19 TEP Tak2019
19 TEP Tak2019
19 TEP Tak2019
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
Abstract Pulmonary embolism (PE) affects over 300,000 individuals each year in the United
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
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-
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
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
Table 4 Pooled sensitivity and specificity of Gestalt and clinical decision rules
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-
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
Abbreviations: AF, atrial fibrillation; BID, two times a day; DOACs, direct oral anticoagulants; OD, once daily; TID, three times a day; VTE, venous
thromboembolic.
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
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
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
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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