Clinical Outcomes Utilizing Revascularization And Aggressive Drug Evaluation
Synonyms and keywords: COURAGE, 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 outcomes 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.  The rates of death and MI did not differ between the two groups, but PCI was associated with an improvement in quality of life measures and anginal symptoms for up to 3 years.

# Study Population
2,287 patients with chronic stable angina from 50 hospitals (19 US Non-VA hospitals, 15 VA hospitals and 16 Canadian hospitals) were randomized to either PCI along with optimal medical therapy (n=1,149) or an initial strategy of medical therapy with cross-over to PCI as needed (n=1,138).

# Treatment Strategies

## PCI
Drug eluting stents were introduced in April of 2003 after many of the patients had already been enrolled, and 85% of the PCI patients were treated with bare metal stents.

## Optimal Medical Therapy
All patients who were randomized to upfront optimal medical therapy 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 were treated aspirin along with aggressive lipid and blood pressure lowering as a part of optimal medical therapy.

# Study Entry Criteria

## 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%, or coronary lesions deemed unsuitable for PCI.

# Results

## Primary Endpoint
The primary endpoint of all cause mortality or non-fatal MI during a median follow-up of 4.6 years (range 2.5 to 7 years) did not differ between the two groups: 19% in the PCI group and 18.5% in the medical therapy group (p=0.62).

## Secondary Endpoints
- There was no significant difference in hospitalization for acute coronary syndrome, stroke, MI or 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).
- During the first two years of follow-up, PCI was associated with improved quality of life and less angina compared with optimal medical therapy alone. By three years, however, there was no difference in quality of life or angina between the two strategies.

# Limitations of the COURAGE Study

## Bare Metal and not Drug Eluting Stents were used
The trial has been criticized because 85% of the PCI patients were treated with bare metal stents while only 15% of the patients were treated with drug eluting stents which further reduce angiographic restenosis and modestly reduce symptomatic restenosis.  On the other hand, it should be noted that only 11% of patients underwent repeat revascularization by one year, so the potential impact of drug eluting stents in further reducing revascularization may be modest.  It is unlikely that drug eluting stents would have reduced the risk of death or MI.  Drug eluting stents were introduced in April of 2003 after many of the patients had already been enrolled.

## Nearly a Third of Patients who were Treated with Medical Therapy Crossed over to PCI
Given that COURAGE was essentially a strategy trial, the data were analyzed based upon the intent to treat principle were patients were included in the group they were originally assigned to. The crossover rate in COURAGE was 32.6%, so nearly a third of the optimal medical therapy patients were eventually treated with PCI.
Randomization of subjects at the beginning of a trial assures that any imbalances in risk factors, demographics and confounders will be minimized.  An ITT analysis preserves that initial randomization, and avoids the effects of crossover and drop-out, which may break the randomization to the treatment groups in a study.  Patients who discontinue study drug therapy may do so due to side effects or a perceived lack of effectiveness.  As a result, the remaining population is enriched with those patients who could tolerate the drug or perhaps had their symptoms improved on the treatment.  Simply put, this remaining "per protocol" cohort harvests out those subjects who were "success stories", and eliminates those patients who failed. An ITT analysis is a more conservative form of analysis because it incorporates patients who failed therapy, could not take therap and who may have crossed over to other therapies.  A per protocol analysis of those patients who successfully followed the protocol may overestimate the efficacy of a treatment.

## COURAGE has been said to be a low risk Population
COURAGE actually enrolled a medium to high risk population of patients.  Patients enrolled in COURAGE had had angina for 26 months and had an average of 10 anginal episodes per week (medians of 5 months and 3 episodes per week).
- 40% of patients had sustained a prior MI,
- One third were diabetic
- Two thirds were hypertensive.
- Seventy-one percent were being treated for dyslipidemia at baseline.
- Two-thirds had multivessel coronary disease.
- 95% had myocardial ischemia on stress testing.
- Two-thirds had multiple reversible perfusion defects.
- Less than 10% of the screened patients with coronary artery disease were enrolled in the study.
- Vast majority of the population enrolled were white males.
- 80% had no or mild symptoms.

# 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 ), particularly in recent trials.
In a COURAGE substudy of serial rest/stress myocardial perfusion single photon emission computed tomography (MPS), 314 of the COURAGE patients were enrolled. At follow-up, the reduction in ischemic myocardium was greater with PCI plus optimum medical therapy (-2.7%) than with optimum medical therapy (-0.5%). More PCI plus optimum medical therapy patients exhibited significant ischemia reduction (33% versus 19%; P=0.0004). Thus, it was concluded that adding PCI to optimum medical therapy reduces ischemia more compared to when medical therapy is used alone.

# Educational Resources
Video: Dr. C. Micheal Gibson and lead author William Boden debate the results of COURAGE
Slides:
Results of the COURAGE trial in english
Results of the COURAGE trial in spanish
Results of the economic substudy of the COURAGE trial
Dr. Dean Kereiakes offers a critique of the COURAGE trial
Dr. Duane Pinto puts the COURAGE results into perspective