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 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 ± 10.563.3 ± 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 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

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