COURAGE

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Boden WE, et al. "Optimal medical therapy with or without PCI for stable coronary disease". The New England Journal of Medicine. 2007. 356:1503-16.
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Clinical Question

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

Bottom Line

In patients with stable CAD, there were no differences in death and MI between optimal medical therapy plus PCI vs. OMT alone.

Major Points

The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial randomly assigned ~2,300 patients with stable CAD to either optimal medical therapy (OMT) alone or OMT plus PCI. All patients received anti-ischemic therapy with ß-blockers, calcium channel blockers, and nitrates; antiplatelet therapy with aspirin and/or clopidogrel; and lipid-lowering statin therapy. 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. After a median follow-up of 4.6 years, COURAGE demonstrated no significant differences between the two treatment strategies for the primary outcome of death from any cause and non-fatal MI. There was also no significant difference in the rates of ACS hospitalizations between groups. Followup of the cohorts demonstrated that significantly more patients in the PCI arm were free of angina and had higher overall quality of life by 6 months, but this benefit disappeared by 36 months, likely reflecting the progression of underlying CAD. Fifteen-year follow-up data published in 2015 found no difference in mortality between the groups.[1]

COURAGE (2007) and BARI 2D (2009) made a strong case against routine revascularization via PCI for stable coronary disease; however, the FAME (2009) and subsequent FAME 2 (2012) trials demonstrated the benefit of PCI for selected patients with hemodynamically significant coronary lesions. FAME 2, in particular, demonstrated a reduction in the composite of death, MI, or urgent revascularization when FFR-guided revascularization was added to OMT.

Guidelines

In the absence of clear indications for revascularization with PCI or CABG (eg, unprotected left main disease), the AHA/ACCF guidelines support the use of FFR-guided revascularization among patients with stable coronary disease.[2]

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

Population

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

Baseline Characteristics

From the PCI group.

  • Demographics: Age 61.5 years, male 85%, white race 86%, black race 5%, Hispanic 6%
  • CCS anginal class:
    • 0: 12%
    • I: 30%
    • II: 36%
    • III: 23%
  • Anginal duration: 5 months
  • Weekly anginal episodes: 3
  • PMH: DM 32%, HTN 66%, HF 5%, cerebrovascular disease 9%, MI 38%, previous PCI 15%, CABG 11%
  • Stress test: Any 85%
    • Treadmill 57% (duration 7 min)
    • Pharmacologic 6%
    • Echocardiography 6%
    • Nuclear study 70%
      • Single reversible defect 22%
      • Multiple reversible defects 65%
  • Diseased vessels:
    • 1: 31%
    • 2: 39%
    • 3: 30%
    • Graft: 62%
    • Proximal LAD: 31%
  • LVEF: 60.8%

Interventions

  • Randomly assigned to PCI plus OMT vs. OMT alone
  • Both arms received OMT, which included:
    • Antiplatelet: aspirin 81-325mg or clopidogrel 75mg daily (if aspirin intolerant); PCI arm received both
    • Antiischemic: 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
  • 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

Outcomes

Comparisons are PCI plus OMT vs. OMT alone.

Primary Outcomes

Composite of death from any cause and nonfatal MI
19% vs. 18.5% (HR 1.05; 95% CI 0.87-1.27; P=0.62)

Secondary Outcomes

Rate of death, nonfatal MI, nonfatal stroke
20% vs. 19.5% (HR 1.05; 95% CI 0.87-1.27; P=0.62)
Rate of death
7.6% vs. 8.3% (HR 0.87; 95% CI 0.65-1.16; P=NS)
Rate of nonfatal MI
13.2% vs. 12.3% (HR 1.13; 95% CI 0.89-1.43; P=0.33)
Rate of nonfatal stroke
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[3]
  • High rate of excluded patients[3]
  • Inclusion of angioplasty likely worsened outcomes[3]
  • Likely incomplete revascularization given discordance between the incidence of multivessel disease and procedures with multiple stents placed[3]
  • No stratification by ischemic burden[3]
  • Unclear how long patients took clopidogrel[3] or if extended duration of therapy would improve outcomes in the PCI group[4]
  • Unclear use of GP IIb/IIIa inhibitors[3]

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, and GE Healthcare.

Further Reading

  1. Sedlis SP et al. Effect of PCI on Long-Term Survival in Patients with Stable Ischemic Heart Disease. N. Engl. J. Med. 2015. 373:1937-46.
  2. 2011 AHA/ACCF Guidelines
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Multiple authors. "Correspondence: PCI for stable coronary disease." The New England Journal of Medicine. 2007:357:414-418.
  4. Hochman JS and Steg PG. "Does preventive PCI work?" The New England Journal of Medicine. 2007;356(15):1572-1574.