Cypher Stent - SIRIUS Trial
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Transcript of Cypher Stent - SIRIUS Trial
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 2
SIRIUS: Purpose
To assess the safety and effectiveness of the To assess the safety and effectiveness of the sirolimus-eluting Bx VELOCITY™ in reducing target sirolimus-eluting Bx VELOCITY™ in reducing target
vessel failure in de novo native coronary artery lesions vessel failure in de novo native coronary artery lesions compared with the uncoated Bx stent.compared with the uncoated Bx stent.
SIRIUS was a USA-based trial.SIRIUS was a USA-based trial.
SIRIUS
Study design
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 4
SIRIUS: Endpoints• Primary:
– 9m Target Vessel Failure (cardiac death, MI, or TVR).
• Secondary:– MACE at 1, 6, 9, 12m, and annually to 5 years.– Angiographic binary restenosis ( 50% DS) at 8 months.– In-stent and in-lesion MLD at 8 months.– TLR and TVR at 9 months.– Device success, lesion success, and procedure success (in-
hospital).– Economic factors – index hospitalisation costs, length of stay,
and repeat hospitalisations (for up to 12 months).
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 5
SIRIUS: Study DesignPrincipal investigators: Martin Leon and Jeffrey Moses, Lenox Hill
Study coordination: Richard Kuntz, Brigham & Women’s Hospital.
Angiographic core lab: Jeffrey Popma, Brigham & Women’s Hospital.
IVUS core lab: Peter Fitzgerald, Stanford (Palo Alto)
Economic core lab: David Cohen, Beth Israel (Boston)
Industry sponsor: Cordis.
SIRIUS: Study Design
De Novo Coronary Lesions
Diameter: 2.5-3.5 mmLength: 15-30 mm
De Novo Coronary Lesions
Diameter: 2.5-3.5 mmLength: 15-30 mm
Control Bx VELOCITYTM
n = 556
Control Bx VELOCITYTM
n = 556
CYPHERTM
n = 545CYPHERTM
n = 545n = 1101 patientsn = 1101 patients
Angiographic Sub-study: first 850 pts (FU at 8 months) IVUS Substudy: 250 pts at selected sites (FU at 8 months)
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 7
SIRIUS: Pharmacologic Regimen• Pre-procedurePre-procedure
– Aspirin (325mg) > 24 hrs.
– Clopidogrel (loading dose, 75mg/day) orTiclopidine (loading dose, 250mg/2x day)
• During procedureDuring procedure– Heparin (bolus and additional to maintain ACT > 250 secs)
– IIb/IIIa inhibitors – operator discretion
• Post-procedurePost-procedure– Aspirin (325mg/day) – indefinitely
– Clopidogrel (75mg/day) orTiclopidine (250mg/2x day)
}} >> 24hrs 24hrs
}} 3 months3 months
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 8
SIRIUS: Inclusion Criteria
• Single de novode novo coronary lesion
• Reference vessel > 2.5mm and > 3.5 mm*
• Lesion length: > 15mm and < 30mm*
• Diameter Stenosis: > > 50% and < 100%
• CCS angina or unstable angina (Braunwald B&C, I-II) or documented silent ischaemia
** Visual estimate Visual estimate
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 9
SIRIUS: Exclusion Criteria• Recent MI (< 24 hours)
• Unprotected left main disease
• Ostial location
• Total occlusion (TIMI 0 flow)
• Angiographic evidence of thrombus
• Calcified lesion which cannot be predilated
• LV ejection fraction < 25%
• Impaired renal function
• Pretreatment with devices other than balloon angioplasty
• Allergy to aspirin or clopidogrel (ticlopidine)
• Prior or planned intervention within 30 days
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 10
SIRIUS: Study Procedure
n = 1100 ptsn = 1100 pts
Single de novo native coronary
lesion
Single de novo native coronary
lesion
Pre-dilation(balloons only)
Pre-dilation(balloons only)
Post-dilation(high pressure balloons)
Post-dilation(high pressure balloons)
Bx – Sirolimus vs. non-coated
Bx – Sirolimus vs. non-coated
SIRIUS: Study FlowAll Randomised All Randomised
PatientsPatientsn = 1101n = 1101
All Randomised All Randomised PatientsPatientsn = 1101n = 1101
CYPHERCYPHERn = 533n = 533
CYPHERCYPHERn = 533n = 533
Control Control Bx VELOCITYBx VELOCITYTMTM
n = 525n = 525
Control Control Bx VELOCITYBx VELOCITYTMTM
n = 525n = 525
Angio FU at 8 Months = 85.4%
Clinical FU at 9 Months = 95.7%
Angio FU at 8 Months = 85.4%
Clinical FU at 9 Months = 95.7%Angio FU at 8 Months = 84.7%
Clinical FU at 9 Months = 95.8%
Angio FU at 8 Months = 84.7%
Clinical FU at 9 Months = 95.8%
De-registeredCYPHER
(n=23)
De-registeredCYPHER
(n=23)
De-registeredControl
Bx VELOCITYTM
(n=20)
De-registeredControl
Bx VELOCITYTM
(n=20)
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 12
SIRIUS: Patient DemographicsCYPHER (%)
(n=533)Control (%)
(n=525)
MaleMale 72.672.6 69.769.7
Mean age (years)Mean age (years) 62.162.1 62.462.4
Prior MIPrior MI 28.228.2 32.932.9
Prior PCIPrior PCI 26.326.3 23.123.1
Diabetes MellitusDiabetes Mellitus 24.624.6 28.228.2
HyperlipidaemiaHyperlipidaemia 72.672.6 74.674.6
HypertensionHypertension 67.667.6 67.867.8
Current SmokerCurrent Smoker 17.717.7 22.422.4
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 13
SIRIUS: Baseline Lesion Characteristics
CYPHER (%)(n=533)
Control (%)(n=525)
LADLAD 44.244.2 43.243.2
LCxLCx 25.325.3 23.923.9
RCARCA 30.030.0 32.432.4
OtherOther 0.60.6 0.60.6
AHA/ACC AAHA/ACC A 7.47.4 7.87.8
B1B1 34.034.0 38.138.1
B2B2 32.632.6 33.533.5
CC 26.026.0 20.620.6
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 14
SIRIUS: Baseline Lesion Characteristics (2)
CYPHER (%)(n=533)
Control (%)(n=525)
No. of diseased coronaries 1No. of diseased coronaries 1 59.359.3 57.557.5
22 25.325.3 28.828.8
33 15.415.4 13.713.7
Lesion length <10mmLesion length <10mm 20.020.0 20.420.4
10-20mm10-20mm 64.864.8 66.266.2
>20mm>20mm 15.215.2 13.413.4
Mean Lesion lengthMean Lesion length 14.4 14.4 ±± 5.7 5.7 14.4 14.4 ±± 5.8 5.8
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 15
SIRIUS: Stents ImplantedCYPHER (%) Control (%)
Diameter 2.5Diameter 2.5 19.319.3 17.217.2
3.03.0 45.645.6 45.845.8
3.53.5 35.135.1 37.037.0
Number of stents per patient 1Number of stents per patient 1 65.065.0 64.964.9
22 28.628.6 29.529.5
33 4.94.9 4.64.6
44
1.51.5 0.80.8
Stent length (mm)Stent length (mm) 21.5 21.5 ± 6.7± 6.7 21.2 21.2 ± 6.8± 6.8
Mean stents per patient (n)Mean stents per patient (n) 1.4 1.4 ± 0.7± 0.7 1.4 1.4 ± 0.6± 0.6
Patients with overlapping stentsPatients with overlapping stents 28.528.5 26.926.9
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 16
SIRIUS: Other Procedural
CYPHER Control
Mean hospital stay (days)Mean hospital stay (days) 1.2 1.2 ± 0.9± 0.9 1.2 1.2 ± 0.6± 0.6
IIbIIIa during procedures (%)IIbIIIa during procedures (%) 60.460.4 59.259.2
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 17
SIRIUS: Control Group
From 9,000 patient HCRI stent database, adjusting for SIRIUS case mix (vessel size,
lesion length, % diabetes)
Predicted in-segment restenosis = 31%
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 18
SIRIUS: QCA Definitions
• In-stent QCA = within the margins of the stent.
• In-segment QCA = in-stent + 5mm prox & distal margins.
5 mm 5 mm 5 mm 5 mm 5 mm 5 mm
in-stentin-stentproximalproximal distaldistal
In-segment
SIRIUS: QCA Late Loss Analysis (9-month)
0.17 0.17
0.04
0.33
1.00
0.24
0
0.2
0.4
0.6
0.8
1
1.2
Proximal Margin In-stent Distal Margin
Lat
e L
oss
(m
m)
CYPHER (n=348)
Control (n=353)
Margins = 5mm either side of stent
P < 0.001P < 0.001
P < 0.001
SIRIUS 12-month Results
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 21
SIRIUS: Clinical events (all events to 360 days)
EventsCYPHER %
n = 533
Control %
n = 525P-value
DeathDeath 1.3 (7)1.3 (7) 0.8 (4)0.8 (4) 0.5470.547
MI (all)MI (all) 3.0 (16)3.0 (16) 3.4 (18)3.4 (18) 0.7230.723
Non Q-waveNon Q-wave
TLRTLR
TLR-CABGTLR-CABG
2.3 (12)2.3 (12)
4.9 (26)4.9 (26)
0.9 (5)0.9 (5)
3.0 (16)3.0 (16)
20.0 (105)20.0 (105)
1.7 (9)1.7 (9)
0.4490.449
<0.001<0.001
0.2950.295
TLR-PCITLR-PCI 4.3 (23)4.3 (23) 19.2 (101)19.2 (101) <0.001<0.001
TVR (non TLR)TVR (non TLR)
TVR-CABGTVR-CABG
TVR-PCITVR-PCI
3.6 (19)3.6 (19)
0.6 (3)0.6 (3)
3.2 (17)3.2 (17)
6.7 (35)6.7 (35)
1.3 (7)1.3 (7)
5.5 (29)5.5 (29)
<0.001<0.001
MACEMACE 8.3 (44)8.3 (44) 22.3 (117)22.3 (117) <0.001<0.001
TVFTVF 9.8 (52)9.8 (52) 24.8 (130)24.8 (130) <0.001<0.001
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 22
SIRIUS: Clinical events (diabetics only to 360 days)
EventsCYPHER %
n = 131
Control %
n = 148
DeathDeath 1.5 (2)1.5 (2) 0.7 (1)0.7 (1)
MI (all)MI (all) 2.3 (3)2.3 (3) 4.1 (6)4.1 (6)
Non Q-waveNon Q-wave
TLRTLR
TLR-CABGTLR-CABG
1.5 (2)1.5 (2)
8.4 (11)8.4 (11)
0.8 (1)0.8 (1)
4.1 (6)4.1 (6)
26.4 (39)26.4 (39)
2.0 (3)2.0 (3)
TLR-PCITLR-PCI 8.4 (11)8.4 (11) 25.0 (37)25.0 (37)
TVR (non TLR)TVR (non TLR)
TVR-CABGTVR-CABG
TVR-PCITVR-PCI
5.3 (7)5.3 (7)
0.0 (0)0.0 (0)
5.3 (7)5.3 (7)
8.1 (12)8.1 (12)
0.0 (0)0.0 (0)
8.1 (12)8.1 (12)
MACEMACE 11.5 (15)11.5 (15) 29.1 (43)29.1 (43)
Note that TLR & TVR rates are clinically driven only and do not include angiographically driven procedures
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 23
Reduction in TLR by Patient Characteristics
Reference Vessel Diameter
Lesion Length
< 12mm 12mm - 15mm > 15mm
Non-DiabeticsNon-Diabetics
RVD > 3.0mmRVD > 3.0mm 77.877.8 77.677.6 77.077.0
2.5mm < RVD < 3.0mm2.5mm < RVD < 3.0mm 77.077.0 76.676.6 75.775.7
RVD < 2.5mmRVD < 2.5mm 75.975.9 75.375.3 74.174.1
DiabeticsDiabetics
RVD > 3.0mmRVD > 3.0mm 76.976.9 76.576.5 75.675.6
2.5mm < RVD < 3.0mm2.5mm < RVD < 3.0mm 75.575.5 74.874.8 73.473.4
RVD < 2.5mmRVD < 2.5mm 73.873.8 72.872.8 70.870.8
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 24
0
20
40
60
80
100
0 30 60 90 120 150 180 210 240 270 300 330 360
CP1104360-1
Freedom from events
(%)
Freedom from events
(%)
Post procedure (days)Post procedure (days)
Cypher TLRControl TLRCypher MACEControl MACECypher TVFControl TVF
Cypher TLRControl TLRCypher MACEControl MACECypher TVFControl TVF
Event-free survival at 1 year for TLR, MACE & TVF
Overall 4.9 20.0 0.0001 152
Male 5.2 20.5 0.0001 153
Female 4.1 19.0 0.0002 149
Diabetes 8.4 26.4 0.0002 180
No Diabetes 3.7 17.6 0.0001 138
LAD 6.0 23.0 0.0001 170
Non-LAD 4.1 18.0 0.0001 140
Small Vessel (<2.75) 6.6 22.3 0.0001 157
Large Vessel 3.1 18.2 0.0001 151
Short Lesion 4.0 18.6 0.0001 146
Long Lesion (>13.5) 6.0 21.9 0.0001 158
Overlap 5.7 23.2 0.0001 175
No Overlap 4.5 18.6 0.0001 141
Hazards Ratio 95% CI 1.00.90.80.70.60.50.40.30.20.10 0.70.80.9
SIRIUS: TLR Events# events
prevented per1,000 patientsCYPHER Control P-value
CYPHER better
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 26
SIRIUS: Stent Thrombosis
CYPHERn=533 % (n)
Controln=525 % (n)
Acute (Acute ( 24 hours) 24 hours) 00 00
Sub-acute (1-30 days)Sub-acute (1-30 days) 0.2 (1)0.2 (1) 0.2 (1)0.2 (1)
Late (31-Late (31-36360 days)0 days) 0.2 (1)*0.2 (1)* 0.6 (3)**0.6 (3)**
TotalTotal 0.4 (2)0.4 (2) 0.8 (4)0.8 (4)
* 234 days post-procedure** 40, 150 and 181 days post-procedure
04/11/23 22:06 © Cordis Johnson & JohnsonSlide 27
SIRIUS: 12-month summary• Safety
– Death & MI rates equivalent to control group.
– Low Thrombosis rate despite only 3-months anti-platelet therapy.
– Cypher overlap continues to be safe.
• Clinical– Reduction in TLR rates from 20% to 4.9% for overall study group.
– Diabetic TLR reduced from 26.4% to 8.4%.
– 70-80% relative reduction in TLR in high risk sub-groups.