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Ultrasound Assisted Thrombolysis for Massive and Submassive Pulmonary Embolism Scott M Lilly, MD PhD Interventional Cardiology Fellows School August 15 th , 2014

Ultrasound Assisted Thrombolysis for Massive and Submassive Pulmonary Embolism Scott M Lilly, MD PhD Interventional Cardiology Fellows School August 15

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Ultrasound Assisted Thrombolysis for Massive and Submassive Pulmonary Embolism

Scott M Lilly, MD PhDInterventional Cardiology

Fellows School

August 15th, 2014

Acknowledgements

Peter Bittenbender, MD

Ray Magorien, MD

Michael Bray, EKOS Corporation

Outline

Background and Definitions

How to Determine Risk

Treatment of High Risk patients

Practical Points and Program Experience

Background and Definitions

300k-600k per year 1-2 per 1000 people, or as high as 1 in 100 if > 80

10-30% overall 30 day mortality Sudden death is presenting symptom in ~ 25%

2012: 166,665 primary admissions for PE In-hospital mortality ~ 3%

Most commonly from lower extremity DVT Evidence of DVT in > 50%

4

cdc.gov; Agency for Healthcare Research and Quality

Massive PE Submassive PE Minor/Nonmassive PE

High risk Moderate/intermediate risk Low risk

• Sustained hypotension (systolic BP <90 mmHg for 15 min)

• Inotropic support• Pulseless• Persistent profound bradycardia

(HR <40 bpm with signs or symptoms of shock)

• Systemically normotensive (systolic BP 90 mmHg)

• RV dysfunction• Myocardial necrosis

• Systemically normotensive (systolic BP 90 mmHg)

• No RV dysfunction• No myocardial necrosis

RV dysfunction• RV/LV ratio > 0.9 or RV systolic dysfunction on

echo• RV/LV ratio > 0.9 on CT• Elevation of BNP (>90 pg/mL)• Elevation of NTpro-BNP (>500 pg/mL)• ECG changes:

• new complete or incomplete RBBB• anteroseptal ST elevation or depression• anteroseptal T-wave inversion

Jaff et al. Circulation 2011;123(16):1788-1830.

LVRV

Jaff et al. Circulation 2011;123(16):1788-1830.

Background and Definitions

Background and Definitions

Massive PE [High risk]5% PE population

Submassive PE [Moderate risk]40% PE population

Minor PE [Low risk]55% PE population

Massive PE [High risk]5% PE population

Minor PE [Low risk]55% PE population

Outline

Background and Definitions

How to Determine Risk

Treatment of High Risk patients

Practical Points and Program Experience

Massive PE Submassive PE Minor/Nonmassive PE

High risk Moderate/intermediate risk Low risk

• Sustained hypotension (systolic BP <90 mmHg for 15 min)

• Inotropic support• Pulseless• Persistent profound bradycardia

(HR <40 bpm with signs or symptoms of shock)

• Systemically normotensive (systolic BP 90 mmHg)

• RV dysfunction• Myocardial necrosis

• Systemically normotensive (systolic BP 90 mmHg)

• No RV dysfunction• No myocardial necrosis

Jaff et al. Circulation 2011;123(16):1788-1830.

How to Determine Risk

MortalityIn hospital ~ 25% (MAPPET)

90-day ~ 50% (ICOPER)

?

Massive PE Submassive PE Minor/Nonmassive PE

High risk Moderate/intermediate risk Low risk

• Sustained hypotension (systolic BP <90 mmHg for 15 min)

• Inotropic support• Pulseless• Persistent profound bradycardia

(HR <40 bpm with signs or symptoms of shock)

• Systemically normotensive (systolic BP 90 mmHg)

• RV dysfunction• Myocardial necrosis

• Systemically normotensive (systolic BP 90 mmHg)

• No RV dysfunction• No myocardial necrosis

Jaff et al. Circulation 2011;123(16):1788-1830.

How to Determine Risk

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− Registry of 1,416 patients

− Mortality rate: 1.9% if RV/LV ratio < 0.96.6% if RV/LV ratio ≥ 0.9

Fremont et al. CHEST 2008;133:358-362

How to Determine Risk

11

− Retrospective analysis of 120 patients with hemodynamically stable PE based on chest CT

− PE-related mortality at 3 months:

17% if RV/LV ≥ 1.5 8% if 1.0 ≤ RV/LV < 1.5 0% if RV/LV < 1.0

Van der Meer et al. Radiology 2005; 235:798-803.

How to Determine Risk

12

− Retrospective analysis of 63 patients with chest CT

− Adverse event rate at 30 days: 80.3% if RV/LV ratio > 0.9 51.3% if RV/LV ratio ≤ 0.9

Quiroz et. al. Circulation. 2004;109:2401-2404

How to Determine Risk

Risk Stratification

*ACC/AHA Guidelines 2011 Circulation 2006;113:577-82

Outline

Background and Definitions

How to Determine Risk

Treatment of High Risk patients

Practical Points and Program Experience

Degree of PE Treatment* Bleeding Risk

Non-Massive Heparin (I) Less

Sub-Massive Lytics (IIb)

Massive Lytics (IIa) More

20% risk of major bleeding3% risk of intracranial hemorrhage

*ACC/AHA Guidelines 2011 Circulation 2006;113:577-82

Treatment of High Risk patients

*ACC/AHA Guidelines 2011 Circulation 2006;113:577-82

Treatment of High Risk patients

17

Study Intracranial Hemorrhage (Fibrinolysis

Group)

ICOPER(Goldhaber SZ, et al. 1999)

9/304 (3%)

PEITHO (Meyer G, et al. 2014)

10/506 (2%)

Treatment of High Risk patients

Status of TrialsTreatment of High Risk patients

The ULTIMA TrialA Prospective, Randomized, Controlled Study of Ultrasound Accelerated Thrombolysis for the Treatment of Acute Pulmonary Embolism

Annual Meeting of the American College of Cardiology, March 9, 2013

Treatment of High Risk patients

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Hypothesis: Ultrasound-assisted, catheter-directed thrombolysis is superior to treatment with heparin alone for reversing RV enlargement within 24 hours

ULTrasound Accelerated ThrombolysIs of PulMonAry Embolism

The ULTIMA TrialTreatment of High Risk patients

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Symptoms < 14 days

No hemodynamic collapse at presentation

No active bleeding

Acute symptomatic PE confirmed by contrast-enhanced chest CT with embolus located in at least one main or proximal lower lobe pulmonary artery

RV/LV ratio > 1 on echocardiography

Enrollment Criteria

The ULTIMA TrialTreatment of High Risk patients

 EKOS + Heparin Heparin

 p-value

N = 30 N = 29

Age, mean ± SD 64 ± 15 62 ± 13 0.33

Body mass index, mean ± SD 31 ± 7 29 ± 7 0.28

Women 19 63% 12 41% 0.12

Coronary artery disease 2 7% 1 3% 1.00

Tobacco use 4 14% 7 24% 0.50

Diabetes mellitus 6 20% 4 14% 0.73

Cancer 5 17% 2 7% 0.42

Renal insufficiency 4 13% 5 17% 0.73

Previous deep vein thrombosis

4 13% 8 28% 0.21

Previous pulmonary embolism 4 13% 2 7% 0.67

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The ULTIMA TrialTreatment of High Risk patients

Nils Kutcher, ACC.13

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 EKOS + Heparin Heparin

 p-value

N = 30 N = 29

Troponin test positive, n (%) 16/20 (80%) 17/22 (77%) 1.00

Pulmonary occlusion score (CT)1, mean ± SD 26 ± 7 24 ± 8 0.24Pulmonary occlusion score (CT)1, median (min-max) 26 (9-36) 22 (13-38)

1Qanadli Am J Roentgenology 2001;176:1415-20

Pulmonary occlusion score1

• Multiply score points for non-occlusive embolus by one

• Multiply score points for occlusive embolus by two

• Maximum score is 40.

20

10

3

2

5

1 1

2

1

1

1

1

1111

11

1

1

5

10

3

11

1

111

1

The ULTIMA TrialTreatment of High Risk patients

Nils Kutcher, ACC.13

EKOS + HeparinN = 30

HeparinN = 29 p-value

Total heparin dose from randomization to 24 hours, IU 30939 ± 7907 34277 ± 5632 0.08

Technical success device placement 100% -

Device placement time, minutes, median (min-max)

42(15 – 102)

-

Dual device procedure 25 (83%) -

Total rt-PA dose two devices, mg 20.7 ± 2.5 -

Single device procedure 5 (17%) -

Total rt-PA dose single device, mg 12.2 ± 3.8 -

Length of stay in ICU/IMC, days 2.6 ± 1.3 1.7 ± 1.3 0.01

Length of hospital stay, days 8.8 ± 3.5 8.7 ± 3.9 0.88

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The ULTIMA TrialTreatment of High Risk patients

Nils Kutcher, ACC.13

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RV/LV Ratio (Echocardiography)

EKOS + Heparin Heparin Alone

The ULTIMA TrialTreatment of High Risk patients

Nils Kutcher, ACC.13

Right Ventricular Dysfunction

The ULTIMA TrialTreatment of High Risk patients

Nils Kutcher, ACC.13

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 Clinical outcomes at 90 days

EKOS + Heparin Heparin

 p-value

N = 30 N = 29

Death 0 0% 1* 3% 0.49

Recurrent venous thromboembolism 0 0% 0 0% 1.00

Major bleeding 0 0% 0 0% 1.00

Minor bleeding 3** 10% 1§ 3% 0.61• rehospitalization and death from advanced pancreatic cancer** two patients with transient mild hemoptysis without medical intervention, one patient with groin hematoma requiring manual compression§ one patient with transient anal bleeding following endoscopic removal of colon polyp

The ULTIMA TrialTreatment of High Risk patients

Systemic Lytics vs EKOS

Systemic Lytics v Heparin

EKOS v Heparin

Total Lytics Dose 100mg 20.7mg (12.2mg)

Mortality 5.9% -> 4.3% 1/29 -> 0/30

RV Size Improved Improved

RV Function Improved Improved

Major Bleeding 20% 0/30

ICH 3% 0/30

A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism

(SEATTLE II)

The SEATTLE II TrialTreatment of High Risk patients

The SEATTLE II TrialTreatment of High Risk patients

A prospective, single-arm, multicenter trial to:

Evaluate the efficacy of ultrasound-facilitated, catheter-directed low-dose fibrinolysis to reverse RV dysfunction as measured by CT-determined

RV/LV diameter ratio in patients with acute massive and submassive PE

Assess the safety of ultrasound-facilitated, catheter-directed low-dose fibrinolysis in patients

with acute massive and submassive PE

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Main Inclusion Criteria:

Proximal PE on CT (filling defect in ≥ 1 main, lobar, or segmental pulmonary artery) AND

Age ≥ 18 years AND

PE symptom duration ≤ 14 days AND

Massive PE (syncope, systemic arterial hypotension, cardiogenic shock, or resuscitated cardiac arrest) OR

Submassive PE (RV/LV diameter ≥ 0.9 on contrast-enhanced chest CT)

Main Exclusion Criteria:

Stroke/TIA, head trauma, or intracranial or intraspinal disease within 1 year

Active or recent (within 1 month) bleeding from a major organ

Major surgery within 7 days

Hematocrit < 30%, platelets < 100k/μL, INR > 3, aPTT > 50 seconds on no anticoagulation

Serum creatinine > 2 mg/dL

Clinician-determined high-risk for catastrophic bleeding

Hemodynamic instability despite medical therapy

Pregnancy

The SEATTLE II TrialTreatment of High Risk patients

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The SEATTLE II TrialTreatment of High Risk patients

Procedure CompletionPost-Procedure Right Heart Catheter Measurements Catheter Removal

Ultrasound-Facilitated, Low-Dose, Catheter-Directed Fibrinolysist-PA Infusion Activation of high frequency, low power ultrasound

Baseline Right Heart Catheter MeasurementsIncluding pulmonary artery systolic pressure

Catheter Placement and Treatment Based on Extent of DiseaseUnilateral: 1 catheter infusing t-PA 1 mg/hour for 24 hours Bilateral: 2 catheters infusing t-PA 1 mg/hour/catheter for 12 hours

Standard Anticoagulation for PEUFH goal PTT 40-60 sec during procedure

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The SEATTLE II TrialTreatment of High Risk patients

Procedural CharacteristicsMean dose of t-PA ± SD*, mg 23.7 ± 2.9Successful device placement**, n (%) 278 (97.5)Access sites***, n (%)

Right femoral veinLeft femoral veinRight internal jugular veinOther

177 (63.7)61 (21.9)31 (11.2)9 (3.2)

Number of devices per patient*, n (%)012

1 (0.7)20 (13.3)129 (86)

Completed infusion of t-PA***, n (%) 272 (97.8)

*N = 150 patients (1 patient died before devices could be placed)**N = 285 devices attempted***N = 278 devices placed

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The SEATTLE II TrialTreatment of High Risk patients

Characteristics of PE, n (%) N = 150Duration of symptoms≤14 days>14 days

149 (99.3)1 (0.7)

Any symptoms of PE 150 (100)PE subtypeSubmassiveMassive

119 (79.3)31 (20.7)

Pre-procedure anticoagulation*Intravenous unfractionated heparinEnoxaparinWarfarinOtherNone

76 (50.7)54 (36)

16 (10.7)7 (4.7)24 (16)

*Patients could have received more than one anticoagulant.

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Pre-Procedure

48 Hours

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

The SEATTLE II TrialTreatment of High Risk patients

RV to LV Ratio

38

Mean Decrease PA Systolic Pre...

11.5

12

12.5

13

13.5

14

14.5

Submassive PE

Massive PE

Mean Decrease RV/LV Ratio

0

0.1

0.2

0.3

0.4

0.5

Submassive PE

Massive PE

0.43

p = 0.31 p = 0.61

14.3

12.6

0.51

The SEATTLE II TrialTreatment of High Risk patients

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The SEATTLE II TrialTreatment of High Risk patients

Clinical outcomes* N = 150Mean length of stay ± SD, days 8.8 ± 5In-hospital death, n (%) 3 (2)30-day mortality**, n (%) 4 (2.7)Serious adverse events due to device, n (%) 2 (1.3)Serious adverse events due to t-PA, n (%) 2 (1.3)IVC filter placed, n (%) 24 (16)Major bleeding within 30 days**, n (%)GUSTO moderate**GUSTO severe**

17 (11.4)16 (10.7)

1 (0.7)

Intracranial hemorrhage, n (%) 0 (0)

*All death, serious adverse, and bleeding events were adjudicated by an independent safety monitor.**N = 149 (1 patient lost to follow-up)

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Study Intracranial Hemorrhage (Fibrinolysis

Group)

ICOPER(Goldhaber SZ, et al. 1999)

9/304 (3%)

PEITHO (Meyer G, et al. 2014)

10/506 (2%)

SEATTLE II(Piazza G, et al. 2014)

0/150 (0%)

The SEATTLE II TrialTreatment of High Risk patients

Lysis vs Placebo 13 placebo controlled, randomized trials of

lysis vs placebo Minority for massive PE, total 480 patients. Variable drugs, dosing, timing and adjunctive

therapies No independent mortality effect Meta-analyses reduction in death/recurrent PE Improvement in RV size/function, mPA

pressures

EKOS v Heparin No study large enough to evaluate

death/recurrent PE Improved RV size/function at 24hrs, catch up

at 90days Improved RV function at 90 days

Status of TrialsTreatment of High Risk patients

Outline

Background and Definitions

How to Determine Risk

Treatment of High Risk patients

Practical Points, Program Experience

Who is an EKOS Candidate?

Large, Central PE – symptoms <14 days SBP<90 (not responsive to fluids) Need for inotrope HR<40 w/ s/s Shock PEA (after return of circulation)

RV:LV ratio > 1.0 (CTPE) RV:LV ratio > 1.0 (TTE) Signs of RV dysfxn (TTE)

MASSIVE

SUBMASSIVE

Activate a PE Alert by dialing the Transfer Center

Hotline phone number: 366-8111

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The PE Guideline is Located on One Source

Listed under“Venous

Thromboembolism”