Courage TRIAL 2007

1. OPTIMAL MEDICAL THERAPY WITH
OR WITHOUT PCI FOR STABLE
CORONARY DISEASE.
the COURAGE Trial Research group.
N Engl J Med.
Volume 356(15):1503-1516.
April 12, 2007.
Valmiki Seecheran.
Y5 MBBS |UWI Cave Hill | QEH.
Dr. Jeffrey Massay | Cardiology Clinic.

2. COURAGE?
• Clinical.
• Outcomes
• Utilizing .
• Revascularization and.
• Aggressive.
• druG.
• Evaluation.

3. Clinical Question.
In patients with stable CAD, how does
optimal medical therapy plus PCI compare to
optimal medical therapy alone in improving
survival?

4. Overview.
• Randomized trial.
• 2287 patients with CAD & evidence of Ischemia.
• Medical therapy with or without Percutaneous Coronary Intervention.
• Median -> 4.6 years
• % of Death & MI were 19% in the PCI group.
• % of Death & MI were 18.5% in the Medical Therapy group.

5. Funding.
• Funding provided by US Department of Veterans Affairs Office of
Research and Development and Canadian Institutes of Health
Research, with grants from:
• Merck, Pfizer
• Bristol-Myers Squibb, Fujisawa.
• Kos Pharmaceuticals, Datascope.
• Astra-Zeneca, Key Pharmaceuticals.
• Sanofi-Aventis, First Horizon, GE Healthcare.

6. Study Design.
• Multicenter, open-label, parallel-group, randomized, controlled trial.
• N=2,287.
• PCI plus OMT (n=1,149)
• OMT alone (n=1,138)
• Setting: 50 centers in US and Canada.
• Enrollment: June 1999 to January 2004.
• Median follow-up: 4.6 years.
• Analysis: Intention-to-treat.
• Primary outcome: Composite of death from any cause and nonfatal
MI.

7. Inclusion criteria.
• Stable CAD.
• Canadian Cardiovascular Society (CCS) class I, II, III or stabilized class
IV angina.
• ≥70% stenosis in at least one coronary artery.
• Objective myocardial ischemia, with any of:
• Substantial changes in ST segment depression.
• T wave inversion on the resting EKG.
• Inducible ischemia with either exercise or pharmacologic stress test.
• 80% stenosis with classic angina without provocative testing.

8. Exclusion Criteria.
• Persistent CCS class IV angina.
• Markedly positive treadmill test (significant ST segment depressions
and/or hypotensive response during stage I of Bruce protocol).
• LVEF <30%
• Refractory CHF.
• Cardiogenic shock.
• ≥50% left main disease.
• Revascularization within the previous 6 months.
• Coronary lesions deemed unsuitable for PCI.

10. Interventions.
Oral Medical Therapy.
• Antiplatelet:
• Aspirin 81-325mg or clopidogrel 75mg daily (if aspirin intolerant); PCI
arm received both.
• Anti-ischemic:
• Metoprolol, amlodipine, Isosorbide mononitrate, alone or in
combination.
• Lisinopril or losartan regardless of LVEF or history of prior MI.
• Lipid-lowering: Statins ±ezetimibe to goal LDL 60-85 mg/dl.
• Niacin ±fibrates to goal HLD >40 mg/dl and TG <150 mg/dl.
• Exercise recommended.

11. Interventions.
For PCI arm:
• Target-lesion revascularization always attempted.
• Complete revascularization performed if appropriate clinically.
• PCI success seen as normal coronary flow and <50% stenosis in luminal diameter after
balloon angioplasty and <20% after stent, based on visual estimation of angiogram.
• Clinical success defined as PCI success without in-hospital MI, emergent CABG, or death.

12. Treatment targets
• Patients had a high rate of receiving Multiple, Evidence-Based
therapies after randomization during follow-up, with similar rates in
both study groups.
• At the 5-year follow-up visit:
• 70% of subjects had an LDL <85mg/dL.
• 65% had sBP target of <130 mmHg.
• 94% had dBP target of <85 mmHg.
• 45% of patients with DM had HbA1c < 7.0%.
• Patients had high rates of adherence to the regimen of Diet, Regular
Exercise, and Smoking Cessation as recommended by CPG.

13. Follow up.
• Median follow up -> 4.6 years.
• 9% of patients were lost to follow-up in the two groups before the
occurrence of a primary outcome or at the end of follow up.

14. Outcomes
• Clinical Outcome was adjudicated by an Independent Committee
whose members were unaware of Treatment Assignments.
• Primary Outcome Measure.
• Composite of Death from any Cause & NFMI.
• Secondary Outcomes.
• Composite of Death, MI, Stroke and Hospitalization for USA.

15. Outcomes
• PRIMARY OUTCOMES: Comparisons are PCI plus OMT vs. OMT alone.
Composite of death from any cause and NFMI.
19% vs. 18.5% (HR 1.05; 95% Cl 0.87-1.27; P=0.62)

16. Outcomes
• SECONDARY OUTCOMES: Comparisons are PCI plus OMT vs. OMT alone.
• Rate of death, NFMI, NFS.
• 20% vs 19.5% (HR 1.05; 95% CI 0.087-1.27; P=0.062)
• Rate of death.
• 7.6% vs 8.3% (HR 0.87; 95% CI 0.65-1.16; P=NS)
• Rate of NFMI.
• 13.2% vs. 12.3% (HR 1.13; 95% CI 0.89-1.43; P=0.33)
• Rate of NFS.
• 2.1% vs. 1.8% (HR 1.56, 95% CI 0.80-3.04, P=0.19)
• Rate of ACS hospitalization.
• 12.4% vs. 11.8% (HR 1.07; 95% CI 0.84-1.37; P=0.56)
• Rate of revascularization.
• 21.1% vs. 32.6% (HR 0.60; 95% CI 0.51-0.71; P<0.001)
• Rate of CABG.
• 6.7 % vs 7.1%.

17. Criticisms
• The high degree of male patients reduces generalizability of the results.
• The majority of patients in the PCI arm received bare metal stents,
because drug-eluting stents were not yet approved for use until the final 6
months of the study period.
• The authors assert that 85% of those undergoing PCI do so electively, this
is probably closer to 30% with many of those likely meeting COURAGE
exclusion criteria.
• High rate of excluded patients.

18. Criticisms
• Inclusion of angioplasty likely worsened outcomes.
• Likely incomplete revascularization given discordance between the
incidence of multivessel disease and procedures with multiple stents
placed.
• No stratification by ischemic burden.
• Unclear how long patients took clopidogrel or if extended duration of
therapy would improve outcomes in the PCI group.
• Unclear use of GP IIb/IIIa inhibitors.

20. Conclusion – COURAGE (2007)
• Among patients with stable but severe coronary disease, treatment
with PCI was not associated a difference in death or MI compared
with medical therapy through 5 years of follow up but was associated
with much higher costs.

21. Conclusion – Circumspective.
• BARI 2D (2009) - Bypass Angioplasty Revascularization Investigation 2
Diabetes
• Among patients with T2DM and stable CAD, how does revascularization with either
CABG or PCI compare to OMT in reducing CV events and death?
• 88.3% vs 87.8% (95% CI -2.0 to 3.1; P=0.97) - Comparisons are revascularization vs. optimal medical
therapy at 5 years.
• FAME 2 (2012) - The Fractional Flow Reserve versus Angiography for
Multivessel Evaluation (FAME)
• Among patients with stable CAD undergoing PCI, does fractional flow reserve (FFR)-
guided PCI reduce the composite of all-cause mortality, non-fatal MI, or urgent
revascularization when compared to optimal medical therapy (OMT) alone?
• 4.3% VS 12.7% (HR 0.32; 95% CI 0.19-0.53; P<0.001) - Comparisons are FFR-guided PCI vs. OMT
alone.

22. References.
[1] PCI for Stable Coronary Disease - N Engl J Med 2007; 357:414-418
July 26, 2007DOI: 10.1056/NEJMc071317
[2] Does Preventive PCI Work? - Judith S. Hochman, M.D., and P.
Gabriel Steg, M.D. N Engl J Med 2007; 356:1572-1574April 12,
2007DOI: 10.1056/NEJMe078036
[3] 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary
Intervention