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