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Angiographic Results of the First Human Experience With the BiolimusA9 Drug-Eluting Stent for De Novo Coronary Lesions

Ricardo A. Costa, MDa, Alexandra J. Lansky, MDa,*, Alexandre Abizaid, MDb,Ralph Müeller, MDc, Yoshihiro Tsuchiya, MDa, Ken Mori, MDa, Ecaterina Cristea, MDa,

Martin B. Leon, MDa, J. Eduardo Sousa, MD, PhDb, Thomas Schmidt, MDc,Karl E. Hauptmann, MDd, and Eberhard Grube, MDc

This report describes angiographic findings of the first-in-human evaluation of the Bioli-mus A9 drug-eluting stent (Biolimus stent) in the treatment of noncomplex coronarylesions. In total, 120 patients with 122 de novo coronary lesions (2.75- to 4.00-mm vessels,<24-mm lesion length) were prospectively randomized in a 2:1 ratio to receive the Biolimusstent (n � 80, 82 lesions) or the control uncoated stent (n � 40). Baseline lesion andangiographic characteristics were similar between groups. At 6-month follow-up, latelumen loss was significantly decreased with the Biolimus stent in the stent (0.26 � 0.43 vs0.74 � 0.45 mm, p <0.001) and in the segment (0.14 � 0.45 vs 0.40 � 0.41 mm, p � 0.004).In-stent restenosis was 3.9% in the Biolimus stent group versus 7.7% in the control group(p � 0.40). There was no exaggerated hyperplasia at the proximal and/or distal edge of the

stent. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98:443–446)

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rug-eluting stents have been shown to decrease restenosisnd target lesion revascularization compared with metallictents (MSs) in previous randomized, clinical trials.1–4 Theiolimus A9 stent (Biosensors International, Singapore) is aovel drug-eluting stent that incorporates the S-Stent plat-orm, a thin, stainless steel, laser-cut, tubular stent with6.3% to 18.4% metal surface area and 0.0054-in struthickness. Biolimus is a sirolimus analogue5 (Figure 1) thats coated onto the S-Stent platform with a bioabsorbable,olylactic acid, polymer matrix that releases the drug�70% eluted in 30 days); subsequently the polymer isbsorbed over time locally into cells. We report the angio-raphic outcomes of the Stent Eluting A9 Biolimus Trial inuman (STEALTH) trial, the first-in-human trial compar-

ng the Biolimus A9 stent with the MS.

• • •he STEALTH trial was a prospective, randomized,linded, multicenter, safety, and feasibility trial that com-ared the Biolimus A9 drug-eluting stent (Biolimus stent)ith the control MS (S-Stent, Biosensors International) in

he treatment of de novo coronary lesions.Patients were enrolled at 3 clinical sites from Septem-

er 2003 to April 2004 after obtaining written informedonsent. Clinical inclusion criteria were age �18 years,ymptoms of angina or ischemia, and acceptable candi-

The aCardiovascular Research Foundation and Columbia Universityedical Center, New York, New York; the bInstitute Dante Pazzanese ofardiology, Sao Paulo, Sao Paulo, Brazil; the cSiegburg Heart Center,iegburg, Germany; and dBrüderkrankenhaus Trier, Trier, Germany.anuscript received October 26, 2005; revised manuscript received and

ccepted February 13, 2006.* Corresponding author: Tel: 212-851-9320; fax: 212-851-9321.

mE-mail address: alansky@crf.org (A.J. Lansky).

002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2006.02.051

acy for coronary artery bypass surgery. Angiographicriteria included de novo coronary lesions �24 mm inength, reference diameter 2.75 to 4.00 mm, stenosis 50%o 99%, and agreement to undergo all protocol-requiredollow-up examinations including angiographic fol-ow-up at 6 months. Exclusion criteria were cardiogenichock, left ventricular ejection fraction �30%, lesionsequiring �2 stents, ostial lesion location, major surgeryithin 6 weeks before planned stenting procedure, ste-osis �50% of the left main coronary artery, angio-raphic evidence of thrombus or poor distal flow at theesion site, lesion at a junction of a side branch with aiameter �2 mm, and staged procedure planned within 3onths of the index procedure.Patients selected for coronary stenting received aspirin

300-mg loading dose if not already taken and 250 mg/dayndefinitely) and clopidogrel (300-mg loading dose imme-iately and 75 mg/day for 6 months). Lesions were predi-ated with a conventional balloon equal to or smaller thanhe diameter of the reference vessel. Stents were available in.5-, 3.0-, 3.-5, and 4.0-mm diameters and in lengths of 8,4, 18, and 28 mm.

After intracoronary nitrate administration, a serial coro-ary angiogram was obtained in multiple views at baseline,fter the procedure, and 6-month follow-up. Quantitativeoronary angiography was performed using the CMS-GFTlgorithm (MEDIS, Leiden, The Netherlands). All cinean-iograms were analyzed at an independent core laboratoryCardiovascular Research Foundation Angiographic Coreaboratory, New York, New York) that was blinded to the

reatment protocol. Minimum lumen diameter and meaneference diameter, obtained from averaging 5-mm seg-

ents proximal and distal to the target lesion location, were

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444 The American Journal of Cardiology (www.AJConline.org)

sed to calculate diameter stenosis (diameter stenosis �1 � minimum lumen diameter/reference diameter] �00). Acute gain was the change in minimum lumen diam-ter from baseline to final intervention; late lumen loss washe change in minimum lumen diameter from the finalntervention to follow-up. Binary restenosis was defined as

50% diameter stenosis at follow-up and was classified asocal (�10 mm in length) or diffuse (�10 mm in length).ll quantitative measurements were performed (1) within

he stented segment, (2) spanning the stented segmentlus the 5-mm proximal and distal peristent areas, and (3)n the 5-mm proximal and distal “peristent” areas imme-iately adjacent to the stent.

The primary end point of the study was late lumen lossy quantitative angiography in the treated segment. Theecondary end point was the absence of major adverselinical events (death, myocardial infarction, coronary ar-ery bypass graft surgery, or any repeat percutaneous inter-ention procedure to the target lesion) at 30 days and 6onths.A sample of 120 patients would have 90% power to

etect a 50% decrease in late loss between study groups,ssuming a late loss of 0.80 � 0.60 mm for MSs. Data are

Figure 1. Chemical structure of the macroc

resented as mean � SD or frequencies. Statistical analyses s

ere performed with StatView 5.0 (SAS Institute, Cary,orth Carolina). A 2-tailed, unpaired Student’s t test wassed for comparisons of continuous variables. Categoricalata were compared by chi-square or Fisher’s exact tests.n-stent and in-segment restenosis rates are summarizedsing percentages or means � SDs and 95% confidencentervals. A p value �0.05 was considered statistically sig-ificant.

In total, 120 patients with 122 lesions were randomlyssigned in a 2:1 ratio to the Biolimus stent group (n � 80,2 lesions) and the MS group (n � 40). Baseline clinicalemographics have previously been reported5 and were sim-lar in the 2 groups, including hyperlipidemia (80% foriolimus vs 71.4% for MS, p � 0.34), diabetes (26.6% foriolimus vs 22.5% for MS, p � 0.66), hypertension (83.8%

or Biolimus vs 85% for MS, p �0.99), and smoking46.3% for Biolimus vs 61.5% for MS, p � 0.12). Baselineesion characteristics were also similar in the 2 groupsTable 1). Mean lesion length was 15.37 � 4.64 versus3.75 � 3.77 mm (p � 0.06), and vessel size was 2.95 �.40 versus 2.97 � 0.42 mm (p � 0.79) for the Biolimustent versus the MS, respectively. In addition, patients withhe Biolimus stent had more calcium compared with control

ctone “family” of sirolimus and analogues.

ubjects. All but 1 stent was implanted successfully (final

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445Coronary Artery Disease/Biolimus-Coated Stent for Coronary Lesions

hrombolysis In Myocardial Infarction grade 3 flow andesidual stenosis �20%); 1 patient presented with acutetent thrombosis and underwent successful reinterventionith balloon angioplasty.Angiographic data are presented in Table 2. Prepro-

edure and final angiographic measurements were similarn the 2 groups. Six-month angiographic follow-up wasvailable in 116 lesions (96.7% of the initial cohort), andatients with a Biolimus stent had larger in-stent andn-segment minimum lumen diameters and significantlyower in-stent and in-segment late lumen losses. Con-ersely, mean in-stent and in-segment diameter stenosesere lower in the Biolimus group than in the controlroup. Figures 2 and 3 show the cumulative frequencyistribution curves for in-stent and in-segment minimumumen diameters and late lumen losses. Three of 80atients (3.9%) in the Biolimus group had in-stent reste-osis (2 focal and 1 diffuse) versus 3 of 40 patients7.7%) with in-stent restenosis (2 focal and 1 diffuse) inhe control group. There was no subacute or late stent

able 1aseline angiographic characteristics

ariable Biolimus Stent Control MS p Value(n � 82) (n � 40)

oronary artery involvedLeft anterior descending 23 (28%) 17 (42.5%) 0.15Left circumflex 31 (37.8%) 12 (30%) 0.43Right 28 (34.1%) 11 (27.5%) 0.54esion locationProximal 40 (48.8%) 17 (42.5%) 0.57Mid 34 (41.5%) 19 (47.5%) 0.56Distal 6 (7.3%) 4 (10%) 0.73Ostial 0 (0%) 1 (6.7%) 0.23esion length (mm) 15.37 � 4.64 13.75 � 3.77 0.06�10 3 (3.7%) 4 (10%) 0.2210–20 64 (78%) 32 (80%) 1.00�20 15 (18.3%) 4 (10%) 0.29ccentric bend 21 (25.6%) 6 (15%) 0.25�45 3 (3.7%) 3 (7.5%) 0.39�90 0 (0%) 0 (0%) —hrombusTortuosity

0 (0%) 0 (0%) —

Any 3 (3.7%) 1 (2.5%) 1.00Moderate 3 (3.7%) 1 (2.5%) 1.00Severe 0 (0%) 0 (0%) —

alciumNone/mild 63 (76.8%) 37 (92.5%) 0.04Moderate 18 (22%) 3 (7.5%) 0.07Severe 1 (1.2%) 0 (0%) 1.00lceration 6 (7.3%) 0 (0%) 0.18neurysm 0 (0%) 0 (0%) —

ntimal flap 0 (0%) 0 (0%) —otal occlusionYes 1 (1.2%) 0 (0%) 1.00No 81 (98.8%) 40 (100%) 1.00

Values are expressed as mean � SD (median) or frequency (percentagef column total). A 2-tailed, unpaired Student’s t test was used for com-arisons of continuous variables. Categorical data were compared by chi-quare test or Fisher’s exact test.

hrombosis at follow-up in either group, and 1 aneurysm a

ormation (1.3% in the Biolimus group) in a patient wassymptomatic and not treated.

• • •

he present study was the first experience with implantationf the Biolimus A9 stent in human coronary arteries. Bioli-us (a rapamycin derivate/analogue) is a compound from the

ame macrocyclic family as sirolimus, exhibiting similar im-unosuppressive and anti-inflammatory properties. When ad-inistered directly to the vascular lumen, it shows specific

argeted effects, including decreased inflammation and sup-ression of smooth muscle cell proliferation.6

In the present analysis, which encompasses relativelyonger lesions compared with previous first-in-human ran-omized sirolimus and everolimus drug-coated stent tri-

able 2uantitative coronary angiographic results

ariable Biolimus Stent Control MS p Value(n � 82) (n � 40)

efore procedureReference diameter (mm) 2.95 � 0.40 2.97 � 0.42 0.79Minimum lumen

diameter (mm)1.02 � 0.27 1.07 � 0.28 0.30

Diameter stenosis 65.5 � 7.8% 64.1 � 7.7% 0.34inal procedureReference diameter (mm) 3.05 � 0.37 3.02 � 0.41 0.70In stent

Minimum lumendiameter (mm)

2.89 � 0.37 2.92 � 0.33 0.68

Diameter stenosis 4.6 � 9.7% 2.6 � 8.9% 0.28Acute gain (mm) 1.88 � 0.38 1.85 � 0.31 0.67

In segmentMinimum lumen

diameter (mm)2.48 � 0.38 2.48 � 0.41 0.93

Diameter stenosis 18.6 � 7.7% 18.1 � 8.0% 0.71Acute gain (mm) 1.47 � 0.41 1.41 � 0.38 0.43

ollow-upReference diameter (mm) 3.00 � 0.37 2.99 � 0.43 0.82In stent

Minimum lumendiameter (mm)

2.64 � 0.50 2.18 � 0.56 �0.001

Diameter stenosis 11.9 � 14.6% 27.4 � 13.9% �0.001Late loss (mm) 0.26 � 0.43 0.74 � 0.45 �0.001Restenosis 3 (3.9%) 3 (7.7%) 0.40

In segmentMinimum lumen

diameter (mm)2.34 � 0.45 2.08 � 0.51 0.01

Diameter stenosis 22.0 � 12.1% 30.1 � 11.9% �0.001Late loss (mm) 0.14 � 0.45 0.40 � 0.41 0.004Restenosis 3 (3.9%) 3 (7.7%) 0.40

Proximal edgeLate loss (mm) 0.10 � 0.25 0.17 � 0.32 0.23Restenosis 0 (0%) 0 (0%) —

Distal edgeLate loss (mm) 0.08 � 0.28 0.10 � 0.36 0.73Restenosis 0 (0%) 0 (0%) —

Values are expressed as mean � SD (median) or frequency (percentagef column total). A 2-tailed, unpaired Student’s t test was used for com-arisons of continuous variables. Categorical data were compared by chi-quare test or Fisher’s exact test.

ls,3,4,7 late lumen loss was significantly decreased by 65%

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nd restenosis occurred in only 3.9% with the Biolimus-oated stent, thus supporting the effectiveness of this devicen decreasing neointimal hyperplasia. Importantly, in theroximal and distal peristent areas, there was no evidence ofny increased peristent hyperplasia with the Biolimus stent.

Late lumen loss, a surrogate of neointimal proliferation,as become 1 of the most sensitive and operator-indepen-ent angiographic measurements of the effect of drug-elut-ng stents. As is the case in the STEALTH trial, the late lossnd point allows studies with small samples to detect po-entially important therapeutic differences. Whether the dif-erence in late loss translates into clinically meaningfulutcomes of decreased restenosis or lesion revascularizationill require further evaluation. In the STEALTH trial, therimary end point of late loss was achieved, although there

Figure 2. Cumulative frequency distribution curves fo

igure 3. In-stent and in-segment late losses at 6-month follow-up with theiolimus stent (white bars) versus the MS (black bars).

as no significant effect on restenosis, suggesting the prom-

se of this new technology for the prevention of restenosis.here were no obvious safety concerns, and the singleneurysmal formation found at follow-up had no clinicalmpact. A larger efficacy trial is planned.

. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M,Colombo A, Schuler G, Barragan P, Guagliumi G, et al. A randomizedcomparison of a sirolimus-eluting stent with a standard stent for coro-nary revascularization. N Engl J Med 2002;346:1773–1780.

. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT,Turco M, Caputo R, Bergin P, Greenberg J, et al. A polymer-based,paclitaxel-eluting stent in patients with coronary artery disease. N EnglJ Med 2004;350:221–231.

. Grube E, Sonoda S, Ikeno F, Honda Y, Kar S, Chan C, Gerckens U,Lansky AJ, Fitzgerald PJ. Six- and twelve-month results from firsthuman experience using everolimus-eluting stents with bioabsorbablepolymer. Circulation 2004;109:2168–2171.

. Costa RA, Lansky AJ, Mintz GS, Mehran R, Tsuchiya Y, Negoita M,Gilutz Y, Nikolsky E, Fahy M, Pop R, et al. Angiographic results of thefirst human experience with the everolimus-eluting stents for the treat-ment of coronary lesions (the FUTURE I trial). Am J Cardiol 2005;95:113–116.

. Grube E, Hauptmann KE, Buellesfeld L, Lim V, Abizaid A. Six-monthresults of a randomized study to evaluate safety and efficacy of aBiolimus A9� eluting stent with a biodegradable polymer coating.Eurointervention 2005;1:53–57.

. Kar S, Aragon J, Tio F, Betts R, Shulze J, Reiver S, Savage D, Grant G,Kimchi E, Eigler N, Litvack F. Biolimus A9: a new rapamycin deriv-ative developed for stent applications inhibits intimal proliferation in aporcine model. Am J Cardiol 2004;94(suppl 6A):151E.

. Sousa JE, Costa MA, Abizaid A, Abizaid AS, Feres F, Pinto IMF,Seixas AC, Staico R, Mattos LA, Sousa AGMR, et al. Lack of neoin-timal proliferation after implantation of sirolimus-coated stents in hu-man coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2001;103:192–

-stent and (B) in-segment minimum lumen diameters.

195.