1. COURAGE What Should the Impact of the COURAGE Trial
Be on Interventional Cardiology?:
Optimal Medical Therapy First
William S. Weintraub, MD
Chief of Cardiology
Christiana Care Health System
Professor of Medicine, Thomas Jefferson University

2. William S. Weintraub, MD DISCLOSURES Consulting Fees
Bristol Myers Squibb, Cardionet, Eli Lilly and Company, Humana, sanofi-aventis U.S. LLC
Grants/Contracted Research
Bristol Myers Squibb, AstraZeneca, Abbott Vascular, Otsuka America, Inc., sanofi-aventis U.S. LLC
Other
Bayer AG - Expert witness
Pfizer - Expert witness

3. Funding/Disclosures COURAGE Funding
Cooperative Studies Program (CSP) of the U.S. Department of Veterans Affairs (DVA) Office of Research and Development
Canadian Institutes of Health Research
Merck, Pfizer, Bristol-Myers Squibb, Fujisawa, Kos Pharmaceuticals, Datascope, Astra-Zeneca, Key Pharmaceutical, Sanofi-Aventis, First Horizon, GE Healthcare; all industrial funds were unrestricted and payable to the DVA CSP; no direct industry involvement in the trial design, conduct or analysis
Presenter Disclosures
Grants: Bristol-Myers Squibb, Sanofi-Aventis, Otsuka, CVT, Merck, Pfizer
Consultant: Bristol-Myers Squibb, Sanofi-Aventis, Otsuka, CVT, Glaxo Smith Klein, Lilly, Indigo

4. Stable CAD: PCI vs Conservative Medical Management
Meta-analysis of 11 randomized trials; N = 2,950
Favors PCI
Favors Medical Management
Death
Cardiac death or MI
Nonfatal MI
CABG
PCI P
0.68
0.28
0.12
0.82
0.34 1 2
Risk ratio
(95% Cl)
Katritsis DG et al. Circulation. 2005;111:

5. Patient Expectations About Elective PCI
52 consecutive patients scheduled for first elective PCI completed semi-structured questionnaire prospectively
Do you think the angioplasty will prevent a heart attack?
Yes
75%
Do you think the angioplasty will help you live longer?
71%
Holmboe et al. J Gen Intern Med 2000;15:632.

6. Most PCIs are Emergent? Elective Urgent Emergent NY State1 87% --- 13%
NCDR2
49%
36%
15%
APPROACH3
26%
54%
19%
BCIS4
56%
44%
1Am J Cardiol 2006;98: Based on 82,140 cases in NY State Angioplasty Registry
2ACC National Cardiovascular Data Registry. Based on 610,436 cases.
3APPROACH Registry, Province of Alberta, Based on 4,922 cases.
4UK 2005 PCI Audit Data, British Cardiovascular Intervention Society, Based on ,142 cases.

7. BARI
COURAGE
25,200
Patients Undergoing
Coronary Angiogram
35,539
Patients Undergoing
Coronary Angiogram
12,530 (50%)
18,360 (52%)
Clinically Eligible
Clinically Eligible
67%
Exclusion Criteria
86%
Exclusion Criteria
Eligible for Both
CABG and PTCA
4,110
3,071
Eligible for Both
OMT and PCI
Refused Randomization
Refused Randomization
55%
26%
1,829 (7%)
2,287 (6.4%)
Enrolled and Randomized
Enrolled and Randomized
CABG
PTCA
OMT
OMT + PCI
914
915
1,138
1,149
NEJM 1996:335:217
NEJM 2007;356:1503

8. COURAGE Enrolled Low Risk Patients?
DM 34%
Dyslipidemia 71 %
HTN 67%
Smoker 29%
Prior MI 39%
Prior Revasc 26%
Angina 88%
Prox LAD 34%
MVD 70%
Multiple defects 67%
Event rate/yr 4%

9. Optimal Medical Therapy
Pharmacologic
Anti-platelet: aspirin; clopidogrel in accordance with established practice standards
Statin: simvastatin ± ezetimibe or ER niacin
ACE Inhibitor or ARB: lisinopril or losartan
Beta-blocker: long-acting metoprolol
Calcium channel blocker: amlodipine
Nitrate: isosorbide 5-mononitrate
Lifestyle
Smoking cessation
Exercise program
Nutrition counseling
Weight control
The medical therapy in the COURAGE Trial is aggressive and multifaceted and conforms to the most recent ACC/AHA Treatment Guidelines. It consists of an individualized lifestyle interventions: diet, weight loss, smoking cessation/relapse prevention, and regular exercise routine, as well as of the aggressive use of the following pharmacologic agents. A
ll patients in both arms received :
anti-thrombotic therapy with aspirin (or clopidogrel 75 mg/day, if aspirin allergy was present).
Additionally, clopidogrel plus aspirin use evolved as an accepted standard for PCI management during the course of the study, including clopidogrel loading prior to (or during) PCI.
Medical anti-ischemic therapy in both arms included long-acting metoprolol, amlodipine, and isosorbide 5-mononitrate, alone or in combination.
Post-MI patients received standard secondary prevention with beta-blockers (unless contraindicated) and an lisinopril or, for those unable to take lisinopril, losartan for left ventricular ejection fraction <40% or anterior MI location.
The centerpiece of medical therapy was aggressive LDL lowering with a target of mg/dL ( mmol/L) using up to 80 mg of simvastatin daily, alone or in combination with ezetimibe, in conformity with established.
Patients with high-density lipoprotein-cholesterol <40 mg/dL (1.04 mmol/L) were treated with extended release niacin (Niaspan).
Discussion:
Drug-eluting stents were not approved for clinical use until very late during patient accrual and, subsequently, few patients received these intracoronary devices.
Applied to Both Arms by Protocol and Case-Managed

10. OMT not Achievable in Real World?
♥ OMT with risk factor control is our responsibility
♥ PCI does not relieve us of that responsibility
♥ How are you going to assure DAPT compliance?

11. Long-Term Improvement in Treatment Targets (Group Median ± SE Data)
Baseline
60 Months
PCI +OMT
OMT
SBP
131 ± 0.77
130 ± 0.66
124 ± 0.81
122 ± 0.92
DBP
74 ± 0.33
70 ± 0.81
70 ± 0.65
Total Cholesterol mg/dL
172 ± 1.37
177 ± 1.41
143 ± 1.74
140 ± 1.64
LDL mg/dL
100 ± 1.17
102 ± 1.22
71 ± 1.33
72 ± 1.21
HDL mg/dL
39 ± 0.39
39 ± 0.37
41 ± 0.67
41 ± 0.75
TG mg/dL
143 ± 2.96
149 ± 3.03
123 ± 4.13
131 ± 4.70
BMI Kg/M²
28.7 ± 0.18
28.9 ± 0.17
29.2 ± 0.34
29.5 ± 0.31
Moderate Activity (5x/week)
25%
42%
36%

12. Poor Quality PCI in VA Centers?
Angiographic Success by Health Care System
US-VA
US-nonVA
Canada N
Success
All Segments
719
94%
282
91%
646
POBA segments 94
81% 39
77% 57
72%
Stented segments
625
96%
243
93%
589

13. Incomplete Revascularization?
♥ Similar to PCI results in MASS II and the NY State Registry
♥ CABG did not decrease events in EAST, BARI and ARTS despite more complete revascularization

14. Drug-Eluting Stents Were Not Used
♥ ASA, Statins, BB, ACEi decrease Death/MI
♥ Stents decrease TVR, not Death/MI
♥ DES would have decreased TVR, but not Death/MI
♥ DES would decrease transient recurrent angina due to restenosis

15. Cross-over problem, Less TVR with PCI?
Strategy trial, not PCI vs Medical Therapy
16.5% of OMT patients crossed-over by 11 mo, 16.5% between month 11 and 7 years, 2.75%/year after year 1
Repeat revascularization: PCI, 228; OMT, 348
Total revascularization: PCI, 1331; OMT, 348

16. Survival Free of Death from Any Cause and Myocardial Infarction
Number at Risk
Medical Therapy
PCI
Years 1 2 3 4 5 6
0.0
0.5
0.6
0.7
0.8
0.9
1.0
PCI + OMT
Optimal Medical Therapy (OMT)
Hazard ratio: 1.05
95% CI ( )
P = 0.62 7
♥ Make it a non-inferiority design?
♥ Add 2000 or more patients?
♥ The events curves are still superimposed

17. Results Due to Periprocedural MI?
♥ Definition: 1. CK-MB 3x ULN or troponin 5 x ULN
2. Signs or symptoms of ischemia
♥ Death and MI: HR 1.05 ( ); p = 0.62
♥ Exclude periprocedural MI: HR 0.9 ( );p = 0.29

18. Overall Survival PCI + OMT OMT Hazard ratio: 0.87 95% CI (0.65-1.16)
1.0
0.9
OMT
0.8
Hazard ratio: 0.87
95% CI ( )
P = 0.38
0.7
0.6
0.5
0.0 1 2 3 4 5 6 7
Years
Number at Risk
Medical Therapy
PCI

19. Freedom From Hospitalization for ACS
1.0
OMT
0.9
PCI + OMT
0.8
0.7
Hazard ratio: 1.07
95% CI ( )
P = 0.56
0.6
0.5
0.0 1 2 3 4 5 6 7
Years
Number at Risk
Medical Therapy
PCI

20. Freedom From Myocardial Infarction
OMT
1.0
0.9
PCI + OMT
0.8
0.7
Hazard ratio: 1.13
95% CI ( )
P = 0.33
0.6
0.5
0.0 1 2 3 4 5 6 7
Years
Number at Risk
Medical Therapy
PCI

21. Baseline Characteristics Medical Therapy Better
Subgroup Analyses
Baseline Characteristics
Hazard Ratio (95% Cl)
PCI
Medical Therapy
Overall ( )
Sex
Male ( )
Female ( )
Age
> ( )
≤ ( )
Race
White ( )
Not White ( )
Health Care System
Canadian ( )
U.S. Non-VA ( )
U.S. VA ( )
0.25
0.50
1.00
1.50
1.75
2.00
PCI Better
Medical Therapy Better

22. Baseline Characteristics Medical Therapy Better
Subgroup Analyses
Baseline Characteristics
Hazard Ratio (95% Cl)
PCI
Medical Therapy
Myocardial Infarction
Yes ( )
No ( )
Extent of CAD
Multi-vessel disease 1.10 ( )
Single-vessel disease 1.00 ( )
Diabetes
Yes ( )
No ( )
Angina
CCS 0-I ( )
CCS II-III ( )
Ejection Fraction
≤ 50% ( )
> 50% ( )
Previous CABG
No ( )
Yes ( )
0.25
0.50
1.00
1.50
1.75
2.00
PCI Better
Medical Therapy Better

23. PCI Better in Non-VA U.S. Population?
If this conclusion from subgroup analysis is to be applied to COURAGE, then OMT is preferred in men, non-diabetics, single vessel disease, and in the absence of prior MI.
No statistically significant interactions.

24. Can we define a subgroup with benefit?
Subgroup Analyses
Can we define a subgroup with benefit?
Stay tuned!

25. SAQ Data – Angina Frequency
Follow-up
PCI+OMT
OMT Only
Unadjusted P Value
Baseline 68 69
0.20
1 Month 82 76
<
3 Months 85 80
6 Months 87 83
0.0001
12 Months 84
0.003
24 Months 89 86
0.002
36 Months 88
0.37

26. SAQ Data – Angina Frequency Clinically Significant Improvement
Follow-up
PCI+OMT
OMT Only
Unadjusted P Value
1 Month
47%
40%
0.004
3 Months
50%
44%
0.010
6 Months
52%
46%
0.016
12 Months
54%
0.012
24 Months
57%
0.045
36 Months
39%
30%
0.0002
NNT 12.5 for 1 to improve at 6 months
Wyrwich KW et al. Clinically important differences in health status for patients with heart disease: an expert consensus panel report. Am Heart J 2004;147

27. Clinically Significant Improvement
SAQ Data – Angina Frequency Tercile Scores
(Mean Interaction P=0.008, Clinically Significant Improvement Interaction P<0.0001)
PCI + OMT
OMT
Clinically Significant Improvement
Tercile
Follow-up
Mean
P Value
PCI+OMT
1st
Baseline 35
0.75
3 months 74 65
0.0004
80%
73%
0.092
6 months 78 72
0.023
85%
81%
0.26
12 months 79 75
0.090
86%
84%
0.56
36 months 83 82
0.94
92%
88%
0.14
2nd 71
0.18 86
<
61%
50%
0.009 87
0.002
64%
56%
0.042 88 85
67%
58%
0.037 89
0.28
71%
0.11
3rd 97
0.61 91 90
0.67 92
0.015 93
0.022 94
0.31

28. Lifetime QALY

29. Conclusions
COURAGE did not show that PCI as an initial management strategy prevents events
COURAGE did show that PCI improves symptoms
About 1/3 of patients crossed over at median time of 10 months.
COURAGE suggests that as an initial management strategy optimal medical therapy is safe, and that PCI can be deferred or avoided