Evolving Paradigm Shifts

Acute PE management
 Paradigm Shift

a concept identified by the American physicist and

philosopher Thomas Kuhn, is a fundamental change in
the basic concepts and experimental practices of a 
scientific discipline
The outpatient management of CTPA confirmed pulmonary embolic
disease
J. W. Dodd, R. Nadama. Department of Respiratory Medicine, Royal
Devon & Exeter Hospital, Devon, UK

Thorax 2006 Dec;61 (Suppl 2):ii1-133

 Case 1
• 48 year old male
• A&E
• Sudden onset shortness breath
• Spo2 60% on arrival started HFNC 60L/min Spo2 94%
• BP 85/50mmhg HR 122/min
 Case 1
• Iv fluid resuscitation
• Inotropes
• CTPA
Case 1
 Case 1
• Thrombolysed

• 1 hr oxygen requirement significantly reduced and hemodynamically

stable off inotropes
 Case 2
• 23 year old Male
• 10 days post bariatric surgery
• Pleurisy and SOB
• Afebrile Heart Rate H 118 RR 22 BP 118 /79
• Oxygen requirement reasonable

Impression: Acute PE
CTPA
• Trop 405
• ECG T wave inversion inferior
leads
 Progress
• Anticoagulation
• More tachypneic with Oxygen requirement increasing
• Hemodynamically stable

What next
? Systemic Thrombolysis, ? Full dose vs low dose
? Surgical Embolectomy
? Catheter related locally directed approach
• Catheter: Aspiration of Clots
• Catheter Directed Thrombolysis

• Significant improvement of
symptoms
• Normalization of oxygenation and
hemodynamic parameters
Acute PE Risk Prediction tools
• PESI
• sPESI
• Hestia
CTA Risk prediction Parameters
Echocardiographic signs of RVD
Cardiac Biomarkers
• Trop T or I
• BNP
Risk of Bleeding
 ESC 2019 Guidelines: Risk-Adjusted Management Strategy for Acute
Pulmonary Embolism

Konstantinides SV et al, Eur Heart J 2019: doi:10.1093/eurheartj/ehz405

The Eternal Clinician’s Dilemma

First do no harm
vs
The desire to do something more
 Thrombolysis
• “We don’t have evidence of any real proven mortality difference yet
in the intermediate-high risk PE group by being more aggressive. I
think if the right patients were studied we could see a mortality
difference. But one thing I’ve noted is that by being more aggressive
– in a cautious manner, in selected patients – we clearly shorten the
hospital stay by doing catheter-directed therapy in some of these
folks. It saves money,” he [Vic Tapson] observed.

• Risk stratification key in acute pulmonary embolism.

• https://www.the-hospitalist.org/hospitalist/article/227014/pulmonology/risk-stratification-key-acute-pulmonary-embolism
PEITHO: Full dose lysis in intermediate-high risk
pulmonary embolism
Overview of study design
 PEITHO: Safety outcomes within 7 days of randomization
Tenecteplase Placebo
Outcome (N=506) (N=499) p-value
n (%) n (%)
Bleeding by day 7
44 bleeding
Major extracranial 32 6.3 6 1.2 <0.001
7
Minor bleeding 165 32.6 43 8.6
12†
Major bleeding 58 11.5 12 2.4 16†
All strokes by day 7 12 2.4 1 0.2 0.003
Haemorrhagic 10 2.0 1 0.2
Ischaemic 2 0.4 0 0
Serious adverse events by day 30 55 10.9 59 11.8 0.63

†Deaths by day 30

PEITHO Investigators. N Engl J Med 2014;370:1402–1411

 Meta-analysis of thrombolysis

ICH, intracranial haemorrhage; NNH, number needed to harm; NNT, number needed to treat
Chaterjee S et al, JAMA 2014;311:2414–2421
Article Copyright © 2019 Authors, Source DOI: 10.1177/1076029619853037. See content reuse guidelines at: sagepub.com/journals-permissions
 Low dose rtPA
• MOPETT Trial2
• 50 mg rtPA vs anticoagulation

• 50 mg vs 100 mg rtPA1

50 vs 100mg rtPA
Death: 2 vs 6% (p=0.472)
Bleeding complications: 17 vs 32% (p=0.054)
1. Wang et al., CHEST 2010 ; 137(2):254–262;
Major bleeding: 3 vs 10% (p=0.29) 2. Sharifi et al., Am J Cardiol 2013;111:273-277
Half-dose versus full-dose thrombolysis

• Kiser et al., Crit Care Med 2018; 46:1617–

1625
Half-dose versus full-dose thrombolysis

Kiser et al., Crit Care Med 2018; 46:1617–1625

Acoustic Pulse Thrombolysis™ treatment
Mechanism of action
Fibrin Separation Active Drug Delivery
Ultrasound separates fibrin Drug is actively driven into clot by
without fragmentation of emboli “Acoustic Streaming”

Fibrin without Fibrin With Ultrasound Acoustic streaming drives

Ultrasound lytic into clot
EKOS® Acoustic Pulse Thrombolysis™ treatment is a minimally invasive system for
accelerating thrombus dissolution.
ULTIMA Trial

rtPA
1 mg/h 5 hrs
0.5 mg/h 10 hrs
TOTAL DOSE = 10 mg
Kucher et al., Circulation. 2014;129:479-486.
ULTIMA Trial

Kucher et al., Circulation. 2014;129:479-486.

ULTIMA Trial

Kucher et al., Circulation. 2014;129:479-486.

SEATTLE II

rtPA
TOTAL DOSE = 24 mg
Unilateral 1mg/hr 24hrs; bilateral 1mg/hr 12 hrs
Piazza et al., J Am Coll Cardiol Intv 2015;8:1382–92)
SEATTLE II

Age

Mean 66
Median 70

Mean 59

Piazza et al., J Am Coll Cardiol Intv 2015;8:1382–92)

OPTALYSE-PE
• Can we reduce dose / infusion time even further???

• Male or female ≥ 18 years of age and ≤ 75 years of age

• CTA evidence of proximal PE (filling defect in at least one main or lobar
pulmonary artery)
• PE symptom duration ≤14 days
• Intermediate risk PE:
• RV/LV diameter ≥ 0.9 from CTA;
• Haemodynamically stable; and
• An elevated cardiac biomarker was NOT required
Tapson et al., J Am Coll Cardiol Intv 2018;11:1401–10
Study Cohorts

Tapson et al., J Am Coll Cardiol Intv 2018;11:1401–10

Change in RV Systolic Pressure and Miller Index from Baseline
to 48hrs

Tapson et al., J Am Coll Cardiol Intv 2018;11:1401–10

OPTALYSE PE – Results at 48 hours after START of APT
Procedure
All cohorts showed significant reduction in RV/LV ratio

* Total mg r-tPA: one/two catheters

40
Tapson et al., J Am Coll Cardiol Intv 2018;11:1401–10
Bleeding / ICH

• 2 episodes of ICH
• 1 directly related to
thrombolysis (Arm 4)
• 1 indirectly related – head
injury after a fall ? Related to
anaemia (Arm 2)

Tapson et al., J Am Coll Cardiol Intv 2018;11:1401–10

Is US-assisted CDL better than standard CDL?

• PERFECT registry
• Prospective study of catheter-based therapy in massive and submassive
PE
• Incl. lysis, fragmentation
• Initial results:
• 101 patients - 73 submassive; 28 massive
• 100 received lysis – 64 standard; 36 ultrasound-assisted catheter

Kuo et al., CHEST 2015; 148 ( 3 ): 667 - 673

Is US-assisted CDL better than standard
CDL?

Kuo et al., CHEST 2015; 148 ( 3 ): 667 - 673

Is US-assisted CDL better than standard
CDL?

Kuo et al., CHEST 2015; 148 ( 3 ): 667 - 673

Is US-assisted CDL better than standard CDL?

Kuo et al., CHEST 2015; 148 ( 3 ): 667 - 673

 Low-dose vs full-dose vs catheter-directed thrombolysis?
Anticoagulation

16
a
tri

tri
1

2,

al
nt

01
tie

s
6
pa

pa
1

t ie
12

nt
s
4 trials
Low-dose Full-dose
thrombolysis 298 patients thrombolysis

59 patients
1 trial
Catheter-directed
thrombolysis
Network of included studies with available direct comparisons for all-cause mortality

Jimenez D et al, Thorax 2017: doi:10.1136/thoraxjnl-2017-210040.

 Low-dose vs full-dose vs catheter-directed
thrombolysis?

Jimenez D et al, Thorax 2017 doi:10.1136/thoraxjnl-2017-210040.

Current studies
• Pulmonary Embolism
International THrOmbolysis
Study-3 (PEITHO-3)
• Efficacy and safety of alteplase
single intravenous infusion of 0.6
mg/kg (max 50 mg given over 15
minutes) in addition to LMWH
versus LMWH alone in patients
with intermediate-high-risk PE
• Ultrasound-facilitated, Catheter-
directed, Thrombolysis in
Intermediate-high Risk Pulmonary
Embolism (HI-PEITHO)
• Clinical benefit of the ultrasound-
facilitated local delivery of 2 mg
bolus/catheter + 1 mg/hour/catheter
for 7 hours (total of 9 or 18 mg and
anticoagulation versus anticoagulation
alone in patients with intermediate-
high-risk PE
What about catheter aspiration?

Courtesy of Prof Andrew Sharp, Cardiff

Conclusions

• There is no current good evidence to support routine full-dose, half-

dose or catheter-directed lysis in intermediate-high risk pulmonary
embolism
• PERTs can assist in deciding who needs more aggressive intervention
• Half-dose lysis may be safer, but ? may result in more escalation of
therapy
• Catheter-directed lysis allows lowest dose of lytic to be delivered, but
real-world data are lacking
• Is USAT any better than standard CDT??
 Teaching Points

A pulmonary embolus response team is now considered a standard of

care for institutions treating pulmonary embolisms.
This allows expeditious and efficient use of CDT and other invasive
modalities to treat patients with high-risk PEs.
PERT
Single Centre retrospective review
• 30 day inpatient mortality (4.7 versus 8.5 percent)
• major bleeding (8.3 versus 17 percent)
• time to therapeutic anticoagulation (12.6 versus 16.3 hours)
• use of inferior vena cava filters (22.2 versus 16.4 percent)
• Mortality benefit; intermediate- and high-risk PE (5.3 versus 10
percent)

Am J Cardiol. 2019;124(9):1465.
Reminder
• Most pulmonary embolisms (PE) are small and low risk.
• Approximately 20% to 25% of patients with a PE have a (submassive)
Intermediate Risk PE.
• Approximately 5% to 10% of patients with pulmonary embolism have
a high Risk (massive) pulmonary embolism.