long term benefits of biodegradable polymer des in complex

Long-term benefits of biodegradable

polymer DES in complex populations:

Insights into the LEADERS trial

3 year follow-up

Patrick W. Serruys

Rotterdam

Biolimus-A9™ Eluting Stent

• Biolimus is a semi-synthetic sirolimus analogue with 10x higher lipophilicity and similar potency as sirolimus.

• Biolimus is immersed at a concentration of 15.6 g/mm into a biodegradable polymer, polylactic acid, and applied solely to the abluminal stent surface by a fully automated process.

• Biolimus is co-released with polylactic acid and completely desolves into carbon dioxide and water after a 6-9 months period.

• The stainless steel stent platform has a strut thickness of 120 m with a quadrature link design.

1o endpoint: CV death, MI, clinically-indicated TVR (9 month)2o endpoints: Death, CV death, MI, TLR, TVR

Stent thrombosis according to ARC

Angiographic study: In-stent % diameter stenosis

Late loss, binary restenosis

DAPT recommended for 12 months

BioMatrix Flex™ (BES)*

N=850

Cypher® Select™ (SES)

N=850

Trial Design

Stable and ACS Patients Undergoing PCI

N=1700 Patients

1:3 Randomisation

Clinical F/U

N=640

Angio F/U

N=210

Clinical F/U

N=640

Angio F/U

N=210

Assessor-blind

1:1 Randomisation

*The product is not available for sale in the USA and certain other countries

BioMatrix Flex™ Cypher® Select™

857 Patients 850 Patients

Acute coronary syndrome 55% 56%

- Unstable angina 22% 21%

- Non-ST-elevation MI 17% 18%

- ST-elevation MI 16% 17%

Left ventricular ejection fraction 56 11% 55 12%

Number of lesions per patient 1.5 0.7 1.4 0.7

Lesions per patient

- 1 lesion 63% 69%

- 2 lesions 29% 22%

- 3 lesions 7% 8%

- > 4 lesions 1% 2%

De novo lesions 92% 91%

Long lesions (>20 mm) 31% 27%

Small vessels (RVD <2.75 mm) 68% 69%

Off label use 81% 78%

Patient Characteristics

Patient Flow - Clinical

Randomized

(N=1,707)

BES (N=857) SES (N=850)

1-year follow-up

(N=1,666; 97.6%)

BES (N=837) SES (N=829)

2-year follow-up

(N=1,655; 97.0%)

Lost to F/U = 17

Patient withdrawal = 11

Other = 17

20 = Lost to F/U

11 = Patient withdrawal

10 = Other

BES (N=812)

BES (N=832) SES (N=823)

3-year follow-up

(N=1,621; 95.0%)

SES (N=809)

Serruys, P. W., oral presentation ,TCT 2010

MACE

%

Number at risk

BES 857 851 761 743 729 712 668

SES 850 846 749 732 713 686 639

Months

13.0%

15.4%

2-year HR0.84 [0.65 to 1.08]

P = 0.18*

Δ 2.4%12.1%

10.7%

1-year HR0.88 [0.66 to 1.17]

P = 0.37*

Δ 1.4%

0

5

10

15

20

0 6 12 18 24

BES

SES

3630

15.7%

19.0%

Δ 3.3%

3-year HR0.82 [0.65 to 1.03]

P = 0.09*

* P values for superiority

MACE = Cardiac Death, MI, or Clinically-Indicated TVR

Serruys P.W., oral presentation, TCT 2010

Overall 132/857 157/850 0.80 (0.63 to 1.03) nsDiabetes mellitus ns

Yes 53/223 45/191 1.02 (0.68 to 1.52) 0.92No 79/634 112/659 0.72 (0.54 to 0.96) 0.02

Acute coronary nsYes 68/470 87/473 0.77 (0.56 to 1.06) 0.11No 64/387 70/377 0.88 (0.63 to 1.25) 0.48

ST-elevation MI 0.03Yes 13/135 29/140 0.43 (0.22 to 0.83) 0.01No 119/722 128/710 0.91 (0.71 to 1.18) 0.48

Left anterior nsYes 59/407 71/417 0.84 (0.59 to 1.17) 0.32No 73/449 86/431 0.81 (0.59 to 1.11) 0.18

Multivessel disease nsYes 33/209 42/176 0.65 (0.41 to 1.03) 0.06No 99/648 115/674 0.89 (0.68 to 1.16) 0.39

Off-label use nsYes 116/696 135/665 0.81 (0.63 to 1.04) 0.09No 16/160 22/183 0.83 (0.44 to 1.59) 0.58

De-novo lesions nsYes 114/788 136/774 0.82 (0.64 to 1.05) 0.11No 18/68 21/74 0.92 (0.49 to 1.73) 0.79

Small-vessel disease nsYes 96/585 104/568 0.89 (0.68 to 1.18) 0.43No 36/271 53/280 0.68 (0.45 to 1.04) 0.08

Long lesions nsYes 46/262 52/225 0.74 (0.50 to 1.10) 0.14No 86/594 105/623 0.85 (0.64 to 1.13) 0.27

Stratified Analysis of MACE @ 3 YearsBES SES

PValueRisk Ratio (95% CI)

P Int

.25 .5 1 2 4

*P values for superiority

Serruys, P. W., oral presentation ,TCT 2010

MACE STEMI

%

Number at risk

BES 135 132 121 120 118 116 108

SES 140 138 115 114 111 106 101

Months

8.4%

19.7%

Δ11.3%15.9%

6.8%

Δ9.1%

0

5

10

15

20

0 6 12 18 24



Windecker S., oral presentation, TCT 2010

BES

SES

3630

10.0%

21.3%

Δ11.3%

3-year HR0.43 [0.23 to 0.84]

P = 0.01*

25 2-year HR

0.40 [0.20 to 0.80]

P = 0.01*

1-year HR

0.40 [0.19 to 0.87]

P = 0.02*

Cardiac Death STEMI

Months

%

6.5%

1.5%

Δ5.0%

2.3%

8.7%

Δ6.4%5

10

20BES

SES



Number at risk

BES 135 132 127 127 126 124 115

SES 140 138 127 127 125 121 115

0 6 12 18 24 3630

3.1%

9.5%

3-year HR0.31 [0.01 to 0.95]

P = 0.03*

Δ6.4%

15

2-year HR

0.25 [0.07 to 0.90]

P = 0.03*

1-year HR

0.23 [0.05 to 1.05]

P = 0.06*

0

MACE Multi-vessel




%

Number at risk

BES 209 208 180 177 172 170 158

SES 176 176 149 144 139 129 115

Months

15.0%

23.5%

Δ8.5%17.1%

13.0%

Δ4.1%

0

5

10

15

20

0 6 12 18 24

BES

SES

3630

16.0%

24.1%

Δ8.1%

3-year HR

0.65 [0.41 to 1.03]

P = 0.06*

25

2-year HR

0.63 [0.40 to 1.00]

P = 0.05*

1-year HR

0.76 [0.45 to 1.28]

P = 0.30*

Cardiac Death Multi-vessel

Months

%

3.4%

2.4%

Δ1.0%

2.9%

5.7%

Δ2.8%5

10

20BES

SES

Number at risk

BES 209 207 201 198 195 194 181

SES 176 176 169 168 167 160 146

0 6 12 18 24 3630

3.9%

7.0%

3-year HR

0.56 [0.23 to 1.37]

P = 0.20*

Δ3.1%

15

2-year HR

0.51 [0.19 to 1.40]

p = 0.19*

1-year HR

0.71 [0.22 to 2.32]

p =0.57*

0



MACE Bifurcations

%

Number at risk

BES 258 257 225 222 217 211 200

SES 239 239 204 199 195 189 172

Months

15.6%

18.9%

Δ3.3%16.4%

12.9%

Δ3.6%

0

5

10

15

20

0 6 12 18 24

BES

SES

3630

18.5%

23.3%

Δ4.8%

3-year HR

0.79 [0.53 to 1.16]

P = 0.22*

25

2-year HR

0.82 [0.54 to 1.26]

P = 0.37 *

1-year HR

0.79 [0.50 to 1.25]

P = 0.31*




Cardiac Death Bifurcations

Months

%

2.9%

2.7%Δ0.2%

3.5%

3.8%

Δ0.3%

5

10

20BES

SES

Number at risk

BES 258 257 251 247 244 241 229

SES 239 239 231 231 231 224 210

0 6 12 18 24 3630

3.9%

5.5%

3-year HR

0.71 [0.31 to 1.63]

P = 0.42*

Δ1.6%

15

2-year HR

0.93 [0.37 to 2.34]

P = 0.88*

1-year HR

0.92 [0.32 to 2.63]

P = 0.88*

0



Number at risk

Sx Low 464 444 440 437 425 409 402 399 393

Sx Mid 472 445 443 437 428 424 417 414 406

Sx High 461 419 412 399 390 382 375 373 369

SYNTAX Score in LEADERS

MACE Rate

Months

%

12.0%

18.4%

2-year HR

1.45 [1.21 to 1.74]

P <0.001*

0

10

15

20

0 3 6 9 12 15 18 21 24

Sx High

5

9.4%

Sx Low

Sx Mid

Wykrzykowska et al. , J Am Coll Cardiol 56, 272-277 (2010)


MACE in High Syntax Score (>16)

%

Number at risk

BES 239 238 207 203 199 195 190

SES 222 221 183 179 174 166 154

Months

15.3%

21.8%

2-year HR

0.68 [0.44 to 1.04]

P = 0.08*

Δ6.5%

18.6%

12.7%

1-year HR

0.66 [0.41 to 1.06]

P = 0.09*

Δ5.9%

0

5

10

15

20

0 6 12 18 24

BES

SES

3630

17.0%

23.8%

Δ6.8%

3-year HR

0.69 [0.46 to 1.04]

P = 0.08*

25




Cardiac Death in High Syntax Score (>16)

Months

%

7.3%

3.0%

Δ4.3%

4.7%

9.5%

Δ4.8%

5

10

20BES

SES

Number at risk

BES 239 238 228 226 224 220 213

SES 222 221 205 204 201 193 180

0 6 12 18 24 3630

4.7%

10.5%

3-year HR0.43 [0.21 to 0.89]

P = 0.02*

Δ5.8%

15

2-year HR

0.48 [0.23 to 0.99]

P = 0.05*

1-year HR

0.40 [0.16 to 0.97]

P = 0.04*

0



Very Late Stent Thrombosis

Signs of Safety Benefits Beyond

One Year

Definite ST through 3 years

1.0

2.0

3.0

% 2.2%

2.9%

BES

SES


0 6 12 18 24 3630Months

2.2%

2.5%

2-year HR

0.90 [0.48 to 1.67

P = 0.73*

2.0%

2.0%

1-year HR

0.99 [0.51 to 1.94]

P = 0.98*

3-year HR

0.78 [0.43 to 1.43]

P = 0.43*

0

4.0

Number at risk

BES 857 846 808 797 787 774 732

SES 850 841 801 792 779 758 715

Δ 0.0%

Δ 0.3%

-22%

Effect of DAPT Discontinuation%

N=0/165 N=4/169 N=2/515N=0/540

Overall Population Patient who d/c DAPT

P = 0.12*

P = 0.24*

*P values for superiority (Fisher Exact Test)

Serruys, P., TCT 2010

Definite ST in Complex PatientsSTEMI


Windecker, S., TCT 2010

1.0

2.0

3.0

%

2.6%

5.1%

0 6 12 18 24 3630Months

2.6%

5.1%4.6%

2.6%

3-year HR

0.50 [0.18 to 1.34]

P = 0.16*

0

4.0

Δ2.0% Δ3.5% Δ3.5%

5.0

6.0

High SYNTAX SCORE (>16)

1.0

2.0

3.0

%

2.0%

4.3%

0 6 12 18 24 3630Months

2.0%

3.8%

2.5%

2.0%

3-year HR

0.46 [0.16 to 1.35]

P = 0.15*

0

4.0

Δ0.5%Δ1.8%

Δ2.3%

5.0

6.0

Bifurcation

1.0

2.0

3.0%

1.5%

5.2%

0 6 12 18 24 3630

Months

1.5%

5.2%

3.4%

1.5%

3-year HR

0.28 [0.08 to 1.03]

P = 0.04*

0

4.0

Δ1.9%Δ3.7% Δ3.7%

5.0

6.0

Multi Vessel

2.0

4.0

6.0%

BES

SES

0 6 12 18 24 3630Months

3.8%

8.1%8.1%

3.0%

3-year HR

0.45 [0.16 to 1.31]

P = 0.14*

0

8.0

Δ 5.1%Δ 4.3%

3.8%

8.1%

Δ 4.3%

10.0

Superior Strut Coverage

and Stent Apposition

Lesions with at least 5% uncovered struts

3.6

39.4

0204060

BioMatrix Flex™ (n=26)

Cypher® Select™ (n=20)

Lesions with at least 5% malapposed struts

0.3

6.7

02468

BioMatrix Flex™ (n=26)

Cypher® Select™ (n=20)

p = 0.005

10 x

n strut = 6476 n strut = 4592

p = 0.04 20 x

n strut = 6476 n strut = 4592

The BioMatrix Flex™ stent with an abluminal biodegradable polymer achieved

a 10 x better strut coverage and a 20 x better stent apposition

vs. the Cypher® Select™ stent with a symmetric durable polymer at 9 months

Barlis. et al. , Eur Heart J 31, 165-176 (2010).

% %

Overall population

• Non-inferiority of BES vs SES in an all-comers population was sustained up to 3 years

• In the overall LEADERS population there were similar outcomes for BES and SES with respect to MACE, Cardiac Death, MI and clinically-indicated TVR

• The Kaplan-Meier curves for MACE continue to diverge showing lower event rates for BES

Conclusions

Subgroup analysis

• Biolimus eluting stent appears to offer an advantage in treating patients with complex CAD

– Bifurcations

– Multi-vessel disease

– STEMI

– High SYNTAX score

Very Late Stent Thrombosis

• Although this was an all-comers study, definite very late stent thrombosis events were rare (BES 0.2% vs SES 0.9% PSup= 0.43)

• There were no VLST events in BES patients between 2 and 3 year clinical FU

• No VLST events in patients where a BES was implanted in native coronary arteries

Conclusions

Back up slides

Patient Eligibility

Inclusion Criteria

Coronary artery disease

- Stable angina

- Silent ischemia

- Acute coronary syndrome

including UA, NSTEMI and STEMI

At least one lesion with

- Diameter stenosis > 50%

- RVD: 2.25-3.5 mm

- Number of lesions: no limitation

- Number of vessels: no limitation

- Lesion length: no limitation

Written informed consent

Exclusion Criteria

Known allergy to

- aspirin, clopidogrel, heparin,

stainless steel, sirolimus, biolimus,

contrast material

Planned, elective surgery

within 6 months of PCI unless

dual APT could be maintained

Pregnancy

Participation in another trial

BioMatrix Flex™ Cypher® Select™

857 Patients 850 Patients

Age in years 65 11 65 11

Male gender 75% 75%

Arterial hypertension 74% 73%

Diabetes mellitus 26% 23%

- insulin-dependent 10% 9%

Hypercholesterolemia 65% 68%

Family history 40% 44%

Smoking 24% 25%

Previous MI 32% 33%

Previous PCI 36% 37%

- with drug-eluting stent 12% 14%

Previous CABG 11% 13%

Chronic stable angina 45% 44%

Patient Demographics

0

5

10

15

0 1 2 3 4 5 6 7 8 9

Months of Follow-up

Cypher® Select™ 10.5%

BioMatrix Flex™ 9.2%

pnon-inferiority = 0.003

Primary EndpointMACE (Cardiac Death, MI and TVR) @ 9 Months

BioMatrix Flex™ reached its primary endpoint

Windecker S. et al., The Lancet 2008; 372 No. 9644: 1163-1173

-12%

MA

CE

%

Cardiac Death

Months

%

1-year HR0.77[0.42 to 1.44]

P = 0.42*

2.7%

2.1%

Δ0.6%

3.2%

4.1%

2-year HR0.81 [0.49 to 1.35]

P = 0.42*

Δ0.9%5

15

BES

SES

Number at risk

BES 857 849 822 812 803 790 747

SES 850 846 815 807 797 777 733

0 6 12 18 24 3630

4.2%

5.2%

3-year HR0.81[0.52 to 1.26]

P = 0.34*

Δ1.0%

20

10



All MI

5

10

20

%

7.1%

7.2%

BES

SES

0 6 12 18 24 3630Months

15

Number at risk

BES 857 848 781 771 762 747 709

SES 850 841 781 772 759 734 689

5.9%

4.6%

1-year HR1.27 [0.84 to 1.94]

P = 0.25*

2-year HR1.12 [0.76 to 1.65]

P = 0.58*

3-year HR1.01 [0.70 to 1.44]

P = 0.97*

Δ0.1%Δ1.3%

5.7%

6.4%

Δ0.7%



7.2%

6.0%

1-year HR0.82 [0.56 to 1.19]

P = 0.29*

Δ1.2%

Clinically-Indicated TVR

Months

8.8%

7.7%

2-year HR0.86 [0.62 to 1.20]

P = 0.37*

Δ1.1%

BES

SES

Number at risk

BES 857 847 790 769 754 735 692

SES 850 841 772 752 733 710 665

0 6 12 18 24 3630

%

5

10

15

20

11.1%

9.4%

3-year HR0.84 [0.62 to 1.13]

P = 0.24*

Δ1.7%



All MISTEMI

5

10

20

%

3.1%

6.8%

BES

SES

0 6 12 18 24 3630Months

15

Number at risk

BES 135 131 124 124 122 120 113

SES 140 135 122 121 119 115 109

2.3%

5.2%

3-year HR0.45 [0.14 to 1.45]

P = 0.17*

Δ3.7%Δ2.9%

6.0%

3.1%

Δ2.9%

2-year HR0.51 [0.15 to 1.68]

P = 0.27*

1-year HR0.44 [0.11 to 1.69]

P = 0.23*

0



10.4%

4.6%

Δ5.8%

Clinically-Indicated TVRSTEMI

Months

11.2%

6.2%

Δ5.0%

BES

SES

Number at risk

BES 135 131 122 121 119 115 108

SES 140 135 116 114 111 108 103

0 6 12 18 24 3630

%

5

10

15

20

12.1%

7.1%

3-year HR0.55 [0.24 to 1.23]

P = 0.14*

Δ5.0%

2-year HR

0.52 [0.22 to 1.23]

p = 0.14*

1-year HR

0.42 [0.16 to 1.10]

P = 0.08*

0



All MI Multi-vessel

5

10

20

%

9.2%

9.4%

BES

SES

0 6 12 18 24 3630Months

15

Number at risk

BES 209 206 185 182 179 177 167

SES 176 175 159 158 154 146 132

9.2%

6.3%

3-year HR

1.02 [0.52 to 1.97]

P = 0.97*

Δ0.2%Δ2.9%

8.7%

9.2%

Δ0.5%

2-year HR

1.08 [0.55 to 2.13]

P = 0.82*

1-year HR

1.48 [0.70 to 3.10]

P = 0.30*

0



3-year HR

0.37 [0.19 to 0.72]

P = 0.002*

Number at risk

BES 209 205 195 190 184 181 169

SES 176 175 156 150 143 136 122

12.1%

3.9%

Δ8.2%

Clinically-Indicated TVR Multi-vessel

Months

15.7%

6.0%

Δ9.7%

BES

SES

0 6 12 18 24 3630

%

5

10

15

20

16.3%

6.5%

Δ9.8%

2-year HR

0.36 [0.18 to 0.71]

P = 0.003*

1-year HR

0.31[0.14 to 0.70]

P = 0.005*

0



All MI Bifurcations

5

10

20

% 9.8%

9.1%

BES

SES

0 6 12 18 24 3630Months

15

Number at risk

BES 258 256 229 226 224 220 212

SES 239 237 219 219 217 210 195

9.0%

5.5%

3-year HR1.13 [0.63 to 2.01]

P = 0.69*

Δ0.7%Δ3.5%

6.8%

9.4%

Δ2.6%

2-year HR1.42 [0.75 to 2.67]

P = 0.28*

1-year HR1.67 [0.85 to 3.30]

P = 0.14*

0



Number at risk

BES 258 255 242 237 231 225 214

SES 239 237 212 206 201 194 180

11.5%

4.3%

Δ7.2%

Clinically-Indicated TVR Bifurcations

Months

13.2%

6.8%

Δ6.4%

BES

SES

0 6 12 18 24 3630

%

5

10

15

20

16.0%

8.9%

3-year HR

0.53 [0.31 to 0.89]

P = 0.015*

Δ7.1%

2-year HR

0.49 [0.27 to 0.89]

P = 0.018*

1-year HR

0.37 [0.18 to 0.74]

P= 0.005*

0



All MIin High Syntax Score (>16)

5

10

20

%

7.7%

6.2%

BES

SES

0 6 12 18 24 3630Months

15

Number at risk

BES 239 236 212 211 208 206 201

SES 222 217 197 195 192 185 171

7.2%

4.6%

3-year HR1.29 [0.63 to 2.63]

P = 0.49*

Δ1.5%Δ2.6%

5.1%

7.2%

Δ1.9%

2-year HR

1.45 [0.68 to 3.09]

P = 0.34*

1-year HR

1.59 [0.73 to 3.47]

P = 0.24*

0



Number at risk

BES 239 236 220 214 209 204 198

SES 222 217 186 181 175 169 156

11.7%

6.0%

1-year HR

0.49 [0.25 to 0.94]

P = 0.03*

Δ5.7%

Clinically-Indicated TVR in High Syntax Score (>16)

Months

12.7%

8.7%

2-year HR

0.65 [0.36 to 1.15]

P = 0.14*

Δ4.0%

BES

SES

0 6 12 18 24 3630

%

5

10

15

20

13.7%

10.0%

3-year HR

0.69 [0.40 to 1.12]

P = 0.17*

Δ3.7%

0



Definite Stent Thrombosis

0 1 2 3

1,6

1,6

0,5

0,4

0,9

0,2

early (30d) late (>30d-1 year) very late (>1year)

BES

SES

Definite Stent Thrombosis %According to ARC Definition

Serruys, P. W., oral presentation, TCT 2010

long term benefits of biodegradable polymer des in complex

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