courage nuclear substudy ii optimal medical therapy with or without pci to reduce ischemic burden:...
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COURAGE Nuclear Substudy IICOURAGE Nuclear Substudy II
Optimal Medical Therapy with or without Optimal Medical Therapy with or without PCI to Reduce Ischemic Burden: PCI to Reduce Ischemic Burden: Results from Results from CClinical linical OOutcomes utcomes UUtilizing tilizing
RRevascularization & evascularization & AAggressive ggressive GGuideline-Driven uideline-Driven Drug Drug EEvaluation Trial Nuclear Substudyvaluation Trial Nuclear Substudy
Leslee J. Shaw, Daniel S. Berman, David J. Maron, G. B. John Mancini, Leslee J. Shaw, Daniel S. Berman, David J. Maron, G. B. John Mancini, Sean Sean W. Hayes, Pamela M. Hartigan, William S. Weintraub, Robert A. O’Rourke, W. Hayes, Pamela M. Hartigan, William S. Weintraub, Robert A. O’Rourke, Marcin Dada, John A. Spertus, Bernard R. Chaitman, John Friedman, Piotr Marcin Dada, John A. Spertus, Bernard R. Chaitman, John Friedman, Piotr
Slomka, Gary V. Heller, Guido Germano, Gilbert Gosselin, Peter Berger, Slomka, Gary V. Heller, Guido Germano, Gilbert Gosselin, Peter Berger, William J. Kostuk, Ronald Schwartz, Merill Knudtson, Emir Veledar, Eric R. William J. Kostuk, Ronald Schwartz, Merill Knudtson, Emir Veledar, Eric R.
Bates, Benjamin McCallister, Koon K. Teo, William E. Boden for the Bates, Benjamin McCallister, Koon K. Teo, William E. Boden for the COURAGE InvestigatorsCOURAGE 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
15 US VA
19 US Non-VA
1,355 patients
16 Canadian
Hospitals
932 patients
COURAGE Trial – 50 North COURAGE Trial – 50 North American HospitalsAmerican Hospitals
Funding: Funding: • Cooperative Studies Program of Dep’t of Veterans Affairs Office of Research & DevelopmentCooperative Studies Program of Dep’t of Veterans Affairs Office of Research & Development• Canadian Institutes of Health ResearchCanadian Institutes of Health Research• Bristol-Myers Squibb Medical Imaging, Astellas Pharma, Merck, Pfizer; othersBristol-Myers Squibb Medical Imaging, Astellas Pharma, Merck, Pfizer; others
Survival Free of Death or MI
YearsYears00 11 22 33 44 55 66
0.00.0
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
PCI +PCI + OMTOMT
Optimal Medical Therapy (OMT)Optimal Medical Therapy (OMT)
Hazard ratio: 1.05(95% CI: 0.9-1.3)p=0.62
77
Source: Boden et al. N Engl J Med 2007 Apr 12;356(15):1503-16.
• 2,287 Stable CAD Patients Randomized to:
PCI+OMT vs. OMT
• PCI - Complete Revascularization
• Both Groups Received Intensive, Guideline-Driven Medical Therapy & Lifestyle Intervention
Main Trial Results – No Difference in Main Trial Results – No Difference in Long Term OutcomeLong Term Outcome
Effects of Medical Therapy & Effects of Medical Therapy & PCI/CABG on Myocardial IschemiaPCI/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 / Nuclear Substudy (n=314 /
2,287)2,287)
Source: Shaw et al. J Nucl Cardiol 2006;13:685-98.
Documented Documented Pre-Rx IschemiaPre-Rx Ischemia
Documented Documented Pre-Rx IschemiaPre-Rx Ischemia
PCI + OMTPCI + OMT(n=159)(n=159)
OMT OMT (n=155)(n=155)
Repeat MPS*Repeat MPS*at 6-18mat 6-18m
Repeat MPS*Repeat MPS*at 6-18mat 6-18m
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)Serial Rest/Stress Myocardial Perfusion SPECT (MPS)
*Timing Chosen to *Timing Chosen to Occur Beyond Occur Beyond Window of In-Stent Window of In-Stent Restenosis & Restenosis & Delayed to Allow Delayed to Allow Effects of Medical Effects of Medical Rx to be ObservedRx to be Observed
• Pre-Rx = Pre-Rx = Off MedsOff Meds
To Compare Patient Management Strategy for Ischemia ReductionTo Compare Patient Management Strategy for Ischemia Reduction
• 6-18m = 6-18m = On MedsOn Meds
Mean = 374 ±50 daysMean = 374 ±50 days
Cedars-Sinai Medical Center MPS Cedars-Sinai Medical Center MPS Core Laboratory (PI: Daniel S. Core Laboratory (PI: Daniel S. Berman, MD)Berman, MD)
Type of Stress - Paired From Pre-Rx to 6-18m MPSType of Stress - Paired From Pre-Rx to 6-18m MPS n=234 Adenosine / Dipyridamole Stressn=234 Adenosine / Dipyridamole Stress n=80 ETT (Radiopharmaceutical Injected at Similar n=80 ETT (Radiopharmaceutical Injected at Similar
Workload on 6-18m and Pre-Rx)Workload on 6-18m and Pre-Rx)
MPS Protocol Standardized Across 25 HospitalsMPS Protocol Standardized Across 25 Hospitals Rest Tl-201 or Tc-99m Sestamibi Rest Tl-201 or Tc-99m Sestamibi Stress Tc-99m SestamibiStress Tc-99m Sestamibi
Core Lab Evaluation: 95% MPS of Excellent-Good Image Core Lab Evaluation: 95% MPS of Excellent-Good Image QualityQuality
*
*Analyses by Type of Stress Did Not Alter Results Presented Herein.
Substudy MethodsSubstudy Methods: :
% Ischemic Myocardium:% Ischemic Myocardium: (Stress TPD-Rest TPD)(Stress TPD-Rest TPD)• < 5%: < 5%: Minimal (“No Ischemia”)Minimal (“No Ischemia”)• 5.0%-9.9%: 5.0%-9.9%: MildMild 10%: 10%: Moderate-to-SevereModerate-to-Severe
Significant Reduction in Ischemia:Significant Reduction in Ischemia: 5% Reduction in Ischemic Myocardium*5% Reduction in Ischemic Myocardium*
MPS Ischemia Based onMPS Ischemia Based onTotal Perfusion Deficit (TPD)Total Perfusion Deficit (TPD)
Source: Slomka et al. J Nucl Cardiol 2005;12:66-77 *Threshold Exceeds Test Repeatability
Defect Extent Defect Extent
TPDTPD Lower NlLower NlLimitLimitLower NlLower NlLimitLimit
DefectDefectSeveritySeverityDefectDefectSeveritySeverity
TPD: Quantitative Measure of Defect Extent & SeverityTPD: Quantitative Measure of Defect Extent & Severity
Pre-Rx TPD: 28%Pre-Rx TPD: 28%
12 m12 mPre-RxPre-Rx
12m TPD: 2%12m TPD: 2%
OMTOMT
Statistical MethodsStatistical Methods
• Primary EndpointPrimary Endpoint: : % Patients by Rx with ≥5% Reduction in Ischemic % Patients by Rx with ≥5% Reduction in Ischemic Myocardium Comparing Follow-up → Pre-Rx MPSMyocardium Comparing Follow-up → Pre-Rx MPS• Based on Sample Size of 314 Patients, Estimated 80% Power To Detect Based on Sample Size of 314 Patients, Estimated 80% Power To Detect
Differences by Rx (1% Two-sided Significance Level)Differences by Rx (1% Two-sided Significance Level)• Statistical AnalysesStatistical Analyses
– Paired Paired tt Tests & Wilcoxin Rank Sum or Signed Rank Test Tests & Wilcoxin Rank Sum or Signed Rank Test– General Linear Model : Compare % Ischemic Myocardium By RxGeneral Linear Model : Compare % Ischemic Myocardium By Rx
• Exploratory Prognostic Analysis with Limited Statistical PowerExploratory Prognostic Analysis with Limited Statistical Power– Mean of 3.6y of Follow-up (post-2Mean of 3.6y of Follow-up (post-2ndnd MPS) = 68 Death or MI (75% MI) MPS) = 68 Death or MI (75% MI)– Periprocedural MI – Censored Periprocedural MI – Censored – Rates Calculated from Kaplan-Meier Survival CurveRates Calculated from Kaplan-Meier Survival Curve• Wald ΧWald Χ2 2 Statistics From Cox PH ModelStatistics From Cox PH Model
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
Rest gated LVEF 57%±11% 58%±9% 0.97
% Ischemic Myocardium (95% CI)Moderate-to-Severe Ischemia**
8.2% (7.2%-9.3%)
34%
8.6% (7.5%-9.8%)
33%
0.63
0.81
Pre-Treatment Clinical Pre-Treatment Clinical Characteristics and MPS ResultsCharacteristics and MPS Results
*CCS=Canadian Cardiovascular Society
Compared to main trial, substudy pts. more often CCS* class I-II angina (p=0.013) 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)& less multivessel CAD (p=0.05); with similar % of MPS ischemia (p=0.55)
**≥10% Ischemic Myocardium
Angiographic Outcomes in PCI (n=159)
*Angiographic Success is Defined as <50% in Non-Stented Lesion and <20% in Stented Lesion.
• 156 Patients Underwent PCI156 Patients Underwent PCI• 2 Patients = Failure to Cross Lesion2 Patients = Failure to Cross Lesion• 1 Patient = Non-Critical Stenosis1 Patient = Non-Critical Stenosis
• Mean Pre-PCI Stenosis Diameter: 82%±12%Mean Pre-PCI Stenosis Diameter: 82%±12%• Mean Number of Lesions Attempted: 1.7±0.9Mean Number of Lesions Attempted: 1.7±0.9
• Angiographic Success: 93%*Angiographic Success: 93%*
OMT (n=155)PCI + OMT (n=159)PCI + OMT (n=159)
Mean=-2.7% Mean=-2.7% (95% CI=-3.8% to -1.7%)(95% CI=-3.8% to -1.7%)
8.6% 8.1% 8.1%
(6.9%-9.4%)(6.9%-9.4%)
8.2% 5.5% 5.5%
(4.7%-6.3%)(4.7%-6.3%)
MPS % Ischemic Myocardium (95% CI) Pre-Rx & 6-18m
Mean=-0.5% Mean=-0.5% (95% CI=-1.6% to 0.6%)(95% CI=-1.6% to 0.6%)
p<0.0001p<0.0001
Primary Endpoint: % with Ischemia Reduction ≥5% Myocardium (N=314)
19.8% p=0.004
33.3%
Isch
emia
Red
uctio
n ≥5
%
52.0% p=0.007p=0.007
78.0%
Isch
emia
Red
uctio
n ≥5
%
% with Ischemia Reduction ≥5% Myocardium
(n=105 Moderate-to-Severe Pre-Rx Ischemia)
Angina Class Improvement & Angina-Free Status at 6-18 mos.
p=0.15
p=0.0077
% Nitrate Use: 64% 75% (p=0.03)
82%82%70%70% 63%63%70%70%
*CCS=Canadian Cardiovascular Society
RR=0.47 (95% CI=0.23-0.95)
p=0.037
Rates of Death or MI by Ischemia ReductionD
eath
or M
I Rat
e (%
)D
eath
or M
I Rat
e (%
)
24.7%24.7%
13.4%13.4%
(n=82)(n=82) (n=232)(n=232)
p=0.001p=0.001
Rates of Death or MI By Ischemia Reduction in Subset of 105 Patients withModerate-to-Severe Pre-Rx Ischemia
(n=68)(n=68) (n=37)(n=37)
32.4%32.4%
16.2%16.2%
Dea
th o
r MI R
ate
(%)
Dea
th o
r MI R
ate
(%)
Rates of Death or MI by Residual Ischemia on 6-18m MPS
p=0.063
p=0.023
p=0.002
(n=23)(n=23) (n=88)(n=88)(n=141)(n=141) (n=62)(n=62)
22.3%22.3%
0.0%0.0%
39.3%39.3%
15.6%15.6%
Dea
th o
r MI R
ate
(%)
Dea
th o
r MI R
ate
(%)
Study LimitationsStudy Limitations
• Selected sample – not identical to main trial - Selected sample – not identical to main trial - representing 14% of total COURAGE populationrepresenting 14% of total COURAGE population
• Observations pertain to a nonrandomized comparisonObservations pertain to a nonrandomized comparison
• The follow-up MPS was performed at 6-18m and, thus, The follow-up MPS was performed at 6-18m and, thus, we cannot exclude the possibility of a delayed we cannot exclude the possibility of a delayed response to medical rxresponse to medical rx
• Prognostic analyses are statistically underpowered but Prognostic analyses are statistically underpowered but were generated for exploratory purposes - planning of were generated for exploratory purposes - planning of future controlled clinical trialsfuture 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