JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 67, NO. 8, 2016

2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2015.12.024

COUNCIL PERSPECTIVES

Acute Pulmonary Embolism

With an Emphasis on an Interventional Approach
Wissam A. Jaber, MD,a Pete P. Fong, MD,b Giora Weisz, MD,c Omar Lattouf, MD,d James Jenkins, MD,e
Kenneth Roseneld, MD, MHCDS,f Tanveer Rab, MD,a Stephen Ramee, MDg

ABSTRACT
Compared with recent advances in treatment of serious cardiovascular diseases, such as myocardial infarction and
stroke, the treatment and outcome of acute pulmonary embolism (PE) have remained relatively unchanged over the
last few decades. This has prompted several experts to call for the formation of multidisciplinary PE response teams
with a more proactive approach to the treatment of PE. In the current document, we discuss the formation of such
teams and describe the available treatment options beyond anticoagulation, with a focus on the interventional
approach. Acknowledging the paucity of data to support widespread adoption of such techniques, we call for the
collection of outcomes data in multicenter registries and support for randomized trials to evaluate interventional
treatments in patients with high-risk PE. (J Am Coll Cardiol 2016;67:9911002) 2016 by the American College of
Cardiology Foundation.

he American Heart Association classies

high case fatality rate, most patients with massive

pulmonary embolism (PE) into low-risk,

and submassive PE continue to be treated conserva-

intermediate-risk (submassive), and high-

tively with anticoagulation alone. This has prompted

risk (massive) categories (1). Whereas massive PE is

alternate, intensive treatment options, including

dened by the presence of persistent hypotension,

systemic brinolysis, catheter-based therapy, and

submassive PE is dened as occurring in normoten-

surgical embolectomy. Because adequate studies

sive patients with evidence of right ventricular (RV)

evaluating these therapies are scarce, and given the

strain by echocardiogram, computed tomography

difculty in managing PE patients, multiple centers

(CT) scan, or cardiac biomarkers. The most recent

have formed multidisciplinary pulmonary embolism

European Society of Cardiology guidelines further

response teams (PERT, a trademark of the National

divide the intermediate-risk group into intermediate-

PERT Consortium) to engage specialists from different

low and intermediate-highrisk subgroups, with

backgrounds to discuss treatment options and pro-

the latter dened by the presence of both RV dysfunc-

vide immediate advice and therapy for patients in

tion and increased cardiac biomarkers (2). Despite a

the massive and submassive categories (3,4).

The views expressed in this manuscript by the American College of Cardiology (ACCs) Interventional Council do not necessarily
reect the views of the Journal of the American College of Cardiology or the ACC.
From the aDivision of Cardiology, Emory University School of Medicine, Atlanta, Georgia; bVanderbilt Heart and Vascular Institute,
Listen to this manuscripts

Nashville, Tennessee; cDivision of Cardiology, Shari Zadek Medical Center, Jerusalem, Israel; dDivision of Cardiothoracic Surgery,

audio summary by

Emory University School of Medicine, Atlanta, Georgia; eOchsner Medical Center, New Orleans, Louisiana; fSection of Vascular

JACC Editor-in-Chief

Medicine, & Intervention, Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts; and the gStructural and

Dr. Valentin Fuster.

Valvular Heart Disease Program, Ochsner Medical Center, New Orleans, Louisiana. Dr. Roseneld has served as a consultant to
Abbott, Cardinal Health, Inari Medical, Surmodics, Volcano, Capture Vascular, and Shockwave; has served as a board member for
VIVA Physicians, a 501c3 organization; has received research support from the National Institutes of Health, Atrium, Lutonix-Bard,
Abbott Vascular, and Gore; and has personal equity in CardioMems, Embolitech, MD Insider, Primacea, and Vortex. All other
authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received September 28, 2015; revised manuscript received November 17, 2015, accepted December 14, 2015.

992

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

ABBREVIATIONS

This document summarizes current inva-

AND ACRONYMS

sive

records, imaging systems, virtual meeting rooms,

coagulation available to intermediate- and

and STEMI or acute stroke activation protocols.

high-risk PE patients, with the understand-

Furthermore, teams should identify the admission

ing that data supporting any of them is

location best able to manage sick patients with sub-

therapy

either inconclusive or lacking, and therefore

massive and massive PE. A dened area enables

CT = computed tomography

not covered by American and European

consistency and further development of expertise in

guidelines. Most PE patients only require

management of complex PE patients. A cardiovascu-

simple anticoagulation; patients with high-

lar intensive care unit where the surgeon, cardiovas-

risk features deserve consideration for an

cular specialist, and critical care specialist round

invasive treatment approach.

together is a reasonable choice. This type of team

brinolysis

CDT = catheter-directed

IV = intravenous
PA = pulmonary artery
PE = pulmonary embolism
PERT = pulmonary embolism

options

beyond

existing systems, such as hospital electronic medical

anti-

CDF = catheter-directed

treatment

response team

BUILDING AN ACUTE PE TEAM AND

RV = right ventricle/ventricular

MANAGEMENT PATHWAY

t-PA = tissue-type
plasminogen activator

Intensive management of acute PE begins

with formation of a PERT. Assembling a team of
specialists and coordinating care through a system
similar to the management of ST-segment elevation
myocardial infarction (STEMI) has been described at
several institutions (3,5,6). A PERT may consist of
specialists from vascular medicine, pulmonary critical
care, emergency medicine, interventional cardiology/
radiology, hematology, vascular surgery, and cardiothoracic surgery. Not every hospital system will
engage all of these subspecialists, but we recommend,
at a minimum, representatives from medicine, interventional cardiology/radiology, and surgery, as the
decisions to be made require an understanding of
the risks and benets of all treatment modalities.
The PERTs responsibility is to assess each case in a

approach is a well-established Class I recommendation for management of ischemic heart disease (8).
In May 2015, the National PERT Consortium
launch meeting, sponsored by the Massachusetts
General Hospital PERT, was held in Boston, Massachusetts, and was attended by approximately 40
hospital-based PE teams. There was an important
call to action to gather and share data on patients
with PE. We encourage PERTs to establish institutional review boardapproved databases that can be
shared among like-minded institutions for further
advancement of PE management, such as Research
Electronic Data Capture (RedCap). Participation in a
multicenter registry, such as that under development
by the National PERT Consortium, will enable systematic, broad-based assessment of outcomes and
further our knowledge regarding optimal care and
best practices.

PRE-INTERVENTION

timely manner, examine the patient, review the

available data, perform any additional testing, and

Unless contraindicated, anticoagulation should be

then (in conjunction with the patient, family mem-

initiated when PE is suspected, prior to additional

bers, and care team) develop a consensus regarding

work-up. Intravenous heparin is a good initial choice

the optimal treatment plan. In certain patients with

while alternative options (such as invasive therapies)

massive PE and rapid deterioration, the decision to

are being evaluated. After conrmation, the rst

give brinolytic agents, go to the interventional lab-

question is whether the PE is low risk versus sub-

oratory, or proceed to the operating room will need to

massive to massive. Massive PE is currently dened

be made urgently by a limited number of PERT

by hypotension with a systolic blood pressure

members. In such cases, prior experience assessing

(SBP) <90 mm Hg for >15 min or the requirement of

multiple patients with PERT colleagues will lend

inotropic support to maintain SBP >90 mm Hg. Sub-

advantage to the on-call team members and inform

massive PE is dened by SBP >90 mm Hg with evi-

their decision making. As a foundation, we recom-

dence of right heart dysfunction, as noted by a

mend that the local PERT review current published

dilated RV with an RV to left ventricle ratio >0.9 in

reports and society guidelines (1,2,7) and establish an

the 4-chamber view by CT or echocardiogram, or

institutional acute PE protocol, as in the Central

elevated biomarkers, such as troponin or B-type

Illustration (6). The key to team management is acti-

natriuretic peptide. The echocardiogram has the

vation of the PERT with a single phone call. Team

advantage of demonstrating depressed RV function

members should have an easily accessible online

and providing an estimate of pulmonary arterial

system allowing all members to review the available

systolic pressure. Other high-risk markers of sub-

medical information, including computed tomogra-

massive PE include tachycardia, tachypnea, and

phy (CT) scans, echocardiograms, electrocardiograms,

hypoxia, which may be less specic, and thus less

and laboratory data. PE teams should leverage

helpful in management selection. Special attention

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

should be given to patients who had syncope, which

may represent transient hemodynamic instability

C EN T RA L IL LUSTR AT I ON

PERT Protocol

and the potential for higher risk (9). Hemodynamically stable patients without evidence of RV strain

Patient with suspected pulmonary embolism (PE)

are considered to be at low risk, may not require

PERT activation, and can be treated with anticoagulation alone. That said, the PERT might help the

Anticoagulation initiated, unless contraindicated

clinical team dene the level of risk and optimal

therapy for each individual patient.
Once the PERT has been activated, members typi-

Acute PE confirmed by Computed Tomography (CT) scan

cally meet, either at the patients bedside or virtually,

and review all patient-related data. The most important data include the presenting history, with a focus

Multidisciplinary PE response team (PERT) alerted:

Interventionalist, cardiac surgeon,
radiology, pulmonary/critical care medicine

on symptoms and signs of hemodynamic instability,

vital signs, CT, echocardiogram, and laboratory data.
Team members should discuss indications and contraindications to brinolytic therapy, catheter-based

PERT members review the available medical information

and develop optimal treatment plan

intervention, and surgical embolectomy, followed

by discussion with the patient and family members,
including the risks and benets of each therapy proposed. A sample algorithm to help in triaging patients
presenting to the emergency room of a hospital with a
PERT is provided (Figure 1). The PERT should
consider the degree of hemodynamic compromise
and the existence of variable contraindications. The

Catheter
directed therapy

Medical therapy

simplied PE severity index may be a useful aid when

Surgical
embolectomy

further considering the risks and benets of interventional therapies (10).

Jaber, W.A. et al. J Am Coll Cardiol. 2016; 67(8):9911002.

SYSTEMIC FIBRINOLYSIS

Example of an intensive PE management pathway utilizing a single phone call to the PE

Traditionally, intravenous (IV) brinolysis has been

team leader. Further review with PERT members can occur while the patient is transferred
to the critical care unit, interventional laboratory, or operating room. Adapted with

considered the primary intensive therapy option in

permission from Bloomer et al. (6). CT computed tomography; PE pulmonary

patients with high-risk PE, although the data sup-

embolism; PERT pulmonary embolism response team.

porting its use in massive PE is poor. Most trials that

randomized patients with PE to brinolytics versus
standard anticoagulation included submassive PE

expected in both groups (3.4% in the alteplase and

only. A meta-analysis of trials including patients with

2.2% in the placebo group; p 0.71). More recently,

massive PE showed a reduction in the composite of

the PEITHO (Pulmonary Embolism Thrombolysis) trial

recurrent PE and death with use of IV brinolytic

(14) randomized 1,006 patients with submassive

agents, but not in death alone (11). Univariate analysis

PE (normal blood pressure, RV enlargement, and

of a large inpatient sample found that among unsta-

increased troponin level) to tenecteplase or placebo.

ble patients with PE, use of IV brinolytic therapy was

The PEITHO trial showed a reduction in the primary

associated with a lower mortality rate (12), but only

endpoint of hemodynamic collapse at 7 days with

30% of unstable patients received such therapy.

tenecteplase, but a signicant increase in hemorrhagic

Patients with submassive PE were better repre-

stroke (most in patients older than 75 years of age),

sented in randomized trials. The MAPPET (Manage-

with similar mortality in both groups. The smaller

ment,

Pulmonary

MOPETT (Moderate Pulmonary Embolism Treated

Embolism)-3 trial (13) randomized 256 patients with

With Thrombolysis) trial (15) randomized 121 patients

PE and pulmonary hypertension or RV dysfunction to

with

100 mg of IV alteplase or placebo infused over 2 h plus

(maximum 50 mg over 2 h) with anticoagulation versus

anticoagulation. IV alteplase was associated with a

anticoagulation alone. Low-dose alteplase was asso-

lower risk of further need to escalate the treatment and

ciated with lower pulmonary pressure at 28 months

with a similar risk of death. Mortality was lower than

and no major bleeding. A 1,700 patient meta-analysis

Strategies

and

Prognosis

of

moderate-risk

PE

to

half-dose

alteplase

993

994

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

F I G U R E 1 ER PE Protocol Utilizing PERT Consultation and sPESI Score

PE confirmed:
Anticoagulate

Unstable patient
Massive PE
(SBP < 90)

Stable patient

PERT consult

Low risk PE pt
sPESI* 0

Submassive PE
suspected
sPESI 1

1. Discuss IV lytics/
catheter/surgery
with PERT leader
2. If lytics,
consider
initiation in ER

Echo
+
Troponin

Echo and troponin

(-) for RV
dysfunction

Echo or troponin (+)

for RV dysfunction

PERT consult
Anticoagulate,
admit to medicine
floor

Admit to critical
care unit

*Simplied pulmonary embolism severity index (sPESI) score 1 point for age >80 years, cancer, chronic heart failure or chronic pulmonary
disease, heart rate >110 beats/min, SBP <100 mm Hg, or O2 saturation <90%. Adapted with permission from Bloomer et al. (6). Echo
echocardiography; ER emergency room; IV intravenous; PE pulmonary embolism; PERT pulmonary embolism response team;
RV right ventricular; SBP = systolic blood pressure.

of all brinolysis trials, including patients with

with an increased risk of severe bleeding and intra-

catheter-directed brinolysis (CDF), demonstrated a

cranial hemorrhage (14).

statistically signicant mortality benet from brinolysis in patients with intermediate-risk PE (16). There

CATHETER-BASED THERAPIES

was a signicantly increased risk of hemorrhage, but

the benet appeared to outweigh the risk when the

Catheter-based therapies aim to relieve obstruction

analysis excluded patients older than 65 years of age.

quickly and restore pulmonary blood ow, thus

Importantly, subanalyses of patients younger than 65

improving cardiac output and converting a hemody-

years of age were performed post hoc in the trials

namically unstable situation into a stable one. This

included in the meta-analysis.

is accomplished with reduced or no doses of brino-

Taken together, these studies show that the use of

lytic agents. Catheter-directed therapies (CDT) might

IV brinolytic therapy in patients with massive or

include clot fragmentation, aspiration, and low-dose

submassive PE leads to improved hemodynamic sta-

brinolytic injection. The American Heart Associa-

bilization and, possibly, a lower risk of recurrent PE

tion and American College of Chest Physicians

and PE-attributed death. However, this benet comes

guidelines address catheter-based management of

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

995

Pulmonary Embolism

acute PE, giving advanced therapies a limited

recommendation because of a lack of randomized

T A B L E 1 Catheter-Based Therapies

Device

control data (1,7).

Size

Mechanism of Action

Pigtail catheter

6- to 8-F

Peripheral balloon

5 to 10 mm

Fragmentation

Catheter-directed
brinolysis

4- to 6-F

Direct infusion of brinolytic agent

Ultrasound-accelerated
thrombolysis

6-F

Direct infusion of brinolytic agent

plus ultrasound for clot separation.
Currently the only catheter-based
therapy FDA-approved for PE treatment.

These techniques have been poorly studied, and they

Guide catheter

6- to 10-F

Manual aspiration

face the challenge of trying to remove large, some-

Pronto Xl catheter

6- to 14-F

times organized thrombi from a large space with

Penumbra Indigo system 6- to 8-F

Suction pump aspiration

numerous 3-dimensional

Inari FlowTriever

22-F sheath

Disruption, retraction, and aspiration of clot

AngioVac

26-F sheath
Large-volume aspiration with return of
and 18-F cannula
ltered blood utilizing a centrifugal pump

Multiple

percutaneous

techniques

have

been

described for treatment of unstable patients with PE

(Table 1). They aim at relieving the obstruction in the
pulmonary circulation, thus immediately improving
the patients hemodynamics and potentially reducing
the long-term risk of pulmonary hypertension (17).

branches

and multiple

angles. The simplest and most commonly performed

Fragmentation

Manual aspiration

catheter-based therapy is a local, slow infusion of a

brinolytic

agent

through

low-prole

catheters

FDA Food and Drug Administration; PE pulmonary embolism.

placed in the obstructed pulmonary artery (PA). CDF

is best suited for more stable patients or those who

PA branches. Fragmentation alone may cause distal

have been hemodynamically stabilized, as thrombus

embolization and potentially worsen distal branch

resolution may take several hours.

obstruction (21). Fragmentation is frequently com-

For unstable patients who require immediate

bined with local infusion of small-dose brinolytic

intervention and/or those with contraindication to

agents (e.g., 4 to 10 mg of tissue-type plasminogen

brinolysis, mechanical thrombus fragmentation,

activator [t-PA]), delivered either at the time of the

debulking, or aspiration of occlusive thrombi may be

procedure or subsequently via an infusion catheter

attempted.

left in place. Concomitant aspiration can reduce the

Potential complications of any catheter-based

risk of worsening obstruction (21). Fragmentation can

therapy may include pulmonary arterial injury, peri-

also be performed by ination of an angioplasty

cardial tamponade, major bleeding, hemodynamic

balloon, with care to keep ination in larger vessels

deterioration, distal embolization and no-reow

and to choose a balloon smaller than the artery

phenomenon, and access site bleeding. A meta-

diameter. Injection through a diagnostic catheter

analysis of CDT using #10-F low-prole devices

(e.g., a multipurpose catheter) placed distal to the

reported minor and major procedural complications

intended ination site can help determine the size of

of 7.9% and 2.4%, respectively (18). Minor complica-

the distal artery before selecting a balloon catheter.

tions included: groin hematomas not requiring transfusion,

transient

bradyarrhythmia,

heart

Aspiration can be attempted using regular 8-F

block,

guide catheters or specialized catheters. One of the

hemoglobinuria, mild hemoptysis, temporary renal

rst aspiration catheters was the Greeneld embo-

insufciency, embolus dislocation (n 1), and PA

lectomy catheter (22), which consisted of a suction

dissection (n 1). Major complications included: groin

cup at the tip of a straight catheter. Its complexity

hematomas requiring transfusion, massive hemopty-

and the requirement for a surgical cutdown for access

sis requiring transfusion, renal failure requiring

prevented it from being widely adopted. Other

hemodialysis, cardiac tamponade (n 1), and death

specialized devices used to treat peripheral thrombi

(n 5; 1 each from bradyarrhythmia and apnea,

have also been used off-label to treat PE. These

distal embolization, and cerebral vascular hemor-

include the 10-F Aspirex thrombectomy catheter

rhage, plus 2 procedure-related deaths not otherwise

(Straub Medical, Wangs, Switzerland), currently un-

specied) (18).

available in the United States, which combines rota-

FRAGMENTATION AND ASPIRATION. Fragmentation

tional thrombus fragmentation with aspiration (23);

and aspiration of PE may be helpful in stabilizing

the 7-F Helix Clot Buster (ev3, Plymouth, Minnesota),

patients with massive PE, especially when systemic

approved for dialysis graft thrombosis treatment (24);

brinolysis is contraindicated or has failed. Multiple

and 8- to 14-F Pronto XL manual extraction catheters

techniques have been tried with some success (19). By

(Vascular Solutions, Minneapolis, Minnesota).

rotating a pigtail catheter in the PA, the PE can be

The Angiojet Rheolytic Thrombectomy System

fragmented (20). The aim is to reduce the load on the

(Possis, Minneapolis, Minnesota) deserves special

RV by partially relieving the obstruction in the main

mention. This 8-F peripheral catheter utilizes the

Jaber et al.

996

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

Venturi-Bernoulli

high-

intravascular material, including fresh, soft thrombi

velocity saline jets introduced through the distal

effect,

using

multiple

or emboli. The AngioVac catheter consists of a

tip, creating a low-pressure vacuum through small

balloon-expandable, funnel-shaped distal tip, which

slits in the catheter that can entrain and fragment

improves removal of large clots en masse. Patients are

thrombi. A meta-analysis reported higher mortality

prepped in 2 body locations that will allow for large

and morbidity, including massive hemoptysis, renal

venous sheath placements (common femoral or in-

failure, and death from bradycardia and apnea or

ternal jugular veins). A 26-F sheath is placed in 1 vein

from widespread distal embolization (18), which

and an 18-F reinfusion cannula is placed in another

resulted in a black-box warning from the Food and

vein. The AngioVac cannula is then attached to the

Drug Administration (FDA) for use of Angiojet in

inow tubing of the centrifuge pump and the outow

acute PE.

tubing connected to the 18-F reinfusion cannula,

Additional embolectomy devices are discussed in

creating a veno-veno bypass circuit. The cannula is

the following sections.

inserted into the 26-F sheath and is advanced to the

A n g i o V a c t h r o m b e c t o m y d e v i c e . The AngioVac

thrombus, which is suctioned out and captured by a

Cannula (Angiodynamics, Latham, New York), a 22-F

ltration canister inserted proximal to the centrifuge

venous catheter that can remove soft thrombi utiliz-

pump; ltered blood is returned continuously via the

ing the centrifugal pump and venous reinfusion

reinfusion cannula. Limitations of this device include

cannula used in cardiopulmonary bypass (Figure 2), is

the large dual sheaths required for access, leading to a

FDA

higher likelihood of bleeding complications, and the

approved for

the

removal of

undesirable

relatively stiff suction catheter, which is difcult to

maneuver into the RV and PA. Furthermore, the
F I G U R E 2 AngioVac Device

active participation of an experienced perfusionist is

required for AngioVac setup and operation, as there is

a learning curve for its use. AngioVac has been utilized in PE, although it is more commonly used to
retrieve thrombi from the vena cava and right atrium
(25). The rapidity of initiation may limit its use in
massive PE situations; future iterations may render it
more useful for PE.
FlowTriever

d e v i c e . The

FlowTriever

catheter

(Inari Medical, Irvine, California) is a recently

released device that has FDA 510(k) approval for
removal of emboli and thrombi from blood vessels

AngioVac Cannula

(Figure 3). The FlowTriever Infusion Aspiration System requires a 22-F venous sheath and consists of

Saline Bag

3 parts: the Flow Restoration Catheter, which is made

up of 3 self-expanding nitinol disks; the Aspiration
Guide Catheter; and the Retraction Aspirator Device.
The FlowTriever device is advanced over the wire and
into the thrombus, where the expandable disks are

Filter

deployed using a pin and pull method. The disks and

disrupted thrombus are then retracted and removed
Centrifugal Pump Console

through the aspiration catheter. Set-up is rapid, and

Reinfusion
Cannula

there is a modest learning curve for device utilization.

Limitations include the large size requirement of the
access sheath, and manipulation of the large-bore

AngioVac
Circuit

catheter into the PA.

Penumbra

Indigo

thrombectomy

s y s t e m . The

Indigo mechanical thrombectomy system (Penumbra,

(A) AngioVac cannula. (B) Diagram of AngioVac insertion and reinfusion circuit. The cannula
has been inserted into the right internal jugular vein. Blood and thrombus is aspirated
through the lter canister, allowing clot capture utilizing a centrifugal pump canister,

Inc., Alameda, California) consists of a pump, 6- to

8-F straight or angled catheters, and a Separator de-

prior to return of blood to the patient via the reinfusion cannula placed into the femoral

vice (Figure 4). It is approved for thrombus removal

vein. (C) Example of thrombus captured in the lter canister. Images from Angiodynamics.

in both peripheral arterial and venous systems.

An advantage is that it only requires an 8-F venous

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

sheath and can be placed into the PA system quickly,

in an over-the-wire technique. Once placed proximal
to the clot, the thrombectomy catheter is advanced
while suction is supplied with the ACER pump. The

F I G U R E 3 FlowTriever Device

provided Separator wire is used to clear the system of

thrombus as the catheter is manipulated inside the
artery.
A distinct limitation of these last 3 devices is the
absence of published data on their overall success and
safety.
CATHETER-DIRECTED

FIBRINOLYSIS. G e n e r a l

c o n s i d e r a t i o n s . Given that full-dose systemic brinolysis is helpful in stabilizing high-risk PE patients

AGC

and reducing pulmonary pressure, but at the cost of

FRC

increased systemic bleeding, interest has risen in local

delivery of low-dose brinolytics close to or into
the PA thrombus. Unfortunately, data supporting
such therapy is limited and mostly from small

B
RAD

case series (18,2628). One small trial randomized

34 patients with angiographically large PE to IV- or
catheter-based infusion of t-PA at a dose of 50 mg over
2 h (29), and showed similar safety and angiographic
and hemodynamic results by both techniques. However, the local brinolytic dose used in this older trial
was much higher than what is currently used. In a
more recent prospective registry of 101 massive and
submassive PE patients treated with catheter-based
therapy (mostly local brinolysis), there was a signicant decrease in PA pressure and improvement in
RV function, with no reported major complications,
major bleeding, or strokes (26). Given the low risk for
major complications, it is reasonable to consider CDF

(A) The ow restoration catheter (FRC) is used to enmesh clots and is pulled through the
aspiration guide catheter (AGC) utilizing (B) the retraction aspirator device (RAD). Images
from Inari Medical.

in patients with already stabilized massive PE who

have contraindications to systemic brinolysis and in
patients with intermediate-highrisk PE (those with
RV dysfunction and increased biomarkers), particu-

selectively into each PA can be performed to identify

larly those deemed at increased bleeding risk with

the location of the thrombi; these are typically in the

full-dose systemic brinolysis. In a series of 52 PE

main and/or lower main PA branch (Figure 5). If

patients treated with CDF, a more prominent hemo-

the location of the thrombi is not clear by manual

dynamic benet was obtained in patients with symp-

injection, or the anatomy has not been previously

tom duration <14 days, as compared with those with a

established by CT, and if the pulmonary pressure is

longer symptom duration (28).

not severely elevated, a power injection may be

T e c h n i q u e . CT images, if available, are the basis for

necessary (e.g., at 15 to 20 m/s for a total of 30 ml

planning the CDT procedure. Most high-risk patients

selectively in each main PA, with a 15  to 20 left

have bilateral PE, although some have a major

anterior oblique projection for the left PA and 0 to

thrombus in 1 PA and only require unilateral treat-

20 right anterior oblique projection for right PA). The

ment. Internal jugular or femoral venous access with

volume of contrast injected can be adjusted on the

ultrasound guidance is obtained. For femoral access,

basis of the CT ndings. An exchange-length soft- or

ultrasound is used to rule out iliofemoral thrombus.

j-tipped wire is placed in the lower PA branch, and the

A catheter (e.g., balloon-tipped, pigtail, or multipur-

diagnostic catheter is exchanged for an infusion

pose) is carefully advanced to the main PA, where

catheter, which has a treatment zone of 6 to 12 cm

pressure and blood oxygen saturation sampling are

through which t-PA may be infused into the clot.

obtained. Contrast injection into the main PA or

A second infusion catheter may be placed in the

997

998

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

brinolytic agent, hence theoretically achieving a

F I G U R E 4 Penumbra Indigo Aspiration System

faster thrombus breakdown (30). The technique

used for in vivo insertion is similar to other infusion

catheters,

as

described

earlier.

Once

the

catheter is in position over the 0.035-inch guidewire, the guidewire is replaced with the microsonic
cable, which is then locked into place. The catheter has 2 infusion ports: 1 for the brinolytic
infusion, and the other for a coolant solution
(normal saline at $35 ml/h).
Limited evidence supports the use of ultrasoundaccelerated thrombolysis (discussed in detail by
Konstantinides et al. [31]). It is uncertain whether
this treatment is suitable for patients who are
hemodynamically unstable and need faster resolution of the PE or if there is long-term benet of the
prolonged treatment in prevention of future pulmonary hypertension, underscoring the need for more
evidence.
(A) The 6- to 8-F straight or angled aspiration catheter (CAT6 or CAT8, respectively)
is advanced to the thrombus and aspiration performed with the (B) ACER pump. Separator
wires may be inserted into the catheter and utilized in a gentle back-and-forth motion to

EXTRACORPOREAL MECHANICAL
OXYGENATION AND RV ASSIST DEVICES

clear the catheter of thrombus. Images from Penumbra, Inc.

Extracorporeal membrane oxygenator (ECMO) placement has been described in case reports of patients
contralateral PA through a second venous sheath, if
needed, using the same technique. Alternatively, a
10- to 12-F sheath may be placed at the beginning of
the procedure and both catheters placed through the
larger sheath. A commonly used t-PA dose is 0.5 to 1.0
mg/h per catheter. The total t-PA dose is typically
between 12 and 24 mg, delivered over 6 to 24 h. Lowdose, weight-adjusted heparin infusion is usually
continued during t-PA infusion, with a target partial
thromboplastin time on the low end of the therapeutic range (e.g., 40 to 60 s).
Commonly available infusion catheters used offlabel for PE include the Cragg-McNamera catheter

with massive PE, as it has the potential to unload

the RV and, importantly, provides oxygenation during massive PE to allow for RV recovery (32,33). The
ability of the interventional team to place the ECMO
underscores the importance of a multidisciplinary
approach. In many institutions, PERT members
are also ECMO service members.
Technologies such as the percutaneous RV assist
device (Impella RP, Abiomed, Danvers, Massachusetts) may one day be considered for use in massive
PE, either as a bridge to denitive therapy, or to
support RV recovery after thrombus removal.

SURGICAL EMBOLECTOMY

(ev3 Endovascular Inc.), the Fountain catheter (Merit

Medical, South Jordan, Utah), and the Unifuse cath-

Currently, surgical therapy is considered a last resort

eter (Angiodynamics). The EkoSonic catheter, (EKOS

for acute PE and is offered only to patients in

Corp., Brothell, Washington), discussed later, is

extremis. This concept is on the basis of data from

currently the only catheter specically approved by

the 1960s, when the surgical pulmonary embolectomy mortality rate was in excess of 50% (34). This

FDA for the treatment of high-risk PE.

The risk of serious complications, including major

may have been due, in part, to selection bias, as only

hemorrhage, using CDT has been low in published

patients with very poor prognosis were brought to

studies. The risk of intracranial hemorrhage is <0.2%

the operating room. Signicant advances in cardiac

(18,2628).

surgical techniques have led to an impressive

U l t r a s o u n d a c c e l e r a t e d b r i n o l y s i s . The

Eko-

reduction in operative mortality, which is as low as

Sonic catheter (Figure 6) consists of a 5.2-F con-

6% in the current era (35,36). Furthermore, there is

ventional infusion catheter with an inner cable

evidence to support reduced long-term mortality in

that transmits high-frequency, low-power ultra-

patients

sound signals, designed to loosen the brin strands

(37,38). In a 2013 report on 27 consecutive surgical

and

pulmonary embolectomy patients, there was no

enhance

thrombus

penetration

of

the

undergoing

pulmonary

embolectomy

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

F I G U R E 5 Example of a PE Treated With CDF

(A and B) CT angiogram of a patient with acute submassive PE, with thrombi seen in bilateral main PAs extending into the lower branches
(yellow arrows). (C) Pulmonary angiography of the same patient, demonstrating hand injection of contrast into the lower left PA branches,
with thrombus noted by the orange arrow. (D) Infusion catheters noted in both PAs. Manual injection of contrast agent performed through the
left catheter (orange arrows), documenting that the catheter is imbedded in the clot. Note EkoSonic catheter markers in the right PA (red
arrow). CDF catheter-directed brinolysis; CT computed tomography; PA pulmonary artery; PE pulmonary embolism.

in-hospital mortality and a 10-year actuarial survival

typically not adhered to the artery wall, and thus are

rate of 93%; both late mortalities were unrelated to

easily removable in acute PE cases.

PE or related therapy (39).

VENA CAVA FILTER

SURGICAL TECHNIQUE. After median sternotomy,

patients are anticoagulated with heparin and placed

Placement of an inferior vena cava (IVC) lter is

on cardiopulmonary bypass. Dual venous cannula-

indicated in patients with acute PE who have absolute

tion allows excellent venous drainage and full access

contraindications to anticoagulation or in patients

to the right heart. The PA is typically opened longi-

who have recurrent PE, despite adequate anti-

tudinally, distal to the pulmonic valve, to a length of

coagulation (1,2). The position of the lter below or

approximately 5 cm. Sponge forceps are used to grasp

above the renal veins depends on the absence or

and remove visible clots. Small clot fragments may be

presence

extracted using targeted gentle suction. The aorta

Retrievable lters are preferable because they are

may be circumferentially freed and gently retracted

associated with lower complication rates (40). Both

to allow deeper visualization of the right PA.

the American and the European guidelines do not

of

renal

vein

thrombus,

respectively.

Occasionally, a secondary distal incision of the right

recommend routine use of IVC lters in patients

PA is made to allow even more distal access. Clots are

with PE (1,2). These recommendations are supported

999

1000

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

anticoagulants, including rivaroxaban, dabigatran,

F I G U R E 6 EkoSonic Endovascular Device

apixaban, and edoxaban, can be used (4548). However, no guidelines indicate when or how these
agents should be initiated post-CDT, especially if
brinolytic agents have been administered. If an
alternative anticoagulant agent is utilized, we suggest
heparin alone for the rst 24 to 48 h post-intervention
and then discontinuation of the heparin at the time of
the rst alternative anticoagulant agent dosing. This
strategy does not include dabigatran or edoxaban
usage, which require at least 5 days of parenteral
therapy before initiation.
Appropriate transition of the patient from the
inpatient to the outpatient setting is important. This
includes assessment of adequacy of anticoagulation
or affordability of novel anticoagulant agents, if prescribed. Outpatient follow-up with a medical provider
familiar with PE care is imperative; several institutions incorporate a PE follow-up clinic as part of
the PERT program. To be addressed at follow-up are:
monitoring of anticoagulation; assessment of length

The 5.2-F infusion catheter (A), which contains 3 lumens: 1 each for the inner ultrasound

of anticoagulation and bleeding risk; retrieval of IVC

cable, drug infusion, and normal saline as a coolant. The inner cable (B) is shown with

lter, if appropriate; screening for the development

ultrasound crystals (arrows). Ultrasound energy separates brin strands, allowing for

of chronic pulmonary hypertension in patients at risk;

enhanced thrombus penetration of brinolytic agent. Images from EKOS Corporation.

and completion of a hypercoagulable prole, when

indicated.

by the PREPIC2 (Prevention of Recurrent Pulmonary

Embolism by Vena Cava Interruption 2) study,
recently conducted in intermediate- and low-risk
patients (41). However, 3 large analyses, including a
U.S. nationwide hospital sample (42) and a study from
Japan (43), suggest that IVC lters may result in better
outcomes in patients with massive or intermediatehighrisk PE. In the International Cooperative Pulmonary Embolism registry, IVC lter use in patients
with massive PE was associated with reduced rates of
recurrent PE and mortality at 90 days (44).

CONCLUSIONS
At this time, there is not enough evidence to strongly
support routine utilization of any of the previously
discussed techniques in the management of submassive or massive PE, beyond anticoagulation. Most
PE patients should continue to be treated conservatively, with aggressive treatment options reserved for
those at high- or intermediate-highrisk without
contraindications. Several studies have shown benet
from systemic brinolysis in this patient population,
at the expense of an increased bleeding risk.

POST-INTERVENTION

Currently, CDF with use of the EKOS catheter is the

only FDA-approved catheter-based therapy for use in

Maintenance of anticoagulation post-intervention is

treatment of acute PE, although adequate compara-

critical to prevent recurrent clot formation. However,

tive studies are lacking. Other catheter-based thera-

patients who have had a recent catheter-based inter-

pies focus on direct thrombus removal without use of

vention are at risk of access site bleeding. One strategy

brinolytic agents and may be an option for patients

to potentially reduce bleeding risk is to hold the hep-

who either cannot receive brinolysis or cannot wait

arin drip for 1 to 2 h after sheath removal, then restart

for CDF to take effect. Although some centers have

without a bolus. Warfarin is administered on the night

reported favorable outcomes with surgical embolec-

of the procedure, and parenteral anticoagulation and

tomy as a rst-line management of intermediate-

warfarin are overlapped until the international

high and high-risk PE, it is reasonable to reserve it

normalized ratio is 2 to 3 for at least 24 h, as per

for patients with massive PE and shock, who have

American College of Chest Physicians guidelines (7).

contraindications to brinolysis, who have failed

Low molecular weight heparin can be utilized in

lieu

of

IV

heparin.

Alternatively,

novel

oral

other treatments, or who have concomitant intracardiac thrombus or paradoxical embolus.

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

Until appropriate studies ll knowledge gaps, we

PERT programs and collaboration across multiple in-

recommend utilization of multidisciplinary PERTs

stitutions through the National PERT Consortium can

and collection and sharing of data in registries or

provide the foundation for global prospective regis-

formal studies. We have provided sample algorithms

tries and much-needed randomized trials.

and pathways to coordinate response to PE and

encourage multidisciplinary decision making. Similar

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

to a Code Stroke or Code STEMI, PE should

Tanveer Rab, Division of Cardiology, Emory Univer-

be considered as a lung attack, and appropriate

sity Hospital, 1364 Clifton Road Northeast, F-606,

resources

Atlanta, Georgia 30322. E-mail: srab@emory.edu.

utilized.

Formation

of

hospital-based

REFERENCES
1. Jaff MR, McMurtry MS, Archer SL, et al., for the
American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, Council on Peripheral Vascular Disease,
and Council on Arteriosclerosis, Thrombosis and
Vascular Biology. Management of massive and
submassive pulmonary embolism, iliofemoral deep
vein thrombosis, and chronic thromboembolic
pulmonary hypertension: a scientic statement
from the American Heart Association. Circulation
2011;123:1788830.
2. Konstantinides SV, Torbicki A, Agnelli G, et al.,
for the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the
European Society of Cardiology (ESC). 2014 ESC
guidelines on the diagnosis and management of
acute pulmonary embolism. Eur Heart J 2014;35:
303369, 3069ak.
3. Kabrhel C, Jaff MR, Channick RN, et al.
A multidisciplinary pulmonary embolism response
team. Chest 2013;144:17389.
4. Provias T, Dudzinski DM, Jaff MR, et al. The
Massachusetts General Hospital Pulmonary
Embolism Response Team (MGH PERT): creation
of a multidisciplinary program to improve care
of patients with massive and submassive pulmonary embolism. Hosp Pract (1995) 2014;42:
317.
5. Sista AK, Friedman OA, Horowitz JM, et al.
Building a pulmonary embolism lysis practice.
Endovascular Today 2013;12:614.
6. Bloomer TL, Thomassee EJ, Fong PP. Acute
pulmonary embolism network and multidisciplinary response team approach to treatment. Crit
Pathw Cardiol 2015;14:906.
7. 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 evidencebased clinical practice guidelines. Chest 2012;141:
e419S94S.
8. Fihn SD, Blankenship JC, Alexander KP, et al.
2014 ACC/AHA/AATS/PCNA/SCAI/STS focused
update of the guideline for the diagnosis and
management of patients with stable ischemic
heart disease: a report of the American College
of Cardiology/American Heart Association Task
Force on Practice Guidelines, and the American
Association for Thoracic Surgery, Preventive
Cardiovascular Nurses Association, Society for
Cardiovascular Angiography and Interventions,
and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;64:192949.

9. Kabrhel C, Rempell JS, Avery LL, et al. Case

records of the Massachusetts General Hospital.
Case 29-2014. A 60-year-old woman with syncope. N Engl J Med 2014;371:114350.
10. Jimnez D, Aujesky D, Moores L, et al., for
the RIETE Investigators. Simplication of the
pulmonary embolism severity index for prognostication in patients with acute symptomatic
pulmonary embolism. Arch Intern Med 2010;170:
13839.
11. Wan S, Quinlan DJ, Agnelli G, et al. Thrombolysis compared with heparin for the initial
treatment of pulmonary embolism: a metaanalysis of the randomized controlled trials. Circulation 2004;110:7449.
12. Stein PD, Matta F. Thrombolytic therapy in
unstable patients with acute pulmonary embolism:
saves lives but underused. Am J Med 2012;125:
46570.
13. Konstantinides S, Geibel A, Heusel G, et al., for
the Management Strategies and Prognosis of
Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism.
N Engl J Med 2002;347:114350.
14. Meyer G, Vicaut E, Danays T, et al., for the
PEITHO Investigators. Fibrinolysis for patients
with intermediate-risk pulmonary embolism.
N Engl J Med 2014;370:140211.
15. Shari M, Bay C, Skrocki L, et al., for the
MOPETT Investigators. Moderate pulmonary
embolism treated with thrombolysis (from the
MOPETT Trial). Am J Cardiol 2013;111:2737.
16. Chatterjee S, Chakraborty A, Weinberg I, et al.
Thrombolysis for pulmonary embolism and risk of
all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 2014;311:
241421.
17. Todoran TM, Sobieszczyk P. Catheter-based
therapies for massive pulmonary embolism. Prog
Cardiovasc Dis 2010;52:42937.
18. Kuo WT, Gould MK, Louie JD, et al. Catheterdirected therapy for the treatment of massive
pulmonary embolism: systematic review and
meta-analysis of modern techniques. J Vasc Interv
Radiol 2009;20:143140.
19. Kuo WT. Endovascular therapy for acute pulmonary embolism. J Vasc Interv Radiol 2012;23:
16779.e4, quiz 179.
20. Schmitz-Rode T, Janssens U, Duda SH, et al.
Massive pulmonary embolism: percutaneous

emergency treatment by pigtail rotation catheter.

J Am Coll Cardiol 2000;36:37580.
21. Nakazawa K, Tajima H, Murata S, et al. Catheter fragmentation of acute massive pulmonary
thromboembolism: distal embolisation and pulmonary arterial pressure elevation. Br J Radiol
2008;81:84854.
22. Greeneld LJ, Proctor MC, Williams DM, et al.
Long-term experience with transvenous catheter
pulmonary embolectomy. J Vasc Surg 1993;18:
4507, discussion 4578.
23. Kucher N, Windecker S, Banz Y, et al. Percutaneous catheter thrombectomy device for acute
pulmonary embolism: in vitro and in vivo testing.
Radiology 2005;236:8528.
24. Uacker R, Strange C, Vujic I. Massive pulmonary embolism: preliminary results of treatment with the Amplatz thrombectomy device.
J Vasc Interv Radiol 1996;7:51928.
25. Donaldson CW, Baker JN, Narayan RL, et al.
Thrombectomy using suction ltration and venovenous bypass: single center experience with a
novel device. Catheter Cardiovasc Interv 2015;86:
E817.
26. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary
Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT):
initial results from a prospective multicenter registry. Chest 2015;148:66773.
27. Piazza G, Hohlfelder B, Jaff MR, et al., for the
SEATTLE II Investigators. A prospective, singlearm, multicenter trial of ultrasound-facilitated,
catheter-directed, low-dose brinolysis for acute
massive and submassive pulmonary embolism: The
SEATTLE II Study. J Am Coll Cardiol Intv 2015;8:
138292.
28. Engelberger RP, Moschovitis A, Fahrni J, et al.
Fixed low-dose ultrasound-assisted catheterdirected thrombolysis for intermediate and high-risk
pulmonary embolism. Eur Heart J 2015;36:597604.
29. Verstraete M, Miller GA, Bounameaux H, et al.
Intravenous and intrapulmonary recombinant
tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation 1988;77:35360.
30. Braaten JV, Goss RA, Francis CW. Ultrasound
reversibly disaggregates brin bers. Thromb
Haemost 1997;78:10638.
31. Konstantinides SV, Barco S, Lankeit M,
Meyer G. Management of pulmonary embolism: an
update. J Am Coll Cardiol 2016;67:97690.

1001

1002

Jaber et al.

JACC VOL. 67, NO. 8, 2016

MARCH 1, 2016:9911002

Pulmonary Embolism

32. Misawa Y. Extracorporeal membrane oxygenation support for acute pulmonary embolism. Circulation 2004;109:e229.

embolism: results in 47 consecutive patients after

rapid diagnosis and aggressive surgical approach.
J Thorac Cardiovasc Surg 2005;129:101823.

44. Kucher N, Rossi E, De Rosa M, et al. Massive

pulmonary embolism. Circulation 2006;113:
57782.

33. Carroll BJ, Shah RV, Murthy V, et al. Clinical

features and outcomes in adults with cardiogenic
shock supported by extracorporeal membrane

39. Lattouf O, Leeper K, Kelli H. Life-threatening

pulmonary embolism: a multidisciplinary approach
to diagnosis and management. World J Cardiovasc

45. Schulman S, Kearon C, Kakkar AK, et al., for

the RE-COVER Study Group. Dabigatran versus
warfarin in the treatment of acute venous throm-

oxygenation. Am J Cardiol 2015;116:162430.

Surg 2013;3:1907.

boembolism. N Engl J Med 2009;361:234252.

34. Cross FS, Mowlem A. A survey of the current

status of pulmonary embolectomy for massive
pulmonary embolism. Circulation 1967;35:I8691.

40. Weinberg I, Kaufman J, Jaff MR. Inferior vena

46. EINSTEINPE Investigators. Oral rivaroxaban

for the treatment of symptomatic pulmonary
embolism. N Engl J Med 2012;366:128797.

35. Stulz P, Schlpfer R, Feer R, et al. Decision

making in the surgical treatment of massive pulmonary embolism. Eur J Cardiothorac Surg 1994;
8:18893.

PREPIC2 Study Group. Effect of a retrievable

inferior vena cava lter plus anticoagulation vs
anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA
2015;313:162735.

36. Yalamanchili K, Fleisher AG, Lehrman SG, et al.

Open pulmonary embolectomy for treatment of
major pulmonary embolism. Ann Thorac Surg

cava lters. J Am Coll Cardiol Intv 2013;6:53947.

41. Mismetti P, Laporte S, Pellerin O, et al., for the

2004;77:81923.

42. Stein PD, Matta F, Keyes DC, et al. Impact of

vena cava lters on in-hospital case fatality rate
from pulmonary embolism. Am J Med 2012;125:

37. Digonnet A, Moya-Plana A, Aubert S, et al. Acute

47884.

pulmonary embolism: a current surgical approach.

Interact Cardiovasc Thorac Surg 2007;6:279.

43. Isogai T, Yasunaga H, Matsui H, et al. Effec-

38. Leacche M, Unic D, Goldhaber SZ, et al.

Modern surgical treatment of massive pulmonary

tiveness of inferior vena cava lters on mortality

as an adjuvant to antithrombotic therapy. Am J
Med 2015;128:312.e2331.

47. Agnelli G, Buller HR, Cohen A, et al., for the

AMPLIFY Investigators. Oral apixaban for the
treatment of acute venous thromboembolism.
N Engl J Med 2013;369:799808.
48. Hokusai-VTE Investigators. Edoxaban versus
warfarin for the treatment of symptomatic venous
thromboembolism. N Engl J Med 2013;369:
140615.

KEY WORDS embolectomy, brinolysis,

interventional management, pulmonary
artery