ultrasound assisted thrombolysis for massive and submassive pulmonary embolism scott m lilly, md phd...
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Ultrasound Assisted Thrombolysis for Massive and Submassive Pulmonary Embolism
Scott M Lilly, MD PhDInterventional Cardiology
Fellows School
August 15th, 2014
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%
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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
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− 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
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− 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
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
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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%)
Treatment 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.
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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
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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
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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