Evidence for USAT in PE Patients - Login - NMSuite · The Problems with Systemic PE Thrombolysis •In clinical practice, ... EKOS EkoSonic® Mach 4e Endovascular System. The ULTIMA
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Evidence for USAT in PE Patients
Prof Nils Kucher
University Hospital Bern
Bern, Switzerland
nils.kucher@insel.ch
nilskucher.com
Disclosure
Speaker name:
Nils Kucher
I have the following potential conflicts of interest to report:
Consulting/Honoraria: BTG, Optimed, Cook, Volcano, BSCI
Employment in industry
Stockholder of a healthcare company
Owner of a healthcare company
Other(s)
I do not have any potential conflict of interest
X
X
VTE is estimated to cause >500,000 deathsEurope every year1
1. Cohen AT et al. Thromb Haemost 2007;98:756–764; 2. Heit JA et al. Blood 2005;106:Abstract 910
An estimated 300,000 VTE-related deaths occur in the US each year2
VTE is estimated to cause at least 3 million deaths a year worldwide
VTE: third most common cardiovascular cause of death
2014 ESC Guidelines Risk-adjusted PE management algorithm
2014 ESC Guidelines Recommendations for acute phase treatment (I)
2014 ESC Guidelines Recommendations for acute phase treatment (II)
Tenecteplase(n=506)
Placebo(n=499) P value
n (%) n (%)
All-cause mortality or hemodynamic collapse within 7 days of randomization
13 (2.6) 28 (5.6) 0.015
ITT population
PEITHO: Primary efficacy outcome
1.00 0
0.23 0.44
2.00
Odds ratio
Thrombolysis superior
0.88
The PEITHO Steering Committee. N Engl J Med 2014
Tenecteplase(n=506)
Placebo(n=499) P value
n (%) n (%)
Non-intracranial bleeding
Major 32 (6.3) 6 (1.5) <0.001
Minor 165 (32.6) 43 (8.6) <0.001
ITT population The PEITHO Investigators
PEITHO: Safety outcomes (within 7 days of randomization)
Strokes by day 7 12 (2.4) 1 (0.2) 0.003
Hemorrhagic 10 1
Ischemic 2 0
PE mortality reduction from systemic thrombolysis???Meta-analysis (16 RCT, 2115 patients)
Chatterjee et al; JAMA 2014; 311: 2414-21 Mortality: RRR 47%; NNT 59
PE systemic thrombolysis: major bleeding …
Chatterjee et al; JAMA 2014; 311: 2414-21
OR 2.7 !
PE systemic thrombolysis: Intracranial hemorrhage…
Chatterjee et al; JAMA 2014; 311: 2414-21
OR 4.6 !
The Problems withSystemic PE Thrombolysis
• In clinical practice, systemic thrombolysis is withheld in up tothree quarters of patients with massive PE1
• The proportion of unstable PE patients receiving thrombolytic therapy in the United States decreased from 40% in 1999 to 23% in 20082
1ICOPER. Circulation 2006;113:577-822Am J Med. 2012;125:465-470
The evidence for mechanical interventions is poorMeta-analysis on PE catheter interventions
(35 studies)Clinical
success*
Clinical success
in studies with
>80% patients
receiving
thrombolysis
Clinical success
in studies with
<80% patients
receiving
thrombolysis
Major
complications
Minor
complications
N = 594 86% 91% 83% 2% 8%
*defined as stabilization of hemodynamic parameters, resolution of hypoxia, and survival to discharge
Kuo WT, et al. J Vasc Interv Radiol. 2009;20:1431-1440
Pharmacomechanical Thrombolysis= Local thrombolysis + mechanical intervention
AngioJet Power Pulse thombolysis + thrombectomy
(Venturi effect)
EKOS Ultrasound-assisted thrombolysis
Ultrasound assisted thrombolysis
Fibrin separation
Fibrin without Ultrasound
Fibrin With Ultrasound
Active drug deliveryby acoustic streaming
Mechanism of Action
Braaten et al. Thromb Haemost 1997; 78:1063-8.
Ultrasound delivered in:High frequency (2.2 Mhz)Low power (0.5 W per element)Pulses of varying waveforms
Ultrasound pulses
Ultrasound assisted thrombolysis
5.4 F Drug Delivery Catheter
Ultrasound Core wire
• Infusion side-hole catheter with a multielement ultrasound core• 12 cm nominal treatment zone length typically used for PE therapy
EKOS EkoSonic® Mach 4e Endovascular System
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
Hemodynamically stable patients with acute symptomatic PE UFH 80 U/kg Bolus IV, UFH continuous infusion of 18 U/kg/min
IV (max 1800 U/h)
Contrast-Enhanced Chest CT: Filling defect in at least one main or proximal lower lobe pulmonary artery
Baseline ECHO: RV/LV ratio > 1
Secondary endpoints: Mortality, recurrent PE,major & minor bleeding at 90 days
UFH IV alone(N=25 with evaluable RV/LV ratio on
echocardiograms at baseline and 24 hours)
Primary endpoint assessed by blinded core-lab: Reduction in RV/LV ratio from baseline to 24h
UFH IV + EkoSonic procedure: Ultrasound-assisted tPA of 10 mg over 15 hours per
catheter (Maximum total dose 20 ± 1 mg over 15 ± 1 hours)
(N=25 with evaluable RV/LV ratio on echocardiograms at baseline and 24 hours)
≤ 4 hours
1 cm
Measurement of subannular RV/LV ratio (apical 4-CH view)
2. Obtain center line through interventricular septum
3. Obtain tricuspid annular line at septal insertion pointof tricuspid valve, perpendicular to interventricularseptum line
4. Obtain subannular line 1 cm above and parallel to annular line
5. Obtain RV and LV dimensions on the subannular lineusing endocardial borders
6. Calculate the RV/LV ratio: RVEDD divided by LVEDD
1. Obtain an end-diastolic image defined as last available image prior to the onset tricuspid valveclosure
RVEDD LVEDD
ULTrasound Accelerated ThrombolysIs of
PulMonAry Embolism
Primary endpoint: Reduction in RV/LV ratio (echo)
0.30
0.0
0.2
0.4
0.6
Baselineto 24 hrs
Baselineto 90 days
Re
du
ctio
n in
RV
/LV
Rat
io
EKOS+Heparin
0.03
Baselineto 24 hrs
Baselineto 90 days
Heparin
P<0.0001
0.30
0.38
0.0
0.2
0.4
0.6
Baselineto 24 hrs
Baselineto 90 days
Re
du
ctio
n in
RV
/LV
Rat
io
EKOS+Heparin
0.03
0.22
Baselineto 24 hrs
Baselineto 90 days
Heparin
P<0.0001
P=0.03
Primary endpoint: Reduction in RV/LV ratio (echo)
Ultrasound-Assisted PE ThrombolysisDose Regimens
Studies N Massive PE
N (%)
Total r-tPA dose,
mg (mean ± SD)
Thrombolysis
duration, h
(mean ± SD)
Chamsuddin 2008 10 NA 21.8 24.8 ± 8.4
Lin 2009 11 2 (18) 17.2 ± 2.4 17.4 ± 5.2
Engelhardt 2011 24 5 (21) 33.5 ± 15.5 19.7 ± 8.1
Quintana 2013 10 2 (20) 18 (7-38)* 20.8 (12-49)*
Kennedy 2013 60 12 (20) 35.1 ± 11.1 19.6 ± 6.0
Engelberger 2013 52 14 (27) 21.0 ± 5.7 15.2 ± 1.7
Kucher 2013 30 0 (0) 20.8 ± 3.0 15.0 ± 1.0
Piazza 2014 150 31 (21) 23.7 ± 2.9 12 or 24
Total 347 66 (19) 24 18* Median (ranges); §pooled mean without study by Quintana et al.
Ultrasound-Assisted PE ThrombolysisClinical Outcomes
Studies N Massive PE
N (%)
Major
bleeding
N (%)
Minor
bleeding
N (%)
Mortality
3 mts
N (%)
Chamsuddin 2008 10 NA 0 (0) 2 (20) 0 (0)
Lin 2009 11 2 (18) 0 (0) 0 (0) 1 (9)
Engelhardt 2011 24 5 (21) 4 (17) 2 (8) 0 (0)
Quintana 2013 10 2 (20) 0 (0) 2 (20) 0 (0)
Kennedy 2013 60 12 (20) 1 (2) 1 (2) 4 (7)
Engelberger 2013 52 14 (27) 2 (4) 11 (21) 2 (4)
Kucher 2013 30 0 (0) 0 (0) 3 (10) 0 (0)
Piazza 2014 150 31 (21) 17 (11) N/A 4 (3)
Total 347 66 (19) 24 (6.9) 21 (10.7) 11 (3.2)
Engelberger & Kucher. Eur Heart J 2014
Ultrasound-assisted PE thrombolysis and intracranial hemorrhage (ICH)
Study ICH
(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%)
USAT REVIEW
(Engelberger, Kucher 2014)
0/197 (0%)
Non-Massive PEDefinition: stable, BP sys > 90, no shock
Massive PEDefinition: unstable, BP sys < 90, CPR, or shock
ECG, BNP, Troponin, RV/LV >1 on CT
PERT Team: Emergency Physician 181 7520; Angiologist 181 6413
Cardiologist 181 6248; CV Surgeon181 6519
Echocardiography < 90 min Emergency-Echocardiography
Negative
Low-Risk PE:
No Revascularisation
No RV Dysfunction
Conclusions
• Systemic thrombolysis carries a 2-3% risk of ICH and shouldno longer be used routinely in PE patients at intermediate risk
• In centers of excellence and with PERT teams, surgicalembolectomy and catheter-directed thrombolysis are thepreferred revascularization strategies
• Among the catheter techniques, ultrasound-assisted catheter-directed PE thrombolysis has the largest body of evidence
• Ultrasound-assisted catheter-directed PE thrombolysisrapidly reverses RV dysfunction and hemodynamic instabilityand is associated with a low risk of bleeding and mortality
Evidence for USAT in PE Patients
Prof Nils Kucher
University Hospital Bern
Bern, Switzerland
nils.kucher@insel.ch
nilskucher.com
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