Titledrpauthor: 41BKGersh, B SubdrpJob

1
Optimal Management of Chronic Stable Angina
Implications of the COURAGE Trial
Lake Louise 2008 BJ Gersh Mayo Clinic
CP1283095-2
2
5-Year Clinical Outcomes After Coronary Stenting

• 1,228 pt
• 3 trials
• 2nd generation stents

Cutlip Circ, 2004
CP1165076-1
3
Indications for Coronary Revascularization
Chronic stable angina

• Persistent limiting symptoms or strongly positive
  stress test
• Drug intolerance

Lifestyle

• Patient preference

Occupation

• LV dysfunction
• Compelling anatomy
• Prior MI

CP1282966-12
4
Coronary Revascularization has Revolutionized the
Therapy of Ischemic Heart Disease
Survival Benefits

• Acute coronary syndromes
• Chronic stable CAD
• LMCA disease
• MVD and LV dysfunction
• MVD and severe angina/ischemia
• Severe LV dysfunction and extensive myocardial
  viability
• Severe angina/ischemia and proximal LAD disease?
• Post MI
• Residual angina/ischemia

Symptom relief failure of drug therapy
CP1282966-21
5
Class III Recommendations Chronic Stable
AnginaPCI or CABG

• 1-2 vessel disease without prox LAD
• (1) Mild symptoms unlikely to be due to
  myocardial ischemia
• (2) Have not received an adequate trial of
  medical therapy Small area of viable
  myocardium orNo demonstrable ischemia on
  exercise testing

• Pt with stenoses 50-60 (other than LMCA) No
  demonstrable ischemia on stress testing
• Stenoses lt50

CP1283095-3
6
Implications of the COURAGE Trial
COURAGE
ENCOURAGE
DISCOURAGE
DISPARAGE
A matter of perception
Media
Organizations
General cardiologists
Interventional cardiologists/ surgeons
CP1282966-26
7
With acknowledgements to Audubon
CP947135-31
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Impact of CV Clinical Trials Often Exceeds
Conclusions from the Study Results Alone
Physicians (interventional and non-interventionali
sts) Professional societies (ACC, SCAI, AHA,
ESC) Regulatory bodies (FDA Panel ,NICE
DES) Political interest groups Pharmaceutical and
device industry
CP1303832-5
9
Coronary Revascularization in Mild-Moderate
Chronic Stable Angina 30 yrs. of Clinical
Trials
CABG vsmedical therapy
PTCA vsmedical therapy
Lack ofbenefit indeath/MI
Exceptions

• ACIP pilot study

PTCA vs stents PCI vs medical therapy
Davies Circ, 1997

• SWISSI II trialErne JAMA, 2007

Benefit noted in LMCA disease, severe angina or
LV dysfunction
CP1266714-2
10
Lack of Benefit from PCI in CS Angina in RCT
CP1278209-2
11
Generalization to Population at Large

• Trials by design include highly selected patients
  eligible for both procedures

• Trials entry bias
• Registries selection bias

COURAGE Screened 35,539 pt Randomized 2,287
pt (6.4)
Baseline clinical and demographic
characteristics Care received Compliance

• Trial pt dobetter thanhistorical controls

CP1285789-5
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Inadequate Statistical Power
All trials of revascularization therapies are
probably underpowered
Logistical constraints
Clinical relevance vs statistical significance
CP1282966-1
13
All Trials of Coronary Revascularizationin CSA
are Underpowered
Therapies Trial (no.) Pt (no.) Range
CABG vs medical 7 2,649 100-780
PCI vs medical 11 2,905 41-1,019
CABG vs PCI 15 8,826 127-1,829
Before COURAGE
CP1284276-2
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Inducible Ischemia at Baseline and 18
MonthsCOURAGE Substudy
PCI OMT (n159)
OMT (n155)
33.3 with ?5ischemia reductionP0.0004
18.9 with ?5ischemia reduction


8.6(7.5-9.8)
8.2(7.2-9.3)
8.1(6.9-9.4)
5.5(4.7-6.3)
Plt.001
Plt0..63
Mean -2.7 (95 CI -1.7 to -3.8)
Mean -0.5 (95 CI -1.67 to 0.6)
Shaw Circ, 2008
CP1301231-2
15
Late Revascularization Proceduresin COURAGE
RevascularizationOver 4.5 Years
Differenceis 120 pt
100 PCI performed at the time of evaluation to
avoid 10.4 revascularization procedures over the
next 4.5 years
Pt (no.)
PCI groupn1,149
Medical therapyn1,138
NEJM, 2007
CP1301000-4
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COURAGE Patients Were Low or Moderate Risk?

• High prevalence of comorbidities Diabetes
  (33.5) Hypertension (66.5)

• 58 CHC class II-III30 CHC class I12
  asymptomatic
• 2/3 multiple perfusion defects on scintigraphy
  ?70 MVD (LAD disease 34)
• Preserved LV function

Death/MI/Stroke 5-Year Rates in PCI Arm of RCT
Pt ()
Death/MI
Trial
CP1288632-11
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PCI Results in COURAGE

• Angiographic success 93 (1,576 of 1,688
  lesions)
• Clinical success 89(successful PCI and (958
  of 1,077 pt)no in-hospitalcomplications)

46 pt no PCI 27 pt lesion not crossed
Clinical success 83
Boden NEJM, 2007
CP1285789-4
18
COURAGE Subgroup Analyses
Event rate forprimary outcome
Baseline characteristics HR (95 CI) PCI Med Rx P
Sex 0.03 Male 1.15 (0.93-1.42) 0.19 0.18 Female
0.65 (0.40-1.06) 0.18 0.26
MI 0.15 Yes 0.91 (0.69-1.21) 0.23 0.25 No 1.22
(0.93-1.60) 0.17 0.14
Diabetes 0.33 Yes (766 pt) 0.99
(0.73-1.32) 0.25 0.24 No (1,468 pt) 1.20
(0.92-1.56) 0.17 0.15
Race 0.43 White 1.08 (0.87-1.34) 0.19 0.18 Nonw
hite 0.87 (0.54-1.42) 0.19 0.24
Heath care system 0.17 Canadian (932 pt) 1.27
(0.90-1.78) 0.17 0.14 U.S. non-VA (387 pt) 0.71
(0.44-1.14) 0.15 0.21 U.S. VA (968 pt) 1.06
(0.80-1.38) 0.22 0.22
0.25 0.50 1.00 1.50 1.75 2.00
PCI better
Med Rx better
Boden NEJM, 2007
CP1288707-1
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PCI vs CABG in Patients with MedicallyRefractory
IschemiaAWESOME Trial

• 232 pt
• VA system
• 1995-2000
• 3 vessel disease 45

Morrison JACC, 2001
CP1012234-1
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Medical treatment targets are unrealistic
Will patients who cannot tolerate beta-blockers
or CCBs remain compliant on aspirin and
clopidogrel?
CP1288632-10
21
Management of Chronic Stable AnginaInterpretation
s of the COURAGE Trials

• PCI is a waste of time
• Medical therapy alone will sufficefor majority

• COURAGE Trial
• Worthless
• Flawed
• Limited generalizability

CP1285925-2
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Revascularization Rates in 11 USA States

• Pt agedgt20 yr
• 1999
• AHCPR

WA354
OR335
NY377
WI448
IA474
CO374
CA371
MD382
AZ420
SC447
Rates/100,000
FL517
HannanBMC Health Services Research, 2006
CP1270454-1
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Determinants of Utilization ofRevascularization
Procedures
Multivariate analysis
Accounts for94 of variation
Accounts for89 of variation
Hannan BMC Health Services Research, 2006
CP1270454-2
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Overutilization of PCI
CP1265929-1
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Patient Perceptions of Benefit from PCI
Reasons for undergoing PCI(cited by patient)

• 52 pt
• First PCI
• Prospective questionnaire

Perceptions of Outcomes

• Improve symptoms 65(uncertain 21)
• Prevent future MI 75
• Increase survival 71

Holmboe J Gen Int Med, 2006
CP1303832-10
26
Potential Impact of Recent Trials onUtilization
of Coronary Revascularization

• Indications
• Inappropriate

• Utilization
• Reduced

?

• Appropriate

• No change

CP1278210-4
27
Finally the appropriate rates of use are of a
major concernThe credibility of what we as
cardiologists do and how we implement coronary
revascularization places the onus of
responsibility on us.
CP1303832-1
28
"I'd recommend the plain scarf"
CP947135-16
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(No Transcript)
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Event-Free Survival According to ReductionIn
Ischemia 6-18 Months After Treatment COURAGE
Substudy
Patients with Moderate-Severe Pretreatment
Ischemia
Overall
Cumulative event-free survival
Cumulative event-free survival
?5 reduction in ischemic myocardium (n82) No
significant reduction in ischemia (n232)
?5 reduction in ischemic myocardium (n68) No
significant reduction in ischemia (n37)
Unadjusted P0.037 Risk-adjusted P0.26
Unadjusted P0.001 Risk-adjusted P0.82
Follow-up (years)
Follow-up (years)
Shaw Circ, 2008
CP1301231-3
31
COURAGE, Encourage, Discourage, Disparage ?

• Entry Bias in randomized trials vs. Selection
  bias in registries
• Generalizability---women, minorities, DES and
  compliance with medical therapy
• Results in Non VA vs. VA centers
• Underpowered
• Lack of complete revascularization
• Low vs. moderate risk population
• Appropriate rate of "cross-overs ?-- Trials of
  therapeutic strategies vs. therapy received

CP1269168-1
32
Stents vs PTCA a Meta-Analysis
29 trials 9,918 Patients
Brophy Annals Int Med, 2003
CP1124369-5
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PCI vs Conservative Therapy in Nonacute CAD
Cardiac Death or Myocardial Infarction

• Meta-analysis
• 11 trials
• 2,905 pt

Death
0.1
0.2
0.5
1
2
5
10
Risk ratio (95 CI)
Favors PCI
Favors conservative
Katritsis Circ, 2005
CP1208581-10
34
Management of Stable CAD in the 2000s
Future directions
Clinical impact ?

• BARI 2D
• COURAGE
• FREEDOM

Ongoingtrials
CP1163618-4
35
Patient Perceptions of Benefit from PCI
Reasons for undergoing PCI(cited by patient)

• 52 pt
• First PCI
• Prospective questionnaire

• Symptom relief 57
• Abnormal test orperception of pathology 62
• Recommendation ofphysician 19

Perceptions of Outcomes

• Improve symptoms 65(uncertain 21)
• Prevent future MI 75
• Increase survival 71

Holmboe J Gen Int Med, 2006
CP1303832-10
36
What is 'Optimal' Medical Therapy ?

• Beta-blockers/calciumchannel antagonists

Aggressive riskfactor modification

• Statin

• Nitrates long-acting,prophylactic

• Aspirin

• Smoking cessation

• ACEi/ARB

• Exercise

LV function

• BP control

Diabetes
Hypertension

• Wt loss

All ?

• Treat sleep apnea

• Ranolazine/Ivabridine

EECP
Refractorypt
Spinal cord stimulator
CP1280696-1