Submassive Pulmonary Emboli:
New Therapeutic Strategies
Thomas Jefferson University Hospital
Critical Care Grand Rounds
Ryan D. Reber, D.O.
Lankenau Medical Center
Pulmonary and Critical Care Medicine Fellow
March 29, 2013
Submassive Pulmonary Emboli
Goals and Objectives:


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Overview of venous thromboembolism
Massive pulmonary embolism and thrombolytics
Normotensive pulmonary embolism and the need
to identify the subset of submassive pulmonary
emboli at risk of mortality/morbidity
Therapeutic approaches to submassive pulmonary
emboli
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Thrombolysis
Half Dose Thrombolysis
Ultrasound Accelerated Thrombolysis
IVC Filter
Venous Thromboembolism
Overview

Estimated 300,000-600,000 affected yearly in USA
 60,000-100,000 Americans will die

30% mortality rate if left untreated

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Primarily as a result of recurrent embolism
Majority dying with in first 30 days
Mortality reduced to 2-10% with accurate
diagnosis and effective therapy
Centers For Disease Control and Prevention; Data and Statistics: 2012
JVIR 2008; 19:372-376
Stratifying Pulmonary Emboli
Massive PE (5-10%):
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Sustained hypotension (SBP < 90 mmHg for 15 minutes or
requiring inotropes)
Pulselessness
Persistent and profound bradycardia
Submassive PE (20-25%):

RV dysfunction or myocardial necrosis without hypotension
Low Risk PE (70%):
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Normotensive and no markers of adverse prognosis
Circulation 2011; 123: 1788-1830
Stratifying Pulmonary Emboli
Massive PE (5-10%):



Sustained hypotension (SBP < 90 mmHg for 15 minutes or
requiring inotropes)
Pulselessness
Persistent and profound bradycardia
Submassive PE (20-25%):

RV dysfunction or myocardial necrosis without hypotension
Low Risk PE (70%):

Normotensive and no markers of adverse prognosis
Circulation 2011; 123: 1788-1830
Chest 2002; 121: 878
Chest 2002; 121: 878
Mortality Associated with Pulmonary
Emboli
Massive Pulmonary Embolism
ACCP 2012 Guidelines

“Acute PE associated with hypotension who
do not have a high bleeding risk, we
suggest systemically administered
thrombolytic therapy…(Grade 2C)”
Chest. 2012; 141(Suppl 2): 24S
Reduction in clot burden:
Heparin vs Heparin and Thrombolytics
By day 7, similar 65-70%
reduction in total defect
Compared to heparin alone, thrombolysis
and heparin result in 30-35% reduction in
perfusion defect at 24 hours
Arch Int Med 1997; 157: 2550-2556
Impact of Systemic Thrombolytics
in Unstable PE* on Mortality
AJM 2012; 125:465-470
*Defined as Shock or VDRF
Thrombolysis is Not Without Risk
Lancet 1999; 353: 1386-1389
(ICOPER)
Thrombolysis is Not Without Risk
Lancet 1999; 353: 1386-1389
(ICOPER)
Normotensive Pulmonary Emboli:
Submassive and Low Risk
Thought to have more favorable
outcomes because of hemodynamic
stability
JVIR 2008; 19:372-376
Chest 2002; 121: 878
Normotensive PE with RV
dysfunction (ie Submassive)
up to 30% mortality!!!
thus
Relying soley on BP may fail to
identify key prognostic features
and delay more appropriate
therapy
Chest 2002; 121: 878
Stratifying Pulmonary Emboli
Massive PE (5-10%):



Sustained hypotension (SBP < 90 mmHg for 15 minutes or
requiring inotropes
Pulselessness
Persistent and profound bradycardia
Submassive PE (20-25%):

RV dysfunction or myocardial necrosis without hypotension
Low Risk PE (70%):

Normotensive and no markers of adverse prognosis
Circulation 2011; 123: 1788-1830
Submassive Pulmonary Emboli
ANY ONE OF THE FOLLOWING:
RV Dysfunction

RV dilation on echo
 (RV d/LV d > 0.9)
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Myocardial Necrosis
 Elevation in Troponin
RV systolic dysfunction
on echo
RV dilation on CT
 (RV d/LV d > 0.9)


Elevated BNP
EKG
 New RBBB, anteroseptal
STE/D/TWI
Circulation 2011; 123: 1788-1830
CAUTION:
Submassive Pulmonary Emboli:
All are not with same mortality
RV DYSFUNCTION/ TN ELEVATION
COMBO in PE: PROGNOSIS (n=1,273)
Stein et al. Am J Cardiol 2010; 106: 558-563
Submassive PE:
Combining Prognosticators
30 Day Mortality
ECHO+
DVT+
19.6%
Trop+
DVT+
17.1%
Trop+
ECHO+
15.2%
Thorax. 2011; 66:75-81
Submassive Pulmonary Emboli:
All are not with the same mortality
AHA defines submassive pulmonary emboli
solely on hemodynamic, electrocardiogram,
biomarkers and echo/CT parameters and fails
to identify clinical risk factors associated with
increased morbidity/mortality…thus with
POOR CARDIOPULMONARY RESERVE

Role of clinical risk scores may help further stratify
the submassive group
PESI INDEX
AJRCCM 2005;172:1041-1046
Submassive PE and Benefit of Systemic Thrombolytics?
Given increased mortality associated with
submassive PE, is there mortality benefit from
thrombolytics like in massive PE?
To date:
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Reduction in clinical deterioration requiring escalation of
care*
Reduction in RV dysfunction at 24 hours based on
ECHO**
No difference in mortality*/**
*NEJM. 2002;347:1143-1150/**Thromb Res. 2010;125:e82-86
Systemic Thrombolysis and
Submassive PE
Limitations of studies
Not all submassive PEs are equivalent
(PE with slight trop/-ECHO VS. PE with hi
trop/+ECHO)
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Pulmonary Embolism Thrombolysis Study
PEITHO (ACC 2013 Meeting-3/11/13)
Normotensive acute PE with abnormal
RV on echo/CT and a positive troponin
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More “high risk” submassive PEs
Tenecteplase/heparin (506 pts) vs
placebo/heparin (499 pts)
Pulmonary Embolism Thrombolysis Study
PEITHO
Combined mortality and hemodynamic collapse
within 7 days of randomization
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Tenecteplase/UFH 2.6%
Placebo/UFH 5.6%
(no difference in mortality alone but difference in
collapse…also no 30 day mortality difference)
Pulmonary Embolism Thrombolysis Study
PEITHO
Non-intracranial bleeds
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Tenecteplase/UFH 6.3%
Placebo/UFH 1.5%
Strokes (predom. Hemorrhagic)
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Tenecteplase/UFH 2.4%
Placebo/UFH 0.2%
Pulmonary Embolism Thrombolysis Study
PEITHO
Conclusions:
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
Lysis/UFH reduces combined endpoint of
death and hemodynamic collapse at 7 days,
but no improvement in mortality alone at end
of day 7 and 30
Benefits came at risk of both major and
intracranial bleeds
Submassive PE and Systemic Lytics
No mortality improvement
Reduction in RV dysfunction
Significant risk of major hemorrhagic
complications
What about “low dose systemic lysis” or even
“catheter based lytics”
Submassive PE and Systemic Lytics
No mortality improvement
Reduction in RV dysfunction
Significant risk of major hemorrhagic
complications
What about “low dose systemic lysis”
or even “catheter based lytics”
“Safe Dose” tPA in Submassive PE
Moderate Pulmonary Embolism Treated with
Thrombolysis-”MOPETT” Trial
“Moderate” acute PE based on clot
burden/perfusion defects and signs and
symptoms, not RV dysfunction or cardiac
biomarker elevation
tPA/heparin (61 pt) vs heparin alone (60 pt)
“MOPETT” AJC. 2013; 111: 273-277
Moderate Pulmonary Embolism Treated
with Thrombolysis-”MOPETT” Trial
Reduced PASP on
ECHO
“MOPETT” AJC. 2013; 111: 273-277
Moderate Pulmonary Embolism Treated
with Thrombolysis-”MOPETT” Trial
While there was no bleeding events there was No
change in mortality at end of 22 month
“MOPETT” AJC. 2013; 111: 273-277
Catheter Techniques:
“Pharmacomechanical” Therapy
Mechanical Fragmentation
Hydrodynamic (AngioJet®)
Ultrasound-Accelerated
Fibrinolysis (EKOS®)
Suction Embolectomy
(AngioVac®)
EKOS® DRUG DELIVERY CATHETER
ULTRASOUND
TRANSDUCERS
Ultrasound Accelerated Thrombolysis
Fibrin without
Ultrasound
Fibrin With
Ultrasound
The premise: Low-power ultrasound energy loosens fibrin
strands, increases thrombus surface area, enhances lytic
penetration, speeding thrombolysis, and facilitates reduction in
fibrinolytic drug dose.
Ultrasound Accelerated Thrombolysis of
Pulmonary Embolism (ULTIMA)
Preliminary data from the ACC 2013
Meeting, March 9, 2013
59-patients, European study
Ultrasound accelerated thrombolysis
(EKOS) and UFH versus UFH alone
<20 mg of rt-PA used
Ultrasound Accelerated Thrombolysis
of Pulmonary Embolism (ULTIMA)
EKOS reduced right heart enlargement by 23% vs only
3% in UFH at 24 hours
No serious bleeding events in either group
Minimal to no systemic lytic effect???
EKOS greater reduction in right heart dysfunction at 90
days
AWAITING SECONDARY ENDPOINT OF
MORTALITY…….
Complications of Catheter based
Ultrasound Accelerated Thrombolysis
Bleeding at catheter site, non fatal hemoptysis
(10 mass)

JVIR. 2008; 19:372-376
Bleeding at catheter site (24 mass and sub)

Thrombosis Res. 2011; 128: 149-154
No bleeding complications vs 21.4%(CDT 18 vs
UAT 15 mass)

Vascular. 2009; 17: (Supp 3): S137-S147
Additional Considerations
Pulmonary hemorrhage/ pericardial
tamponade
RV failure from distal embolization
Reperfusion edema
Systemic bleeding from anticoagulation
Contrast-induced anaphylaxis
Contrast-induced nephropathy
Vascular access complications
Trial Summary
Short Term Mortality Reduction
compared to anticoagulation
alone
Therapeutic Modality
Intracranial Bleed
Non-Intrancranial
Bleeds
Full dose tPA*
(100 mg total, given as a 10 mg bolus over
10 min then remaining 90 mg over next 110
minutes for 2 hr total infusion)
2%
6.3%
No difference
Low dose tPA**
(50 mg total, given as a 10 mg IV push
within 1 minute then remaining 40 mg over
next 119 minutes for 2 hour total infusion
0%
0%
No difference
Ultrasound Accelerated Thrombolysis***
(20 mg total tPA given over 12 hours)
0%
0%
UNKNOWN
Heparin alone
0.2%*
1.5%*
<3 % overal mortality with
anticoagulation alone^^
*PEITHO Trial
**MOPETT Trial
***ULTIMA Trial
^^Circulation 2011; 123: 1788-1830
Submassive Pulmonary Embolism
ACCP 2012 Guidelines


“In most patients with acute PE not associated with
hypotension, recommend against systemically administered
thrombolytic therapy…(Grade 1C)”
“In selected patients with acute PE not associated with
hypotension and with a low bleeding risk whose initial
clinical presentation, or clinical course after starting AC
therapy, suggests a high risk of developing hypotension,
suggest administration of thrombolytic therapy…(Grade 2C)”
Chest. 2012; 141(Suppl 2): 24S
Submassive Pulmonary Embolism
ACCP 2012 Guidelines

“In patients with acute PE assoc. with hypotension
and who have contraind. to thrombolysis, failed
lysis, or has shock likely to cause death before
systemic lysis can take effect (within hours), if
appropriate resources available, suggest catheter
assisted thrombus removal over no such
intervention…(Grade 2C)”
Chest. 2012; 141(Suppl 2): 24S
Timing of Recurrent PE
Timing of recurrent thrombotic events
Nijkeuter, M. et al. Chest 2007;131:517-523
Risk of PE with Proximal DVTs
IVC Filters Reduce Recurrent PE
Decousus H et al. N Engl J Med 1998;338:409-416
Impact of IVC Filter on Mortality
AJM. 2012; 125:478-484
IVC Filter on PE Mortality
Caution:
Long Term IVC Filters Increase DVT
Circ. 2005;112: 416-422
IVC Filter Summary
IVC Filters:

Reduce recurrent PE’s
 Most of which occur within first 30 days

Reduce mortality in massive PE’s
Certain submassive PE’s have higher 30 day mortality

High Troponin with RV dysfunction on ECHO/CT and lower
extremity DVT
Pts with submassive PE and poor cardiopulmonary
reserve may not be able to tolerate an additional PE
insult and thus may benefit from reduced incidence of
recurrent PE gained from temporary filter placement

Long term IVC filter placement increases incidence of DVT
and attempts should be had to remove*
*Circ. 2005;112: 416-422
AHA 2011 Recommendations
IVC Filter Placement:
“Placement of an IVC filter may be considered
for patients with acute PE and very poor
cardiopulmonary reserve, including those with
massive PE...(Class IIB Level C)”
“An IVC filter should not be used routinely as
an adjuvant to anticoagulation and systemic
fibrinolysis in the treatment of acute PE…Class
III Level C)”
Circulation 2011; 123: 1788-1830
Conclusions
Submassive PE’s have varying degrees of
mortality
RV dysfunction on echo/CT and the presence
of a DVT are a “high risk” groups within the
submassive category
Severity Indices Scores help predict the
patient with poor cardiopulmonary reserve
that may benefit from additional therapy
beyond anticoagulation
Conclusions
To date, thrombolysis of any kind has yet to
prove mortality benefit in submassive PE
Half dose tPA and ultrasound accelerated
thrombolysis appear to have less bleeding
risks with improvement in hemodynamic
parameters
Ultrasound accelerated thrombolysis/EKOS
uses less lytic, may reduce mortality, and thus
may have a role in the “high risk” submassive
PE’s
Conclusions
While we focused strictly on a early mortality
benefit; data show that an RASP on echo >50
mmHg on presentation and after 12 weeks of
anticoagulation is a predictor for CTEPH*.
Improvements in hemodynamic parameters
may alter the prevalence of CTEPH
*Circ. 1999;99:1325-1330