Milestone for Left Milestone for Left Main PCI: Main PCI: Upcoming Upcoming

EXCEL TrialEXCEL TrialGregg W. Stone MDGregg W. Stone MD

Columbia University Medical CenterColumbia University Medical CenterThe Cardiovascular Research FoundationThe Cardiovascular Research Foundation

Left Main Disease(isolated, +1, +2 or +3 vessels)

N=705

3 Vessel Disease(revasc all 3 vascular territories)

N=1095

SYNTAX Eligible PatientsSYNTAX Eligible PatientsDe novo disease (n=1800)

Limited Exclusion CriteriaPrevious interventions Acute MI with CPK>2xConcomitant cardiac surgery

Serruys PWSerruys PW et alet al. NEJM . NEJM 2009;360:9612009;360:961--7272

Primary endpoint = death/MI/stroke/repeat revasc at 1 year

MACCE to 1 Year 1 Year (primary endpoint)(All-cause death, stroke, MI, any repeat revasc)

P=0.0015*

0 6 12

10

20

0

Months Since Allocation

Cum

ulat

ive

Even

t Rat

e (%

)

ITT population

12.1%

17.8%

TAXUS (N=903)CABG (N=897)

Serruys PWSerruys PW et alet al. NEJM . NEJM 2009;360:9612009;360:961--7272

SYNTAX: 2 Year Outcomes in the LM Subgroup (N=705)

TAXUSCABG

Pat

ient

s, %

11.8 10.4

19.3

10.2

17.3

22.9

0

5

10

15

20

25

30

Death/CVA/MI MACCERevasc

P=0.48

P=0.01

P=0.27

CABG PCI P-value

Death 4.1% 10.4% 0.04

CVA 4.2% 0.8% 0.08

MI 6.1% 8.4% 0.48

Death, CVA or

MI11.5% 15.6% 0.32

Revasc. 9.2% 21.8% 0.003

P=0.02

TAXUS (N=135)

CABG (N=149)

MACCE to 2 Years by SYNTAX Score Tercile Left Main SYNTAX Score ³33

29.7%

17.8%

Site-reported data; ITT populationCumulative KM Event Rate ± 1.5 SE; log-rank P value

Months Since Allocation

Cum

ulat

ive

Even

t Rat

e (%

)

0 12 24

40

0

20

30

10

Left Main

CABG PCI P-value

Death 7.9% 2.7% 0.02

CVA 3.3% 0.9% 0.09

MI 2.6% 3.8% 0.59

Death, CVA or

MI12.1% 6.9% 0.06

Revasc. 11.4% 14.3% 0.44Months Since Allocation

Cum

ulat

ive

Even

t Rat

e (%

)

0 12 24

40

0

20

30

10

P=0.48

TAXUS (N=221)

CABG (N=196)

MACCE to 2 Years by SYNTAX Score Tercile Left Main SYNTAX Scores 0-32

18.3%20.5%

Site-reported Data; ITT populationCumulative KM Event Rate ± 1.5 SE; log-rank P value

Left Main

ACC/AHA Guidelines Post SYNTAX

ACC/AHA 2009 Focused Updates for STEMI and PCI. Circulation 2009;120:2271–2306

Stenting of the LMCA as an alternative Stenting of the LMCA as an alternative to CABG may be considered in pts to CABG may be considered in pts with anatomic conditions that are with anatomic conditions that are associated with a associated with a low risk of PCI low risk of PCI procedural complications procedural complications and clinical and clinical conditions that predict an conditions that predict an increased increased risk of adverse surgical outcomesrisk of adverse surgical outcomes

IIbIIb

IIb = “may or might be considered; may or might IIb = “may or might be considered; may or might be reasonable; usefulness/effectiveness is be reasonable; usefulness/effectiveness is

unknown/unclear/uncertain or not well established”unknown/unclear/uncertain or not well established”

•• It wouldn’t be an It wouldn’t be an allall--comers trial!comers trial!-- Exclude pts who clearly should go to CABG, e.g. high Exclude pts who clearly should go to CABG, e.g. high

SYNTAX scoresSYNTAX scores•• Optimize PCI techniqueOptimize PCI technique

-- PrePre--specify specify when/how to use IVUS, when/how to use IVUS, staged procedures, staged procedures, RX of distal bifurcationRX of distal bifurcation, no routine angio FU, , no routine angio FU, etcetc..

-- Use the best stent and adjunctive pharmacologyUse the best stent and adjunctive pharmacology•• Optimize CABG techniqueOptimize CABG technique

-- Minimize waiting time to CABG, maximize panMinimize waiting time to CABG, maximize pan--arterial arterial revascularization, adjunctive pharmacology, revascularization, adjunctive pharmacology, etc.etc.

•• Use a meaningful 1Use a meaningful 1º º endpoint: endpoint: Death, CVA or MIDeath, CVA or MI•• ~2500 randomized pts~2500 randomized pts

What Would an Informative Trial of Left Main DES vs. CABG Look Like?

R

Clinical followClinical follow--up: 30 days, 6 months, yearly through 5 yearsup: 30 days, 6 months, yearly through 5 years

EXCEL: Study Design4000 pts with left main disease4000 pts with left main disease

SYNTAX score ≤32SYNTAX score ≤32Consensus agreement by heart teamConsensus agreement by heart team

YesYes(N=2500)(N=2500)

NoNo(N=1500)(N=1500)

PCI and CABGPCI and CABGregistriesregistries

(limited in(limited in--hosp data)hosp data)

PCI (Xience Prime)PCI (Xience Prime)(N=1250)(N=1250)

CABGCABG(N=1250)(N=1250)

EXCEL: Inclusion Criteria•• Clinical and anatomic eligibility for both PCI Clinical and anatomic eligibility for both PCI

and CABG by heart team consensusand CABG by heart team consensus•• Silent ischemia, stable angina, unstable Silent ischemia, stable angina, unstable

angina or recent MI angina or recent MI •• Significant Significant LM LM dsds. by heart team consensus. by heart team consensus

-- Angiographic DS ≥70%, orAngiographic DS ≥70%, or

-- Angiographic DS ≥50% to <70% with Angiographic DS ≥50% to <70% with -- a markedly positive noninvasive study, and/ora markedly positive noninvasive study, and/or

-- IVUS MLA <6.0 IVUS MLA <6.0 mmmm22, and/or, and/or

-- FFR <FFR <0.800.80

QC

A la

bQ

CA

lab

Clinical siteClinical site

100100

00 10010000

Fisher et al. Cathet Cardiovasc Diagn 1982;8:565-75Fisher et al. Cathet Cardiovasc Diagn 1982;8:565-75

Comparison in DS% assessment from the Comparison in DS% assessment from the core lab core lab ((QCA) vs QCA) vs the clinical site (CASS Study)the clinical site (CASS Study)

*area of the square is proportional to the number of cases*area of the square is proportional to the number of cases

Of all the coronary segments, the LMCA has the greatest angiographic variability

Which of these LMCA lesions are significant and therefore should be treated?

And which are not??

* * *

LMCA IVUS usually shows LMCA IVUS usually shows either either insignificant insignificant or critical diseaseor critical disease

MLA 4.6 mm2 MLA 5.0 mm2 MLA 3.2 mm2

Independent predictors of MACE @11.7 months: Independent predictors of MACE @11.7 months: DM (p=0.004), DM (p=0.004), untreated lesion >50% (p=0.037), and IVUS MLD (p=0.005)untreated lesion >50% (p=0.037), and IVUS MLD (p=0.005)

IVU

S M

LD (m

m)

IVU

S M

LD (m

m)

QCA MLD (mm)QCA MLD (mm)

r=0.364r=0.364

00

11

22

33

44

55

66

77

00 11 22 33 44 55 66 77

IVU

S re

f (m

m)

IVU

S re

f (m

m)

QCA ref (mm)QCA ref (mm)001122334455667788

00 11 22 33 44 55 66 77 88

r=0.495r=0.495IV

US

DS%

IVU

S D

S%

QCA DS%QCA DS%

00

2020

4040

6060

8080

100100

00 2020 4040 6060 8080 100100

p=0.106p=0.106

1-Year FU of 122 pts with moderate LM disease

Abizaid et al. JACC 1999;34:707Abizaid et al. JACC 1999;34:707--1515

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.41.8

2.22.6

3.03.4

3.84.2

4.65.0

5.45.8

DM and ≥1 untreated vessel (DS>50%)

DM and no untreated vessels

No DM and ≥1 untreated

vessel (DS>50%)

MACEMACE

IVUS MLD (mm)IVUS MLD (mm)

No DM and no untreated vessels

IVUS determinants of LMCA FFR <0.75

MLA <6.0 MLA <6.0 mmmm22 (or MLD <3.0 mm) is the suggested criterion for (or MLD <3.0 mm) is the suggested criterion for significant significant LMCA LMCA stenosis. stenosis. JastiJasti et al. Circulationet al. Circulation 2004;110:28312004;110:2831--66

MLD MLA

Perc

ent

00101020203030404050506060707080809090

100100110110

11 22 33 44 55

2.8 mm2.8 mm

Sensitivity 93%Sensitivity 93%Specificity 98%Specificity 98%

00101020203030404050506060707080809090

100100110110

11 22 88 1212 1414

5.9 mm5.9 mm22

Sensitivity 93%Sensitivity 93%Specificity 94%Specificity 94%

Cross sectional narrowing Area stenosis

Perc

ent

Sensitivity 90%Sensitivity 90%Specificity 88%Specificity 88%

00101020203030404050506060707080809090

50%50%

Sensitivity 86%Sensitivity 86%Specificity 80%Specificity 80%

67%67%

100100110110

00 1010 2020 3030 4040 5050 6060 7070 8080 909000

101020203030404050506060707080809090

100100110110

2020 3030 4040 5050 6060 7070 8080 9090

44 66 1010

FFR Guidance for Left Main Treatment

Hamilos M et al. Circulation. 2009;120:1505-1512.Hamilos M et al. Circulation. 2009;120:1505-1512.

FFR was performed in 213 pts with angiographically FFR was performed in 213 pts with angiographically borderline (DS 30% borderline (DS 30% -- 70%) LM lesions70%) LM lesions

FFR ≥0.80 FFR ≥0.80 ÞÞ medical Rx (n=138); medical Rx (n=138); FFR <0.80 FFR <0.80 ÞÞ CABG (n=75)CABG (n=75)

FFR0.5

r=0.38, P<0.001

0.6 0.7 0.8 0.9 1.00

20

40

60

80%

Dia

met

er S

teno

sis

Correlation between angiography and FFR in unprotected left main disease

Hamilos M et al. Circulation. 2009;120:1505-1512.Hamilos M et al. Circulation. 2009;120:1505-1512.

Hamilos M et al. Circulation. 2009;120:1505-1512.Hamilos M et al. Circulation. 2009;120:1505-1512.

FFR was performed in 213 pts with angiographically FFR was performed in 213 pts with angiographically borderline (DS 30% borderline (DS 30% -- 70%) LM lesions70%) LM lesions

FFR ≥0.80 FFR ≥0.80 ÞÞ medical Rx (n=138); medical Rx (n=138); FFR <0.80 FFR <0.80 ÞÞ CABG (n=75)CABG (n=75)

40

FFR >0.80 med RxFFR <0.80 CABG

p=0.50p=0.48

Months

% S

urvi

val

100

No. at riskFFR >0.80FFR <0.80

10356

13673

5230

7241

3814

2610

0 12 24 36 48 60

80

60

40

20

0

FFR >0.80 med RxFFR <0.80 CABG

Months%

MA

CE

Free

No. at riskFFR >0.80FFR <0.80

10656

13673

5729

7740

4215

3010

0 12 24 36 48 60

80

60

20

0

100

FFR Guidance for Left Main Treatment

Botman CJ et al. Ann Thorac Surg 2007;83:2093–7.Botman CJ et al. Ann Thorac Surg 2007;83:2093–7.

Why not revascularize pts with borderline LM lesions in the absence of ischemia?≤FFR was performed in 525 lesions in 153 pts before bypassFFR was performed in 525 lesions in 153 pts before bypass

Baseline FFR was ≤0.75 in 337 (64%) and >0.75 in 168 (36%)Baseline FFR was ≤0.75 in 337 (64%) and >0.75 in 168 (36%)Repeat angiography was performed at 1Repeat angiography was performed at 1--yearyear

Graft closure at 1Graft closure at 1--year according to baseline native year according to baseline native corcor FFRFFR::

8.9

21.4

5.9

20.0

13.7

21.9

0

5

10

15

20

25

FFR ≤0.75 FFR >0.75

Gra

ft c

losu

re (%

)

All grafts Vein grafts Arterial grafts

P<0.01

1-yr LIMA patency 93.8%1-yr radial patency 71.0%

EXCEL: IVUS is recommended over FFRfor invasive evaluation of intermediate LM ds.

Possible False Negative FFR

Possible False Positive FFR

LCX

LAD

EXCEL: Clinical Exclusion Criteria•• Prior PCI within 1 year, or prior LM PCI anytimePrior PCI within 1 year, or prior LM PCI anytime

•• Prior CABG anytimePrior CABG anytime

•• Need for any cardiac surgery other than CABGNeed for any cardiac surgery other than CABG

•• Additional surgery required within 1 yearAdditional surgery required within 1 year

•• Unable Unable to tolerate, obtain or comply with dual to tolerate, obtain or comply with dual antiplatelet therapy for 1 yearantiplatelet therapy for 1 year

•• Non Non cardiac cocardiac co--morbidities with life morbidities with life expectancy expectancy < 3 < 3 yearsyears

•• Clinical equipoise not presentClinical equipoise not present

EXCEL: AngiographicExclusion Criteria

•• Left main DS <50% (visually assessed)Left main DS <50% (visually assessed)

•• SYNTAX score ≥33SYNTAX score ≥33

•• Left main RVD <2.25 mm or >Left main RVD <2.25 mm or >4.5 4.5 mmmm

EXCEL: Use of XIENCE Prime

Enhanced stentEnhanced stentNew SDSNew SDS

--More flexible and More flexible and deliverabledeliverable

-- Shorter balloon tapersShorter balloon tapers-- Higher RBPHigher RBP

XIENCE Prime for LM Ds: LeMaX Pilot

Salvatella N. AHA 2009

174 pts with ULM 174 pts with ULM dsds. were treated with XIENCE Prime at . were treated with XIENCE Prime at 4 French centers between 12/07 and 5/094 French centers between 12/07 and 5/09

-- AllAll--comers, except STEMI and shock excludedcomers, except STEMI and shock excluded-- Mean age 69, 42% NSTEMI, 46% 3VD, mean 2.1 Mean age 69, 42% NSTEMI, 46% 3VD, mean 2.1 lsnslsns/pt/pt-- Mean SYNTAX score 25.1, 81% distal bifurcationMean SYNTAX score 25.1, 81% distal bifurcation

One-year MACE (in 122 eligible pts)

14.7

4.12.5 1.6

11.4

1.60

5

10

15

20

MACCE Death MI Stroke Revasc Stent thrombosis

N=21 subacute (d4), LM1 subacute (d4), Dg%

N=52 cardiac

3 non-cardiac

XIENCE Prime for LM Ds: LeMaX Pilot

Salvatella N. AHA 2009

174 pts with ULM ds. were treated with XIENCE Prime174 pts with ULM ds. were treated with XIENCE Prime-- Mean SYNTAX score 25.1 Mean SYNTAX score 25.1 ±± 10.1 10.1 --

Low Score – 10.0%Int. Score – 11.6%

High Score – 27.6%

1-year MACCE

Free

dom

from

MA

CCE

(%) N=122N=122

90.0%

88.4%

72.4%12 Mo

p Log Rank <0.0001

10 Mo8 Mo6 Mo4 Mo2 Mo070

75

80

85

90

95

100

EXCEL: Endpoints•• Primary endpointPrimary endpoint: : Death, MI, or stroke at Death, MI, or stroke at

median followmedian follow--up of 3 yearsup of 3 years

•• Major secondary endpointMajor secondary endpoint: : Death, MI, stroke Death, MI, stroke or or unplanned revascularization at median unplanned revascularization at median followfollow--up of 3 up of 3 yearsyears

vvPower analysisPower analysis: : Both Both endpoints are powered for endpoints are powered for sequential noninferiority and superiority sequential noninferiority and superiority testingtesting

•• Quality of life and costQuality of life and cost--effectiveness effectiveness assessmentsassessments: : At regular intervalsAt regular intervals

EXCEL: Organization (i)•• Principal Investigators:Principal Investigators:

-- InterventionalInterventional: Patrick W. Serruys, Gregg W. Stone: Patrick W. Serruys, Gregg W. Stone-- SurgicalSurgical: A. Pieter Kappetein, Joseph F. Sabik : A. Pieter Kappetein, Joseph F. Sabik

•• Executive Executive Operations Committee: Operations Committee: -- 4 principal investigators, Peter4 principal investigators, Peter--Paul Kint, Martin B. Paul Kint, Martin B.

Leon, Alexandra Lansky, Roxana Mehran, Leon, Alexandra Lansky, Roxana Mehran, MarieMarie--AngèleAngèleMorel, Chuck Simonton, David Taggart, Lynn Vandertie, Morel, Chuck Simonton, David Taggart, Lynn Vandertie, GerritGerrit--Anne van Anne van EsEs, Jessie , Jessie Coe, Poornima Sood, Ali Coe, Poornima Sood, Ali AkavandAkavand, Krishnankutty Sudhir, Thomas Engels, Krishnankutty Sudhir, Thomas Engels

•• Optimal Therapy Committee ChairsOptimal Therapy Committee Chairs-- PCIPCI: Martin B. Leon: Martin B. Leon-- SurgerySurgery: David Taggart: David Taggart-- MedicalMedical: Bernard Gersh: Bernard Gersh

Academically driven studyAcademically driven study; 50% interventionalists, 50% cardiac surgeons; 50% interventionalists, 50% cardiac surgeons

EXCEL: Organization (ii)•• Countries and Country Leaders (PCI and CABG)Countries and Country Leaders (PCI and CABG)

-- United StatesUnited States: David Kandzari and John Puskas: David Kandzari and John Puskas-- EuropeEurope (10): (10): MarieMarie--Claude Morice and David TaggartClaude Morice and David Taggart-- BrazilBrazil: Alex Abizaid and Luis Carlos Bento Sousa: Alex Abizaid and Luis Carlos Bento Sousa-- ArgentinaArgentina: Jorge Belardi and Daniel Navia : Jorge Belardi and Daniel Navia -- CanadaCanada: Erick Schampaert and Marc Ruel: Erick Schampaert and Marc Ruel-- S. KoreaS. Korea: Seung: Seung--Jung Park and JayJung Park and Jay--Won Lee Won Lee

•• Statistical CommitteeStatistical Committee-- Stuart Pocock, ChairStuart Pocock, Chair

-- Data Safety and Monitoring BoardData Safety and Monitoring Board-- Lars Wallentin, Chair Lars Wallentin, Chair

•• Academic Research OrganizationsAcademic Research Organizations-- Cardiovascular Research Foundation and CardialysisCardiovascular Research Foundation and Cardialysis

•• Sponsor: Sponsor: Abbott VascularAbbott Vascular

EXCEL: EXCEL: StatusStatus•• After 12 months of preparation the After 12 months of preparation the

protocol is finalizedprotocol is finalized

•• The site selection process is underwayThe site selection process is underway

•• FDA meetings and global regulatory FDA meetings and global regulatory submissions are being preparedsubmissions are being prepared

•• First patient enrolled: 3First patient enrolled: 3rdrd Quarter Quarter 20102010