Drug-Eluting Stents for Multivessel PCI: Indications and Outcomes

Ajay J. Kirtane, MD, SM

Center for Interventional Vascular Therapy Columbia University Medical Center / New York Presbyterian Hospital

Conflict of Interest Disclosure

Ajay J. Kirtane

None Off-label use will be discussed

Two Goals of Therapy in Patients with Stable CAD

1. Improve Symptoms and Quality

of Life

Measured by soft endpoints (i.e. angina/QOL scales)

Measured by hard endpoints (i.e. death, MI)

2. Improve Prognosis

It is generally accepted that revascularization makes symptomatic patients feel better but it is also a FACT that The Presence of Severe CAD is Prognostically Important!

Lets not forget our History

Workload / Exercise Tolerance Burden of Disease / Ischemia

Patients with prior MI / Decreased Ventricular Function may have even more to gain / or lose

Meta-Analysis of CABG vs. Medical Therapy: 7 RCTs

Mortality

Yusuf S et al, Lancet 1994

Mitigatated Gradient with Revasuclarization

10%

Medical Rx
Cardiac Death Rate
8%

Revasc

P <.0001

6.7%
6%

4.8%
4%

3.7% 2.9%

3.3% 2.0%

2%

1.8% 1.0%

0%

1331 56

718 109

545 243

252 267

1- 5%

5-10%

11-20%

>20%

% Total Ischemic Myocardium

Hachamovitch et al Circulation. 2003; 107:2900-2907.

MPS % Ischemic Myocardium (95% CI) Pre-Rx & 6-18 Months

40 35

PCI + OMT (n=159)

Mean = -2.7%

40 35

OMT (n=155)
Mean = -0.5%

30 25

(95% CI = -3.8% to -1.7%)

30 25

(95% CI = -1.6% to 0.6%)

20
15

p<0.0001 20
15

10
5 0

8.2%

5.5%
(4.7%-6.3%)

10
5 0

8.6%

8.1%
(6.9%-9.4%)

Pre-Rx

6-18m

Pre-Rx

6-18m

Shaw, et al, AHA 2007 and Circulation 2008

Why Could Revascularization of HigherRisk Ischemic Territories Be Important?

Less progression to decreased
ventricular function / ischemic cardiomyopathy

Better tolerance of events in other

coronary distibutions

Altered rheology within target vessel Less occlusion?

BARI 2D: Patient Flow

Coronary angiography in pts with type 2 diabetes 2368 pts were enrolled
Exclusions: Revasc not indicated Imm. revasc required LM disease S. Cr. >2.0 mg/dL HgbA1C >13.0%, Cl III or IV HF Hepatic dysfunction PCI or CABG w/i 1 yr

763 were selected for CABG vs. OMT

1605 were selected for PCI vs. OMT

385 assigned to OMT

378 assigned to CABG

807 assigned to OMT

798 assigned to PCI

A study of prophylactic revascularization among patients with no definite need for invasive intervention
IP = insulin provision IS = insulin sensitization

The BARI 2D Study Group. NEJM 2009;360:2503-15

BARI 2D: CABG Stratum

Survival Freedom from MACE (death, MI, or stroke)
86.4
80 Survival (%) 60 40 20 0 0 1 2 3 4 5

Event-free Survival (%)

100

Revascularization

100 80 60 40 20 0 0 1

Revascularization

77.6
Medical Therapy

Medical Therapy

83.6

69.5

P=0.33

P=0.01
2 3 4 5

Years
N at Risk 763 734 718 692 586 333 N at Risk 763 668

Years
634 568 421 230

The BARI 2D Study Group. NEJM 2009;360:2503-15

BARI 2D: Who got Revascularized?

PCI Stratum N=1176 USA 73.7% CABG Stratum N=1192 41.4% <0.0001 <0.05 <0.05 <0.0001 <0.0001 p

Prior MI
Proximal LAD disease Pts without prior procedures N lesions 50% DS, mean N lesions 70% DS, mean N of diseased vessels -0 -1 -2

30.1%
10.3% 2.1 1.5 0.8 1.0 4% 41% 36%

36.0%
19.4% 3.6 1.7 1.7 1.3 1% 9% 37%

<0.0001

-3
Any total occlusions

19%
7%

53%
14% <0.0001 <0.0001

Jeopardy index, %

38 22

61 21

The BARI 2D Study Group. NEJM 2009;360:2503-15 Schwartz L et al. AJC 2009;103:632638

ISCHEMIA Trial Proposed Design

Ischemia-Eligible Stable Patient (Stable CAD, Moderate-Severe Ischemia)
Blinded Coronary CTA Eligible Anatomy?
YES

NO

CT Exclusion Ancillary Study

RANDOMIZE

Invasive Strategy (Cath with Optimal Revasc + OMT)

OMT Strategy (OMT Alone)

J. Hochman, TCT 2010

Bare Metal Stents vs. CABG

4 randomized trials, 3,051 randomized pts,
5-year follow-up (patient level pooled analysis)

Freedom from Death, Stroke and MI (%)

100
90 80 70 5-year D/MI/CVA PCI vs. CABG 16.7% vs. 16.9%, P=0.69 HR [95%CI] = 0.96 [0.79-1.16]

PCI 83.3%
CABG 83.1%

PLR = 0.64

60
50

365

730

1095

1460

1825

Days
Daemen J et al. Circulation 2008;118:1146-1154

10 RCTs 7812 Pts: CABG vs. PCI: No Difference in Death and MI

35 30 25

Death or myocardial infarction (%)

8

CABG PCI

35 30 25 20 15 10 5 0

Mortality (%)

20 15 10 5 0 0 1 2 3 4 5 6 7

No. of patients*
CABG PCI 3889 3923 3767 3675 3798 3709

Years of follow-up
3415 3431 3180 3205 2693 2658 1853 1828 1609 1576 1477 1452 CABG PCI 3695 3725 3369 3269 3419 3310

Years of follow-up
3001 3023 2763 2797 2294 2267 1501 1491 1269 1253 1161 1150

Hlatky et al, The Lancet 2009;373:1190-1197

CABG vs PCI :Death and Diabetic Status

35 30 Mortality (%)
CABG no diabetes CABG diabetes PCI no diabetes PCI diabetes

25
20 15

10
5 0 0 1
3169 587 3217 574

Number of patients* CABG no diabetes 3263 CABG diabetes 615 PCI no diabetes 3298 PCI diabetes 618

2 3 4 5 6 Years of follow-up
3089 575 3148 555 2877 532 2918 508 2677 498 2725 475 2267 421 2281 373 1592 257 1608 218

7
1380 225 1393 179

8
1274 200 1288 160

Hlatky et al, The Lancet 2009;373:1190-1197

SYNTAX Trial Design

62 EU Sites

23 US Sites

Heart Team (surgeon & interventionalist) All Pts with de novo 3VD and/or
Amenable for both Amenable for only one treatment options treatment approach Treatment preference (9.4%)

Total enrollment LM disease (N=4,337) N=3075

Stratification: Referring MD or pts. refused Stratification: LM and informed consent (7.0%) LM and Diabetes Diabetes Inclusion/exclusion (4.7%) RandomizedWithdrew Arms before consent Two Registry Arms (4.3%) N=1800Other (1.8%) N=1275 Randomized Arms * Two Registry Arms Medical treatment (1.2%) PCI CABG PCI CABG CABG n=1800 TAXUS CABG TAXUS vs all captured w/ 2500 N=903 N=198 N=1077 N=897 n=1077 n=897 n=903 n=198 follow up 750 w/ f/u no f/u 71% 5yr f/u LM vs 3VD 3VD LM enrolled * TAXUS Express n=428 n=649 (N=3,075) 66.3% 33.7% 65.4% 34.6%

SYNTAX: All-Cause Death to 3 Years

Cumulative Event Rate (%)
40 CABG (N=897) P=0.13
Before 1 year* 3.5% vs 4.4% P=0.37 1-2 years* 1.5% vs 1.9% P=0.53 2-3 years* 1.9% vs 2.6% P=0.32

TAXUS (N=903)

20

8.6% 6.7%

0
0 12 24 Months Since Allocation 36

Cumulative KM Event Rate 1.5 SE; log-rank P value;*Binary rates Event Rate 1.5 SE. * Fishers Exact Test

SYNTAX: All-Cause Death/CVA/MI to 3 Years

Cumulative Event Rate (%)
40 CABG (N=897) P=0.21
Before 1 year* 7.7% vs 7.6% P=0.98 1-2 years* 2.2% vs 3.5% P=0.11 2-3 years* 2.5% vs 3.8% P=0.14

TAXUS (N=903)

20

14.1% 12.0%

0
0 12 24 Months Since Allocation 36
ITT population

Cumulative KM Event Rate 1.5 SE; log-rank P value;*Binary rates Event Rate 1.5 SE. * Fishers Exact Test

SYNTAX: MACCE to 3 Years

Cumulative Event Rate (%)
40 CABG (N=897) P<0.001
Before 1 year* 12.4% vs 17.8% P<0.002

TAXUS (N=903)
2-3 years* 4.8% vs 6.7% P=0.10

1-2 years* 5.7% vs 8.3% P=0.03

28.0%

20

20.2%

0 0 12 24 Months Since Allocation 36

ITT population

Cumulative KM Event Rate 1.5 SE; log-rank P value;*Binary rates Event Rate 1.5 SE. * Fishers Exact Test

SYNTAX: Repeat Revascularization to 3 Years

Cumulative Event Rate (%)
40 CABG (N=897) P<0.001
Before 1 year* 5.9% vs 13.5% P<0.001 1-2 years* 3.7% vs 5.6% P=0.06 2-3 years* 2.5% vs 3.4% P=0.33

TAXUS (N=903)

19.7%

20

10.7%

0
0 12 24 Months Since Allocation 36
ITT population

Cumulative KM Event Rate 1.5 SE; log-rank P value;*Binary rates Event Rate 1.5 SE. * Fishers Exact Test

SYNTAX: Generic QOL and Utilities

SF-36 SF- Physical Component Summary
55

SF-36 Mental Component Summary

50

50

45

40

40

35

P<0.001

P<0.001 P=0.23 P=0.43

P=0.50 P=0.07
30

30

Baseline

1 month

6 months

12 months

Baseline

1 month

6 months

12 months

EQ-5D Utilities (US)

1

PCI

CABG

0.9

0.8

0.7

0.6

P<0.001 P=0.16 P=0.99

0.5

Baseline

1 month

6 months

12 months

SAQ-AF: Angina-Free*
100%

PCI
80%

CABG

P=0.05

P=NS
68.5% 72.0% 71.6% 76.3%

P=NS
64.4%

61.6%

60%

40%

20%

0% 1 month 6 months 12 months

* Defined as SAQ-AF score = 100

SYNTAX Health Economics/Quality of Life ACC 2009 Orlando, FL 32

PCI and CABG Post-SYNTAX

Each strategy can have great
outcomes in appropriately selected patients

Hard clinical outcomes

(death/MI/CVA) are generally similar

Need to weigh the risk of potential

repeat procedures with PCI vs. the greater morbidity of CABG

SYNTAX: One-year MACCE Rates by Site

50

TAXUS Stent MACCE (%)

40

30

20

10

0 10 20 30 40 50

CABG MACCE (%)

Size of circle adjusted for number of patients

MACCE to 3 Years by SYNTAX Score Tercile Low Scores (0-22)

Cumulative Event Rate (%)
40
Mean baseline SYNTAX Score CABG 16.6 4.0 TAXUS 16.7 4.1

CABG (N=275)

TAXUS (N=299)

P=0.98

22.7%

20
22.5%

0
0 12 24 Months Since Allocation 36
Calculated by core laboratory; ITT population

Cumulative KM Event Rate 1.5 SE; log-rank P value;*Binary rates Event Rate 1.5 SE. * Fishers Exact Test

MACCE to 3 Years by SYNTAX Score Tercile Intermediate Scores (23-32)

Cumulative Event Rate (%)
40
Mean baseline SYNTAX Score CABG 27.4 2.8 TAXUS 27.3 2.8

CABG (N=300)

TAXUS (N=310) 27.4%

P=0.02

20 18.9%

0
0 12 24 Months Since Allocation 36
Calculated by core laboratory; ITT population

Cumulative KM Event Rate 1.5 SE; log-rank P value;*Binary rates Event Rate 1.5 SE. * Fishers Exact Test

MACCE to 3 Years by SYNTAX Score Tercile High Scores (>33)

Cumulative Event Rate (%)
40
Mean baseline SYNTAX Score CABG 41.5 7.1 TAXUS 41.7 7.8

CABG (N=315)

TAXUS (N=290)

34.1%

P<0.001

20 19.5%

0
0 12 24 Months Since Allocation 36
Calculated by core laboratory; ITT population

Cumulative KM Event Rate 1.5 SE; log-rank P value;*Binary rates Event Rate 1.5 SE. * Fishers Exact Test

Indications for CABG vs PCI in stable patients with lesions suitable for both procedures and low predicted surgical mortality
Subset of CAD by anatomy 1VD or 2VD non proximal LAD 1VD or 2VD proximal LAD 3VD simple lesions, full functional revascularization achievable with PCI, SYNTAX score 22 Favours CABG IIb C IA IA IA IA IA IA IA Favours PCI IC IIa B IIa B III A IIa B IIb B IIb B III B

3VD complex lesions, incomplete revascularizarion achievable with PCI, SYNTAX score > 22
Left main (isolated or 1VD, ostium/shaft) Left main (isolated or 1VD, bifurcation) Left main + 2VD or 3VD, SYNTAX score 32 Left main + 2VD or 3VD, SYNTAX score 33

ESC guidelines 2010

Pitfalls and issues relevant to SYNTAX score application in clinical practice

Time-consuming, with Interobserver and intraobserver variability Does not account for clinical or procedural variables that are known to impact outcomes during and after PCI Underpowered outcomes based upon subgroup analysis

Does not include any subset of lesions (i.e. in-stent restenosis, stenotic bypass grafts, coronary anomalies, muscular bridges, aneurysms)
Does not account for patient choice!
Capodanno, et al. Am Heart J 2011;161:462-70

In observational registries, the intermediate tertile is frequently poorly calibrated with respect to the outcomes of the high and low tertiles
1-year MACCE 1-year MACE 32-month MACE 3-year MACCE

+14.0%

-11.2%

+6.5%

SYNTAX
Circulation 2010

Capodanno et al.
Circ Card Interv 2009

Brito et al.
EuroPCR 2010

MAIN COMPARE
JACC Interv 2010

Expected risk for the intermediate stratum

Capodanno, et al. Am Heart J 2011;161:462-70

Mortality with Complete vs. Incomplete Revascularization in MVD

Categorization by SYNTAX Score

Kim YH et al, Circulation 2011

FAME: Optimizing Complete Revascularization

1005 pts with MVD undergoing PCI with DES were randomized to FFR-guided vs. angio-guided intervention
Freedom from death, MI, revasc
1.00
0.95 0.90

Absolute difference in MACE-free survival

FFR-guided (n=509)
30 days 2.9% 90 days 3.8%

0.85
0.80 0.75

180 days Angio-guided 4.9% 360 days (n=496) 5.3% MACE 13.3% vs. 18.2% P=0.02
60 120 180 240 300 360

0.70
0

Days
Tonino PAL et al. NEJM 2009;360:21324

Angiographic vs. Functional Severity of Coronary Stenosis

~20%

FFR

~35% 50-70 71-90 91-99

Stenosis classification by angiography

Of 509 pts with angiographically-defined MVD, 46% had functional MVD

Tonino et al, NEJM 2009
3056029-1

FAME : Downgrading Multivessel Disease with FFR

3 Vessel Disease 0-VD 3-VD
9% 14%

2 Vessel Disease 0-VD 2-VD

12%

43% 34% 43% 45%

1-VD 2-VD

1-VD

86% 3VD and 57% 2VD reclassified >1 vessel

Tonino et al, JACC 2010;55:2816-21

Change in SYNTAX Score after FFR

SYNTAX score ~500 FAME patients after FFR
Lowest Tertile Middle Tertile Highest Tertile
Lowest Tertile Middle Tertile Highest Tertile

160 (32%)

166 (34%)

95 (19%)

119 (24%)

281 (57%)

170 (35%)

Without FFR

With FFR

CW Nam (preliminary data); presented TCT 2010

FAME II Study Design

Stable Patient scheduled for 1, 2, or 3-vessel PCI
FFR in all stenoses FFR0.80 in 1 lesion
YES

NO

OMT Alone Registry

RANDOMIZE (n=1600)

PCI + OMT (Indicated stenoses)

OMT Alone

W. Fearon, TCT 2010

SPIRIT II, III, IV and COMPARE trials Pooled database analysis (n=6,789) Ischemic TLR
10

EES (n=4,247) PES (n=2,542)

Ischemic TLR (%)

HR: 0.60 [0.48, 0.75] P<0.001

6.6%

4.7%

4.1%
2.3%
0 0 3 6 9 12 15 18 21 24

Time in Months
Number at risk XIENCE TAXUS 4247 2542 4143 2416 4004 2328 3891 2260 3363 2018

SPIRIT II, III, IV and COMPARE trials Pooled database analysis (n=6,789) Stent thrombosis (ARC definite/probable)
3

Stent thrombosis ARC def or prob (%)

EES (n=4,247) PES (n=2,542)

HR: 0.30 [0.19, 0.47] p<0.001 2.3%

0.7%
0 0 3 6 9 12 15 18 21 24

Time in Months
Number at risk XIENCE TAXUS 4247 2542 4177 2463 4082 2408 3998 2350 3479 2110

Potential SYNTAX MACCE with 2nd Gen DES

Cumulative Event Rate (%)
40 CABG (N=897) P<0.001 TAXUS (N=903)

28.0%
30%

20.2%
20

0 0 12 24 Months Since Allocation 36

ITT population

Cumulative KM Event Rate 1.5 SE; log-rank P value; * Binary rates Event Rate 1.5 SE. * Fishers Exact Test

FREEDOM Trial (NHLBI)

Eligibility: DM patients with MV-CAD eligible for stent or surgery Exclude: Patients with acute STEMI, cardiogenic shock

N=1900 at 100 centers from NA, SA, EU, Rand. 1:1

MV DES stenting (Cypher or TAXUS) and abciximab

CABG with or without cardiopulmonary bypass

PRIMARY Endpoint: 3-year death, MI, stroke SECONDARY Endpoints: 12-month MACCE, 3-year Quality of Life PI: Valentin Fuster

Key Decision Points in Multivessel Revascularization

What are the goals of therapy? Can the patient take/adhere to DAPT? Is the patient high surgical risk?
Is the patient insulin dependent? WHAT DOES THE PATIENT WANT?

Conclusions: Multivessel Disease

These are high-risk coronary lesions and the
least stable subtypes of stable CAD

PCI and CABG have very similar rates of

hard clinical endpoints and Sx/QOL will largely depend on completeness of revasc

Greater rates of repeat revascularization with PCI, especially in complex disease

Patient selection and patient preference will

generally dictate the best and most appropriate care!