JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 84, NO.

16, 2024

ª 2024 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

JACC GUIDELINE COMPARISON

International Clinical Practice

Guideline Recommendations for
Acute Pulmonary Embolism
Harmony, Dissonance, and Silence

Marco Zuin, MD, MS,a,b,* Behnood Bikdeli, MD, MS,c,d,e,* Jennifer Ballard-Hernandez, DNP, NP,f,g
Stefano Barco, MD, PHD,h,i Elisabeth M. Battinelli, MD, PHD,j George Giannakoulas, MD, PHD,k
David Jimenez, MD, PHD,l,m Frederikus A. Klok, MD, PHD,n Darsiya Krishnathasan, MS,c,d Irene M. Lang, MD, PHD,o
Lisa Moores, MD,p Katelyn W. Sylvester, PHARMD,q Jeffrey I. Weitz, MD,r,s Gregory Piazza, MD, MSc,d

ABSTRACT

Despite abundant clinical innovation and burgeoning scientific investigation, pulmonary embolism (PE) has continued to
pose a diagnostic and management challenge worldwide. Aging populations, patients living with a mounting number of
chronic medical conditions, particularly cancer, and increasingly prevalent health care disparities herald a growing burden
of PE. In the meantime, navigating expanding strategies for immediate and long-term anticoagulation, as well as
advanced therapies, including catheter-based interventions for patients with more severe PE, has become progressively
daunting. Accordingly, clinicians frequently turn to evidence-based clinical practice guidelines for diagnostic and man-
agement recommendations. However, numerous international guidelines, heterogeneity in recommendations, as well as
areas of uncertainty or omission may leave the readers and clinicians without a clear management pathway. In this review
of international PE guidelines, we highlight key areas of consistency, difference, and lack of recommendations (silence)
with an emphasis on critical clinical and research needs. (JACC. 2024;84:1561–1577) © 2024 by the American College of
Cardiology Foundation.

From the aDepartment of Translational Medicine, University of Ferrara, Ferrara, Italy; bDepartment of Cardio-Thoraco-Vascular
Sciences and Public Health, University of Padova, Padova, Italy; cDivision of Cardiovascular Medicine, Department of Medi-
cine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; dThrombosis Research Group,
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; eYNHH/Yale Center for Outcomes Research
and Evaluation (CORE), New Haven, Connecticut, USA; fCardiology Division, Department of Medicine, Department of Veterans
Affairs, VA Long Beach Healthcare System, Long Beach, California, USA; gSue and Bill Gross School of Nursing University of
California-Irvine, Irvine, California, USA; hDepartment of Angiology, University Hospital Zurich, Zurich, Switzerland; iCenter for
Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany;
j
Division of Hematology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mas-
sachusetts, USA; kDepartment of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki,
Greece; lRespiratory Department, Hospital Ramón y Cajal and Universidad de Alcalá (IRYCIS), Madrid, Spain; m
CIBER de Enfer-
medades Respiratorias (CIBERES), Madrid, Spain; nDepartment of Medicine–Thrombosis and Hemostasis, LUMC, Leiden, the
Listen to this manuscript’s Netherlands; oDepartment of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria; pThe
audio summary by Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA; qDepartment of Pharmacy Services, Brigham and
Editor Emeritus Women’s Hospital, Boston, Massachusetts, USA; rDepartments of Medicine and Biochemistry and Biomedical Sciences, McMaster
Dr Valentin Fuster on University, Hamilton, Ontario, Canada; and the sThrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada.
www.jacc.org/journal/jacc. *Drs Zuin and Bikdeli contributed equally to this work.
Review and acceptance occurred under Dr Valentin Fuster’s term as Editor-in-Chief.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received March 8, 2024; revised manuscript received July 1, 2024, accepted July 2, 2024.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2024.07.044

1562 Zuin et al JACC VOL. 84, NO. 16, 2024

Pulmonary Embolism Guidelines Comparison OCTOBER 15, 2024:1561–1577

D METHODOLOGY
ABBREVIATIONS espite abundant clinical practice
AND ACRONYMS innovation and burgeoning scienti-
fic investigation, acute pulmonary For consideration of professional society recommen-
ASH = American Society of
Hematology
embolism (PE) still poses a major diagnostic dations (hereafter referred to as guidelines), we
and management challenge worldwide. Ag- focused on those that were published in English lan-
CDI = catheter-directed
intervention ing populations comprised of patients living guage from European or North American societies and
CTEPH = chronic with a mounting number of chronic medical were based on systematic evidence review (ie, pre-
thromboembolic pulmonary conditions that predispose to venous throm- defined and preferentially reproducible search
hypertension
boembolism (VTE), such as cancer, obesity, criteria) and evidence synthesis (such as those of
CTPA = computed tomography and cardiovascular disease, portend a Grading of Recommendations Assessment, Develop-
pulmonary angiography
growing global burden of PE. Climbing ment and Evaluation [GRADE] criteria 11).
DOAC = direct oral
annual incidence rates for PE from 1997 to Certain professional societies provided summary
anticoagulant
2013 in the United States, Europe, and documents related to PE without systematic review
IVC = inferior vena cava
Australia have confirmed such a predic- and critiquing of evidence. Although many such
LMWH = low-molecular-
weight-heparin
tion. 1,2 Although overall case fatality and documents have value based on expert input, such
mortality rates have declined in the United documents often lack reproducible processes and
NICE = National Institute for
Health and Care Excellence States and Europe, the number of deaths ap- are comparable to expert narrative review papers. It
PE = pulmonary embolism pears to be increasing in key subpopulations, was prespecified to refer to such documents on a
PERT = Pulmonary Embolism
including young and middle-aged adults and case-by-case basis, but not to include them in the
Response Team those with more severe presentations.3-6 main summary figures for diagnosis, prognosis, or
PESI = Pulmonary Embolism Evidence-based clinical practice guide- management recommendations. Recognizing that
Severity Index lines serve a critical role in standardizing care guidelines are meant to provide evidence summary
RCT = randomized controlled for patients with PE and help guide clinicians and general guidance rather than individualized
trial
by providing comprehensive management care for every patient, a summary of guidelines, as
RV = right ventricular recommendations. 7 However, as with other provided herein, is also meant to provide general
TTE = transthoracic areas of cardiovascular medicine, heteroge- recommendations for daily clinical practice.
echocardiography
neity in the clinical care of patients with PE, Although there are many patient groups that may
UFH = unfractionated heparin
especially as related to social determinants of require special considerations surrounding the
VKA = vitamin K antagonist health, runs counter to this effort.8,9 Further diagnosis and management of PE, we elected to
V/Q = ventilation/perfusion complicating the care of patients with PE is highlight specific guidance for 2 common and clin-
lung scan
the rapidly expanding number of interven- ically challenging populations: patients with preg-
VTE = venous
tional options, including catheter-based nancy and those with cancer. These subgroups of
thromboembolism
therapies and mechanical circulatory sup- patients were selected for their epidemiological
port devices, many with only limited evidence of ef- importance and impact on prognosis.
ficacy and safety from randomized trials.10 In the present review, the professional society
Inadequate data for integration of device therapy for documents, in English language, were primarily
PE as well as other key aspects of management, such selected based on consensus between the co-lead
as lifestyle modification and follow-up for short- and authors (M.Z. and B.B.) and the senior author
long-term complications, hamper the ability of (G.P.), in discussion with coauthors. A search of
guideline writing committees to provide clear or PubMed was performed to ensure that no poten-
consistent recommendations. The multiplicity of tially relevant guideline was missed (“Pulmonary
guidelines, scientific statements, and standardization Embolism”[MAJR] OR pulmonary*[TI] AND [embo-
documents as well as numerous areas of disagree- lism*(TI) OR thromboembo*(TI)] AND guideline*[TI],
ment and inconsistency in recommendations may date last searched: December 31, 2023). Differences
leave the clinician without a clear management and disagreements in opinion were addressed
pathway. through meetings and electronic communications.
In this review, we highlight key areas of consis- Areas of uncertainty were also noted with the hopes
tency, difference, and lack of recommendation be- that future basic and clinical research will advance
tween North American and European evidence-based knowledge in this field.
clinical practice guidelines for PE, scientific state- The guidelines identified for this review were
ments, and standardization documents, with an authored by the European Society of Cardiology and
emphasis on critical clinical and research needs and European Respiratory Society (ESC/ERS),2 Pulmonary
pathways forward. Embolism Response Team Consortium (PERT),12
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OCTOBER 15, 2024:1561–1577 Pulmonary Embolism Guidelines Comparison

F I G U R E 1 Summary of Professional Society Recommendations About Diagnosis of Acute PE

ESC/
ERS2 PERT12 CHEST13 AHA14 ASH15 NICE20
Suggested Not Addressed Not Recommended

Assessment of pretest probability a a f

Use of D-dimer in patients with low or intermediate
pretest probability of PE
Use of age-adjusted or probability-adjusted D-Dimer in g g
patients with low or intermediate pretest probability of PE
Use of D-dimer in patients with a high pretest probability
of PE

Use of the Pulmonary Embolism Rule-out Criteria (PERC) b b

Use of CTPA as initial imaging modality c d e

Use of V/Q lung scan as initial imaging modality d

Diagnostic approaches in pregnancy h i

a. Assessment using either clinical judgment and/or a validated clinical prediction rule, such as the Wells22 or
the Geneva scores23.
b. PERT recommends the use of PERC in patients with a low pretest PE probability based on another validated
tool (such as Wells or Geneva)22,23.
c. ESC/ERS offers further recommendations based upon the results of the CTPA. They also offer
recommendations for alternative imaging strategies that may be utilized.
d. PERT makes a specific recommendation for the use of portable V/Q scanning or echocardiography in cases
where CTPA is contraindicated or not available.
e. ASH guidelines recommend the use of CTPA when V/Q scan is not feasible.
f. NICE recommends the two-level Wells Score.
g. ASH and NICE recommend age-adjusted d-Dimer in patients >50 years
h. ESC/ERS comments on the approach to PE in pregnancy.
i. ASH provides specific comments regarding the approach to PE in pregnancy into a dedicated guideline19.

AHA ¼ American Heart Association; ASH ¼ American Society of Hematology; CTPA ¼ computed tomography pulmonary angiography; ERS
European Society of Cardiology; ESC ¼ European Society of Cardiology; NICE ¼ National Institute for Health and Care Excellence;
PE ¼ pulmonary embolism; PERT ¼ Pulmonary Embolism Response Team; V/Q ¼ ventilation/perfusion lung scan.

CHEST (previously referred to as the American Col- are offered by the current author group. Of note,
lege of Chest Physicians guidelines),13 the American differences in guideline recommendations are likely
Heart Association (AHA),14 the American Society of multifactorial, and are partly driven by the time
Hematology (ASH), 15-19 and the National Institute for of publication (and evidence review) or regional
Health and Care Excellence (NICE).20,21 Some profes- variation in resource availability and treatment
sional societies provided all recommendations in one strategies.
document, and others published them in multiple
documents. If the latter was the case for any given DIAGNOSIS OF ACUTE PE
question, the reference was to the most updated
document that followed the eligibility criteria. In The need for early diagnosis is emphasized by mul-
addition to summarizing those guidelines, at the tiple societal guidelines 2,12,15,20 (Figure 1). ESC/ERS,
conclusion of each section, practical considerations NICE, ASH, and PERT guidelines propose utilization
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Pulmonary Embolism Guidelines Comparison OCTOBER 15, 2024:1561–1577

of stepwise diagnostic algorithms.2,12,15,20 Most cur- primary imaging approach to rule out PE in this
rent guidelines emphasize initial patient assessment population, especially if the chest x-ray is abnormal,
using validated pretest probability scores, with such that the accuracy of a V/Q scan may be nega-
different preferences between documents for tools tively impacted. 2 Because D-dimer levels are often
22,23
such as the Wells’ or the Geneva score. Further- elevated in pregnancy, particularly in the third
more, all recommend D-dimer testing to exclude trimester, the usual cutoff level is not suitable during
acute PE in case of non–high-pretest probability; ESC/ pregnancy or the perinatal period. Instead, the ESC/
ERS 2 and PERT 12 suggest using age-adjusted 24 or ERS guidelines 2 suggest that the use of customized
25 20
probability-adapted cutoffs, whereas NICE and strategies, such as the modified YEARS algorithm,
ASH 15 suggest the use of age-adjusted cutoffs in pa- may limit unnecessary CTPAs.28 A separate ASH
15 20 12
tients over 50 years of age. ASH, NICE, and PERT guideline addresses VTE in the context of pregnancy,
suggest the use of the Pulmonary Embolism Rule-out with a single recommendation for the use of V/Q
Criteria (PERC) 26 in patients felt to have a low pretest scanning as the primary imaging modality. 19 None of
probability of PE, allowing the identification of a pa- the societies specifically address diagnostic strategies
tient subgroup in whom no further testing is indi- in patients with cancer.
cated. The ESC/ERS2 does not incorporate the PRACTICAL CONSIDERATIONS. Suspicion of PE should
Pulmonary Embolism Rule-out Criteria,26 noting that be assessed using a validated pretest probability
the evidence for its use is still limited and may be score. In patients with low pretest probability, a
unsafe to rule out acute PE in settings with an ex- negative D-dimer result excludes the diagnosis of PE,
pected higher prevalence of PE. whereas a positive test or a high initial pretest prob-
Much like routine practice, there is variation across ability must be followed by imaging. The diagnostic
guidelines for the imaging modality of choice. 27 ESC/ imaging test of choice should be the one that is most
ERS,2 NICE,20 and PERT 12 highlight that computed readily available and reliable at a particular site. Due
tomographic pulmonary angiography (CTPA) is the to the widespread availability of CT and diminishing
primary diagnostic imaging tool for acute PE. In expertise with V/Q scanning at many centers, CTPA is
contrast, the ASH guidelines recommend the use of frequently the modality of choice.
ventilation/perfusion (V/Q) lung scan over CTPA to
limit radiation exposure, in centers able to perform RISK STRATIFICATION
studies rapidly and with the expertise to interpret the
results in a timely manner.15 The use of CTPA is Once the diagnosis of acute PE is objectively
suggested when V/Q scanning and review by experts confirmed, determining the severity of illness,
are not feasible. 15 Both the ESC/ERS 2 and PERT 12 assessing prognosis, and synthesizing such informa-
documents suggest the use of transthoracic echocar- tion to risk-stratify patients with PE play critical
diography (TTE), V/Q lung scintigraphy, or pulmo- roles.29,30 Risk stratification can assist physicians in
nary angiography, when available, in case of selecting the location of care (home, general medical
contraindications or inability to obtain CTPA. wards, intermediate care unit, or intensive care unit)
Furthermore, in patients with clinical deterioration and the optimal treatment (ie, whether advanced
and suspected PE, the ESC/ERS guidelines recom- therapies should be considered).
mend bedside echocardiography or emergency CTPA, There is heterogeneity in international guidelines
depending on availability and clinical circumstances, with respect to grading of PE severity and recom-
for diagnosis and prognostication. 2 Additionally, the mended prognostication tools. Five guidelines2,12-15
2
ESC/ERS guidelines suggest the use of compression provided recommendations for identification of
ultrasound of the lower limbs as a diagnostic tool in high-risk (massive) PE and acknowledged that this
patients who have signs or symptoms of PE but subgroup should be defined as sustained hypotension
cannot undergo chest imaging for PE. Other profes- (systolic blood pressure <90 mm Hg 2,12-14,16 or a
sional societies are silent on this approach. decrease in systolic blood pressure $40 mm Hg from
During pregnancy, the ESC/ERS guidelines assert baseline 2,12,14,16 or need for vasopressor support 2,14 ).
that the diagnosis of PE should be further considered Although the AHA 14 guidelines identify low-risk PE
in the presence of a high pretest probability (Geneva patients as those who are hemodynamically stable
score) or intermediate/low probability with a positive and without evidence of right ventricular (RV) strain,
unadjusted D-dimer result. 2 In this context, a chest that document was published earlier than the others
x-ray may be the first imaging test. 2 Moreover, and did not address the incorporation of prognostic
according to these guidelines, CTPA, employing a scores. Guideline documents vary in their approach to
low-dose radiation protocol, is recommended as the the definition of RV dysfunction based on imaging.
JACC VOL. 84, NO. 16, 2024 Zuin et al 1565
OCTOBER 15, 2024:1561–1577 Pulmonary Embolism Guidelines Comparison

The 2019 ESC/ERS guidelines emphasize a compre- been used to guide treatment decisions in random-
hensive echocardiographic assessment, with param- ized controlled trials.2
eters such as an RV/left ventricular (LV) diameter PRACTICAL CONSIDERATIONS. Risk stratification
ratio of >1.0 and tricuspid annular plane systolic synthesizing an assessment of clinical severity, car-
excursion (TAPSE) <16 mm consistent with RV diac biomarkers, and imaging evidence of RV
dysfunction.2 Based on CTPA assessment, the 2019 dysfunction is a critical component of the evaluation
ESC/ERS guidelines state that an RV/LV diameter ra- of patients with PE.
tio of at least 1.0 is consistent with RV dysfunction.2
The 2011 AHA scientific statement defines RV TRIAGE OF PE AND LEVEL OF CARE
dysfunction on imaging as an RV/LV diameter ratio of
>0.9 or RV systolic dysfunction on echocardiography A recent shift toward home-based care and early
or an RV/LV diameter ratio of >0.9 on CTPA. 14
The discharge for low-risk acute PE patients is supported
PERT document endorses assessment of RV by the ESC/ERS,2 CHEST,13 NICE,20 and ASH 16 guide-
dysfunction via echocardiography or CTPA but does lines. ESC/ERS2 and ASH 16 offer specific patient se-
not provide specific definitions.12 The CHEST, ASH, lection criteria, suggesting the use of clinical scores.
and NICE documents do not provide specific recom- ESC/ERS2 suggest the use of PESI or simplified PESI
mendations for assessment and definition of RV rules 31,32 (or, alternatively, the Hestia criteria 34 ) for
dysfunction.13,15,20 clinical triage. Specifically, in the absence of
The use of a validated prognostic score, such as abnormal RV imaging on echocardiography or CTPA
the Pulmonary Embolism Severity Index (PESI) 31 or and with a favorable PESI/simplified PESI/Hes-
its simplified version, 29,32
is endorsed by guidelines tia31,32,34 score, the feasibility of early discharge and
from ESC/ERS, 2 PERT,12 and ASH. 16 The PESI score is home treatment must be considered. The CHEST
based on 11 differently weighted variables, allowing guidelines13 address practical home care aspects such
the identification of patients at low risk for 30-day as the use of direct oral anticoagulants (DOACs). The
mortality (PESI classes I and II). 31
However, recent HOME-PE study 35 has confirmed the safety and
because of the complexity of the PESI, a simplified feasibility of home treatment of PE patients selected
version, evaluating age, history of cancer, history of with either simplified PESI or Hestia criteria. 32 All
chronic cardiopulmonary disease, heart rate, systolic documents emphasize the importance of adequate
blood pressure, and oxyhemoglobin saturation level, access to follow-up health care and patient commit-
is often used to identify patients at low risk for ment to medication adherence. The AHA 2011 state-
30-day mortality. 32 ESC/ERS 2 and CHEST 13 guide- ment14 excludes discussion of home-based care,
lines also suggest an assessment of the RV size and focusing on more severe PE cases.
function for the identification of low-risk patients Multidisciplinary pulmonary embolism response
with acute PE. Only 4 guidelines (ESC/ERS, 2 PERT,12 teams (PERTs) 12 are now considered integral compo-
AHA,14 and ASH15) provide guidance on how to nents of PE care at many institutions and guide early
identify hemodynamically stable patients with management decisions, particularly in patients with
intermediate-risk (submassive) PE. Although AHA 14 more severe presentations. Of the guideline docu-
and ASH 15 recommend diagnosing intermediate-risk ments, only ESC/ERS2 and PERT 12 advocate for their
PE when RV dysfunction or strain are detected, the role, recommending consideration of establishing
ESC/ERS 2 and PERT 12 guidelines further subdivide PERTs when resources permit. There is heterogeneity
this group into an intermediate-low risk and an regarding which specialties comprise a multidisci-
intermediate-high risk category, requiring both RV plinary PE response team from one institution to
dysfunction on imaging and elevation of at least 1 another. Although guidelines recommend inclusive
biomarker, typically conventional cardiac troponin.33 multidisciplinary team care for PE, documents do not
In a recent study, comparing high-sensitivity and specify which subspecialties are required. Addition-
conventional care troponin I, high-sensitivity ally, the ESC/ERS2 and PERT 12 guidelines highlight
troponin I identified additional patients as having a the role of team-based care in clinical decision-
“positive” troponin but did not improve the identi- making for reperfusion therapy. Although ASH16 ac-
fication of patients who suffered from adverse knowledges the growing use of PERTs, it recognizes
events 33
(Figure 2). the lack of high-quality evidence demonstrating
An elevation of markers of RV dysfunction, such as improved outcomes in PE patients and thus does not
B-type natriuretic peptide or N-terminal pro–B-type provide a specific recommendation (Figure 2).
natriuretic peptide may provide additional prognostic PRACTICAL CONSIDERATIONS. Home-based care is
information. However, these markers have not yet encouraged in patients with low-risk PE, reliable
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F I G U R E 2 Recommendations for Risk Stratification, Home-Based Care, and the Use of Multidisciplinary Response Teams for Acute PE
Across Guideline Documents

ESC/
ERS2 PERT12 CHEST13 AHA14 ASH15 NICE20
Suggested Not Addressed Not Recommended

Recommendation for risk stratification a

Definition provided for low-risk PE

Definition provided for intermediate-risk (submassive) PE

Definition provided for intermediate-low risk PE

Definition provided for intermediate-high risk PE

Definition provided for PE deterioration

Definition provided for high-risk (massive) PE

Early discharge or entirely home-based care for low-risk PE c b

Use of a multidisciplinary PERT b d

a. While the CHEST guidelines focused on antithrombotic therapy for VTE, the general concept of
risk stratification is discussed in the document.
b. The AHA Statement does not address home-based care. It also predated the development of PERTs and
does not address the use of PERTs.
c. The ESC/ERS also considers whether assessment of right ventricular function, in addition to the clinic
assessment, is necessary prior to sending patients home. Though not part of the recommendation, the authors
note that given "the ease and minimal additional effort of assessing RV size and function at presentation by
echocardiography, or on the CTPA performed to diagnose the PE event itself, it is wise to exclude
RV dysfunction and right heart thrombi if immediate or early (within the first 24-48h) discharge of the patient
is planned.”
d. The use of PERT is addressed but without specific recommendation based on lack of data.

Abbreviations as in Figure 1.

medication adherence, and adequate health care ERS2 guidelines recommend anticoagulation with
support. Multidisciplinary PE response teams are unfractionated heparin (UFH), including a weight-
recommended, based on consensus opinion, in the adjusted bolus injection, as soon as possible, in pa-
context of limited high-quality evidence indicative of tients with suspected high-risk PE. Similarly, the ESC/
improved outcomes. ERS,2 PERT,12 and NICE20 guidelines recommend UFH
for hemodynamically unstable PE if advanced thera-
IMMEDIATE ANTICOAGULATION pies such as thrombus extraction, fibrinolysis, or
surgery are being considered. UFH is frequently uti-
In patients with suspected PE, there is consensus lized in high-risk and intermediate high-risk PE to
across professional societies to consider empiric minimize periprocedural bleeding when adminis-
therapeutic anticoagulation while awaiting the re- tering advanced therapies, such as systemic fibrino-
sults of confirmatory tests in patients with interme- lysis or catheter-based intervention. However, most
diate or high pretest probability of PE, provided that patients fail to achieve and consistently maintain
the risk of bleeding is low 2,14,20 (Figure 3). In patients therapeutic activated partial thromboplastin times
with confirmed PE, therapeutic anticoagulation is the within the first 48 hours after diagnosis with standard
cornerstone of treatment. The choice of anticoagulant UFH dosing nomograms.36 Due to the concern of
differs depending on the severity of the PE. The ESC/ subtherapeutic or supratherapeutic anticoagulation
JACC VOL. 84, NO. 16, 2024 Zuin et al 1567
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F I G U R E 3 Professional Society Recommendations for Immediate Anticoagulation for Acute PE

ESC/
ERS2 PERT12 CHEST13 AHA14 ASH16 NICE20
Suggested Not Addressed Not Recommended

Therapeutic anticoagulation should be initiated while

awaiting diagnostic results if the pretest probability of PE a
is intermediate or high and the bleeding risk is low

Therapeutic anticoagulation should be given to all patients

b
with confirmed PE who do not have a contraindication

Immediate anticoagulant choice in high-risk PE if advanced

therapies are considered: unfractionated heparin

Immediate anticoagulant in intermediate-high risk PE not

requiring advanced therapies: LMWH or DOAC (unless c
contraindications)

Immediate anticoagulant choice in low-risk PE: DOAC

d c
(unless contraindications)

Immediate anticoagulant choice in patients with HIT or a

history of HIT: parenteral direct thrombin inhibitor or e f g
fondaparinux
For oral anticoagulation in the treatment phase of PE,
DOAC is recommended over VKA unless there is severe f
kidney disease, concomitant use of interacting drugs, or
antiphospholipid syndrome
a. If PE unlikely, but D-dimer cannot be offered within 4 hours, NICE 2020 guidelines recommend interim
anticoagulation while awaiting results.
b. Therapeutic anticoagulation with LMWH, IV/SC heparin, or fondaparinux is recommended for all patients with
confirmed PE.
c. ASH does not differentiate the choice of agents based on acuity of care.
d. For immediate treatment with DOACs, apixaban and rivaroxaban can start immediately, whereas edoxaban
and dabigatran need a short course of initial treatment with heparin-based regimens.
e. No preference for parenteral or oral anticoagulation for intermediate or low-risk PE in the formal
recommendations; LMWH or fondaparinux preferred over UFH.
f. AHA recommends danaparoid, lepirudin, argatroban, or bivalirudin; ESC/ERS 2019 recommends fondaparinux
if allergic or adverse reaction to LMWH.
g. ASH provides specific comments on the management of HIT in VTE in a dedicated guideline18.

DOAC ¼ direct oral anticoagulant; HIT ¼ heparin-induced thrombocytopenia; LMWH ¼ low-molecular-weight heparin; VKA ¼ vitamin K
antagonist; other abbreviations as in Figure 1.

in the early hours after PE diagnosis, closer moni- from diagnosis, although dabigatran and edoxaban
2,12,13
toring of the adequacy of UFH may be considered. need a short course of initial heparin therapy
Although anti-Xa testing has been proposed as a Parenteral direct thrombin inhibitors, such as arga-
preferred modality for UFH monitoring, consensus troban or bivalirudin, can be used in place of
among evidence-based clinical practice guidelines is UFH, while fondaparinux can be used in place of
lacking and data supporting such a recommendation LMWH, in patients with a history of or suspected
are limited.37,38 Moderate-quality evidence demon- heparin-induced thrombocytopenia. 2,14,18 Oral anti-
strates that fixed-dose low-molecular-weight-heparin coagulation with DOACs is recommended over
(LMWH) is associated with a lower incidence of vitamin K antagonists (VKAs), such as warfarin,
recurrent VTE and major hemorrhage compared with except for patients with severe kidney disease with a
UFH. 39 Patients with low-risk PE, and those with creatinine clearance of <15 mL/min; those taking
intermediate-low-risk PE, can be treated with a DOAC potent p-glycoprotein and/or CYP3A4 inducers or
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Pulmonary Embolism Guidelines Comparison OCTOBER 15, 2024:1561–1577

inhibitors such as phenytoin, carbamazepine, or The decision to start supportive care with venoar-
conazoles; and those with antiphospholipid syn- terial extracorporeal membrane oxygenation should
drome.2,12-14,16,20 be based on local expertise, hemodynamic parame-
In patients with nongastrointestinal cancer and PE ters, and an assessment of likelihood of long-term
who do not require UFH, guidelines from CHEST 13 freedom from disability or complications. 42
20
and NICE recommend the use of a DOAC over Although the 2019 ESC/ERS guidelines 2 defined
2 17
LMWH. Conversely, ESC/ERS and ASH guidelines shock, the most recent CHEST 13 and ASH16 guidelines
recommend either a DOAC or LMWH. Apixaban or did not. Unfortunately, a universal shock definition
LMWH may be the preferred option in patients with for acute PE is still lacking.
luminal GI malignancies according to the CHEST13 PRACTICAL CONSIDERATIONS. In the absence of
guidelines. For initial anticoagulation in pregnant consensus recommendations and rigorous clinical
patients with PE, only the ESC/ERS guidelines2 evidence, the selection of supportive care for patients
comment and suggest use of LMWH. with PE remains at the discretion of the clinician and
PRACTICAL CONSIDERATIONS. Anticoagulation ther- local expertise and an important area of unmet
apy should be started while awaiting the results of research need.
confirmatory diagnostic testing if the pretest proba-
ADVANCED THERAPIES
bility is intermediate or high, and the bleeding risk is
low. Once the diagnosis of PE is confirmed, all pa-
Although all referenced guidelines recommend
tients without contraindications should receive anti-
reperfusion therapy as first-line for high-risk PE,
coagulation. Those with low- and probably
the certainty (or level) of evidence supporting rec-
intermediate-low-risk PE can be treated with a
ommendations varies across documents. 2,12-14,16
DOAC. For patients with intermediate-high-risk PE,
Additionally, the heterogeneity in risk factors, patho-
the guidelines do not provide detailed recommenda-
physiology, clinical presentation of VTE, and social
tions and there is heterogeneity in practice. The
determinants of health may modify the utilization of
choice of UFH, LMWH, or a DOAC depends on local
reperfusion therapy across populations.
experience and case-specific considerations.
According to all guidelines, patients with hemo-
SUPPORTIVE CARE dynamically unstable PE, defined as a systolic blood
pressure <90 mm Hg, or in cardiac arrest require rapid
Considering the limitations within the evidence base restoration of pulmonary perfusion and gas exchange
and the lack of a specific focus on this aspect, most as well as alleviation of increased RV afterload to
guidelines are silent about details of supportive care. prevent deterioration and death.2,12-15 Although sys-
2
The 2019 ESC/ERS guidelines provide general con- temic fibrinolysis is recommended as the primary
siderations on pharmacological supportive care. reperfusion therapy in high-risk PE,2,12-14,16 the cer-
Modest fluid challenges are reasonable in patients tainty (or level) of evidence supporting recommen-
with low central venous pressure, guided by invasive dations varies across documents (Supplemental
monitoring, ultrasound, or clinical monitoring. The Table 1). The primary evidence for systemic fibrino-
use of furosemide in normotensive patients with lysis for high-risk PE comes from a single randomized
intermediate-risk PE improves urine output but not controlled trial (RCT) that enrolled 8 patients. 43
40
early hemodynamic outcomes and has not been Additional evidence is derived from observational
discussed in the guidelines. Vasopressors, such as studies and epidemiological analyses. In clinical
norepinephrine, can improve hemodynamics in practice, systemic fibrinolysis remains underused in
shock, whereas the roles of dobutamine and levosi- high-risk patients.44 Although it has been hypothe-
mendan remain under review and are limited to sized that reperfusion therapy may impact long-term
specific conditions such as low cardiac index. Vaso- outcomes, there is no current evidence supporting
dilators, including inhaled nitric oxide and inhaled or its use for preventing post-PE sequelae, including
intravenous prostanoids, may improve RV function chronic thromboembolic pulmonary hypertension
especially in patients with signs of elevated pulmo- (CTEPH).45 Surgical embolectomy remains an alter-
nary vascular resistance, but evidence supporting native to systemic fibrinolysis in centers with appro-
their safety and efficacy are lacking.41 No formal priate infrastructure, clinical staff, and procedural
recommendations concerning the use of pharmaco- experience.2,12,14 There is broad agreement among
logical therapy for the supportive care of patients European and American guidelines with respect to
with high-risk PE are presented in any of the avoiding routine administration of systemic fibrino-
considered guidelines. lysis in intermediate-high risk (submassive) PE caused
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F I G U R E 4 Summary of Professional Society Recommendations for Advances Therapies in Acute PE

ESC/
ERS2 PERT12 CHEST13 AHA10,14 ASH16 NICE20
Suggested Not Addressed Not Recommended

Systemic fibrinolysis in hemodynamically unstable PE

patients
Systemic fibrinolysis in hemodynamically stable
experiencing hemodynamic and/or respiratory worsening

Reduced dose systemic fibrinolysis b

Routine use of systemic fibrinolysis in hemodynamically
stable PE patients
Surgical embolectomy in hemodynamically unstable PE
patients e
CDIs in hemodynamically unstable PE patients in whom
systemic fibrinolysis has failed or is contraindicated c f
CDIs in hemodynamically stable experiencing
hemodynamic and/or respiratory worsening d f

Extracorporeal Membrane Oxygenation (ECMO) a

a. ECMO may be considered in combination with surgical embolectomy or catheter-directed therapies in patients
with refractory cardiogenic shock.
b. In high-risk patients with relative contraindications to systemic fibrinolysis.
c. In centers with the appropriate infrastructure, clinical staff, and procedural experience.
d. ASH prefers systemic fibrinolysis and endorses close cardiovascular monitoring to promptly identify
the development of hemodynamic compromise.
e. Surgical thrombectomy may occasionally be performed for patients with a life-threatening PE.
f. Catheter-based embolectomy should only be used within the confines of research protocols due the absence
of adequate supporting clinical trials.

CDI ¼ catheter-directed intervention; ECMO ¼ extracorporeal membrane oxygenation; other abbreviations as in Figure 1.

by the risk of major hemorrhage, especially intracra- patients with intermediate-high-risk PE, several on-
nial bleeding.2,10,12-14 going randomized trials (NCT04790370, NCT05111613,
Over the past decade, catheter-directed in- NCT06055920, NCT05684796, NCT05591118) are
terventions (CDIs) have generated growing interest investigating the efficacy and safety of CDIs in
for PE reperfusion in those with contraindications to terms of early and long-term clinical outcomes.
systemic fibrinolysis (or after its failure).10 These Randomized trials47-49 and single-arm studies with
treatments can be classified into 2 main categories: hemodynamic outcomes have demonstrated that
catheter-directed fibrinolysis and catheter-based catheter-directed reperfusion techniques are associ-
embolectomy. 46 All guidelines suggest the use of ated with temporal improvement in RV dysfunction
CDI, with different grades of recommendations, within 24 to 48 hours and reduced thrombus
as rescue treatment after failure of systemic reper- burden.47-54 Available evidence comparing the safety
fusion or in individuals having a high bleeding and efficacy of CDIs with standard anticoagulation in
risk.2,12-14,16,20 However, there is no universal intermediate-risk PE patients remains limited.
consensus regarding the use of CDI among different Notably, none of the current guidelines address the
international guidelines, in large part caused by utility of advanced therapies to reduce long-term
evidence gaps. Recently, the NICE20 guidance stated mortality, prevent persistent RV dysfunction,
that for intermediate- or high-risk PE, when alterna- improve quality of life, and avert sequelae of post-PE
tive reperfusion treatments are suitable, catheter- syndrome and CTEPH. 45
based embolectomy should only be used within the PRACTICAL CONSIDERATIONS. Systemic fibrinolysis
confines of research protocols due the absence of remains the most widely recommended reperfusion
adequate supporting clinical trials 21 (Figure 4). In technique to reduce mortality in high-risk PE. The
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Pulmonary Embolism Guidelines Comparison OCTOBER 15, 2024:1561–1577

role of reperfusion and the optimal modality in identifying mismatched perfusion defects. 2,12,14
2 12
intermediate-high risk PE remain unclear and are best Guidelines from the ESC/ERS, PERT, and AHA 14
addressed by a multitude of ongoing and forth- suggest that symptomatic patients with pulmonary
coming RCTs. hypertension and/or mismatched perfusion defects
should be evaluated at a referral center with experi-
INFERIOR VENA CAVA FILTERS ence in chronic thromboembolic disease, including
CTEPH. Discussion of the management of post-PE
Current best evidence derived from pooled results of syndrome is limited across the international guide-
prospective controlled studies across a heterogenous lines (Supplemental Figure 2).
indications suggests that inferior vena cava (IVC) fil-
PRACTICAL CONSIDERATIONS. Although guideline
ter use, compared with nonuse, is associated with
recommendations are limited and many guidelines
reduced risk of subsequent PE, at the expense of an
are silent on clear directives regarding how to
increase in subsequent deep vein thrombosis,
monitor patients over time, clinical follow-up,
without a significant difference in mortality. 55 For
including imaging, after acute PE serves several
patients with PE who can receive anticoagulant
important purposes: to assess for recurrent events, to
therapy, an RCT did not show additive benefit from
screen for bleeding complications, to identify poten-
the routine use of IVC filters. 56 The most widely
tial post-PE sequelae, and to evaluate patients with
agreed-upon indications for IVC filters across the
persistent or new-onset dyspnea as well as signs of
guidelines are acute contraindication to systemic
CTEPH. The routine use of follow-up CTPA or V/Q is
anticoagulation in patients with acute PE, and
not warranted. However, consideration of a follow-up
recurrent PE despite adequate administration and
TTE or V/Q scanning may be reasonable to further
adjustment of anticoagulation. For several other
assess patients with residual symptoms or severe RV
clinical scenarios, there is marked heterogeneity
dysfunction, respectively.
across guidelines, in large part because of limited
available high-quality evidence (Supplemental
LIFESTYLE MODIFICATIONS
Figure 1).2,12-14,16
PRACTICAL CONSIDERATIONS. IVC filter use is rec-
Clinical practice guidelines and scientific statements
ommended in patients with acute PE and a contra-
on PE management remain largely silent on the role
indication to anticoagulation or recurrent PE despite
and relevance of lifestyle modification recommenda-
appropriate therapeutic anticoagulation.
tions after PE 2,12-14,16,20 (Figure 5, Supplemental
FOLLOW-UP IMAGING AND CLINICAL Figure 3). This is likely because of the lack of well-
ASSESSMENT designed RCTs focusing on lifestyle modification.
Nonetheless, lifestyle modification, such as smoking
Appropriate follow-up after a PE diagnosis includes cessation and regular physical activity, may mitigate
visits with routine health care workers and special- the increased risk of arterial cardiovascular disease as
ists, clinical examination, and noninvasive imaging. well as post-PE syndrome.57 Despite the paucity of
This long-term care is crucial to assess optimal re- high-quality evidence specifically examining lifestyle
covery, the efficacy of anticoagulation, and potential modifications in the post-PE population, a recent
bleeding complications as well as to evaluate for clinical position paper by the ESC/ERS58 proposed
recurrent VTE events; potential PE-related compli- performance of a systematic cardiovascular risk
cations, such as post-PE syndrome and CTEPH; and assessment in PE survivors, and especially in those
impact on quality of life. 2 Only the ESC/ERS2 and the with unprovoked PE or with obesity, in accordance
PERT 12 guidelines recommend a follow-up visit 3 to with other current guidelines for the general popu-
6 months after discharge. lation.58,59 The AHA Life’s Essential 8 provides a
2 14 12
The ESC/ERS, AHA, and PERT guidelines sup- comprehensive framework for focusing on key life-
port the use of noninvasive imaging techniques, style modifications to improve cardiovascular health
including TTE and, in selected cases, natriuretic highlighting components of healthy diet, physical
peptides, and a 6-minute walk test12 and/or cardio- activity, avoidance of nicotine exposure, sleep
pulmonary exercise testing2 to evaluate for the pres- health, maintenance of healthy body mass index and
ence of pulmonary hypertension, especially in control of blood lipids, blood glucose, and blood
patients with persistent and otherwise unexplained pressure.60 After acute PE, care should focus on life-
dyspnea or impaired exercise tolerance 3 months af- style modifications aimed at fostering recovery and
ter the acute event. V/Q scanning can be helpful to minimizing the risk of future cardiovascular
JACC VOL. 84, NO. 16, 2024 Zuin et al 1571
OCTOBER 15, 2024:1561–1577 Pulmonary Embolism Guidelines Comparison

F I G U R E 5 Summary of Post-PE Lifestyle Recommendations

Post-PE Lifestyle Recommendations

First Weeks First Months Long Term

Early Ambulation Post-PE Syndrome Travel

• Encourage early ambulation • CTEPH evaluation and • Counsel patients who
as soon as effective cardiopulmonary exercise testing discontinue anticoagulation
anticoagulation is in case of residual unexplained about predictable major
achieved.8 dyspnea.4 transient risk factors.4

Lifestyle Modification Post-PE Syndrome

Physical Activity
• Support patients toward a • Screen for anxiety or depression
healthy lifestyle including • Continue encouraging a healthy
as contributors to incomplete
adequate physical activity and lifestyle including adequate
recovery, refer to experts
smoking cessation.4 physical activity.4
as needed.4

Physical Activity Cardiovascular Risk Factors Antithrombotic Regimen

• Encourage stepwise • General cardiovascular risk • Review the use of antiplatelet
resumption of sporting assessment and optimization, agents. Most anticoagulated
activities and screen for sexual based on evidence-based patients do not need them for
dysfunction.4 guidelines.4 stable atherosclerosis.4

Resumption of ambulation is recommended upon starting therapeutic anticoagulation,72 with activities escalated as tolerated. Lifestyle
modifications and cardiovascular risk optimization should be considered both initially and during follow-up visits. Early follow-up should
assess symptoms of post-pulmonary embolism (PE) syndrome and consider testing exercise limitations as a sign of for chronic thrombo-
embolic pulmonary hypertension, along with mental health screening. Long-term follow-up should counsel on prophylactic measures if
anticoagulation is discontinued, and major surgery is upcoming. Most with stable atherosclerotic cardiovascular disease on anticoagulation
likely do not need continued antiplatelet therapy.57

disease.57 Cardiopulmonary exercise testing is sug- for VTE, whereas the ESC/ERS 2 guidelines have clas-
gested in selected cases after PE by the ESC/ERS sified patients into 3 distinct risk categories for long-
guidelines. 2 term VTE recurrence: low, intermediate, and high
PRACTICAL CONSIDERATIONS. Although limita- risk. Patients with major transient or reversible risk
tions in the evidence have resulted in relative silence factors (associated with a >10-fold increased risk of
among PE guidelines, lifestyle modifications, VTE), such as surgery under general anesthesia last-
including smoking cessation, can be justified to ing for >30 minutes or experiencing immobilization
mitigate risk factors for recurrent VTE and other for $3 days caused by acute illness or exacerbation of
cardiovascular complications. a chronic condition, are categorized as low risk, with
an estimated VTE recurrence rate of <3% per year.
INTENSITY AND DURATION OF ANTICOAGULATION Conversely, those with transient or reversible factors
(associated with a #10-fold increased risk of VTE),
The International Society on Thrombosis and Hae- including inflammatory bowel disease or active
mostasis,61 CHEST,13 and ESC/ERS2 guidelines pro- autoimmune disease, are placed in the intermediate-
vide insights into major and minor provoking factors risk group, with a VTE recurrence risk estimated
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F I G U R E 6 International Guideline-Based Algorithm for Optimal Duration and Intensity of Anticoagulation for Pulmonary Embolism

Acute Pulmonary Embolism

≥3 Months of Therapeutic Anticoagulation

Consider Circumstances Surrounding Event, Presence of Persistent Risk

Factors, Bleeding Risk, and Lifestyle/Occupation Implications

Shared Decision-Making Discussion

Active No Identifiable Antiphospholipid Recurrent Event Minor Transient Risk Major Major
Cancer Risk Factor Antibodies Factor Transient Transient
With Persistent Without Persistent
Risk Factor Risk Factor

Continue Continue Continue Major Transient Minor Consider Stop Individualized Stop
Anticoagulation Anticoagulation Anticoagulation Risk Factor Transient Extended Anticoagulation Decision Anticoagulation
Risk Factor Anticoagulation

Standard Low vs VKA with Stop Continue Low vs Standard

Intensity Standard INR 2-3, Anticoagulation Anticoagulation Intensity
DOAC or LMWH Intensity Especially for
Triple-Positive
Antiphospholipid
Antibodies Low vs
Standard
Intensity

Guideline GeneraI Consensus Guideline Heterogeneity Guidelines Unclear

INR ¼ International Normalized Ratio; other abbreviations as in Figure 3.

between 3% per year and 8% per year. Finally, pa- suggest extended anticoagulation for patients with
tients who have experienced PE and have active active cancer, and those with ongoing inflammatory
cancer, have had 1 or more previous episodes of VTE disease or unprovoked PE (although with varying
without major transient or reversible factors, or have strength of recommendation). In contrast, guidance
antiphospholipid syndrome, are considered at high documents demonstrate heterogeneity in recom-
risk for VTE recurrence, with an estimated risk mendations about the duration of anticoagulant
exceeding 8% per year. therapy for PE provoked by minor transient risk fac-
The ESC/ERS,2 ASH,16 and CHEST 13 guidelines tors. The NICE 20 and ASH16 guidelines do not distin-
recommend at least 3 months of therapeutic anti- guish between major (eg, hospitalization, prolonged
coagulation for the primary treatment period unless immobilization, surgery, and trauma) and minor
there is a contraindication. Conversely, for secondary transient risk factors (eg, oral contraceptives, preg-
prevention or extended-duration therapy, guidance nancy, and prolonged travel) and suggest that anti-
documents recommend considering the circum- coagulation be discontinued after the primary
stances surrounding the incident event and the treatment period. The ESC/ERS2 guidelines recom-
presence of persistent risk factors.2,13,16,20 Guidelines mend that extended anticoagulation beyond
that address the duration of anticoagulation are 3 months be considered in patients with persistent
consistent in recommendations to discontinue anti- risk factors or those with PE in the setting of a minor
coagulants in patients with PE provoked by major transient risk factor.2 Recommendations for this
transient risk factors in the absence of enduring risk category are supported by lower grades of evidence
factors. 2,13,16,20 Likewise, guidelines recommend or and expert opinion and should be accompanied by
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OCTOBER 15, 2024:1561–1577 Pulmonary Embolism Guidelines Comparison

consideration of bleeding risk as part of shared questions related to prognostication, anticoagulation,

decision-making. For recurrent PE in the setting of a and advanced management of PE remain unan-
transient provoking risk factor (ESC/ERS 2 guidelines swered, leading to heterogeneity in recommenda-
qualify this as a major transient or reversible risk tions or silence in the existing guidelines (Central
factor), only the ASH 16 guidelines specifically suggest Illustration). The role of artificial intelligence in the
stopping anticoagulation after primary treatment for timely and accurate diagnosis of PE remains to be
the recurrent event. Outside of this setting, guide- seen. Innovation in risk stratification to synthesize
lines recommend or suggest continuing anti- the plethora of vital signs, clinical variables, and
coagulation indefinitely for recurrent events. laboratory33 and imaging biomarkers will be critical.
Guidelines recommend that DOACs be preferen- Time-varying measures (such change in heart rate or
tially used over VKA during both the primary treat- hypoxemia) may assist in the identification of a pre-
ment and secondary prevention periods.2,13,16,20 For shock state.50 Such detailed prognostication, paired
extended-duration treatment (secondary preven- with findings from several ongoing clinical trials and
tion), both the CHEST 13 and ESC/ERS 2 guidelines studies of laboratory or imaging markers, may iden-
suggest a reduced dose (low-intensity) 62 of apixaban tify subgroups that may benefit the most from specific
(2.5 mg twice daily) or rivaroxaban (10 mg once daily) interventions. 29,62,65 A more precise definition of the
over the standard full-dose treatment dose regimens. optimal therapeutic window for reperfusion may be
The ESC/ERS2 and CHEST 13 guidelines suggest that needed, much like what has been done for patients
this dose reduction be considered after at least with myocardial infarction.66 Findings from clinical
3 months of full-dose dose anticoagulation. The ASH trials should also inform the minimal fibrinolytic
guidelines suggest either a standard treatment dose doses required to achieve effective reperfusion and
or a low-intensity treatment in this phase.16 Patients criteria for when to select nonfibrinolytic options. 66
with antiphospholipid syndrome require indefinite For clinical questions unlikely to have RCT data
oral anticoagulation with a VKA.2,13,16,63 For treat- shortly, such as those related to the use of IVC filters
ment of PE in the setting of active cancer (persistent and mechanical circulatory support, rigorous
risk factor), guidelines recommend extending anti- matched analyses from observational studies may be
coagulation indefinitely or until there no longer evi- informative. Besides procedural therapies, findings
dence of malignant disease. 2,13,17 The ESC/ERS from ongoing prospective studies and trials will be
guidelines2 recommend using weight-adjusted highly informative to determine the optimal duration
LMWH over a VKA or edoxaban or rivaroxaban in and intensity of anticoagulation for patients with PE,
those with gastrointestinal cancer. Of note, those including those with a first unprovoked PE, or those
guidelines preceded the publication of results for with provoked events who have enduring risk fac-
apixaban in cancer-associated venous thrombosis.64 tors.65,67 There is also an unmet need for high-quality
The CHEST 13 and ASH17 guidelines suggest apixaban, comparative effectiveness studies focusing on the
edoxaban, or rivaroxaban over LMWH or a VKA supportive care of high-risk PE or appropriate use of
(Figure 6). Apixaban or LMWH may be the preferred various advanced therapy options, particularly
option in patients with luminal GI malignancies ac- studies that incorporate the latest definitions of
cording to the CHEST13 guidelines. cardiogenic shock. 2,68,69 Similarly, additional high-
PRACTICAL CONSIDERATIONS. Evidence-based guide- quality studies are needed to better define the
lines recommend a minimum of 3 months of thera- optimal therapeutic strategies in patients who are at
peutic anticoagulation after the diagnosis of PE. risk but without clinically overt shock, such as those
Beyond this acute treatment phase, recommendation with preshock or normotensive shock and those with
of secondary prevention or extended-duration ther- right heart thrombi or clot-in-transit.50,70 Gaps in the
apy should consider the presence of provoking cir- published reports exist for patients who present
cumstances, persistent conditions that predispose to outside of these larger categories such as those with
recurrence, risk of bleeding, and lifestyle implications PE and a major transient risk but with additional
as part of a shared decision-making process. Except persistent risk factors and those with risk factors that
for specific patient populations, DOACs are preferred are anticipated to improve over an extended period. 67
over VKAs for secondary prevention. Similarly, rigorous research is needed to define
post-PE syndrome and to test strategies that may
ADDITIONAL EVIDENCE/KNOWLEDGE GAPS improve patient-centered outcomes in those who
experience long-term non-CTEPH sequelae of PE.
Notwithstanding the enormous progress that has Social determinants of health and sex and ethnoracial
been made over the past 4 decades, many critical differences require further investigation to
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Pulmonary Embolism Guidelines Comparison OCTOBER 15, 2024:1561–1577

C E NT R AL IL L U STR AT IO N Consensus on Pulmonary Embolism Care Across U.S. and European Guidelines

Zuin M, et al. JACC. 2024;84(16):1561–1577.

PE remains a major cardiovascular cause of mortality, despite clinical advancements. Clinicians encounter challenges in determining optimal anticoagulant strategies
and interventions mainly because of the heterogeneity and uncertainty exhibited across numerous international guidelines. Among these guidelines, general
agreement exists on most PE care recommendations, with variability in specifics. There is notable lack of consensus regarding lifestyle and usage of reduced dose of
systemic fibrinolysis. AC ¼ anticoagulation; CDI ¼ catheter-directed intervention; CTED ¼ chronic thromboembolic disease; CTEPH ¼ chronic thromboembolic
pulmonary hypertension; DOAC ¼ direct oral anticoagulant; IVC ¼ inferior vena cava; PE ¼ pulmonary embolism; VTE ¼ venous thromboembolism.

disentangle those related to biologically distinct mechanism for the identification of areas in the
pathways from those resulting from disparities that published reports for which data are inconsistent and
require population-level mitigation strategies. 9,71 associated recommendations are limited or conflict-
Finally, RCTs are needed to help inform guidelines ing. Harmonization of recommendations and research
about the optimal lifestyle and dietary interventions priorities across the various evidence-based clinical
to minimize the risk of incident PE, recurrent PE, and practice guidelines may ultimately represent a key
its adverse short-term or durable consequences step in reducing heterogeneity of care and improving
(Supplemental Figure 4). patient and population outcomes.

CONCLUSIONS FUNDING SUPPORT AND AUTHOR DISCLOSURES

Evidence-based clinical practice guidelines for diag- Outside of the submitted work, Dr Bikdeli is supported by a Career
nosis and management of PE serve a critical role in Development Award from the American Heart Association and VIVA
Physicians (#938814); was supported by the Scott Schoen and Nancy
summarizing state-of-the-art research and providing
Adams IGNITE Award; is supported by the Mary Ann Tynan
strategies for its integration in clinical care. However, Research Scientist award from the Mary Horrigan Connors Center for
guideline documents also provide an important Women’s Health and Gender Biology at Brigham and Women’s
JACC VOL. 84, NO. 16, 2024 Zuin et al 1575
OCTOBER 15, 2024:1561–1577 Pulmonary Embolism Guidelines Comparison

Hospital, and the Heart and Vascular Center Junior Faculty Award consultant for AOP Health, Merck Sharp and Dohme, PULNOVO, United
from Brigham and Women’s Hospital; was a consulting expert, on Therapeutics, and Janssen; has received grants from AOP Health; and
behalf of the plaintiff, for litigation related to 2 specific brand models has served on the Speakers Bureau for Merck Sharp and Dohme and
of IVC filters (he has not been involved in the litigation in 2022-2024 Janssen. Dr Klok has received research funding from Bayer, Bristol
nor has he received any compensation in 2022-2024); is a member of Myers Squibb, BSCI, AstraZeneca, Merck Sharp and Dohme, Leo
the Medical Advisory Board for the North American Thrombosis Pharma, Actelion, Farm-X, the Netherlands Organisation for Health
Forum; serves in the Data Safety and Monitory Board of the NAIL-IT Research and Development, The Dutch Thrombosis Foundation, The
trial funded by the National Heart, Lung, and Blood Institute, and Dutch Heart Foundation, and the Horizon Europe Program, all outside
Translational Sciences; and is a collaborating consultant with the of this work and paid to his institution. Dr Weitz holds the Canada
International Consulting Associates and the U.S. Food and Drug Research Chair (Tier 1) in Thrombosis and the Heart and Stroke Foun-
Administration in study to generate knowledge about utilization, dation J.F. Mustard Chair in Cardiovascular Research. Dr Piazza has
predictors, retrieval, and safety of IVC filters. Dr Barco has received received research grants (paid to his institution) from Bristol Myers
institutional research support from Boston Scientific, Medtronic, Squibb/Pfizer, Janssen, Alexion, Bayer, Amgen, BSC, Esperion, and the
Bayer, and Sanofi; and has received personal fees/honoraria from National Institutes of Health (1R01HL164717-01); and has received
Boston Scientific, Penumbra, and Viatris. Dr Giannakoulas has consulting fees for advisory roles from BSC, Amgen, PERC, NAMSA,
received fees for lectures and/or consultations from Actelion/Jans- Bristol Myers Squibb, Janssen, Penumbra, and Thrombolex. All other
sen, Bayer, Boehringer Ingelheim, ELPEN Pharmaceuticals, Ferrer- authors have reported that they have no relationships relevant to the
Galenica, GlaxoSmithKline, Gossamer-Bio, Merck Sharp and Dohme, contents of this paper to disclose.
Pfizer, Lilly, and United Therapeutics. Dr Jimenez has served as a
speaker for Bristol Myers Squibb, ROVI, and Sanofi. Dr Lang, in addition
to being an investigator in trials involving these companies, has re- ADDRESS FOR CORRESPONDENCE: Dr Marco Zuin,
lationships including consultancy service, research grants, and mem-
Department of Translational Medicine, University of
bership of scientific advisory boards for drug companies including
AOP-Health, Actelion-Janssen, Merck Sharp and Dohme, United Ferrara, Via Luigi Borsari 46, 44141 Ferrara, Italy.
Therapeutics, Medtronic, Neutrolis, and Novo Nordisk; has served as a E-mail: [email protected].

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