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SPIRIT IVSPIRIT IV
A Prospective, Randomized Trial Comparing an A Prospective, Randomized Trial Comparing an
Everolimus-Eluting Stent and a Paclitaxel-Eluting Everolimus-Eluting Stent and a Paclitaxel-Eluting
Stent in Patients with Coronary Artery Disease Stent in Patients with Coronary Artery Disease
One Year One Year
Clinical ResultsClinical Results
Gregg W. Stone, MDGregg W. Stone, MD
for the SPIRIT IV Investigatorsfor the SPIRIT IV Investigators
• Gregg W. Stone, MD Advisory board for Abbott Vascular
and Boston Scientific
Disclosures
• The safety and efficacy of the XIENCE V EES The safety and efficacy of the XIENCE V EES have been demonstrated in the SPIRIT FIRST, have been demonstrated in the SPIRIT FIRST, SPIRIT II, and SPIRIT III randomized trials SPIRIT II, and SPIRIT III randomized trials
• However, these trials were not powered for However, these trials were not powered for superiority for clinical endpoints, nor to assess low superiority for clinical endpoints, nor to assess low frequency event rates (death, MI, stent thrombosis)frequency event rates (death, MI, stent thrombosis)
• Routine angiographic follow-up may have affected Routine angiographic follow-up may have affected the resultsthe results
• Whether the performance of EES is different from Whether the performance of EES is different from PES in pts with diabetes remains uncertain PES in pts with diabetes remains uncertain
SPIRIT IV Background
Everolimus-eluting
XIENCE VPaclitaxel-eluting
TAXUS
3690 pts enrolled at 66 U.S. sitesRVD ≥2.5 mm - ≤3.75 mm; Lesion length ≤28 mm
Max. 3 lesions with a maximum of 2 per epicardial vessel
Pre-rand:Pre-rand: ASA ≥300 mg, clopidogrel ASA ≥300 mg, clopidogrel ≥300 mg load unless on chronic Rx≥300 mg load unless on chronic Rx
Randomized 2:1 XIENCE V®:TAXUS® Express2
Stratified by diabetes and presence of complex lesionsPre-dilatation mandatory
Clinical f/u only: 1, 6, 9 months and yearly for 1-5 years
Aspirin ≥80 mg QD for 5 years; clopidogrel 75mg QD for at least 12 mos (if not at high risk for bleeding)
SPIRIT IV Study Algorithm
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
N patients 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
N pts with diabetes mellitus 290/999 (29.0%) 1185/3683 (32.2%)
N pts with intended angio F/U 564 (56.3%) 0
SPIRIT III / SPIRIT IV Differences
• 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 Major Endpoints
• 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 and sponsor: Santa Clara, CA
SPIRIT IV Trial Organization
Patients PatientsA. RizviThe Heart Center of IN, Indianapolis, IN
292 J. WilliamsPresbyterian Hospital, Charlotte, NC
112
W. NewmanWake Medical Center, Raleigh, NC
263 M. CollinsColumbia Univ. Med. Ctr., New York, NY
86
K. MastaliSt. Joseph Medical Center, Towson, MD
196 P. GordonThe Miriam Hospital, Providence, RI
82
J. WangUnion Memorial Hospital, Baltimore, MD
155 M. TurcoWA Adventist Hosp., Takoma Park, MD
81
D. KereiakesThe Christ Hospital, Cincinnati, OH
153 S. HearnePeninsula Reg. Med. Ctr., Salisbury, MD
78
R. CaputoSt. Joseph’s Hospital, Syracuse, NY
153 H. DauermanFletcher Allen Healthcare, Burlington, VT
71
N. FarhatEMH Regional Medical Center, Elyria, OH
138 F. FleischhauerSacred Heart Hospital, Pensacola, FL
70
R. ApplegateN. Carolina Baptist Hosp., NC
124 C. HirschThe Valley Hospital, Ridgewood, NJ
62
L. CannonNorthern Michigan Hospital, Petoskey, MI
123 K. SkeldingGeisinger Medical Center, Danville, PA
57
J. MadduxSt. Patrick Hospital, Missoula, MT
114 T. FischellBorgess MedicalCenter, Kalamazoo, MI
57
SPIRIT IV Top 20 Enrollers
XIENCE VXIENCE V(N=2416)(N=2416)
RandomizedRandomized(N=3687)(N=3687)
XIENCE VXIENCE V(N=2458)(N=2458)
TAXUSTAXUS(N=1229)(N=1229)
1-Year Follow-up*1-Year Follow-up*(N=3611; 97.9%)(N=3611; 97.9%)
Lost to f/u = 35Withdrawal = 7
Other = 0
24 = Lost to f/u 8 = Withdrawal2 = Other
*F/U window: ± 28 days
SPIRIT IV Patient FlowEnrolledEnrolled(N=3690)(N=3690)
3 = Randomization errors
TAXUSTAXUS(N=1195)(N=1195)
XIENCE V 2458 pts
TAXUS 1229 pts
P value
Age (in years) 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
- Insulin requiring (%) 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
Baseline Demographics
XIENCE V 3142
lesions
TAXUS 1585 lesions
P value
Lesion location
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% -
QCA
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
Baseline Angiography
XIENCE V 2458 pts 3142 lsns
TAXUS 1229 pts 1585 lsns
P value
# lesions/patient 1.3 ± 0.5 1.3 ± 0.5 0.53
1 lesion 75.2% 74.7% 0.75
2 lesions 21.7% 21.6% 0.97
3 lesions 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
Procedural Results
XIENCE V 2458 pts
TAXUS 1229 pts
P value
Aspirin
- 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
Thienopyridine
- 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
Antiplatelet Agent Utilization
Ta
rge
t le
sio
n f
ailu
re (
%)
101/2416 81/1195
XIENCE V TAXUS
Primary Endpoint: TLF Through 1 Year
TLF = cardiac death, target vessel MI, or ischemia-driven TLR1 Year = 365 ± 28 days
Diff [95%CI] = -2.6% [-4.2%, -1.0%]RR [95%CI] = 0.62 [0.46, 0.82]
pNI<0.0001 pSup=0.001
Number at risk
XIENCE V 2458 2390 2362 2323 2298
TAXUS 1229 1165 1137 1119 1104
6.6%
3.9%
Tar
get
les
ion
fai
lure
(%
)
Months
p=0.0008
HR [95%CI] = 0.61 [0.46, 0.82]
Δ 2.7%
TLF Through 1 YearXIENCE V
TAXUS
TLF = cardiac death, target vessel MI, or ischemia-driven TLR
TVF
RR [95%CI] =0.71 [0.55, 0.92]
p=0.009 RR [95%CI] =0.62 [0.46, 0.82]
p=0.001
RR [95%CI] =0.62 [0.46, 0.82]
p=0.0009
82/1195102/241681/1195101/241694/1195135/2416
TLF MACE
%
TVF, TLF, and MACE Through 1 Year
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
XIENCE V TAXUS
Isc
he
mia
-dri
ve
n T
LR
(%
)
61/2416 55/1195
XIENCE V TAXUS
Major 2° Endpoint: ID-TLR Through 1 Year
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
Isch
emia
-dri
ven
TL
R (
%)
Ischemia-Driven TLR Through 1 Year
Number at risk
XIENCE V 2458 2419 2392 2353 2328
TAXUS 1229 1185 1158 1140 1125
Months
p=0.0008
HR [95%CI] =0.54 [0.38, 0.78]
XIENCE V
TAXUS
4.5%
2.3%
Δ 2.2%
Ca
rdia
c d
ea
th o
r M
I (%
)
53/2416 38/1195
XIENCE V TAXUS
Major 2° EP: Cardiac Death or TV MI Through 1 Yr
TV MI = target vessel MI1 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
Ca
rdia
c d
ea
th o
r M
I (%
)
MI = Target Vessel MI
Cardiac Death or TV MI Through 1 Year
Number at risk
XIENCE V 2458 2393 2378 2353 2339
TAXUS 1229 1179 1165 1154 1146
3.1%
2.2%
Months
p=0.08
HR [95%CI] = 0.69 [0.46, 1.05]
Δ 0.9%
XIENCE V
TAXUS
Cardiac Death
RR [95%CI] =0.99 [0.34, 2.89]
p=1.00
RR [95%CI] =0.62 [0.40, 0.96]
p=0.04
RR [95%CI] =0.55 [0.38, 0.78]
p=0.001
55/119561/241635/119544/24165/119510/2416
XIENCE V TAXUS
Target Vessel MI ID-TLR
%
TLF Components Through 1 Year
TLF = cardiac death, target vessel MI, or ischemia-driven TLR1 Year = 365 ± 28 days
XIENCE V 2458 pts
TAXUS1195 pts
Pvalue
Death, all 1.0% 1.3% 0.61
- Cardiac 0.4% 0.4% 1.00
- Non cardiac 0.6% 0.8% 0.52
MI, all 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
MI = Target Vessel MI + Non-Target Vessel MI Categorical data, 365 ± 28 days
Death and MI at 1 Year
Ste
nt
thro
mb
osi
s (%
)
*ACS + angiographic thrombus, or unexplained death or STEMI/Q-wave MI in TL distribution within 30 days
Stent Thrombosis (Protocol Definition)*
Number at risk
XIENCE V 2458 2427 2413 2389 2377
TAXUS 1229 1198 1187 1177 1169
0.82%
0.16%
Months
p=0.002
HR [95%CI] = 0.20 [0.06, 0.63]
Δ 0.66%
XIENCE V
TAXUS
XIENCE VN=2458
TAXUSN=1229
Stent thrombosis (%)
0.17 %
0.85%
p=0.004p=0.004
Stent Thrombosis (Protocol Definition)*
Acute (0 – 24 hours) Subacute (>24 hours – 30 days) Late (>30 days – 1 year)**
*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)
Number at risk
XIENCE V 2458 2426 2412 2388 2376
TAXUS 1229 1195 1184 1174 1166
1.06%
0.29%
Months
p=0.003
HR [95%CI] = 0.27 [0.11, 0.67]
Δ 0.77%
Ste
nt
thro
mb
osi
s (%
)XIENCE V
TAXUS
XIENCE VN=2458
TAXUSN=1229
Stent thrombosis (%)
0.29%
1.10%
p=0.004p=0.004
Stent Thrombosis (ARC Definition)*
Acute (0 – 24 hours) Subacute (>24 hours – 30 days) Late (>30 days – 1 year)**
*Definite or Probable per ARC definition**Categorical data, 365 ± 28 days
SPIRIT IV: 11 Subgroups Examined
- Diabetics not requiring insulin (n=826)- Diabetics requiring insulin (n=314)
Diabetes (n=1140)No diabetes (n=2467)
- Lesion number = 2 (n=784)- Lesion number = 3 (n=117)
Lesion number = 1 (n=2710)Lesion number = 2 or 3 (n=901)
RVD ≤ median (2.75 mm; n=1352)RVD > median (2.75 mm; n=1351)
Lesion length ≤ median (13.3 mm; n=1349)Lesion length > median (13.3 mm; n=1346)
Age < 65 (n=1993)Age ≥ 65 (n=1618)
RVD and lesion length from single lesion treated subgroup.* Requiring medicationRVD 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)
Bailout stent required (n=221)No bailout stent required (n=3390)
Hypertension* (n=2778)No hypertension* (n=828)
Hypercholesterolemia* (n=2701)No hypercholesterolemia* (n=852)
BMI ≥ 30 (n=1758)BMI < 30 (n=1853)
Stable angina (n=2085)No stable angina (n=1458)
Male (n=2450)Female (n=1161)
GroupEES(%)
PES(%)
Relative Risk (95% CI)
Relative Risk (95% CI)
P interaction
All randomized (n=3687) 4.2 6.8 0.62 [0.46, 0.82] —
Age ≥ 65 yrs (n=1618) 3.8 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]0.44
No stable angina (n=1458) 4.3 6.0 0.70 [0.45, 1.11]
SPIRIT IV Subgroup Analysis: TLF at 1 Year
TLF = cardiac death, target vessel MI, or ischemia-driven TLR; 1 Year = 365 ± 28 days. *Requiring medication
0.1 1 10
EES better PES better
GroupEES(%)
PES(%)
Relative Risk (95% CI)
Relative Risk (95% CI)
P interaction
All randomized (n=3687) 4.2 6.8 0.62 [0.46, 0.82] —
Single lesion treated (n=2710) 3.9 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]0.19
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]0.02
No diabetes (n=2467) 3.1 6.7 0.47 [0.32, 0.68]
SPIRIT IV Subgroup Analysis: TLF at 1 Year
TLF = cardiac death, target vessel MI, or ischemia-driven TLR; 1 Year = 365 ± 28 daysSingle lesion treated data are used for RVD & lesion length subgroup analyses
0.1 1 10
EES better PES better
RR [95%CI] =0.47 [0.32, 0.68]
p<0.0001
49/761 26/37952/1652 55/815
RR [95%CI] =0.94 [0.59, 1.49]
p=0.80
XIENCE V TAXUS
Impact of Diabetes on TLFT
LF
(%
)
Pinteraction = 0.02TLF = cardiac death, target vessel MI, or ischemia-driven TLR
Clinical Outcomes Through 1 Year - No Diabetes Mellitus -
XIENCE V 1669 pts
TAXUS829 pts
Pvalue
Death, all 0.8% 1.5% 0.13
- Cardiac death 0.2% 0.5% 0.23
MI, all 1.5% 2.8% 0.03
- Target vessel MI 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
ST, protocol 0% 0.62% 0.004
ST, ARC def/prob 0.06% 1.00% 0.0009TLF = 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
XIENCE V 786 pts
TAXUS399 pts
Pvalue
Death, all 1.6% 0.8% 0.41
- Cardiac death 0.9% 0.3% 0.28
MI, all 2.6% 3.7% 0.36
- Target vessel MI 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% 0.52TLF = 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 TAXUS
Impact of Diabetes Type on TLFT
LF
(%
)
Pinteraction = 0.56TLF = cardiac death, target vessel MI, or ischemia-driven TLR
16/199 8/11533/562 18/264
RR [95%CI] =0.86 [0.49, 1.50]
p=0.64
RR [95%CI] =1.16 [0.51, 2.62]
p=0.83
Diabetes not requiring insulin
Diabetesrequiring insulin
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
SPIRIT IV Conclusions
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
Recommended