Transcript No Slide Title

COURAGE Nuclear Substudy II
Optimal Medical Therapy with or without
PCI to Reduce Ischemic Burden:
Results from Clinical Outcomes Utilizing
Revascularization & Aggressive Guideline-Driven
Drug Evaluation Trial Nuclear Substudy
Leslee J. Shaw, Daniel S. Berman, David J. Maron, G. B. John Mancini, Sean
W. Hayes, Pamela M. Hartigan, William S. Weintraub, Robert A. O’Rourke,
Marcin Dada, John A. Spertus, Bernard R. Chaitman, John Friedman, Piotr
Slomka, Gary V. Heller, Guido Germano, Gilbert Gosselin, Peter Berger,
William J. Kostuk, Ronald Schwartz, Merill Knudtson, Emir Veledar, Eric R.
Bates, Benjamin McCallister, Koon K. Teo, William E. Boden for the
COURAGE Investigators
Presenter Conflict Disclosure
Name: Leslee J. Shaw, PhD
Within the past 12 months, presenter or spouse/partner have had financial
interest/arrangement/ affiliation w/ organization listed below.
Company Name:
Relationship:
BMS Medical Imaging
Research grant support
Astellas Healthcare
Research grant support; Speaker’s Bureau
GE Healthcare
Research grant support/Speaker’s Bureau
CV Therapeutics
Research Grant; Consultant
COURAGE Trial – 50 North
American Hospitals
15 US VA
16 Canadian
19 US Non-VA
Hospitals
1,355 patients
932 patients
Funding:
• Cooperative Studies Program of Dep’t of Veterans Affairs Office of Research & Development
• Canadian Institutes of Health Research
• Bristol-Myers Squibb Medical Imaging, Astellas Pharma, Merck, Pfizer; others
Survival Free of Death or MI
Main Trial Results – No Difference in
Long Term Outcome
• 2,287 Stable CAD Patients
Randomized to:
PCI+OMT vs. OMT
• PCI - Complete
Revascularization
• Both Groups Received
Intensive, Guideline-Driven
Medical Therapy & Lifestyle
Intervention
1.0
Optimal Medical Therapy (OMT)
0.9
PCI + OMT
0.8
0.7
Hazard ratio: 1.05
(95% CI: 0.9-1.3)
p=0.62
0.6
0.5
0.0
Source: Boden et al. N Engl J Med 2007 Apr 12;356(15):1503-16.
0
1
2
3
Years
4
5
6
7
Effects of Medical Therapy &
PCI/CABG on Myocardial Ischemia
 Published Evidence In Chronic CAD Patients Reveals that
Revascularization, Anti-Ischemic Rx, and Statin Rx Result in
Reduction in Ischemic Defect Size on Stress Myocardial Perfusion
SPECT (MPS)
…Prior reports were often small patient series
 COURAGE Entry Criteria Included Objective Evidence of Ischemia
• Spontaneous ST-T ∆
• > 1 mm ST Deviation on Treadmill
• Ischemic Imaging Defect
 Role of Stress Imaging Not Explored in Prior Subset Analyses
Source: Shaw et al. J Nucl Cardiol 2006;13:685-98.
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
• 6-18m = On Meds
Documented
Pre-Rx Ischemia
PCI + OMT
(n=159)
OMT
(n=155)
Repeat MPS*
at 6-18m
Repeat MPS*
at 6-18m
Source: Shaw et al. J Nucl Cardiol 2006;13:685-98.
Mean = 374 ±50 days
*Timing Chosen to
Occur Beyond
Window of In-Stent
Restenosis &
Delayed to Allow
Effects of Medical
Rx to be Observed
Cedars-Sinai Medical Center MPS Core
Laboratory (PI: Daniel S. Berman, MD)
Substudy Methods:
 Type of Stress - Paired From Pre-Rx to 6-18m MPS

*



n=234 Adenosine / Dipyridamole Stress
n=80 ETT (Radiopharmaceutical Injected at Similar
Workload on 6-18m and Pre-Rx)
MPS Protocol Standardized Across 25 Hospitals

Rest Tl-201 or Tc-99m Sestamibi

Stress Tc-99m Sestamibi
Core Lab Evaluation: 95% MPS of Excellent-Good Image
Quality
*Analyses by Type of Stress Did Not Alter Results Presented Herein.
MPS Ischemia Based on
Total Perfusion Deficit (TPD)
TPD: Quantitative Measure of Defect Extent & Severity
% Ischemic Myocardium:
(Stress TPD-Rest TPD)
• < 5%:
Minimal (“No Ischemia”)
• 5.0%-9.9%: Mild
• 10%:
Moderate-to-Severe
Defect Extent
Defect
Severity
TPD
Lower Nl
Limit
Significant Reduction in Ischemia:
• 5% Reduction in Ischemic Myocardium*
Source: Slomka et al. J Nucl Cardiol 2005;12:66-77
*Threshold Exceeds Test Repeatability
Pre-Rx
12 m
OMT
Pre-Rx TPD: 28%
12m TPD: 2%
Statistical Methods
• Primary Endpoint: % Patients by Rx with ≥5% Reduction in
Ischemic Myocardium Comparing Follow-up → Pre-Rx MPS
• Based on Sample Size of 314 Patients, Estimated 80% Power To
Detect Differences by Rx (1% Two-sided Significance Level)
• Statistical Analyses
– Paired t Tests & Wilcoxin Rank Sum or Signed Rank Test
– General Linear Model : Compare % Ischemic Myocardium By Rx
• Exploratory Prognostic Analysis with Limited Statistical Power
– Mean of 3.6y of Follow-up (post-2nd MPS) = 68 Death or MI (75% MI)
– Periprocedural MI – Censored
– Rates Calculated from Kaplan-Meier Survival Curve
• Wald Χ2 Statistics From Cox PH Model
Pre-Treatment Clinical
Characteristics and MPS Results
Compared to main trial, substudy pts. 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%
8.2%
58%±9%
8.6%
0.97
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
Angiographic Outcomes in PCI
(n=159)
• 156 Patients Underwent PCI
• 2 Patients = Failure to Cross Lesion
• 1 Patient = Non-Critical Stenosis
• Mean Pre-PCI Stenosis Diameter: 82%±12%
• Mean Number of Lesions Attempted: 1.7±0.9
• Angiographic Success: 93%*
*Angiographic Success is Defined as <50% in Non-Stented Lesion and <20% in Stented Lesion.
MPS % Ischemic Myocardium
(95% CI) Pre-Rx & 6-18m
PCI + OMT (n=159)
OMT (n=155)
Mean=-0.5%
Mean=-2.7%
(95% CI=-1.6% to 0.6%)
(95% CI=-3.8% to -1.7%)
p<0.0001
8.2%
5.5%
(4.7%-6.3%)
8.6%
8.1%
(6.9%-9.4%)
Ischemia Reduction ≥5%
Primary Endpoint: % with Ischemia
Reduction ≥5% Myocardium (N=314)
33.3%
p=0.004
19.8%
% with Ischemia Reduction ≥5%
Myocardium
Ischemia Reduction ≥5%
(n=105 Moderate-to-Severe Pre-Rx
Ischemia)
78.0%
p=0.007
52.0%
Angina Class Improvement &
Angina-Free Status at 6-18 mos.
p=0.15
p=0.0077
82%
% Nitrate Use:
*CCS=Canadian Cardiovascular Society
70%
64%
70%
63%
75%
(p=0.03)
Rates of Death or MI by
Ischemia Reduction
Death or MI Rate (%)
RR=0.47 (95% CI=0.23-0.95)
p=0.037
24.7%
13.4%
(n=82)
(n=232)
Rates of Death or MI By Ischemia
Reduction in Subset of 105 Patients with
Moderate-to-Severe Pre-Rx Ischemia
Death or MI Rate (%)
p=0.001
32.4%
16.2%
(n=68)
(n=37)
Rates of Death or MI by Residual
Ischemia on 6-18m MPS
p=0.002
Death or MI Rate (%)
39.3%
p=0.023
p=0.063
22.3%
15.6%
0.0%
(n=23)
(n=141)
(n=88)
(n=62)
Study Limitations
• Selected sample – not identical to main trial representing 14% of total COURAGE population
• Observations pertain to a nonrandomized comparison
• The follow-up MPS was performed at 6-18m and, thus,
we cannot exclude the possibility of a delayed
response to medical rx
• Prognostic analyses are statistically underpowered but
were generated for exploratory purposes - planning of
future controlled clinical trials
Conclusions
• PCI added to OMT was more effective in reducing ischemia
and improving angina than OMT, particularly in patients with
moderate-to-severe pre-rx ischemia
• Exploratory outcomes data:
– Ischemia reduction ≥5% associated with lower risk of death/MI
– Residual ischemia ≥5% associated with higher risk of death/MI
• Randomized trials of management strategies should evaluate
quantitative measures of myocardial perfusion ischemia to
guide clinical decisions regarding revascularization during
long-term management