12
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, MD g 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. T he American Heart Association classies pulmonary embolism (PE) into low-risk, intermediate-risk (submassive), and high- risk (massive) categories (1). Whereas massive PE is dened by the presence of persistent hypotension, submassive PE is dened as occurring in normoten- sive patients with evidence of right ventricular (RV) strain by echocardiogram, computed tomography (CT) scan, or cardiac biomarkers. The most recent European Society of Cardiology guidelines further divide the intermediate-risk group into intermediate- lowand intermediate-highrisk subgroups, with the latter dened by the presence of both RV dysfunc- tion and increased cardiac biomarkers (2). Despite a high case fatality rate, most patients with massive and submassive PE continue to be treated conserva- tively with anticoagulation alone. This has prompted alternate, intensive treatment options, including systemic brinolysis, catheter-based therapy, and surgical embolectomy. Because adequate studies evaluating these therapies are scarce, and given the difculty in managing PE patients, multiple centers have formed multidisciplinary pulmonary embolism response teams (PERT, a trademark of the National PERT Consortium) to engage specialists from different backgrounds to discuss treatment options and pro- vide immediate advice and therapy for patients in 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 a Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; b Vanderbilt Heart and Vascular Institute, Nashville, Tennessee; c Division of Cardiology, Shari Zadek Medical Center, Jerusalem, Israel; d Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia; e Ochsner Medical Center, New Orleans, Louisiana; f Section of Vascular Medicine, & Intervention, Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts; and the g Structural and 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. Listen to this manuscripts audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO. 8, 2016 ª 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

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Page 1: Acute Pulmonary  · PDF fileAcute Pulmonary Embolism ... specialists from vascular medicine, pulmonary critical care, ... and develop optimal treatment plan

Listen to this manuscript’s

audio summary by

JACC Editor-in-Chief

Dr. Valentin Fuster.

J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 6 7 , N O . 8 , 2 0 1 6

ª 2 0 1 6 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N I S S N 0 7 3 5 - 1 0 9 7 / $ 3 6 . 0 0

P U B L I S H E D B Y E L S E V I E R h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 5 . 1 2 . 0 2 4

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 Rosenfield, MD, MHCDS,f Tanveer Rab, MD,a Stephen Ramee, MDg

ABSTRACT

Th

refl

Fro

Na

Em

Me

Va

Ab

VIV

Ab

au

Ma

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;67:991–1002) © 2016 by the American College of

Cardiology Foundation.

T he American Heart Association classifiespulmonary embolism (PE) into low-risk,intermediate-risk (submassive), and high-

risk (massive) categories (1). Whereas massive PE isdefined by the presence of persistent hypotension,submassive PE is defined as occurring in normoten-sive patients with evidence of right ventricular (RV)strain by echocardiogram, computed tomography(CT) scan, or cardiac biomarkers. The most recentEuropean Society of Cardiology guidelines furtherdivide the intermediate-risk group into intermediate-low– and intermediate-high–risk subgroups, withthe latter defined by the presence of both RV dysfunc-tion and increased cardiac biomarkers (2). Despite a

e views expressed in this manuscript by the American College of Cardiolo

ect the views of the Journal of the American College of Cardiology or t

m the aDivision of Cardiology, Emory University School of Medicine, Atlan

shville, Tennessee; cDivision of Cardiology, Shari Zadek Medical Center, Je

ory University School of Medicine, Atlanta, Georgia; eOchsner Medical C

dicine, & Intervention, Division of Cardiology, Massachusetts General Hos

lvular Heart Disease Program, Ochsner Medical Center, New Orleans, Lou

bott, Cardinal Health, Inari Medical, Surmodics, Volcano, Capture Vascula

A Physicians, a 501c3 organization; has received research support from the

bott Vascular, and Gore; and has personal equity in CardioMems, Embo

thors have reported that they have no relationships relevant to the conte

nuscript received September 28, 2015; revised manuscript received Nove

high case fatality rate, most patients with massiveand submassive PE continue to be treated conserva-tively with anticoagulation alone. This has promptedalternate, intensive treatment options, includingsystemic fibrinolysis, catheter-based therapy, andsurgical embolectomy. Because adequate studiesevaluating these therapies are scarce, and given thedifficulty in managing PE patients, multiple centershave formed multidisciplinary pulmonary embolismresponse teams (PERT, a trademark of the NationalPERT Consortium) to engage specialists from differentbackgrounds to discuss treatment options and pro-vide immediate advice and therapy for patients inthe massive and submassive categories (3,4).

gy (ACC’s) Interventional Council do not necessarily

he ACC.

ta, Georgia; bVanderbilt Heart and Vascular Institute,

rusalem, Israel; dDivision of Cardiothoracic Surgery,

enter, New Orleans, Louisiana; fSection of Vascular

pital, Boston, Massachusetts; and the gStructural and

isiana. Dr. Rosenfield has served as a consultant to

r, and Shockwave; has served as a board member for

National Institutes of Health, Atrium, Lutonix-Bard,

litech, MD Insider, Primacea, and Vortex. All other

nts of this paper to disclose.

mber 17, 2015, accepted December 14, 2015.

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ABBR EV I A T I ON S

AND ACRONYMS

CDF = catheter-directed

fibrinolysis

CDT = catheter-directed

therapy

CT = computed tomography

IV = intravenous

PA = pulmonary artery

PE = pulmonary embolism

PERT = pulmonary embolism

response team

RV = right ventricle/ventricular

t-PA = tissue-type

plasminogen activator

Jaber et al. J A C C V O L . 6 7 , N O . 8 , 2 0 1 6

Pulmonary Embolism M A R C H 1 , 2 0 1 6 : 9 9 1 – 1 0 0 2

992

This document summarizes current inva-sive treatment options beyond anti-coagulation available to intermediate- andhigh-risk PE patients, with the understand-ing that data supporting any of them iseither inconclusive or lacking, and thereforenot covered by American and Europeanguidelines. Most PE patients only requiresimple anticoagulation; patients with high-risk features deserve consideration for aninvasive treatment approach.

BUILDING AN ACUTE PE TEAM AND

MANAGEMENT PATHWAY

Intensive management of acute PE begins

with formation of a PERT. Assembling a team ofspecialists and coordinating care through a systemsimilar to the management of ST-segment elevationmyocardial infarction (STEMI) has been described atseveral institutions (3,5,6). A PERT may consist ofspecialists from vascular medicine, pulmonary criticalcare, emergency medicine, interventional cardiology/radiology, hematology, vascular surgery, and car-diothoracic surgery. Not every hospital system willengage all of these subspecialists, but we recommend,at a minimum, representatives from medicine, inter-ventional cardiology/radiology, and surgery, as thedecisions to be made require an understanding ofthe risks and benefits of all treatment modalities.

The PERT’s responsibility is to assess each case in atimely manner, examine the patient, review theavailable data, perform any additional testing, andthen (in conjunction with the patient, family mem-bers, and care team) develop a consensus regardingthe optimal treatment plan. In certain patients withmassive PE and rapid deterioration, the decision togive fibrinolytic agents, go to the interventional lab-oratory, or proceed to the operating room will need tobe made urgently by a limited number of PERTmembers. In such cases, prior experience assessingmultiple patients with PERT colleagues will lendadvantage to the on-call team members and informtheir decision making. As a foundation, we recom-mend that the local PERT review current publishedreports and society guidelines (1,2,7) and establish aninstitutional acute PE protocol, as in the CentralIllustration (6). The key to team management is acti-vation of the PERT with a single phone call. Teammembers should have an easily accessible onlinesystem allowing all members to review the availablemedical information, including computed tomogra-phy (CT) scans, echocardiograms, electrocardiograms,and laboratory data. PE teams should leverage

existing systems, such as hospital electronic medicalrecords, imaging systems, virtual meeting rooms,and STEMI or acute stroke activation protocols.Furthermore, teams should identify the admissionlocation best able to manage sick patients with sub-massive and massive PE. A defined area enablesconsistency and further development of expertise inmanagement of complex PE patients. A cardiovascu-lar intensive care unit where the surgeon, cardiovas-cular specialist, and critical care specialist roundtogether is a reasonable choice. This type of teamapproach is a well-established Class I recommenda-tion for management of ischemic heart disease (8).

In May 2015, the National PERT Consortiumlaunch meeting, sponsored by the MassachusettsGeneral Hospital PERT, was held in Boston, Massa-chusetts, and was attended by approximately 40hospital-based PE teams. There was an importantcall to action to gather and share data on patientswith PE. We encourage PERTs to establish institu-tional review board–approved databases that can beshared among like-minded institutions for furtheradvancement of PE management, such as ResearchElectronic Data Capture (RedCap). Participation in amulticenter registry, such as that under developmentby the National PERT Consortium, will enable sys-tematic, broad-based assessment of outcomes andfurther our knowledge regarding optimal care andbest practices.

PRE-INTERVENTION

Unless contraindicated, anticoagulation should beinitiated when PE is suspected, prior to additionalwork-up. Intravenous heparin is a good initial choicewhile alternative options (such as invasive therapies)are being evaluated. After confirmation, the firstquestion is whether the PE is low risk versus sub-massive to massive. Massive PE is currently definedby hypotension with a systolic blood pressure(SBP) <90 mm Hg for >15 min or the requirement ofinotropic support to maintain SBP >90 mm Hg. Sub-massive PE is defined by SBP >90 mm Hg with evi-dence of right heart dysfunction, as noted by adilated RV with an RV to left ventricle ratio >0.9 inthe 4-chamber view by CT or echocardiogram, orelevated biomarkers, such as troponin or B-typenatriuretic peptide. The echocardiogram has theadvantage of demonstrating depressed RV functionand providing an estimate of pulmonary arterialsystolic pressure. Other high-risk markers of sub-massive PE include tachycardia, tachypnea, andhypoxia, which may be less specific, and thus lesshelpful in management selection. Special attention

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CENTRAL ILLUSTRATION PERT Protocol

Medical therapy Catheter directed therapy

Surgicalembolectomy

Acute PE confirmed by Computed Tomography (CT) scan

Patient with suspected pulmonary embolism (PE)

Multidisciplinary PE response team (PERT) alerted:Interventionalist, cardiac surgeon,

radiology, pulmonary/critical care medicine

PERT members review the available medical informationand develop optimal treatment plan

Anticoagulation initiated, unless contraindicated

Jaber, W.A. et al. J Am Coll Cardiol. 2016; 67(8):991–1002.

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

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

permission from Bloomer et al. (6). CT ¼ computed tomography; PE ¼ pulmonary

embolism; PERT ¼ pulmonary embolism response team.

J A C C V O L . 6 7 , N O . 8 , 2 0 1 6 Jaber et al.M A R C H 1 , 2 0 1 6 : 9 9 1 – 1 0 0 2 Pulmonary Embolism

993

should be given to patients who had syncope, whichmay represent transient hemodynamic instabilityand the potential for higher risk (9). Hemodynami-cally stable patients without evidence of RV strainare considered to be at low risk, may not requirePERT activation, and can be treated with anti-coagulation alone. That said, the PERT might help theclinical team define the level of risk and optimaltherapy for each individual patient.

Once the PERT has been activated, members typi-cally meet, either at the patient’s bedside or virtually,and review all patient-related data. The most impor-tant data include the presenting history, with a focuson symptoms and signs of hemodynamic instability,vital signs, CT, echocardiogram, and laboratory data.Team members should discuss indications and con-traindications to fibrinolytic therapy, catheter-basedintervention, and surgical embolectomy, followedby discussion with the patient and family members,including the risks and benefits of each therapy pro-posed. A sample algorithm to help in triaging patientspresenting to the emergency room of a hospital with aPERT is provided (Figure 1). The PERT shouldconsider the degree of hemodynamic compromiseand the existence of variable contraindications. Thesimplified PE severity index may be a useful aid whenfurther considering the risks and benefits of inter-ventional therapies (10).

SYSTEMIC FIBRINOLYSIS

Traditionally, intravenous (IV) fibrinolysis has beenconsidered the primary intensive therapy option inpatients with high-risk PE, although the data sup-porting its use in massive PE is poor. Most trials thatrandomized patients with PE to fibrinolytics versusstandard anticoagulation included submassive PEonly. A meta-analysis of trials including patients withmassive PE showed a reduction in the composite ofrecurrent PE and death with use of IV fibrinolyticagents, but not in death alone (11). Univariate analysisof a large inpatient sample found that among unsta-ble patients with PE, use of IV fibrinolytic therapy wasassociated with a lower mortality rate (12), but only30% of unstable patients received such therapy.

Patients with submassive PE were better repre-sented in randomized trials. The MAPPET (Manage-ment, Strategies and Prognosis of PulmonaryEmbolism)-3 trial (13) randomized 256 patients withPE and pulmonary hypertension or RV dysfunction to100 mg of IV alteplase or placebo infused over 2 h plusanticoagulation. IV alteplase was associated with alower risk of further need to escalate the treatment andwith a similar risk of death. Mortality was lower than

expected in both groups (3.4% in the alteplase and2.2% in the placebo group; p ¼ 0.71). More recently,the PEITHO (Pulmonary Embolism Thrombolysis) trial(14) randomized 1,006 patients with submassivePE (normal blood pressure, RV enlargement, andincreased troponin level) to tenecteplase or placebo.The PEITHO trial showed a reduction in the primaryendpoint of hemodynamic collapse at 7 days withtenecteplase, but a significant increase in hemorrhagicstroke (most in patients older than 75 years of age),with similar mortality in both groups. The smallerMOPETT (Moderate Pulmonary Embolism TreatedWith Thrombolysis) trial (15) randomized 121 patientswith moderate-risk PE to half-dose alteplase(maximum 50mg over 2 h) with anticoagulation versusanticoagulation alone. Low-dose alteplase was asso-ciated with lower pulmonary pressure at 28 monthsand no major bleeding. A 1,700 patient meta-analysis

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FIGURE 1 ER PE Protocol Utilizing PERT Consultation and sPESI Score

PE confirmed:Anticoagulate

Stable patientUnstable patient

Massive PE(SBP < 90)

PERT consult

Low risk PE ptsPESI* 0

Submassive PEsuspectedsPESI ≥ 1

1. Discuss IV lytics/ catheter/surgery with PERT leader2. If lytics, consider initiation in ER

Echo+

Troponin

Echo and troponin(-) for RV

dysfunction

Echo or troponin (+)for RV dysfunction

Anticoagulate,admit to medicine

floorAdmit to critical

care unit

PERT consult

*Simplified pulmonary embolism severity index (sPESI) score ¼ 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 ¼echocardiography; ER ¼ emergency room; IV ¼ intravenous; PE ¼ pulmonary embolism; PERT ¼ pulmonary embolism response team;

RV ¼ right ventricular; SBP = systolic blood pressure.

Jaber et al. J A C C V O L . 6 7 , N O . 8 , 2 0 1 6

Pulmonary Embolism M A R C H 1 , 2 0 1 6 : 9 9 1 – 1 0 0 2

994

of all fibrinolysis trials, including patients withcatheter-directed fibrinolysis (CDF), demonstrated astatistically significant mortality benefit from fibrino-lysis in patients with intermediate-risk PE (16). Therewas a significantly increased risk of hemorrhage, butthe benefit appeared to outweigh the risk when theanalysis excluded patients older than 65 years of age.Importantly, subanalyses of patients younger than 65years of age were performed post hoc in the trialsincluded in the meta-analysis.

Taken together, these studies show that the use ofIV fibrinolytic therapy in patients with massive orsubmassive PE leads to improved hemodynamic sta-bilization and, possibly, a lower risk of recurrent PEand PE-attributed death. However, this benefit comes

with an increased risk of severe bleeding and intra-cranial hemorrhage (14).

CATHETER-BASED THERAPIES

Catheter-based therapies aim to relieve obstructionquickly and restore pulmonary blood flow, thusimproving cardiac output and converting a hemody-namically unstable situation into a stable one. Thisis accomplished with reduced or no doses of fibrino-lytic agents. Catheter-directed therapies (CDT) mightinclude clot fragmentation, aspiration, and low-dosefibrinolytic injection. The American Heart Associa-tion and American College of Chest Physiciansguidelines address catheter-based management of

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TABLE 1 Catheter-Based Therapies

Device Size Mechanism of Action

Pigtail catheter 6- to 8-F Fragmentation

Peripheral balloon 5 to 10 mm Fragmentation

Catheter-directedfibrinolysis

4- to 6-F Direct infusion of fibrinolytic agent

Ultrasound-acceleratedthrombolysis

6-F Direct infusion of fibrinolytic agentplus ultrasound for clot separation.Currently the only catheter-basedtherapy FDA-approved for PE treatment.

Guide catheter 6- to 10-F Manual aspiration

Pronto Xl catheter 6- to 14-F Manual aspiration

Penumbra Indigo system 6- to 8-F Suction pump aspiration

Inari FlowTriever 22-F sheath Disruption, retraction, and aspiration of clot

AngioVac 26-F sheathand 18-F cannula

Large-volume aspiration with return offiltered blood utilizing a centrifugal pump

FDA ¼ Food and Drug Administration; PE ¼ pulmonary embolism.

J A C C V O L . 6 7 , N O . 8 , 2 0 1 6 Jaber et al.M A R C H 1 , 2 0 1 6 : 9 9 1 – 1 0 0 2 Pulmonary Embolism

995

acute PE, giving advanced therapies a limitedrecommendation because of a lack of randomizedcontrol data (1,7).

Multiple percutaneous techniques have beendescribed for treatment of unstable patients with PE(Table 1). They aim at relieving the obstruction in thepulmonary circulation, thus immediately improvingthe patient’s hemodynamics and potentially reducingthe long-term risk of pulmonary hypertension (17).These techniques have been poorly studied, and theyface the challenge of trying to remove large, some-times organized thrombi from a large space withnumerous 3-dimensional branches and multipleangles. The simplest and most commonly performedcatheter-based therapy is a local, slow infusion of afibrinolytic agent through low-profile cathetersplaced in the obstructed pulmonary artery (PA). CDFis best suited for more stable patients or those whohave been hemodynamically stabilized, as thrombusresolution may take several hours.

For unstable patients who require immediateintervention and/or those with contraindication tofibrinolysis, mechanical thrombus fragmentation,debulking, or aspiration of occlusive thrombi may beattempted.

Potential complications of any catheter-basedtherapy may include pulmonary arterial injury, peri-cardial tamponade, major bleeding, hemodynamicdeterioration, distal embolization and “no-reflow”

phenomenon, and access site bleeding. A meta-analysis of CDT using #10-F low-profile devicesreported minor and major procedural complicationsof 7.9% and 2.4%, respectively (18). Minor complica-tions included: groin hematomas not requiring trans-fusion, transient bradyarrhythmia, heart block,hemoglobinuria, mild hemoptysis, temporary renalinsufficiency, embolus dislocation (n ¼ 1), and PAdissection (n ¼ 1). Major complications included: groinhematomas requiring transfusion, massive hemopty-sis requiring transfusion, renal failure requiringhemodialysis, cardiac tamponade (n ¼ 1), and death(n ¼ 5; 1 each from bradyarrhythmia and apnea,distal embolization, and cerebral vascular hemor-rhage, plus 2 procedure-related deaths not otherwisespecified) (18).

FRAGMENTATION AND ASPIRATION. Fragmentationand aspiration of PE may be helpful in stabilizingpatients with massive PE, especially when systemicfibrinolysis is contraindicated or has failed. Multipletechniques have been tried with some success (19). Byrotating a pigtail catheter in the PA, the PE can befragmented (20). The aim is to reduce the load on theRV by partially relieving the obstruction in the main

PA branches. Fragmentation alone may cause distalembolization and potentially worsen distal branchobstruction (21). Fragmentation is frequently com-bined with local infusion of small-dose fibrinolyticagents (e.g., 4 to 10 mg of tissue-type plasminogenactivator [t-PA]), delivered either at the time of theprocedure or subsequently via an infusion catheterleft in place. Concomitant aspiration can reduce therisk of worsening obstruction (21). Fragmentation canalso be performed by inflation of an angioplastyballoon, with care to keep inflation in larger vesselsand to choose a balloon smaller than the arterydiameter. Injection through a diagnostic catheter(e.g., a multipurpose catheter) placed distal to theintended inflation site can help determine the size ofthe distal artery before selecting a balloon catheter.

Aspiration can be attempted using regular 8-Fguide catheters or specialized catheters. One of thefirst aspiration catheters was the Greenfield embo-lectomy catheter (22), which consisted of a suctioncup at the tip of a straight catheter. Its complexityand the requirement for a surgical cutdown for accessprevented it from being widely adopted. Otherspecialized devices used to treat peripheral thrombihave also been used off-label to treat PE. Theseinclude the 10-F Aspirex thrombectomy catheter(Straub Medical, Wangs, Switzerland), currently un-available in the United States, which combines rota-tional thrombus fragmentation with aspiration (23);the 7-F Helix Clot Buster (ev3, Plymouth, Minnesota),approved for dialysis graft thrombosis treatment (24);and 8- to 14-F Pronto XL manual extraction catheters(Vascular Solutions, Minneapolis, Minnesota).

The Angiojet Rheolytic Thrombectomy System(Possis, Minneapolis, Minnesota) deserves specialmention. This 8-F peripheral catheter utilizes the

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FIGURE 2 AngioVa

A

B

Centrifugal Pump

(A) AngioVac cannula

has been inserted int

through the filter ca

prior to return of blo

vein. (C) Example of

Jaber et al. J A C C V O L . 6 7 , N O . 8 , 2 0 1 6

Pulmonary Embolism M A R C H 1 , 2 0 1 6 : 9 9 1 – 1 0 0 2

996

Venturi-Bernoulli effect, using multiple high-velocity saline jets introduced through the distaltip, creating a low-pressure vacuum through smallslits in the catheter that can entrain and fragmentthrombi. A meta-analysis reported higher mortalityand morbidity, including massive hemoptysis, renalfailure, and death from bradycardia and apnea orfrom widespread distal embolization (18), whichresulted in a black-box warning from the Food andDrug Administration (FDA) for use of Angiojet inacute PE.

Additional embolectomy devices are discussed inthe following sections.AngioVac thrombectomy dev ice . The AngioVacCannula (Angiodynamics, Latham, New York), a 22-Fvenous catheter that can remove soft thrombi utiliz-ing the centrifugal pump and venous reinfusioncannula used in cardiopulmonary bypass (Figure 2), isFDA approved for the removal of undesirable

c Device

C

AngioVac Cannula

Saline Bag

Filter

Console

ReinfusionCannula

AngioVacCircuit

. (B) Diagram of AngioVac insertion and reinfusion circuit. The cannula

o the right internal jugular vein. Blood and thrombus is aspirated

nister, allowing clot capture utilizing a centrifugal pump canister,

od to the patient via the reinfusion cannula placed into the femoral

thrombus captured in the filter canister. Images from Angiodynamics.

intravascular material, including fresh, soft thrombior emboli. The AngioVac catheter consists of aballoon-expandable, funnel-shaped distal tip, whichimproves removal of large clots en masse. Patients areprepped in 2 body locations that will allow for largevenous sheath placements (common femoral or in-ternal jugular veins). A 26-F sheath is placed in 1 veinand an 18-F reinfusion cannula is placed in anothervein. The AngioVac cannula is then attached to theinflow tubing of the centrifuge pump and the outflowtubing connected to the 18-F reinfusion cannula,creating a “veno-veno” bypass circuit. The cannula isinserted into the 26-F sheath and is advanced to thethrombus, which is suctioned out and captured by afiltration canister inserted proximal to the centrifugepump; filtered blood is returned continuously via thereinfusion cannula. Limitations of this device includethe large dual sheaths required for access, leading to ahigher likelihood of bleeding complications, and therelatively stiff suction catheter, which is difficult tomaneuver into the RV and PA. Furthermore, theactive participation of an experienced perfusionist isrequired for AngioVac setup and operation, as there isa learning curve for its use. AngioVac has been uti-lized in PE, although it is more commonly used toretrieve thrombi from the vena cava and right atrium(25). The rapidity of initiation may limit its use inmassive PE situations; future iterations may render itmore useful for PE.FlowTr iever dev ice . The FlowTriever catheter(Inari Medical, Irvine, California) is a recentlyreleased device that has FDA 510(k) approval forremoval of emboli and thrombi from blood vessels(Figure 3). The FlowTriever Infusion Aspiration Sys-tem requires a 22-F venous sheath and consists of3 parts: the Flow Restoration Catheter, which is madeup of 3 self-expanding nitinol disks; the AspirationGuide Catheter; and the Retraction Aspirator Device.The FlowTriever device is advanced over the wire andinto the thrombus, where the expandable disks aredeployed using a pin and pull method. The disks anddisrupted thrombus are then retracted and removedthrough the aspiration catheter. Set-up is rapid, andthere is a modest learning curve for device utilization.Limitations include the large size requirement of theaccess sheath, and manipulation of the large-borecatheter into the PA.Penumbra Ind igo thrombectomy system. TheIndigo mechanical thrombectomy system (Penumbra,Inc., Alameda, California) consists of a pump, 6- to8-F straight or angled catheters, and a Separator de-vice (Figure 4). It is approved for thrombus removalin both peripheral arterial and venous systems.An advantage is that it only requires an 8-F venous

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FIGURE 3 FlowTriever Device

A

B

AGC

FRC

RAD

(A) The flow 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.

J A C C V O L . 6 7 , N O . 8 , 2 0 1 6 Jaber et al.M A R C H 1 , 2 0 1 6 : 9 9 1 – 1 0 0 2 Pulmonary Embolism

997

sheath and can be placed into the PA system quickly,in an over-the-wire technique. Once placed proximalto the clot, the thrombectomy catheter is advancedwhile suction is supplied with the ACER pump. Theprovided Separator wire is used to clear the system ofthrombus as the catheter is manipulated inside theartery.

A distinct limitation of these last 3 devices is theabsence of published data on their overall success andsafety.

CATHETER-DIRECTED FIBRINOLYSIS. Genera lcons iderat ions . Given that full-dose systemic fibri-nolysis is helpful in stabilizing high-risk PE patientsand reducing pulmonary pressure, but at the cost ofincreased systemic bleeding, interest has risen in localdelivery of low-dose fibrinolytics close to or intothe PA thrombus. Unfortunately, data supportingsuch therapy is limited and mostly from smallcase series (18,26–28). One small trial randomized34 patients with angiographically large PE to IV- orcatheter-based infusion of t-PA at a dose of 50 mg over2 h (29), and showed similar safety and angiographicand hemodynamic results by both techniques. How-ever, the local fibrinolytic dose used in this older trialwas much higher than what is currently used. In amore recent prospective registry of 101 massive andsubmassive PE patients treated with catheter-basedtherapy (mostly local fibrinolysis), there was a sig-nificant decrease in PA pressure and improvement inRV function, with no reported major complications,major bleeding, or strokes (26). Given the low risk formajor complications, it is reasonable to consider CDFin patients with already stabilized massive PE whohave contraindications to systemic fibrinolysis and inpatients with intermediate-high–risk PE (those withRV dysfunction and increased biomarkers), particu-larly those deemed at increased bleeding risk withfull-dose systemic fibrinolysis. In a series of 52 PEpatients treated with CDF, a more prominent hemo-dynamic benefit was obtained in patients with symp-tom duration <14 days, as compared with those with alonger symptom duration (28).Techn ique . CT images, if available, are the basis forplanning the CDT procedure. Most high-risk patientshave bilateral PE, although some have a majorthrombus in 1 PA and only require unilateral treat-ment. Internal jugular or femoral venous access withultrasound guidance is obtained. For femoral access,ultrasound is used to rule out iliofemoral thrombus.A catheter (e.g., balloon-tipped, pigtail, or multipur-pose) is carefully advanced to the main PA, wherepressure and blood oxygen saturation sampling areobtained. Contrast injection into the main PA or

selectively into each PA can be performed to identifythe location of the thrombi; these are typically in themain and/or lower main PA branch (Figure 5). Ifthe location of the thrombi is not clear by manualinjection, or the anatomy has not been previouslyestablished by CT, and if the pulmonary pressure isnot severely elevated, a power injection may benecessary (e.g., at 15 to 20 m/s for a total of 30 mlselectively in each main PA, with a 15� to 20� leftanterior oblique projection for the left PA and 0� to20� right anterior oblique projection for right PA). Thevolume of contrast injected can be adjusted on thebasis of the CT findings. An exchange-length soft- orj-tipped wire is placed in the lower PA branch, and thediagnostic catheter is exchanged for an infusioncatheter, which has a treatment zone of 6 to 12 cmthrough which t-PA may be infused into the clot.A second infusion catheter may be placed in the

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FIGURE 4 Penumbra Indigo Aspiration System

(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

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

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contralateral PA through a second venous sheath, ifneeded, using the same technique. Alternatively, a10- to 12-F sheath may be placed at the beginning ofthe procedure and both catheters placed through thelarger sheath. A commonly used t-PA dose is 0.5 to 1.0mg/h per catheter. The total t-PA dose is typicallybetween 12 and 24 mg, delivered over 6 to 24 h. Low-dose, weight-adjusted heparin infusion is usuallycontinued during t-PA infusion, with a target partialthromboplastin time on the low end of the thera-peutic range (e.g., 40 to 60 s).

Commonly available infusion catheters used off-label for PE include the Cragg-McNamera catheter(ev3 Endovascular Inc.), the Fountain catheter (MeritMedical, South Jordan, Utah), and the Unifuse cath-eter (Angiodynamics). The EkoSonic catheter, (EKOSCorp., Brothell, Washington), discussed later, iscurrently the only catheter specifically approved byFDA for the treatment of high-risk PE.

The risk of serious complications, including majorhemorrhage, using CDT has been low in publishedstudies. The risk of intracranial hemorrhage is <0.2%(18,26–28).Ultrasound acce lerated fibr inolys i s . The Eko-Sonic catheter (Figure 6) consists of a 5.2-F con-ventional infusion catheter with an inner cablethat transmits high-frequency, low-power ultra-sound signals, designed to loosen the fibrin strandsand enhance thrombus penetration of the

fibrinolytic agent, hence theoretically achieving afaster thrombus breakdown (30). The techniqueused for in vivo insertion is similar to other infu-sion catheters, as described earlier. Once thecatheter is in position over the 0.035-inch guide-wire, the guidewire is replaced with the microsoniccable, which is then locked into place. The cath-eter has 2 infusion ports: 1 for the fibrinolyticinfusion, and the other for a coolant solution(normal saline at $35 ml/h).

Limited evidence supports the use of ultrasound-accelerated thrombolysis (discussed in detail byKonstantinides et al. [31]). It is uncertain whetherthis treatment is suitable for patients who arehemodynamically unstable and need faster resolu-tion of the PE or if there is long-term benefit of theprolonged treatment in prevention of future pulmo-nary hypertension, underscoring the need for moreevidence.

EXTRACORPOREAL MECHANICAL

OXYGENATION AND RV ASSIST DEVICES

Extracorporeal membrane oxygenator (ECMO) place-ment has been described in case reports of patientswith massive PE, as it has the potential to unloadthe RV and, importantly, provides oxygenation dur-ing massive PE to allow for RV recovery (32,33). Theability of the interventional team to place the ECMOunderscores the importance of a multidisciplinaryapproach. In many institutions, PERT membersare also ECMO service members.

Technologies such as the percutaneous RV assistdevice (Impella RP, Abiomed, Danvers, Massachu-setts) may one day be considered for use in massivePE, either as a bridge to definitive therapy, or tosupport RV recovery after thrombus removal.

SURGICAL EMBOLECTOMY

Currently, surgical therapy is considered a last resortfor acute PE and is offered only to patients inextremis. This concept is on the basis of data fromthe 1960s, when the surgical pulmonary embolec-tomy mortality rate was in excess of 50% (34). Thismay have been due, in part, to selection bias, as onlypatients with very poor prognosis were brought tothe operating room. Significant advances in cardiacsurgical techniques have led to an impressivereduction in operative mortality, which is as low as6% in the current era (35,36). Furthermore, there isevidence to support reduced long-term mortality inpatients undergoing pulmonary embolectomy(37,38). In a 2013 report on 27 consecutive surgicalpulmonary embolectomy patients, there was no

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FIGURE 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 ¼ catheter-directed fibrinolysis; CT ¼ computed tomography; PA ¼ pulmonary artery; PE ¼ pulmonary embolism.

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in-hospital mortality and a 10-year actuarial survivalrate of 93%; both late mortalities were unrelated toPE or related therapy (39).

SURGICAL TECHNIQUE. After median sternotomy,patients are anticoagulated with heparin and placedon cardiopulmonary bypass. Dual venous cannula-tion allows excellent venous drainage and full accessto the right heart. The PA is typically opened longi-tudinally, distal to the pulmonic valve, to a length ofapproximately 5 cm. Sponge forceps are used to graspand remove visible clots. Small clot fragments may beextracted using targeted gentle suction. The aortamay be circumferentially freed and gently retractedto allow “deeper” visualization of the right PA.Occasionally, a secondary distal incision of the rightPA is made to allow even more distal access. Clots are

typically not adhered to the artery wall, and thus areeasily removable in acute PE cases.

VENA CAVA FILTER

Placement of an inferior vena cava (IVC) filter isindicated in patients with acute PE who have absolutecontraindications to anticoagulation or in patientswho have recurrent PE, despite adequate anti-coagulation (1,2). The position of the filter below orabove the renal veins depends on the absence orpresence of renal vein thrombus, respectively.Retrievable filters are preferable because they areassociated with lower complication rates (40). Boththe American and the European guidelines do notrecommend routine use of IVC filters in patientswith PE (1,2). These recommendations are supported

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FIGURE 6 EkoSonic Endovascular Device

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

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

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

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

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by the PREPIC2 (Prevention of Recurrent PulmonaryEmbolism by Vena Cava Interruption 2) study,recently conducted in intermediate- and low-riskpatients (41). However, 3 large analyses, including aU.S. nationwide hospital sample (42) and a study fromJapan (43), suggest that IVC filters may result in betteroutcomes in patients with massive or intermediate-high–risk PE. In the International Cooperative Pul-monary Embolism registry, IVC filter use in patientswith massive PE was associated with reduced rates ofrecurrent PE and mortality at 90 days (44).

POST-INTERVENTION

Maintenance of anticoagulation post-intervention iscritical to prevent recurrent clot formation. However,patients who have had a recent catheter-based inter-vention are at risk of access site bleeding. One strategyto potentially reduce bleeding risk is to hold the hep-arin drip for 1 to 2 h after sheath removal, then restartwithout a bolus. Warfarin is administered on the nightof the procedure, and parenteral anticoagulation andwarfarin are overlapped until the internationalnormalized ratio is 2 to 3 for at least 24 h, as perAmerican College of Chest Physicians guidelines (7).

Low molecular weight heparin can be utilized inlieu of IV heparin. Alternatively, novel oral

anticoagulants, including rivaroxaban, dabigatran,apixaban, and edoxaban, can be used (45–48). How-ever, no guidelines indicate when or how theseagents should be initiated post-CDT, especially iffibrinolytic agents have been administered. If analternative anticoagulant agent is utilized, we suggestheparin alone for the first 24 to 48 h post-interventionand then discontinuation of the heparin at the time ofthe first alternative anticoagulant agent dosing. Thisstrategy does not include dabigatran or edoxabanusage, which require at least 5 days of parenteraltherapy before initiation.

Appropriate transition of the patient from theinpatient to the outpatient setting is important. Thisincludes assessment of adequacy of anticoagulationor affordability of novel anticoagulant agents, if pre-scribed. Outpatient follow-up with a medical providerfamiliar with PE care is imperative; several in-stitutions incorporate a PE follow-up clinic as part ofthe PERT program. To be addressed at follow-up are:monitoring of anticoagulation; assessment of lengthof anticoagulation and bleeding risk; retrieval of IVCfilter, if appropriate; screening for the developmentof chronic pulmonary hypertension in patients at risk;and completion of a hypercoagulable profile, whenindicated.

CONCLUSIONS

At this time, there is not enough evidence to stronglysupport routine utilization of any of the previouslydiscussed techniques in the management of sub-massive or massive PE, beyond anticoagulation. MostPE patients should continue to be treated conserva-tively, with aggressive treatment options reserved forthose at high- or intermediate-high–risk withoutcontraindications. Several studies have shown benefitfrom systemic fibrinolysis in this patient population,at the expense of an increased bleeding risk.Currently, CDF with use of the EKOS catheter is theonly FDA-approved catheter-based therapy for use intreatment of acute PE, although adequate compara-tive studies are lacking. Other catheter-based thera-pies focus on direct thrombus removal without use offibrinolytic agents and may be an option for patientswho either cannot receive fibrinolysis or cannot waitfor CDF to take effect. Although some centers havereported favorable outcomes with surgical embolec-tomy as a first-line management of intermediate-high– and high-risk PE, it is reasonable to reserve itfor patients with massive PE and shock, who havecontraindications to fibrinolysis, who have failedother treatments, or who have concomitant intracar-diac thrombus or paradoxical embolus.

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Until appropriate studies fill knowledge gaps, werecommend utilization of multidisciplinary PERTsand collection and sharing of data in registries orformal studies. We have provided sample algorithmsand pathways to coordinate response to PE andencourage multidisciplinary decision making. Similarto a “Code Stroke” or “Code STEMI,” PE shouldbe considered as a “lung attack,” and appropriateresources utilized. Formation of hospital-based

PERT programs and collaboration across multiple in-stitutions through the National PERT Consortium canprovide the foundation for global prospective regis-tries and much-needed randomized trials.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Tanveer Rab, Division of Cardiology, Emory Univer-sity Hospital, 1364 Clifton Road Northeast, F-606,Atlanta, Georgia 30322. E-mail: [email protected].

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KEY WORDS embolectomy, fibrinolysis,interventional management, pulmonaryartery