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


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).


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)


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


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


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


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%


Clinical FU at 9 Months = 95.7%Angio FU at 8 Months = 84.7%




De-registeredCYPHER

(n=23)

De-registeredCYPHER

(n=23)

De-registeredControl

Bx VELOCITYTM

(n=20)

De-registeredControl

Bx VELOCITYTM

(n=20)


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


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


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


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


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


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%


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


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


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


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


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


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


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.

cypher stent - sirius trial

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