The “Truth and Consequences” of Objective
Ischemia: The COURAGE Trial Nuclear Substudy
Dean J. Kereiakes, M.D.
Medical Director, The Christ Hospital Heart and Vascular
Center and the Lindner Research Center
Chairman,Executive Committee, The Ohio Heart and Vascular
Center, Cincinnati, Ohio
Professor of Medicine, Ohio State University
Objectives
• Identify pivotal observation(s) from the
COURAGE trial nuclear substudy
• Is this observation(s) novel?
• Is the obsevation realistic and applicable to
clinical practice?
• What are the limitations & caveats regarding
COURAGE observations?
• Summary and Conclusions
Nuclear Substudy
(n=314 / 2,287)
Hypothesis: Reduction in ischemia will be greater for patients
Randomized to PCI+OMT than for those randomized to OMT
Serial rest/stress myocardial perfusion SPECT (MPS)
To compare patient management strategy for ischemia reduction
•Pre-Rx = off meds
•Post-Rx = on meds
Documented
Pre-Rx Ischemia
PCI + OMT
(n=159)
OMT
(n=155)
Repeat MPS*
at 6-18m
Repeat MPS*
at 6-18 m
*Timing chosen
to occur beyond
window of instent restenosis
and delayed to
allow effects of
medical Rx to
be observed
Source: Shaw et al. J Nucl Cardiol 2006;13:685
MPS Ischemia Based on
Total Perfusion Defect (TPD)
•
•
•
•
•
TPD: Quantitative measure of defect extent and severity
% Ischemic myocardium = (Stress TPD-Rest TPD)
< 5%:
Minimal (“no ischemia”)
5.0%-9.9%: Mild
 10%:
Moderate to severe
Defect Extent
Defect
Severity
•
Significant reduction in ischemia
•  5% reduction in ischemic myocardium*
Source: Simoka et al. J Nucl Cardiol 2005;12:66
TPD
Lower NI
Limit
*Threshold exceeds test repeatability
Pre-Treatment Clinical Characteristics and MPS Results
Compared to main trial, substudy patients more often CCS* class I-II angina (p=0.013)
& less multivessel CAD (p=0.05); with similar % of MPS ischemia (p=0.55)
PCI + OMT
N=159
OMT
N=155
P value
Angina CCS* Class I-II
74%
73%
0.99
Angiographic 2-3 vessel CAD
73%
77%
0.38
57%11%
58%9%
0.97
8.2%
8.6%
0.63
(7.2-9.3%)
(7.5-9.8%)
34%
33%
Rest gated LVEF
% Ischemic myocardium
(95% CI)
Moderate to Severe Ischemia**
*CCS=Canadian Cardiovascular Society
0.81
** 10% ischemic myocardium
Primary Endpoint: % with Ischemia
Reduction  5% Myocardium (n=314)
Ischemia Reduction  5%
50
40
33.3
30
P=0.004
19.8
20
10
0
PCI + OMT (n=159)
OMT (n=155)
% with Low Risk* MPS
Ischemia Normalization* on Follow-Up MPS
In Patients with Significant Ischemia Resolution
50
P=0.007
40
31.4
30
17.8
20
10
0
PCI + OMT (n=53)
*1% ischemic myocardium
OMT (n=29)
Rates of Death or MI by Ischemia Reduction
Death or MI rate (%)
50
RR=0.47 (95% CI=0.23-0.95)
40
30
20
24.7
13.4
P=0.037
10
0
Ischemia Reduction  5%*
n=82
No Ischemia Reduction
n=232
*primary endpoint
Rates of Death or MI by Ischemia Reduction
in Subset of 105 Patients with Moderate to
Severe Pre-Rx Ischemia*
Death or MI rate (%)
50
P=0.001
40
32.4
30
20
16.2
10
0
Ischemia Reduction  5% No Ischemia Reduction
n=68
n=37
*50% reduction
Rates of Death or MI by Residual Ischemia
on 6-18m MPS
P=0.002
Death or MI rate (%)
50
P=0.023
40
30
P=0.063
39.3
22.3
15.6
20
10
0
0.0
0%
(n=23)
1 - 4.9%
(n=141)
5 -9.9%
(n=88)
 10%
(n=62)
Conclusions
• PCI added to OMT was more effective in
reducing ischemia and improving angina
than OMT alone, particularly in patients
with moderate to severe pre-RX ischemia
• Is this Observation Novel?
Cardiac Death or Myocardial Infarction Rate/Year Stratified by
SPECT Quantitative Ischemia
5
Myocardial Infarction
Cardiac Death
4
Event Rate %
4.2*
2.9
2.7 **
3
2.9*
2.3
2
1
0.3
0
0.5
Normal
N=
2946
0.8
Mildly Normal
884
Moderately Abnormal
455
Severely Abnormal
898
* Statistically significant increase as function of scan result
** Increased rate of MI vs cardiac death within scan stratum
Hachamovitch, Diamond et al. Circ 1998;97:535
Cardiac Death Rate Stratified by Spect Quantification of
Ischemia and Treatment Modality†
Medical RX
Cardiac Death Rate (%)
10
Revasc
*
8
6.7 §
6.3
6
4.8
3.7
4
2
2.9
1.0
0.7
3.3
2.0
1.8
0
7110 16
1331 56
718 109
545 243
252 267
0%
1-5%
5-10%
11-20%
>20%
*p < 0.0001
% Total Myocardium Ischemic
†10,627 Consecutive patients followed 1.9 + 0.6 years.
Hachamovitch et al. Circ 2003;107:2900
Mortality Hazard by Treatment Modality and
% Ischemic Myocardium
log Hazard Ratio (Mortality)
6
5
Medical Rx *
4
3
Revasc *
2
1
0
0
12.5%
*p<0.001
Interaction: p=0.030
25%
32.5%
50%
% of Total Myocardium Ischemic
Hachamovitch et al. Circ 2003;107:2900
Relationship Between Baseline Findings and Treatment
Strategies with Adverse Outcomes* to 1 Year: ACIP Study**
O.R. (95% CI)
P
Ischemia Driven
Medial Therapy
0.80 (0.39 – 1.61)
0.41
Revascularization
0.56 (0.26 – 1.2)
0.05
1.06 (1.01 – 1.12)
0.002
Strategy
AECG Ischemia†
0.25
0.5
1.0
1.5
1.75
Adapted from Pepine et al. JACC 1997;29:1483
† 48
hours monitor qualifying visit
*Death, non-fatal MI, hospital admission for ischemic event, **558 pts. Objective ischemia
Ambulatory ECG and SPECT Perfusion Imaging:
Lack of Concordance (ACIP Ancillary Study*)
AECG
+
+
-
45 / 48
33 / 34
20 / 17
8/7
SPECT
-
50% Concordance ( 3% perfusion defect)
52% Concordance (+ any ischemic defect)
Adapted from Mahmarian et al. JACC 1997;29:764-9
ACIP Study Two-Year Follow-Up
Death or MI
16
12.1% Angina Guided Med Rx
12
percent
8.8% Ischemia Guided Med Rx
8
4.7% Revascularization *
4
0
0
4
8
12
16
20
Months of Follow-up
*P<0.01 vs. angina guided med Rx
24
Davies et al. Circ 1997;95:2037
Cardiovascular Death or Myocardial Infarction Stratified by
Self-Reported Angina and/or Inducible Ischemia*:
The Heart and Soul Study
Adjusted HR† (95% CI)
p
No angina or ischemia
1 (Reference)
Angina alone
1.4 (0.7, 2.9)
0.31
Ischemia alone
2.2 (1.4, 3.5)
0.005
Angina & Ischemia
3.2 (1.4, 7.2)
0.006
0.5
1
2
3
4
5
6
7
8
9
*stress echo (937 pts. Stable CHD followed 3.9 yrs.)
† Adjusted for age, sex, race, Hx MI, Hx CHF, HgA1c, CrCl, LVEF, SBP, DBP, CRP
Adapted from Gehi, Schiller, Whooley et al. Arch Int Med 2008;168:1423
• Is the COURAGE Trial observation
Realistic and Applicable to Practice?
COURAGE : Demographics
19 US Non-VA Hospitals
387 pts (0.5 pts/mo/hosp)
*(17% of total)
15 VA Hospitals
968 pts (1.6 pts/mo/hosp)
(42% of total)
50 Hospitals
2,287 pts*
enrolled between
6/99-1/04
1 pt per hospital
16 Canadian Hospitals
per month
932 pts (1.5 pts/mo/hosp)
(41% of total)
* 15% women,14% non-caucasian
Boden WE et al. NEJM 2007;356:1503-16
Does COURAGE Represent U.S. PCI Practice ?
2000
US VA
US non VA
1800
1,422
1600
1400
(96.5%)
962,732
1,200,000
(98.5%)
1,000,000
800,000
1200
600,000
1000
800
600
400
400,000
52
200,000
(3.5%)
14,268
(1.5%)
200
0
0
Hospitals with PCI *
* 2006
Total PCI Volume*
Boden WE et al. NEJM 2007;356:1503-16 ; US data on file, Boston Scientific
COURAGE : Inadequate and Incomplete PCI
PCI success
1149 patients total
46 (4%) procedure not attempted
27 (2%) no lesions crossed
14% PTCA
only
86% stents
97% BMS
3% DES
1077 pts had PCI attempted / 958 (89%) success
[really 958/1149 (83.4%)or 958/1122(87%) success]*
Complete Peri-PCI
revascularization MIs
1577/1688(1730)* lesions had PCI success (93%)
Few PCI pts received GPIIb/IIIa inhibitors, bivalirudin *Really <8991%*(add 1.6
or adequate clopidogrel pre-loading
lesn x27 pts)
787 pts (69%) had 2 or 3 vessel ds.
416 pts (36%) received ≥2 stents
At least 371 of 787 pts (47%) with multivessel
disease had incomplete revascularization
*SITE
COURAGE : Variable PCI Outcomes by Location
Original Trial Hypothesis: 22% reduction D/MI with PCI
OMT
Death/MI (%) at 4.6 years
30%
PCI+OMT
P≈0.02
25%
22% 22%
20%
15%
17%
21%
15%
14%
10%
5%
27%↑

29%↓
Canada
US VA
US non-VA
0%
COURAGE: Mortality by Healthcare System and
Randomized Treatment Strategy
% Mortality
14
OMT
12.1
12
P =0.07
10
8.6
8
7.9
PCI + OMT
7.7
6.0
6
4.7
4
2
0
USVA
USNVA
Canadian
Adapted from Chaitman et al. JACC 2008;51:A222 (abstract)
COURAGE Issues :? Geographic Selection Bias
Original Projection: 3-year death/MI for OMT = 21%
Death/MI (%) at 4.6 years
30%
25%
20%
Very low risk pts!
Hard to improve upon
22%
19%
21%
14%
15%
Probably
~10% at
3 years
10%
5%
N=2287
N=932
N=968
N=387
All
Canada
US
VA
US
non-VA
0%
~ 0.4% /Yr Cardiac Mortality in COURAGE
NEJM 2007;356:1503 AHJ 2006;151:1173
Imputed* Effect of Drug-Eluting Stents in
the COURAGE Trial: Death / MI
RR (95% CI)
BMS+OMT vs. OMT
(COURAGE)
1.05 (0.87,1.27)
DES+OMT vs. BMS+OMT
(historical meta-analysis)
1.30 (0.91,1.86)
1.03 (0.84,1.26)
DES vs. OMT
(indirect comparison)
0.00
BMS
*Annals Int Med 2006Meta-analysis
Favors
Favors
PCI
OMT
0.50
1.00
1.50
SES (Cypher)
2.00
2.50
1.36 (0.91, 2.04)
1.08 (0.82, 1.43)
PES (Taxus)
Diamond, Kaul Viewpoint JACC 2007;50:1604-1609
Clinical Events Following BMS or DES*+
24
20
16
TARGET LESION REVASCULARIZATION
CLINICALLY DRIVEN TLR
(Taxus IV Non-Angio Cohort)
24
BMS (EXP+Bx)
PES
SES
BMS (Exp) n = 295
PES n = 287
20
16
12
12
%
%
p=0.0005)
8
8
4
4
0
0
0
SES vs. BMS:
PES vs. BMS:
SES vs. PES:
BMS 4763
PES 6328
SES 6621
1
2
3
4
HR 0.30 (0.24-0.37; p<0.0001)
HR 0.42 (0.33-0.53; p<0.0001)
HR 0.70 (0.56-0.84; p=0.0021)
820/4746 53/2795 22/1871
448/6280 98/3950 15/1999
356/6580 68/3801 16/2153
*Stettler et al. Lancet 2007;370:937
n=18,023 patients / 38 trials
10/1543
6/832
14/999
0
1
PES vs. BMS:
2
3
4
HR 0.39 (0.23-0.67; p=0.0005)
BMS 295 37/254
PES 287 8/272
5/249 3/239 1/229 2/218
4/271 3/258 2/246 3/235
+Boston Scientific data on file
5
Clinical Events Following BMS or DES*
ALL DEATH
Cumulative Incidence in %
10
14
BMS
PES
SES
8
6
DEATH OR MYOCARDIAL INFARCTION
Cumulative Incidence in %
BMS
PES
SES
12
10
8
6
4
4
2
2
0
0
0
SES vs. BMS:
PES vs. BMS:
SES vs. PES:
1
2
3
4
0
HR 1.00 (0.82-1.25; p=0.89)
HR 1.03 (0.84-1.22; p=0.75)
HR 0.96 (0.83-1.24; p=0.80)
BMS 4921 109/4904
PES 6331 138/6283
SES 6771 139/6730
48/3340
78/4263
72/4041
*Stettler et al. Lancet 2007;370:937
n=18,023 patients/38 trials
31/2264
32/2187
38/2340
44/1875
15/869
24/10810
1
2
3
4
HR 0.92 (0.77-1.08; p=0.32)
HR 1.00 (0.84-1.23; p=0.97)
HR 0.92 (0.79-1.08; p=0.27)
4921
6331
6771
301/4904 62/3208 45/2161 46/1780
376/6283 115/4087 43/2082 22/833
356/6730 86/3888 44/2241 28/1032
Mortality (DES vs. BMS) from 29 Trials / Registries
Patient Year Weighted Regression*
Slope = 1.0
14
TSEARCH
2
BASKET
3
DEScover
4
STENT
5
Steinberg et al.
6
REAL
7
ONASSIS
Slope = 0.85 8
[95% CI]
12
Slope = 0.79
19
24
8
6
29
26
27
4
18
2
12
17
10
7
17
Ortolani
18
Cypher meta-analysis
19
Taxus SR meta -analysis
20
Ontario PCI Registry
21
WAKE Forest
DES Death = 0.79 BMS Death
22
ACUITY
95% CI Slope = 0.79 ± 0.06
R2 = 0.96
23
PASSION
24
RESEARCH
25
SESAMI
26
NY State
27
ASAN
28
GHOST
29
MIDAS
1
11
9
0
0
28
21% Decrease
16
13
2
4
6
8
% Death BMS
SCANDSTENT
MISSION
21
25
11
16
20
22
DIABETES
SCAAR
3
2
10
15
5
8
PRISON II
Western Denmark
14
23
9
14
15
4
6
Pache et al.
Slope = 0.73 12 TYPHOON
[95% CI]
13 SES Smart
10
% Death DES
1
10
12
14
Size of circle adjusted for number of patients
DES vs. BMS Registries: All Cause Mortality
%
BMS
20
DES
18
11.0
7.9
7.8
Follow-up:
3 year
3 year
2 year
2 year
3 year
5,441
5,441
MIDAS NY STATE ONTARIO MASS-DAC STENT
3,751
GHOST
3,751
ASAN
6,384
5,399
5,719
4.8
6.4
5.7
5.5
871
483
0
4.2
p=0.004
9.4
5.6
5.2
p<0.001
4,061
3,180
2
11.9
8.6
5.9
p<0.001
2 year
2 year
3,548
10
4
p<0.001
11.5
12
6
p<0.05
12.9
14
8
p<0.0001
8,847
p=0.052
1,359
5,996
p<0.001
7,834
16
Western
Denmark
2 year
DJK
Late (3 Year) Results of the SCANDSTENT Randomized Trial*
p<0.001
SES
BMS
40
p<0.001
p<0.001
37.6
34.4
33.8
35
Events, %
30
25
20
p=0.14
p=0.69
p=0.04
12.3
15
10
5
0
9.6
5.6
1.9
Death
2.5 1.3
3.7
Cardiac
death
Myocardial
infarction
* CTO, ostial, bifurcation, angulated
8
4.9
TLR
TVR
MACE
Kelbaek et al. JACC 2008;51:2011
DES Outcomes (2 Years) in the Elderly:
Medicare Case-Control Comparison*
50
p<0.001
DES
BMS
p<0.001
p<0.001
p<0.001
% Patients
40
34.4
29.8
30
17.2 19.1
20
10.7
13.5
10
0
Death
9.2
11.2
Myocardial
Infarction
*n=76,525 DES Rx vs. contemporary
(April-Dec 2003) controls
Coronary
Combined
Revascularization Endpoints
Adapted from Groeneveld et al. JACC 2008;51:2017
Outcomes Following Coronary Stenting in Medicare Beneficiaries*
Repeat Revascularization
0.30
Death/STEMI
0.12
Cumulative Hazard
0.10
0.20
0.08
0.06
0.10
0.04
0.02
0.00
0.00
1
90
180
# at risk
BMS 38917 35610 33155
DES 28086 25660 24386
365
30437
22737
730
26822
19943
1
90
180
365
38917 38001 37362
28086 27473 27021
36332
26301
730
34275
24311
*BMS 38,917 10/02 - 3/03
DES 28,086 09/03 - 12/03
BMS era
DES era
Malenka et al. JAMA 2008;299:2868
DES Versus BMS and All-Cause Mortality: CCF Experience
Non-Propensity Matched*
Event Free
Propensity Matched
Event Free
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.6 1
Drug-Eluting Stent
Bare-Metal Stent
Confidence Interval
0.7
HR (95% CI)
0.62( 0.53 - 0.73)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
No. At Risk
Years after Procedure
Drug Eluting Stent:
6053 5467 4771 3939 3145 2295 1552 791 170
Bare-Metal Stent:
1983 1538 1241 1082 990 905 815 723 515
*p<0.001
0.6 1
0.0
Drug-Eluting Stent
Bare-Metal Stent
Confidence Interval
0.5
1.0
1.5
2.0
HR (95%CI)
0.54(0.45-0.66)
2.5 3.0
3.5
4.0
No. At Risk
Years after Procedure
Drug Eluting Stent:
1801 1654 1466 1251 1037 791 536 261 57
Bare-Metal Stent:
1801 1390 1117 969 884 809 733 653 471
Shishenbor et al. JACC 2008 52:1041
COURAGE : Freedom from Angina with OMT
PCI + OMT
100
OMT
P=NS
Angina free (%)
80
74
40%
P<0.001
72
CCS Class 0 / 1
P=NS
60
42
43
<10%
crossovers*
prespecified!
40
32
22
20
0
Angina free at 5
years
Baseline absent or
minimal symptoms
Revascularization
after discharge
*due to severe / progressive angina ; remain OMT by ITT
Multivariate Predictors of Crossover to PCI
OR (95% CI)
Hypercholesterolemia
1.4 (1.0 - 2.0)
3 VD
1.6 (1.1-2.3)
SAQ angina frequency
score
0.5
0.86 (0.81-0.91)
1.0
1.5
2.0
2.5
Adapted from Spertus et al. JACC 2008;51:A264 (abstract)
COURAGE : “COURAGE” OMT not Realistic
Compliance
Follow-up
Aspirin
Statins
Beta
blockers
1 years
95%
95%
89%
3 years
95%
92%
86%
5 years
94%
93%
86%
Treatment to Targets

LDL < 85 mg per deciliter in ~70% of pts
SBP <130 mmHg in ~65% of pts
DBP <85 mmHg in ~ 94% of pts
HgBA1C <7.0% in ~45% of diabetic pts
Medication Compliance
CRUSADE Registry (1-Year)
vs. 95% in COURAGE
vs. 95%
vs. 89%
vs. >90%
vs. >90%
Mehta HR et al. Circulation 2005;112:II-793.
Compliance with Guideline Recommended Therapies in
Patients with Established Atherosclerosis:
The REACH International Registry
Previous PCI (n=12,759)
Previous Medical Rx (n=13,784)
100
90
% Patients
80
70
82
69
86
70
66
55
60
50
40
30
20
10
0
Aspirin
B-Blocker
Statin/Lipid Lowering
Adapted from Steinberg, et al. Am J Cardiol 2007;99:1212
Medical Compliance Effects Survival in CAD
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
BETA-BLOCKERS
Survival (adjusted)
Survival (adjusted)
STATIN
0
1
2
3
4
5
6
Years
Adherent
7
8
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0
1
2
3
4
5
6
7
8
Years
Non-Adherent
Ho et al. Am Heart J 2008;155:772
% Patients
Optimal (<140/90 )* Blood Pressure Control in
Clinical Practice
1J
31%
37%
33%
Three City
Study1
Silvia
Study2
NHANES
2003 – 20043
(n=9090)
(n=2775)
(n=1614)
HTN 2006;24:51, 2J HTN 2004;22:2387, 3HTN 2007;49:69
* < 130(65%) / 85(94%) COURAGE
Freedom from Angina ( SAQ ) Stratified by Treatment
60
PCI + OMT
OMT
P<0.001
P<0.001
P=0.005
P=0.010
P=0.30
50
Angina-free (%)
P<0.001
40
30
P=0.35
20
10
0
Baseline
n = 21 23
1
3
42 33
53 42
6
12
24
36
56 47
57 50
59 53
59 56
Months
Weintraub et al. N Engl J Med 2008;359:677
Angina Stability and Frequency by SAQ over Time Stratified
by Treatment Strategy
Angina Stability
Angina Frequency
90
PCI + OMT
90
OMT
80
*
*
*
Mean Score
100
Mean Score
100
*
70
60
50
0 0
*
70
60
50
6
12
24
Months from Baseline
*p<0.01
80 *
* *
*
36
0 0 6
12
24
36
Months from Baseline
Weintraub et al. N Engl J Med 2008;359:677
Quality of Life by SAQ Over Time Stratified by Treatment
Strategy
PCI + OMT
OMT
100
Mean Score
90
80
*
*
*
6
12
*
*
70
60
50
0
0
24
36
Months from Baseline
*p<0.01
Weintraub et al. N Engl J Med 2008;359:677
COURAGE Objective Ischemia : Conclusions
• Ischemia (SPECT,AECG,SECHO) is qualitatively and
quantitatively correlated with adverse clinical outcomes
(CVD,MI)
• Revascularization (PCI) is more effective in reducing
ischemia than medical therapy (OMT)
• COURAGE PCI was inadequate (83-87% per-patient ;
<89-91% per-lesion success rate) and incomplete (47%
MVD) with suboptimal technology (14% POBA, 3% DES)
COURAGE Objective Ischemia : Conclusions
• COURAGE OMT was unrealistic (>90% compliance
through 5 years) in part due to free nurse case
management and free medications
• Contemporary “real world practice management” (more
complete revascularization with DES, less optimal
medical compliance) would likely enhance the relative
magnitude and durability of demonstrated PCI benefit
(angina relief, improved QOL, ischemia reduction)