BRIGHAM AND
WOMEN’S HOSPITAL
A Prospective, Single-Arm,
Multicenter Trial of UltrasoundFacilitated, 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
HARVARD MEDICAL
SCHOOL
TEACHING AFFILIATE
Acute Pulmonary Embolism:
A Spectrum of Risk
32% In-Hospital Mortality
In-Hospital Death or Clinical Deterioration
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 2012;130:847
Becattini C, et al. CHEST 2013;144: 1539
Increased RV/LV Ratio on CT
and PE-Related Mortality
Trujillo-Santos J, et al. J Thromb Haemost 2013;11: 1823-1832
Intracranial Hemorrhage:
Efficacy at the Cost of Safety
Study
ICOPER
(Goldhaber SZ, et al.
1999)
PEITHO
(Meyer G, et al.
2014)
Intracranial
Hemorrhage
(Fibrinolysis
Group)
9/304 (3%)
10/506 (2%)
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
Patient Selection
Main Inclusion Criteria:
Main Exclusion Criteria:
•
Proximal PE on CT (filling defect in ≥ 1
main, lobar, or segmental pulmonary
artery) AND
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Age ≥ 18 years AND
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•
•
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)
•
•
•
•
•
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
Study Overview
CT-confirmed
PE
• Symptoms ≤ 14
days
• Massive or
submassive
• Meets all
inclusion and
no exclusion
criteria
RV
enlargement
as
documented
by initial CT
• RV:LV ratio ≥
0.9
Ultrasoundfacilitated
fibrinolysis
• t-PA 1 mg/hr for
24 hours (1
device)
• t-PA 1 mg/hr for
12 hours (2
devices)
• TOTAL t-PA
Dose = 24 mg
Study Sites = 21
Total Trial Population = 150
Follow-up at 48
±6 hours after
start of the
procedure
• CT
measurement of
RV:LV ratio
• Echocardiogram
to estimate PA
systolic
pressure
Intervention
Standard Anticoagulation for PE
UFH goal PTT 40-60 sec during procedure
Catheter Placement and Treatment Based on Extent of Disease
Unilateral: 1 catheter infusing t-PA 1 mg/hour for 24 hours
Bilateral: 2 catheters infusing t-PA 1 mg/hour/catheter for 12 hours
Baseline Right Heart Catheter Measurements
Including pulmonary artery systolic pressure
Ultrasound-Facilitated, Low-Dose, Catheter-Directed Fibrinolysis
t-PA Infusion
Activation of high frequency, low power ultrasound
Monitoring in intermediate care or ICU setting
Procedure Completion
Post-Procedure Right Heart Catheter Measurements
Catheter Removal
Study Outcomes
• Primary Efficacy:
Change in core labmeasured RV/LV ratio
from baseline to 48 hours
as assessed by chest CT
• Primary Safety:
Adjudicated major
bleeding within 72 hours
of the start of the
procedure
• Secondary Efficacy:
Change in invasively
measured PA systolic
pressure from baseline to
device removal and as
estimated on 48-hour
echocardiogram
• Secondary Safety:
Adjudicated recurrent PE
or death within 30 days of
the procedure, or major
technical procedural
complications
Patients
Study Enrollment
Baseline Characteristics
Patient Demographics
Mean age ± SD, years
Mean BMI ± SD, kg/m2
Female gender , n (%)
Race/Ethnicity, n (%)
Caucasian
African American
Hispanic
Co-morbid Conditions, n (%)
Concomitant use of antiplatelet agents
Immobility within 30 days of PE
Diabetes mellitus
Previous DVT
Previous PE
N = 150
59 ± 16.1
35.6 ± 9.1
77 (51.3)
119 (79.3)
22 (14.7)
9 (6)
N = 150
52 (34.7)
45 (30)
42 (28)
30 (20)
15 (10)
Characteristics of PE
Characteristics of PE, n (%)
Duration of symptoms
≤14 days
>14 days
Any symptoms of PE
PE subtype
Submassive
Massive
Pre-procedure anticoagulation*
Intravenous unfractionated heparin
Enoxaparin
Warfarin
Other
None
*Patients could have received more than one anticoagulant.
N = 150
149 (99.3)
1 (0.7)
150 (100)
119 (79.3)
31 (20.7)
76 (50.7)
54 (36)
16 (10.7)
7 (4.7)
24 (16)
Procedural Characteristics
Procedural Characteristics
Mean dose of t-PA ± SD*, mg
Successful device placement**, n (%)
Access sites***, n (%)
Right femoral vein
Left femoral vein
Right internal jugular vein
Other
Number of devices per patient*, n (%)
0
1
2
Completed infusion of t-PA***, n (%)
23.7 ± 2.9
278 (97.5)
177 (63.7)
61 (21.9)
31 (11.2)
9 (3.2)
1 (0.7)
20 (13.3)
129 (86)
272 (97.8)
*N = 150 patients (1 patient died before devices could be placed)
**N = 285 devices attempted
***N = 278 devices placed
Outcomes: RV/LV Ratio
p < 0.0001
RV/LV Ratio
1.55
1.13
Outcomes: PA Systolic Pressure
p < 0.0001
Mean PA Systolic
Pressure (mmHg)
51.4
p < 0.0001
37.5
36.9
Massive vs. Submassive PE
p = 0.31
p = 0.61
0.51
0.5
14.3
0.43
0.4
12.6
0.3
0.2
0.1
Massive PE
0
Submassive PE
Mean
Decrease
RV/LV
Ratio
Outcomes: Modified Miller Score
Mean Modified Miller Score
p < 0.0001
22.5
15.8
Clinical Outcomes
Clinical outcomes*
Mean length of stay ± SD, days
In-hospital death, n (%)
30-day mortality**, n (%)
Serious adverse events due to device, n (%)
Serious adverse events due to t-PA, n (%)
IVC filter placed, n (%)
Major bleeding within 30 days**, n (%)
GUSTO moderate**
GUSTO severe**
Intracranial hemorrhage, n (%)
N = 150
8.8 ± 5
3 (2)
4 (2.7)
2 (1.3)
2 (1.3)
24 (16)
17 (11.4)
16 (10.7)
1 (0.7)
0 (0)
*All death, serious adverse, and bleeding events were adjudicated by an
independent safety monitor.
**N = 149 (1 patient lost to follow-up)
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.
Overcoming the Hurdle of
Intracranial Hemorrhage
Study
ICOPER
(Goldhaber SZ, et al. 1999)
PEITHO
(Meyer G, et al. 2014)
SEATTLE II
(Piazza G, et al. 2014)
Intracranial
Hemorrhage
(Fibrinolysis
Group)
9/304 (3%)
10/506 (2%)
0/150 (0%)
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.
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 “gamechanger” in treatment of high-risk PE patients.
SEATTLE II Investigators
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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.
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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)
Back-Up Slides
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 2014;129:479