• Enhancement of thrombolysis in AMI is an unmet clinical need

• Increase the rate of reperfusion without increasing bleeding

• Reduce the time to complete reperfusion• Reduce the incidence of reocclusion and

reinfarction

  Ultrasound - Facilitated Thrombolysis

W. Douglas Weaver, M.D.Henry Ford Heart and Vascular Institute

Detroit, MI on Behalf of the PLUS Investigators

Ultrasound Mechanism of ActionUltrasound Mechanism of Action

• Reversible change to fibrin

structure• Large diameter fiber bundles (d 1)

disaggregate into a greater number of

smaller diameter fiber bundles (d 2)

• Increased number of accessible

binding sites

• Decreased flow resistance increases

fluid dispersion into clot

(Francis et al, Ultrasound Med Biol 1995;21:419

Braaten et al, Throm Haemost 1997;78:1063)

Without Ultrasound

With Ultrasound

d 1

d 2

• In vitro studies on thrombolytic agents exposed to ultrasound

• Reteplase, alteplase, tenecteplase (Centocor, Genentech)

• No effect on functional activity of the drugs (purified clot lysis assay)

• No effect on structural integrity of the molecules (SDS polyacrylamide GEL electrophoresis)

• In vivo rabbit ilio-femoral artery studies of thrombolysis and ultrasound therapy

• Experimental occlusion using sutures (Suchkova et al, Circulation 2000; 101:2296) or electric current (Luo et al, Circulation 1996; 94:775)

• Treatment with streptokinase, ultrasound, or combination

• Enhanced reperfusion using combination by Doppler flow meter (Suchkova) and angiographic patency (Luo)

In Vivo Canine Experimental AMI Studies

0%

25%

50%

75%

100%

TIMI 3 at 30 min TIMI 3 at 90 min TIMI 3 at 180 min

Angiographic Results: t-PA alone vs. t-PA + US

(Luo et al, Circulation 2001; 104:II-725)

t-PA alone

t-PA+US

26%

72%

26%

78%

21%

78%

5 19

5 19

4 19

23 32

25 32

29 32

% of Animals

p=0.003 p=0.0004 p=0.0001

Thrombolysis Augmented by Ultrasound in a Canine Model of AMI

A. Baseline left coronary angiogram and ECGB. Thrombotically-occluded LADC. Reperfusion after 20 minutes of t-PA and ultrasound

(Siegel et al, Circulation 2000; 101:2026)

Ultrasound System (Timi3 Systems, Inc.)Ultrasound System (Timi3 Systems, Inc.)

• Components

• Generator

• Transducer

• Ultrasound Energy

• Low frequency

• Low intensity

• Unfocused beam

Clinical Feasibility StudyClinical Feasibility Study

• Argentine Pilot Study • Hospital Italiano • Policlinica Bancaria• Instituto Cardiovascular de Rosario• Hospital Santojanni

• Health authority (ANMAT) and IEC approvals

• 25 pts enrolled

• ST elevation AMI within 6 hrs of symptoms 

• Thrombolytic drug: reteplase or tenectaplase

• Ultrasound treatment for 60 min

• Coronary angiography at 90 min to determine TIMI flow grade

• Serial ECG’s to determine ST-segment resolution

• In-hospital and 30-day follow-up

Clinical Feasibility Study –Clinical Feasibility Study – Protocol Protocol

HFCC Core Lab, N = 25

• Infarct-related artery• RCA in 15 pts (60%)• LAD in 9 pts (36%)• LCx in 1 pt (4%)

• Residual fixed stenosis of IRA 92%• PCI performed in 13 pts after angiography

Clinical Feasibility Study – Clinical Feasibility Study – Angiographic ResultsAngiographic Results

Clinical Feasibility Study - Clinical Feasibility Study - TIMI Flow Grade TIMI Flow Grade

4%12%

20%

64%

84%

0%

25%

50%

75%

100%

0 1 2 3 2+3

TIMI Flow Grade

13

5

1621

% of Patients

Clinical Feasibility Study – ECG Results

• ST-Segment Elevation Recovery >50%

• At 60 minutes 13/24 pts (54%)

• At 90 minutes 13/21 pts (62%)

• No Deaths, Strokes, or Re-infarctions• No Unanticipated Major Adverse Events

• Cardiac Events – enrollment to 30 days• PTCA/stent (non-urgent) 3 pts• Recurrent ischemia/ urgent PTCA/stent or CABG 3

pts

• Minor Related Adverse Events• Skin blisters 3 pts

Clinical Feasibility Study – Safety

PLUS – Perfusion by ThromboLytic

and UltraSound

• Study design• Randomized, double-blinded, controlled trial

• Standard thrombolysis alone vs. standard thrombolysis with ultrasound therapy

• 560 patients at up to 75 sites

• Standard thrombolytic agents: tenecteplase and reteplase

PLUS - Primary Objectives

• To assess whether the Timi3 Ultrasound System improves the proportion of patients achieving TIMI grade 3 flow at 60- minute angiography

and• To determine whether the Timi3 Ultrasound

System improves the proportion of patients with ST-segment resolution at 60 minutes

PLUS - Patient Population

• Inclusion criteria• Age between 18 and 75 years• Onset of AMI within 6 hours• ST-segment elevation greater or equal to 0.1

mV in two contiguous ECG leads

• Exclusion criteria• Contraindications to thrombolytic agents• Others

PLUS - Study Methods

• Patients enrolled at hospital presentation• Stratified by anterior vs. other infarct• Randomization:

• Thrombolytic and placebo ultrasound transducer• Thrombolytic and active ultrasound transducer

• Simultaneous administration of thrombolytic and ultrasound therapy

PLUS - Trial Design

3 0 -d ay fo llo w -up

H o sp ita l D isch a rge

6 0 m in . a ng iog ramS e ria l E C G 's

2 8 0 p ts

3 0 -d ay fo llo w -up

H o sp ita l D isch a rge

6 0 m in . a ng iog ramS e ria l E C G 's

2 8 0 p ts

5 6 0 p ts