Transcript Title Slide

SPIRIT IV
A Prospective, Randomized Trial Comparing an
Everolimus-Eluting Stent and a Paclitaxel-Eluting
Stent in Patients with Coronary Artery Disease
One Year Clinical Results
Gregg W. Stone, MD
for the SPIRIT IV Investigators
Disclosures
• Gregg W. Stone, MD
 Advisory board for Abbott Vascular
and Boston Scientific
SPIRIT IV Background
• The safety and efficacy of the XIENCE V EES
have been demonstrated in the SPIRIT FIRST,
SPIRIT II, and SPIRIT III randomized trials
• However, these trials were not powered for
superiority for clinical endpoints, nor to assess low
frequency event rates (death, MI, stent thrombosis)
• Routine angiographic follow-up may have affected
the results
• Whether the performance of EES is different from
PES in pts with diabetes remains uncertain
SPIRIT IV Study Algorithm
3690 pts enrolled at 66 U.S. sites
RVD ≥2.5 mm - ≤3.75 mm; Lesion length ≤28 mm
Max. 3 lesions with a maximum of 2 per epicardial vessel
Pre-rand: ASA ≥300 mg, clopidogrel
≥300 mg load unless on chronic Rx
Randomized 2:1 XIENCE V®:TAXUS® Express2
Stratified by diabetes and presence of complex lesions
Pre-dilatation mandatory
Everolimus-eluting
Paclitaxel-eluting
XIENCE V
TAXUS
Aspirin ≥80 mg QD for 5 years; clopidogrel 75mg QD for at least 12 mos
(if not at high risk for bleeding)
Clinical f/u only: 1, 6, 9 months and yearly for 1-5 years
Major Exclusion Criteria
• Any target lesion or vessel meets any of the following:
• Left main or ostial LAD/LCX
• In or distal to a bypass graft conduit
• Bifurcation with sidebranch diameter ≥2 mm
AND ostial DS >50% OR requiring pre-dilatation
• Total occlusion, thrombus, restenotic, excessive
tortuosity, angulation or heavy calcification
• Prior coronary brachytherapy
• High probability of additional PCI within 9 mos
SPIRIT III / SPIRIT IV Differences
SPIRIT III
SPIRIT IV
1002
3687
Max. N lesions per pt
2
3
Max. N vessels per pt
2
3
Max. N lesions per vessel
1
2
Bifurcation lesions
<50% ostial DS and
<2.0 mm
<50% ostial DS
or <2.0 mm
Ostial RCA lesions
No
Yes
290/999 (29.0%)
1185/3683 (32.2%)
564 (56.3%)
0
N patients
N pts with diabetes mellitus
N pts with intended angio F/U
SPIRIT IV Endpoints
• Primary endpoint:
• Target lesion failure (TLF) at 1 year
• Major secondary endpoints:
• Ischemia-driven TLR at 1 year
• Composite endpoint of cardiac death
or target vessel MI at 1 year
• All 3 endpoints powered for sequential
noninferiority and superiority testing
TLF = cardiac death, target vessel MI, or ischemia-driven TLR
SPIRIT IV Trial Organization
• Principal Investigator:
Gregg W. Stone, MD
Columbia University Medical Center, NY
• Angiographic Core Lab:
Alexandra Lansky, MD
CRF, NY, NY
• CEC:
Don Cutlip, MD
Harvard Clinical Research Institute, MA
• DSMB:
Robert N. Piana, MD (chair)
Vanderbilt, Nashville, TN
• Randomization Service:
ICON Clinical Research
Sugarland, TX
• Electronic Data Capture:
Phase Forward
Waltham, MA
• Data management
Abbott Vascular
Santa Clara, CA
and sponsor:
SPIRIT IV Top 20 Enrollers
Patients
A. Rizvi
The Heart Center of IN, Indianapolis, IN
W. Newman
Wake Medical Center, Raleigh, NC
K. Mastali
St. Joseph Medical Center, Towson, MD
J. Wang
Union Memorial Hospital, Baltimore, MD
D. Kereiakes
The Christ Hospital, Cincinnati, OH
R. Caputo
St. Joseph’s Hospital, Syracuse, NY
N. Farhat
EMH Regional Medical Center, Elyria, OH
R. Applegate
N. Carolina Baptist Hosp., NC
L. Cannon
Northern Michigan Hospital, Petoskey, MI
J. Maddux
St. Patrick Hospital, Missoula, MT
Patients
292
J. Williams
263
M. Collins
196
P. Gordon
155
M. Turco
153
S. Hearne
153
H. Dauerman
138
F. Fleischhauer
124
C. Hirsch
123
K. Skelding
114
T. Fischell
Presbyterian Hospital, Charlotte, NC
Columbia Univ. Med. Ctr., New York, NY
The Miriam Hospital, Providence, RI
WA Adventist Hosp., Takoma Park, MD
Peninsula Reg. Med. Ctr., Salisbury, MD
Fletcher Allen Healthcare, Burlington, VT
Sacred Heart Hospital, Pensacola, FL
The Valley Hospital, Ridgewood, NJ
Geisinger Medical Center, Danville, PA
Borgess MedicalCenter, Kalamazoo, MI
112
86
82
81
78
71
70
62
57
57
SPIRIT IV Patient Flow
Enrolled
(N=3690)
3 = Randomization errors
Randomized
(N=3687)
XIENCE V
(N=2458)
TAXUS
(N=1229)
Lost to f/u = 35
Withdrawal = 7
Other = 0
24 = Lost to f/u
8 = Withdrawal
2 = Other
1-Year Follow-up*
(N=3611; 97.9%)
XIENCE V
(N=2416)
*F/U window: ± 28 days
TAXUS
(N=1195)
Baseline Demographics
XIENCE V
2458 pts
TAXUS
1229 pts
P
value
63.3 ± 10.5
63.3 ± 10.2
0.80
Male (%)
67.7
67.8
1.00
Hypertension (%)
77.4
76.1
0.41
Hypercholesterolemia (%)
76.1
75.5
0.74
Diabetes mellitus (%)
32.0
32.5
0.79
8.5
9.7
0.24
Current smoker (%)
21.9
22.4
0.70
Prior MI (%)
21.1
19.9
0.41
Unstable angina (%)
27.7
28.9
0.46
Age (in years)
- Insulin requiring (%)
Baseline Angiography
XIENCE V
3142 lesions
TAXUS
1585 lesions
P
value
LAD
40.5%
39.8%
0.68
LCX
24.2%
25.4%
0.35
RCA
35.4%
34.8%
0.68
LMCA
0.0%
0.0%
-
RVD (mm)
2.75 ± 0.48
2.75 ± 0.46
0.59
MLD (mm)
0.75 ± 0.38
0.76 ± 0.39
0.36
% DS
72.3 ± 12.6
72.0 ± 12.8
0.44
Lsn length (mm)
14.8 ± 6.7
14.5 ± 6.6
0.24
Lesion location
QCA
Procedural Results
XIENCE V
2458 pts
3142 lsns
TAXUS
1229 pts
1585 lsns
P
value
1.3 ± 0.5
1.3 ± 0.5
0.53
1 lesion
75.2%
74.7%
0.75
2 lesion
21.7%
21.6%
0.97
3 lesion
3.1%
3.7%
0.33
# stents/patient
1.5 ± 0.8
1.5 ± 0.8
0.35
# stents/lesion
1.17 ± 0.44
1.14 ± 0.41
0.01
Max. stent diameter/lesion (mm)
3.01 ± 0.39
3.01 ± 0.38
0.70
Max. stent diameter/RVD/lesion
1.11 ± 0.15
1.11 ± 0.14
0.85
Total stent length/lesion (mm)
22.4 ± 8.9
20.9 ± 8.9
<0.0001
Total stent length/lesion length
1.65 ± 0.72
1.55 ± 0.71
<0.0001
# lesions/patient
Antiplatelet Agent Utilization
XIENCE V
2458 pts
TAXUS
1229 pts
P
value
- At 180 days
98.8%
98.5%
0.54
- At 270 days
98.1%
98.0%
0.90
- At 365 days
97.1%
97.1%
1.00
- At 180 days
98.8%
99.2%
0.49
- At 270 days
97.8%
98.0%
0.81
- At 365 days
94.9%
95.1%
0.87
Aspirin
Thienopyridine
Primary Endpoint: TLF Through 1 Year
Target lesion failure (%)
10
Diff [95%CI] = -2.6% [-4.2%, -1.0%]
RR [95%CI] = 0.62 [0.46, 0.82]
pNI<0.0001
pSup=0.001
8
6,8
6
4,2
4
2
0
101/2416
81/1195
XIENCE V
TAXUS
TLF = cardiac death, target vessel MI, or ischemia-driven TLR
1 Year = 365 ± 28 days
TLF Through 1 Year
HR [95%CI] =
0.61 [0.46, 0.82]
p=0.0008
Target lesion failure (%)
XIENCE V
TAXUS
6.6%
Δ 2.7%
3.9%
Months
Number at risk
XIENCE V
2458
2390
2362
2323
2298
TAXUS
1229
1165
1137
1119
1104
TLF = cardiac death, target vessel MI, or ischemia-driven TLR
TVF, TLF, and MACE Through 1 Year
RR [95%CI] =
0.71 [0.55, 0.92]
p=0.009
XIENCE V
TAXUS
RR [95%CI] =
0.62 [0.46, 0.82]
p=0.001
RR [95%CI] =
0.62 [0.46, 0.82]
p=0.0009
%
135/2416
94/1195
TVF
101/2416
81/1195
TLF
TLF = cardiac death, target vessel MI, or ID-TLR; MACE = cardiac death, all MI, or ID-TLR;
TVF = cardiac death, all MI, or ID-TVR. 1 Year = 365 ± 28 days
102/2416
82/1195
MACE
Ischemia-driven TLR (%)
Major 2° Endpoint: ID-TLR Through 1 Year
6
5
4,6
4
3
2,5
2
1
0
1 Year = 365 ± 28 days
Diff [95%CI] = -2.1% [-3.4%, -0.7%]
RR [95%CI] = 0.55 [0.38, 0.78]
pNI<0.0001
pSup=0.001
61/2416
55/1195
XIENCE V
TAXUS
Ischemia-Driven TLR Through 1 Year
HR [95%CI] =
0.54 [0.38, 0.78]
p=0.0008
Ischemia-driven TLR (%)
XIENCE V
TAXUS
4.5%
Δ 2.2%
2.3%
Months
Number at risk
XIENCE V
2458
2419
2392
2353
2328
TAXUS
1229
1185
1158
1140
1125
Major 2° EP: Cardiac Death or TV MI Through 1 Yr
Cardiac death or MI (%)
5
4
3,2
3
2,2
2
1
0
TV MI = target vessel MI
1 Year = 365 ± 28 days
Diff [95%CI] = -1.0% [-2.1%, 0.2%]
RR [95%CI] = 0.69 [0.46, 1.04]
pNI<0.0001
pSup=0.09
53/2416
38/1195
XIENCE V
TAXUS
Cardiac Death or TV MI Through 1 Year
Cardiac death or MI (%)
XIENCE V
TAXUS
HR [95%CI] =
0.69 [0.46, 1.05]
p=0.08
3.1%
Δ 0.9%
2.2%
Months
Number at risk
XIENCE V
2458
2393
2378
2353
2339
TAXUS
1229
1179
1165
1154
1146
MI = Target Vessel MI
TLF Components Through 1 Year
XIENCE V
RR [95%CI] =
0.55 [0.38, 0.78]
p=0.001
TAXUS
RR [95%CI] =
0.62 [0.40, 0.96]
p=0.04
%
RR [95%CI] =
0.99 [0.34, 2.89]
p=1.00
10/2416
44/2416
5/1195
Cardiac Death
35/1195
Target Vessel MI
TLF = cardiac death, target vessel MI, or ischemia-driven TLR
1 Year = 365 ± 28 days
61/2416
55/1195
ID-TLR
Death and MI at 1 Year
XIENCE V
2458 pts
TAXUS
1195 pts
P
value
1.0%
1.3%
0.61
- Cardiac
0.4%
0.4%
1.00
- Non cardiac
0.6%
0.8%
0.52
1.9%
3.1%
0.02
- Q-wave
0.1%
0.4%
0.13
- Non Q-wave
1.7%
2.8%
0.05
All death or MI
2.8%
4.1%
0.05
Cardiac death or MI
2.2%
3.3%
0.07
Death, all
MI, all
MI = Target Vessel MI + Non-Target Vessel MI
Categorical data, 365 ± 28 days
Stent Thrombosis (Protocol Definition)*
Stent thrombosis (%)
XIENCE V
TAXUS
HR [95%CI] =
0.20 [0.06, 0.63]
p=0.002
0.82%
Δ 0.66%
0.16%
Months
Number at risk
XIENCE V
2458
2427
2413
2389
2377
TAXUS
1229
1198
1187
1177
1169
*ACS + angiographic thrombus, or unexplained death or
STEMI/Q-wave MI in TL distribution within 30 days
Stent Thrombosis (Protocol Definition)*
Acute (0 – 24 hours)
XIENCE V
N=2458
Subacute (>24 hours – 30 days)
Late (>30 days – 1 year)**
0.17 %
p=0.004
TAXUS
0.85%
N=1229
Stent thrombosis (%)
*ACS + angiographic thrombus, or unexplained death or
STEMI/Q-wave MI in TL distribution within 30 days
**Categorical data, 365 ± 28 days
Stent Thrombosis (ARC Def or Prob)
Stent thrombosis (%)
XIENCE V
TAXUS
HR [95%CI] =
0.27 [0.11, 0.67]
p=0.003
1.06%
Δ 0.77%
0.29%
Months
Number at risk
XIENCE V
2458
2426
2412
2388
2376
TAXUS
1229
1195
1184
1174
1166
Stent Thrombosis (ARC Definition)*
Acute (0 – 24 hours)
XIENCE V
N=2458
Subacute (>24 hours – 30 days)
Late (>30 days – 1 year)**
0.29%
p=0.004
TAXUS
1.10%
N=1229
Stent thrombosis (%)
*Definite or Probable per ARC definition
**Categorical data, 365 ± 28 days
SPIRIT IV: 11 Subgroups Examined
Age < 65 (n=1993)
Age ≥ 65 (n=1618)
Male (n=2450)
Female (n=1161)
Lesion number = 1 (n=2710)
Lesion number = 2 or 3 (n=901)
- Lesion number = 2 (n=784)
- Lesion number = 3 (n=117)
Hypertension* (n=2778)
No hypertension* (n=828)
Lesion length ≤ median (13.3 mm; n=1349)
Lesion length > median (13.3 mm; n=1346)
Hypercholesterolemia* (n=2701)
No hypercholesterolemia* (n=852)
RVD ≤ median (2.75 mm; n=1352)
RVD > median (2.75 mm; n=1351)
BMI ≥ 30 (n=1758)
BMI < 30 (n=1853)
Stable angina (n=2085)
No stable angina (n=1458)
No diabetes (n=2467)
Diabetes (n=1140)
- Diabetics not requiring insulin (n=826)
- Diabetics requiring insulin (n=314)
Bailout stent required (n=221)
No bailout stent required (n=3390)
RVD and lesion length from single lesion treated subgroup.
* Requiring medication
RVD range (min, max; mm): X = (1.39, 4.71), T = (1.36, 4.70)
Lesion length range (min, max; mm): X = (1.99, 54.80), T = (1.72, 47.10)
SPIRIT IV Subgroup Analysis: TLF at 1 Year
EES
(%)
PES
(%)
All randomized (n=3687)
4.2
Age ≥ 65 yrs (n=1618)
3.8
Group
Relative Risk
(95% CI)
Relative Risk
(95% CI)
P
interaction
6.8
0.62 [0.46, 0.82]
—
5.5
0.69 [0.43, 1.09]
0.53
Age < 65 yrs (n=1993)
4.5
7.8
0.57 [0.40, 0.82]
Male (n=2450)
4.2
6.3
0.67 [0.47, 0.95]
0.43
Female (n=1161)
4.1
7.8
0.53 [0.33, 0.85]
Hypertension* (n=2778)
4.1
7.2
0.57 [0.41, 0.78]
0.30
No hypertension* (n=828)
4.4
5.3
0.83 [0.44, 1.55]
Hypercholesterolemia* (n=2701)
4.2
6.4
0.65 [0.47, 0.91]
0.52
No hypercholesterolemia* (n=852)
4.2
8.0
0.53 [0.30, 0.92]
BMI ≥ 30 (n=1758)
4.7
7.2
0.66 [0.45, 0.98]
0.63
BMI < 30 (n=1853)
3.7
6.4
0.57 [0.38, 0.87]
Stable angina (n=2085)
4.2
7.4
0.56 [0.39, 0.81]
No stable angina (n=1458)
4.3
6.0
0.70 [0.45, 1.11]
0.44
0.1
1
EES better
TLF = cardiac death, target vessel MI, or ischemia-driven TLR; 1 Year = 365 ± 28 days. *Requiring medication
10
PES better
SPIRIT IV Subgroup Analysis: TLF at 1 Year
EES
(%)
PES
(%)
All randomized (n=3687)
4.2
Single lesion treated (n=2710)
3.9
Group
Relative Risk
(95% CI)
Relative Risk
(95% CI)
P
interaction
6.8
0.62 [0.46, 0.82]
—
5.7
0.68 [0.48, 0.96]
0.34
Two or more lesions treated (n=901)
5.1
10.0
0.51 [0.32, 0.83]
RVD > 2.75 mm (n=1351)
3.9
4.7
0.83 [0.49, 1.41]
0.29
RVD ≤ 2.75 mm (n=1352)
3.9
6.8
0.57 [0.35, 0.91]
Lesion length > 13.3 mm (n=1346)
4.5
6.9
0.65 [0.41, 1.03]
0.79
Lesion length ≤ 13.3 mm (n=1349)
3.2
4.5
0.71 [0.41, 1.23]
Bailout stent required (n=221)
5.0
14.5
0.35 [0.14, 0.86]
No bailout stent required (n=3390)
4.1
6.4
0.65 [0.48, 0.87]
Diabetes (n=1140)
6.4
6.9
0.94 [0.59, 1.49]
No diabetes(n=2467)
3.1
6.7
0.47 [0.32, 0.68]
0.19
0.02
0.1
EES better
TLF = cardiac death, target vessel MI, or ischemia-driven TLR; 1 Year = 365 ± 28 days
Single lesion treated data are used for RVD & lesion length subgroup analyses
1
10
PES better
Impact of Diabetes on TLF
XIENCE V
TAXUS
RR [95%CI] =
0.94 [0.59, 1.49]
p=0.80
TLF (%)
RR [95%CI] =
0.47 [0.32, 0.68]
p<0.0001
52/1652
TLF = cardiac death, target vessel
MI, or ischemia-driven TLR
55/815
49/761
Pinteraction = 0.02
26/379
Clinical Outcomes Through 1 Year
- No Diabetes Mellitus XIENCE V
1669 pts
TAXUS
829 pts
P
value
0.8%
1.5%
0.13
0.2%
0.5%
0.23
1.5%
2.8%
0.03
1.5%
2.7%
0.04
Cardiac death or TV-MI
1.6%
2.9%
0.04
TLR
1.8%
4.5%
<0.0001
TLF
3.1%
6.7%
<0.0001
MACE
3.2%
6.7%
<0.0001
TVF
4.3%
7.6%
0.0009
0%
0.62%
0.004
0.06%
1.00%
0.0009
Death, all
- Cardiac death
MI, all
- Target vessel MI
ST, protocol
ST, ARC def/prob
TLF = cardiac death, target vessel MI, or ID-TLR; MACE = cardiac death, all MI, or ID-TLR;
TVF = cardiac death, all MI, or ID-TVR. 1 Year = 365 ± 28 days
Clinical Outcomes Through 1 Year
- Diabetes Mellitus XIENCE V
786 pts
TAXUS
399 pts
P
value
1.6%
0.8%
0.41
0.9%
0.3%
0.28
2.6%
3.7%
0.36
2.6%
3.4%
0.46
Cardiac death or TV-MI
3.4%
3.7%
0.87
TLR
4.2%
4.7%
0.65
TLF
6.4%
6.9%
0.80
MACE
6.4%
7.1%
0.71
TVF
8.4%
8.4%
1.00
ST, protocol
0.53%
1.33%
0.17
ST, ARC def/prob
0.80%
1.33%
0.52
Death, all
- Cardiac death
MI, all
- Target vessel MI
TLF = cardiac death, target vessel MI, or ID-TLR; MACE = cardiac death, all MI, or ID-TLR;
TVF = cardiac death, all MI, or ID-TVR. 1 Year = 365 ± 28 days
Impact of Diabetes Type on TLF
XIENCE V
TAXUS
RR [95%CI] =
1.16 [0.51, 2.62]
p=0.83
TLF (%)
RR [95%CI] =
0.86 [0.49, 1.50]
p=0.64
33/562
18/264
16/199
Diabetes not
requiring insulin
TLF = cardiac death, target vessel
MI, or ischemia-driven TLR
8/115
Diabetes
requiring insulin
Pinteraction = 0.56
SPIRIT IV Conclusions
In the large-scale, prospective multicenter randomized SPIRIT IV
trial, the everolimus-eluting XIENCE V stent compared to the
paclitaxel-eluting TAXUS Express stent at 1-year follow-up
demonstrated:
• Primary endpoint: Significantly reduced rate of TLF
• Major secondary endpoints: Significantly reduced rate of TLR and
noninferior rate of cardiac death or target vessel MI
• Other secondary endpoints: Significantly reduced rates of stent
thrombosis (protocol and ARC), target vessel MI and all MI, with
comparable rates of cardiac death and all-cause death
• Diabetic subgroup: Comparable rate of TLF in pts with diabetes, and
a marked reduction in TLF in pts without diabetes
• Other subgroups: Consistent relative reductions in TLF independent
of clinical features, vessel size, and # and length of treated lesions
Clinical Implications
• The results with the XIENCE V stent demonstrating
enhanced safety and efficacy compared to TAXUS
EXPRESS in this large-scale study without routine
angiographic follow-up and with 100% monitoring set
a new standard for event-free survival after DES
• The simultaneous reduction of stent thrombosis, MI and
TLR with XIENCE V demonstrates that “low late loss”
may be achieved with DES without sacrificing safety
• Outcomes in pts with diabetes may still be improved,
and should represent an area of focus for future
development of novel drugs and enhanced stent design