Long-term benefits of biodegradable polymer DES in complex populations: Insights into the LEADERS trial 3 year follow-up Patrick W. Serruys Rotterdam
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
* P values for superiority
MACE = Cardiac Death, MI, or Clinically-Indicated TVR
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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
* P values for superiority
MACE = Cardiac Death, MI, or Clinically-Indicated TVR
Windecker S., oral presentation, TCT 2010
%
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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*
* P values for superiority
MACE = Cardiac Death, MI, or Clinically-Indicated TVR
Windecker S., oral presentation, TCT 2010
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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)
* P values for superiority
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
* P values for superiority
MACE = Cardiac Death, MI, or Clinically-Indicated TVR
Windecker S., oral presentation, TCT 2010
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
*P values for superiority
Serruys P.W., oral presentation, TCT 2010
Definite ST through 3 years
1.0
2.0
3.0
% 2.2%
2.9%
BES
SES
*P values for superiority
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
*P values for superiority
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
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
*P values for superiority
Serruys P.W., oral presentation, TCT 2010
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%
*P values for superiority
Serruys P.W., oral presentation, TCT 2010
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%
*P values for superiority
Serruys P.W., oral presentation, TCT 2010
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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
*P values for superiority
Windecker S., oral presentation, TCT 2010
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
*P values for superiority
Windecker S., oral presentation, TCT 2010