Ultrasound contrast agents to facilitate sonothrombolysis in patients with acute myocardial infarction

The optimal treatment strategy in patients with acute ST-elevated myocardial
infarction (STEMI) is immediate restoration of epicardial coronary blood flow.
Thrombolytic therapy is the most widely used therapy, however, important
limitations are a relatively low recanalization rate, and hemorrhagic
complications. Currently, primary percutaneous coronary intervention (PCI) is
the treatment of choice in STEMI patients, however, its widespread use is
hampered by limited availability of specialized facilities and trained staff.
Therefore, there is a need for simpler and low-risk methods for effective
recanalization of thrombosed arteries that can be initiated early in the
disease process.
In this respect, the application of ultrasound, and ultrasound in combination
with thrombolytic agents have been investigated and were found to enhance
thrombus dissolution in vitro and in vivo. Recently, in vivo studies using
thrombo-occlusive canine and rabbit models demonstrated that ultrasound
contrast agents (UCAs) enhance this thrombus dissolving effect of ultrasound,
resulting in higher recanalization rates of occluded arteries. We hypothesize
that under influence of ultrasound, UCAs enhance dissolution of thrombus in
patients with acute ST-elevation myocardial infarction premedicated with a low
dose of alteplase, prasugrel, aspirin and heparin.

Primary objective:
Can application of diagnostic ultrasound and microbubbles enhance epicardial
coronary recanalization with a lower and safer dose of a thrombolytic agent
such as alteplase 50mg when combined with normal care consisting of prasugrel,
aspirin and heparin?

Secondary objectives:
* To investigate whether ultrasound in combination with UCAs has a beneficial
effect on echocardiographic and enzymatic infarct size in patients with acute
myocardial infarction pretreated with a low dose of alteplase, prasugrel,
aspirin and heparin

Randomized controlled single blinded multi-center study.

Immediately before treatment with primary PCI, patients presenting with an
STEMI will be randomized to undergo intravenous infusion of an UCA and
diagnostic ultrasound or saline, both for 15 minutes

Visits: This study requires four additional visits to the hospital, all other
measurements will be performed in the periprocedural period.
Blood samples: No additional measurements beside normal care.
Coronary angiography: During or immediately after ultrasound application, the
patient is catheterized and a diagnostic angiogram, and if needed primary PCI,
is performed. At the beginning of the procedure, an intravenous bolus of
heparin (5000 IU) is given. Angiography is performed by manual injection
through the contrast-filled guiding catheter, synchronized to an acoustic heart
beat signal, to enable measurement of the TIMI frame count and myocardial blush
grade prior to the start of the procedure (20).
Echocardiography: Resting echocardiography is performed minimally 24 hours
after primary PCI for assessment of global and regional wall motion. In short,
parasternal long axi, parasternal short axis, and three standard apical views
will be acquired. Three-dimensional echocardiography is performed with the HP
Ie33. Echocardiography will be repeated 6 weeks after presentation.
MRI: Patients are studied on a clinical 1.5 Tesla scanner within 2 to 9 days
after primary PCI, and for 4-month follow up. In short, the following
parameters are assessed.
Functional Imaging: ECG-gated cine SSFP (Steady State Free Precession) MR
images are obtained during repeated breath-holds in the three standard long
axis views (four-, three- and two-chamber view). Additional short axis slices
are acquired covering the entire left ventricle, to examine regional and global
left ventricular function.
Perfusion Imaging: During i.v. injection of Gd-DTPA first-pass perfusion
imaging is performed with a saturation-recovery gradient-echo pulse sequence.
Delayed contrast-enhanced images are acquired 10 minutes post-contrast with an
inversion-recovery gradient-echo pulse sequence to identify the location and
extent of myocardial infarction. The data are obtained with slice locations
identical to the functional images.