Chronic stable angina COURAGE trial

Overview
The COURAGE (Clinical Outcomes Utilizing Revascularization and AGgressive Drug Evaluation) trial, was a large-scale, randomized, multicenter, multinational trial conducted between 1999 and 2004. The trial compared the benefits of PCI versus optimal medical therapy as the initial treatment strategy in patients with stable angina and significant underlying coronary artery disease on cardiac catheterization.

Study Population
A total of 2,287 patients were randomized to either PCI (1,149 patients) which consisted of PCI with optimal medical therapy or medical therapy (1,138 patients) which consisted of upfront optimal medical therapy alone. It should be noted that medical therapy patients could cross over to PCI.

PCI
The trial has been criticized because the PCI patients were treated predominantly with bare metal stents and only 15% of the patients were treated with drug eluting stents.

Optimal Medical Therapy
All patients who were randomized to optimal medical therapy alone were treated with beta blockers, calcium channel blockers, nitrates, antiplatelet therapy (either aspirin or clopidogrel), and aggressive lipid-lowering therapy with statin (attained median LDL-cholesterol was 72 mg/dL at five years). Exercise was recommended to achieve further improvements in the lipid profile when necessary.

Both Groups
Both groups received aspirin along with aggressive lipid and blood pressure lowering as a part of optimal medical therapy.

Inclusion Criteria
Patients were required to have both objective evidence of ischemia and significant coronary heart disease in a least one vessel (87% were symptomatic and 58% had Canadian Cardiovascular Society CCS class II or III angina). Approximately, two thirds of the patients had multi-vessel disease.

Exclusion Criteria
Patients were excluded if they had CCS class IV angina, ≥50 percent left main disease, a markedly positive treadmill test (significant ST segment depressions and/or a hypotensive response during stage I of the Bruce protocol), an LVEF less than 30 percent, or coronary lesions deemed unsuitable for PCI.

Primary Endpoint
The primary endpoint of the study was the composite endpoint of death from any cause or non-fatal MI. There was no significant difference reported in the primary endpoint event rate between the two treatment groups during the median follow-up of 4.6 years (range 2.5 to 7 years): 19% in the PCI group and 18.5% in the medical therapy group, P=0.62.

Secondary Endpoints

 * There was no significant difference observed between the incidence of hospitalization for acute coronary syndrome, stroke, rates of MI and death.


 * However, patients in the PCI group underwent significantly fewer subsequent revascularization procedures (21 versus 33 percent, HR 0.60, 95% CI 0.51-71).


 * The COURAGE trial also addressed the issue of whether patients who receive PCI plus optimal medical therapy have a better quality of life and less angina than those who receive optimal medical therapy alone.


 * The rate of patients who were free from angina between the 2 groups at 1 and 3 years was statistically significant (74% patients who underwent PCI were angina free at 5 years in comparison to the 72% patients who received medical therapy alone, P=0.35).
 * However, there was no statistically significant difference noted at baseline, or at 3 year follow up.
 * 22% patients who underwent PCI were angina free at baseline.
 * 53% patients who underwent PCI were angina free versus 42% patients who received medical therapy alone noted at 3-month.
 * However, there was no significant difference between the 2 groups observed at 36 months (59% patients who underwent PCI versus 56% who received medical therapy alone).


 * Patients in both groups showed significant improvements from baseline values in various measures of quality of life.
 * At 6-month follow up, the percent of patients with clinically significant improvement in the parameters such as physical limitation, angina stability, angina frequency, and overall quality of life was significantly higher in the PCI group in comparison to that of the medical group.
 * However, there was no significant difference in these rates at 36 months.


 * The results of COURAGE trail demonstrate that no benefit was observed with revascularization by PCI over aggressive medical management when performed in patients with chronic stable angina and suggest that PCI may be deferred as long as medical therapy is optimized and maintained in patients with chronic stable disease.

Meta-analyses Including the COURAGE trial that Compare Medical and PCI Therapy
A meta-analysis of 25,388 patients with stable coronary artery disease who were enrolled in 61 randomized trials comparing at least two of the four interventions (PTCA, BMS, DES, and medical therapy) demonstrated no statistically significant difference in the rates of death and MI among patients treated with either PCI or medical therapy.

Another recent meta-analysis compared the angina relief in 7,818 patients with stable coronary artery disease who were enrolled in 14 randomized trials comparing PCI and medical therapy. Similar to COURAGE, PCI was associated with greater angina relief than medical therapy (odds ratio, 1.69 [95% CI, 1.24 to 2.30]), particularly in recent trials.