Title: A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II)
1A 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
2Acute 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
3Increased RV/LV Ratio on CT and PE-Related
Mortality
Trujillo-Santos J, et al. J Thromb Haemost
201311 1823-1832
4Intracranial 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)
5Objectives
- 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
6Patient 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
7Study Overview
Study Sites 21 Total Trial Population 150
8Intervention
Monitoring in intermediate care or ICU setting
9Study 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
10Study Enrollment
Patients
11Baseline 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)
12Characteristics 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.
13Procedural 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
14Outcomes RV/LV Ratio
p lt 0.0001
1.55
1.13
RV/LV Ratio
15Outcomes PA Systolic Pressure
p lt 0.0001
p lt 0.0001
51.4
37.5
36.9
Mean PA Systolic Pressure (mmHg)
16Massive vs. Submassive PE
p 0.31
p 0.61
0.51
14.3
0.43
12.6
17Outcomes Modified Miller Score
p lt 0.0001
22.5
15.8
Mean Modified Miller Score
18Clinical 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)
19Discussion
- 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.
20Overcoming 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)
21Limitations
- 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.
22Conclusions
- 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.
23SEATTLE 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)
24Back-Up Slides
25Rationale 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