirect.com

REVIEW

Effective diagnosis and treatment of

pulmonary embolism: Improving patient
outcomes
Des changements dans le diagnostic et la thérapeutique pour
améliorer le pronostic de l’embolie pulmonaire

Guy Meyer a,b,∗

a
Division of respiratory and intensive care, hôpital européen Georges-Pompidou, 20, rue
Leblanc, 75015 Paris, France
b
Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France

Received 4 April 2014; received in revised form 2 May 2014; accepted 5 May 2014
Available online 9 July 2014

KEYWORDS Summary Pulmonary embolism can be life threatening and difficult to diagnose as signs
Anticoagulants; and symptoms are not specific. European guidelines recommend stratification of pulmonary
Diagnostic embolism by risk of early mortality. Patients with suspected pulmonary embolism should be
techniques; assessed for clinical probability of pulmonary embolism using a validated risk score. A low
Pulmonary embolism or intermediate clinical probability plus a negative high-sensitivity D-dimer test excludes
pulmonary embolism. Anticoagulation is indicated in patients with a positive multidetector
computed tomography or high-probability lung scan. An important part of the management of
patients with pulmonary embolism has traditionally been anticoagulant treatment with par-
enteral heparins and oral vitamin K antagonists. Although effective, this dual-drug approach is
associated with limitations. Direct oral anticoagulants that may overcome some of these prob-
lems have been tested in phase III clinical trials for the treatment of venous thromboembolism.
Of these, rivaroxaban and apixaban have demonstrated non-inferiority to standard therapy
when given as single-drug approaches for venous thromboembolism treatment, and provided

Abbreviations: CI, Confidence interval; CrCl, Creatinine clearance; CT, Computed tomography; DVT, Deep vein thrombosis; GARFIELD,
Global Anticoagulant Registry in the FIELD; HR, Hazard ratio; LMWH, Low-molecular-weight heparin; OAC, Oral anticoagulant; PE, Pul-
monary embolism; RIETE, Registro Informatizado de Pacientes con Enfermedad TromboEmbólica; VKA, Vitamin K antagonist; VTE, Venous
thromboembolism.
∗ Correspondence to: Division of respiratory and intensive care, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France.

E-mail address: guy.meyer@egp.aphp.fr

http://dx.doi.org/10.1016/j.acvd.2014.05.006
1875-2136/© 2014 Elsevier Masson SAS. All rights reserved.
Improving patient outcomes in pulmonary embolism 407

significant reductions in major bleeding rates. Dabigatran and edoxaban were non-inferior to
standard therapy when given as part of a dual-drug approach after initial parenteral antico-
agulation, and reduced clinically relevant bleeding rates. There may be a benefit to extended
anticoagulation with direct oral anticoagulants for the prevention of recurrent venous throm-
boembolism. Registry studies will provide more information on the use of these agents in
real-world populations. Accurate diagnosis and risk stratification of patients with pulmonary
embolism, together with simplified anticoagulation therapy, is likely to improve outcomes.
© 2014 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Résumé L’embolie pulmonaire est une pathologie potentiellement létale et est difficile à
Traitement diagnostiquer. Les signes et les symptômes de l’embolie pulmonaire ne sont pas spécifiques.
anticoagulant ; Les recommandations européennes recommandent de stratifier les malades selon leur risque
Diagnostic ; de mortalité. La probabilité clinique de l’embolie pulmonaire doit être évaluée à l’aide d’un
Embolie pulmonaire score devant toute suspicion clinique d’embolie pulmonaire. Une probabilité clinique faible ou
intermédiaire associée à un taux de D-dimère normal élimine le diagnostic. Le diagnostic est
affirmé par l’angioscanner thoracique ou la scintigraphie pulmonaire. Le traitement initial asso-
cie traditionnellement une héparinothérapie parentérale et un antagoniste de la vitamine K.
Ce traitement est efficace mais comporte certains inconvénients. Des inhibiteurs oraux directs
de la coagulation, qui pourraient limiter ces inconvénients, ont été testés dans de grands essais
de phase III. Parmi eux, le rivaroxaban et l’apixaban administrés dès l’inclusion ont démontré
leur non-infériorité par rapport au traitement standard en termes d’efficacité tout en obtenant
une réduction des hémorragies majeures. Le dabigatran et l’edoxaban sont également non
inférieurs au traitement standard après un traitement parentéral initial et sont également asso-
ciés à une réduction des saignements cliniquement significatifs. La prolongation du traitement
au-delà de six mois en cas de thrombose non provoquée pourrait être associée à une réduc-
tion des récidives. Des études de registres devraient apporter des informations sur l’utilisation
de ces nouvelles molécules en situation de soin courant. Un diagnostic rigoureux, associé à
une stratification du risque et à un traitement anticoagulant simplifié devraient permettre une
amélioration du pronostic de l’embolie pulmonaire.
© 2014 Elsevier Masson SAS. Tous droits réservés.

Introduction is associated with some limitations, including the need to

Pulmonary embolism (PE) is a relatively common disease,
with an incidence ranging from 60 to 112 per 100,000 inhabi-
tants of the United States [1], and is the third most common
cause of death among patients with cardiovascular diseases
[2]. Patients are at particular risk in the acute stage of the
disease, with 30-day mortality rates in excess of 15% for PE
associated with shock and/or hypotension [3]. PE is diffi-
cult to diagnose because of the wide range of presentations
of the disease. Among those patients who die of PE, 94%
do so before diagnosis [4]. The mainstay of treatment for
most patients with PE is anticoagulation, and the risk of
death is much reduced in optimally anticoagulated patients.
The recurrence rate of venous thromboembolism (VTE) after
stopping anticoagulant treatment varies with the cause of
the disease and is much higher in patients with unprovoked
VTE than in patients with VTE provoked by a major tran-
sient risk factor [5]. Duration of anticoagulant treatment is
tailored to the risks of VTE recurrence and bleeding for each
individual patient [3,6].
Treatment of PE has predominantly involved the use
of low-molecular-weight heparins (LMWHs), unfractionated
heparin or fondaparinux in combination with vitamin K
antagonists (VKAs) [3,6]. However, this dual-drug approach
co-administer the parenteral agent and VKA concurrently
for several days at the start of treatment, and the sub-
sequent need for regular coagulation monitoring and dose
adjustments during VKA monotherapy. The recently devel-
oped direct oral anticoagulants circumvent some of these
limitations, and several have completed large phase III clin-
ical trials in the treatment of acute VTE. In Europe, only
rivaroxaban is currently approved for the treatment and sec-
ondary prevention of deep vein thrombosis (DVT) and PE. In
the USA, rivaroxaban and, more recently, dabigatran have
been approved for VTE treatment.
This review covers the diagnosis and treatment of PE,
focusing on data for direct oral anticoagulants.
Clinical presentations of PE
Most patients with suspected PE present with some degree
of chest pain and dyspnoea, a frequent cause of refer-
ral to the emergency department. These symptoms are
non-specific and can be confused with other differential
diagnoses, such as acute coronary syndromes, exacerbation
of chronic obstructive pulmonary disease or pneumonia [7].
The most specific symptoms of PE—haemoptysis and calf
408
pain—are encountered in only up to 10% and 42% of patients
with PE, respectively [8,9]. In the most severe cases of
PE, patients may present with shock and/or haemodynamic
instability [3]. The lack of specific symptoms and the pres-
ence of underlying disease in a significant proportion of
patients with PE probably explain the significant diagnostic
delay observed in some cases.
Risk stratification for suspected PE
Risk stratification is a relatively new concept in the field
of PE. The size of the emboli and degree of vessel occlu-
sion do not accurately describe the risk of death of a
patient with suspected PE, and the terms ‘massive’ and
‘sub-massive’ are misleading [3]. Therefore, other methods
are required to assess mortality risk and inform manage-
ment decisions. Accordingly, the guidelines of the European
Society of Cardiology categorize patients presenting with
suspected PE by their predicted risk of early mortality.
Patients are divided into high-risk or non-high-risk (which is
further divided into intermediate- and low-risk) categories
based on the presence of shock, myocardial injury and right
ventricular dysfunction detected by echocardiography and
cardiac biomarkers [3]. The risk category to which a patient
is assigned informs the approach, whether it be emergency
thrombolysis or embolectomy (high-risk: > 15% early mortal-
ity risk) or further confirmatory diagnostic steps and, if PE
is confirmed, management with anticoagulants (non-high-
risk: < 1—15% early mortality risk) [3]. Risk stratification also
allows for the selection of patients who may be suitable for
outpatient anticoagulant treatment [10].
The Pulmonary Embolism Severity Index is a clinical tool
designed to assess the risk of death in patients with PE.
According to this, patients with PE can be divided into five
groups with different outcomes. The 30-day risk of death in
patients belonging to the low-risk categories I and II is usu-
ally < 3%, whereas that in patients belonging to the high-risk
category V varies between 10% and 25% [11,12]. A simpli-
fied version of the rule, based on six variables that all carry
the same weight (one of which is a composite of two origi-
nal variables), has been shown to have the same sensitivity
and specificity as the original [13]. Right ventricular dilata-
tion on echocardiography or computed tomography (CT)
pulmonary angiography, and right ventricular dysfunction or
injury detected by brain natriuretic peptide and troponin
testing, allow further risk stratification of clinically stable
patients with PE [14].
Confirmatory diagnosis in suspected
high-risk PE
In patients with suspected high-risk PE, CT pulmonary
angiography is the preferred technique to confirm the diag-
nosis (Fig. 1) [3]. Echocardiography is an alternative if CT
pulmonary angiography is unavailable or the patient is too
unstable. In haemodynamically unstable patients, acute pul-
monary hypertension and right ventricular overload seen on
echocardiography may justify a decision for thrombolysis
G. Meyer
or embolectomy, particularly when other tests cannot be
performed (Fig. 1) [3].
Confirmatory diagnosis in suspected
non-high-risk PE
If a diagnosis of non-high-risk PE is suspected, the first step
is to assess the clinical probability of PE using a standard-
ized clinical prediction rule (Fig. 1) [3]. According to the
result, patients can be divided into three (low, interme-
diate or high probability of PE) or two (‘PE unlikely’ and
‘PE likely’) groups, each with different probabilities of PE.
A negative result from a high-sensitivity D-dimer test in
patients with either low—intermediate probability or ‘PE
unlikely’ safely excluded PE in about 30% of outpatients pre-
senting to seven Dutch hospitals with suspected PE [15]. In
patients with either a high clinical probability or an elevated
D-dimer plasma concentration, three options for confirma-
tory diagnosis are available: CT pulmonary angiography,
ventilation—perfusion lung scanning or venous compression
ultrasound [3].
Nowadays, multidetector spiral CT pulmonary angiog-
raphy is considered the standard option for confirming
non-high-risk PE (Fig. 1). Using multidetector spiral CT pul-
monary angiography, the rate of recurrent VTE within 3
months after a negative examination has been reported to
be as low as 0.3% with or without additional ultrasound,
confirming a high sensitivity [16]. Compared with single-
detector CT pulmonary angiography and the first generation
of multidetector devices, the recent 64-detector systems
detect a higher rate of isolated subsegmental PEs, the clin-
ical significance of which has been questioned [17].
Ventilation—perfusion lung scanning has been used to
diagnose PE for many years. A normal ventilation—perfusion
lung scan virtually eliminates the diagnosis of PE, but about
50% of examinations are non-diagnostic and do not by them-
selves allow exclusion or confirmation of the diagnosis of PE
[18]. On the other hand, a high-probability scan is strongly
correlated with a diagnosis of PE, but further tests may be
considered in patients with a low clinical probability risk
score [3].
Compression ultrasound allows diagnosis of DVT in
patients with clinically suspected PE, and the finding of a
proximal DVT in a patient with clinically suspected PE is
accepted as a surrogate for the diagnosis of PE and does not
need to be confirmed by an examination of the chest [3].
However, a normal proximal compression ultrasound does
not exclude the diagnosis of PE [19], and only 10% of exami-
nations are positive in patients with suspected PE [20]. Thus,
compression ultrasound cannot be considered an efficient
diagnostic method for most patients with suspected PE.
Current treatment options for PE
In the relatively few patients with high-risk PE (presence
of shock and/or hypotension), thrombolytic therapy is rec-
ommended. In cases where thrombolytic therapy fails or
is contraindicated, catheter-assisted thrombus removal or
surgical embolectomy provides a back-up option [3,6]. Such
patients should also receive immediate anticoagulation with
Improving patient outcomes in pulmonary embolism 409

Figure 1. Recommended diagnostic pathway for patients with suspected PE—European Society of Cardiology guidelines 2008 [3]. Notes:
CT is defined as not immediately available if the patient’s critical condition allows only bedside diagnostic tests. Confirmation of DVT via
compression venous ultrasound may also assist with clinical decisions. CT is considered diagnostic of PE if the most proximal thrombus is
at least segmental. If single-detector CT is negative, a negative proximal lower limb venous ultrasound is required to safely exclude PE.
If MDCT is negative in patients with a high clinical probability of PE, further investigations may be considered. CT: computed tomography;
CTPA: computed tomography pulmonary angiography; DVT: deep vein thrombosis; echoCG: echocardiography; MDCT: multidetector spiral
computed tomography; PE: pulmonary embolism; RV: right ventricular.

unfractionated heparin with haemodynamic and respira-
tory support as required. Anticoagulation is the mainstay
treatment option for haemodynamically stable patients with
non-high-risk PE and should be started as soon as the diag-
nosis is suspected, at least in patients with a high clinical
probability of PE and no contraindication to anticoagulant
therapy [3,6].
Traditional anticoagulants for the treatment
of PE
The traditional parenteral anticoagulants employed in
the initial treatment of non-high-risk PE include LMWH,
intravenous or subcutaneous unfractionated heparin or fon-
daparinux. Except for patients with VTE and cancer, LMWH
is normally given for the first 5—7 days of treatment and is
overlapped with and followed by treatment with an oral VKA
until the international normalized ratio reaches between
2.0 and 3.0 [3,6]. Owing to their slow onset of action,
VKAs must initially be used in conjunction with the faster-
acting parenteral anticoagulants. During treatment with a
VKA, patients require frequent coagulation monitoring to
maintain treatment within a therapeutic range (interna-
tional normalized ratio 2.0—3.0). The initial dosage varies
greatly between patients and, because of drug and food
interactions, the subsequent dosage may vary according to
changes in associated treatment and diet. Even under con-
trolled conditions, the time in the therapeutic range usually
does not exceed 65% [21—24]. VKAs represent one of the
most frequent causes of referral to emergency departments
because of adverse drug reactions, especially in the elderly
[25]. These limitations underscore the need for simpler
anticoagulant drugs for the initial and long-term treatment
of PE.
410
Direct oral thrombin and Factor Xa inhibitors
for the treatment of PE
A series of novel anticoagulant drugs have recently been
developed. These drugs are direct inhibitors of Factor IIa
(thrombin) or Factor Xa, are not subject to food interac-
tions and have minimal drug interactions compared with
VKAs. They can be administered orally at a fixed dosage
without the need for routine coagulation monitoring [26].
Among these drugs, rivaroxaban, dabigatran, apixaban and
edoxaban have been tested for the initial and/or secondary
prevention of VTE in large phase III studies [21—24,27—30].
In 2012, rivaroxaban became the first direct oral antico-
agulant to be approved for the treatment of DVT and PE
and the prevention of recurrent VTE [31,32]. In contrast to
the combination of LMWH and VKA, rivaroxaban provides a
fixed-dose, single-drug approach to the initial and contin-
ued treatment of PE in patients who are haemodynamically
stable and do not require thrombolysis or embolectomy.
Phase III studies of the direct oral
anticoagulants in the treatment of acute
VTE
The EINSTEIN PE study was an open-label, randomized,
non-inferiority study that compared oral rivaroxaban with
standard therapy in patients with acute, symptomatic PE
with or without DVT [23]. Among other criteria, patients
were excluded if they had haemodynamic instability, cre-
atinine clearance (CrCl) < 30 mL/min, clinically significant
liver disease, had received therapeutic parenteral anti-
coagulation for > 48 hours, or more than a single dose of
a VKA before randomization. Rivaroxaban was given at a
dose of 15 mg twice daily for the first 3 weeks followed
by 20 mg once daily. Standard therapy was subcutaneous
enoxaparin 1.0 mg/kg twice daily followed by either war-
farin or acenocoumarol for 3, 6 or 12 months. A total
of 2419 patients were assigned to rivaroxaban and 2413
to standard therapy. Recurrent VTE occurred in 2.1% of
patients who were given rivaroxaban compared with 1.8%
who received standard therapy (P = 0.003 for non-inferiority;
Fig. 2). Major or non-major clinically relevant bleeding
occurred in 10.3% and 11.4% of patients, respectively (haz-
ard ratio [HR] 0.90, 95% confidence interval [CI] 0.76—1.07;
P = 0.23; Fig. 2). Major bleeding occurred in 1.1% and
2.2% of patients, respectively (HR 0.49, 95% CI 0.31—0.79;
P = 0.003), representing a 51% relative risk reduction (Fig. 2)
[23]. Subgroup analysis demonstrated that rates of recur-
rent VTE and bleeding were similar in both treatment groups
regardless of age, weight, sex, renal function or extent of
PE.
The EINSTEIN DVT study enrolled patients with acute,
symptomatic proximal DVT without symptomatic PE [22].
General exclusion criteria were similar to those applied
in EINSTEIN PE. As in EINSTEIN PE, rivaroxaban was non-
inferior to standard therapy (P < 0.001 for non-inferiority)
[22]. Major or non-major clinically relevant bleeding and
major bleeding alone occurred with similar incidences in
both treatment groups [22]. In a pooled analysis of EIN-
STEIN DVT and EINSTEIN PE, rivaroxaban was non-inferior
G. Meyer
to standard therapy for efficacy and led to a 46% relative
risk reduction in major bleeding (Fig. 3) [33]. Rivaroxa-
ban was associated with a significant improvement in net
clinical benefit (defined as the composite incidence of recur-
rent VTE and major bleeding) in fragile patients (age > 75
years, CrCl < 50 mL/min or weight ≤ 50 kg; HR 0.51, 95% CI
0.34—0.77), primarily as a result of a 63% relative risk reduc-
tion in major bleeding in this group compared with standard
therapy [33].
AMPLIFY (Apixaban for the Initial Management of Pul-
monary Embolism and Deep-Vein Thrombosis as First-line
Therapy) was a randomized, double-blind study comparing
apixaban (10 mg twice daily for 7 days followed by 5 mg
twice daily for 6 months) with conventional therapy (subcu-
taneous enoxaparin followed by warfarin) in 5395 patients
with acute VTE [24]. Reasons for ineligibility included con-
traindications to standard anticoagulant therapy, cancer,
provoked thrombosis without a persistent risk factor for
recurrence, if < 6 months of treatment was planned, treat-
ment with > 165 mg aspirin daily or CrCl < 25 mL/min. No
more than two doses of once-daily LMWH, fondaparinux or
VKA; three doses of twice-daily LMWH; or > 36 hours of con-
tinuous intravenous heparin were permitted. Apixaban was
non-inferior to standard therapy for the primary efficacy
outcome of recurrent symptomatic VTE or VTE-related death
(P < 0.001 for non-inferiority), with a 69% relative risk reduc-
tion in major bleeding (Fig. 3) [24]. Outcomes in subgroups,
including elderly patients and those weighing > 100 kg were
consistent with the overall population.
RE-COVER was a double-blind, randomized trial that com-
pared 6 months of treatment with dabigatran (fixed dose
of 150 mg twice daily) with dose-adjusted warfarin ther-
apy in patients with proximal DVT or PE [21]. Patients were
excluded for reasons of haemodynamic instability, symptoms
lasting > 14 days, recent unstable cardiovascular disease,
high bleeding risk, clinically significant liver disease,
CrCl < 30 mL/min, or a requirement for aspirin > 100 mg/day.
All patients were initially given an approved parenteral
anticoagulant (generally unfractionated heparin or LMWH).
Dabigatran was non-inferior to standard therapy for the pre-
vention of recurrent VTE (P < 0.001 for non-inferiority), with
a significant reduction in clinically relevant bleeding but
not major bleeding (Fig. 3) [21]. Outcomes were consistent
regardless of variations in demographic factors. The RE-
COVER II study had essentially the same design as RE-COVER
and the results, recently published, support the outcomes
of RE-COVER [27].
Edoxaban was compared with warfarin in the Hokusai-
VTE study, a randomized, double-blind, non-inferiority study
of 8292 patients with VTE [30]. Patients were excluded if
they had contraindications to standard anticoagulant treat-
ment, had received > 48 hours of heparin treatment or more
than one dose of VKA, had cancer with anticipated long-
term LMWH treatment, were receiving aspirin > 100 mg/day
or dual antiplatelet therapy, or had CrCl < 30 mL/min. As
with dabigatran, treatment with edoxaban (60 mg once daily
or 30 mg once daily in patients with CrCl 30—50 mL/min
or weight ≤ 60 kg or who were receiving treatment with
potent P-glycoprotein inhibitors) was initiated after initial
parenteral anticoagulation [30]. Edoxaban was non-inferior
to standard therapy for the prevention of symptomatic
recurrent VTE (P < 0.001 for non-inferiority) [30]. Clinically
Improving patient outcomes in pulmonary embolism 411

Figure 2. Primary efficacy, safety and net clinical benefit outcomes in patients with PE with or without DVT in the phase III EINSTEIN
PE study of single-drug rivaroxaban compared with standard therapy (enoxaparin/VKA). Efficacy endpoints (recurrent VTE and net clinical
benefit) were evaluated in the intention-to-treat population. Bleeding outcomes were evaluated in the safety population. Net clinical benefit
was defined as the composite incidence of recurrent VTE and major bleeding. Clinically relevant bleeding was defined as the composite
of major and non-major clinically relevant bleeding. CI: confidence interval; DVT: deep vein thrombosis; PE: pulmonary embolism; VKA:
vitamin K antagonist; VTE: venous thromboembolism.

Figure 3. Published, phase III clinical studies of direct oral anticoagulants for the treatment of acute venous thromboembolism
[21,24,30,33]. a 12 months after the start of treatment. CI: confidence interval; OAC: oral anticoagulant; VTE: venous thromboembolism.
412
relevant bleeding was significantly reduced with edoxaban,
but major bleeding was not (Fig. 3) [30]. Efficacy with
edoxaban was also confirmed in a subset of patients with
severe PE (N-terminal prohormone of brain natriuretic pep-
tide level ≥ 500 pg/mL) [30].
Secondary prevention of VTE with direct
oral anticoagulants
Patients with unprovoked PE (i.e. occurring in the absence
of a major risk factor such as trauma, surgery, immobiliza-
tion or cancer) have a high risk of recurrent VTE after the
end of anticoagulant treatment [5]. Approximately 5—10%
of these patients will have a recurrent event during the first
year after a 3- or 6-month course of anticoagulant ther-
apy, and about 30% of them will have a recurrence within
5 years [34]. Dabigatran, rivaroxaban and apixaban have
been investigated for the prevention of these recurrent
events. Dabigatran and rivaroxaban were administered using
a single-dose regimen (150 mg twice daily for dabigatran and
20 mg once daily for rivaroxaban), whereas apixaban was
given at two different doses of 2.5 mg and 5 mg twice daily
[22,28,29]. The three drugs achieved a relative risk reduc-
tion of recurrent VTE compared with placebo of 64—92%
(Fig. 4). This was obtained at the cost of a significant
Figure 4. Published phase III clinical studies of direct oral anticoagulants for the prolonged treatment of acute VTE [22,28,29]. a P = 0.11.
b P = 1.0. bid: twice daily; CI: confidence interval; OAC: oral anticoagulant; od: once daily; VTE: venous thromboembolism.
G. Meyer
increase in major plus non-major clinically relevant bleed-
ing with rivaroxaban and dabigatran, although not apixaban,
but without a significant increase in major bleeding for any
agent. The net increase in major bleeding did not exceed
1%, whereas the net decrease in recurrent VTE (plus or
minus VTE-related or all-cause mortality, depending on the
study) varied from 5.2% to 7.8% [22,28,29]. Only dabiga-
tran has been compared with warfarin for the secondary
prevention of VTE [28]. The two treatments were equally
efficacious for the prevention of recurrent VTE (P = 0.01
for non-inferiority) and the incidence of major bleeding
was similar (HR 0.52, 95% CI 0.27—1.02). Dabigatran was
associated with an increase in the rate of acute coronary
syndromes (0.9% vs 0.2%; P = 0.02) [28].
Discussion
Previous results in patients with VTE explain why, in phase
III trials, dabigatran and edoxaban were started only after a
standard course of parenteral treatment with LMWH, and
why rivaroxaban and apixaban were started immediately
after randomization, but at a higher dosage during the acute
treatment phase. These treatment schedules were selected
to optimize the efficacy of the direct oral anticoagulant regi-
mens during the initial period of treatment where the risk
of recurrent VTE is high. Previous experience with ximela-
Improving patient outcomes in pulmonary embolism
gatran and idraparinux, which were the first drugs designed
to challenge the usual combination of heparin or fonda-
parinux and warfarin, suggested a higher risk of recurrent
VTE with the new compounds during the first month of
therapy [35,36]. These results, and those of other stud-
ies, highlight the need for a highly effective anticoagulation
regimen early in the course of VTE.
The results of clinical studies of direct oral anticoagu-
lants were obtained in selected patients who were relatively
young and had few associated diseases, but at least for
rivaroxaban [22,23] and edoxaban [30], the results also
apply for important subgroups of PE patients. Additionally,
the VKA time in therapeutic range was potentially higher in
these studies than in real life, and so VKAs can be consid-
ered to have been given optimally in these trials. Therefore,
the observed benefits of the direct oral anticoagulants may
be more pronounced in routine clinical practice than in the
study settings. Several registries and real-world studies are
underway or planned to investigate the epidemiology and
treatment outcomes of VTE encountered in daily clinical
practice, including in groups of patients who would nor-
mally be excluded from clinical trials. Established registries
include the Registro Informatizado de Pacientes con Enfer-
medad TromboEmbólica (RIETE), which has recruited more
than 39,000 patients since its inception in 2001 and has,
among other important data, provided predictive variables
for major bleeding events in patients who present with acute
VTE [37].
More recently, two registries have been created to look
specifically at patterns of treatment and outcomes in acute
and long-term management of VTE with direct oral anticoag-
ulants. The Dresden Registry aims to recruit 2000 unselected
adult patients in Germany (http://www.noac-register.de/),
and the Global Anticoagulant Registry in the FIELD
(GARFIELD) VTE registry will include patients in more than
20 countries (http://www.tri-london.ac.uk/garfield-vte).
Conclusions
Accurate diagnosis and risk stratification of patients with
PE, together with the simplified treatment that the direct
oral anticoagulants can provide, are likely to improve
patient outcomes and reduce mortality associated with this
disease.
Disclosure of interest
G.M. clinical trials: as an investigator for Bayer Health-
Care Pharmaceuticals, Daiichi Sankyo, Leo Pharma and
Sanofi-Aventis. One-off interventions: advisory activity
for Bayer HealthCare Pharmaceuticals, Leo Pharma and
Pfizer. Conferences: invitations as a contributor for
Bayer HealthCare Pharmaceuticals, Boehringer-Ingelheim,
Leo Pharma, and Sanofi-Aventis. Conferences: invita-
tions to attend from Bayer HealthCare Pharmaceuticals,
Boehringer-Ingelheim and Leo Pharma. Research grants or
support to the author’s institution from Bayer HealthCare
Pharmaceuticals, Boehringer-Ingelheim, Leo Pharma and
Sanofi-Aventis.
413
Acknowledgements
The author would like to acknowledge Stephen Purver, who
provided editorial support with funding from Bayer Health-
Care Pharmaceuticals and Janssen Scientific Affairs, LLC.
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