Revascularization First !!

Jeffrey W. Moses, MDProfessor of Medicine

Columbia University Medical Center

Disclosure Statement of Financial Interest

I, Jeffrey Moses, have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

Consultant: BSC (minor)

CASE 1

CCS Class IIStress test: Exercise ECG: 6:50 Minutes of Bruce Protocol, 2mm ST Depression, Stopped Because of Chest PainDuke Treadmill Score: -11Echo: EF: 55-60%, No Significant Valvular Disease

Clinical Presentation

New York, NY

Patient DemographicsAge: 60Gender: Male

Family History↑ LipidsHypertension

RiskFactors

NephrolithiasisPast Medical History

Treatment:Med Rx, No Further Investigation

CASE 2

• 81 y/o man with colon ca s/p chemo and resection 15 y/a, now presents with 3 months progressive L shoulder pain with exertion

• ASA 81 mg daily, doxazosin 1 mg daily

• Nuclear Stress test: small, mild, reversible inferolateral perfusion defect, LVEF 60%

Symptoms and QOL

56 57 59 59

4750

5356

21

42

53

42

33

23

0

10

20

30

40

50

60

Baseline 1 3 6 12 24 36

Months

COURAGE: Freedom from Angina

Weintraub et al, N Engl J Med 2008;359:677-681.

PCI + OMT OMT

An

gin

a-fr

ee (

%)

P=0.35

P<0.001

P<0.001P<0.001 P=0.005 P=0.010 P=0.30

32 % Crossover at a Median of 10.8 months

Top Tercile (weekly)

COURAGE: Angina Frequency

PCI plus OMT OMT P Value

First

Baseline 35 + 14 35 + 14 0.75

1 month 68 + 27 58 + 25 <0.001

3 months 74 + 27 65 + 26 <0.001

6 months 78 + 25 72 + 25 0.02

12 months 79 + 25 75 + 23 0.09

24 months 84 + 21 79 + 23 0.03

36 months 83 + 21 82 + 22 0.94

Weintraub et al, N Engl J Med 2008;359:677-681.

PCI plus OMT OMT P Value

Second

Baseline 71 + 8 71 + 8 0.18

1 month 81 + 19 76 + 20 0.002

3 months 86 + 18 79 + 22 <0.001

6 months 87 + 18 82 + 21 0.002

12 months 88 + 17 85 + 20 0.02

24 months 90 + 16 85 + 19 0.001

36 months 89 + 18 87 + 17 0.28

Middle Tercile (monthly)

COURAGE: Angina Frequency

Weintraub et al, N Engl J Med 2008;359:677-681.

COURAGE: QOL

PCI + OMT

OMT

0

Months from Baseline

6 12 24 360

50

60

70

80

90

100

Mea

n S

core

* * **

Weintraub et al, N Engl J Med 2008;359:677-681.

Safety Endpoint at 4.6 Years%

of

Pat

ien

ts

PCI OMT PCI OMT PCI OMT

Death Spontaneous MI Revascularization

At mean10 mos

At mean10.8 mos

40%P<0.001

13%P=NS

11%P=NS

NEJM 2007;356:1503-16; AHJ 2006;151:1173-9

BARI 2D: Prompt Revascularization Reduces Ischemic Symptoms Over 3 Years

Analysis of the BARI 2D trial

Conclusion: In diabetic patients with stable ischemic heart disease, a strategy of early revascularization and optimal medical therapy achieves better angina outcomes than does optimal medical therapy alone.

Dagenais GR, et al. Circulation.2011;Epub ahead of print.

3-year Follow-Up

PromptRevascularization

(n = 1,173)

Medical Therapy

(n = 1,191) P Value

Worsening Angina 8% 13% <0.001

New Angina 37% 51% 0.001

SubsequentRevascularization 18% 33% 0.001

BARI 2D: QOL by Revasc. Status

DASI Self-rated Health

Rev vs Med:Delta = 1.34, p = 0.002

Delta = 1.70, p = 0.017

DA

SI

Sel

f-ra

ted

Hea

lth

Courtesy of Frederick Feit, MDTCT: September 23, 2010

MedMed

RevRev

Baseline Year 1 Year 2 Year 3 Year 4

35

37

39

41

43

45

47

49

51

53

55

Baseline Year 1 Year 2 Year 3 Year 4

16

24

23

22

21

20

19

18

17

OAT

Costs of OMT

Mark et al NEJM 2009;360:774

PCI MED

Hospital $22,800 $12,700

Year 1 $3400 $5300

Year 2 $1500 $2700

BARI 2D: Lifetime costs PCI vs OMT $200 less

Dagenais GR, et al. Circulation.2011; Epub ahead of print.

PCI plus OMT OMT P Value

Third

Baseline 97 + 5 97 + 5 0.61

1 month 93 + 14 88 + 19 0.002

3 months 91 + 18 90 + 16 0.67

6 months 92 + 15 89 + 19 0.02

12 months 93 + 14 90 + 18 0.02

24 months 92 + 15 91 + 15 0.64

36 months 94 + 14 93 + 14 0.31

Bottom Tercile (none)

Weintraub et al, N Engl J Med 2008;359:677-681

COURAGE: Meds Can Make You Feels Worse! Angina Frequency

>5 Years

0.85 (0.67, 1.07)

Pursnani et al, Circ Cardiovasc Interv. 2012;5:476-490

Meta-analysis of PCI for Chronic CADFreedom From Angina

Study or Subgroup EventsOMT

M-H, Random, 95% CI M-H, Random, 95% CI

ACME-1 (3 years) 1992 50 85 1.23 (0.93, 1.63)

PCITotal Events Total Weight

Risk Ratio

43 90

Risk Ratio

9.6%ACME-2 (5 years) 1997 27 51 1.47 (0.94, 2.31)18 50 5.6%ALKK (5 years) 2003 115 149 1.27 (1.09, 1.48)92 151 13.8%AVERT (1.5 years) 1999 95 177 1.31 (1.04, 1.65)67 164 11.2%BARI 2D (5 years) 2009 486 798 1.03 (0.95, 1.12)476 807 16.1%COURAGE (5 years) 2007 316 1149 1.06 (0.92, 1.21)296 1138 14.4%DEFER (5 years) 2001 51 61 91 11.1%MASS-1 (5 years) 1995

90

MASS-2 (5 years) 200444 69 2.70 (1.72, 4.24)17 72 5.6%

119 205 1.28 (1.06, 1.55)92 203 12.5%TOTAL (95% CI) 2773 2766 100.0%

<1 Year

Favors OMT Favors PCI0.1 0.2 0.5 1 2 5 10

1.20 (1.06, 1.37)

ACME-1 (3 years) 1992 61 96 1.38 (1.06, 1.79)47 102 14.2%ACME-2 (5 years) 1997 27 51 1.47 (0.94, 2.31)18 50 8.0%ALKK (5 years) 2003 134 149 1.10 (1.00, 1.20)124 151 21.3%

319 798 1.66 (1.43, 1.93)194 807 19.0%BARI 2D (5 years) 2009680 1149 1.13 (1.05, 1.22)595 1138 21.8%COURAGE (5 years) 2007107 205 1.43 (1.14, 1.79)74 203 15.7%MASS-1 (5 years) 1995

Subtotal (95% CI) 2448 2451 100.0% 1.32 (1.13, 1.54)10521328Total events

ACME-1 (3 years) 1992 50 85 1.23 (0.93, 1.63)43 90 33.7%AVERT (1.5 years) 1999 95 177 1.31 (1.04, 1.65)67 164 35.8%MASS-1 (5 years) 1995 58 72 2.52 (1.77, 3.60)23 72 30.5%Subtotal (95% CI) 334 326 100.0% 1.57 (1.06, 2.32)

133203Total events

1-5 Years

ALKK (5 years) 2003 115 149 1.27 (1.09, 1.48)92 151 18.6%BARI 2D (5 years) 2009 486 798 1.03 (0.95, 1.12)476 807 21.3%COURAGE (5 years) 2007 316 1149 1.06 (0.92, 1.21)296 1138 19.4%

51 90 0.85 (0.67, 1.07)61 91 15.4%DEFER (5 years) 200144 69 2.70 (1.72, 4.24)17 72 8.1%MASS-1 (5 years) 1995119 205 1.28 (1.06, 1.55)92 203 17.1%MASS-2 (5 years) 2004

Subtotal (95% CI) 2460 2462 100.0% 1.17 (1.00, 1.38)

10341131Total events

Does PCI reduce Death and MI?

Probably YES! (in the right pt)

MASS II 10-year Follow-up

MED203

CABG205

PCI203

CD/MI/CVA 48% 30% 33%

D/MI/CVA 58.5% 43.8% 43.8%

Angina Free 43% 64% 59%

Hueb et al, Circ 2010 August

58% 3VD

0

5

10

15

20

25

30

Cu

mu

lati

ve i

nci

den

ce (

%)

166 156 145 133 117 106 93 74 64 52 41 25 13Registry447 414 388 351 308 277 243 212 175 155 117 92 53PCI+MT441 414 370 322 283 253 220 192 162 127 100 70 37MT

No. at risk

0 1 2 3 4 5 6 7 8 9 10 11 12

FAME 2: Primary Outcomes

MT vs. Registry: HR 4.32 (1.75-10.7); p<0.001

PCI+MT vs. Registry: HR 1.29 (0.49-3.39); p=0.61

PCI+MT vs. MT: HR 0.32 (0.19-0.53); p<0.001

Months after randomization

De Bruyne B et al. NEJM 2012:on-line

0

5

10

15

20

25

30

Cu

mu

lati

ve i

nci

den

ce (

%)

0 7days 1 2 3 4 5 6 7 8 9 10 11 12

Months after randomization

p-interaction = <. 003

>8 days: HR 0.42 (0.17-1.04); p=0.053

≤7 days: HR 7.99 (0.99-64.6); p=0.038

MT alone

PCI plus MT

MT alone

PCI plus MT

≤7 days

>8 days

FAME 2: Kaplan-Meier Plots of Landmark Analysis of Death or MI

0

0.5

1.0

1.5

2.0

2.5

Cu

mu

lati

ve

in

cid

en

ce

(%

)

0 1 2 3 4 5 6 7Days after randomization

JSAP:PCI In Stable Angina365 Patients Randomized PCI vs OMT

Kazuhiko N et al, J. AM. Coll. Cardiol. Intv. 2008;1;469-479

1.0

0 1 2 3 4 5

0.7

0.8

1.0

0

Years

0.9

Hazard ratio, 0.541; 95% CI (0.287-0.983)P=0.045

0 1 2 3 4 50

0.7

0.8

Years

0.9

Hazard ratio, 0.664; 95% CI (0.446-0.981)P=0.040

0.6

PCI plus medical therapy

Initial medical therapy only

PCI plus medical therapy

Initial medical therapy only

Initial-Medical* 176 166 146 97 14 PCI+Medical* 176 169 154 106 9

Initial-Medical* 182 177 166 115 18 PCI+Medical* 183 179 170 123 15

Death+ACS+CVA Death+ACS+CVA+hospitalization

Rates of Spontaneous MI: 12 RCTs 37,000 Patient-years

Test for interaction P=0.53

Bangalore et al. Circ 2013;on-line

.1 1Favors PCI

10

TrialPCI MT

Event IRR (95% CI) % Weight

ACME-1ACME-2ALKK-1AVERTDEFERMASS-1RITA-2SWISS-2

65

12403

2340

Favors Medical Therapy

NNo Stents

IRR (95% CI)Event N

D+L Subtotal (I-squared = 46.3%, P=0.071)I-V Subtotal

Random Effects Poisson Regression

10750

1511649172

514105

10551

1491779072

50496

359423

259

0.51 (0.13, 2.04)0.98 (0.28, 3.39)0.76 (0.32, 1.80)0.92 (0.23, 3.70)5.06 (0.24, 105.30)1.00 (0.20, 4.95)1.11 (0.63, 1.95)0.25 (0.12, 0.51)0.72 (0.43, 1.22)0.71 (0.50, 1.00)

3.003.666.743.000.672.30

12.308.84

40.52

0.76 (0.58, 0.99)

I-V OverallD+L Overall (I-squared = 31.6%, P=0.138) 0.77 (0.60, 0.99)

0.82 (0.69, 0.97)100.00

Stents

D+L Subtotal (I-squared = 0.0%, P=0.556)I-V Subtotal

BARI 2DCOURAGEJSAPMASS-2

621197

31

8071138192203

7981149192205

57108

321

0.93 (0.65, 1.33)0.90 (0.69, 1.17)0.43 (0.11, 1.66)0.67 (0.39, 1.17)0.86 (0.71, 1.05)0.86 (0.71, 1.05)

19.5624.143.13

12.6459.48

Cardiac Mortality

Test for interaction P=0.03

Bangalore et al. Circ 2013;on-line

.1 1Favors PCI

10

TrialPCI MT

Event % Weight

ALKK-1AVERTDEFERMASS-1RITA-2SWISS-2

14132

2222

Favors Medical Therapy

NNo Stents

IRR (95% CI)Event N

D+L Subtotal (I-squared = 36.6%, P=0.162)I-V Subtotal

Random Effects Poisson Regression

1511649172

514105

1491779072

50496

4124

133

I-V OverallD+L Overall (I-squared = 49.7%, P=0.036)

Stents

D+L Subtotal (I-squared = 0.0%, P=0.625)I-V Subtotal

BARI 2DCOURAGEJSAPMASS-2

33253

25

8071138192203

7981149192205

44232

24

0.29 (0.10, 0.88)0.92 (0.06, 14.79)0.67 (0.11, 4.03)2.00 (0.37, 10.92)0.60 (0.30, 1.20)0.15 (0.04, 0.50)

0.47 (0.24, 0.93)0.48 (0.30, 0.77)

8.872.044.394.79

14.697.96

42.74

0.70 (0.44, 1.09)

0.74 (0.49, 1.11)0.86 (0.67, 1.11)

100.00

1.35 (0.86, 2.12)0.91 (0.52, 1.61)0.67 (0.11, 3.99)0.95 (0.54, 1.66)1.08 (0.80, 1.45)1.08 (0.80, 1.45)

19.0516.854.39

16.9757.26

IRR (95% CI)

Rate of MI / Rate of Crossover

Bangalore et al. Circ 2013;on-line

Crossovers (%)

Lo

g I

nci

den

t R

ate

Rat

io (

Dea

th)

MT Better

PCI Better

40

-1.5

0

50 60302010

-1.0

-0.5

Odds Ratio (95% Confidence Interval)

Overall

Trial

Sievers et al.

Dakik et al.ACIP

ACME-1

TIME

ALKK

AVERT

Bech et al.MASS

ACME-2

RITA-2

Year of Publication

1993

19981997

1997

2004

2003

1999

20011999

1997

2003

271/3675

PCI

0/44

1/212/192

16/115

45/153

6/149

1/177

2/906/72

9/51

43/504

335/3838

Medical

1/44

1/2320/366

15/112

40/148

17/151

1/164

4/916/72

10/50

43/514

Deaths/Total

SWISSI II

DANAMI

COURAGE

INSPIRE

Hambrecht et al.

MASS II2007

2006

2007

2006

2004

20066/96

19/503

85/1149

2/10428/205

22/105

24/505

95/1138

1/10135/203

0/50 0/51

1.1 10

Random effects modelFixed effects model

Pheterogeneity=0.263; I2=17%

17 RCTs: PCI vs. Medical TreatmentPrimary End Point: All-Cause Death

Kastrati et al; 2007

0.80 (0.64 to 0.99)

0.80 (0.68 to 0.95)

PCI vs. Med Rx-21Trials: Mortality

Jeremias et al, Am Jour Med 2009;122:152-161.

ACME-1 1.11 0.52 2.37TOPS 0.14 0.00 7.31Sievers et al 0.14 0.00 6.82MASS I (PCI) 1.00 0.31 3.25ACIP 0.31 0.13 0.76RITA-2 1.02 0.66 1.59ACME-2 0.86 0.32 2.32DANAMI 0.82 0.43 1.53Dakik et al 1.16 0.07 19.41Horie et al 0.21 0.04 1.11AVERT 0.93 0.06 14.90TOAT 2.12 0.21 21.13Bech et al 0.51 0.10 2.58TIME 1.12 0.68 1.86ALKK 0.36 0.15 0.84MASS Il (PCI) 0.95 0.56 1.62DECOPI 0.83 0.31 2.23OAT 1.04 0.76 1.42INSPIRE 1.90 0.20 18.51SWISS II 0.30 0.13 0.66COURAGE 0.90 0.64 1.27

0.67 1.00

Study ORLowerLimit

UpperLimit Odds Ratio and 95%

Combined 0.82Favors Revasc. Favors Med.

0.01 0.1 1 10 100

Safety Endpoint at 4.6 Years%

of

Pat

ien

ts

PCI OMT PCI OMT PCI OMT

Death Spontaneous MI Revascularization

At mean10 mos

At mean10.8 mos

40%P<0.001

13%P=NS

11%P=NS

NEJM 2007;356:1503-16; AHJ 2006;151:1173-9

Cardiac Mortality in Medically Treated Patients According to Ischemic Risk – CSMC database

Hachamovitch et al Circulation. 2003;107:2900-07

% Total Myocardial Ischemia

0% 1- 5% 5-10% 11-20% >20%

Car

dia

c D

eath

Rat

e (%

)(1

.9 y

r F

U)

N=7110 N=1331 N=718 N=545 N=252

N=9,956 pts

5.4% cardiac mortality in 1.9 years -

Is this “stable” angina?

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

0

40

5

10

15

20

25

35

30

Pre-Rx 6-18m

8.2%5.5%

(4.7%-6.3%)

PCI + OMT (n=159) OMT (n=155)

0

40

5

10

15

20

25

35

30

Pre-Rx 6-18m

(6.9%-9.4%)

8.6% 8.1%

Mean = -2.7% (95% CI = -3.8% to -1.7%)

Mean = -2.7% (95% CI = -3.8% to -1.7%)

Mean = -0.5%(95% CI = -1.6% to 0.6%)

Mean = -0.5%(95% CI = -1.6% to 0.6%)

p<0.0001

RCTs with Ischemia OMT vs PCI

• Identified 4 randomized controlled trials (RCT) ACME COURAGE AHJ (baseline ischemia substudy) FAME-2 SWISSI-II

• Comprised a total of 1769 patients 871 randomized to PCI 898 randomized to MT alone

• Length of follow-up ranged from ~7 mo – 10 yrs Weighted average of 4.5 years

All-Cause Mortality: HR Analysis

PCI Better

Study ID

ACME

1

All-cause Mortality in Randomized Trials of PCI vs. MT(Patients with Ischemia or Equivalent)

ES(95% CI)

% Weight(I-V)

.1 10MT Better

0.73 (0.24, 2.22) 20.42

COURAGE AHJ 0.62 (0.30, 1.28) 48.00

FAME-2 0.33 (0.03, 3.17) 4.65

SWISSI-II 0.42 (0.16, 1.11) 26.93

Fixed Effects (I2=0.0%, p=0.84) 0.56 (0.34, 0.93) 100.00

Random Effects 0.56 (0.34, 0.93)

Summary of Results: Mortality• Significant 44% reduction in all-cause

mortality was observed with PCI vs. MT HR 0.56; 95% CI [0.34-0.93], p=0.02

• Point estimate of the HR for mortality favoring PCI vs. MT varied from 0.33-0.73; I2=0% Baseline ischemia cohort of the COURAGE

trial comprised 48% weight of the studies

• Analysis Using Count Data: 28/871 (3.2%) deaths with PCI 54/898 (6.0%) deaths with MT RR 0.56; 95% CI [0.36-0.87], p=0.01

PCI Better

Study ID

ACME

1

ES(95% CI)

% Weight(I-V)

.1 10MT Better

0.73 (0.24, 2.22) 11.13

COURAGE AHJ 0.62 (0.30, 1.28) 26.16

FAME-2 0.33 (0.03, 3.17) 2.54

SWISSI-II 0.42 (0.16, 1.11) 14.68

Fixed Effects (I2=0.0%, p=0.76) 0.61 (0.42, 0.89) 100.00

Random Effects 0.61 (0.42, 0.89)

ACIP* 0.24 (0.05, 1.11) 5.73

DANAMI Symptomatic* 0.68 (0.30, 1.55) 20.42

DANAMI Silent* 0.93 (0.40, 2.16) 19.36

All-Cause Mortality: HR AnalysisAll-cause Mortality in Randomized Trials of PCI vs. MT*

(Patients with Ischemia or Equivalent)

*Secondary analysis includes studies with small no. of CABG pts

0

10

20

30

40

50

60

70

80

Inappropriate Uncertain Appropriate

ACC Appropriateness Categories

Underuse and Adverse Outcomes

Ko et al, JACC 2012; in press

CABG

Pro

po

rtio

n o

f C

ard

iac

Cat

her

izat

ion

(%

)

HR: 0.99

HR: 0.57(p=0.12)

n=311 n=326 n=991

PCI

HR: 0.61(p=0.009)

Medical

1625 pts with Chronic CAD and Cath: 3 year risk : Death /ACS

Hazards of Underutilization

• 9300 Patients with recent onset chest pains

• 57% appropriate patients did not get angio median follow-up: three years

Hemingway et al, Annals of Int Med 2008;248:221

Angio + Angio –

11% 22%Death or ACS HR : 2.5

Symptoms Med. Rx

Class llI or lV Max Rx U A A A AClass I or lI Max Rx U U A A AAsympto-matic Max Rx

I I U U UClass llI or lV No/min Rx

I U A A AClass I or lI No/min Rx

I I U U UAsympto-matic No/min Rx

I I U U UCoronary Anatomy

CTO of 1 vz.

no other disease

1-2 vz. disease

no prox. LAD

1 vz. disease of prox.

LAD

2 vz. disease

with prox. LAD

3 vz. disease no Left Main

Low-Risk Findings on Non-invasive Study

Patel et al JACC 2009 53 (February): 530-553

Asymptomatic

Stress Test Med. Rx

High Risk Max Rx U A A A AHigh Risk No/min Rx

U U A A AInt. Risk Max Rx U U U U AInt. Risk No/min Rx

I I U U ALow Risk Max Rx I I U U ULow Risk No/min Rx

I I U U UCoronary Anatomy CTO of 1

vz.no other disease

1-2 vz. disease

no prox. LAD

1 vz. disease of prox.

LAD

2 vz. disease

with prox. LAD

3 vz. disease no Left Main

Appropriateness Ratings by Low-Risk Findings on Noninvasive Imaging Study and Asymptomatic

• If the goal was really best outcomes why aren’t physicians monitored for potential underuse? Overuse may cost money Underuse costs lives

• We have hoodwinked the patients into denying themselves treatment If you have a treatment that may help

and doesn’t harm you take it We have convinced the patient to do

the opposite

Conclusions • In cases of moderate symptoms PCI

provides immediate and superior symptomatic relief vs “OMT” (i.e., crossovers are Rx failure) with no cost of MI, death or CABG

• In cases of demonstrated ischemia or critical anatomy the overwhelming evidence favors revascularization to reduce death and MI

• “OMT” alone is safe for mild symptoms, little or no ischemia and noncritical anatomy …..Period

8000 Ischemia-Eligible Stable Patient(Stable CAD, Moderate-Severe Ischemia)

Blinded Coronary CTA

Eligible Anatomy?

RANDOMIZE

Invasive Strategy(Cath with

Optimal Revasc + OMT)

CT ExclusionAncillary Study

OMT Strategy(OMT Alone)

YESNO

ISCHEMIA Trial Design

J. Hochman, TCT 2010

This is an Untested Hypothesis