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`dllculation.
`vii105, no. 11 (Mar. 19 2002)
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`I Clinician Update
`()ral Anticoagulation tor Acute (‘oi'onarv Syndromes
`Mun-.1. Iii-mum; ill); Frey/r ”.11.
`li'rilieiigl.
`.lll)_ [WNW/:7”
`I Brief Rapid Communications
`’I'reatment oI‘Amiodarone—Indueed 'I‘liyrotmieosis
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`Impression ot‘ IIV-I Reeeptor Antagonist by Plasmid DNA
`[{I'llllgaklt'tlll Hui, I151: «I u/ ..........................................
`('atheter—llased lindoni}oeardial Injection With MRI
`lx’n/m'l .l. Let/Minna .III), e! (I/
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`I“)
`
`I'CIinical Investigation and Reports
`I'rial ol‘a Distal I5mliolie Protection I)e\‘iee®
`I)Ulltl/(/ X.
`lit/i111,
`III), 17 ill ............................................. I335
`Angioeenic tiene I'herap) 'I'rial in Patients With Stable Angina
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`\"enii ietilar Res}nehroni/aiion
`It's/Ir l. Stun/i. III). ('l (I/ .............................................. [304
`I’roinsnlin and (‘oronary Heart Disease
`.]('t'
`lining ()III III). til 11/ ................................................ /.\‘//
`l.el't Ventrienlin' Ih‘modeling. MI. and Ileart I-ailnre
`()t'ltll'I-(N'. lit/til. III). ('I 11/. ........................................... {3/7
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`............... [395'
`
`Actions ol‘ Bal‘ on Ilnman l’orearm Blood Flow
`Alt/II/It’lt' /)(lii'(’,\'. I’III). NRC/3 (’1 (ll .................................. 1333
`(‘arotid Sinus I)enei‘\'ation in Humans
`cll‘l/llH'xLJ, Sin/t. All). PM), 1‘! u/....................................... IL")
`Prosthetic IIearl Valves in Dialysis Patients
`('lic/I'It'x.-l, Hermie. All). vi (4/ ............................................ [3.17)
`Risk Stratification in Brugada Syndrome
`Si/i‘irl (it
`I’I'I'HI'I', Ml). I’lil), cl (II ...................................... I343
`Renal Iiti‘eets ol‘Adenosine Antagonist and Furosemide
`Stephen S, (full/it'll, Ml), u/ 11/........................................... [3‘48
`Sympathetic AetiVity and Sur\'i\al in liSRl)
`('(il'mint' Zoom/i", Ml), cl til............................................... 1354
`
`I Basic Science Reports
`Ir'etal Atherogenesis and Made (iene lixpression®
`(Yum/in Nri/m/I'. MI). 1'! a/ ................................................. [36!)
`[{ziltixileiie Activates I’I3K1’Akt Pathway
`'liHii/imm Si/im/it'ini. Ml), I’M), ('1 u/................................ HM
`
`I’ropranolol and the I’i‘e\ention ol‘ I Ieai't Failure
`Alt/.Wl/Ill'u Hui, MI). ('I u/ ................................................ /.1’ 74
`
`
`('aripoi‘ide and l.osai‘tan in Heart I
`hire
`.ltlll /.’ /.(!(‘IIH('t'/l(’/I. MI), vi 11/ ............................................ USU
`
`I Clinical Cardiology: New Frontiers
`Diastolic IIeart I’ailui'e
`.‘llit'lltit’l lt’ [i/t', ,lll); [Hr/t I.‘
`
`/)’I'III.\'iIt‘I'I, MI) ................... / {N7
`
`I Images in Cardiovascular Medicine
`Arrliythmogenie Right Ventricular ( ‘ardiomyopathy
`./..i. iII<'( 'm/iri/i, sill). I’lil). el (ll ................................. IJ’W
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`CirculatiOn
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`
`
`'JOURNAngor :THE AMERICAN HEAnrAssocmrion.
`
`
`
`Volume 105 I Number 11
`
`March 19, 2002
`
`Circulation Electronic Pages
`
`
`Images in Cardiovascular Medicine
`Foramen Ovale and Duetus Arteriosus in a Fetus With Transposition of the
`Premature Closure of the
`Great Arteries
`Mary T. Donofrio, MD
`
`..................................................... *e65-e66
`
`Clinician Update
`
`Oral Anticoagulation for Acute Coronary Syndromes
`Marc A. Bronwer. MD; Freek W.A. Verhengt, MD, PhD .............................................. 127i)
`
`Brief Rapid Communications
`Successful Treatment of Amiodarone-Induced Thyrotoxicosis
`Faizel Osman, Ml}, MRCI’,‘ Jayne A. Franklyn, MD, PhD, FRCP; Michael C. Sheppard, PhD, FRCP;
`Michael D. Gommage, MD, I’RCP ................................................................ 1275
`Local Expression of Interleukin-l Receptor Antagonist by Plasmid DNA Improves Mortality and Decreases
`Myocardial Inflammation in Experimental Coxsackieviral Myocarditis
`Byung-Kwan Lint, MSC; Seong-Choon Choc, MD, PhD; Jae-0k Shin, BSC; Seong-Hyiin Ho, MSc;
`Jong-Mook Kim, l’hl); Senng-S/lin Yn, PhD; Snnyonng Kim, PhD; Eun—Seok Jeon, MD, PhD ................ 1278
`Catheter-Based Endomyoeardial Injection With Real-Time Magnetic Resonance Imaging
`Robert J. Lederman, MD; Michael A. Gtitttnan, MSC; Dana C. Peters, PhD: Richard 8. Thompson, PhD;
`Jonathan M. Sorger, BS; Alexander J. Dick, MD; Venkatesh K. Ramon, MD; Elliot R. McVeigh. PhD ......... 1282
`
`Clinical Investigation and Reports*
`Randomized Trial of a Distal Embolic Protection Device During Percutaneons Intervention of Saphenons
`Vein Aorta-Coronary Bypass Grafts
`Donald S. Baim, MD; Dennis Waiir, MD; Barry George, Mi); Martin B. Leon, MD; Joel Greenberg, MD;
`Donald E. Cutlip, MD; Unsal Kaya, MS; Jeffrey J. Popma, MD; Kalon K.L. Ho, MD, MSc;
`Richard E. Knntz, MD, MSc; on behalf of the Saphenous vein graft Angioplasty Free of Emboli Randomized
`(SAFER) Trial 1’1“€5fi80’()"5
`..................................................................... 1285@
`Angiogenic Gene Therapy (AGENT) Trial in Patients With Stable Angina Pectoris
`Cindy L. Grines, MD; Matthew W. Watkins, MD; Greg Helmer, MD; William Penny, MD; Jeffrey Brinker, MD;
`Jonathan D. Murmur, MD; Andrew West, MD; Jeffery J. Rade, MD; Pratt Marrott, MRCP. MSc;
`H. Kirk Hammond, MD; Robert L. Ertglcr. MD ...................................................... 1291
`Effect of Azithromycin Treatment on Endothelial Function in Patients With Coronary Artery Disease and
`Evidence of Chlamydia pneumoniae Infection
`Nikltil Pare/lure, MRCP; Emtnanouil G. Zonridakis, MD; Juan Carlos Kaski, MD, DSC, FRCP .............. 1298
`
`*Supportcd in concept as prevention of cardiovascular disease by an unrestricted gift from Merck & Co. Pfizer provides an unrestricted gift for
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`Effects of Long-Term Biventricular Stimulation for Resynchronization on Echocardiograpliic
`Measures of Remodeling
`Leslie A. Saxon, MD; Teresa De Marco, MD; Jill Schafer, MS; Kanu Chattetjee, MB; Uday N. Kutnar. Ml);
`Elyse Foster, MD; for the VIGOR Congestive Heart Failure hivestigators ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 1304
`
`Sex Differences in the Association Between Proinsulin and Intact Insulin With Coronary H ‘art Disease in
`Nondiabetic Older Adults: The Rancho Bernardo Study
`Jee-Young 0h, MD; Elizabeth Barrett-Connor, MD; Nicole M. Wedie/c, MS .............................. 1311
`
`Left Ventricular Volume Reduction by Radiofrequeney Heating of Chronic Myocardial Infarction in
`Patients With Congestive Heart Failure
`Octavio A. Vietal, MD; John R. Teerlink, MD; Efrain Gaxiola, MD; Arthur W. Wallace, MD, PhD;
`Sergio Najar, MD; David H. Camacho, MD; Augustin Gutierrez, MD; Gabriel Herrera, MD;
`Gustavo Zuniga, MD; Fausto Mercado-Rios, MD; Mark B. Ratcliffe, MD ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 1317
`
`Barium Reduces Resting Blood Flow and Inhibits Potassium-Induced Vasodilation in the Human Forearm
`Matthew Dawes, PhD, MRCP; Christine Sieniawska, BSc, MPhil;
`Trevor Delves, PhD, CChem, EurClinChem, FRSC; Rahul Dwivedi, MRCP; Philip J. Chowienezyk, FRCP;
`James M- Ritter, MA, DP/u‘l, FRCP ............................................................... 1323
`
`Long-Term Effects of Carotid Sinus Denervation on Arterial Blood Pressure in Humans
`Arthur A../. Smit, MD, PhD; Henri J.L.M. Timmers, MD; Wouter Wieling, MD, PhD; Mariette Wagenaar, MD;
`Henri A.M. Marres, MD, PhD; Jacques W.M. Lenders, MD, PhD; Gert A. van Montfrans, MD, PhD,-
`John M. Karma/«2r, PhD ....................................................................... 1329
`
`Long-Term Survival of Dialysis Patients in the United States With Prosthetic Heart Valves: Should
`ACC/AIIA Practice Guidelines on Valve Selection Be Modified?
`
`Charles A. Herzog, MD; Jennie Z. Ma, PhD; Allan J. Collins, MD ..................................... 1336
`
`Natural History of Brugada Syndrom -: Insights for Risk Stratification and Management
`Silvia G. Priori, MD, PhD; Carlo Napolltano, MD, PhD; Maurizio Gasparini, MD; Carlo Pap/tone, MD;
`Paolo Della Bella, MD; Umberto Giordano, MD; Raj/aella Bloise, MD; Carla Giustetto, MD;
`Roberto De Nan/is, MD; Massimiliano Grillo, MD; Elena Ronchetti, PhD; Giovanna Faggiano, MD;
`Jami Nasmu. BS .............................................................................. 1342
`
`BG971‘) (CVT-124), an A, Adenosine Receptor Antagonist, Protects Against the Decline in Renal Function
`Observed With Diuretic 'l‘herapy
`Stephen S. Gottliel), Ml); D. Craig Brater, MD; Ignatius Thomas, MD; Edward Havranek, MD;
`Robert Bourge, MD; Steven Goldman, MD; Farere Dyer, MI); Miguel Gomez, MD; Donald Bennett, MD;
`Barry Tic/Io, MD; Evan Beck/nan, MD; William '1'. Abraham, MD ...................................... 1348
`
`Plasma Norepincphrine Predicts Survival and Incident Cardiovascular Events in Patients With End-Stage
`Renal Disease
`Carmine Zoccali. MD; Francesca Mallamaci, MD; Saverio l’arlongo, Ml);
`Sebastiano Cutrupi; Francesco Antonio Benedetto, Ml); Giovanni 'I'ripepi; Graziella Bonanno, MI);
`Francesco Rapisarda, MD; Pasquale Fatuzzo, MD; Giuseppe Seminara, Ml);
`Alessandro Cateliotti; Benedetto Stancanelli, Ml); Lorenzo Salvatore Malatino, Ml) ______________________ [354
`
`Basic Science Reports
`
`
`Maternal Hypercholesterolemia During Pregnancy Promotes Early Atherogenesis in LDL
`Receptor—Deficient Mice and Alters Aortic Gene Expression Determined by Microarray
`Claudio Napoli, MD; Filonzena a’e Nigris, PhD; John S. Welch, BS; Federico B. Calara, I’hD;
`Robert 0. Stuart, MD; Christopher K. Glass, MI); thlf I’alinski, MD __________________________________ 1360®
`
`Nongenomic Mechanisms of Endothelial Nitric Oxide Synthase Activation by the Selective Estrogen
`Receptor Modulator Raloxifene
`Tomntaso Simoncini, MD, PhD; Andrea R. Genazzani, MD, PhD; James K. Liao, Ml) ______________________ 1368
`
`Propranolol Prevents the Development of Heart Failure by Restoring FKBPI2.6-Mediatcd Stabilization of
`Ryanodine Receptor
`Masahiro Doi, MD; Musafumi Yano, MD, PhD; Shigeki Kobayashi, Ml), PhD; Masateru Kohno, Ml);
`Takalziro Toku/zisa, MD; Shinichi Okuda, MD; Masae Suetsugu, BS; Yuhji Hisatnatsu, MD, PhD;
`Tomoko Olzkusa, MD, PhD; Michihiro Kolmo, MD, Phi); Masunori Matsuzaki, MI), PhD ___________________ 1374
`
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`Effects of Cariporide and Losartan on Hypertrophy, Calcium Transients, Contractility, and Gene
`Expression in Congestive Heart Failure
`Jun P. Lnennechen. MD: Ulrik Wislwf/j MSc, PhD; Geir Falck, MD, PhD; Dyvind Ellingsen, MD, PhD ....... 1380
`
`Clinical Cardiology: New Frontiers
`
`
`New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part I: Diagnosis, Prognosis, and
`Measurements of Diastolic Function
`Michael R. 2176. MD; Dirk L. Brutsaert, MD ........................................................ 1387
`
`Images in Cardiovascular Medicine
`
`
`Left Ventricular Involvement in Arrhythmogenic Right Ventricular Cardiomyopathy
`J.A. Mchlmn, MD, PhD; AS. John, MD; C.H. Lorenz, PhD; S. W. Davies, MD; D.J. Pennell, MD .......... 1394
`
`
`Annotated Table of Contents ........................................................... A10
`
`Classified Advertising .................................................................
`
`B1
`
`
`
`The cover figure is from the article in this issue by McCrohon et al. Figure 2. Tl-weighted turbo spin-echo images before
`the application of a fat saturation pulse over the region of interest. The arrows point to areas of fatty infiltration of the
`anterior and inferior myocardium from the epicardial surface. Fatty infiltration is confirmed by the nulling of these areas
`(black regions) using a fat saturation prepulse in the same plane. The RV free wall shows diffuse high signal consistent
`
`with fat (C). See p 1394.
`
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`Clinical Investigation and Reports
`
`Randomized Trial of a Distal Embolic Protection Device
`During Percutaneous Intervention of Saphenous Vein
`Aorto-Coronary Bypass Grafts
`Donald S. Baim, MD; Dennis Wahr, MD; Barry George, MD; Martin B. Leon, MD;
`Joel Greenberg, MD; Donald E. Cutlip, MD; Unsal Kaya, MS; Jeffrey J. Popma, MD;
`Kalon K.L. Ho, MD, MSc; Richard E. Kuntz, MD, MSc; on behalf of the Saphenous vein graft
`Angioplasty Free of Emboli Randomized (SAFER) Trial Investigators
`
`Background—Stents provide effective treatment for stenotic saphenous venous aorto-coronary bypass grafts, but their
`placement carries a 20% incidence of procedure-related complications, which potentially are related to the distal
`embolization of atherosclerotic debris. We report the first multicenter randomized trial to evaluate use of a distal embolic
`protection device during stenting of such lesions.
`Methods and Results—Of 801 eligible patients, 406 were randomly assigned to stent placement over the shaft of the distal
`protection device, and 395 were assigned to stent placement over a conventional 0.014-inch angioplasty guidewire
`(control group). The primary end point—a composite of death, myocardial infarction, emergency bypass, or target lesion
`revascularization by 30 days—was observed in 65 patients (16.5%) assigned to the control group and 39 patients (9.6%)
`assigned to the embolic protection device (P⫽0.004). This 42% relative reduction in major adverse cardiac events was
`driven by myocardial infarction (8.6% versus 14.7%, P⫽0.008) and “no-reflow” phenomenon (3% versus 9%, P⫽0.02).
`Clinical benefit was seen even when platelet glycoprotein IIb/IIIa receptor blockers were administered (61% of patients),
`with composite end points occurring in 10.7% of protection device patients versus 19.4% of control patients (P⫽0.008).
`Conclusions—Use of this distal protection device during stenting of stenotic venous grafts was associated with a highly
`significant reduction in major adverse events compared with stenting over a conventional angioplasty guidewire. This
`demonstrates the importance of distal embolization in causing major adverse cardiac events and the value of embolic
`protection devices in preventing such complications. (Circulation. 2002;105:1285-1290.)
`
`Key Words: embolism 䡲 grafting 䡲 stenosis 䡲 angioplasty 䡲 stents
`
`Catheter-based intervention in saphenous venous aorto-
`
`coronary bypass grafts carries a significant (⬇20%) risk
`of a major adverse clinical event (MACE) (predominantly
`myocardial infarction) or reduced antegrade flow (the no-
`reflow phenomenon).1 Several mechanisms have been of-
`fered, including spasm of the distal microcirculation, platelet
`clumping, and most recently, the distal embolization of pieces
`of friable lipid-rich plaque.2 Preliminary work with the
`PercuSurge GuardWire—a device for transient distal balloon
`occlusion during angioplasty or stent placement that allows
`recovery of any liberated plaque by aspiration before resto-
`ration of antegrade flow— has demonstrated consistent recov-
`ery of plaque constituents (cholesterol crystals, foam cells,
`fibrous plaque) that otherwise would have embolized into the
`myocardial bed.3 This initial experience has also suggested a
`
`reduced incidence of myocardial infarction (⬍6%) compared
`with the 20% historical rate of infarction seen without such
`distal protection.4 The Saphenous vein graft Angioplasty Free
`of Emboli Randomized (SAFER) trial was an 801-patient US
`multicenter study in which patients undergoing saphenous
`vein graft intervention were randomized to undergo either
`stenting with a conventional guidewire or stenting with the
`GuardWire distal protection device. The SAFER trial was the
`pivotal trial that led to US Food and Drug Administration
`approval in August 2001.
`
`Methods
`The primary objective of Saphenous vein graft Angioplasty Free of
`Emboli Randomized (SAFER) trial was to compare the 30-day
`clinical outcome after saphenous vein graft stenting plus GuardWire
`
`Received December 28, 2001; revision received January 31, 2002; accepted January 31, 2002.
`From the Division of Cardiovascular Diseases, Brigham and Women’s Hospital, Boston Mass (D.S.B., J.J.P., R.E.K.); Harvard Clinical Research
`Institute, Boston, Mass (D.S.B., D.E.C., U.K., K.K.L.H., R.E.K.); Riverside Hospital, Columbus, Ohio (B.G.); St Joseph’s Mercy Hospital, Ann Arbor,
`Mich (D.W.); Cardiovascular Research Foundation, Lenox Hill Hospital, New York, NY (M.B.L.); Florida Hospital, Orlando, Fla (J.G.); and Beth Israel
`Deaconess Medical Center, Boston, Mass (D.E.C., K.K.L.H.).
`Dr Leon served as a consultant to PercuSurge Corporation during the trial.
`This article originally appeared Online on February 25, 2002 (Circulation. 2002;105:r13–r18).
`Correspondence to Donald S. Baim, MD, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail dbaim@partners.org
`© 2002 American Heart Association, Inc.
`Circulation is available at http://www.circulationaha.org
`
`DOI: 10.1161/01.CIR.0000012783.63093.0C
`
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`1286
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`Circulation
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`March 19, 2002
`
`Figure 1. Diagram of the GuardWire device. A, The GuardWire is advanced from the guide catheter, through and beyond the saphe-
`nous vein graft (SVG) lesion. B, The compliant occlusion balloon at the GuardWire tip is inflated to occlude flow before the stent is
`deployed. C, After stent deployment, an Export catheter is advanced over the GuardWire and aspirated to remove stagnant column of
`blood with suspended embolic debris. D, The GuardWire balloon is deflated to restore antegrade blood flow.
`
`distal protection versus that performed over a conventional guide-
`wire (control arm). This randomized trial complied with the Decla-
`ration of Helsinki with regard to investigation in humans, was
`approved for Investigational Device Exemption by the US Food and
`Drug Administration, and was approved by the local hospital
`Institutional Review Boards at each of the investigational sites.
`
`Eligibility Criteria
`Patient candidates had a history of angina and signs of myocardial
`ischemia resulting from a target lesion ⬎50% diameter stenosis
`(angiographic visual assessment) located in the mid-portion of a
`saphenous vein graft, with a reference diameter between 3 and 6 mm.
`In the first 142 patients, the lesion could not occupy more than one
`third of the graft length. In subsequent patients, no upper limit on
`lesion length was imposed. Major exclusion criteria included (1)
`recent myocardial
`infarction with baseline elevation of cardiac
`enzymes (creatine kinase-MB fraction), (2) significantly impaired
`left ventricular function (ejection fraction ⬍25%), (3) baseline
`creatinine ⬎2.5 mg/dL (unless on long-term hemodialysis), and (4)
`planned use of an atherectomy device.
`
`Coronary Intervention
`After informed consent, patients were premedicated with aspirin
`(325 mg orally) and brought to the interventional laboratory. During
`the procedure, intravenous heparin was administered to prolong the
`activated clotting time to ⬎250 seconds. A platelet glycoprotein
`IIb/IIIa receptor blocker was used at the discretion of the operator.
`Subjects were randomized to undergo stenting performed over either
`
`a conventional 0.014-inch angioplasty guidewire or a 0.014-inch
`PercuSurge GuardWire balloon occlusion device, with randomiza-
`tion stratified by site and by whether the operator preselected IIb/IIIa
`receptor blockade.
`The series of treatments for both arms of the study involved
`optional pre-stent dilatation of the lesion, deployment of ⱖ1 stent,
`and optional post-stent dilatation (at higher pressure or with a larger
`diameter balloon). In patients assigned to the GuardWire arm (Figure
`1), the 0.014-inch hollow-core GuardWire was advanced across and
`beyond the target lesion and was attached to a proximal adaptor that
`allowed progressive inflation of the elastomeric balloon at its tip
`(range of inflated diameter, 3 to 6 mm) with dilute radiographic
`contrast until the antegrade flow of contrast within the graft was
`halted. The lumen of the GuardWire was then sealed, allowing
`removal of the adaptor and serial performance of the stent procedure
`(using the GuardWire shaft in lieu of a conventional guidewire).
`After satisfactory stent deployment, a 5F (1.7 mm) diameter aspira-
`tion catheter (Export) was advanced over the GuardWire until it lay
`just proximal to the occlusion balloon and was connected to an
`evacuated 20-cc syringe. Between 20 and 40 mL of blood was
`vigorously aspirated through this catheter before the adaptor was
`reattached and the distal occlusion balloon was deflated to restore
`antegrade flow.
`After satisfactory stent deployment, final angiograms were ob-
`tained. Standard post-stent therapy (aspirin 325 mg/d, clopidogrel
`300 mg oral load, followed by 75 mg/d for 2 to 4 weeks) was
`commenced. Serial 12-lead ECGs were performed after the proce-
`dure and daily until discharge, and blood samples for measurement
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`of serum creatine kinase (CK) and its myocardial (MB) fraction were
`collected after the procedure and every 8 hours thereafter until
`discharge.
`
`Data Collection and Core Laboratory Analysis
`Detailed case report forms were completed by the clinical coordina-
`tors at each site, monitored by independent study monitors, and
`submitted to the data-coordinating center (Harvard Clinical Research
`Institute, Harvard Medical School, Boston, Mass). Angiograms
`obtained during the procedure were submitted to the angiographic
`core laboratory (Brigham and Women’s Angiographic Core Labo-
`ratory, Boston, Mass), where they were analyzed with a computer-
`based system (Medis; Leiden, the Netherlands). The diameter of the
`reference coronary and the minimum lumen diameter of the target
`lesion were determined before the procedure, immediately after the
`procedure, and at follow-up.
`
`Study End Points and Statistical Methods
`The primary end point of the study, MACE rate at 30 days, was
`defined as the composite of death, myocardial infarction, emergent
`bypass surgery, or target vessel revascularization within 30 days of
`the index procedure. Death was defined as the occurrence of death
`from any cause. Myocardial infarction was defined as the occurrence
`of an elevated CK-MB fraction ⬎3⫻ the upper limit of normal
`(standardized to each clinical site’s normal range) in at least 1 of 3
`serial protocol-driven cardiac enzyme measurements performed
`during the first 18 to 24 hours after the index procedure or in any
`subsequent clinically driven measurement. Patients with enzymatic
`elevation were further divided into those with and without appear-
`ance of pathological Q waves on serial ECGs. A clinical events
`committee that was blinded to treatment assignment determined all
`clinical end points.
`Technical success for patients assigned to the GuardWire arm was
`defined as delivery of GuardWire system to the intended target site,
`followed by successful inflation, aspiration, and deflation according
`to the Instructions for Use. Other prespecified secondary end points
`included acute thrombosis, postprocedure flow, and vessel injury
`(distal dissection or perforation).
`The study was designed to reject the null hypothesis (ie, that there
`was no difference between the treatment groups) with a 2-tailed 5%
`level of significance and 80% power. On the basis of data from prior
`single-center vein graft intervention study,4 it was assumed that the
`30-day primary end point rate would be 16% in the control arm and
`ⱕ11% in the embolic protection arm. A group sequential analysis
`that allowed for 2 interim analyses and 1 final analysis was
`incorporated using the ␣-spending algorithm of Geller and Pocock.5
`Applying these assumptions and allowing for a 5% lost–to–
`follow-up rate,
`it was determined that 800 patients would be
`randomized, with interim analyses at 350 and 550 patients. The
`nominal probability value assigned for the 3 group sequential
`analyses was 0.014 for 350 subjects, 0.021 for 550 subjects, and
`0.030 for 800 subjects.
`All primary comparisons used the intent-to-treat principle. Con-
`tinuous variables were compared using Student’s t test if normally
`distributed and Wilcoxon rank-sum if not. Binary variables were
`compared using ␹2 with normal approximation or Fisher’s exact test
`when appropriate. A 2-tailed P value of 0.05 was considered
`significant. All statistical analyses were performed using the SAS,
`version 6.12 (SAS Institute, Cary, NC).
`
`Results
`Between June 1999 and August 2000, 801 patients were
`enrolled into the SAFER trial at 47 sites. After 492 patients
`were enrolled, the hospital discharge end point was com-
`pared. Because the difference between the 2 arms of the study
`did not reach the statistical threshold P value of 0.014, the
`trial was continued. At the time of the second interim Data
`and Safety Monitoring Committee review (after enrollment of
`692 patients),
`the required adjusted 2-sided P value
`
`Baim et al
`
`Distal Embolic Protection
`
`1287
`
`TABLE 1. Baseline Clinical Characteristics of 801 Patients
`With Saphenous Vein Graft Lesions Treated by Stenting
`Assigned to Receive GuardWire Embolic Protection or
`Conventional Guidewire
`
`Patient Characteristic
`
`GuardWire
`(n⫽406)
`68⫾10
`332 (82)
`134 (33)
`240 (61)
`46 (11)
`47.6⫾12.0
`303 (75)
`166 (41)
`156 (39)
`
`Control
`(n⫽395)
`69⫾9
`331 (84)
`133 (34)
`248 (64)
`50 (13)
`47.0⫾12.1
`299 (76)
`156 (40)
`156 (40)
`
`Age, y
`Male sex
`Diabetes mellitus
`Prior myocardial infarction
`Prior CVA/TIA
`Left ventricular ejection fraction
`CCS class III or IV
`Worsening exertional angina
`Rest angina
`No. of diseased native coronaries
`Single
`Double
`Triple
`Vein graft age, y (median
`[25th, 75th percentile])
`Values are mean⫾SD or n (%) unless otherwise indicated. CVA indicates
`cardiovascular accident; TIA, transient ischemic attack; and CCS, Canadian
`Cardiovascular Society.
`
`22 (6)
`82 (20)
`298 (74)
`10.4 (6.5, 13.1)
`
`19 (5)
`63 (16)
`311 (79 )
`10.9 (7.2, 14.6)
`
`(P⫽0.024) for GuardWire superiority over conventional
`treatment was met, and the committee recommended early
`termination of the trial on the basis of finding a significant
`benefit for the active arm. An additional 109 patients had
`been enrolled before this could be communicated to all
`investigators, and the present study analysis includes all 801
`randomized patients.
`
`Baseline Demographics
`The baseline demographics are shown in Table 1, reflecting
`the advanced age, severe angina, and multiple risk factors
`common in trials of saphenous aorto-coronary vein graft
`intervention.
`
`Angiographic Findings
`The baseline and postprocedural angiographic data are shown
`in Table 2. They are noteworthy for large graft diameter
`(mean, 3.4 mm), long lesion length (mean, 16 mm; maxi-
`mum, 79 mm), and the common presence of lesion-associated
`thrombus (39%).
`
`Procedural Details
`Stenting was performed in 848 of 875 (96.9%) lesions, using
`either balloon-expandable or self-expanding (9.6% for
`GuardWire-assigned patients and 20.4% for control patients)
`designs. The mean number of stents per lesion was 1.35 and
`1.38 in the GuardWire and control groups, respectively. Most
`involved “primary” stenting—that is, placement of the stent
`without predilatation (79.4% in the GuardWire group and
`67.7% in the control group). Postdilatation after stent deploy-
`ment was performed in 27.3% of GuardWire patients and
`40% of the control patients, using a mean balloon size of
`
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`1288
`
`Circulation
`
`March 19, 2002
`
`TABLE 2. Baseline Angiographic Characteristics of 875 Target
`Lesions in 801 Patients With Saphenous Vein Graft Lesions
`Treated by Stenting Assigned to Receive GuardWire Embolic
`Protection or Conventional Guidewire
`
`TABLE 3. Postprocedure Angiographic Characteristics of 875
`Target Lesions in 801 Patients With Saphenous Vein Graft
`Lesions Treated by Stenting Assigned to Receive GuardWire
`Embolic Protection or Conventional Guidewire
`
`Baseline Target Lesion Characteristics
`
`GuardWire
`(n⫽442)
`
`Control
`(n⫽433)
`
`Postprocedure Target Lesion
`Characteristics*
`
`GuardWire
`(n⫽442)
`
`Control
`(n⫽433)
`
`P
`
`79 (18)
`181 (42)
`173 (40)
`
`92 (21)
`196 (44)
`154 (35)
`
`Target graft coronary bypass distribution
`SVG-LAD
`SVG-LCX
`SVG-RCA
`Target vessel angiographic characteristics*
`TIMI flow
`8 (2.0)
`6 (1.5)
`0, 1
`41 (10)
`50 (12)
`2
`361 (88)
`356 (86)
`3
`163 (40)
`157 (38)
`Thrombus appearance
`143 (35)
`160 (39)
`Eccentric target lesion
`Target vessel angulation ⬎45 degrees
`24 (6)
`25 (6)
`3.42⫾0.66
`3.44⫾0.69
`Reference vessel diameter, mm
`1.08⫾0.61
`1.10⫾0.59
`Minimum lumen diameter, mm
`68.7⫾15.8
`68.1⫾15.5
`Percent diameter stenosis, %
`16.6⫾11.17
`15.6⫾9.12
`Lesion length, mm
`Values are mean⫾SD or n (%). SVG indicates saphenous vein graft; LAD, left
`anterior descending; LCX, left circumflex; and RCA, right coronary artery.
`*Angiographic core laboratory data available for 416 GuardWire and 411
`control lesions.
`
`4.2⫾0.7 mm and a mean maximum inflation pressure of
`13.4⫾4.5 atm. Residual minimum lumen diameter
`(3.22⫾0.63 mm in patients stented with the GuardWire and
`3.20⫾0.58 in control patients) and diameter stenosis
`(5.9⫾13.3% in patients stented with the GuardWire and
`6.1⫾11.3% in control patients) were similar (Table 3).
`In the GuardWire arm, technical success was achieved in
`90.1% of cases (henceforth designated as the per-protocol
`cohort). Technical failures included inability to deliver the
`GuardWire to the intended location (5.4%),
`inability to
`achieve or sustain occlusion of antegrade flow (3.2%), and
`inability to perform at
`least 20 mL of aspiration before
`deflation (1.2%). The median GuardWire occlusion time was
`388 seconds (25th and 75th percentiles, 265 and 640
`seconds).
`
`End Point Results
`There was a 6.9% absolute (42% relative) reduction in the
`30-day primary end point (9.6% for GuardWire patients
`versus 16.5% for control patients; P⫽0.004) (Figure 2 and
`Table 4). This predominantly reflects a reduction in myocar-
`dial infarctions of all magnitudes (Figure 3). In addition, rates
`of TIMI grade 3 flow were higher for the GuardWire arm
`(98%) compared with the control arm (95%; P⫽0.04; Table
`3), and the incidence of clinically evident no-reflow was
`reduced (3% versus 9%; P⫽0.001). There was no significant
`increase in subacute closure of the treated graft (1.7% for
`GuardWire versus 0.5% for conventional treatment; P⫽0.18)
`and a lower rate of perforation for the GuardWire arm (0.2%
`versus 1.5%; P⫽0.05) (Table 3).
`
`TIMI flow
`0, 1
`2
`3
`No reflow
`Angiographic distal cutoff
`No reflow or distal cutoff
`Perforation
`Angiographic dissection
`Subacute closure
`Minimum lumen diameter, mm
`Percent diameter stenosis, %
`Values are mean⫾SD or n (%).
`*Angiographic core laboratory data available for 416 GuardWire and 411
`control lesions.
`
`6 (1.5)
`3 (0.7)
`403 (98)
`14 (3)
`9 (2.2)
`20 (4.8)
`1 (0.2)
`9 (4)
`7 (1.7)
`3.22⫾0.63
`5.9⫾13.3
`
`3 (0.7)
`17 (4.2)
`389 (95)
`36 (9)
`13 (3.2)
`40 (9.7)
`6 (1.5)
`4 (1)
`2 (0.5)
`3.20⫾0.58
`6.1⫾11.3
`
`0.51
`0.001
`0.04
`0.001
`0.40
`0.02
`0.05
`0.12
`0.18
`0.56
`0.85
`
`Beyond this intent-to-treat primary end point, a per-
`protocol analysis