Trial VignettesContemporary trials 3: DES

Angela Hoye

Castle Hill Hospital, Hull

RESOLUTE

MEDISTRA

ABSORB

Conflicts of interest

• Speaker honorarium: Cordis

• Advisory board panel: Eli Lilly

Abbott Vascular

RESOLUTE • Multicenter study, n=130, PI Prof Meridith

• The Endeavor Resolute stent (Medtronic) retains 3 components of Endeavor

Driver Cobalt Chromium StentDriver Cobalt Chromium Stent

Endeavor Delivery SystemEndeavor Delivery System

Zotarolimus Antiproliferative DrugZotarolimus Antiproliferative Drug

Extended drug-elution

The BioLinx Polymer SystemThe BioLinx Polymer System

Hydrophilic

Hydrophobic

Zotarolimus

Hydrophilic polymer: Polyvinyl pyrrolidinone (PVP) for initial drug burst and enhanced biocompatibility

Hydrophobic polymer: based upon hydrophobic butyl methacrylate (C10) for combining with zotarolimus and uniform drug dispersion

Combination polymer: hydrophobic hexyl methacrylate, hydrophilic vinyl pyrrolidinone and vinyl acetate (C19) to support delayed drug elution and biocompatibility

Hydrophilic polymer: Polyvinyl pyrrolidinone (PVP) for initial drug burst and enhanced biocompatibility

Hydrophobic polymer: based upon hydrophobic butyl methacrylate (C10) for combining with zotarolimus and uniform drug dispersion

Combination polymer: hydrophobic hexyl methacrylate, hydrophilic vinyl pyrrolidinone and vinyl acetate (C19) to support delayed drug elution and biocompatibility

Extended in vivo elution kinetics with stent drug content exhausted by 180 daysExtended in vivo elution kinetics with stent drug content exhausted by 180 days

Carter et al TCT2006Carter et al TCT2006

Endeavor Resolute Elution

Endeavor Resolute Efficacy

DRIVER CONTROLDRIVER

CONTROLENDEAVOR RESOLUTEENDEAVOR RESOLUTE

ENDEAVORRESOLUTE

Significant inhibition of neointimal development compared to Driver controls

Significant inhibition of neointimal development compared to Driver controls

Carter et al TCT2006Carter et al TCT2006

28 day results in porcine coronary artery

Single De Novo Native Coronary Artery LesionsLesion Length: 14-27mm

Stent Diameters: 2.5, 3.0, 3.5mmStent Lengths: 18, 24, 30mm (8/9mm bailout)

Drug Dose: 1.6 g/mm2 stent surface areaAntiplatelet therapy for 6 months

Pre-dilatation required

130 Patients (includes 30 PK Sub-Study Patients)12 Sites (New Zealand and Australia)

Endeavor Resolute Stent

Clinical/MACE

Angio/IVUS30d 6mo 4 yr3yr2yr9mo 12mo 5 yr

Primary Endpoint: Late lumen loss (in-stent) at 9 months by QCA

Secondary Endpoints: MACE at 30 days, 6, 9 and 12mths and IVUS and

angiographic parameters at 9mths

9 month results will be compared to ENDEAVOR II DES cohort

30 pt Subset: 4mth MACE and angiographic, IVUS parameters

Primary Endpoint: Late lumen loss (in-stent) at 9 months by QCA

Secondary Endpoints: MACE at 30 days, 6, 9 and 12mths and IVUS and

angiographic parameters at 9mths

9 month results will be compared to ENDEAVOR II DES cohort

30 pt Subset: 4mth MACE and angiographic, IVUS parameters

4mo

Clinical Trial Design

N=30 N=100

Patient Demographics

Male 75.4% (98/130)

Age 61 + 10yrs (130)

Prior MI 45.7% (59/129)

Prior PCI 18.5% (24/130)

Diabetes Mellitus 17.7% (23/130)

Insulin Dependent 2.3% (3/130)

Unstable Angina 29.7% (38/128)

Hyperlipidemia 94.6% (123/130)

Current Smoker – within last 30 days

22.3% (29/130)

Procedural Results

Device success 99.2%

Procedure success 96.2%

Lesion Length 15.56 + 6.27 mm

LAD 34.4% (45/131)

B2/C Lesions 82.4% (108/131)

Lesion success <50% residual in-segment % dsDevice success <50% residual in-segment % ds with assigned stentProcedure success <50% residual in-segment % ds & without 30-day MACE

Lesion success <50% residual in-segment % dsDevice success <50% residual in-segment % ds with assigned stentProcedure success <50% residual in-segment % ds & without 30-day MACE

130 pts/131 lesionsEntire patient cohort

Entire patient cohort n = 130

MACE (%)MACE (%) 3.8 3.8 (5/130) (5/130)

DeathDeath 00 (0/130) (0/130)

Q-Wave MIQ-Wave MI 00 (0/130) (0/130)

Non Q-Wave MINon Q-Wave MI 3.83.8 (5/130)(5/130)

Emergent CABGEmergent CABG 00 (0/130) (0/130)

TLRTLR 00 (0/130) (0/130)

TL-CABGTL-CABG 00 (0/130) (0/130)

TL-PCITL-PCI 00 (0/130) (0/130)

TVR (non-TL) (%)TVR (non-TL) (%) 00 (0/130) (0/130)

Stent Thrombosis (%)Stent Thrombosis (%) 00 (0/130) (0/130)

Clinical Results to 30 daysClinical Results to 30 days

Angiographic results

Subset n=30 In-stent In-segment

RVD (mm)RVD (mm) 2.90±0.382.90±0.38

Lesion Length (mm)Lesion Length (mm) 15.1615.16++5.385.38

MLD (mm) preMLD (mm) pre 0.830.83++0.340.34

postpost 2.81±0.362.81±0.36 2.43±0.452.43±0.45

Acute GainAcute Gain 1.98±0.451.98±0.45 1.61±0.591.61±0.59

MLD (mm) 4 mo f/uMLD (mm) 4 mo f/u 2.68±0.392.68±0.39 2.38±0.402.38±0.40

Late Loss (mm)Late Loss (mm) 0.12±0.26 0.12±0.26 0.05±0.20 0.05±0.20

Late Loss IndexLate Loss Index 0.060.06++0.170.17 0.010.01++0.180.18

% DS% DS 7.18±7.867.18±7.86 17.74±7.57 17.74±7.57

ABR (%)ABR (%) 00 00

IVUS Volumetric ResultsSubset n=30Subset n=30 Post ProcedurePost Procedure 4 mo Follow up4 mo Follow up

EEM VolumeEEM Volume 345.5 345.5 ++ 110 mm 110 mm33 337.5 337.5 ++ 88.1 mm 88.1 mm33

Stent VolumeStent Volume 170.7 170.7 ++ 58.8 mm 58.8 mm33 167 167 ++ 44.8 mm 44.8 mm33

Neointimal VolumeNeointimal Volume 0.42 0.42 ++ 1.15 mm 1.15 mm33 3.72 3.72 ++ 4.21 mm 4.21 mm33

Post Stent Follow up

6.7 ± 1.66.7 ± 1.6 6.8 ± 1.76.8 ± 1.7

00

P=NSP=NS

(mm

2)

(mm

2)

22

66

44

881010

IVUS Cross-sectional area results: (serial IVUS (2D & 3D analysis, n=29)

Conclusions

• Excellent rate of device, lesion and procedural success

• Low clinical adverse event rate at 30 days

• The angiographic and IVUS results observed in the 4 month subset demonstrated low late loss, and minimal neointimal hyperplastic in-growth

• Single center registry of “real world” cases

• PI Dr Santoso, Medistra Hospital, Jakarta

Platform: Platform: S-Stent S-Stent Strut thickness 0.0047”Strut thickness 0.0047”

Drug :Drug :SirolimusSirolimus

Carrier :Carrier :BiodegradableBiodegradable PLA polymerPLA polymer

EXCELEXCELJW JW

TechnologiTechnologieses

Medistra Excel Drug-ElutIng Stent TRiAl

40 ％ of Sirolimus released in an initial 24 h, followed by a constant slow release (3-6

months)Lower cost: $1,200

28-day preclinical study results

without Sirolimus with Sirolimus

Medistra Excel Drug-ElutIng Stent TRiAl

Single center, prospective, observational study (2004-06)Single center, prospective, observational study (2004-06)

Study Study NOTNOT sponsored by the company sponsored by the company

Inclusions: Inclusions: All comers who are candidates for PCI All comers who are candidates for PCI

(“real world cases”)(“real world cases”)

Exclusions:Exclusions: Contraindications to anti-plateletsContraindications to anti-platelets Patients with short life expectancy & serious Patients with short life expectancy & serious

concomitant disease (advanced cancer, etc)concomitant disease (advanced cancer, etc) Lack of patient’s consentLack of patient’s consent

Medistra Excel Drug-ElutIng Stent TRiAl

Primary End-Point: TLR at 6 and 12 months

Secondary End-Points: 6-month in-segment restenosis rate

In-segment late loss

Major Adverse Cardiac Events (MACE):

Death, QMI, NQMI, & / or TLR

QCA analysisQCA analysis was done by an independent core laboratory was done by an independent core laboratory(National Heart Centre - Singapore)(National Heart Centre - Singapore)

(Dr. A. Wong, A/Prof. T.H. Koh)(Dr. A. Wong, A/Prof. T.H. Koh)

Medistra Excel Drug-ElutIng Stent TRiAl

Predilatation is encouraged, even though direct stenting is allowed in simple lesion

Stent selection: Try to always use EXCEL If appropriate size / length not available, use other DES

(Cypher or Taxus) If other DES is not available (logistic problem), use

BMS

• Antiplatelet regimen: • ASA 160 mg indefinitely (unless contraindicated)• Clopidogrel 300 mg (loading), then 75 mg for 6 months

* 1 case when negotiating mildly stenotic, acutely angulated LCX to fix mid-LCX stenosis* 1 case when negotiating mildly stenotic, acutely angulated LCX to fix mid-LCX stenosis 1 case with diffuse, calcified mid-RCA stenosis, during attempted direct stenting1 case with diffuse, calcified mid-RCA stenosis, during attempted direct stenting

MethodsMethods All comers, All comers,

N = 279N = 279 2 stent 2 stent

dislodgement* dislodgement* (“prototype stent”)(“prototype stent”)

277 eligible pts, 631 lesions277 eligible pts, 631 lesions

DES-stenting as default strategy DES-stenting as default strategy (N=771 stents),(N=771 stents), except if there is logistic problem (BMS will be used)except if there is logistic problem (BMS will be used)

EXCELEXCELN=470N=470

CYPHERCYPHERN=137N=137

TAXUSTAXUSN=86N=86

BMSBMSN=46N=46

BIOMATRIXBIOMATRIXN=27N=27

ENDEAVOURENDEAVOURN=5N=5

61% of stents

Demographics (n=277)

• Age (yrs)Age (yrs) 58.5 58.5 ++ 9.4 9.4

• Male Male 226 (81.6%)226 (81.6%)

• Family historyFamily history 97 (35. 0%)97 (35. 0%)

• HypertensionHypertension 152 (54.9%)152 (54.9%)

• DyslipidemiaDyslipidemia 160 (57.8%)160 (57.8%)

• Diabetes mellitusDiabetes mellitus 110 (39.7%)110 (39.7%)

• SmokingSmoking 119 (43.0%)119 (43.0%)

• Prior MIPrior MI 123 (44.4%)123 (44.4%)

• Prior CABGPrior CABG 14 (5.0%)14 (5.0%)

• Prior PCIPrior PCI 77 (22.8%) 77 (22.8%)

Clinical Presentation

Clinical presentation

Stable angina 133 (48.0%) Unstable angina / ACS 32 (11.6%) Acute MI 11 (4.0%) Recent MI ( < 30 days) 15 (5.4%) Silent ischemia 86 (31.0%)

LVEF (%, mean + SD) 59 + 11%

Lesion types

85.3

49.3

39.7

28.1

19.1

18.4

14.1

13.7

5.8

1.2

0.7

0 20 40 60 80 100

Type B2/C

Small vessel

DM

Calcification

Long>25mm

Bifurcation

CTO

Thrombus

ISRS

LM

SVG

%%

37

15

48

2.5 mm 3.0 mm 3.5 mm

30

33

22

15

2.5 mm 2.75 mm3.0 mm 3.5 mm

17

22

24

41

2.5 mm 3.0 mm3.5 mm 4.0 mm

27

33

31

9

2.5 mm 2.75 mm3.0 mm 3.5 mm

EXCELEXCEL (n=470) (n=470) TAXUS (n=86)TAXUS (n=86)

BIOMATRIX (n=27): BIOMATRIX (n=27): 2.5 mm:16; 3 mm:5; 3.5 mm:3; 4 mm:32.5 mm:16; 3 mm:5; 3.5 mm:3; 4 mm:3

ENDEAVOUR (n=5):ENDEAVOUR (n=5): 2.5 mm:2; 3 mm:2; 3.5 mm:2 2.5 mm:2; 3 mm:2; 3.5 mm:2

BMS (n=46)BMS (n=46)

% %

% % % %

% %

Stent Diameter (n=771 stents)Stent Diameter (n=771 stents)

CYPHER (n=137)CYPHER (n=137)

Clinical results

12 months6 months30 days

000CABG

2 (1.3%)2 (1.0%)2 (0.9%)*Stent thrombosis

6 (3.9%)4 (1.9%)1 (0.4%)*TLR/TVR

000Non-fatal MI

2 (1.3%)2 (1.0%)2 (0.9%) **++Death

154 (51%)210 (76%)232 (84%)No. pts

* Pt with diffuse small LAD disease, multiple overlapped Cypher & Excel stents* Pt with diffuse small LAD disease, multiple overlapped Cypher & Excel stents

+ Pt with triple, small vessel disease, died 1 week after PCI (5 stents: Excel, + Pt with triple, small vessel disease, died 1 week after PCI (5 stents: Excel, BioMatrix & Cypher) BioMatrix & Cypher)

CypherCypher TaxusTaxus EXCELEXCEL BMSBMS

(n=34)(n=34) (n=30)(n=30) (n=138)(n=138) (n=15)(n=15)

Lesion length(mm)Lesion length(mm)15.815.8 18.318.3 15.815.8 12.312.3

Stent size (mm)Stent size (mm) 2.852.85 2.872.87 2.862.86 3.503.50

Stent length (mm)Stent length (mm) 22.522.5 26.826.8 21.721.7 16.816.8

QCA analysis: 94 pts with 217 lesionsQCA analysis: 94 pts with 217 lesions

QCA analysis at 6 months (independent QCA lab – NHC, Singapore)

Types of Stents used (per lesion)Types of Stents used (per lesion)

34% of the total 34% of the total patient cohortpatient cohort

Pre proceduralPre proceduralRVD, mm RVD, mm 2.60 2.60 2.572.57 2.532.53 3.203.20MLD, mmMLD, mm 0.93 0.93 0.950.95 0.970.97 1.091.09DS, %DS, % 57.3 57.3 62.262.2 60.060.0 66.066.0

Post proceduralPost proceduralMLD, mmMLD, mm 2.13 2.13 2.112.11 2.082.08 2.732.73DS, %DS, % 17.7 17.7 18.818.8 17.717.7 12.812.8

Follow-up (6 months)Follow-up (6 months)MLD, mmMLD, mm 1.89 1.89 1.781.78 2.072.07 2.062.06DS, %DS, % 29.2 29.2 31.731.7 21.621.6 35.935.9Binary restenosisBinary restenosis 18% 18% 10%10% 5%5% 17%17%Late loss, mmLate loss, mm In-segmentIn-segment 0.24 0.24 0.310.31 0.010.01 0.55 0.55

(p=0.12) (p=0.03) (p=0.003)

In-stentIn-stent 0.25 0.25 0.350.35 0.070.07 0.590.59(p=0.055) (p=0.004) (p<0.001)

CYPHER TAXUS EXCEL BMS

QCA analysis at 6 months QCA analysis at 6 months

Conclusion

Despite the inclusion of challenging “real

world cases” (DM, MVD, small vessel, complex

lesions, long – diffuse disease, calcified stenosis, ostial

stenosis, LM, AMI, CTO, instent restenosis, etc)

the preliminary EXCEL results are

encouraging,

with very low MACE rate & “clean”

angiographic appearance of the stent.

ABSORB study• FIM study of the BVS everolimus-eluting

bioabsorbable stent from Abbott Vascular• Preliminary results presented by Dr J Ormiston

BVS bioabsorbable stent platform

A polymeric stent made from linked polylactic acid molecules that break down into lactic acid

ML VISION™

Balloon SDS

BioabsorbablePolymer Coating

Everolimus

Porcine Coronary Artery Safety Study: Representative Photomicrographs (10x)

28 Day 90 Day 180 Day

BVS

Competitive Metallic DES*

270 Day

*CYPHER

270 Day180 Day90 Day28 Day

®

Product currently in development at Abbott Vascular. Not available for sale. SE 2925096/B

Product currently in development at Abbott Vascular. Not available for sale. SE 2925096/B

ABSORB STUDY• FIM study of 30 patients with single de novo native

lesions• The stent used was 3.0 x 12 mm• Cypher stents were used if necessary as “bailout”• PIs Dr Ormiston, Prof Serruys

Pre Final

Baseline Lesion Characteristics:

Acute Successn=30

Location: LAD 47%RCA 23%

LCx 30%

Lesion classification: B1 60%B2 40%

Clinical device success: 93.5%- successful delivery & deployment of stent with final residual DS of <50%. Bailout patients will be included as device success only if the above criteria for clinical device are met. Clinical procedure success: 100%- definition above and/or using any adjunctive device without occurrence of ischemia driven MACE during first 7 days

Bailout Stents = 4 patients: Two patients had procedure dissections treated with single CYPHER® stents, one patient received a CYPHER® stent for vessel step-down and one patient received three CYPHER® stents to treat the target lesion.

In-Stent Baseline QCA

* Per treatment evaluable population. Four patients excluded that received a non-BVS bail out stent, including one patient that did not receive a BVS stent at the target lesion

N = 30

Pre-procedureLesion length (mm)RVD (mm)MLD (mm)DS (%)

9.05

2.69

1.06

60

N = 26*

Post-procedureMLD (mm)DS (%)Acute gain (mm)

2.31

17

1.22

Acute Recoil (n=27*)

Average of Mean Lumen Diameter (mm)

Stent

Expansion

Post Stent

Expansion

Absolute Stent

Recoil

0.20 6.85%

Relative Stent

Recoil

2.672.86

Ref: S. Tanimoto et al: Acute Stent Recoil of a Bioabsorbable Everolimus Eluting Coronary Stent: In Vivo Evaluation; e-Poster presentation number 306, TCT 2006.

Recoil rate for XIENCE™ V stent 4.27% (p=0.25)

*Subgroup analysis, recoil data not available in three patients

Clinical Results

Hierarchical MACE at 30 Days

N = 26

Cardiac Death % 0Myocardial Infarction %Q-wave MI Non Q-wave MI

0

Ischemia driven TLR %CABGPCI

0

MACE % 0Stent thrombosis % 0

Conclusions

• In this FIM study of a bioabsorbable everolimus-eluting stent, there was low acute stent recoil

• There was a high rate of procedural success (100%)

• At 30 days, there were no cardiac deaths, no MI, no stent thrombosis, and no TLR

Thankyou

• Encouraging preliminary results with all three stents – Zotarolimus-eluting Endeavor Resolute

stent (Medtronic)– Sirolimus-eluting Excel stent (JW

Technologies)– Bioabsorbable everolimus-eluting stent

(Abbott Vascular)

Summary