Clinical Review of

Pulmonary Embolism:
D i a g n o s i s , P ro g n o s i s ,
a n d Tre a t m e n t
James M. Hunt, MD*, Todd M. Bull, MD

KEYWORDS
 Pulmonary embolism  Venous thromboembolic disease
 Biomarkers  Chronic thromboembolic disease

Venous thromboembolism (VTE) refers to the pathologic formation of a thrombus

within the veins, and includes both pulmonary embolism (PE) and deep venous throm-
bosis (DVT). VTE is a common disease causing significant morbidity, mortality, and
substantial socioeconomic costs. Consequently, many resources have been devoted
to improving its diagnosis and management; resulting in an increasing number of well-
designed clinical trials over the past decades. These trials have significantly advanced
our understanding of the optimal approach toward diagnosis and treatment of VTE,
and are helping resolve existing controversies. The clinical landscape of VTE manage-
ment, however, continues to evolve rapidly as novel medications, imaging techniques,
procedures, and devices present new exciting options and challenges.

EPIDEMIOLOGY AND RISK FACTORS

Epidemiology
Although the exact incidence and prevalence of VTE is unknown, modeling based on
epidemiologic studies estimates more than 900,000 incident or recurrent cases in the
United States alone.1 PE is a substantial subset of these cases, with hospital-based
studies estimating it is responsible for 200,000 to 300,000 hospital admissions per
year.2 The majority of deaths secondary to VTE are caused by PE, with a 3-month
disease specific mortality rate of 10% causing an estimated 30,000 to 50,000 deaths
annually.3–5 Symptomatic PE carries an 18-fold higher risk of early death when

Financial disclosures: Dr Hunt has no competing financial disclosures. Dr Bull has received grant
support from the NIH/NHLBI. He has served as a consultant to Actelion.
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver,
Anschutz Medical Campus, Research 2–9th Floor, Mail Stop C-272, 12700 East 19th Avenue,
Aurora, CO 80045, USA
* Corresponding author.
E-mail address: James.hunt@ucdenver.edu

Med Clin N Am 95 (2011) 1203–1222

doi:10.1016/j.mcna.2011.08.003 medical.theclinics.com
0025-7125/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
1204 Hunt & Bull

compared with DVT alone, and the initial clinical presentation is sudden death in 20%
of all cases2,6 The epidemiology for Europe and other parts of the world is generally
similar.7
Although the incidence of VTE and PE has not changed dramatically over the past
25 years,8 the overall mortality rate from PE has decreased substantially in the past
several decades.2,9,10 This decrease has been attributed to improved detection and
treatment of DVT, risk-factor modification including protocolization of VTE prophy-
laxis, and/or improvements in PE diagnostic tests that have increased the specificity
and sensitivity of disease diagnosis. Regardless, the annual hospital mortality has
decreased by roughly 30% from 1998 to 2009.2

Risk Factors
Rudolph Virchow (1821–1902) first coined the term embolism after observing at
autopsy blood clots wedged in the pulmonary arteries.11 From his extensive writings
and descriptions of VTE, later investigators coined the term Virchow’s Triad, which
consists of vascular endothelial injury, hypercoagulability, and venous stasis as the
combination of host factors that predispose to VTE.12 VTE risk factors are traditionally
categorized as either acquired or genetic (inherited thrombophilia).
Inherited thrombophilia
Inherited thrombophilias may result in increased levels or function of coagulation
factors (activated protein C resistance, factor V Leiden mutation, prothrombin gene
mutation, elevated factor VIII levels), defects of coagulation factor inhibitors (anti-
thrombin, protein C, protein S), and defects in fibrolysis, hyperhomocysteinemia, or
altered platelet function. The majority of published data regarding the inherited throm-
bophilias comes from studies of Caucasian populations with VTE.13–15 It is generally
accepted that patients with a “provoked” VTE, such as those with recent surgery,
trauma, immobilization, malignancy, or certain inflammatory disorders such as lupus
or inflammatory bowel, do not require screening of the hereditary thrombophilias.16
Screening patients with unprovoked VTE, however, is still a matter of debate, and it is
recommended to consult with a coagulopathy specialist before initiating an evaluation.
Acquired risk factors
Acquired risk factors account for the majority of VTE cases. The most significant
acquired risk factor for incident VTE is advancing age, especially as age advances
beyond 60 years. The most significant risk factor for recurrent VTE is a previous
episode of VTE. Other important acquired risk factors include obesity, malignancy,
surgery, trauma, hormone replacement therapy, pregnancy, and heparin-induced
thrombocytopenia. Roughly 50% or more of patients with VTE will have multiple risk
factors,17 both acquired and inherited, validating the pathophysiologic and clinical
relevance of Virchow’s Triad.

DIAGNOSIS AND EVALUATION

The diagnosis of PE often presents a significant challenge. The clinical presentations

of pulmonary embolic disease are diverse and often incongruous; many patients will
experience only a subset of the characteristic symptoms, may have atypical symp-
toms, or may even be asymptomatic. The signs and symptoms of PE, such as tachy-
cardia, dyspnea, chest pain, hypoxemia, and shock, overlap considerably with other
common diseases such as coronary artery disease, congestive heart failure, pericar-
ditis, pneumonia, and exacerbations of chronic obstructive pulmonary disease.
Further confounding diagnosis and treatment is that many patients may have a PE
 Clinical Review of Pulmonary Embolism 1205

in addition to one of the aforementioned diagnoses. The clinical consequences of PE

can be equally as diverse, ranging from incidental to catastrophic hemodynamic
collapse and sudden death. Consequently, several clinical prediction tools have
been developed which, combined with the history and examination, aid clinicians in
the choice of appropriate diagnostic tests and therapeutic interventions. Given the
high prevalence, diverse symptoms, and mortality associated with PE, it is essential
that a high clinical index of suspicion be maintained while using these clinical tools
in an efficient and expeditious fashion.

Medical History
Given the diversity and complexity in the clinical presentation of PE, it is crucial to
identify risk factors for VTE by performing a careful history. Specifically, the patient’s
personal and family history of prior VTE, coexisting medical conditions, functional
status, travel history, and current medications are fundamental. Recent immobiliza-
tion, myocardial infarction, cerebrovascular accident, surgery, and recent (within 30
days) trauma are all major risk factors for VTE. Additional major risk factors include
advanced age, malignancy, prior VTE, known thrombophilia (inherited or acquired),
and indwelling venous catheter. Moderate risk factors include use of estrogen or
hormone replacement therapy, obesity, and family history of VTE. These risk factors
are used in clinical prediction tools, such as the Wells criteria and the Geneva score,
to assess the patient’s pretest probability of PE (see the section Clinical Tools).

Clinical Assessment
As previously mentioned, the typical signs and symptoms of PE are nonspecific and
include tachypnea, rales, tachycardia, a fourth heart sound, a loud S2, dyspnea, pleu-
ritic chest pain, cough and, in a minority of patients, hemoptysis. Despite, or perhaps
because of the complexity in diagnosing PE, clinical judgment is a critical first step in
the evaluation and is heavily weighted in diagnostic algorithms. The 1990 PIOPED
(Prospective Investigation of Pulmonary Embolism Diagnosis) study first highlighted
the importance of a clinician’s suspicion in predicting the probability of PE.18
In PIOPED, prior to ventilation/perfusion (V/Q) scan and pulmonary arteriogram,
physicians recorded their clinical suspicion (low, intermediate, or high probability) of
PE in patients evaluated for the disease. A very important finding of PIOPED was
that diagnosis or exclusion of PE required concordance between the clinical impres-
sion and radiographic findings by V/Q (normal, low, intermediate, or high). There have
been many subsequent attempts to quantify and standardize the definition of “clinical
impression,” 2 of the most widely known being the Wells and Geneva scores, dis-
cussed in the Clinical Tools section.

Electrocardiography and Chest Radiography

Chest radiographs (CXR) and electrocardiograms (ECG) are commonly used in the
initial evaluation of patients with chest pain or dyspnea. Both lack adequate sensitivity
or specificity for diagnosis or exclusion of PE, and do not figure prominently in diag-
nostic algorithms. It is nevertheless important to appreciate findings that are sugges-
tive of PE. In the case of ECG, evidence of right heart strain should raise suspicion for
PE. Signs of right ventricular (RV) strain include T-wave inversions in the anterior pre-
cordial leads, new right bundle branch block, or the S1Q3T3 complex (deep S-wave in
lead I, and a Q-wave with T-wave inversions in lead III, Fig. 1). Other common ECG
abnormalities include sinus tachycardia and atrial fibrillation.
Like ECG, CXR is insensitive for PE, but is helpful by excluding other causes of chest
pain such as pneumonia or pneumothorax. Although by itself not sensitive or specific
1206 Hunt & Bull

Fig. 1. Electrocardiographic (ECG) findings of right ventricular (RV) strain: This ECG demon-
strates many classic findings of right heart strain and hypertrophy. The deep S-wave in lead I,
Q-wave in lead III, and inverted T wave in lead III (S1Q3T3 complex) is not sensitive, but is
specific for RV strain and should prompt consideration for pulmonary embolism. The in-
verted T waves in the precordial and inferior leads also suggest RV strain. Of note, there
is evidence of RV hypertrophy with tall R waves in the right precordial leads V1-2, and
borderline right atrial enlargement. Right bundle branch block can also be seen in patients
with acute pulmonary embolism, but is not present in this case. This patient was later diag-
nosed with chronic thromboembolic pulmonary hypertension.

for PE, ipsilateral elevation of the diaphragm on the affected side can be seen. Other
suggestive signs of PE include a wedge-shaped infiltrate (Hampton hump), focal olige-
mia (Westermark sign), or an enlarged right descending pulmonary artery (Palla sign).

Laboratory Tests
The initial evaluation of patients with dyspnea or chest pain includes several laboratory
tests that can aid in the diagnosis and/or prognosis of PE. Common tests include D-
dimer, arterial blood gas (ABG), B-type natriuretic peptide (BNP), serum sodium, and
troponin. D-dimer is included in many diagnostic algorithms, as a normal level carries
a high negative predictive value and is helpful to exclude PE in low to intermediate clin-
ical risk groups. Although not a part of official algorithms at this time, an elevation in
either troponin or BNP, or a depression in serum sodium (hyponatremia) has been sug-
gested as a poor prognostic indicator.16,19,20 Research indicates these markers can
differentiate between low and intermediate risk for PE-related complications, including
hemodynamic collapse and death.21,22 Finally, ongoing investigations continue to
identify new biomarkers of potential use in the prognosis or diagnosis of PE. One
such novel biomarker, growth differentiation factor 15 (GDF-15), is also be discussed
herein.23

Arterial blood gas

Obtaining an ABG documenting an elevation in alveolar-arterial (A-a) gradient was
thought to aid in the diagnosis of PE. It has subsequently been demonstrated,
however, that a normal A-a gradient lacks sufficient negative predictive value to
exclude PE.24 Although PE causes increased alveolar dead space and shunt, patients
with acute PE will often have hypocapnia and respiratory alkalosis. Also, the partial
 Clinical Review of Pulmonary Embolism 1207

pressure of oxygen (PO2) may be decreased, normal, or increased. Thus, although an

ABG may be indicated for other reasons (dyspnea, hypoxemia, or hypercapnia), its
utility in the evaluation of PE is questionable.

D-dimer
D-dimer is a plasmin-derived fibrin degradation product commonly included in the
initial evaluation of patients with dyspnea or chest pain. D-dimer represents a direct
method to measure endogenous fibrinolysis following a thrombotic event, such as
a PE, and is an important screening tool in patients with suspected VTE.25 Although
extremely sensitive, D-dimer lacks specificity for VTE (30%–75%). Many other condi-
tions (eg, trauma, inflammation, surgery) can elevate plasma D-dimer levels; therefore,
an abnormal laboratory result has a low positive predictive value for VTE. The strength
of the D-dimer is its high sensitivity and ability, with a normal test, to essentially rule out
VTE in low-risk and intermediate-risk patients (see Clinical Tools section).
The exact way in which D-dimer is measured has gone through considerable refine-
ment over the past 25 years. Initially several different assays were available, including
quantitative enzyme-linked immunosorbent assay (ELISA), quantitative latex aggluti-
nation, semiquantitative agglutination latex, and whole blood agglutination. These
assays all varied in their sensitivity and specificity, which presented clinicians with
a challenge to correctly interpret results. ELISA, however, has now been established
as the standard D-dimer test, due to its superior sensitivity and high negative predic-
tive value.26 Typically a level greater than 500 ng/mL is considered abnormal. When
combined with a low clinical probability of VTE, a normal D-dimer level (value <500
ng/mL) has a 99% negative predictive value for PE. This finding was demonstrated
in the Christopher study, in which the incidence of PE was on 0.5% at 3 months in
patients with a low probability score (by the “modified” Wells criteria) and a D-dimer
level less than 500 ng/mL.27 Other VTE studies looking at outcomes have had similar
results, with D-dimer sensitivities ranging between 92% and 99%. In patients with
a high clinical suspicion, however, a normal D-dimer cannot adequately rule out
VTE, and additional testing is warranted (see Clinical Tools section).27

B-type natriuretic peptide

Released by ventricular myocardial cells in response to wall stretch and volume over-
load, BNP is a prognostic (not diagnostic) biomarker for PE. In the presence of PE,
elevated BNP levels generally indicate RV strain due to elevated pulmonary vascular
resistance in the clot-burdened lungs. Clinically, BNP levels differentiate between
low and intermediate risk of PE-related complications, and alert the clinician to patients
at increased risk who are otherwise hemodynamically stable. When measured within 4
hours of admission for PE, elevated BNP levels (>90 pg/mL) have a sensitivity of 85%
and specificity of 75% in predicting PE-related clinical outcomes such as need for
emergent thrombolysis, mechanical ventilation, vasopressor therapy, emergency
surgical embolectomy, cardiopulmonary resuscitation, or death.28 Conversely, normal
BNP values in the setting of acute PE have a 97% to 100% negative predictive value for
in-hospital death.29 Given its short half-life and delay in release, if symptoms have been
present for less than 6 hours a repeat test is warranted.

Troponin
Released by damaged myocardial cells, cardiac troponins are extremely sensitive and
specific markers of cardiac ischemia and infarction. When elevated in acute PE, tropo-
nins are presumed to represent myocyte ischemia and microinfarction due to acute
RV strain. Approximately 30% to 50% of patients with large PE will have elevations
in troponins I and T that are mild and short-lived when compared with acute coronary
1208 Hunt & Bull

syndromes. Similar to BNP, elevated troponin levels correlate with worse RV function
and a high incidence of complications while normal troponin T levels have a 97% to
100% negative predictive value for in-hospital death.19,21 Although BNP and troponins
are not a part of diagnostic algorithms at this time, this may change in the future given
their usefulness in prognosis and triage of patients.

Growth differentiation factor 15

GDF-15 is a distant member of the transforming growth factor b family of cytokines,
and is upregulated in cardiomyocytes in response to stress such as pressure overload
or ischemia. GDF-15 levels may also be elevated because of cancer, diabetes,
congestive heart failure, or renal failure. A recent prospective cohort study demon-
strated GDF-15 to be an independent predictor of PE-related complications including
need for vasopressors, mechanical ventilation, cardiopulmonary resuscitation, or
death.23 In this cohort, a cutoff of 4600 ng/L had a positive predictive value of 0.52
and negative predictive value of 0.95 for these PE-related complications. Further
studies are needed to validate these findings, but GDF-15 is a promising new prog-
nostic biomarker with potentially superior differentiating power to BNP or troponins.

Hyponatremia
Hyponatremia has been well described as a poor prognostic indicator in a variety of
disease processes including congestive heart failure, liver failure, and pulmonary
hypertension. Recently, several publications have discussed the prognostic utility of
hyponatremia in acute PE. A retrospective analysis of 13,728 patient hospitalizations
found serum sodium levels of less than 135 mmol/L in 2907 patients (21.1%).20
Sodium levels less than 130 mmol/L were independently associated with increased
30-day mortality and readmission. The investigators also found serum sodium levels
to improve the accuracy of the pulmonary embolism severity index (PESI) classifica-
tion of patients into low-risk, intermediate-risk, and high-risk groups (see Clinical Tools
section). As with GDF-15, validation of these findings awaits further independent
prospective studies.

Advanced Imaging
Venous compression ultrasonography
When initial diagnostic tests are inconclusive, ultrasonography of the deep venous
system is a useful adjunctive test in the diagnosis and treatment of PE. Pragmatically
the approach to treatment (anticoagulation) of both DVT and submassive PE is the
same, and thus a positive ultrasonogram for DVT obviates the immediate need for
further diagnostic studies to demonstrate PE. A negative ultrasonogram, however,
is a somewhat more complicated result and requires appreciation of several caveats.
Ultrasonography of the proximal leg veins detects DVT in roughly 1% to 5% of patients
with clinical symptoms consistent with PE but nondiagnostic chest imaging.30–33 Also,
DVT is detectable by ultrasonography in only approximately 50% of patients with an
acute PE. Thus, a negative ultrasonogram does not rule out PE. It does, however,
slightly reduce the probability of PE and connotes a lower risk of short-term VTE
complications should therapeutic anticoagulation be withheld.34

Echocardiogram
Transthoracic or transesophageal echocardiography has limited diagnostic value for
PE, due to its low sensitivity and specificity. For critically ill patients too unstable for
transport, echocardiography can suggest the diagnosis of PE by demonstrating RV
dilatation or hypokinesis. Rarely, thrombus within the pulmonary arteries or right
ventricle can be visualized on echo. More commonly, acute changes in the RV
 Clinical Review of Pulmonary Embolism 1209

pressure, size, and function are observed, indicating increased RV strain and pulmo-
nary arterial pressures suggestive of PE in the absence of alternative diagnoses (Fig. 2).
Although of limited value in the diagnosis of PE, echocardiography is of great prog-
nostic use in stratifying risk for patients with acute PE. Numerous studies have demon-
strated that RV dysfunction or dilatation in acute PE is associated with worse
outcomes, including increased mortality.35–37

Ventilation/perfusion lung scan

As previously mentioned, the PIOPED study established the role of the V/Q scan in the
diagnosis of PE.18 By correlating the V/Q results (normal, low, high, or indeterminate
probability) with a similar clinical impression (low, intermediate, or high probability),
the diagnosis or exclusion of PE can be made (Fig. 3). It must be noted that a normal
V/Q test essentially rules out PE as a diagnosis. Further testing, often by pulmonary or
computed tomography (CT) angiogram, is required in patients with discordant or inter-
mediate results. In recent years CT angiography has replaced the V/Q scan as the
favored diagnostic test (see CT Angiogram section). V/Q scan remains, however, an
important alternative to CT in patients with pregnancy, contrast allergy, or renal insuf-
ficiency. V/Q may be the modality of choice to evaluate patients for chronic thrombo-
embolic pulmonary hypertension (CTEPH) (see Chronic Thromboembolic Disease
section).

Fig. 2. Echocardiogram of a patient with an RV dysfunction secondary to pulmonary throm-

boembolic disease. (A) Color Doppler of the large tricuspid regurgitant jet. (B) M-mode of
the tricuspid jet, estimating severely elevated pulmonary arterial pressures. (C) Four-
chamber view demonstrating enlarged right ventricle and right atria with a flattened
septum indicated elevated right-sided ventricular pressures.
1210 Hunt & Bull

Fig. 3. (A) Ventilation/perfusion scan. Ventilation images are below their respective perfu-
sion images. There is significant heterogeneity, especially at the lung apices and bases,
consistent with thromboembolic disease. (B) Spiral computed tomographic angiogram of
the chest, demonstrating a large saddle pulmonary embolism with multiple filling defects
of the smaller pulmonary arteries. Modern multidetector computed tomography scanners
have the ability to reliably detect pulmonary emboli in the subsegmental branches of the
pulmonary artery.

CT angiogram
Over the past 10 years, CT pulmonary angiography (CTA) has become the favored
diagnostic study in the evaluation of PE (see Fig. 3). There are several practical advan-
tages of CTA, including: (1) common availability, especially after hours; (2) rapid inter-
pretation; (3) direct visualization of the thrombus; (4) evaluation of the chest for
alternative or concomitant diagnoses; and (5) simultaneous evaluation for DVT and
PE when both the chest and lower extremity deep veins and pelvic veins are imaged.
The ability to evaluate the chest for both PE and alternative pathology is not trivial. Up
to 75% of patients with suspected PE will actually have an alternative diagnosis, some
of which can be just as serious and readily identifiable by CTA, such as thoracic aortic
dissection or pneumonia.27,38
When evaluating the efficacy of CTA to diagnose PE, it is important to appreciate the
improvements in CT technology and the extent these have increased the sensitivity
and specificity of CTA over the past 10 years. Early publications of CTA used
single-detector scanners that were specific (>90%) but relatively insensitive
(w72%), meaning they could not reliably exclude PE.39,40 Multidetector scanners
have significantly improved the sensitivity and specificity as well as the positive and
negative predictive value of CTA. Recent outcome studies such as the Christopher
study have found the sensitivity and specificity of CTA to be greater than 95%, and
a negative CTA carries a 3-month risk of VTE of 1% to 2%, essentially the same as
a negative pulmonary arteriogram.27,30 Current multidetector scanners allow resolu-
tion and evaluation of PE down to the sixth-order branches of the pulmonary arteries.
In fact, the interobserver agreement for CTA is superior to V/Q scanning, and CTA may
be more sensitive than V/Q for subsegmental PE.41,42 As such, CTA is now the
predominant imaging modality used in diagnostic algorithms for the evaluation of PE.

Pulmonary arteriogram
Long considered the gold standard, pulmonary angiography, also known as digital
subtraction angiography (DSA), is nowadays rarely performed. The reasons for this
are both practical and medical. In practical terms DSA is more expensive than CTA,
 Clinical Review of Pulmonary Embolism 1211

and is often unavailable in smaller centers. In medical terms outcome studies have
found comparable results between DSA and CTA; a negative result with either study
confers approximately a 1% VTE rate within 6 months.18,27,33 Also, because of the
invasive nature of DSA, it carries a greater risk of complications and mortality. The
mortality from DSA has been estimated at 0.5% while 1% may experience major
complications including arrhythmias, hypotension, bleeding, and nephrotoxicity.
DSA is also less commonly performed, resulting in fewer clinicians who have experi-
ence in both performing and interpreting the test. All these factors have recently made
DSA a relatively uncommon test in evaluating acute PE. DSA is still an important test,
however, in the evaluation of patients with CTEPH, as discussed later (see Chronic
Thromboembolic Disease section).
Magnetic resonance imaging
The Prospective Evaluation Of Pulmonary Embolic Disease—3 (PIOPED 3) trial
recently evaluated the efficacy of magnetic resonance angiography (MRA), venog-
raphy (MRV), or the combination of the two in the diagnosis of acute PE.43 The gold
standard used for comparison was a composite end point of CTA, CTA-CTV, V/Q
scan, lower extremity ultrasonography, D-dimer assay, and clinical assessment. Over-
all, MRA and MRA-MRV were found to be poor tests in the diagnosis of PE. Approx-
imately 25% of the 371 patients enrolled in the study had a technically inadequate
MRA, and 48% had either an inadequate MRV or MRA. Considering all patients
enrolled, MRA alone identified only 57% of PEs, and had a sensitivity of only 78%
when only patients with adequate studies were considered. The combined MRA-
MRV studies had a sensitivity of 92%, but only about half of the patients had techni-
cally adequate studies. These poor results are generally ascribed to the technical
difficulties of MRA in identifying abrupt vessel termination and capturing adequate
images of the chest vessels secondary to motion artifact. At this time, MRA-MRV is
recommended only in centers with a great deal of experience, and then only when
all other imaging modalities are contraindicated.
Clinical Tools
Wells criteria and Geneva score
Two of the most widely known and validated diagnostic scoring systems are the Wells
criteria (or modified/dichotomous Wells criteria) and Geneva score.27,44–46 These tools
use a combination of physical examination, history, and vital signs to predict the clin-
ical likelihood of VTE, and thereby inform the appropriate choice of laboratory tests
and imaging studies to either diagnose or exclude PE. Notable differences include
the use of CXR and ABG in the original Geneva score (subsequent versions do not
include these tests), while the Wells criteria use a clinical gestalt in their formula by
assigning points to PE if an “alternative diagnosis is less likely.” Both scores have
been modified and simplified throughout the years, now incorporating many common
variables (although scored differently), and have been found to be equally efficacious
(Table 1).
Pulmonary embolism severity index
Published in 2005 by Aujesky and colleagues,47 the PESI was originally derived from
analysis of 10,354 patients discharged with PE from 186 Pennsylvania hospitals. PESI
risk stratifies patients with PE into low (I and II) and high (III, IV, and V) risk groups. In
contrast to the Geneva score, which requires an ABG and ultrasonography, PESI only
uses data available from a brief history, physical, and vital signs. Low-risk groups have
2% 30-day mortality and are candidates for home-based care, whereas high-risk
groups have 14% 30-day mortality and warrant hospitalization and close monitoring.
1212 Hunt & Bull

Table 1
Modified Wells criteria, simplified revised Geneva score, and simplified pulmonary embolism
severity index (PESI)

Clinical Probability Tools

Modified Wells Simplified Revised Simplified PESI
Variable (points) Geneva (points) (points)
Clinical DVT symptoms 3 — —
Unilateral lower limb pain — 1 —
Unilateral edema and pain in — 1 —
deep vein
Previous VTE 1.5 1 —
Hemoptysis 1 1 —
Heart rate (bpm)
75–94 — 1 —
>100 1.5 11 —
>110 — — 1
Malignancy 1 1 1
Recent surgery or fracture — 1 —
Recent surgery or 1.5 — —
immobilization
Age (y)
>65 — 1 —
>80 — — 1
Other diagnosis less likely 3 — —
than PE
Heart failure or chronic — — 1
lung disease
Systolic blood pressure — — 1
Arterial oxyhemoglobin — — 1
saturation <90%

The table lists all the clinical variables considered in the most recent published versions of these 3
algorithms. Both the modified Wells criteria and simplified revised Geneva score are used to predict
the likelihood of pulmonary embolism as a diagnosis. In the most recent iteration, the modified
Wells criteria is split in a dichotomous fashion with pulmonary embolism (PE) being likely if >4
points are assigned. PE can essentially be ruled out with an unlikely score and a negative D-dimer.
The simplified revised Geneva score considers PE likely with >2 points. PE is essentially ruled out
with 2 or fewer points and a negative D-dimer. The PESI score assigns a prognostic likelihood of
poor clinical outcome once the diagnosis of PE is established. A simplified PESI score of 0 is consid-
ered low risk, whereas 1 or greater is high risk. Outpatient treatment of PE can be considered in the
low-risk group.
Abbreviations: DVT, deep venous thrombosis; VTE, venous thromboembolism.

The accuracy of PESI has been validated in numerous studies.48–50 Recently, a simpli-
fied version of PESI (sPESI) has been proposed (see Table 1).51 Initial studies indicate
PESI and sPESI are very similar in most respects, although PESI classifies more
patients as low risk than sPESI (41% vs 37%). Finally, a recent prospective study
has reported a high level of PE-related complications in patients classified as low
risk by PESI.52 Further investigation is warranted, but generally this report highlights
the potential limitations of PESI and other prognostic algorithms, and serves to remind
clinicians to exercise their judgment in conjunction with these clinical prediction tools.
 Clinical Review of Pulmonary Embolism 1213

TREATMENT

Prompt anticoagulation has remained the cornerstone of PE treatment for more than
50 years and is life saving. There have been, however, numerous exciting advances in
recent decades, which have added new options with nuanced risks and benefits for
clinicians to weigh. For example, the number and types of anticoagulant medications
available continues to expand; with newer medications providing the ability to treat PE
outside the hospital setting and with the potential to change future recommendations
for duration of treatment. In addition to medications, widely available minimally inva-
sive interventional techniques placing mechanical barriers in the inferior vena cava
can protect patients otherwise ineligible for anticoagulation. Uncertainties remain,
however, regarding the extent of indications for their use and their long-term risks
and benefits. In addition to these newer therapies, clinical trials continue to refine
the use of older treatments such as thrombolysis. Overall, these advances in care
can be categorized into one of two categories: (1) treatment of acute PE or (2) prophy-
laxis against recurrent VTE.

Treatment of Acute Pulmonary Embolism

Anticoagulation
Heparin and vitamin K antagonists Initial treatment with anticoagulation aims at
rapidly blocking the clotting cascade, stabilizing existing clot, and allowing the body’s
endogenous thrombolytic system to dissolve preexisting thrombi. For many years
now, the standard of care has been to treat nonmassive pulmonary emboli with at least
5 days of heparin concomitant with commencement of an oral vitamin K antagonist
(VKA) for long-term anticoagulation, preferably beginning on the first day of treatment.
Intravenous unfractionated heparin (UFH) was the anticoagulant of choice until being
recently eclipsed by subcutaneous low molecular weight heparin (LMWH) in many
situations. LMWH has many advantages over UFH, including more predictable and
reliable anticoagulation, increased patient satisfaction, and the ability to be self-
administered, making home-based treatment a possibility. LMWH was first studied
and approved for the prevention of DVT.53 Studies with LMWH have subsequently
demonstrated it to have similar morbidity and mortality outcomes to UFH in the treat-
ment of DVT and submassive PE.54,55 Of interest, a small number of patients in these
studies were either discharged early or treated entirely at home, and had similar
outcomes to hospitalized patients.56,57 Combined with risk stratification tools (see
Clinical Tools section) such as PESI, LMWH has revolutionized the treatment of
low-risk PE by making home-based treatment possible for some patients. Although
heparin and VKA continue to play a major role in the treatment of PE, advancements
in anticoagulation medications continue to challenge these existing treatment
paradigms.

Factor Xa inhibitors Factor Xa is a common factor in both the intrinsic and extrinsic
coagulation pathways proximal to fibrin formation, making it ideally positioned as
a target for anticoagulation. For many years, the only available factor Xa inhibitor
has been subcutaneously administered fondaparinux.58 With a relatively long half-
life (17 hours), fondaparinux can be administered once daily. A newer factor Xa inhib-
itor with an even longer half-life (80 hours), idraparinux, is currently under evaluation. If
approved, idraparinux it could dramatically simplify administration to once a week.
Both subcutaneous Xa inhibitors undergo renal clearance, and should be used with
caution in patients with renal insufficiency.
Recently, new oral factor Xa inhibitors such as rivaroxaban have undergone evalu-
ation for the treatment of VTE, and appear likely to gain approval. Similar to the
1214 Hunt & Bull

subcutaneous LMWH and fondaparinux, these oral preparations have predictable and
rapid anticoagulation in addition to excellent bioavailability. The Einstein investigators
recently demonstrated “noninferiority” between 3, 6, and 12 months of rivaroxaban
compared with 5 days of subcutaneous enoxaparin followed by 3, 6, or 12 months
of an oral VKA.59 Of note, both groups had similar low levels of bleeding complica-
tions. Included in this report, the investigators published a long-term continuation
study examining patients with VTE who had previously completed 6 to 12 months of
treatment with oral VKA and were then randomized to either placebo or rivaroxaban
for an additional 6 to 12 months.59 There was a small increased risk of significant
bleeding with rivaroxaban versus placebo, but also a significant decrease in recurrent
VTE. Although further study is warranted, the oral Xa inhibitors have the potential to
dramatically change the current management of VTE. As with LMWH, the ease of
use, efficacy, and predictability of anticoagulation could facilitate outpatient manage-
ment. For long-term anticoagulation, oral Xa inhibitors would relieve the burden of
serial laboratory tests needed with the VKAs. One current point of concern, however,
is the lack of an available antidote should rapid reversal of anticoagulation be neces-
sary. The development of a reversal agent, as well as further prospective studies
demonstrating efficacy, economy, and safety, will help establish whether outpatient
and perhaps prolonged therapy (>6–12 months) with oral Xa inhibitors will become
the new treatment of choice.
Direct thrombin inhibitors There are currently several direct thrombin inhibitors (DTIs)
approved for use in humans, including hirudin, bivalrudin, dabigatran, and argatroban.
There are several potential benefits to these medications. For instance, unlike heparin,
which requires antithrombin III, the DTIs do not require cofactors for efficacy. The DTIs
are also able to inactivate clot-bound thrombin and are unaffected by activated
platelet factors such as heparinase and PF4. These potential benefits are offset,
however, by the practical difficulties of using most of these medications, including
unpredictable anticoagulation, need for intensive laboratory monitoring, continuous
intravenous access, and potential drug-drug interactions. The usefulness of the
DTIs currently lies in their lack of interaction with platelets and inability to potentiate
or cause heparin-induced thrombocytopenia. It is in the treatment of this dangerous
condition that the DTIs are primarily used with respect to VTE, although this may
change in the future. Dabigatran is a new DTI with an oral preparation that appears
not to have these drawbacks. It produces predictable anticoagulation, does not
require monitoring, and is approved for treatment of nonvalvular atrial fibrillation,
and may gain approval for treatment of VTE as an alternative to VKAs.60,61

Thrombolysis
Thrombolytics represent a potentially life-saving intervention, but have potential
complications. Consequently, numerous trials have examined the safety and efficacy
of thrombolytics for VTE and PE. Many trials found that thrombolysis improved hemo-
dynamics, imaging studies, and hastened clot resolution but were unable to demon-
strate improved mortality. Of concern, increased risk of severe bleeding was
observed with thrombolysis. Given these results, investigators have sought to identify
subgroups of patients with PE in whom the benefits of thrombolysis outweigh its risks.
Jerjes-Sanchez and colleagues62 planned to enroll 40 patients into a small prospec-
tive, randomized controlled trial comparing streptokinase with placebo in patients with
massive PE and cardiogenic shock. The study was terminated early after enrolling only
8 patients, due to a clear benefit of thrombolysis: all 4 patients receiving streptokinase
and heparin survived, whereas the 4 patients who received only heparin died within 1 to
 Clinical Review of Pulmonary Embolism 1215

3 hours of arrival. It is now widely accepted that the use of thrombolytics in patients with
cardiogenic shock and massive PE is critical, barring any absolute contraindications. In
the vast majority of patients with PE the use of thrombolytics is more nuanced. As dis-
cussed, RV dysfunction in otherwise hemodynamically stable patients is a poor prog-
nostic indicator for both morbidity and mortality. It would stand to reason, then, that this
group of patients would benefit from thrombolysis. To date two large prospective trials,
the Management Strategies and Prognosis of Pulmonary Embolism (MAPPET) and the
Management Strategies and Prognosis of Pulmonary Embolism—3 (MAPPET-3), have
investigated this issue and have reported potential benefits.63,64 Controversy remains,
however, because of criticism regarding the design of these studies.
In MAPPET, patients with PE and RV dysfunction received either heparin with
thrombolytics (alteplase, streptokinase, or urokinase) or heparin alone as a control
group. The use of thrombolytics improved 30-day survival from 11.1% to 4.7%.
Recurrent PE was also decreased from 18.7% to 7.7% in the thrombolytic group.
The study design, however, was not randomized, and the thrombolytic group was
significantly younger and suffered from less cardiovascular and pulmonary disease
than controls. These imbalances in patient selection may have inflated the observed
benefit of thrombolytics, as age and comorbidities are known risk factors for mortality.
A follow-up study by the same group to address these concerns was the random-
ized, prospective trial MAPPET-3. Patients with RV dysfunction and PE were random-
ized to either alteplase and heparin, or a control group receiving only heparin. In
contrast to MAPPET whereby the end point was mortality, MAPPET-3 used
a combined end point of survival and “escalation in therapy.” At its conclusion,
MAPPET-3 demonstrated a significant benefit in this combined end point in favor of
thrombolysis. On closer analysis, however, critics have pointed out that there was
no survival difference between the two groups; the benefit of thrombolytics was
almost entirely attributable to attenuation in “escalation of therapy.” Furthermore,
the primary event leading to escalation of therapy in the control group was the later
use of thrombolytics. The results of MAPPET-3 continue to generate controversy;
several experts cite them as evidence for the benefit of thrombolytics in patients
with PE and RV dysfunction, whereas others are skeptical of these conclusions and
the significance of the reported benefits.

Pulmonary embolectomy
Pulmonary embolectomy is the surgical removal of an acute PE. It is generally
reserved for specific circumstances due to its high reported mortality (up to 30% in
some series), in large part a reflection of the severity of the PE and hemodynamic
instability before surgery.65,66 In general, patients selected for embolectomy have
had a large PE resulting in RV dysfunction and shock, and have failed or have contra-
indications to thrombolytics and anticoagulation.

RECURRENT VTE PROPHYLAXIS

Inferior Vena Cava Filters
Originally conceptualized by Trousseau in 1868, mechanical obstruction of the vena
cava is now a safe, reliable procedure with the introduction of inferior vena cava
(IVC) filters and minimally invasive placement. More recently, the advent of retrievable
IVC filters has broadened the number of patients considered for this procedure. In
general, the 2 most common indications for IVC filter placement are (1) contraindica-
tions to anticoagulation and (2) inability to adequately anticoagulate patients with VTE.
Consideration for IVC filter placement is also given to patients in high-risk situations
(despite adequate anticoagulation) such as trauma patients with lower extremity or
1216 Hunt & Bull

pelvis fractures, patients at high risk of death from PE, and patients with severe pulmo-
nary hypertension and a known DVT. This being said, there is a remarkable lack of data
regarding the use of IVC filters. There is only one published randomized trial of IVC
filter use, demonstrating a decrease in PE incidence in the first 12 days after place-
ment (1.1% vs 4.8%). Follow-up of patients at 2 years found, however, that IVC filters
increased the incidence of DVT (20% vs 11.6%) with a small decreased incidence of
PE (3.4% vs 6.2%).67 An 8-year follow-up of these same patients found a continuation
of the 2-year trends, with an increased incidence of DVT (35.7% vs 27.5%) in patients
with IVC filters, but a more dramatic decrease in PE (6.2% vs 15.1%).68 There were no
differences in mortality or postphlebitic syndrome between the two cohorts. Most but
not all of the patients in the study were on chronic anticoagulation. Given the high rates
of VTE in patients with IVC filters left in place, it is recommended they receive indefinite
anticoagulation.
In patients with a transient increased risk of VTE, retrievable IVC filters are an option.
Retrievable filters theoretically should protect against PE in the short term while avoid-
ing long-term DVT complications. There are, however, no randomized data demon-
strating the outcomes or efficacy of retrievable filters. In general, the retrievable filters
are placed to cover the days while a patient is off anticoagulation or is at increased
risk of VTE, and should be removed as soon as possible to avoid endothelialization.
Current recommendations for duration of deployment vary by filter type and center
expertise, but are usually 2 to 6 weeks.69 Removal after prolonged use is possible,
but comes at increasingly greater risk the longer the device has been in place.70

Management of Inherited Thrombophilia

The acute management of PE in patients with inherited thrombophilia is no different
from that for other patients. Long-term treatment and prophylaxis is somewhat less
clear, as there are no randomized controlled trials addressing the inherited thrombo-
philias. Guidelines suggest permanent anticoagulation in patients with spontaneous
VTE and multiple prothrombotic mutations (either homozygous for a single mutation
or heterozygous for several), any heritable risk factor and a single idiopathic near-
fatal thrombosis such as massive PE or portal, mesenteric, or cerebral thrombosis,
or a spontaneous thrombosis and an antithrombin deficiency or antiphospholipid anti-
body syndrome.16,71,72 Less consensus exists regarding the treatment length after the
first spontaneous VTE and a single heritable mutation. It is recommended that expert
consultation be sought to determine the length of anticoagulation.

Treatment of Cancer-Associated VTE

The incidence of VTE in cancer can be remarkably high, and is affected by several
factors unique to cancer including tumor type, stage, and total tumor burden. Renal
cell carcinoma, for instance, has a 43% incidence of VTE.73 VTE is also a poor prog-
nostic indicator, with increased 6-month mortality in comparison with similar cancer
patients without VTE. The Comparison of LMWH versus Oral anticoagulation Therapy
for the prevention of VTE in patients with cancer (CLOT) study randomized patients to
receive either 6 months of VKA (warfarin) or LMWH (dalteparin).74 Patients receiving
LMWH had less recurrent VTE (9%) than those receiving VKA (17%). Based on these
data, the current recommendation for VTE treatment in patients with cancer is to use
LMWH as the first-line agent.

Chronic Thromboembolic Disease

In the majority of patients who suffer PE, resolution of the thrombus and restoration of
normal pulmonary artery pressures is complete within 30 days of the event. Pengo and
 Clinical Review of Pulmonary Embolism 1217

colleagues75 reported in a prospective incidence study, however, that up to 4% of PE

survivors may develop CTEPH. The natural history of CTEPH is unknown, as most
patients present late in the clinical course, only after becoming symptomatic with
pulmonary artery hypertension (PAH). The predisposing factors to CTEPH are unclear,
although an increased incidence of anticardiolipin antibodies and elevated factor VIII
levels have been reported. It is thought that CTEPH begins with an acute PE (even an
asymptomatic PE) which, instead of undergoing thrombolysis, becomes covered in
endothelial cells. Once endothelialization is complete, the thrombus is protected
from circulating endogenous or exogenous thrombolytics, and over time obstructs
and remodels the pulmonary vasculature, causing PAH.
Overall, untreated severe CTEPH carries a poor prognosis, with 5-year survival esti-
mated at as low as 10%.76 Chronic anticoagulation is part of the treatment, but will not
resolve the organized, endothelialized thrombi. Instead, clot must be physically
removed via pulmonary endarterectomy (PEA), a process by which the endothelialized
thrombi are carefully dissected from the pulmonary artery wall. PEA is the treatment of
choice for CTEPH, but comes with significant morbidity and 5% to 10% postoperative
mortality. Given the complexity and magnitude of PEA, it is recommended to be per-
formed only at experienced centers.
Many patients, in some cases up to half, may be ineligible for PEA because of
comorbidities or distal clot position. Furthermore, some patients may have persistent
or exercise-limiting PAH even after PEA. In such cases, medical therapy is an alterna-
tive. Medical therapy can be divided into two categories: general therapies and those
specific to PAH. General therapies include correcting hypoxemia with supplementary
oxygen, dieresis, indefinite anticoagulation, and digoxin to augment RV contractility.
PAH-specific therapies include 3 categories of medications designed for the treatment
of idiopathic pulmonary arterial hypertension, and include the phosphodiesterase-5
inhibitors (sildenafil, tadalafil), endothelin receptor antagonists (ambrisentan, bosen-
tan), and the prostacyclin analogues (epoprostenol, treprostinil, and iloprost). The
evidence, however, supporting the use of these medications in CTEPH is generally
limited to retrospective studies, case series, and prospective cohort series. When sub-
jected to randomized controlled trials, medical therapies such as iloprost,77 bosen-
tan,78 and sildenafil79 have not shown significant clinical benefit.

SUMMARY

VTE is a rapidly evolving field, with advances in biomarkers, imaging, clinical algo-
rithms, devices, and medications improving our ability to diagnose and treat PE. For
instance, the development of LMWH, CTA, D-dimer, and clinical scoring tools have
all substantially improved diagnostic accuracy and have decreased morbidity and
mortality associated with PE. Questions in the diagnosis and management of PE
persist, however, such as the significance of heritable thrombophilias or the optimal
use of thrombolytics in hemodynamically stable patients with RV dysfunction. In
some cases such as CTEPH, medical therapy is inadequate. Ongoing study and
advancement in clinical care will attempt to address these deficiencies while
continuing to improve clinical care overall.

REFERENCES

1. Heit J, Cohen A, Anderson FJ. Estimated annual number of incident and recur-
rent, non-fatal and fatal venous thromboembolism (VTE) events in the US. Blood
2005;106:267A.
1218 Hunt & Bull

2. Park B, Messina L, Dargon P, et al. Recent trends in clinical outcomes and

resource utilization for pulmonary embolism in the United States: findings from
the nationwide inpatient sample. Chest 2009;136:983–90.
3. Goldhaber SZ. Epidemiology of pulmonary embolism. Semin Vasc Med 2001;1:
139–46.
4. Lee CH, Cheng CL, Lin LJ, et al. Epidemiology and predictors of short-
term mortality in symptomatic venous thromboembolism. Circ J 2011;75:
1998–2004.
5. Gillum RF. Pulmonary embolism and thrombophlebitis in the United States, 1970-
1985. Am Heart J 1987;114:1262–4.
6. Heit JA, Silverstein MD, Mohr DN, et al. Predictors of survival after deep vein
thrombosis and pulmonary embolism: a population-based, cohort study. Arch
Intern Med 1999;159:445–53.
7. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Eu-
rope. The number of VTE events and associated morbidity and mortality. Thromb
Haemost 2007;98:756–64.
8. Heit J, Petterson T, Farmer S, et al. Trends in incidence of deep vein thrombosis
and pulmonary embolism: a 35-year population-based study. Blood 2006;108:
430a.
9. Skaf E, Stein PD, Beemath A, et al. Fatal pulmonary embolism and stroke. Am J
Cardiol 2006;97:1776–7.
10. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein
thrombosis and pulmonary embolism: a 25-year population-based study. Arch
Intern Med 1998;158:585–93.
11. Cervantes J, Rojas G. Virchow’s legacy: deep vein thrombosis and pulmonary
embolism. World J Surg 2005;29(Suppl 1):S30–4.
12. Dickson BC. Venous thrombosis: on the history of Virchow’s triad. Univ Toronto
Med J 2004;81:166–71.
13. Mateo J, Oliver A, Borrell M, et al. Laboratory evaluation and clinical characteris-
tics of 2,132 consecutive unselected patients with venous thromboembolism–
results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb
Haemost 1997;77:444–51.
14. Ridker PM, Hennekens CH, Lindpaintner K, et al. Mutation in the gene coding for
coagulation factor V and the risk of myocardial infarction, stroke, and venous
thrombosis in apparently healthy men. N Engl J Med 1995;332:912–7.
15. Koster T, Rosendaal FR, de RH, et al. Venous thrombosis due to poor anticoag-
ulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993;
342:1503–6.
16. Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable
thrombophilia. Br J Haematol 2010;149:209–20.
17. Spencer FA, Emery C, Lessard D, et al. The Worcester Venous Thromboembolism
study: a population-based study of the clinical epidemiology of venous thrombo-
embolism. J Gen Intern Med 2006;21:722–7.
18. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of
the prospective investigation of pulmonary embolism diagnosis (PIOPED). The
PIOPED Investigators. JAMA 1990;263:2753–9.
19. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute
pulmonary embolism: a meta-analysis. Circulation 2007;116:427–33.
20. Scherz N, Labarere J, Mean M, et al. Prognostic importance of hyponatremia in
patients with acute pulmonary embolism. Am J Respir Crit Care Med 2010;182:
1178–83.
 Clinical Review of Pulmonary Embolism 1219

21. La VL, Ottani F, Favero L, et al. Increased cardiac troponin I on admission

predicts in-hospital mortality in acute pulmonary embolism. Heart 2004;90:633–7.
22. Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the predic-
tion of adverse outcome in patients with pulmonary embolism: a systematic
review and meta-analysis. Am J Respir Crit Care Med 2008;178:425–30.
23. Lankeit M, Kempf T, Dellas C, et al. Growth differentiation factor-15 for prognostic
assessment of patients with acute pulmonary embolism. Am J Respir Crit Care
Med 2008;177:1018–25.
24. Stein PD, Goldhaber SZ, Henry JW, et al. Arterial blood gas analysis in the
assessment of suspected acute pulmonary embolism. Chest 1996;109:78–81.
25. Righini M, Perrier A, De MP, et al. D-Dimer for venous thromboembolism diag-
nosis: 20 years later. J Thromb Haemost 2008;6:1059–71.
26. Dempfle CE, Suvajac N, Elmas E, et al. Performance evaluation of a new rapid
quantitative assay system for measurement of D-dimer in plasma and whole
blood: PATHFAST D-dimer. Thromb Res 2007;120:591–6.
27. van Belle A, Buller HR, Huisman MV, et al. Effectiveness of managing suspected
pulmonary embolism using an algorithm combining clinical probability, D-dimer
testing, and computed tomography. JAMA 2006;295:172–9.
28. Kucher N, Printzen G, Goldhaber SZ. Prognostic role of brain natriuretic peptide
in acute pulmonary embolism. Circulation 2003;107:2545–7.
29. Coutance G, Le PO, Lo T, et al. Prognostic value of brain natriuretic peptide in
acute pulmonary embolism. Crit Care 2008;12:R109.
30. Perrier A, Roy PM, Sanchez O, et al. Multidetector-row computed tomography in
suspected pulmonary embolism. N Engl J Med 2005;352:1760–8.
31. Righini M, Le GG, Aujesky D, et al. Diagnosis of pulmonary embolism by multide-
tector CT alone or combined with venous ultrasonography of the leg: a rando-
mised non-inferiority trial. Lancet 2008;371:1343–52.
32. Turkstra F, Kuijer PM, van Beek EJ, et al. Diagnostic utility of ultrasonography of
leg veins in patients suspected of having pulmonary embolism. Ann Intern Med
1997;126:775–81.
33. Musset D, Parent F, Meyer G, et al. Diagnostic strategy for patients with sus-
pected pulmonary embolism: a prospective multicentre outcome study. Lancet
2002;360:1914–20.
34. Johnson SA, Stevens SM, Woller SC, et al. Risk of deep vein thrombosis following
a single negative whole-leg compression ultrasound: a systematic review and
meta-analysis. JAMA 2010;303:438–45.
35. Kucher N, Rossi E, De RM, et al. Prognostic role of echocardiography among
patients with acute pulmonary embolism and a systolic arterial pressure of 90
mm Hg or higher. Arch Intern Med 2005;165:1777–81.
36. Kasper W, Konstantinides S, Geibel A, et al. Prognostic significance of right
ventricular afterload stress detected by echocardiography in patients with clini-
cally suspected pulmonary embolism. Heart 1997;77:346–9.
37. Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy
of normotensive patients with pulmonary embolism. Chest 2004;125:1539–45.
38. Hall WB, Truitt SG, Scheunemann LP, et al. The prevalence of clinically relevant
incidental findings on chest computed tomographic angiograms ordered to diag-
nose pulmonary embolism. Arch Intern Med 2009;169:1961–5.
39. Van Strijen MJ, De MW, Kieft GJ, et al. Accuracy of single-detector spiral CT in the
diagnosis of pulmonary embolism: a prospective multicenter cohort study of
consecutive patients with abnormal perfusion scintigraphy. J Thromb Haemost
2005;3:17–25.
1220 Hunt & Bull

40. Perrier A, Howarth N, Didier D, et al. Performance of helical computed tomog-

raphy in unselected outpatients with suspected pulmonary embolism. Ann Intern
Med 2001;135:88–97.
41. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for
acute pulmonary embolism. N Engl J Med 2006;354:2317–27.
42. Blachere H, Latrabe V, Montaudon M, et al. Pulmonary embolism revealed on
helical CT angiography: comparison with ventilation-perfusion radionuclide lung
scanning. AJR Am J Roentgenol 2000;174:1041–7.
43. Stein PD, Chenevert TL, Fowler SE, et al. Gadolinium-enhanced magnetic reso-
nance angiography for pulmonary embolism: a multicenter prospective study
(PIOPED III). Ann Intern Med 2010;152:434–43.
44. 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.
45. 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.
46. Wicki J, Perrier A, Perneger TV, et al. Predicting adverse outcome in patients with
acute pulmonary embolism: a risk score. Thromb Haemost 2000;84:548–52.
47. 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.
48. Chan CM, Woods C, Shorr AF. The validation and reproducibility of the pulmonary
embolism severity index. J Thromb Haemost 2010;8:1509–14.
49. Jimenez D, Yusen RD, Otero R, et al. Prognostic models for selecting patients with
acute pulmonary embolism for initial outpatient therapy. Chest 2007;132:24–30.
50. Donze J, Le GG, Fine MJ, et al. Prospective validation of the Pulmonary Embolism
Severity Index. A clinical prognostic model for pulmonary embolism. Thromb
Haemost 2008;100:943–8.
51. Jimenez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism
severity index for prognostication in patients with acute symptomatic pulmonary
embolism. Arch Intern Med 2010;170:1383–9.
52. Hariharan P, Takayesu JK, Kabrhel C. Association between the Pulmonary Embo-
lism Severity Index (PESI) and short-term clinical deterioration. Thromb Haemost
2011;105:706–11.
53. Nurmohamed MT, Rosendaal FR, Buller HR, et al. Low-molecular-weight heparin
versus standard heparin in general and orthopaedic surgery: a meta-analysis.
Lancet 1992;340:152–6.
54. Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecular-weight heparin compared
with intravenous unfractionated heparin for treatment of pulmonary embolism:
a meta-analysis of randomized, controlled trials. Ann Intern Med 2004;140:175–83.
55. Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-
weight heparin with unfractionated heparin for acute pulmonary embolism. The
THESEE Study Group. Tinzaparine ou Heparine Standard: evaluations dans l’Em-
bolie Pulmonaire. N Engl J Med 1997;337:663–9.
56. Erkens PM, Gandara E, Wells P, et al. Safety of outpatient treatment in acute
pulmonary embolism. J Thromb Haemost 2010;8:2412–7.
57. Kovacs MJ, Hawel JD, Rekman JF, et al. Ambulatory management of pulmonary
embolism: a pragmatic evaluation. J Thromb Haemost 2010;8:2406–11.
58. Buller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus
intravenous unfractionated heparin in the initial treatment of pulmonary embolism.
N Engl J Med 2003;349:1695–702.
 Clinical Review of Pulmonary Embolism 1221

59. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic
venous thromboembolism. N Engl J Med 2010;363:2499–510.
60. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treat-
ment of acute venous thromboembolism. N Engl J Med 2009;361:2342–52.
61. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant
aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation
(PETRO Study). Am J Cardiol 2007;100:1419–26.
62. Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes GM, et al. Streptokinase and
heparin versus heparin alone in massive pulmonary embolism: a randomized
controlled trial. J Thromb Thrombolysis 1995;2:227–9.
63. Kasper W, Konstantinides S, Geibel A, et al. Management strategies and deter-
minants of outcome in acute major pulmonary embolism: results of a multicenter
registry. J Am Coll Cardiol 1997;30:1165–71.
64. Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared
with heparin alone in patients with submassive pulmonary embolism. N Engl J
Med 2002;347:1143–50.
65. Clarke DB, Abrams LD. Pulmonary embolectomy: a 25 year experience. J Thorac
Cardiovasc Surg 1986;92:442–5.
66. Dauphine C, Omari B. Pulmonary embolectomy for acute massive pulmonary em-
bolism. Ann Thorac Surg 2005;79:1240–4.
67. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in
the prevention of pulmonary embolism in patients with proximal deep-vein throm-
bosis. Prevention du Risque d’Embolie Pulmonaire par Interruption Cave Study
Group. N Engl J Med 1998;338:409–15.
68. PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava
filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Ris-
que d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation
2005;112:416–22.
69. Van Ha TG, Chien AS, Funaki BS, et al. Use of retrievable compared to perma-
nent inferior vena cava filters: a single-institution experience. Cardiovasc Inter-
vent Radiol 2008;31:308–15.
70. Given MF, McDonald BC, Brookfield P, et al. Retrievable Gunther Tulip inferior
vena cava filter: experience in 317 patients. J Med Imaging Radiat Oncol
2008;52:452–7.
71. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thrombo-
embolic disease: American College of Chest Physicians evidence-based clinical
practice guidelines (8th edition). Chest 2008;133:454S–545S.
72. Buller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thrombo-
embolic disease: the Seventh ACCP Conference on Antithrombotic and Throm-
bolytic Therapy. Chest 2004;126:401S–28S.
73. Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes.
Circulation 2003;107:I17–21.
74. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus
a coumarin for the prevention of recurrent venous thromboembolism in patients
with cancer. N Engl J Med 2003;349:146–53.
75. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic
pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:
2257–64.
76. Riedel M, Stanek V, Widimsky J, et al. Longterm follow-up of patients with pulmo-
nary thromboembolism. Late prognosis and evolution of hemodynamic and respi-
ratory data. Chest 1982;81:151–8.
1222 Hunt & Bull

77. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary
hypertension. N Engl J Med 2002;347:322–9.
78. Jais X, D’Armini AM, Jansa P, et al. Bosentan for treatment of inoperable chronic
thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopEr-
able Forms of chronIc Thromboembolic pulmonary hypertension), a randomized,
placebo-controlled trial. J Am Coll Cardiol 2008;52:2127–34.
79. Suntharalingam J, Treacy CM, Doughty NJ, et al. Long-term use of sildenafil in
inoperable chronic thromboembolic pulmonary hypertension. Chest 2008;134:
229–36.