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.

COURAGE?

• Clinical.

• Outcomes

• Utilizing .

• Revascularization and.

• Aggressive.

• druG.

• Evaluation.

Clinical Question.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

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%.

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.

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.

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.

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.

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