1 Contemporary PCI with the CYPHER Contemporary PCI with the CYPHER ® ® Stent: Stent: The Standard of Care and Comparison The Standard of Care and Comparison David E. Kandzari, MD, FACC, FSCAI David E. Kandzari, MD, FACC, FSCAI Chief Medical Officer Chief Medical Officer Cordis Corporation Cordis Corporation [email protected][email protected]
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1 Contemporary PCI with the CYPHER ® Stent: The Standard of Care and Comparison David E. Kandzari, MD, FACC, FSCAI Chief Medical Officer Cordis Corporation.
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Contemporary PCI with the CYPHERContemporary PCI with the CYPHER®® Stent: Stent:
The Standard of Care and ComparisonThe Standard of Care and Comparison
David E. Kandzari, MD, FACC, FSCAIDavid E. Kandzari, MD, FACC, FSCAIChief Medical OfficerChief Medical OfficerCordis CorporationCordis Corporation
Patient-level Pooled Analysis of 4 RCTsPatient-level Pooled Analysis of 4 RCTs
*The 2 trials provided to support US indication: Improving coronary lumen diameter in patients with symptomatic ischemic disease due to discrete de novo lesions of ≤ 30 mm with a diameter of ≥ 2.5mm or ≤ 3.5mm.
5
Freedom From TLR Through 4 YearsFreedom From TLR Through 4 YearsF
reed
om
Fro
m T
LR
Fre
edo
m F
rom
TL
R
Time After Initial Procedure (days)Time After Initial Procedure (days)
Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS TrialsPooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials
LR p<0.001LR p<0.001
= 15.7%= 15.7%
®
6
Cumulative Incidence of Myocardial Cumulative Incidence of Myocardial Infarction*: 0 – 1,440 Days (4 Years)Infarction*: 0 – 1,440 Days (4 Years)
# Entered# Entered 0 D0 D 180 D180 D 360 D (1 yr)360 D (1 yr) 720 D (2 yr)720 D (2 yr) 1080 D (3 yr)1080 D (3 yr) 1440 D (4 yr)1440 D (4 yr)
LR p=0.8672LR p=0.8672 (95% CI 0.2%[-2.2%, 2.6%]) (95% CI 0.2%[-2.2%, 2.6%])
Cu
mu
lati
ve I
nci
de
nce
of
MI
Cu
mu
lati
ve I
nci
de
nce
of
MI
Time After Initial Procedure (days)Time After Initial Procedure (days)
6.4%6.4%
Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS TrialsPooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials* Non –Q wave CK levels greater then 2 times normal with elevated CKMB* Non –Q wave CK levels greater then 2 times normal with elevated CKMB
®
7
Cumulative Incidence of Death: Cumulative Incidence of Death: 0 – 1,440 Days (4 Years)0 – 1,440 Days (4 Years)
# Entered# Entered 0 D0 D 180 D180 D 360 D (1 yr)360 D (1 yr) 720 D (2 yr)720 D (2 yr) 1080 D (3 yr)1080 D (3 yr) 1440 D (4 yr)1440 D (4 yr)
(95% CI 1.4%[-1.0%, 3.7%]) (95% CI 1.4%[-1.0%, 3.7%])
Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS TrialsPooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials
Cu
mu
lati
ve I
nci
de
nce
of
Dea
thC
um
ula
tive
In
cid
en
ce o
f D
eath
Time After Initial Procedure (days)Time After Initial Procedure (days)
6.7%6.7%
5.4%5.4%
®
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Cumulative Incidence of Stent Thrombosis Cumulative Incidence of Stent Thrombosis to Latest Follow-up (4-5 Years, 4 Trials)to Latest Follow-up (4-5 Years, 4 Trials)
SESSES
1.2%1.2%
BMSBMS
0.6%0.6%
pp-Value-Value
0.2160.216
Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS TrialsPooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS TrialsData between 4 and 5 years are from the RAVEL and SIRIUS TrialsData between 4 and 5 years are from the RAVEL and SIRIUS Trials
ProtocolProtocol
BMSBMSSESSES
SESSES
1.7%1.7%
BMSBMS
1.9%1.9%
pp-Value-Value
0.7030.703
SESSES
4.1%4.1%
BMSBMS
5.1%5.1%
pp-Value-Value
0.7950.795Definite or Definite or Probable ARCProbable ARC
Any ARCAny ARC
SESSES
1.4%1.4%
BMSBMS
1.0%1.0%
pp-Value-Value
0.4960.496Definite ARCDefinite ARC
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Clinical Impact Following TLR and Clinical Impact Following TLR and ARC (Definite/Probable) STARC (Definite/Probable) ST
CYPHERCYPHER®® Stent Stentn = 878n = 878
BMSBMSn = 870n = 870
4 Deaths4 Deaths13 MI13 MI
13 D/MI13 D/MI
7714141717
13 ST13 ST
Deaths (n)Deaths (n)MI (n)MI (n)D/MI (n)D/MI (n)
5 Deaths5 Deaths13 MI13 MI
15 D/MI15 D/MI
5 Deaths5 Deaths9 MI9 MI
13 D/MI13 D/MI
194 TLRs194 TLRs 15 ST15 ST
101022222828
Deaths (n)Deaths (n)MI (n)MI (n)D/MI (n)D/MI (n)
3 C3 C2 NC2 NC
8 C8 C2 NC2 NC
5 C5 C2 NC2 NC
Cardiac Death = CCardiac Death = CNon-Cardiac Death = NCNon-Cardiac Death = NC
4-year Follow-up of 4 Key RCTs4-year Follow-up of 4 Key RCTs
3 Deaths3 Deaths1 MI1 MI
4 D/MI4 D/MI
56 TLRs56 TLRs1 C1 C2 NC2 NC
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Meta-Analysis: Any MI up to 1 Year in Meta-Analysis: Any MI up to 1 Year in SES vs. BMS RCTsSES vs. BMS RCTs
DIABETESDIABETES DECODEDECODE SCORPIUSSCORPIUS1 year1 year
p=0.043p=0.043
62%62%
8 months8 monthsp=0.002p=0.002
75%75%
TYPHOONTYPHOON SESAMISESAMI1 year1 year
p<0.0001p<0.0001
71%71%
1 year1 yearp<0.05p<0.05
62%62%
STRATEGYSTRATEGY8 months8 monthsp=0.006p=0.006
72%72%
MISSIONMISSION1 year1 year
p=0.005p=0.005
72%72%
BMS ControlBMS ControlCYPHERCYPHER®® Stent Stent
4 RCTs: 4 RCTs: Leon M., et al.,Leon M., et al., TCT TCT 2005; Oral Presentation. 2005; Oral Presentation.PRISON 2: Suttorp MJ., et al., PRISON 2: Suttorp MJ., et al., CirculationCirculation 2006;114:921-8. 2006;114:921-8.SES-SMART: Ardissino., SES-SMART: Ardissino., JAMA JAMA 2004; 292:2727-34.2004; 292:2727-34.DIABETES: Sabaté M., et al., DIABETES: Sabaté M., et al., Circulation Circulation 2005;112:2175-83.2005;112:2175-83.DECODE: Chan C., et al., AHA 2005; Oral Presentation.DECODE: Chan C., et al., AHA 2005; Oral Presentation.
SCORPIUS: Baumgart D., et al.,SCORPIUS: Baumgart D., et al., TCT TCT 2006; Oral Presentation.2006; Oral Presentation.TYPHOON: Spaulding C., et al., TYPHOON: Spaulding C., et al., N Engl J MedN Engl J Med 2006;355:1093-104. 2006;355:1093-104.SESAMI: Menichilli, M., et al., PCR 2006; Oral Presentation.SESAMI: Menichilli, M., et al., PCR 2006; Oral Presentation.STRATEGY: Vaglimigli M., et al., STRATEGY: Vaglimigli M., et al., J Am Med AssocJ Am Med Assoc 2005;293:2109-17. 2005;293:2109-17.MISSION: Jukema JW.,MISSION: Jukema JW., AHA AHA 2006, Oral Presentation. 2006, Oral Presentation.
Diabetes*Diabetes*CTO*CTO* Small Small Vessels*Vessels* AMI*AMI*4 RCT 4 RCT
Test for Heterogeneity: p=0.33Test for Heterogeneity: p=0.33Test for Inconsistency: Test for Inconsistency: II2 2 = 13% (95% CI, 0%-57%)= 13% (95% CI, 0%-57%)Test for Overall Effect: p=0.001Test for Overall Effect: p=0.001 Adapted from Kastrati, A., et al., Adapted from Kastrati, A., et al., JAMA JAMA 2005; 294:819-25.2005; 294:819-25.
0.20.2 0.50.5 1.01.0 2.02.0 5.05.0Odds Ratio (95% CI)Odds Ratio (95% CI)
Favors SESFavors SES Favors PESFavors PES
Kastrati, et al., Meta-analysis of CYPHER vs. Taxus RCTsKastrati, et al., Meta-analysis of CYPHER vs. Taxus RCTsSignificantly Lower Angiographic Restenosis with CYPHERSignificantly Lower Angiographic Restenosis with CYPHER
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Risk RatioRisk Ratio (95% CI)(95% CI) % Weight% Weight
Risk RatioRisk Ratio Favours SESFavours SES Favours PESFavours PES
SIRPACT Meta-analysis of CYPHER vs. Taxus RCTsSIRPACT Meta-analysis of CYPHER vs. Taxus RCTsSignificantly Lower TLR with CYPHERSignificantly Lower TLR with CYPHER
Windecker S., et al., TCT 2005; Poster Presentation.Windecker S., et al., TCT 2005; Poster Presentation.
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Source: A. Kastrati, FDA Panel Presentation, Washington, DC, December 2006
Kastrati, et al., Meta-analysis of CYPHER vs. Taxus RCTsKastrati, et al., Meta-analysis of CYPHER vs. Taxus RCTsSignificantly Lower MACE with CYPHERSignificantly Lower MACE with CYPHER
N=5,074. Mean follow-up 25.1 months
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A. Kastrati, FDA Panel Presentation, Washington, DC, December 2006
N=5,074. Mean follow-up 25.1 months
Kastrati, et al., Meta-analysis of Cypher vs. Taxus RCTsKastrati, et al., Meta-analysis of Cypher vs. Taxus RCTsTrend for Lower Death or MI with CypherTrend for Lower Death or MI with Cypher
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Difference in TLR Rates vs. Average TLR for Difference in TLR Rates vs. Average TLR for the CYPHER Stent vs. Taxus Stentthe CYPHER Stent vs. Taxus Stent
y = 0.9809x - 2.5203
R2 = 0.7788
-4
-2
0
2
4
6
8
10
12
0 5 10 15
* TVR rates
TAXi
SORT OUT II
REALITY
ISAR-DESIRE*
ISAR-SMART 3
ISAR-DIABETES
SIRTAX
CORPALBASKET* (TVR)
PROSIT
Long DES II
The difference between TLR rates for the CYPHER® Stent and Taxus Stent in a given trial correlates with the average TLR for that trial.
The higher the risk, the greater the difference in outcomes..
2 years2 years 3 years3 years1.8 y1.8 y 4 y 5 y4 y 5 y
** ** ** **
Valglimigli L, et al. JAMA 2005;293:2109-17.REALITY: Morice MC, ESC 2006; Poster Presentation.SIRTAX: Windecker S, ESC 2006; Poster Presentation.de la Torre, et al., Rev Esp Cardiol 2006; 59:225-31.
ISAR-SMART 3: Mehilla J., et al., AHA 2006; Oral Presentation.DIABETES, et al., ESC 2006; Oral Presentation.Kaiser Perm: TCT 2006; Oral Presentation.SES-SMART: ACC 2005; Oral Presentation.
SVELTE: TCT 2006; Oral Presentation.TROPICAL: TCT 2006; Oral Presentation.RESEARCH: Daemen J., et al., Am J Cardiol 2006; 98:895-901.ARTS II: Serruys PW, et al., TCT 2006; Oral Presentation.4 and 2 RCTs: Internal Data, Cordis Corporation.
NCNC NCNC NCNC
* RCTs* RCTsNC = No ControlNC = No Control
****
2,645 SES Patients Outside of 4 Key Trials with > 1 Year Follow-up2,645 SES Patients Outside of 4 Key Trials with > 1 Year Follow-up
NotNotAvail.Avail.
In addition Registries with longer-term follow-up were presented at the FDA Panel Meeting that can be found on In addition Registries with longer-term follow-up were presented at the FDA Panel Meeting that can be found on www.fda.gov/cdrh/panel/www.fda.gov/cdrh/panel/* The safety and effectiveness of the CYPHER® Stent in these sub-populations have not been established.
Valglimigli L, et al. JAMA 2005;293:2109-17.REALITY: Morice MC, ESC 2006; Poster Presentation.SIRTAX: Windecker S, ESC 2006; Poster Presentation.de la Torre, et al., Rev Esp Cardiol 2006; 59:225-31.
ISAR-SMART 3: Mehilla J., et al., AHA 2006; Oral Presentation.DIABETES, et al., ESC 2006; Oral Presentation.Kaiser Perm: TCT 2006; Oral Presentation.SES-SMART: ACC 2005; Oral Presentation.
SVELTE: TCT 2006; Oral Presentation.TROPICAL: TCT 2006; Oral Presentation.RESEARCH: Daemen J., et al., Am J Cardiol 2006; 98:895-901.ARTS II: Serruys PW, et al., TCT 2006; Oral Presentation.4 and 2 RCTs: Internal Data, Cordis Corporation.
** ** ** **
Long-Term Mortality Rates Long-Term Mortality Rates (> 1 Year) in CYPHER(> 1 Year) in CYPHER®® Stent Studies Stent Studies
NCNC NCNC NCNC
****
In addition Registries with longer-term follow-up were presented at the FDA Panel Meeting that can be found on In addition Registries with longer-term follow-up were presented at the FDA Panel Meeting that can be found on www.fda.gov/cdrh/panel/www.fda.gov/cdrh/panel/* The safety and effectiveness of the CYPHER® Stent in these sub-populations have not been established.
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CYPHER Stent: Final ConclusionsCYPHER Stent: Final Conclusions
The CYPHER stent has demonstrated clinically meaningful, The CYPHER stent has demonstrated clinically meaningful, sustained benefit in reducing the need for repeat sustained benefit in reducing the need for repeat revascularizations in a wide array of clinical settings and revascularizations in a wide array of clinical settings and lesion complexitieslesion complexities
– Standard of care, standard for comparison Standard of care, standard for comparison
No difference in overall risk of stent thrombosis in 4 RCTs No difference in overall risk of stent thrombosis in 4 RCTs comparing CYPHER with BMS comparing CYPHER with BMS
– No significant difference in death, and death or MINo significant difference in death, and death or MI
– Temporal distribution of stent thrombosis may vary Temporal distribution of stent thrombosis may vary between CYPHER Stent and BMSbetween CYPHER Stent and BMS
Systematic overview of CYPHER vs. Taxus RCTs demonstrate Systematic overview of CYPHER vs. Taxus RCTs demonstrate significantly lower TLR and MACE in favor of the CYPHER significantly lower TLR and MACE in favor of the CYPHER StentStent
– Trend for lower death/MI Trend for lower death/MI (OR 95% CI: 0.86 [0.72, 1.02])(OR 95% CI: 0.86 [0.72, 1.02])
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In high-risk patient subgroups, different risk: benefit In high-risk patient subgroups, different risk: benefit ratio compared to 4 key CYPHER trials:ratio compared to 4 key CYPHER trials:
Benefit similar to lower risk groups:Benefit similar to lower risk groups:– Significant relative reductions in TLR/TVR of the Significant relative reductions in TLR/TVR of the
CYPHER Stent:CYPHER Stent:• 62-80% vs. BMS62-80% vs. BMS• 41-45% vs. PES 41-45% vs. PES
Risk: Risk: – Rates of death, MI, or stent thrombosis Rates of death, MI, or stent thrombosis
numerically higher than on-label trials:numerically higher than on-label trials:• No significant differences between the CYPHER Stent No significant differences between the CYPHER Stent
and BMSand BMS• Elevated risk related to patient and lesion subgroupsElevated risk related to patient and lesion subgroups• Some data suggest differential risk profile of SES vs. Some data suggest differential risk profile of SES vs.
PESPES
CYPHER Stent: Final ConclusionsCYPHER Stent: Final Conclusions
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Commitments to Interventional CommunityCommitments to Interventional Community
Extend follow-up of 3 SIRIUS Trials to 8 yearsExtend follow-up of 3 SIRIUS Trials to 8 years
Coordinate the extended follow-up of 10 RCTs Coordinate the extended follow-up of 10 RCTs (n=4,500 patients) to 5 years(n=4,500 patients) to 5 years
Collaborate with regulatory agencies and Collaborate with regulatory agencies and professional societies to develop approval pathways professional societies to develop approval pathways for expanded indicationsfor expanded indications
Enable Interventional Cardiologists to improve Enable Interventional Cardiologists to improve patient outcomes through new device design and patient outcomes through new device design and clinical trialsclinical trials
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Back-Up SlidesBack-Up Slides
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1-year RCTs1-year RCTs
DECODEDECODE SCORPIUSSCORPIUS
P=NSP=NS P=NSP=NS
0.0
6.95.3
4.26.3
5.0
9.111.0 11.8
4.3
9.6
0
10
20
30
0.0
6.95.3
4.26.3
5.0
9.111.0 11.8
4.3
9.6
0
10
20
304-year 4-year post-hocpost-hoc
subgroup analysessubgroup analyses
DIABETESDIABETES
P=NSP=NS
2-year RCT2-year RCT
Summary of Contemporary Diabetic Summary of Contemporary Diabetic Mortality DataMortality Data
*Lee T et al., Am J Cardiol, 2006; 98:718-721*Lee T et al., Am J Cardiol, 2006; 98:718-721DIABETES: Sabaté M., et al., DIABETES: Sabaté M., et al., ESCESC 2006; Oral Presentation. 2006; Oral Presentation. DECODE: Chan C., et al., AHA 2005; Oral Presentation.DECODE: Chan C., et al., AHA 2005; Oral Presentation.SCORPIUS: Baumgart D., et al.,SCORPIUS: Baumgart D., et al., TCT TCT 2006; Oral Presentation. 4 key RCTs CYPHER® Stent: Internal Data, Cordis Corporation.2006; Oral Presentation. 4 key RCTs CYPHER® Stent: Internal Data, Cordis Corporation.Letter from Don Baim, M.D.Letter from Don Baim, M.D.
BMSBMSSESSES PESPES
% P
atie
nts
% P
atie
nts P=NSP=NS
4 Key RCTs4 Key RCTsTaxus StentTaxus Stent
P=0.006P=0.006
4 Key RCTs4 Key RCTsCYPHER® StentCYPHER® Stent
5-year 5-year Follow-up Follow-up of BMS Published of BMS Published
DataData**
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Low Mortality in BMS arm of CYPHER Low Mortality in BMS arm of CYPHER TrialsTrials
Four-Year Follow-up of Sirolimus-eluting Stents in Comparison with Bare Metal Stents: A Pooled Safety Analysis of the RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS Trials in 1,748 Patients, Patrick Serruys, Erasmus Medical Center: Downloaded