BRIGHAM AND BRIGHAM AND WOMEN’S HOSPITALWOMEN’S HOSPITAL

HARVARD MEDICAL HARVARD MEDICAL SCHOOLSCHOOLTEACHING AFFILIATETEACHING AFFILIATE

A Prospective, Single-Arm, A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Multicenter Trial of Ultrasound-

Facilitated, Low-Dose Fibrinolysis Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II)Pulmonary Embolism (SEATTLE II)

Gregory Piazza, MD, MSGregory Piazza, MD, MSon behalf of the SEATTLE II Investigatorson behalf of the SEATTLE II Investigators

March 30, 2014March 30, 2014

Sponsored by the EKOS Corporation

Acute Pulmonary Embolism: Acute Pulmonary Embolism: A Spectrum of RiskA Spectrum of Risk

UnstableUnstable

StableStable

32% In-Hospital Mortality32% In-Hospital Mortality

3.4% In-Hospital Mortality3.4% In-Hospital Mortality

Casazza F, et al. Thromb Res 2012;130:847

Becattini C, et al. CHEST 2013;144: 1539

In-Hospital Death or Clinical DeteriorationIn-Hospital Death or Clinical Deterioration

RV Dysfunction with +TroponinRV Dysfunction with +Troponin

RV Dysfunction OR +TroponinRV Dysfunction OR +Troponin

Normal RV and TroponinNormal RV and Troponin

Increased RV/LV Ratio on CT Increased RV/LV Ratio on CT and PE-Related Mortalityand PE-Related Mortality

Trujillo-Santos J, et al. J Thromb Haemost 2013;11: 1823-1832

Intracranial Hemorrhage: Intracranial Hemorrhage: Efficacy at the Cost of SafetyEfficacy at the Cost of Safety

StudyStudy Intracranial Intracranial Hemorrhage Hemorrhage (Fibrinolysis (Fibrinolysis

Group)Group)

ICOPERICOPER(Goldhaber SZ, et al. (Goldhaber SZ, et al. 1999)1999)

9/304 (3%)9/304 (3%)

PEITHO PEITHO (Meyer G, et al. (Meyer G, et al. 2014)2014)

10/506 (2%)10/506 (2%)

ObjectivesObjectives

A prospective, single-arm, multicenter trial to:A prospective, single-arm, multicenter trial to:• Evaluate the efficacy of ultrasound-facilitated, Evaluate the efficacy of ultrasound-facilitated,

catheter-directed low-dose fibrinolysis to reverse catheter-directed low-dose fibrinolysis to reverse RV dysfunction as measured by CT-determined RV dysfunction as measured by CT-determined RV/LV diameter ratio in patients with acute RV/LV diameter ratio in patients with acute massive and submassive PEmassive and submassive PE

• Assess the safety of ultrasound-facilitated, Assess the safety of ultrasound-facilitated, catheter-directed low-dose fibrinolysis in patients catheter-directed low-dose fibrinolysis in patients with acute massive and submassive PEwith acute massive and submassive PE

Patient SelectionPatient SelectionMain Inclusion Criteria:Main Inclusion Criteria:

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

• Age ≥ 18 years Age ≥ 18 years ANDAND

• PE symptom duration ≤ 14 days PE symptom duration ≤ 14 days ANDAND

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

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

Main Exclusion Criteria:Main Exclusion Criteria:

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

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

• Major surgery within 7 daysMajor surgery within 7 days• Hematocrit < 30%, platelets < 100k/μL, Hematocrit < 30%, platelets < 100k/μL,

INR > 3, aPTT > 50 seconds on no INR > 3, aPTT > 50 seconds on no anticoagulationanticoagulation

• Serum creatinine > 2 mg/dLSerum creatinine > 2 mg/dL• Clinician-determined high-risk for Clinician-determined high-risk for

catastrophic bleedingcatastrophic bleeding• Hemodynamic instability despite Hemodynamic instability despite

medical therapymedical therapy• PregnancyPregnancy

Study OverviewStudy Overview

Study Sites = 21Study Sites = 21Total Trial Population = 150Total Trial Population = 150

InterventionIntervention

Monitoring in intermediate care or ICU setting

Study OutcomesStudy Outcomes• Primary Efficacy: Primary Efficacy:

Change in core lab-Change in core lab-measured RV/LV ratio measured RV/LV ratio from baseline to 48 hours from baseline to 48 hours as assessed by chest CTas assessed by chest CT

• Secondary Efficacy: Secondary Efficacy: Change in invasively Change in invasively measured PA systolic measured PA systolic pressure from baseline to pressure from baseline to device removal and as device removal and as estimated on 48-hour estimated on 48-hour echocardiogramechocardiogram

• Primary Safety: Primary Safety: Adjudicated major Adjudicated major bleeding within 72 hours bleeding within 72 hours of the start of the of the start of the procedureprocedure

• Secondary Safety: Secondary Safety: Adjudicated recurrent PE Adjudicated recurrent PE or death within 30 days of or death within 30 days of the procedure, or major the procedure, or major technical procedural technical procedural complicationscomplications

Study EnrollmentStudy EnrollmentP

atie

nts

Pat

ien

ts

Baseline CharacteristicsBaseline Characteristics

Patient Demographics N = 150Mean age ± SD, years 59 ± 16.1Mean BMI ± SD, kg/m2 35.6 ± 9.1Female gender , n (%) 77 (51.3)Race/Ethnicity, n (%)CaucasianAfrican AmericanHispanic

119 (79.3)22 (14.7)

9 (6)

Co-morbid Conditions, n (%) N = 150Concomitant use of antiplatelet agents 52 (34.7)Immobility within 30 days of PE 45 (30)Diabetes mellitus 42 (28)Previous DVT 30 (20)Previous PE 15 (10)

Characteristics of PECharacteristics of PECharacteristics 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.*Patients could have received more than one anticoagulant.

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

Outcomes: RV/LV RatioOutcomes: RV/LV Ratio

1.551.55

1.131.13

RV

/LV

Rat

ioR

V/L

V R

atio

p < 0.0001p < 0.0001

Outcomes: PA Systolic PressureOutcomes: PA Systolic PressureM

ean

PA

Sys

toli

c M

ean

PA

Sys

toli

c P

ress

ure

(m

mH

g)

Pre

ssu

re

(mm

Hg

)

51.451.4

36.936.937.537.5

p < 0.0001p < 0.0001

p < 0.0001p < 0.0001

Massive vs. Submassive PEMassive vs. Submassive PE

0.430.43

p = 0.31p = 0.31 p = 0.61p = 0.61

14.314.3

12.612.6

0.510.51

Outcomes: Modified Miller ScoreOutcomes: Modified Miller Score

22.522.5

15.815.8

p < 0.0001p < 0.0001

Mea

n M

od

ifie

d M

ille

r S

core

Mea

n M

od

ifie

d M

ille

r S

core

Clinical OutcomesClinical Outcomes

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

DiscussionDiscussion• We observed a 30% decrease in CT-measured RV/LV We observed a 30% decrease in CT-measured RV/LV

ratio over 48 hours in patients with massive and ratio over 48 hours in patients with massive and submassive PE treated with ultrasound-facilitated submassive PE treated with ultrasound-facilitated catheter-directed low-dose fibrinolysis.catheter-directed low-dose fibrinolysis.

• Ultrasound-facilitated catheter-directed low-dose Ultrasound-facilitated catheter-directed low-dose fibrinolysis rapidly relieved pulmonary artery obstruction fibrinolysis rapidly relieved pulmonary artery obstruction and reduced pulmonary hypertension.and reduced pulmonary hypertension.

• Ultrasound-facilitated catheter-directed low-dose Ultrasound-facilitated catheter-directed low-dose fibrinolysis minimized the risk of intracranial hemorrhage.fibrinolysis minimized the risk of intracranial hemorrhage.

Overcoming the Hurdle of Overcoming the Hurdle of Intracranial HemorrhageIntracranial Hemorrhage

StudyStudy Intracranial Intracranial Hemorrhage Hemorrhage (Fibrinolysis (Fibrinolysis

Group)Group)

ICOPERICOPER(Goldhaber SZ, et al. 1999)(Goldhaber SZ, et al. 1999)

9/304 (3%)9/304 (3%)

PEITHO PEITHO (Meyer G, et al. 2014)(Meyer G, et al. 2014)

10/506 (2%)10/506 (2%)

SEATTLE IISEATTLE II(Piazza G, et al. 2014)(Piazza G, et al. 2014)

0/150 (0%)0/150 (0%)

LimitationsLimitations

• The single-arm study design precluded The single-arm study design precluded direct comparison with the efficacy and direct comparison with the efficacy and safety of systemic fibrinolysis or safety of systemic fibrinolysis or anticoagulation alone.anticoagulation alone.

• Our study design did not allow for Our study design did not allow for evaluation of clinical end points such as evaluation of clinical end points such as hemodynamic collapse or mortality.hemodynamic collapse or mortality.

ConclusionsConclusions

• Ultrasound-facilitated catheter-directed low-dose Ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute PE improves RV function fibrinolysis for acute PE improves RV function and decreases pulmonary hypertension and and decreases pulmonary hypertension and angiographic obstruction. angiographic obstruction.

• By minimizing the risk of intracranial bleed, By minimizing the risk of intracranial bleed, ultrasound-facilitated catheter-directed low-dose ultrasound-facilitated catheter-directed low-dose fibrinolysis represents a potential “game-fibrinolysis represents a potential “game-changer” in treatment of high-risk PE patients.changer” in treatment of high-risk PE patients.

SEATTLE II InvestigatorsSEATTLE II Investigators• Gregory Piazza, M.D., M.S.Gregory Piazza, M.D., M.S.

• Tod C. Engelhardt, M.D.Tod C. Engelhardt, M.D.

• Keith M. Sterling, M.D.Keith M. Sterling, M.D.

• Noah J. Jones, M.D.Noah J. Jones, M.D.

• John C. Gurley, M.D.John C. Gurley, M.D.

• Rohit Bhatheja, M.D.Rohit Bhatheja, M.D.

• Robert Kennedy, M.D.Robert Kennedy, M.D.

• Nilesh Goswami, M.D.Nilesh Goswami, M.D.

• Kannan Natarajan, M.D.Kannan Natarajan, M.D.

• John Rundback, M.D.John Rundback, M.D.

• Immad Sadiq, M.D.Immad Sadiq, M.D.

• Stephen K. Liu, M.D.Stephen K. Liu, M.D.

• Narinder Bhalla, M.D.Narinder Bhalla, M.D.

• M. Laiq Raja, M.D.M. Laiq Raja, M.D.

• Barry S. Weinstock, M.D.Barry S. Weinstock, M.D.

• Jacob Cynamon, M.D.Jacob Cynamon, M.D.

• Fakhir F. Elmasri, M.D.Fakhir F. Elmasri, M.D.

• Mark J. Garcia M.D.Mark J. Garcia M.D.

• Mark Kumar, M.D.Mark Kumar, M.D.

• Juan Ayerdi, M.D.Juan Ayerdi, M.D.

• Peter Soukas, M.D.Peter Soukas, M.D.

• William Kuo, M.D.William Kuo, M.D.

• Samuel Z. Goldhaber, M.D.Samuel Z. Goldhaber, M.D.

Special thanks to:Special thanks to:•Benjamin Hohlfelder, B.S. (Thrombosis Research Group) Benjamin Hohlfelder, B.S. (Thrombosis Research Group)

Back-Up SlidesBack-Up Slides

Rationale for Study DesignRationale for Study Design• Timely enrollment in randomized controlled trials for PE has Timely enrollment in randomized controlled trials for PE has

historically been problematic. historically been problematic.

• A single-arm design allowed for efficient evaluation of the safety and A single-arm design allowed for efficient evaluation of the safety and efficacy of ultrasound-facilitated, catheter-directed low-dose efficacy of ultrasound-facilitated, catheter-directed low-dose fibrinolysis for treatment of PE. fibrinolysis for treatment of PE.

• Our study provided clinicians performing ultrasound-accelerated Our study provided clinicians performing ultrasound-accelerated catheter-directed low-dose fibrinolysis with a standardized protocol catheter-directed low-dose fibrinolysis with a standardized protocol for the procedure, which had been performed with little for the procedure, which had been performed with little standardization among operators. standardization among operators.

• Our study design allowed for more rigorous monitoring and reporting Our study design allowed for more rigorous monitoring and reporting of adverse events. of adverse events.

Meyer G, et al. N Engl J Med 2014; in press Kucher N, et al. Circulation 2014;129:479