Therapeutic Use of Ultrasound in Acute Coronary Artery Disease

Study Overview
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Brief Summary
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In acute coronary artery disease, pre-clinical studies have indicated that, during a continuous infusion of intravenous perfluorocarbon containing microbubbles, the ultrasonic power delivered from a diagnostic ultrasound transducer is capable of restoring microcirculatory flow and improving epicardial recanalization rates obtained by conventional therapy, a process known by Sonothrombolysis. The investigators proposed to examine the feasibility, safety and efficacy of such an ultrasound guided approach in 100 patients with ST segment elevation myocardial infarction (STEMI).

Detailed Description
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In acute coronary artery disease, pre-clinical studies have indicated that, during a continuous infusion of intravenous perfluorocarbon containing microbubbles, the ultrasonic power delivered from a diagnostic ultrasound transducer is capable of restoring microcirculatory flow and improving epicardial recanalization rates obtained by conventional therapy, a process known by Sonothrombolysis. Since both diagnostic ultrasound and intravenous infusions of microbubbles are a Class I indication to assess regional and global left ventricular function and risk area in patients with ST segment elevation myocardial infarction (STEMI). The investigators propose to examine the effectiveness of microvascular sonothrombolysis. A total of 100 patients with acute STEMI will be randomized to receive diagnostic ultrasound guided high mechanical index (MI) impulses in different approaches applied within and outside the risk area during a continuous infusion of intravenous 3% Definity® or placebo. The different ultrasound regimens are: Group I - a custom designed high mechanical index (MI) impulses at 4-20 usec and >1.0 MI designed for the 1.7 MHz S5-1 transducer; Group II - repeated diagnostic high MI impulses (all <2 usec pulse duration; MI=1.0 whenever very low MI perfusion imaging detected microbubbles within the microvasculature; Group III (control), where a few limited diagnostic high MI impulses (n<5 per patient) will be applied to assess myocadial perfusion before and after percutaneous coronary intervention (PCI). All patients will receive the conventional PCI approach, including 325 milligrams Aspirin, 600 milligrams Clopidogrel, and heparin bolus (5000 units), followed by primary PCI using glycoprotein 2b/3a inhibitors as anti-thrombotic agents using established protocols. Besides angiographic recanalization rates at the time of presentation to the catheterization laboratory, the patients will have a magnetic resonance exam performed at 72-96 hours post infarcton to quantify the myocardial salvagability index. Quantitative assessments of ejection fraction will be made at this time as well.Overall survival (OS), defined as the time from the start of treatment to death from any cause, will be evaluated.Comparisons between the three groups will be made on door to dilation times, survival, angiographic recanalization rates (ARR) at initial angiography, and reduction in infarct size determined by the salvagability index (SI) at magnetic resonance imaging 72-96 hours post STEMI. Left ventricular function and perfusion parameters by echocardiography will also be evaluated during, at 72-96 hours and at 6 months in all subjects.

Official Title
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Therapeutic Use of Ultrasound in Acute Coronary Artery Disease

Conditions
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Acute Myocardial Infarction

Intervention / Treatment
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* Procedure: Therapeutic ultrasound with 20 usec
* Procedure: Repeated diagnostic high mechanical index


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥30 years with STEMI with less than 12 hours of chest pain onset. Eligible for emergent PCI therapy. No contraindications or hypersensitivities to ultrasound contrast agents Exclusion Criteria: Known or suspected hypersensitivity to ultrasound contrast agent used for the study. Cardiogenic Shock. Life expectancy of less than two months or terminally ill. Known bleeding diathesis or contraindication to glycoprotein 2b/3a inhibitors, anticoagulants, or aspirin. Known large right to left intracardiac shunts or severe pulmonary hypertension. Patients who received thrombolytic therapy previously to enrollment.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group I<br>Patients with acute STEMI will receive intravenous infusion of microbubbles (3% Definity) with Therapeutic ultrasound with 20 usec: custom designed high mechanical index (MI) impulses at 4-20 usec and >1.0 MI designed for the 1.7 MHz S5-1 transducer while waiting for percutaneous coronary intervention. Treatment will continue after procedure untill complete a total of 60 minutes. | Procedure: Therapeutic ultrasound with 20 usec<br>* A custom designed high mechanical index (MI) impulses at 4-20 usec and >1.0 mechanical index designed for the 1.7 MHz S5-1 transducer<br>|
| Group II<br>Patients with acute STEMI will receive intravenous infusion of microbubbles (3% Definity) with therapeutic ultrasound with repeated diagnostic high mechanical index impulses (all <2 usec pulse duration; MI=1.0) whenever very low MI perfusion imaging detected microbubbles within the microvasculature. Treatment will be applied while patient waits for percutaneous coronary intervention. Treatment will continue after procedure untill complete a total of 60 minutes. | Procedure: Repeated diagnostic high mechanical index<br>* Repeated diagnostic high mechanical index impulses (all <2 usec pulse duration; MI=1.0) whenever very low mechanical index perfusion imaging detected microbubbles within the microvasculature<br>|
| Group III<br>Patients with acute STEMI will receive intravenous infusion of microbubbles (3% Definity) while few limited diagnostic high MI impulses (n<5 per patient) will be applied to assess myocardial perfusion before and after percutaneous coronary intervention (PCI). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Angiographic recanalization rate | Percentage of patients with acute STEMI and open artery at initial angiography (TIMI I) | At initial angiography | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Salvagability index | Percentage of myocardium with viability within the risk area obtained by magnetic ressonance imaging | 72-96 hours post infarction | 
| Overall survival | The time from the start of treatment to death from any cause | 30 days post infarction | 
| Left ventricular function and perfusion parameters | left ventricular volumes, ejection fraction, longitudinal strain, diastolic function and infarct size by myocardial contrast echocardiography | 72-96 hours and at 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Therapeutic ultrasound, Angiographic recanalization rate, Salvagability index, Sonothrombolysis