the remedee study: a randomized comparison of a combination sirolimus eluting epc capture stent with...
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The REMEDEE Study: A Randomized Comparison of a Combination
Sirolimus Eluting EPC Capture Stent with a Paclitaxel Eluting Stent
Michael Haude, MD
On behalf of the REMEDEE Investigators
TCT 2011 Late Breaking Clinical Trial
November 11, 2011
Disclosure Statement of Financial Interest
• Grant/Research Support
• Consulting Fees/Honoraria
• Orbus Neich• Biotronik• Abbott Vascular• Medtronic• Volcano
Within the past 12 months, I , Michael Haude, MD, or my spouse/ Within the past 12 months, I , Michael Haude, MD, or my spouse/ partner have had a financial interest/arrangement or affiliation with the partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.organization(s) listed below.
Affiliation/Financial Relationship Company
Combo Dual Therapy Stent
Design features:
• Abluminal biodegradable polymer matrix
• Sirolimus elution
• Genous technology for accelerated endothelial coverage
316L Stainless Steel Stent Strut
Cross-section
Lumen Side
Vessel Side
Outer Immobilized Anti-CD34 Antibody Treatment
Abluminal Sirolimus Release
Matrix
100 μm
3-5 μm
Antibody Monolayer;
nanometers thick
In vitro elution of Combo and CYPHER® (% of total drug eluted over time)
0
20
40
60
80
100
0 0.25 1 3 7 14 28 35
Time (days)
% Elution over time
Combo
Cypher
Combo StentSirolimus Drug Elution
• Drug – Sirolimus
• Polymer - biodegradable Surmodics SynBiosys™ proprietary blend of urethane-linked block co-polymers of lactide, glycolide, and ε-caprolactone; degradation time <90 days
• Drug content is 5 µg/mm stent length, approximately half the dose of CYPHER™ but with a similar release profile
Granada et al., Circ Cardiovasc Intervent. 2010; 3:257-266
REMEDEE Study Design
Objective:
• To demonstrate non-inferiority of the Combo Stent compared to the TAXUS Liberté ® stent for the primary endpoint of 9-month angiographic in-stent late lumen loss
Major Inclusion Criteria:
• Single de-novo lesions in native coronary arteries
• Lesion length < 20 mm
• 2.5 mm to 3.5 mm in diameter
Major Exclusion Criteria:
• Acute Myocardial Infarction
• Ostial lesions
• Unprotected left main with > 50% stenosis
REMEDEE Study Overview
Single De Novo Native Coronary Artery LesionsReference Vessel Diameter: 2.5-3.5 mm
Lesion Length: < 20 mm
COMBOTM
Dual Therapy Stent(n=124)
TAXUS Liberté®
PES(n=59)
30 Day 9 Mo 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr30 Day 9 Mo 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr
Clinical / MACE
Angio - 109 Combo: 52 Taxus LibertéIVUS Sub-group - 35 Combo: 15 Taxus Liberté
2:1 Randomization
Principal Investigators..…………..…..Principal Investigators..…………..….. Alexandre Abizaid, MD, PhDAlexandre Abizaid, MD, PhDMichael Haude, MDMichael Haude, MDIan Meredith, MBBS, PhDIan Meredith, MBBS, PhDStephan Windecker, MDStephan Windecker, MD
CRO……………………………..…………CRO……………………………..…………-organization & managementorganization & management-QCA / IVUS Core LabQCA / IVUS Core Lab-Statistical analysisStatistical analysis-CEC/DSMB coordinationCEC/DSMB coordination
Cardiovascular Research FoundationCardiovascular Research Foundation Roxana Mehran, MD, CSO Clinical Trial CenterRoxana Mehran, MD, CSO Clinical Trial Center Helen Parise, ScD, Director BiometricsHelen Parise, ScD, Director Biometrics Ecaterina Cristeria, MD, Director Angio Core LabEcaterina Cristeria, MD, Director Angio Core Lab Akiko Maehara, MD, Director Intravascular ImagingAkiko Maehara, MD, Director Intravascular Imaging Madan Mohan, MD, Clinical Trial Safety ManagerMadan Mohan, MD, Clinical Trial Safety Manager LaTosha Eligon, Program ManagerLaTosha Eligon, Program Manager
Executive Committee…....………………Executive Committee…....……………… Alexandre Abizaid, MD, PhDAlexandre Abizaid, MD, PhDMichael Haude, MDMichael Haude, MDRoxana Mehran, MDRoxana Mehran, MDIan Meredith, MBBS, PhDIan Meredith, MBBS, PhDStephen Rowland, PhDStephen Rowland, PhDStephan Windecker, MDStephan Windecker, MD
REMEDEETrial Management
Participating Investigative Sites
• Michael Haude, Lukaskrankenhaus Neuss, Neuss, Germany (32)
• Stephen W.L. Lee, Queen Mary Hospital, Hong Kong (31)
• Sigmund Silber, Cardiology Practice & Hospital, Munich, Germany (14)
• Stephen Worthley, Royal Adelaide Hospital, Adelaide, SA, Australia (14)
• Sandra Erbs, Herzzentrum Leipzig, Leipzig, Germany (13)
• Stefan Verheye, Algemeen Ziekenhuis Middelheim, Antwerp, Belgium (13)
• Mohd Ali Rosli, Institut Jantung Negara, Kuala Lumpur, Malaysia (12)
• Roberto Botelho, Instituto de Cardiologia de Triangulo Mineiro, Uberlandia, Brazil (11)
• Ian Meredith, Monash Medical Center, Melbourne, Victoria, Australia (9)
• Kiu Hian Sim, Sarawak General Hospital, Kota Samarahan, Sarawak, Malaysia (7)
• Pieter Stella, UMC Utrecht, Utrecht, The Netherlands (6)
• Huay-Cheem Tan, National University Hospital, Singapore (5)
• Robert Whitbourn, St. Vincent's Hospital, Melbourne, Victoria, Australia (5)
• Alexandre Abizaid, Institute Dante Pazzanese, Ibirapuera, Sao Paulo, Brazil (4)
• Sukumaran Thambar, John Hunter Hospital, Newcastle, NSW, Australia (4)
• Tian Hai Koh, Singapore General Hospital, Singapore (2)
• Peter den Heijer, Amphia Ziekenhuis, Breda, The Netherlands (1)
REMEDEE: Key Endpoints
Primary endpoint:
• Angiographic 9-month in-stent late lumen loss
Secondary endpoints:
• All-cause and cardiac mortality, MI, MACE
• Stent thrombosis (ARC definition, definite and probable)
• Clinically (ischemia)-driven TLR, TVR, TLF, TVF
• Device, lesion, procedure success
• In-stent / in-segment binary restenosis, MLD, proximal & distal late lumen
• NIH volume and % in-stent volume obstruction at 9 months by IVUS
• Change in human anti-murine antibody (HAMA) levels (30d & 9mo)
Statistical RationaleHypothesis
•Non-inferiority; Angiographic In-Stent Late Loss
•H0: µCombo ≥ µTAXUS + Δ
•Ha: µCombo < µTAXUS + Δ
Assumptions:
•µTAXUS = 0.40 mm; SD = 0.53 mm
•µCombo = 0.30 mm; SD = 0.53 mm
•Non-inferiority Margin, Δ = 0.20 mm
•One sided α=0.025; 90% Power
•Randomization 2:1
Sample Size (20% margin for loss to angiographic FU):
120 Combo: 60 Taxus Liberté
+ 0.53
+ 0.53
Baseline Patient Characteristics
Combo(N=124)
TAXUS(N=59)
p-value
Age (mean ± SD, yrs) 64.2 ± 9.5 64.0 ± 10.5 0.92
Male 71.8% 71.2% 0.93
Smoking /tobacco usage 57.3% 47.5% 0.21
Diabetes mellitus 33.1% 37.3% 0.57
Insulin dependent 7.3% 11.9% 0.30
History of hypertension 80.6% 76.3% 0.50
History of hyperlipidemia 82.3% 72.9% 0.14
Left ventricular ejection fraction (%)
mean ± SD 63.9 ± 11.9 63.3 ± 11.6 0.77
Previous Congestive Heart Failure 13.7% 10.2% 0.50
Previous MI 25.0% 27.1% 0.76
Previous PCI 23.4% 20.3% 0.64
Previous CABG 3.2% 3.4% 1.00
History of renal insufficiency 6.5% 1.7% 0.28
Pre-procedure Cardiac Status
Combo(N=124)
TAXUS(N=59)
p-value
Baseline, pre-procedure
Angina status:
Silent ischemia 10.5% 10.2% 0.95
Stable angina 73.4% 72.9% 0.94
CCS I 10.5% 16.9% 0.22
CCS II 48.4% 49.2% 0.92
CCS III 12.1% 6.8% 0.27
CCS IV 2.4% 0.0% 0.55
Unstable angina 16.1% 16.9% 0.89
Braunwald I 4.8% 3.4% 1.00
Braunwald II 6.5% 3.4% 0.50
Braunwald III 4.8% 10.2% 0.21
Device & Procedure CharacteristicsCombo(N=124)
TAXUS(N=59)
p-value
Number of Lesions Treated per Patient; mean ± SD
1.1 ± 0.3 1.1 ± 0.4 0.36
Target lesion type – de novo 100.0% 100.0% N/A
Location of target lesion
RCA 25.0% 16.9% 0.22
LCX 31.5% 28.8% 0.72
LAD 43.5% 54.2% 0.18
Lesion Location
Ostial 0.8% 1.7% 0.54 Proximal 35.5% 39.0% 0.65 Mid 54.0% 47.5% 0.41 Distal 9.7% 11.9% 0.65Number of study stents deployed per patient; mean ± SD
1.1 ± 0.3 1.0 ± 0.2 0.42
(min, max) (0, 3) (1, 2) N/A
Baseline Lesion CharacteristicsCombo(N=124)
TAXUS(N=59)
p-value
Lesion Length (mm)
mean ± SD 13.69 ± 5.07 14.64 ± 4.41 0.22 (min, max) (5.08, 45.57) (5.25, 24.83) N/A
Eccentric 3.2% 8.5% 0.15
Angulation > 45o 9.7% 6.8% 0.52
Thrombus 0.0% 0.0% N/A
Tortuosity None 96.0% 96.6% 1.00 Moderate 3.2% 3.4% 1.00 Severe 0.8% 0.0% 1.00
Calcification
None or Mild 78.2% 86.4% 0.19 Moderate 21.0% 13.6% 0.23 Severe 0.8% 0.0% 1.00
TIMI Score
TIMI 0 0.0% 0.0% N/A TIMI 1 0.8% 1.7% 0.54 TIMI 2 4.0% 3.4% 1.00 TIMI 3 95.2% 94.9% 1.00
Acute Success
Combo(N=124)
TAXUS(N=59)
p-value
Device Success1 99.2% 100.0% 1.00
Lesion Success2 100.0% 100.0% N/A
Procedure Success (Protocol Def.)3 96.8% 98.3% 1.00
Procedure Success (ARC)4 91.9% 94.9% 0.55
1 – attainment of a final in-stent residual diameter stenosis of <50% (by QCA), using the assigned device only and without device malfunction 2 – attainment of <50% residual stenosis using any percutaneous method3 – achievement of a final in-stent residual diameter stenosis of <50% (by QCA), using the assigned device, without the occurrence of cardiac death, Q wave or non-Q wave MI adjudicated using protocol definition, or repeat revascularization of the target lesion during the hospital stay4 – achievement of a final in-stent residual diameter stenosis of <50% (by QCA), using the assigned device, without the occurrence of cardiac death, Q wave or non-Q wave MI adjudicated using Academic Research Consortium (ARC) definition, or repeat revascularization of the target lesion during the hospital stay
Angiographic In-Stent Late Lumen LossStatistical Analysis
Combo(N=124)
TAXUS(N=59)
Margin of Non-Inf, Δ
(mm)
Non-inferiority
p-value
Difference[95% CI]
Superiorityp-value
In-stent Late Lumen Loss at 9 months (mm)
N 109 52
mean ± SD 0.39 ± 0.45 0.44 ± 0.56 0.2 0.0012-0.05
[-0.21,0.11]0.5514
(min, max) (-0.34, 2.63) (-0.40, 1.97) N/A N/A
Full analysis set: ITT patients with qualifying 9-month angiographic follow-up included in the analyses.
Late loss estimated by Angiographic Core Lab for patients with available 9-month qualifying angiogram.
Non-inferiority Testing for AngiographicIn-stent Late Lumen Loss
In-stent Late Lumen Loss at 9 MonthsCumulative Frequency Distribution
2.52.01.51.00.50.0-0.5
100
80
60
40
20
0
In Stent Late Loss @ 9 mo [mm]
Perc
ent
ComboTaxus
LLL (mean ± SD) Combo: 0.39 ± 0.45mm Taxus: 0.44 ± 0.56mm
Cumulative Frequency Distribution PlotsBaseline MLD, Post-Stent MLD, In Lesion MLD
3.53.02.52.01.51.00.50.0
100
80
60
40
20
0
MLD [mm]
Perc
ent
Baseline MLD ComboBaseline MLD TaxusFinal MLD ComboFinal MLD TaxusIn Lesion MLD @ 9 mo ComboIn Lesion MLD @ 9 mo Taxus
9-Month Binary Angiographic Restenosis and In-Segment Late Loss
Combo(N=124)
TAXUS(N=59)
p-value
Restenosis (%)
In-stent 5.5% 9.6% 0.34
In-segment 8.3% 13.5% 0.30
Minimum Lumen Diameter (MLD) (mm)
In-stent, mean ± SD 2.31 ± 0.58 2.30 ± 0.56 0.86
In-segment, mean ± SD 2.09 ± 0.56 1.97 ± 0.57 0.19
In-stent late lumen loss (mm)
mean ± SD 0.39 ± 0.45 0.44 ± 0.56 0.55
In-segment late lumen loss (mm)
mean ± SD 0.27±0.46 0.41±0.54 0.08
Proximal In-segment, mean ± SD 0.19 ± 0.44 0.29 ± 0.53 0.24
Distal In-Segment, mean ± SD 0.09 ± 0.30 0.13 ± 0.30 0.45
Neointimal Hyperplasia Volume andIn-stent Volume Obstruction (IVUS)
Combo(N=35)
TAXUS(N=15)
p-value
IVUS endpoints
Neointimal hyperplasia volume (mm3)
mean ± SD 21.53 ± 21.71 25.95 ± 18.65 0.50
Relative difference of NIH Volume (17% less NIH volume)
In-stent volume obstruction (%)
mean ± SD 15.24 ± 14.22 14.59 ± 8.38 0.84
30 Day Secondary Effectivenessand Safety Endpoints
Combo(N=124)
TAXUS(N=59)
p-value
30 day follow up
Death 0.0% 0.0% N/A
Cardiac death 0.0% 0.0% N/A
Myocardial infarction (Protocol def.) 2.4% 1.7% 0.75 Q-Wave 0.0% 0.0% N/A
non Q-Wave 2.4% 1.7% 0.75
Clinically-driven TLR 0.0% 0.0% N/A
MACE (Protocol def.) 2.4% 1.7% 0.75
Stent thrombosis (ARC def.) 0.0% 0.0% N/A
Clinically-driven TVR 0.0% 0.0% N/A
Clinically-driven TVF (Protocol def.) 2.4% 1.7% 0.75
Clinically-driven TLF (Protocol def.) 2.4% 1.7% 0.75
9-Month Secondary Effectivenessand Safety Endpoints
Combo(N=124)
TAXUS(N=59)
p-value
Measures at 9 months
Death 1.0% 0.0% 0.49
Cardiac death 0.0% 0.0% N/A
Myocardial infarction (Protocol def.) 2.4% 1.7% 0.75
Q-Wave 0.0% 0.0% N/A
non Q-Wave 2.4% 1.7% 0.75
Clinically-driven TLR 5.2% 9.5% 0.35
MACE (Protocol def.) 8.7% 11.0% 0.69
Stent thrombosis (ARC def.) 0.0% 0.0% N/A
Clinically-driven TVR 7.0% 9.5% 0.65
Clinically-driven TVF (Protocol def.) 10.4% 11.0% 0.97
Clinically-driven TLF (Protocol def.) 8.7% 11.0% 0.69
To 9-Months + 30 Days: Protocol clinical assessment 270±30 days
Conclusions
In this First-In-Man study, the COMBO Dual Therapy Stent
effectively controls neointimal proliferation:
• 0.39 mm average angiographic in-stent late loss at 9
months with the Combo stent is non-inferior to the Taxus
Liberté stent
• In-stent and In-segment Late Loss, and Binary Restenosis
Rates are accordingly low and comparable to the Taxus
Liberté stent
• Overall low rate of clinical events in both groups, including
no stent thrombosis
• Combo shown to be effective & safe