Adjunctive Transcutaneous Ultrasound With Thrombolysis: Results of the PLUS (Perfusion by ThromboLytic and UltraSound) Trial

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djunctive Transcutaneous Ultrasoundith Thrombolysis

esults of the PLUS (Perfusion by ThromboLytic and UltraSound) Trial

ichael Hudson, MD, MHS,* Adam Greenbaum, MD,* Laura Brenton, BSN,*. Michael Gibson, MD, MS,† Robert Siegel, MD,‡ Lisa R. Reeves, MS,§iguel Fiol Sala, MD,� George McKendall, MD,¶ Jorge Bluguermann, MD,#ebra Echt, MD,** E. Magnus Ohman, MD,†† W. Douglas Weaver, MD*

etroit, and Ann Arbor, Michigan; Boston, Massachusetts; Los Angeles, and Santa Clara,alifornia; Palma de Mallorca, Spain; Providence, Rhode Island; Buenos Aires, Argentina;nd Durham, North Carolina

bjectives We investigated whether transcutaneous ultrasound (TUS) augments coronary thrombol-sis and achieves higher rates of Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 and ST-egment resolution in patients with ST-segment elevation myocardial infarction (STEMI).

ackground In animal coronary and peripheral artery thrombosis models, low-frequency TUSnhances and accelerates thrombolysis.

ethods In a double-blind, randomized, controlled international clinical trial, 396 patients withTEMI �6 h were randomized to thrombolysis alone or thrombolysis plus TUS. The 60 minute TIMIow grade, ST-segment resolution (primary end points) and other angiographic, electrocardio-raphic, and clinical outcomes were compared between treatment groups.

esults The trial was halted after Safety and Efficacy Monitoring Committee interim analysis thatemonstrated lack of treatment efficacy. In total, 360 patients were evaluable for angiographic, elec-rocardiographic, or clinical end points. Sixty minutes after thrombolytic administration, the propor-ion of patients achieving TIMI flow grade 3 did not differ between TUS and control groups (40.7%s. 48.5%, respectively; p � 0.10). Achievement of �50% ST-segment resolution at 60 min did notiffer between TUS and control groups (53.2% vs. 50.0%; p � 0.93). Thirty-day mortality and com-osite clinical events—death, reinfarction, recurrent ischemia, stroke, major bleed, left ventricularupture (9.7 % vs. 10.2%; p � 0.88)—did not differ between TUS and control patients.

onclusions Thrombolysis plus TUS failed to improve 60-min TIMI flow grade or ST-segment resolu-ion versus thrombolysis alone. (J Am Coll Cardiol Intv 2010;3:352–9) © 2010 by the Americanollege of Cardiology Foundation

rom the *Henry Ford Heart and Vascular Institute, Detroit, Michigan; †TIMI Core Laboratory and Data Coordinatingenter/Harvard Medical School, Boston, Massachusetts; ‡Cedars-Sinai Medical Center/UCLA School of Medicine, Los Angeles,alifornia; §STATPROBE, Inc., Ann Arbor, Michigan; �Hospital San Dureta, Palma de Mallorca, Spain; ¶Rhode Islandospital, Providence, Rhode Island; #Polyclinica Bancaria, Buenos Aires, Argentina; **Timi3 Systems, Inc., Santa Clara,alifornia; and the ††Duke Clinical Research Institute, Durham, North Carolina. The PLUS (Perfusion by ThromboLytic andltraSound) study was funded by Timi3 Systems, Inc., Santa Clara, California. Drs. Hudson, Weaver, Greenbaum, Gibson, andhman received research grant support from Timi3 Systems, Inc. Dr. Echt was an employee of Timi3 Systems, Inc. Dr. Siegel waspaid consultant to Timi3 Systems, Inc., and owned stock in the company. Drs. Hudson, Greenbaum, and Weaver and Ms. Brenton

eceived research grant support paid to the Henry Ford Coordinating Center. Dr. Gibson has received research grants from Timi3ystems, Acosphere, AstraZeneca, Aventis, Bard, Boston Scientific, Bristol-Myers Squibb, Ciba Geigy, Cor Therapeutics, Eli Lilly,enentech, Merck, PercuSurge, Inc., Pfizer, Pharmadigm, Point Biomedical, SmithKline Beecham, Sonus, and Thoratec.

anuscript received August 26, 2009; revised manuscript received November 25, 2009, accepted November 27, 2009.

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urrently used thrombolytic reperfusion regimens improveurvival in patients with acute ST-segment elevation myo-ardial infarction (STEMI) (1). This clinical benefit isargely dependent on their ability to: 1) achieve timely andomplete restoration of anterograde epicardial blood flow inhe infarct-related artery (Thrombolysis In Myocardialnfarction [TIMI] flow grade 3) (2–4); and 2) improveicrovascular or myocardial tissue level perfusion as deter-ined by ST-segment resolution, contrast echocardiogra-

hy, or TIMI perfusion grade/“blush score” (5–7). Hence,he absence of TIMI flow grade 3 and the lack of electro-ardiographic ST-segment resolution after thrombolysis aretrongly associated with death and poor outcome in patientsith STEMI (2,3,7,8).Approximately one-half of STEMI patients fail to

chieve optimal infarct artery patency and/or myocardialissue perfusion with current thrombolytic regimens (1–3).

ore aggressive antithrombotic regimens modestly increaseatency rates but are associated with more bleeding and nolear mortality benefit. Therapeutic low-frequency transcu-aneous ultrasound (TUS) is a potential adjunctive therapyo thrombolysis that might enhance coronary thrombolysisithout increased bleeding (9). In preclinical studies, the

ombination of TUS and thrombolytic agents improvesatency in coronary and peripheral artery thrombosis mod-ls compared with thrombolysis alone (9–15). Mechanisti-ally, this enhanced thrombolysis effect has been attributedo TUS effects on fibrin bundle disaggregation, acousticavitation, microstreaming, increased clot permeability tohrombolytic agents, and coronary vasodilatation (9,16–18).

In a pilot feasibility study, we earlier tested the combi-ation of TUS and thrombolysis in 25 STEMI patients andchieved TIMI flow grade 3 in 65% of patients at 90-minngiography (19). Therefore, we conducted the multicenter,andomized controlled PLUS (Perfusion by ThromboLyticnd UltraSound) trial to investigate whether TUS couldmprove the proportion of STEMI patients achieving TIMIow grade 3 and �50% ST-segment resolution 60 min afterhrombolysis.

ethods

tudy population. The PLUS trial was a randomized,ouble-blind, active-control trial conducted at 44 centers inurope, Argentina, Canada, and the U.S. (see Onlineppendix). The study was conducted according to princi-les of the Declaration of Helsinki and standards of thenternational Committee on Harmonisation Good Clinicalractice. The institutional review board at each site ap-roved the protocol, and all patients provided writtennformed consent before enrollment.

Eligible patients were 18 to 75 years of age, with onset ofTEMI symptoms within 6 h, ST-segment elevation �0.1
V in 2 contiguous electrocardiographic (ECG) leads, and w
bility to provide informed consent. Exclusion criteria wereregnancy, cardiogenic shock (systolic BP �90 mm Hg),ncontrolled hypertension (�180/110 mm Hg), left bundleranch block or pacemaker ECG rhythm, prior coronaryypass surgery, percutaneous coronary intervention (PCI)ithin past 14 days, active internal bleeding or coagulopa-

hy/bleeding diathesis, previous hemorrhagic stroke, orschemic stroke within past 1 year.tudy design and randomization. Patients who met eligibilityriteria were randomly assigned in a 1:1 ratio to: 1) thrombol-sis plus TUS, or 2) control therapy (thrombolysis plus shamltrasound transducer/therapy). Randomization was per-ormed via centralized telephone hotline that assignedatients to active versus sham transducers with sealednvelopes. Trial randomization was stratified by infarctocation (anterior vs. other), and randomization blocks of 6atients were maintained at each site.tudy interventions. Aspirin (162 to 325 mg at presentationnd daily) and unfractionated heparin (60 U/kg bolus) � 12/kg/h) or enoxaparin (30 mg IV � 1 mg/kg administeredC) were given to all patients.pen-label thrombolytic ther-

py, either reteplase/retavase orenecteplase/TNKase, was ad-inistered in both treatment

roups at full dose according tohe manufacturer’s instructionor acute STEMI. Within 5 minf thrombolytic administration,ltrasound gel and a single-useltrasound transducer was ap-lied to the anterior chest wall ashown in Figure 1A. The TUSatients received transcutaneous,

ow-frequency ultrasound therapy via the Timi3 Systemsltrasound System (Timi3 Systems, Inc., Santa Clara,alifornia) (Fig. 1B). This device delivered low-frequency

28.3 � 0.3 kHz) ultrasound at maximum power (23.0 �.4 W) over an effective radiating area of 57.6 � 5.5 cm2.coustic output was pulsed for 12-ms duration at a pulse

epetition rate of 25 Hz yielding peak temporal averagentensity of 0.12 W/cm2 and a spatial peak pulse averagentensity of 0.38 W/cm.2 Control patients were attached tohe same ultrasound generator plus a sham transducer andxperienced mild warmth and vibration to the chest wallithout therapeutic ultrasound. Ultrasound transmissionas to be delivered for 60 � 5 min unless worsening

schemia or hemodynamic compromise necessitated earlieresuscitation or angiography. Coronary angiography wasandated at 60 min after thrombolytic administration, and

ll subsequent revascularization decisions were left to thenvestigator’s discretion.tudy end points. Primary end points of the PLUS trial

Abbreviationsand Acronyms

ECG � electrocardiogram

PCI � percutaneouscoronary intervention

STEMI � ST-segmentelevation myocardialinfarction

TIMI � Thrombolysis InMyocardial Infarction

TUS � transcutaneousultrasound

ere the proportion of STEMI pati
ents achieving: 1) TIMI

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ow grade 3; and 2) �50% cumulative ST-segment reso-ution 60 min after initial thrombolytic administration.

nly angiograms and ECGs performed between 55 and 79in after thrombolytic administration and before a PCIere included in these primary end point analyses. To be

valuable for the primary end points, the transducer mustave also been placed within 10 min of thrombolytic bolusdministration and TUS continued for �40-min duration.respecified secondary end points included 60-min and0-min comparisons of combined TIMI flow grades 2 and, TIMI frame count (20,21), TIMI myocardial perfusionblush” grade (22,23), quantitative and categorical ST-egment resolution (24,25), and 30-day composite andndividual clinical outcomes. It was anticipated that someatients would have early or “rescue” PCI after infarct arteryngiography. Therefore, 90-min (80- to 100-min) angio-raphic and ECG secondary end point analyses were alsoerformed.ata collection and statistical analysis. Study data wereollected on standardized case report forms. Coronaryngiograms were forwarded to the PERFUSE Angio-raphic Core Laboratory (Boston, Massachusetts) for inde-

Figure 1. Transcutaneous Ultrasound Device

(A) Schematic diagram of transcutaneous ultrasound transducer applied topatient’s mid-chest. (B) Transcutaneous Ultrasound Generator andTransducer.

endent interpretation blinded to treatment assignment. t

he ECGs were obtained at baseline and 60, 90, and 180in after thrombolytic administration and forwarded to thearvard Clinical Research Institute ECG Core Laboratory

Boston, Massachusetts). The ST-segment resolution wasetermined with the method described by Schroeder et al.ith percentage ST-segment resolution calculated accord-

ng to formula: (� baseline ST-segment elevation ��ollow-up ST-segment elevation)/� baseline ST-segmentlevation (24,25).

Treatment groups were compared for baseline character-stics with analysis of variance and the Cochran-Mantel-

aenszel test, controlling for infarct location. Statisticalnalysis of the treatment groups for the 2 primary end pointsnd all binary angiographic, clinical, or ST-segment reso-ution outcomes were performed with logistic regression.ontinuous outcomes were analyzed with analysis of covari-

nce. The TUS was expected to improve the proportion ofatients achieving 60-min TIMI grade 3 flow (60% or mores. 45%) and �50% ST-segment resolution (55% or mores. 40%) versus control. Therefore, allowing for 15% rate ofon-evaluable patients, we sought to enroll 560 patients inhe PLUS trial to generate �80% power for both end pointsith an overall 2-sided alpha � 0.05. The Hochberg

tep-down procedure was planned for assessing overall trialignificance. All statistical analyses were performed byTATPROBE, Inc. (Ann Arbor, Michigan) with SASersion 8.2 (SAS, Cary, North Carolina). The authors hadull access to the data and take responsibility for integrity ofhe data. All authors have read and agree to the manuscripts written.

An independent Safety and Efficacy Monitoring Com-ittee collected adverse event reports, monitored patient

afety, and reviewed interim results. Interim analyses werelanned after angiographic assessment of 150 and 400atients. After the 150 patient interim analysis, the Safetynd Efficacy Monitoring Committee requested an updatedeview of all available 60-min angiographic (n � 315) andCG (n � 181) data. On the basis of this review, the Safety

nd Efficacy Monitoring Committee recommended discon-inuation of the PLUS trial in July 2003 because of lowikelihood of TUS achieving significant differences in TIMIow grade or ST-segment resolution.

esults

atient characteristics. Figure 2 depicts the overall flow oftudy participants in the PLUS trial. As shown, 391 patientseceived experimental TUS or sham therapy and are ana-yzed for safety and clinical outcomes. Three hundred sixtyatients met protocol eligibility criteria, began TUS therapyithin 10 min of thrombolytic bolus, received TUS for40-min duration, and had data available for primary or

econdary efficacy end point(s). These patients comprised
he “Efficacy Evaluable” group and were subsequently com-

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ared for baseline characteristics, angiographic results, andT-segment resolution. Due to absent data, angiograms/CGs performed outside the 55- to 79-min evaluationindow, or PCI performed before angiogram/ECG, 329atients contributed to primary end point TIMI flow gradenalysis and 266 patients contributed to the primary endoint ST-segment resolution analysis.Table 1 compares, among the 360 “Efficacy Evaluable”

atients, baseline characteristics between the TUS andontrol groups. There were no significant differences in age,ender, comorbidities, symptom duration, thrombolyticgent, baseline cardiac troponin I concentration, infarctocation, or cumulative ST-segment elevation betweenreatment groups. Investigators initiated the TUS/controlsham” therapy within 1 min of thrombolytic administrationnd continued the experimental therapy for 58 min in bothreatment groups before infarct artery angiogram. Investi-ators performed early PCI in nearly three-fourths ofatients in both groups. All 6 cases of clinically emergentescue PCI occurred in the control group.ngiographic and ST-segment resolution outcomes.igures 3 and 4 demonstrate the primary end point resultsetween TUS and control groups. There was no significant

N= 396 Randomized

(Intended enrollment = 560)

N=5 Not ITT Evaluable Device Not Applied

N= 391 Intent-to-Treat

N= 360 Efficacy Evaluable

N= 329 Evaluable TIMI Flow

At 60 min

N= 266 Evaluable ST Resolution

at 60 min

Not Efficacy Evaluable Protocol Violation (N=16)

Too much time between lytic and TUS (N=9) < 40 minutes of TUS (N=9)

N=31 Not Evaluable for TIMI Flow at 60 min N=94 Not Evaluable for ST Resolution at 60 min

Angiogram/ ECG out of window, un-interpretable ECG, Emergent PCI

Figure 2. Study Population: Flow of Study Participants Depicting PatientsEvaluable for Primary End Points

ECG � electrocardiogram; ITT � intention to treat; TIMI � Thrombolysis InMyocardial Infarction.

ifference in the proportion of patients achieving TIMI flow

rade 3 at 60 min (TUS 40.7% vs. control 48.5%, p � 0.10).here was also no significant difference in the proportion ofatients achieving �50% ST-segment resolution at 60 minTUS 53.2% vs. control 50.0%, p � 0.69). Prespecifiedecondary ECG analysis at 90 min, including patient results

Table 1. Comparison of Baseline Characteristics Between TUS andControl Treatment Groups

TUS(n � 178)

Control(n � 182) p Value

Age (yrs) 56.1 � 9.3 57.8 � 10.1 0.10

Female (%) 17.4 14.8 0.48

Prior MI (%) 13.6 13.7 0.95

Diabetes (%) 10.2 15.9 0.10

Location of infarct (%) 0.70

Anterior 36.0 37.9

Other 64.0 62.1

Baseline ST-segment elevation(cumulative, mm)

9.5 � 7.5 8.8 � 6.4 0.57

Baseline troponin I (ng/ml) 3.0 � 11.9 2.9 � 9.1 0.22

Symptom onset to lysis (min) 179.8 � 77.3 195.4 � 77.2 0.07

Lysis to TUS (min) 0.0 � 2.9 �0.1 � 2.6 0.91

TUS duration (min) 57.5 � 5.0 58.4 � 3.2 0.69

Thrombolytic agent 0.60

TNK t-PA (%) 61.8 61.0

Reteplase (%) 37.6 39.0

Infarct artery (%) 0.30

LAD 35.4 37.2

RCA 48.0 48.3

LCx 15.4 11.1

Other 1.1 3.4

Early “rescue” PCI (%) 73.4 71.3 0.59

LAD � left anterior descending coronary artery; LCx � left circumflex coronary artery;

MI � myocardial infarction; PCI � percutaneous coronary intervention; RCA � right coronary

Figure 3. Angiographic Outcomes

Analysis of Thrombolysis In Myocardial Infarction (TIMI) flow grade 60 minafter thrombolytic administration.

artery; t-PA � tissue-type plasminogen activator; TUS � transcutaneous ultrasound.

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fter PCI, demonstrated that significantly more TUS pa-ients achieved �50% ST-segment resolution (76.1% vs.9.3%, p � 0.007). Other secondary angiographic andT-segment resolution end points are shown in Table 2. Noifferences between treatment groups were present in 60-in TIMI flow grade, corrected TIMI frame count, TIMIyocardial perfusion “blush” grade, or 60-min ST-segment

esolution outcomes.linical outcomes. The PLUS trial was not designed toompare clinical outcomes between treatment groups. Nev-rtheless, the incidence of major clinical and safety out-omes are presented in Table 3 for the intent-to-treatopulation. There were no differences in the rates of death,einfarction, bleeding events, or composite adverse eventsetween treatment groups. Only the rate of cutaneous injuryas significantly increased in TUS-treated patients (4.6%s. 0.5%, relative risk: 9.1, 95% confidence interval: 1.2 to9.7, p � 0.01).

iscussion

ajor findings. In this first randomized trial of TUS plushrombolysis for STEMI, TUS failed to improve infarctrtery patency (TIMI flow grade), tissue reperfusion (ST-egment resolution at 60 min), and clinical outcomesompared with thrombolytic therapy alone. Most angio-raphic, ECG, and clinical outcomes showed no beneficialffect of TUS therapy, with the exception of improved0-min ST-segment resolution. The TUS therapy wasell-tolerated and did not did not impair patient monitor-

ng or delay transit to the catheterization lab. No reported

Figure 4. ST-Segment Resolution Outcomes

Achievement of �50% ST-segment resolution at 60 min (primary endpoint) and 90 min (pre-specified secondary end point). PCI � percutaneouscoronary intervention.

oronary artery ruptures or dissections occurred in the TUS

reatment group, and only 1 patient in the TUS treatmentroup suffered left ventricular rupture. Amongst all reporteddverse events, only minor cutaneous injury occurred morerequently in the TUS group.

Ninety minutes after thrombolysis administration, thereas a significantly greater proportion of patients achieving50% ST-segment resolution in the TUS versus control

roup (76% vs. 59%, p � 0.012), including a subset of 106atients without early PCI (84% TUS vs. 61% control, p �.029). These favorable ST-resolution outcomes should benterpreted cautiously, because only 57% of treated patientsad interpretable baseline plus 90-min ECGs, and becauseost patients had PCI performed before this ECG assess-ent. Nonetheless, these finding suggest that TUS might

avorably impact myocardial tissue perfusion and benefithrombolytic-treated patients with prolonged delays to an-iography/PCI.

Comparison groups in the PLUS trial were well-matchedor clinical characteristics, and all patients received contem-orary thrombolytic regimens. The study investigated aovel technology; yet, we were able to blind patients and

nvestigators to treatment assignment through centralizedandomization and the use of sham, nonfunctional trans-ucers. Protocol adherence was excellent, as shown bypplication of the experimental TUS device within 1 min ofhrombolytic administration and similar duration of TUSherapy (58 min) in both treatment groups. All angiographicnd ST-segment resolution determinations were generatedy core laboratories blinded to treatment assignment.rior TUS studies. During the past 30 years, researchers havenvestigated various intravascular and external ultrasound

Table 2. Secondary End Points: Comparison of Angiographic and ECGResults Between TUS and Control Groups

TUS Control p Value

Angiography evaluable, 60 min (n � 329) n � 162 n � 167

TIMI flow grade 3 40.7% 48.5% 0.10

TIMI flow grade 2/3 72.8% 76.0% 0.39

Corrected TIMI frame count �40 38.4% 44.8% 0.23

Myocardial perfusion grade 3 39.4% 34.1% 0.33

Myocardial perfusion grade 2/3 40.6% 35.3% 0.54

ECG evaluable, 60 min (n � 266) n � 126 n � 140

�50% ST-segment resolution 53.2% 50.0% 0.69

�30% “no” ST-segment resolution 34.9% 35.0% 0.70

�30%–70% “partial” ST-segment resolution 29.4% 28.6%

�70% “complete” ST-segment resolution 35.7% 36.4%

ECG evaluable, 90 min, expanded efficacy evaluablepatients, (n � 221)

n � 113 n � 108

�50% ST-segment resolution 76.1% 59.3% 0.007

�30% “no” ST-segment resolution 16.8% 26.9% 0.24

�30%–70% “partial” ST-segment resolution 33.6% 25.9%

�70% “complete” ST-segment resolution 49.6% 47.2%

ECG � electrocardiographic; TUS � transcutaneous ultrasound; TIMI � Thrombolysis In Myocar-

dial Infarction.

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nergy modalities for the purpose of recanalizing occludedessels (9). These studies largely show that therapeuticltrasound alone has less ability to restore flow to occludedessels compared with thrombolytic agents but that recan-lization is facilitated after combined thrombolytic agentlus intravascular or extraluminal ultrasound. Such researchfforts began with dissolution of thrombus in peripheralrteries and veins in animal models (11–13) and haverogressed to TUS application in canine myocardial infarc-ion (14), human peripheral arteries (25), and even humanschemic stroke (26). Iida et al. (27) have demonstrated thatUS dilates human brachial arteries with 4% to 6% in-

reases in artery diameter occurring after 5 min of TUSxposure. Siegel et al. (14) demonstrated, most pertinent tour study, that tissue plasminogen activator � TUS improved0-min TIMI flow grade versus tissue-type plasminogenctivator alone (2.4 � 1.0 vs. 0.9 � 1.4, p � 0.006) in 24 dogsith experimental left anterior descending coronary artery

nfarcts. This group additionally showed that low-frequencyltrasound improves myocardial perfusion and pH in theresence of fixed coronary artery occlusion (15). Miyamoto etl. (18) demonstrated in dogs that TUS produced directoronary artery vasodilation—yielding 21% increase in epicar-ial artery cross-sectional area within 5 min of application.easons for device failure. Adjunctive TUS failed to im-rove 60-min TIMI flow grade or ST-segment resolution inur study population, contrary to these preclinical results.ow-frequency ultrasound generators and chest wall trans-ucers have capably delivered nonionizing mechanical en-

Table 3. Secondary End Points: Comparison of Adver

Death

Reinfarction

Death or reinfarction

Cardiogenic shock

Recurrent ischemia

Stroke

Cardiac rupture/tamponade

Coronary dissection

Major bleeding

Minor bleeding

Cutaneous injury

Erythema

Pain

Bulla/epidermis disruption

Other (not specified)

Composite events/efficacy (death, reinfarction, cardiogenicshock, recurrent ischemia)

Composite events/efficacy and safety (death, reinfarction, stmajor bleed, recurrent ischemia, rupture, tamponade)

CI � confidence interval; RR � relative risk; other abbreviations as in T

rgy to occluded coronary arteries in prior animal models. s

he exact mechanism responsible for the effect of ultra-ound on thrombus dissolution, however, is not completelynown; and proposed mechanisms for clot dissolutionnclude acoustic cavitation, microstreaming, direct mechan-cal or thermal effect, and increased clot permeability toirculating thrombolytic agents (16–18). Prior experimentsf TUS in canine acute thrombotic coronary occlusionnvolved animals weighing approximately 20 kg, whereasLUS trial human subjects weighed approximately 80 kg.hus, we speculate that coronary thrombolysis was not

ugmented in the PLUS trial, because our experimentalUS device failed to deliver adequate ultrasound energy

hrough the larger mass of the human chest wall to thentracoronary thrombus. The U.S. Food and Drug Admin-stration and the International Electrotechnical Commis-ion (IEC) have not issued specific maximal power orntensity limits for human therapeutic ultrasound. Theurrently used device has spatial peak temporal averagentensity and spatial peak pulse average effective intensityhat easily comply with proposed IEC diagnostic ultrasoundimits of 3 W/cm2 and 24 W/cm2, respectively. It isnknown whether a different ultrasound frequency, pulseuration and cycle length, or power settings would haveielded different results. Increased TUS power or intensityight, however, lead to unacceptable rates of skin thermal

njury; thus additional work is needed to develop improvedltrasound technology, skin cooling measures, or adjunctiveharmacological treatments.Our negative results are likely not related to trial design,

nical Outcomes Between TUS and Control Group

TUS(n � 195)

Control(n � 196)

RR(95% CI) p Value

4.1% (8) 3.1% (6) 1.34 (0.47–3.8) 0.58

1.0% (2) 2.0% (4) 0.50 (0.09–2.7) 0.24

5.1% (10) 4.6% (9) 1.12 (0.46–2.7) 0.81

2.1% (4) 3.6% (7) 0.57 (0.17–1.9) 0.36

2.6% (5) 3.6% (7) 0.72 (0.23–2.3) 0.56

0.5% (1) 0.5% (1) 1.01 (0.06–16.0) 0.99

0.5% (1) 0.0% (0) — 0.50

0% (0) 1.0% (2) — 0.25

4.1% (8) 4.1% (8) 1.01 (0.39–2.6) 0.99

9.7% (19) 9.7% (19) 1.01 (0.55–1.8) 0.99

4.6% (9) 0.5% (1) 9.05 (1.2–70.7) 0.01

4 1 —

3 0 —

2 0 —

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7.7% (15) 7.7% (15) 1.01 (0.51–2.0) 0.99

9.7% (19) 10.2% (20) 0.95 (0.53–1.7) 0.88

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tatistical analysis, or end point selection issues. As stated in

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he preceding text, investigators adhered to the protocollosely and enrolled patients with representative STEMIlinical, ECG, and angiographic features. Primary end pointubgroup analyses showed no significant treatment benefitn patient subgroups with left anterior descending coronaryrtery infarcts or non–left anterior descending coronaryrtery infarcts, patients receiving reteplase, patients receiv-ng tenecteplase, or in patients with symptom duration �2 hersus 2 to 4 h versus �4 h. The 60 minute TIMI flow grades an accepted measure to compare thrombolytic regimens inhase II trials (28,29). Strong data also link attainment of 50%T-segment resolution at 60-min with post-STEMI mortality30–33). Anticipated rates of �50% ST-segment resolutionnd TIMI flow grade 3 in the control group closely matchedistorical outcomes and pre-study estimates. Angiographicatency and ST-segment resolution at �90 min after throm-olysis are more widely validated STEMI trial end points. Yet,e selected 60-min TIMI flow grade and ST-segment reso-

ution, because we did not want early PCI procedures to impactrimary end point results or be delayed in critically ill patients.

hether our positive 90-min ST-segment resolution resultsignify a type I statistical error or rather a late enhancedhrombolysis effect is uncertain.

onclusions

n the first randomized trial of adjunctive TUS and throm-olysis in patients with STEMI, we showed no enhancednfarct artery patency or ST-segment resolution with TUS0 min after thrombolytic administration. These negativeesults should stimulate TUS investigation in STEMIatients treated exclusively with thrombolytics and shouldncourage additional bioengineering research, device mod-fications, or combined TUS use with microbubbles/harmacologic contrast agents (34) in the future.

eprint requests and correspondence: Dr. Michael Hudson,enry Ford Hospital (K-14), 2799 West Grand Boulevard,etroit, Michigan 48202. E-mail: [email protected].

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ey Words: acute myocardial infarction � angioplasty �brinolysis � reperfusion � ultrasound.

APPENDIX

or a list of the participants in the PLUS trial, please see the online version
f this article.

Documents

Adjunctive Transcutaneous Ultrasound With Thrombolysis: Results of the PLUS (Perfusion by ThromboLytic and UltraSound) Trial