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Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation - COURAGE
Contribution To Literature:
The COURAGE trial failed to show that PCI reduced the risk of death or nonfatal myocardial infarction (MI) among patients with stable coronary artery disease.
Description:
The goal of the trial was to evaluate the efficacy of percutaneous coronary intervention (PCI) compared with optimal medical therapy among patients with stable coronary artery disease.
Study Design
Patients Screened: 35,539
Patients Enrolled: 2,287
Mean Follow-Up: Median, 4.6 years (range 2.5-7.0 years); and 15 years
Mean Patient Age: 62 years
Female: 15%
Patient Populations:
Stable coronary artery disease; initial Canadian Cardiovascular Society (CCS) class IV angina subsequently stabilized medically; either 1) stenosis ≥70% in ≥1 proximal epicardial coronary artery with objective evidence of myocardial ischemia (including either substantial changes in ST-segment depression or T-wave inversion on the resting ECG or inducible ischemia with either exercise or pharmacologic stress test), or 2) ≥1 coronary stenosis of ≥80% and classic angina without provocative testing
Exclusions:
Persistent CCS class IV angina; a markedly positive stress; refractory heart failure or cardiogenic shock; an ejection fraction <30%; revascularization within the previous 6 months; and coronary anatomy not suitable for PCI
Primary Endpoints:
Composite of death from any cause and nonfatal MI
Secondary Endpoints:
Composite of death, MI, and stroke; hospitalization for unstable angina with negative biomarkers; quality of life; use of resources; and cost-effectiveness
Drug/Procedures Used:
Patients were randomized to optimal medical therapy alone (n = 1,138) or PCI in addition to optimal medical therapy (n = 1,149). Optimal medical therapy included antiplatelet therapy with aspirin (81-325 mg/day), or clopidogrel (75 mg/day) if aspirin intolerant in the medical therapy group, and aspirin plus clopidogrel in the PCI group. All patients also received aggressive lipid-lowering therapy to a target low-density lipoprotein (LDL) of 60-85 mg/dl. Anti-ischemic therapy included long-acting metoprolol, amlodipine, and isosorbide mononitrate, alone or in combination, and either lisinopril or losartan as secondary prevention.
Principal Findings:
The large majority of patients (95%) had objective evidence of myocardial ischemia. Multivessel disease was present in 69% of patients, with only 31% having single-vessel disease. One-third of patients had proximal disease of the left anterior descending artery. CCS class II or III angina was present in 58% of patients at study entry.
PCI was performed in 94% of the PCI cohort, with successful PCI in 93%. Optimal medication use during the study was high in both treatment groups, with use at 5 years of angiotensin-converting enzyme inhibitors in 64% of patients, statins in 93%, aspirin in 95%, and beta-blockers in 85%. LDL levels were reduced to a median of 71 mg/dl. Diet, exercise, and smoking cessation were also high in both groups.
The primary endpoint of death or MI did not differ for the PCI group compared with the medical therapy group (19.0% for PCI vs. 18.5% for medical therapy, hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.87-1.27, p = 0.62). Findings were similar during extended follow-up to 15 years.
There was also no difference between PCI and medical therapy in the secondary composite endpoint of death, MI, or stroke (20.0% for PCI vs. 19.5% for medical therapy, HR 1.05, 95% CI 0.87-1.27, p = 0.62) or in the secondary endpoint of hospitalization for ACS (12.4% for PCI vs. 11.8% for medical therapy, HR 1.07, 95% CI 0.84-1.37, p = 0.56). Components of the composite endpoints did not differ between groups, including death (7.6% for PCI vs. 8.3% for medical therapy, HR 0.87, p = 0.38), nonfatal MI (13.2% vs. 12.3%, HR 1.13, p = 0.33), or stroke (2.1% for PCI vs. 1.8% for medical therapy, p = 0.19). Angina was significantly reduced in both groups during follow-up, with no difference in the reduction between PCI and medical therapy at 5 years (freedom from angina in 74% of the PCI group and 72% of the medical therapy group, p = 0.35) but slightly higher rates of freedom from angina in the early time frame with PCI (at 1 year: 66% for PCI vs. 58% for medical therapy, p < 0.001; at 3 years: 72% for PCI vs. 67% for medical therapy, p = 0.02).
In a cost economic analysis, PCI costs averaged $6,020 higher than medical therapy during the index hospitalization (p < 0.0001), a difference that narrowed slightly over time, but remained at an increased cost of $5,295 by 3 years (p < 0.0001). In a cost-effectiveness analysis, PCI was estimated at $217,000 per quality-adjusted life-year gained. $50,000 is often used as the benchmark for acceptable cost-effective therapies.
The strongest predictor of improved 1-year survival was being a nonsmoker, regular physical activity, systolic blood pressure <130 mm Hg, and following the American Heart Association step 2 diet.
Interpretation:
Among patients with stable coronary artery disease, treatment with PCI was not associated with a difference in death or MI compared with treatment with medical therapy through 15 years of follow-up.
Freedom from angina occurred slightly more frequently with PCI early in the trial but did not differ between the PCI and medical therapy groups by 5 years, with both arms showing marked reductions in angina throughout the trial.
Findings from the present study apply to stable angina patients and cannot be extrapolated to the acute coronary syndrome population, which has different pathophysiologic characteristics. The majority of the PCI group did not receive drug-eluting stents since most of the enrollment was completed prior to the introduction of these stents. The greater the number of risk factors in control during follow-up, the greater probability of 1-year survival.
References:
Maron DJ, Mancini GB, Hartigan PM, et al., on behalf of COURAGE Trial Group. Healthy Behavior, Risk Factor Control, and Survival in the COURAGE Trial. J Am Coll Cardiol 2018;72:2297-2305.
Editorial Comment: Bittner V. Do Not Smoke, Eat Healthy, and Exercise. J Am Coll Cardiol 2018;72:2306-8.
Sedlis SP, Hartigan PM, Teo KK, et al., on behalf of the COURAGE Trial Investigators. Effect of PCI on long-term survival in patients with stable ischemic heart disease. N Engl J Med 2015;373:1937-46.
Weintraub WS, Spertus JA, Kolm P, et al., on behalf of the COURAGE Trial Research Group. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med 2008;359:677-87.
Boden WE, O'Rourke RA, Teo KK, et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. N Engl J Med 2007;356:1503-16.
Presented by Dr. William E. Boden at the American College of Cardiology Annual Scientific Session, New Orleans, LA, March 2007.
Clinical Topics: Acute Coronary Syndromes, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Interventions and ACS, Interventions and Coronary Artery Disease, Diet, Chronic Angina
Keywords: Losartan, Coronary Artery Disease, Angina, Stable, Ticlopidine, Electrocardiography, Coronary Stenosis, Confidence Intervals, Metoprolol, Exercise Test, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Drug-Eluting Stents, Constriction, Pathologic, Percutaneous Coronary Intervention, Isosorbide Dinitrate, Lipoproteins, LDL, Lisinopril, Secondary Prevention, Amlodipine, Diet, Smoking Cessation, Secondary Prevention
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