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100 Invited Article: Pulmonary Arterial Hypertension

Acute Pulmonary Embolism: Contemporary Approach


to Diagnosis, Risk-Stratification, and Management
Tahir Tak, MD, PhD1 Swetha Karturi, MD2 Umesh Sharma, MD2 Lee Eckstein, MD3
Joseph T. Poterucha, DO4 Yader Sandoval, MD1

1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Address for correspondence Tahir Tak, MD, PhD, FACC, FESC, FICA,
Minnesota Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street,
2 Department of Hospital Medicine, Mayo Clinic Health System, SW, Rochester, MN 55905 (e-mail: tak.tahir@mayo.edu).
La Crosse, Wisconsin
3 Department of Imaging Services, Mayo Clinic Health System,
La Crosse, Wisconsin
4 Division of Critical Care Medicine, Mayo Clinic Health System,
La Crosse, Wisconsin

Int J Angiol 2019;28:100–111.

Abstract Pulmonary embolism (PE) affects over 300,000 individuals each year in the United

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States and is associated with substantial morbidity and mortality. Improvements in the
diagnostic performance and availability of computed tomographic pulmonary angio-
graphy and D-dimer testing have facilitated the evaluation of patients with suspected
PE. High clinical suspicion is required in those with risk factors and/or those that
manifest signs or symptoms of venous thromboembolic disease, with validated clinical
risk scores such as the Wells and modified Wells score or the PE rule-out criteria helpful
Keywords in estimating the likelihood for PE. For those with confirmed PE, patients should be
► pulmonary embolism categorized and triaged according to the presence or absence of shock or hypotension.
► pulmonary Normotensive patients can be further risk-stratified using validated prognostic risk
hypertension scores, as well as by using imaging and cardiac biomarkers, with those having either
► deep venous signs of right ventricular dysfunction on imaging studies and/or abnormal cardiac
thrombosis biomarkers categorized as being at intermediate-risk and requiring close monitoring
► dyspnea and hospital admission. Early discharge and/or home therapy are possible in those that
► anticoagulation do not manifest any high-risk features. The initial treatment for most patients that are
► thrombolytic stable consists of anticoagulation, with advanced therapies such as thrombolysis,
► echocardiography catheter-based therapies, or surgical embolectomy deferred for those at high risk.
► right heart strain Given the heterogeneous presentations of PE and various management strategies
► tumor emboli available, the development of multidisciplinary PE response teams has emerged to help
► vena cava filters facilitate decision-making in these patients.

Venous thromboembolic (VTE) disease is frequently encoun- of vascular disease in the United States after acute myocar-
tered in clinical practice as either deep vein thrombosis dial infarction and stroke.2
(DVT) and/or pulmonary embolism (PE), affects as many as Numerous advancements have occurred in recent years in
900,000 individuals in the United States each year, and is the diagnostic evaluation of patients with suspected PE, as
associated with substantial morbidity and mortality.1 PE, well as in the risk-stratification and management of patients
defined as an obstruction of the pulmonary vasculature, is a with confirmed PE. The use of validated pre-test probability
subset of VTE that represents the third most common cause clinical risk scores, D-dimer testing, and computed

published online Copyright © 2019 by Thieme Medical DOI https://doi.org/


July 5, 2019 Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1692636.
New York, NY 10001, USA. ISSN 1061-1711.
Tel: +1(212) 584-4662.
Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al. 101

tomographic pulmonary angiography has facilitated the diogenic shock and/or sudden death in the context of mas-
diagnostic evaluation of patients with suspected PE. Simi- sive saddle embolism. Typical symptoms and/or signs
larly, novel risk-stratification algorithms integrating prog- include pleuritic chest pain, dyspnea, fever, cough, hemop-
nostic risk scores, echocardiography, and/or cardiac tysis, and syncope. Physical examination may reveal tachy-
biomarkers have facilitated the triage and management of cardia, tachypnea, fever, and hypoxia, as well as reduced
patients with confirmed normotensive PE. The management breath sounds or rales, jugular venous distention, and right
of PE has also evolved significantly with the availability and ventricular (RV) heave.
use of direct oral anticoagulants (DOACs) and catheter-based
therapies, with or without fibrinolysis, that have emerged as
Pathophysiology
potential options to treat higher-risk, unstable patients.3
Given the wide variation in clinical presentations ranging PE usually results from a DVT traveling proximally toward the
from low-, mid-, to high-risk, and distinct management lungs, lodging in the pulmonary circulation, and resulting in
options available, several centers have instituted multidisci- vascular occlusion. PE leads to ventilation–perfusion (VQ)
plinary pulmonary embolism response teams (PERT) to mismatch and resulting hypoxia. Hypoxia-mediated pulmon-
facilitate the evaluation and decision-making for these ary vasoconstriction leads to the elevation of pulmonary
patients.2 The purpose of this review is to provide an over- vascular resistance and pulmonary artery (PA) pressure. Ele-
view of the contemporary approach to diagnosis, risk-stra- vated PA pressure results in the reduction in RV stroke volume
tification, management, and prognosis of these patients, as and RV dilatation. Elevated RV end-diastolic pressures cause
well as delineate future directions moving forward. neurohumoral stimulation, increased oxygen demand, and
resultant subendocardial hypoperfusion, myocardial ische-

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mia, and subsequent infarction. RV dilatation can lead to RV
Epidemiology
failure.9 Progression of RV failure can lead to impairment in left
PE affects over 300,000 individuals each year in the United ventricular filling and may result in myocardial ischemia due
States.4 The incidence of PE increases with age.4 Men typically to inadequate coronary artery filling with potential for hypo-
have a higher overall incidence of VTE compared with women tension, syncope, or sudden death.
(1.2:1). Women have a higher incidence after age 75.5 Hypoxia, elevated alveolar-arterial (A-a) gradient, and
At the age of 45 years, there is a lifetime risk of venous hypocapnea are frequently observed arterial blood gas find-
thromboembolism of 8.1% with some patient subsets having ings in PE. VQ mismatch, right to left shunt, impaired
even higher life time risk, such as African Americans—11.5%, diffusion, and reduced mixed venous oxygen saturation
those that are obese—10.9%, those identified to be hetero- contribute to hypoxia. Massive PE can markedly increase
zygous for factor V Leiden—17.1%, or those who have sickle physiological dead space and impair CO2 exchange.9–14
cell disease—18.2%.6 Importantly, not all patients are hypoxemic (32% of PE
The number of PE related admissions has increased from cases demonstrate PaO2 > 80 mm Hg), and that the majority
23 to 65 per 100,000 from 1993 to 2012 with the cost per PE of patients (81%) hyperventilate despite the increased dead
hospitalization steadily increasing from $5,198 to $6,928 in space with nearly one-third of patients have normal A-a
2000 to $8,764 in 20107 gradient.12,13
Following Virchow’s triad for thrombosis, patients should
be evaluated for factors that increase the risk for VTE based
Diagnostic Evaluation
on the presence or absence of issues affecting endothelial
injury, stasis of blood flow, and hypercoagulability.8 Careful clinical history, including detailed assessment of
Endothelial injury can result from surgery, trauma, venous potential risk factors, and physical examination are essential
catheters, and superficial vein thrombosis. Stasis can be in guiding the appropriate diagnostic evaluations. Those
caused by prolonged immobilization during travel, surgery, with high-clinical suspicion; for example, patients presenting
obesity, and polycythemia vera, with most emboli develop- pleuritic chest discomfort and dyspnea who have a history of
ing in the lower extremity veins. Hypercoagulability can be malignancy and recent immobility that manifest hypoxia,
either genetic (e.g., factor V Leiden mutation, prothrombin tachycardia, and hypotension and are unstable require a
gene mutation, antithrombin III deficiency, protein C, S distinct evaluation than those with low-clinical suspicion in
deficiency, and increased homocysteine levels) or an whom typical symptoms and/or risk factors are not present.
acquired disorder (e.g., antiphospholipid syndrome, infec- Basic evaluations often performed in these patients
tion, inflammatory conditions, cancer, nephrotic syndrome, include 12-lead electrocardiography (ECG) and/or chest X-
smoking, estrogen (e.g., hormonal contraceptives, hormone ray (CXR).
replacement therapy, or pregnancy).3,5–11 Patients with Abnormal ECG findings are seen in 15 to 25% of
severe obesity (body mass index [BMI] >35) have a six times patients.15 The ECG often, but not always, reveals sinus
higher risk of developing VTE compared with patients with tachycardia. Patients can also present with supraventricular
normal BMI (<25).8 arrhythmias and there may also be evidence of right axis
The clinical presentations of PE are heterogeneous and deviation, S1Q3T3 (►Fig. 1) pattern indicating RV strain
range from asymptomatic in incidentally discovered small (►Fig. 1), incomplete or complete right bundle branch block,
subsegmental embolus to massive saddle embolism to car- and/or inverted T waves.9,14,16 CXR features of acute PE

International Journal of Angiology Vol. 28 No. 2/2019


102 Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al.

Fig. 1 Electrocardiogram (ECG) of patient with pulmonary embolism.


The most common ECG finding in the setting of a pulmonary
embolism is sinus tachycardia. However, the “S1Q3T3” pattern of
acute cor pulmonale is classic and is sometimes referred to as the

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McGinn-White Sign.

include enlarged PA (Fleischner sign), regional oligemia


(Westermark sign), and Hampton hump (wedge-shaped
distal infarct) (►Fig. 2A and 2B). The Westermark sign, like
Hampton hump, has low sensitivity (11%) but high specificity
(92%).17
Bedside-focused ultrasound performed by trained per-
sonnel is increasingly being utilized in acute care setting and
can provide an immediate assessment of RV size and func-
tion, especially in patients with high-clinical suspicion who
demonstrate an enlarged and poorly contracting RV who
could be rapidly identified and managed accordingly.18,19

Risk Scores
To assist with routine clinical assessment and the clinical
Gestalt (i.e., unstructured estimate of the likelihood for PE),
prediction rules have been developed that are able to more
precisely quantify the pre-test probability of PE and help
guide the diagnostic process and triaging of patients with
Fig. 2 (A) A chest X-ray showing the Westermark sign (http://pixelrz.
suspected PE. Several pre-test probability scores have been
com/lists/suggestions/hamptons-hump/). (B) Chest X-ray showing
studied, including the Wells and modified Wells score,20,21 the “Hampton hump.” PE, pulmonary embolism.
the revised Geneva score,22 and the pulmonary embolism
rule out criteria (PERC)23 (►Tables 1–3).
Wells score and modified Wells score are simple clinical Geneva score is a clinical prediction rule used to deter-
tools to help rule out PE, especially in combination with D- mine the pre-test probability of PE based on a patient’s risk
dimer levels and reduce unnecessary testing.20,21 Forty factors and clinical findings. It has been shown to be as
clinical variables were initially considered, of which seven accurate as the Wells score and is less reliant on the experi-
were ultimately to derive the rule which had two scoring ence of the doctor applying the rule. It identifies character-
systems (►Table 1). The first scoring system had three istics associated with PE which are easily assessed and can be
grades, namely, low, moderate, and high, which were later combined into a score.19
simplified to two grades, namely, PE likely and PE unli- It is subdivided into low, intermediate, and high prob-
kely.20,21 With this model, PE was diagnosed in 7.8% of ability results. The prevalence of PE in 10% is low probability,
patients with scores < 4 and only in 2.2% when combined in 38% is intermediate probability, and in 81% is high prob-
with a negative D-dimer. The score has the limitation that ability.22 This score has variables that are completely stan-
one of the variables (no alternative diagnosis) is based on the dardized and are not dependent on the clinician’s judgment.
clinician’s judgement. The prevalence of PE is 10% in low probability, 38% in

International Journal of Angiology Vol. 28 No. 2/2019


Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al. 103

Table 1 Wells criteria and modified Wells criteria: clinical Table 3 The pulmonary embolism rule out criteria (PERC rule)a
assessment for pulmonary embolism
Age <50 years
Clinical symptoms of DVT 3.0 Heart rate <100 bpm
(leg swelling, pain with palpation)
Oxyhemoglobin saturation 95%
Other diagnosis less likely than 3.0
No hemoptysis
pulmonary embolism
No estrogen use
Heart rate >100 1.5
No prior DVT or PE
Immobilization (3 days) or surgery in 1.5
the previous 4 weeks No unilateral leg swelling
Previous DVT/PE 1.5 No surgery/trauma requiring hospitalization within the
prior 4 weeks
Hemoptysis 1.0
Malignancy 1.0 Abbreviations: bpm, beats per minute; DVT, deep venous thrombosis;
PE, pulmonary embolus; PERC, PE rule-out criteria.
Probability Score a
This rule is only valid in patients with a low clinical probability of PE
Traditional clinical probability assessment (Wells criteria) (Gestalt estimate <15%). In patients with a low probability of PE who
fulfill all eight criteria, the likelihood of PE is low and no further testing
High >6.0 is required. All other patients should be considered for further testing
Moderate 2.0–6.0 with sensitive D-dimer or imaging.
Source: Kline JA, Courtney DM, Kabrhel C, et al. Prospective multicenter
Low <2.0 evaluation of the pulmonary embolism rule-out criteria. J Thromb

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Simplified clinical probability assessment (modified Wells Haemost 2008;6:772.
criteria)
PE likely >4.0 PE.21–26 The pooled sensitivity and specificity of Gestalt
and clinical decision rules are shown in ►Table 4.27 Some
PE unlikely 4.0
studies have shown that Wells and Geneva scores are not as
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism. accurate in ruling out PE in pregnant and critically ill
Source: Data from van Belle A, Buller HR, Huisman MV, et al. Effectiveness of patients.21–23
managing suspected pulmonary embolism using an algorithm combining
The PERC is used in patients with low probability of PE
clinical probability, D-dimer testing, and computed tomography. JAMA
2006;295:172.
(►Table 3).
Validated clinical decision tools like the Wells and mod-
intermediate probability, and 81% in high probability. This ified Wells criteria are helpful in determining the pre-test
score has variables that are standardized and not dependent probability of PE. Modified Wells score of <4 makes PE
on the clinician’s judgement. The Geneva score needs arterial less likely, especially when combined with a negative D-
blood gas values while breathing room air which is not dimer.14,15,21,28
always available. As such, the modified/revised Geneva score
was developed based on readily available clinical variables, D-Dimer
independent of clinicians’ judgement, associated with For normotensive patients in whom PE is deemed to be
unlikely (low or intermediate clinical probability) using clin-
ical judgment or guideline-recommended prediction rules,
Table 2 Revised Geneva Score
laboratory testing using D-dimer, a sensitive marker of
Variable Score
thrombosis, is the next diagnostic step. D-dimer is a soluble
fibrin degradation product for which numerous assays exist
Age 65 years or over 1
(e.g., whole-blood agglutination assays, enzyme-linked
Previous DVT or PE 3 immunosorbent or immunofluorescent assays, and latex
Surgery or fracture within 1 month 2 agglutination assays) for its measurement in whole blood
Active malignant condition 2 or plasma.3 Due to the high diagnostic sensitivity and
Unilateral lower limb pain 3 negative predictive value, it is primarily used to help exclude
PE when the levels are normal. D-dimer, however, has poor
Hemoptysis 2
diagnostic specificity, and when elevated, it can be due to
Heart rate 75–94 beats per minute 3 other various conditions such as sepsis, trauma, cancer,
Heart rate 95 or more beats per minute 5 surgery, other thrombosis, or disseminated intravascular
Pain on deep palpation of lower limb 4 coagulation, among others.
and unilateral edema
0–3 Points indicates low probability Imaging
4–10 Points indicates intermediate probability In patients in whom PE is likely (high clinical probability),
for example, those with high-risk features such as hypo-
11 Points or more indicates high probability
tension or shock, or those found to have abnormal D-dimer
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism. concentrations, computed tomography angiography (CTA) is

International Journal of Angiology Vol. 28 No. 2/2019


104 Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al.

Table 4 Pooled sensitivity and specificity of Gestalt and clinical decision rules

Gestalt or r le Studies, Prevalence, Pooled Pooled Estimated sensitivity Estimated


n % sensitivity specificity at a prevalence of specificity at a
(95% CI) (95% CI) 15% (95% CI)a prevalence of
15% (95% CI)a
Gestalt 15 16.7 0.85 (0.78–0.90) 0.51 (0.39–0.63) 0.83 (0.81–0.84) 0.52 (0.43–0.62)
Wells cutoff 19 14.7 0.84 (0.78–0.89) 0.58 (0.52–0.65) 0.85 (0.80–0.89) 0.58 (0.52–0.63)
value <2
Cutoff value 4 11 16.3 0.60 (0.49–0.69) 0.80 (0.75–0.84) 0.58 (0.47–0.68) 0.81 (0.76–0.85)
Geneva 5 29.0 0.84 (0.81–0.87) 0.50 (0.29–0.72) 0.76 (0.71–0.79) 0.61 (0.41–0.78)
Revised Geneva 4 23.7 0.91 (0.73–0.98) 0.37 (0.22–0.55) 0.82 (0.78–0.86) 0.45 (0.32–0.59)

Abbreviation: CI, confidence interval.


a
Using a theoretical population with a 15% prevalence of pulmonary embolism.
Source: Lucassen W, Geersing GJ, Erkens PM, et al. Clinical decision rules for excluding pulmonary embolism: a meta-analysis. Ann Intern Med
2011;155(7):448–460.

the next immediate diagnostic step. Using dose reduction Risk-Stratification for Confirmed PE
technologies can provide high-quality diagnostic imaging
with a significant reduction in patient radiation dose. The Numerous advancements have been made in the risk-stratifi-

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first-choice imaging examination in patients with sus- cation of patients with confirmed PE to assist with the triaging
pected PE is pulmonaryCTA.29 The rationale for using this and management of these patients. For those with confirmed
test is based on the high sensitivity and specificity in PE, patients should be categorized and triaged according to the
detecting PE while also helping assess for other clinical presence or absence of shock or hypotension.
conditions in the differential diagnosis. Refinements in CT High-risk patients: Patients identified as “high-risk” are
technology have improved acquisition times to < 2 sec- those who are hypotensive or in shock. Shock at presentation
onds, providing relatively motion-free images in patients is associated with a 30 to –50% risk of death.16 These patients
who are suffering from dyspnea. Fast scanning times also require immediate CTA to confirm the diagnosis and undergo
allow use of smaller amounts of iodinated contrast dye, reperfusion.
thereby reducing the risk of nephrotoxicity. In general, CTA Low or intermediate risk: Patients who are normotensive
provides good image quality with minimal patient discom- patients can be risk-stratified using validated prognostic risk
fort. The major risks associated with CTA are those of scores, as well as by using imaging and cardiac biomarkers,
contrast-induced nephropathy and risk of malignancy with those having signs of RV dysfunction on imaging studies
from radiation exposure.30–32 and/or abnormal cardiac biomarkers categorized as being at
The VQ scan is an alternative imaging modality to rule out intermediate-risk and requiring close monitoring and hos-
PE. It is usually used in situations where CT scan is contra- pital admission. Conversely, those identified to be at low-risk
indicated, like pregnancy, acute renal failure, and/or contrast may qualify for early discharge and/or home therapy.
allergy since it does not expose subject to contrast or radia-
tion.3,9,11,14–16,28 The original multicenter Prospective Inves-
Prognostic Tools to Assess Risk
tigation of Pulmonary Embolism Diagnosis (PIOPED) study
classified VQ scans as high-probability, intermediate-prob- The simplified Pulmonary Embolism Severity Index (sPESI)
ability, low-probability, and indeterminate. The PIOPED (►Table 5) is a practical and simplified approach that attri-
study assessed the value of VQ scan in acute PE and con- butes a score of 1 for age >80 years, cancer, heart failure,
cluded that high probability results usually indicated PE; pulse >110beats /minute, systolic blood pressure < 100 mm
however, only a small proportion of patients with actual PE Hg, and arterial oxygen saturation <90%. Typically, a score of
had high probability results and that low probability results zero is an indicator of low risk, and with a brain natriuretic
accurately rule out PE with limited value in those with peptide (BNP) level <100 pg/mL, has been validated and
intermediate results. Based on PIOPED study, the VQ scans predicts excellent outcomes with a very high negative pre-
with high probability had a sensitivity of 41% and specificity dictive value (99–100%).
of 97%.33 If all three probabilities (high, intermediate, and Cardiac troponins (cTn) (I and T) and BNP are cardiac
low) were combined into one result, then VQ scan has high biomarkers that when elevated are associated with less
sensitivity but low specificity (sensitivity, 98%; specificity, favorable outcomes (death and complications) and are,
10%).33 The modified PIOPED II criteria classify studies as therefore, used to help risk-stratify patients with PE. Nor-
high probability, very low probability, normal, and nondiag- mal cardiac biomarkers in an otherwise normotensive
nostic. Using PIOPED II criteria, the sensitivity and specificity patient with PE are an indicator of good prognosis as
of VQ scanning were 85% and 93%, respectively.33–35 compared with those with increased biomarkers.9,16 For
A previous history of PE reduces the validity of a high normotensive patients, contemporary risk-stratification
probability result as it could be falsely positive.36,37 models endorse the use of cardiac biomarkers to help

International Journal of Angiology Vol. 28 No. 2/2019


Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al. 105

Table 5 Pulmonary Embolism Severity Index (PESI) scores: full however, are numerous. PE is a condition where cTn
and simplified increases can occur through various mechanisms, including
myocardial oxygen/supply mismatch, occurring from RV
PESI—Full strain, coronary hypoperfusion, and/or systemic hypoxe-
Clinical feature Points mia. For those with fatal massive PE, pathologic studies
Age x (e.g., 65) demonstrate that patients may suffer from RV infarction in
the absence of coronary artery disease.
Male gender 10
Echocardiography can be used to facilitate diagnosis based
History of cancer 30 on the presence or absence of RV overload especially when CTA
Heart failure 10 is not available. Its primary use is to assist with risk-stratifica-
Chronic lung disease 10 tion in those with confirmed PE based on the presence or
absence of RV dysfunction. PE may result in right heart strain,
Pulse 110/min 20
especially in the case of a “saddle embolus”; RV strain/dilata-
Systolic blood pressure 30 tion, hypokinesis (McConnell sign—RV free wall hypokinesia/
<100 mm Hg
akinesia with preserved or hyperkinetic apical segment wall
Respiratory rate 30/min 20 motion), and elevated right atrial pressure.9,14,18 It can also
Temperature <36°C 20 cause right heart failure and cardiogenic shock due to obstruc-
Altered mental status 60 tion. Echocardiography can help determine the severity of RV
strain and the need for thrombolysis. Echocardiography is not
Arterial oxygen saturation <90% 20
usually used as a first-line tool since a negative result does not
Class I Low risk <66

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rule out PE and evidence of right heart strain can also be seen in
Class II 66–85 several conditions other than PE, such as chronic obstructive
Class III High risk 86–105 pulmonary disease (COPD) and obstructive sleep apnea. Echo-
cardiographic findings of right heart strain are generally
Class IV 106–125
associated with worse outcomes.27 Imaging predictors of
Class V >125 poor outcome include RV dysfunction with twice the risk of
Simplified PESI (sPESI) mortality in all-comers and RV thrombus with an increased 2-
Clinical feature Points week risk of mortality.38–40
Age >80 years 1
History of cancer 1 Treatment
Chronic cardiopulmonary 1 Treatment of PE depends upon the presentation of the
disease patient. The initial treatment should begin with oxygenation
Pulse 110/min 1 and stabilization of the patient. Hereafter, a decision should
Systolic blood pressure 1 be made whether to initiate anticoagulation with warfarin/
<100 mm Hg DOACs or to use a thrombolytic agent.
Arterial oxygen saturation <90% 1 A. Patients without shock, or without malignancy, with a
Low risk 0 sPESI score of ¼ 0 are considered “low risk” and may be
High risk 1 treated with anticoagulation agents as outpatients.
B. Patient with cardiogenic shock due to “saddle embolism”
The full PESI score is rarely calculated in clinical practice since it is with significant RV strain, then hemodynamic and respira-
generally considered cumbersome. In contrast, sPESI is brief, contains a
tory support are of paramount importance and should be
limited number of easily accessible parameters, and is therefore, much
more practical. instituted immediately. In cardiogenic shock, echocardio-
Adapted from: graphy is helpful.41 If significant RV strain/hypokinesis
1. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a with presence of pulmonary hypertension by Doppler
prognostic model for pulmonary embolism. Am J Respir Crit Care Med echocardiography is identified, it may be sufficient evi-
2005;172:1041.
dence to consider thrombolysis and reperfusion in such
2. Jiménez D, Aujesky D, Moores L, et al. Simplification of the pulmonary
embolism severity index for prognostication in patients with acute “unstable” patients. Volume expansion has not been
symptomatic pulmonary embolism. Arch Intern Med 2010;170:1383. shown to be significantly effective, since it may cause
overstretch of the RV which can further depress its con-
tractility. Norepinephrine has been shown to be the best
categorize patients as low-risk or intermediate-high and
inotrope in this setting since it improves RV contractility
intermediate-low risk based on the presence of normal or
in addition to improving RV coronary perfusion by
increased biomarker concentrations.3 Similar to D-dimer,
increasing systemic blood pressure.42
the measurement of cTn using contemporary and high-
sensitivity cTn assays offers improved diagnostic sensitivity Anticoagulation
and negative predictive value that can help exclude myo- Anticoagulation is the mainstay of therapy for PE. Parenteral
cardial injury. The mechanisms leading to increased cTn, anticoagulation is essential as first-line therapy with

International Journal of Angiology Vol. 28 No. 2/2019


106 Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al.

Table 6 Pharmacological properties of the DOACs

Dabigatran Rivaroxaban Apixaban Edoxaban


Target Factor IIa Factor Xa Factor Xa Factor Xa
Half-life (hour) 12–17 5–9 12 6–10
Time to peak 1–3 2–4 1–3 1–2
effect (hour)
Dosing in 150 mg BID 20 mg OD 5 mg BID 60 mg OD
nonvalvular AF
Dosing in 150 mg BID after 5–10 days 15 mg BID for 10 mg BID for 60 mg OD after 5 days of
VTE treatment of parenteral anticoagulation 21 days followed 7 days followed parenteral anticoagulation
by 20 mg OD by 5 mg BID
Renal clearance as 80 33 27 50
unchanged drug (%)
Drug interactions P-gp 3A4/P-gp 3A4/P-gp 3A4/P-gp
pathways

Abbreviations: AF, atrial fibrillation; BID, two times a day; DOACs, direct oral anticoagulants; OD, once daily; TID, three times a day; VTE, venous
thromboembolic.

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eventual transition to oral anticoagulation with Warfarin or will lyse the clot(s) and restore circulation and reduce RV
novel oral anticoagulation agents (DOACs).42–45 Parenteral pressures immediately (►Fig. 3). The beneficial effects of
agents include either unfractionated heparin or low mole- thrombolytics are apparent in the first week post ther-
cular weight heparin (Lovenox). Oral anticoagulation with apy.42 The most common thrombolytic used is tissue
warfarin should be started at the same time and there should plasminogen activator (tPA). Current European Society of
be an overlap of heparin or Lovenox with warfarin for at least Cardiology guidelines recommend infusing 100 mg over
5 days until international normalized ratio is therapeutic 2 hours. First-generation thrombolytics (streptokinase
between a value of 2 and 3. Anticoagulation therapy is and urokinase) are rarely used due to the long duration
usually continued for 3 to 6 months or “lifelong” if there of treatment and higher incidence of allergic reactions.
have been previous DVTs or PEs. The DOACs have their Low-dose heparin infusion is typically concomitantly admi-
characteristic pharmacologic properties. They carry many nistered after tPA infusion. Peripheral infusion of throm-
advantages over warfarin and are considered by some clin- bolytic is considered first, and if this fails, then catheter-
icians as first-line anticoagulation agents. Their pharmaco- directed thrombolysis should be considered. Thrombolytic
kinetic properties are important to keep in mind when therapy is not recommended when there is no hemody-
initiating them in patients with multiple comorbidities namic instability.46
and medications. There is a high risk of bleeding associated with this
There are four major DOACs available in the market: therapy. The Absolute and Relative Contraindications to
dabigatran, rivaroxaban, apixaban, and edoxaban.42–45 Their thrombolytic therapy are listed in ►Table 8.
pharmacological properties are listed in ►Table 6.

Catheter Based and Surgical Therapies


Thrombolytic Therapy
Thrombolysis is often reserved for patients presenting with Catheter-Based Therapy
hypotension and/or severe hypoxemia. This form of treat- Catheter-assisted thrombus removal is recommended when
ment may also be used in patients who demonstrate severe appropriate resources are available for patients with acute PE
RV dysfunction by echocardiography with concomitant associated with hypotension who are of high bleeding risk,
tachycardia (►Table 7). Treatment with thrombolytics have failed systemic thrombolysis, or when cardiogenic

Table 7 Potential indications for thrombolytic therapy in venous thromboembolism

High-risk (massive) PE; i.e., presence of hypotension related to PEa


Presence of severe hypoxemia (particularly in those with a contribution from concomitant cardiopulmonary disease)
Patients with acute PE who appear to be decompensating but are not yet hypotensive
Patients with severe right ventricular dysfunction and tachycardia due to PE
Clot-in-transit (i.e., right atrium or ventricle)
Extensive deep vein thrombosis

Abbreviation: PE, pulmonary embolism.


a
This indication is widely accepted; the other potential indications require careful review of the risks of thrombolytic therapy and potential benefits.

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Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al. 107

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Fig. 3 Pre- and post-computed tomography angiography (CTA) images following thrombolysis showing significant improvement in pulmonary
blood flow following intervention.

shock is likely to cause death prior to systemic lytic therapy shown that CDT with tPA (10 mg per lung over 15 hours)
taking effect.46–48 The goal of these therapies is to relieve improves clinical outcomes in addition to reducing RV/LV
obstructive shock, restore pulmonary blood flow and return ratio from baseline to 24 hours when compared with heparin
blood to the left heart to improve cardiac output, and achieve alone.42 Ultrasound-assisted CDT utilizes a dual lumen
hemodynamic stability.48 Various modalities include cathe- catheter to direct tPA and low energy ultrasound energy
ter-directed thrombolysis (CDT), ultrasound-assisted CDT, lysis. Two prospective studies have shown promising results
rheolytic, rotational, or aspiration thrombectomy.2 CDT is indicating that this therapy may be superior to systemic tPA,
the simplest, most studied and utilized catheter-based ther- with the added benefit of less tPA use and reduced intracra-
apy. Local delivery of low dose slow tPA infusion via catheter nial bleeding events.
proximal to the obstructed PA creates a channel for targeted It remains unclear on whether ultrasound lysis is superior
drug delivery and maximizes drug to clot surface area. to CDT alone. Mechanical thrombectomy may be suitable as
Theoretical benefit of this therapy involves increased throm- salvage therapy in patients with contraindications to throm-
bolytic efficacy with less bleeding risk, including intracranial bolysis or when systemic tPA has failed.48 However, mechan-
hemorrhage.2 While no controlled investigations comparing ical thrombectomy has fallen out of favor due to device
CDT with systemic tPA have been performed, studies have bulkiness and rigidity making these devices challenging to

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108 Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al.

Table 8 Contraindications to fibrinolytic therapy for deep venous thrombosis or acute pulmonary embolism

Absolute contraindications
Prior intracranial hemorrhage
Known structural cerebral vascular lesion
Known malignant intracranial neoplasm
Ischemic stroke within 3 months (excluding stroke within 3 hoursa)
Suspected aortic dissection
Active bleeding or bleeding diathesis (excluding menses)
Significant closed-head trauma or facial trauma within 3 months
Relative contraindications
History of chronic, severe, poorly controlled hypertension
Severe uncontrolled hypertension on presentation (SBP >180 mm Hg or DBP >110 mm Hg)
History of ischemic stroke > 3 months prior
Traumatic or prolonged (>10 minutes) CPR or major surgery < 3 weeks
Recent (within 2–4 weeks) internal bleeding
Noncompressible vascular punctures

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Recent invasive procedure
For streptokinase/anistreplase—Prior exposure (> 5 days ago) or prior allergic reaction to these agents
Pregnancy
Active peptic ulcer
Pericarditis or pericardial fluid
Current use of anticoagulant (e.g., warfarin sodium) that has produced an elevated INR >1.7 or PT >15 seconds
Age >75 years
Diabetic retinopathy

Abbreviations: CPR, cardiopulmonary resuscitation; DBP, diastolic blood pressure; INR, international normalized ratio; PT, prothrombin time; SBP,
systolic blood pressure.
a
The American College of Cardiology suggests that select patients with stroke may benefit from thrombolytic therapy within 4.5 hours of the onset of
symptoms.
Reproduced with permission from the American College of Chest Physicians. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE
disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest 2012;141:e419S. Copyright © 2012.

use in the pulmonary vasculature. Rheolytic (fragmentation) recurrent PE despite anticoagulation.49 There are two kinds
thrombectomy has had variable success, limited by poor out- of filters: nonpermanent filters and permanent filters. Non-
comes from side effect of bradycardia, hemodynamic instabil- permanent filters are classified as temporary and retrievable.
ity and collapse in some cases thought to result from Retrievable inferior vena cava (IVC) filters are appropriate in
vasoactive bradykinin and adenosine release. One meta-ana- patients with PE or DVT. Retrievable filters can be left in place
lysis reported higher mortality with this therapy leading to a for 3 to 6 months (depending on the device-specific time
Food and Drug Administration black box warning on one such window for retrieval).
device—the Angiojet Rheolytic Thrombectomy System (Possis, The complications of leaving a filter long-term include
Minneapolis, MN).48 Outcome data on aspiration thrombect- breaking and migration of filter limbs, infection, perforation
omy for PE is limited, as the role of this therapy has tradition- of caval wall, and thrombosis of the filter device.50 Usually
ally been targeted to iliocaval thrombus, tricuspid valve filters are removed as soon as it is safe to use anticoagula-
vegetations, and thrombus-in-transit.2 Catheter-directed ther- tion.49 However, a randomized clinical trial of 399 patients
apy may have the added benefit of potentially reducing chronic with severe PE comparing anticoagulation alone versus
thrombotic pulmonary hypertension.48 anticoagulation plus retrievable IVC filter demonstrated no
difference in PE recurrence rate at 6 months, DVT, major
Venous Filters bleeding, death with filter thrombosis occurring in 3
Venous filters are placed in patients with PE and lower- patients.51 Prophylactic placement of IVC filters in patients
extremity DVT when there is an absolute contraindication to at risk of DVT is common, though it provides no benefit
anticoagulation, when a patient has a very heavy “clot related to recurrent PE, DVT, reduction in major bleeding, or
burden” which is concerning for recurrence of PE, or for mortality.51

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Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al. 109

Surgical embolectomy. This therapy has been traditionally develop after anticoagulation is discontinued and
thought to be last resort for unstable PE primary due to poor mostly secondary to the same clinical event as the index
outcome data from the 1960s, reporting mortality as high as episode. These recurrent events can lead to the development
50%.48 Teams of cardiac surgeons have, therefore, reintro- of chronic thromboembolic pulmonary hypertension
duced the concept of surgical embolectomy for high-risk PE (CTEPH) with resultant chronic hypoxia and dyspnea.
and for selected patients with intermediate- to high-risk PE, There remains a risk of recurrent thromboembolism in
particularly if thrombolysis has failed or is contraindicated. patients who have had prior PE. About 30% of patients
Embolectomy may be particularly useful in patients with experience a recurrent episode of VTE in subsequent decade,
significant proximal clot burden, thrombus-in-transit, and in with a rate of 4 to 13 per 100,000 person years for PE  DVT
impending paradoxical embolism.2 Surgical embolectomy with maximal risk in first 6 to 12 months.54
has also been successfully performed in patients with right The recurrence rate may be increased in patients who are
heart thrombi straddling the interatrial septum through a inadequately anticoagulated or in those patients who have
patent foramen ovale.50 In the modern area, hospital mor- predisposing comorbidities or are otherwise noncompliant
tality of patients after embolectomy has improved, ranging with medications. Anticoagulation significantly reduces the
from 4.6 to 11.7%.2 This is thought to be due to advances in mortality associated with PE, which is otherwise thought to
cardiac surgical techniques. Long-term outcome after surgi- be in the order of 30%. There are prognostic models which
cal embolectomy in the modern day is favorable with one can predict death or recurrence. These models, called the
study demonstrating a 10-year survival of 93%.48 In fact, PESI and the sPESI, can predict all-cause mortality in patients
some centers utilize surgical embolectomy as front-line who have suffered a PE.16
management of high-risk PE, but it is reasonable to reserve Late complications, especially in the first 2 years after TE,

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this intervention for massive PE with cardiogenic shock.48 can lead to the development of CTEPH with resultant chronic
The decision to do surgical embolectomy versus catheter dyspnea, hypoxia, and even death.10
based intervention requires teamwork among various dis- Patients who have had IVC filters placed should have these
ciplines involving surgeons and interventionists. removed once the contraindication to anticoagulation has
resolved with initiation of anticoagulation. Patients with a
Mechanical Circulatory Support history of PE should be followed in the clinic for complications
Recent data suggests that for PE complicated by refractory after treatment (bleeding, etc.) when anticoagulation is
cardiogenic shock, extracorporeal membrane oxygenation initiated. Therapeutic levels of anticoagulation should be main-
(ECMO) may be a useful form of bridging support. ECMO can tained with routine checks. Appropriate recommendations for
provide a bridge to recovery after failed systemic thrombolysis, lifestyle modifications and adherence to medical therapy
can unload the RV, and aid in stabilizing the patient until should be provided to patients during outpatient clinic visits.15
bleeding risks are abated so catheter or surgical embolectomy
therapies can be implemented.48 One single center series
Conclusion
reported surgical or percutaneous embolectomy while on
ECMO with improved survival to hospital discharge compared PE is a relatively common disorder causing significant mor-
with ECMO alone. Percutaneous RV-assist devices, tradition- bidity and mortality. By combining patient presentation,
ally thought to be contraindicated, are being explored as a tool clinical suspicion, and various scoring systems, diagnosis
for RV support, but outcome data has yet to be described.2 may be streamlined and focused treatment can be instituted.
Increasingly more physicians possess training and have access
to portable ultrasound devices, which may help in the early
Prognosis
recognition and treatment of VTE and PE. The increased
Thirty-day mortality associated with PE was 10.6% and 1- accuracy of CTA and application of guideline-directed thera-
year mortality was 23% based on administrative data from pies have improved our recognition of PE in patients. Several
the Quebec study.52 newer oral anticoagulation drugs are now available and gain-
In general, as the size of PE increases, so does the degree of ing favor among physicians either because they are safer or
hemodynamic compromise and resultant mortality. because they are easier to administer without periodic mon-
Advanced age, poor functional status, chronic advanced itoring of anticoagulation status. Future research will continue
medical disease, hypotension, right heart failure, and to focus on improved and timely diagnosis of PE which will
increased cardiac biomarkers such as cTn and/or BNP are likely lead to improved clinical outcomes.
associated with poor survival.8
Short-term outcome study of PE from the 2013 to 2014
Future Directions
National Readmission Data showed a 21.36% readmission rate.
Heart failure, COPD, anemia, and malignancy were associated
with a higher readmission and 90-day mortality rate.53 1. Establishment of pulmonary embolism response team.
Early complications (2 weeks–6 months) can occur as This model was established in 2015 and is a collaborative
recurrent PE. It is co-related with underlying co-morbidities international network which is gaining momentum. It
like malignancy or failure to achieve therapeutic levels of oral represents a new model for approaching PE patients by
anticoagulation. Late complications (> 6 months) appear to dedicated teams.55

International Journal of Angiology Vol. 28 No. 2/2019


110 Contemporary Approach to Diagnosis, Risk-Stratification, and Management of Acute PE Tak et al.

2. The safety of treating PE in the outpatient setting in 7 Fernandez MM, Hogue S, Preblick R, Kwong WJ. Review of the cost
selected low risk patients’ needs to be further evaluated. of venous thromboembolism. Clinicoecon Outcomes Res 2015;
The American College of Chest Physicians’ guidelines 7:451–462
8 Giordano NJ, Jansson PS, Young MN, Hagan KA, Kabrhel C.
currently give a Grade 2B recommendation for OP man-
Epidemiology, pathophysiology, stratification, and natural his-
agement for low-risk PE Patients.56 tory of pulmonary embolism. Tech Vasc Interv Radiol 2017;20
3. Clinical trials are needed to approach management of PE (03):135–140
in pregnant patients. There is paucity of data at the 9 Marshall PS, Mathews KS, Siegel MD. Diagnosis and management
present time. Evaluation of DOACs in pregnant patients of life-threatening pulmonary embolism. J Intensive Care Med
2011;26(05):275–294
will be difficult and likely based on data obtained from
10 Huisman MV, Barco S, Cannegieter SC, et al. Pulmonary embolism.
case reports.57
Nat Rev Dis Primers 2018;4:18028
4. Treatment duration of anticoagulation in patients with 11 Bĕlohlávek J, Dytrych V, Linhart A. Pulmonary embolism, part I:
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5. Additional research is warranted to evaluate the safety clinical presentation, diagnosis and nonthrombotic pulmonary
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12 Altemeier WA, Robertson HT, McKinney S, Glenny RW. Pulmon-
omy, as it may reduce the risk and subsequent develop-
ary embolization causes hypoxemia by redistributing regional
ment of post-thrombotic complications14 blood flow without changing ventilation. J Appl Physiol (1985)
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14 Doherty S. Pulmonary embolism: an update. Aust Fam Physician

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2017;46(11):816–820
7. Drug-coated balloons, bioresorbable vascular scaffolds, 15 Panos RJ, Barish RA, Whye DW Jr, Groleau G. The electrocardio-
and IVC filters are currently being studied and may graphic manifestations of pulmonary embolism. J Emerg Med
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Conflict of Interest 17 Ray JG. Westermark sign and suspected pulmonary embolism.
Yader Sandoval is presently on Abbott Diagnostics’s Can J Cardiol 2003;19(03):317, author reply 317
18 Moore AJE, Wachsmann J, Chamarthy MR, Panjikaran L, Tanabe Y,
advisory board without personal compensation. In the
Rajiah P. Imaging of acute pulmonary embolism: an update.
past YS was on Roche Diagnostics‘s advisory board Cardiovasc Diagn Ther 2018;8(03):225–243
(nonsalaried). 19 Lebovitz A, et al. Focussed cardiac ultrasound in the emergent
All other authors have nothing to disclose. setting. A consensus statement of the American Society of Echo-
cardiography and American College of Emergency Physicians,
American copyright 2010 by American Soc of Echocardiography
Acknowledgment
20 Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple
The authors wish to acknowledge the expert secretarial
clinical model to categorize patients probability of pulmonary
assistance provided by Jill A. Lorenz in the preparation of embolism: increasing the models utility with the SimpliRED D-
this manuscript. dimer. Thromb Haemost 2000;83(03):416–420
21 Hargett CW, Tapson VF. Clinical probability and D-dimer testing:
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