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(Circulation. 1997;95:1411-1416.)
© 1997 American Heart Association, Inc.

Articles

Analysis of Coronary Ultrasound Thrombolysis Endpoints in Acute Myocardial Infarction (ACUTE Trial)

Results of the Feasibility Phase

Uri Rosenschein, MD; Arie Roth, MD; Tovy Rassin, MD; Samuel Basan, MD; Shlomo Laniado, MD; Hylton I. Miller, MB

From the Cardiac Catheterization Laboratory, Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Israel.

Correspondence to Uri Rosenschein, MD, Catheterization Laboratory, Department of Cardiology, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv 64239, Israel.

	Abstract

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Background It has been demonstrated that therapeutic ultrasound effects ultrasound thrombolysis by selectively disrupting the fibrin matrix of the thrombus. This study was conducted to evaluate the clinical feasibility of percutaneous transluminal coronary ultrasound thrombolysis in acute myocardial infarction (AMI).

Methods and Results Consecutive patients (n=15) with evidence of anterior AMI and Thrombolysis In Myocardial Infarction (TIMI) grade 0 or 1 flow in the left anterior descending artery underwent coronary ultrasound thrombolysis. Angiographic follow-up was performed after 10 minutes and 12 to 24 hours. Ultrasound induced successful reperfusion (TIMI grade 3 flow) in 87% of the patients. Adjunct percutaneous transluminal coronary angioplasty (PTCA) after ultrasound thrombolysis produced a final residual stenosis of 20±12% as determined by quantitative coronary angiographic analysis. There were no adverse angiographic signs or clinical effects during the procedure. There was no change in the degree of flow in any of the patients at the 12- to 24-hour angiograms. During hospitalization, 1 patient had recurrent ischemia on the fifth day after the procedure, and emergent catheterization revealed occlusion at the treatment site. The patient was successfully treated with PTCA.

Conclusions These results suggest that ultrasound thrombolysis has the potential to be a safe and effective catheter-based therapeutic modality in reperfusion therapy for patients with AMI and other clinical conditions associated with intracoronary thrombosis.

Key Words: ultrasonics • thrombolysis • myocardial infarction

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
We have investigated the use of high-power, low-frequency ultrasound for transcatheter arterial recanalization. The data in experimental and clinical settings in the peripheral arteries suggested that thrombus-rich lesions may be the ideal type of lesion to be treated by therapeutic ultrasound.^{1 2} Therapeutic ultrasound was found to selectively lyse thrombi with a wide margin of safety. The ultrasound power level required to lyse thrombi is 1/20 of that required to induce arterial wall damage.³ It has been demonstrated that therapeutic ultrasound effects ultrasound thrombolysis by selective disruption of the fibrin matrix of the thrombus.^{2 3} Evaluation of coronary ultrasound thrombolysis in vitro demonstrated that therapeutic ultrasound could lyse clots rapidly, producing mostly subcapillary-sized particles and limited heat.⁴ In vivo, transluminal coronary sonication had no adverse effects.⁵

The purpose of the present study was to evaluate the feasibility of percutaneous transluminal coronary ultrasound thrombolysis in AMI, the archetypal clinical presentation of intracoronary thrombosis.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patient Population
Consecutive patients admitted to the Tel Aviv Medical Center with anterior AMI from June 1, 1995, were studied. Eligible patients showed evidence of anterior AMI defined by ischemic chest pain for <12 hours, accompanied by ST elevation 1 mm in 2 precordial leads. On angiography, there was TIMI grade 0 or 1 flow in the LAD. Exclusion criteria included one of the following clinical or angiographic findings: prior bypass surgery, previous intervention in the LAD, previous Q-wave anterior infarction, significant left main artery disease, three-vessel disease, Killip class 3, and failure to cross the lesion with the guidewire. All patients signed a written informed consent. The study was approved by the Institutional Review Board at the Tel Aviv Medical Center and the Israeli Ministry of Health.

Coronary Ultrasound Thrombolysis Protocol
The ultrasound thrombolysis device (ACULYSIS System, Angiosonics) is a 140-cm-long, solid-metal probe, ensheathed in a plastic catheter and connected at its proximal end to a piezoelectric transducer. Ultrasonic energy (45 kHz) is transmitted from the transducer as longitudinal vibrations of the probe, which direct the energy into the arterial system. The last 18 cm of the device is a three-wire flexible segment with a 1.6-mm tip designed to optimize the thrombolytic effect of ultrasound. The three-wire design of the distal segment permits the use of solid metal for optimal ultrasound transmission while still achieving the desired flexibility. This is similar to the way in which optic fibers enable effective transmission of light waves through glass while maintaining flexibility. The device fits into a 10F angioplasty guide catheter and accepts a 0.014-in guidewire through a coaxial central lumen in a "monorail" fashion. Power output and frequency at the hand piece (18 W) are controlled by an integrated computer designed to ensure constant power output at the distal tip (10-µm longitudinal displacements) under the variable loading conditions encountered during the procedure.^{4 5}

Before undergoing coronary ultrasound thrombolysis, all patients were treated with intracoronary nitroglycerin (200 µg), aspirin (250 to 325 mg chewable or IV), and heparin (15 000 U IV to obtain an ACT >300 throughout the procedure). Guiding coronary angiograms were obtained in standard fashion with the use of a 10F Judkins left guiding catheter (Sherpa, Medtronics). The lesion was crossed with a 0.014-in guidewire extra support (Advanced Cardiovascular Systems). Then, the ultrasound probe was introduced onto the guidewire and advanced into the LAD under fluoroscopy until the cavitation tip was positioned 1 to 2 mm past the proximal end of the occlusion. Sonication (18 W) was performed at 60-second intervals up to a total period of 3 minutes, the maximal sonication time per probe. To minimize risk of embolization, the lesion was crossed only after effective thrombus ablation and reperfusion were established. During sonication, the probe was either left stationary or moved slowly back and forth with a small amplitude (3 mm).

After sonication and intracoronary nitroglycerin administration (200 µg), angiograms were taken at views identical to those of the guiding angiograms. In the event of failed coronary ultrasound thrombolysis (defined as TIMI grade 0 or 1 flow), PTCA was performed.

A third set of angiograms was obtained 10 minutes after a successful coronary ultrasound thrombolysis and after intracoronary nitroglycerin administration (200 µg). On the basis of the third angiogram, PTCA was performed if there was evidence of suboptimal flow (TIMI grade 0 to 2 flow), significant residual stenosis (30%), or threatened closure. PTCA under the same conditions was limited to other lesions on the LAD. After 12 to 24 hours, another set of coronary angiograms was obtained after intracoronary nitroglycerin administration (200 µg). PTCA was performed if there was suboptimal flow (TIMI grade 0 to 2 flow), significant residual stenosis (30%), or threatened closure. During hospitalization, emergent catheterization was mandatory if symptomatic recurrent ischemia occurred, to provide objective evidence of arterial patency.

Post–Coronary Ultrasound Thrombolysis Care
After coronary ultrasound thrombolysis, patients were monitored in the coronary care unit. All were treated by intravenous nitroglycerin during the first 24 hours and with intravenous heparin (adjusted to give an APTT of 50 to 70 seconds) for the first 4 days. After the 12- to 24-hour coronary angiography, heparin was temporarily stopped, and the sheaths were removed when the APTT decreased to 55 seconds (or when ACT was 150 seconds). Patients were ambulated gradually, 24 hours after sheath removal.

During hospitalization, patients were treated by the attending physician. Mandatory oral therapy included aspirin (250 mg/d) and heparin (intravenous for the first 4 days followed by subcutaneous low-molecular-weight heparin for 2 weeks); other medical therapy was left to the discretion of the physician. There were no specific recommendations concerning angiograms, angioplasty, or bypass surgery. All clinical events were recorded. A predischarge clinical evaluation was performed. The ejection fraction was evaluated by nuclear ventriculography before patient discharge.

Angiographic Analysis
Cineangiograms were obtained with the use of a Philips DCI Angiographic System. Measurements of angiograms were made with selected cine frames at end diastole by an experienced technician using the on-line quantitative coronary angiography system. Vessel edges were determined with computerized algorithms, and luminal diameters were measured with the dye-filled guide catheter used as a reference standard. The diameters of the normal segments proximal and distal to the treated segment were averaged to determine the reference diameter. The MLD, reference diameter, and percentage of stenosis were calculated by measuring the most severe stenosis using a view without foreshortening. All angiograms were reviewed for morphological analysis by two experienced angiographers who used the morphological angiographic definitions provided in the Bypass Angioplasty Revascularization Investigation (BARI Central Radiographic Laboratory Operational Manual, unpublished data, 1989), with specific emphasis on the TIMI grade flow and the presence of the following adverse morphological features: dissection, spasm, perforation, distal embolization, and side-branch occlusion. The morphological analysis was made only by consensus.

Definitions
The flow in the infarct-related artery on the first contrast injection was graded as follows:

TIMI grade 0 (no perfusion): No flow through the obstruction.

TIMI grade 1 (minimal perfusion): The contrast material passes beyond the area of obstruction but fails to make the entire coronary bed distal to the obstruction opaque.

TIMI grade 2 (partial perfusion): The contrast material crosses the obstruction and makes the coronary bed distal to the obstruction opaque, but the rate of entry of contrast material into the vessel distal to the obstruction or its rate of clearance is reduced relative to the nonobstructed vessel.

TIMI grade 3 (complete perfusion): Normal flow and clearance as in a normal vessel.

Dissection: Either the presence of a curvilinear filling defect parallel to the vessel lumen with contrast medium outside of the vessel lumen (but within what the operator judged to be the vessel wall) persisting after passage of contrast medium into the arterial lumen or a spiral-shaped filling defect partially or totally obstructing the coronary artery lumen.

Spasm: The presence of stenosis at the site of sonication that was relieved by intracoronary nitroglycerin.

Vessel perforation: Persistent extramural collection of contrast medium with a well-defined exit port in the absence of angiographically evident dissection.

Distal embolization: A discrete luminal filling defect seen downstream of the site of sonication with or without occlusion of the distal branch.

Threatened closure: Angiographic appearance of the vessel that predicts imminent closure, as judged by the operator and the presence of one of the following four criteria: (1) dissection; (2) angiographic evidence of residual thrombus; (3) significant residual stenosis (30%); or (4) evidence of clinical ischemia (either typical angina or ECG changes).

Recurrent ischemia: Symptoms (eg, chest discomfort, pain in the arm and/or jaw, and nausea), ECG changes, or new hypotension, pulmonary edema, or murmur judged by the physician to represent myocardial ischemia, not relieved by sublingual nitroglycerin and lasting >15 minutes.

Reinfarction: A second myocardial infarction that occurred after the one for which the patient was hospitalized, as assessed by a physician on the basis of at least two of the following criteria: (1) recurrent ischemia; (2) occurrence of new ST-T–wave changes or new Q waves; (3) a second elevation of cardiac enzymes above the upper normal limit (or by an additional 20% if they already were above the upper normal limit); or (4) angiographic evidence of reocclusion of a documented infarct-related artery that was previously patent.

Target-vessel revascularization: A need for revascularization (PTCA or CABG) of the ultrasound-recanalized LAD within the time period between the coronary ultrasound thrombolysis and the follow-up appointment due to acute coronary syndrome. Revascularization indicated as a result of the coronary anatomy, defined before coronary ultrasound thrombolysis, would not qualify as target-vessel revascularization.

Severe bleeding: Bleeding was termed severe when it caused hemodynamic compromise—decompensation in the patient's blood pressure to <90 mm Hg systolic pressure—and required either blood or fluid replacement, surgical intervention, or CPR to maintain sufficient cardiac output. The compromise must have been due to the bleeding, which included intracranial, gastrointestinal, or retroperitoneal bleeding.

Bleeding: Bleeding requiring transfusion of blood but not extensive enough to lead to hemodynamic compromise.

Device success: Normalization of perfusion (TIMI grade 3 flow) without major clinical complications resulting from the coronary ultrasound thrombolysis procedure (death, ventricular fibrillation, cardiac arrest, pulmonary edema, or cardiogenic shock).

Angiographic success: Normalization of perfusion and final diameter stenosis <50% (irrespective of adjunct balloon use) without major clinical complications in the cardiac catheterization laboratory.

Clinical success: Normalization of perfusion, final diameter of the stenosis <50%, and absence of major complications in the cardiac catheterization laboratory and during the hospitalization period (death, cardiogenic shock, pulmonary edema, recurrent ischemia, reinfarction, target-vessel revascularization, stroke, or severe bleeding).

Data Collection and Analysis
The primary end point in the study was normalization of perfusion (TIMI grade 3 flow) induced by coronary ultrasound thrombolysis. Secondary end points were vessel patency (TIMI grade 3 flow) at 10 minutes and 12 to 24 hours and clinical events that occurred in the cardiac catheterization laboratory or during hospitalization. Continuous variables are expressed as mean±SD. Semiquantitative variables are expressed as median and range.

	Results

Top Abstract Introduction Methods Results Discussion References

 
During the recruitment phase for the study, 40 consecutive patients were found to be clinically eligible. Fifteen patients did not undergo cardiac catheterization because either the cardiac catheterization laboratory was unavailable within 1 hour (n=11), the patient had out-of-hospital thrombolytic therapy (n=3), or the patient refused to participate (n=1). Twenty-five patients underwent cardiac catheterization, and only 15 were angiographically eligible and treated by coronary ultrasound thrombolysis (Table). Most treated patients were middle-aged males with a high coronary risk profile; 53% were smokers, 26% had hypercholesterolemia, 26% had systemic hypertension, and 20% had a positive family history. Typically, the patients were in a good hemodynamic state, with systolic blood pressure and heart rate within the normal ranges (135±19 mm Hg, 80±13 bpm). Door-to-reperfusion time was 96±43 minutes. After failure to induce reperfusion in the first patient, the technique and auxiliary hardware were modified, but no change was made in ultrasound frequency, power, or total sonication time. The modification included changing the guiding catheter configuration from C-curve to Judkins left. The probe was held stationary with the distal tip in the thrombus (1 to 2 mm), whereas in the first patient it had been moved back and forth briskly during sonication. Furthermore, sonication intervals were extended from 30 to 60 seconds. This technique, described in "Methods," was maintained in an identical manner in the subsequent 14 patients. The failure in the first patient represents the beginning of the evolutionary iterative learning process in developing the appropriate technique for this device. The second patient failure was a result of a defect in the software driving the device. The software was updated accordingly.

View this table: [in this window] [in a new window]   Table 1. Results of Primary Ultrasound Thrombolysis in AMI

Angiographic Analysis
Coronary ultrasound thrombolysis induced normalization of perfusion (TIMI grade 3 flow) in 13 (87%) of the 15 patients (Fig 1). In all the successful cases, TIMI grade 3 flow was achieved with no adverse angiographic signs. After ultrasound thrombolysis, only 1 patient exhibited asymptomatic reocclusion at the 10-minute angiogram, and he underwent PTCA with restoration of vessel dimensions and a TIMI grade 2 flow. At the 12- to 24-hour angiograms, there was no change in the degree of flow in any of the patients. Adjunct PTCA after ultrasound thrombolysis produced excellent final vessel dimensions (residual stenosis, 20±12% diameter; MLD, 2.4±0.6 mm) with no adverse angiographic signs (Figs 2 and 3).

View larger version (27K): [in this window] [in a new window]   Figure 1. Reperfusion after coronary ultrasound thrombolysis. , Data from the first patient.

View larger version (17K): [in this window] [in a new window]   Figure 2. Percent residual stenosis, detected by quantitative coronary angiography, after coronary ultrasound thrombolysis. , Data from the first patient.

View larger version (100K): [in this window] [in a new window]   Figure 3. A representative angiogram of a patient reveals a large filling defect (arrow) at the proximal LAD with TIMI grade 1 flow at baseline (a). After sonication (1 minute, 18 W), normal flow was restored (TIMI grade 3 flow) with 33% residual stenosis (MLD=2.4 mm). Typically, there is no evidence of dissection, embolization, side-branch occlusion, spasm, or perforation (b). Adjunct balloon angioplasty resulted in an excellent final result (21% residual stenosis, MLD=2.6 mm) (c).

Clinical Events
There were no adverse clinical events (death, ventricular fibrillation, cardiac arrest, pulmonary edema, or cardiogenic shock) during the procedure. Successful reperfusion was accompanied by idioventricular rhythm in 12 (92%) of the 13 patients in whom coronary ultrasound thrombolysis was successful. During hospitalization, 1 patient had recurrent ischemia on the fifth day after the procedure, after abrupt discontinuation of heparin. Emergent catheterization revealed occlusion of the LAD at the treatment site. The patient was treated successfully with PTCA with no elevation of the creatine kinase levels. Coronary angiography after successful coronary ultrasound thrombolysis in another patient revealed diffuse lesions in the LAD and in a dominant right coronary artery. His coronary status was assessed as high risk for percutaneous treatment. The patient underwent successful CABG surgery after an uneventful hospital course. Three patients (20%) had severe congestive heart failure (NYHA class 3 or 4) during hospitalization.

Success
Device success was obtained in 13 (87%) of 15 patients, angiographic success in 13 (87%), and clinical success in 12 (80%).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this study, the feasibility of coronary ultrasound thrombolysis in AMI, the archetypal clinical manifestation of thrombus-rich lesion, was investigated for the first time. Coronary ultrasound thrombolysis was found to attain device success (TIMI grade 3 flow) in 87% of patients, angiographic success in 87%, and clinical success in 80%. Final angiographic results revealed minimal residual stenosis (20%) with no adverse morphological signs on angiography. No adverse clinical side effects were observed during sonication in the coronary tree. Adverse clinical events during hospitalization were limited to reocclusion of the infarct-related artery in only one patient (7%) and severe congestive heart failure in three patients (20%). These excellent results are probably due to the ability of ultrasound to induce rapid, effective, and selective thrombolysis with no need to cross the lesion before treatment. The skills required to operate the coronary ultrasound thrombolysis system are similar to those required for coronary balloon angioplasty. The catheter was easily delivered to the target coronary arterial segment, and precise positioning or coaxiality of the catheter was not crucial. Slight operator mispositioning did not lead to damage of the ultrasound-resistant arterial wall.

Other investigators have studied the coronary application of therapeutic ultrasound. Siegel et al⁶ published their initial clinical experience in coronary ultrasound angioplasty. Unlike our study group, their group consisted primarily of patients with chronic atherosclerotic occlusive lesions (only 3 of 19 patients had acute coronary syndromes). Ultrasound angioplasty resulted in partial arterial recanalization, with reduction in stenosis from 80±12% to 60±18%. Similarly, only partial recanalization was observed (from 94±10% to 55±23% stenosis) when ultrasound angioplasty was attempted on atherosclerotic lesions in the peripheral arteries. Hamm and coworkers⁷ recently published a case report on a patient with AMI who was successfully treated with ultrasound-assisted balloon angioplasty.

Balloon angioplasty and other percutaneous coronary interventions in the presence of intracoronary thrombus are accompanied by a high rate of abrupt closure, myocardial infarction, and death.^{8 9 10 11 12} The use of balloon angioplasty as a primary strategy for recanalization of the infarct-related artery in AMI has been studied recently in randomized trials.^{13 14} Those studies suggest that PTCA might be an effective and safe method for mechanical reperfusion in AMI. Nevertheless, in those studies, PTCA was not found to induce greater myocardial salvage or to reduce infarct size, reinfarction, or overall death rate compared with chemical thrombolysis. The randomized trials of primary PTCA in AMI supply no morphological analyses of their final angiographic results. Other investigations¹⁵ found that primary PTCA in AMI is associated with a high rate of angiographic complications; distal embolization, no reflow, and residual thrombus were found in a large proportion of the treated patients (12%, 16.6%, and 3.5%, respectively). Recent analyses^{16 17 18 19} suggest that primary PTCA might not be the best therapeutic option in certain subgroups of patients. Furthermore, failed PTCA for AMI is associated with high mortality and emergency bypass surgery.²⁰

The high prevalence of angiographically adverse signs and the high reocclusion rate after primary PTCA in AMI, up to 40% within the period of hospitalization,^{21 22 23} may explain the overall limited clinical benefit of primary PTCA in AMI despite the excellent rates of early angiographic patency.

The recently discovered limitations of thrombolytic drugs in AMI and the encouraging results from the studies on PTCA in AMI indicate the need to further explore the implementation of a device solution for reperfusion therapy in the setting of AMI.

Study Limitations
Auxiliary hardware. Currently the device requires a 10F guiding catheter. This size requirement is due to its proximal-end design. Next-generation devices will be compatible with a 7F guiding catheter.

Potential embolization. A theoretical risk of distal embolization exists in treating intracoronary clots. This risk is limited with the use of this device because there is no need to cross the lesion with the device before clot lysis. Furthermore, experimental data show that most clot debris after ultrasound thrombolysis is subcapillary in size.⁴ Indeed, in our study, reperfusion was associated with TIMI grade 3 flow, there was no angiographically defined embolization, and the no-reflow phenomenon was not observed in this small cohort of patients.

Conclusions
The clinical data from the feasibility phase of the ACUTE trial suggest that coronary ultrasound thrombolysis for reperfusion therapy in AMI has the potential to be a safe and effective catheter-based therapeutic modality in patients with AMI and other clinical conditions associated with intracoronary thrombosis, including failed thrombolysis, unstable angina, and degenerated vein grafts. Data from upcoming multicenter studies are needed to better define the clinical role for coronary ultrasound thrombolysis.

	Selected Abbreviations and Acronyms

 

ACT = activated clotting time AMI = acute myocardial infarction APTT = activated partial thromboplastin time CABG = coronary artery bypass graft LAD = left anterior descending artery MLD = minimum lumen diameter PTCA = percutaneous transluminal coronary angioplasty TIMI = Thrombolysis In Myocardial Infarction

	Acknowledgments

 
This work was supported by a grant from the Israeli Ministry of Arts and Sciences and the GSF-Forschungszenter für Unwelt und Gesundheit GmbH, Neuherberg. We thank Prof L.A. Rozenszajn for his continuous advice and helpful criticism. We are grateful to Yvonne Weiden for her editorial and secretarial support.

	Footnotes

 
Dr Rosenschein is a consultant for Angiosonics (Morrisville, NC).

Received June 11, 1996; revision received December 9, 1996; accepted December 14, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

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