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