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

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

• Gregory Piazza, MD, MS
• on behalf of the SEATTLE II Investigators
• March 30, 2014

Sponsored by the EKOS Corporation
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Acute Pulmonary Embolism A Spectrum of Risk
In-Hospital Death or Clinical Deterioration
32 In-Hospital Mortality
RV Dysfunction with Troponin
Unstable
3.4 In-Hospital Mortality
RV Dysfunction OR Troponin
Stable
Normal RV and Troponin
Casazza F, et al. Thromb Res 2012130847 Becattin
i C, et al. CHEST 2013144 1539
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Increased RV/LV Ratio on CT and PE-Related
Mortality
Trujillo-Santos J, et al. J Thromb Haemost
201311 1823-1832
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Intracranial Hemorrhage Efficacy at the Cost of
Safety
Study Intracranial Hemorrhage (Fibrinolysis Group)
ICOPER (Goldhaber SZ, et al. 1999) 9/304 (3)
PEITHO (Meyer G, et al. 2014) 10/506 (2)
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Objectives

• 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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Patient Selection

• 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 lt 30, platelets lt 100k/µL, INR gt 3,
  aPTT gt 50 seconds on no anticoagulation
• Serum creatinine gt 2 mg/dL
• Clinician-determined high-risk for catastrophic
  bleeding
• Hemodynamic instability despite medical therapy
• Pregnancy

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Study Overview
Study Sites 21 Total Trial Population 150
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Intervention
Monitoring in intermediate care or ICU setting
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Study Outcomes

• Primary Efficacy Change in core lab-measured
  RV/LV ratio from baseline to 48 hours as assessed
  by chest CT
• Secondary Efficacy Change in invasively
  measured PA systolic pressure from baseline to
  device removal and as estimated on 48-hour
  echocardiogram

• Primary Safety Adjudicated major bleeding
  within 72 hours of the start of the procedure
• Secondary Safety Adjudicated recurrent PE or
  death within 30 days of the procedure, or major
  technical procedural complications

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Study Enrollment
Patients
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Baseline Characteristics
Patient Demographics N 150
Mean age SD, years 59 16.1
Mean BMI SD, kg/m2 35.6 9.1
Female gender , n () 77 (51.3)
Race/Ethnicity, n () Caucasian African American Hispanic 119 (79.3) 22 (14.7) 9 (6)
Co-morbid Conditions, n () N 150
Concomitant 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)
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Characteristics of PE
Characteristics of PE, n () N 150
Duration of symptoms 14 days gt14 days 149 (99.3) 1 (0.7)
Any symptoms of PE 150 (100)
PE subtype Submassive Massive 119 (79.3) 31 (20.7)
Pre-procedure anticoagulation Intravenous unfractionated heparin Enoxaparin Warfarin Other None 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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Procedural Characteristics
Procedural Characteristics
Mean dose of t-PA SD, mg 23.7 2.9
Successful device placement, n () 278 (97.5)
Access sites, n () Right femoral vein Left femoral vein Right internal jugular vein Other 177 (63.7) 61 (21.9) 31 (11.2) 9 (3.2)
Number of devices per patient, n () 0 1 2 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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Outcomes RV/LV Ratio
p lt 0.0001
1.55
1.13
RV/LV Ratio
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Outcomes PA Systolic Pressure
p lt 0.0001
p lt 0.0001
51.4
37.5
36.9
Mean PA Systolic Pressure (mmHg)
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Massive vs. Submassive PE
p 0.31
p 0.61
0.51
14.3
0.43
12.6
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Outcomes Modified Miller Score
p lt 0.0001
22.5
15.8
Mean Modified Miller Score
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Clinical Outcomes
Clinical outcomes N 150
Mean length of stay SD, days 8.8 5
In-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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Discussion

• We observed a 30 decrease in CT-measured RV/LV
  ratio over 48 hours in patients with massive and
  submassive PE treated with ultrasound-facilitated
  catheter-directed low-dose fibrinolysis.
• Ultrasound-facilitated catheter-directed low-dose
  fibrinolysis rapidly relieved pulmonary artery
  obstruction and reduced pulmonary hypertension.
• Ultrasound-facilitated catheter-directed low-dose
  fibrinolysis minimized the risk of intracranial
  hemorrhage.

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Overcoming the Hurdle of Intracranial Hemorrhage
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)
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Limitations

• The single-arm study design precluded direct
  comparison with the efficacy and safety of
  systemic fibrinolysis or anticoagulation alone.
• Our study design did not allow for evaluation of
  clinical end points such as hemodynamic collapse
  or mortality.

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Conclusions

• Ultrasound-facilitated catheter-directed low-dose
  fibrinolysis for acute PE improves RV function
  and decreases pulmonary hypertension and
  angiographic obstruction.
• By minimizing the risk of intracranial bleed,
  ultrasound-facilitated catheter-directed low-dose
  fibrinolysis represents a potential
  game-changer in treatment of high-risk PE
  patients.

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SEATTLE II Investigators

• Gregory Piazza, M.D., M.S.
• Tod C. Engelhardt, M.D.
• Keith M. Sterling, M.D.
• Noah J. Jones, M.D.
• John C. Gurley, M.D.
• Rohit Bhatheja, M.D.
• Robert Kennedy, M.D.
• Nilesh Goswami, M.D.
• Kannan Natarajan, M.D.
• John Rundback, M.D.
• Immad Sadiq, M.D.
• Stephen K. Liu, M.D.

• Narinder Bhalla, M.D.
• M. Laiq Raja, M.D.
• Barry S. Weinstock, M.D.
• Jacob Cynamon, M.D.
• Fakhir F. Elmasri, M.D.
• Mark J. Garcia M.D.
• Mark Kumar, M.D.
• Juan Ayerdi, M.D.
• Peter Soukas, M.D.
• William Kuo, M.D.
• Samuel Z. Goldhaber, M.D.

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

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Back-Up Slides
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Rationale for Study Design

• Timely enrollment in randomized controlled trials
  for PE has historically been problematic.
• A single-arm design allowed for efficient
  evaluation of the safety and efficacy of
  ultrasound-facilitated, catheter-directed
  low-dose fibrinolysis for treatment of PE.
• Our study provided clinicians performing
  ultrasound-accelerated catheter-directed low-dose
  fibrinolysis with a standardized protocol for the
  procedure, which had been performed with little
  standardization among operators.
• Our study design allowed for more rigorous
  monitoring and reporting of adverse events.

Meyer G, et al. N Engl J Med 2014 in press
Kucher N, et al. Circulation 2014129479