OMT - cardioegypt2011

The COURAGE Trial; When
optimal medical treatment is not
enough
Gamal Aboul Nasr, MD, FACC, FASCI
19/10/2011
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COURAGE
Clinical Outcomes Utilizing
Revascularization and
Aggressive Guideline-Driven
Drug Evaluation
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COURAGGE is not PCI Vs.
OMT
PCI added to Optimal Medical
Therapy
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will be Superior to
Optimal Medical Therapy Alone
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When optimal medical treatment is
vA
• Although OMT & life
style modifications are
being fully
implemented, still
some patients are
symptomatic with
evidence of residual
ischemia
not enough
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vB
• Because No enough
resources.
• Lack of initiatives from
physician side
• lack of compliance
(pts.) to implement
the full scale of OMT
+life style
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modification

A North American Trial
19 US Non-VA Hospitals
15 VA Hospitals
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16 Canadian Hospitals
50 Hospitals
2,287 patients
enrolled between
6/99-1/04
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Design
• Randomization to PCI + Optimal Medical
Therapy vs Optimal Medical Therapy alone
• Intensive, guideline-driven medical therapy
and lifestyle intervention in both groups
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• 2.5 to 7 year (mean 4.6 year) follow-up
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Primary Outcome
Death or Nonfatal MI
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Secondary Outcomes
• Death, MI, or Stroke
• Hospitalization for Biomarker (-) ACS
• Cost, Resource Utilization
• Quality of Life, including Angina
• Cost-Effectiveness
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Smoking
Risk Factor Goals
Variable
Total Dietary Fat / Saturated Fat
Dietary Cholesterol
LDL cholesterol (primary goal)
HDL cholesterol (secondary goal)
Triglyceride (secondary goal)
Physical Activity
Cessation
Goal

Pharmacologic
Optimal Medical Therapy
• 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
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• Nitrate: isosorbide 5-mononitrate
Applied to Both Arms by Protocol and Case-Managed
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Lifestyle
Optimal Medical Therapy
• Smoking cessation
• Exercise program
• Nutrition counseling
• Weight control
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Applied to Both Arms by Protocol and Case-Managed
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Long-Term Improvement in Treatment
Targets (Group Median ± SE Data)
Treatment Targets Baseline 60 Months
PCI +OMT OMT PCI +OMT OMT
SBP 131 ± 0.77 130 ± 0.66 124 ± 0.81 122 ± 0.92
DBP 74 ± 0.33 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
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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% 25% 42% 36%
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1.0
0.9
0.8
0.7
0.6
0.5
0.0
Number at Risk
Survival Free of Death from Any
Cause and Myocardial Infarction
Optimal Medical Therapy (OMT)
PCI + OMT
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Hazard ratio: 1.05
95% CI (0.87-1.27)
P = 0.62
0 1 2 3 4 5 6
Years
Medical Therapy 1138 1017 959 834 638 408 192 30
PCI 1149 1013 952 833 637 417 200 35
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7

1.0
0.9
0.8
0.7
0.6
0.5
0.0
Number at Risk
Overall Survival
PCI + OMT
OMT
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Hazard ratio: 0.87
95% CI (0.65-1.16)
P = 0.38
0 1 2 3 4 5 6
Years
Medical Therapy 1138 1073 1029 917 717 468 302 38
PCI 1149 1094 1051 929 733 488 312 44
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7

1.0
0.9
0.8
0.7
0.6
0.5
0.0
Number at Risk
Survival Free of Hospitalization
OMT
PCI + OMT
for ACS
Hazard ratio: 1.07
95% CI (0.84-1.37)
P = 0.56
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0 1 2 3 4 5 6
Years
Medical Therapy 1138 1025 956 833 662 418 236 127
PCI 1149 1027 957 835 667 431 246 134
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7

1.0
0.9
0.8
0.7
0.6
0.5
0.0
Number at Risk
Survival Free of
Myocardial Infarction
OMT
PCI + OMT
Hazard ratio: 1.13
95% CI (0.89-1.43)
P = 0.33
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0 1 2 3 4 5 6
Years
Medical Therapy 1138 1019 962 834 638 409 192 120
PCI 1149 1015 954 833 637 418 200 134
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7

Conclusions (Courage initial study)
• As an initial management strategy in patients
with stable coronary artery disease, PCI did not
reduce the risk of death, MI, or other major
cardiovascular events when added to optimal
medical therapy
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Still remains an important question at
that time!
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Even if PCI added to OMT did
not affect mortality or
subsequent occurrence of MI
What about effect of
angina & quality of life
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One of the main indications for
PCI in stable CAD, is to improve
symptoms & quality of life
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Freedom from Angina During
Long-Term Follow-up
Characteristic PCI + OMT OMT
CLINICAL
Angina free – no.
Baseline 12% 13%
1 Yr ( P

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Early improvement of angina frequency
& quality of life up to 3 years
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In treating individual symptomatic patients
with effort angina, Should we tell them
“Kindly tolerate yr. symptoms & wait for 3 years
then, PCI will have no additive benefits to your
current R/ in relieving anginal pains”!!
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This may be from subjective side, Do we
have objective evidence for significant
changes in ischemic burden when PCI is
added to OMT
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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
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Ischemia Reduction ‡ 5%
50
40
30
20
10
0
Primary Endpoint: % with Ischemia Reduction ‡
5% Myocardium (n=314)
33.3
PCI + OMT (n=159)
P=0.004
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19.8
OMT (n=155)
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Ischemia Normalization* on Follow-Up MPS
In Patients with Significant Ischemia Resolution
% with Low Risk* MPS
50
40
30
31.4
P=0.007
20
17.8
10
0
PCI + OMT (n=53)
OMT (n=29)
*£1% ischemic myocardium
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Is this significant releive of
ischemic burden by PCI + OMT
can lead to any beneficial effect
on survival or new coronary
events
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Rates of Death or MI by Ischemia Reduction
Death or MI rate (%)
50
40
30
20
10
0
RR=0.47 (95% CI=0.23-0.95)
13.4
P=0.037
Ischemia Reduction ‡ 5%*
n=82
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*primary endpoint
24.7
No Ischemia Reduction
n=232
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Death or MI rate (%)
Rates of Death or MI by Ischemia Reduction in
Subset of 105 Patients with Moderate to Severe Pre-
Rx Ischemia*
50
40
30
20
10
0
16.2
P=0.001
Ischemia Reduction ‡ 5%
n=68
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32.4
No Ischemia Reduction
n=37
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*50% reduction

Death or MI rate (%)
50
40
30
20
10
0
Rates of Death or MI by Residual Ischemia on 6-
18m MPS
0.0
0%
(n=23)
P=0.063
15.6
1 - 4.9%
(n=141)
P=0.023
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22.3
5 -9.9%
(n=88)
P=0.002
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39.3
‡ 10%
(n=62)

Conclusions (Courage nuclear substudy)
• 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
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COURAGE Conclusions!!
Initial conclusion, 2007 Nuclear sub-study, 2008
• As an initial management
strategy in patients with
stable coronary artery
disease, PCI did not
reduce the risk of death,
MI, or other major
cardiovascular events
when added to optimal
medical therapy
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• PCI added to OMT was
more effective in
reducing ischemia and
improving angina, with
survival benefits & less
CV events than OMT
alone, particularly in
patients with moderate to
severe pre-RX ischemia
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Any confirmation from another
RCT
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Cardiac Death Rate (%)
Cardiac Death Rate Stratified by Spect Quantification of Ischemia and
Treatment Modality †
10
8
6
4
2
0
0.7
6.3
Medical RX
1.0
1.8
2.9
Revasc
7110 16 1331 56 718 109 545 243 252 267
3.7
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4.8
3.3
0% 1-5% 5-10% 11-20% >20%
*p < 0.0001 % Total Myocardium Ischemic
†
10,627 Consecutive patients followed 1.9 + 0.6 years.
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6.7
2.0
Hachamovitch et al. Circ 2003;107:2900
*
§

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This when OMT including life style
modification are fully implemented
What about the reallife
situation
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Because No enough resources or
lack of compliance to implement
the full scale of OMT as well as life
style modification
The real life situation
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Many Patients in Need of Lipid Lowering Therapy
Remain Untreated – EUROASPIRE II
39% untreated
Lipid management assessed in 5556 patients with CHD at least 6 months
after discharge who qualify for treatment
EUROASPIRE II. Eur Heart J 2001;22:554–572
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EUROASPIRE II: 61% of patients are taking
lipid-lowering drugs at interview
BEL/GHE
CZE/PP
FIN/KUO
FRA/LLRT
GER/MUNS
GRE/ATCI
HUN/BUD
IRE/DUB
ITA/TV
NET/ROT
POL/CRA
SLO/LJU
SPA/BAR
SWE/MAL
UK/HL
ALL
European Society of Cardiology ESC
42
47
49
0 20 40 60 80 100
51
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57
58
60
62
61
64
65
68
68
69
76
77
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EUROASPIRE II. Eur Heart J 2001; 22:554-72.

Many Patients that are Treated are Still not
1464 (52%) not
at goal on
starting dose
813
(55%) not
titrated
448 (69%)
not at goal
Getting to Goal
2829 patients †
651 (45%)
titrated
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†Patients with and LDL-C goal of

% Patients receiving therapy
60
50
40
30
20
10
0
Cholesterol Goal Attainment in the Real World: The REALITY Study
55
LDL-C Goal Attainment*
24
26
14
(n=3173) (n=605) (n=634) (n=619)
France
Patients with CHD
Germany
Italy
Spain
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*LDL-C goal of

Situation for hypertension R/ is not
even better!!
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Less than 50% of Hypertensive Patients in North
America and Europe Receive Therapy
Percentage (%)
60
55
50
45
40
35
30
25
20
15
Percentage (%)
100
50
40
Country
30 Country
90
80
70
60
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20
Wolf-Maier et al. JAMA 2003;289:2363–9
Patients on therapy
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USA
Canada
Italy
Sweden
England
Spain
Finland
Germany

Awareness, Treatment, and Control of Hypertension Have
Not Increased Significantly in the USA
US population (%)*
80
73
70
60
51
50
55 54
68 70
40
34
31
29
30
27
20
10
10
0
NHANES II
(1976-1980)
*Adults with hypertension aged 18 to 74 years.
†
Controlled: BP

More than 70% of Treated Hypertensive Patients Are
Not at BP Goal (

Poor Blood Pressure Control is
Scotland
Germany
Finland
Spain
Russia
Poland
Italy
Hungary
France
England
Czech Republic
Belgium
Common in Europe
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0 10 20 30 40
Controlled at

Control rate breakdown by country
Canada
16.0
USA
27.4
Scotland Finland
17.5 20.5 Germany
England
22.5
6.0
France
27.0
Spain
15.5
Zaire
2.5 Italy
23.4
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JNC-VI. Arch Intern Med. 1997;157:2413-2446. Burt VL. Hypertension. 1995;26:60-69. Mancia G.
Eur Heart J. 1999;(suppl L):L14-L19.
India
9.0
Australia
7.0
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MR FIT: CHD Deaths Associated with Lack of BP
Deaths
1500
1000
500
0

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Is there really change in clinical
practice after COURAGE
• The the new survey—covering almost 500 000 patients
from >1000 hospitals in the ACC National
Cardiovascular Data Registry (NCDR)—shows that,
at least among patients ultimately treated with PCI,
there was little change in prescribing practice from preto
post-COURAGE. The findings illustrate the difficulty
of translating the results of randomized clinical trials
into mainstream clinical practice, say Dr William B
Borden (Cornell University, New York, NY) and colleagues in their paper
in the May 11, 2011 issue of the Journal of the American Medical
Association.
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• In their observational study, Borden and colleagues
examined the use of OMT in 467 211 patients with
stable CAD undergoing elective PCI and in the NCDR
before (September 1, 2005 to March 25, 2007, before
COURAGE publication) & after (July 1, 2007 to June
30, 2009) the publication of the COURAGE trial.
Analysis compared use of OMT both before PCI and at
the time of discharge.
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• As being very much COURAGE-type patients:,"We
found that less than half of people before PCI were
taking OMT.
• Specifically, before COURAGE, OMT was used in
43.5% of patients prior to PCI, and this increased to
only 44.7% in the period after COURAGE (p

• “When we looked over time, and particularly
with publication of the COURAGE results, it
did not seem like these practice patterns
changed to any meaningful degree.”
» Dr William B Borden,
» main investigator of the COURAGE trial,
» Clinical cardiology, May, 2011
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What are the real reasons for this
much arguments
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“We, as a cardiology community,
have to do a much better job of
educating the non-cardiologists.”
“Responsible interventionalists have always
undertaken intervention against a background
of having tried to control symptoms first with
OMT.”
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To Conclude
• Between this & that , the debate will continue
• We as cardiologists (invasive and non-invasive)
have been in long waiting for new clear
guidelines
• At the time of decision making (to act as
responsible cardiologists!!), we should take our
time to analyze pts’s medications, quantification
of symptoms as well as the degree of ischemic
burden to better reach conclusion about further
benefits from mechanical revascularization
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Thank U 4 your attention
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Subgroup Analyses
Baseline Characteristics Hazard Ratio (95% Cl) PCI Medical Therapy
Myocardial Infarction
Yes 1.15 (0.93-1.42) 0.19 0.18
No 0.65 (0.40-1.06) 0.18 0.26
Extent of CAD
Multi-vessel disease 1.10 (0.83-1.46) 0.24 0.22
Single-vessel disease 1.00 (0.77-1.32) 0.16 0.16
Diabetes
Yes 1.08 (0.87-1.34) 0.19 0.18
No 0.87 (0.54-1.42) 0.19 0.24
Angina
CCS 0-I 1.27 (0.90-1.78) 0.17 0.14
CCS II-III 0.71 (0.44-1.14) 0.15 0.21
Ejection Fraction
≤ 50% 1.06 (0.80-1.38) 0.22 0.22
> 50% 1.06 (0.80-1.38) 0.22 0.22
Previous CABG
No 1.06 (0.80-1.38) 0.22 0.22
Yes 1.06 (0.80-1.38) 0.22 0.22
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0.25 0.50 1.00 1.50 1.75 2.00
PCI Better
Medical Therapy Better

Conclusions
• As an initial management strategy in patients with
stable coronary artery disease, PCI did not reduce
the risk of death, MI, or other major cardiovascular
events when added to optimal medical therapy
• As expected, PCI resulted in better angina relief
during most of the follow-up period, but medical
therapy was also remarkably effective, with no
between–group difference in angina-free status at
5 years
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Implications
• Our findings reinforce existing ACC/AHA clinical
practice guidelines, which state that PCI can be safely
deferred in patients with stable CAD, even in those
with extensive, multivessel involvement and inducible
ischemia, provided that intensive, multifaceted medical
therapy is instituted and maintained
• Optimal medical therapy and aggressive management
of multiple treatment targets without initial PCI can be
implemented safely in the majority of patients with
stable CAD—two-thirds of whom may not require even
a first revascularization during long-term follow-up
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Question
&
Answer
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