From the American College of Cardiology
Cost-Effective, Improved Efficacy in Some Patients

NEW ORLEANS—The critical attack on the COURAGE trial began in earnest even before the results were formally announced. Device makers and cardiac interventionalists refuted the real-world applicability of the trial, and even the hypothesis itself, while the results were being presented at a press briefing a day before they were to be announced at the American College of Cardiology’s annual meeting.

For those who may have been absent from the planet at the time, COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) demonstrated that optimal medical therapy alone is as effective as percutaneous intervention (PCI) plus optimal medical therapy as an initial strategy for preventing death or major cardiovascular events in patients with stable coronary artery disease (CAD) and myocardial ischemia.

The favorable results with aggressive medical care show that stable CAD is modifiable through the control of lipid levels, blood pressure (BP), and hemoglobin (Hb) A_1c, said lead investigator William E. Boden, MD, professor of medicine and public health at the University of Buffalo, New York.

“The disease is part of a decades-long process, and we need to find ways to treat it systemically,” he said. “We may be stabilizing plaques that are about to rupture [with aggressive medical therapy].”

Conversely, “there is no evidence to support PCI and stenting on top of optimal medical therapy as an initial strategy,” he said. “We can say with some conviction that patients were at no more and no less of a risk of having an event or dying if you defer stenting.”

Although PCI is the procedure of choice in patients with acute myocardial infarction (MI), said Dr Boden, “it had not been tested adequately in patients with symptomatic CAD.”

In the trial of 2287 patients who were randomized to 1 of the 2 treatment strategies, the incidence of all-cause mortality and nonfatal MI was 18.5% in those assigned to medical therapy alone and 19% in those assigned to PCI plus medical therapy, a nonsignificant difference, after a median follow-up of 4.6 years.

The incidence of the combined end point of death, MI, or stroke was 19.5% in patients randomized to optimal medical therapy alone and 20% in those randomized to PCI/optimal medical therapy, which was again nonsignificant. There was a nonsignificant trend toward fewer MIs in patients treated with medicine only versus PCI plus medicines (12.3% vs 13.2%; P = .33).

PCI did have an initial advantage in relieving angina, but this advantage declined over time until it virtually disappeared by the study’s conclusion. “Within 1 year, close to 60% of the medically treated patients were angina free,” said Dr Boden, “with no between-group difference in angina-free status at 5 years.” The rates of freedom from angina were 74% in the PCI group and 72% in the medical therapy alone group (P = .35).

All patients received aggressive therapy to lower low-density lipoprotein cholesterol (LDL-C) levels to a target of <85 mg/dL, with aspirin, 81 to 325 mg/day, or clopidogrel (Plavix), 75 mg/day, and medical anti-ischemic therapy.

Critics charged that such an aggressive treatment strategy could not be followed in real-world practice, but Dr Boden defended it by saying that, although labor-intensive, “what we did was nothing magical. It is a very real-world study that applies broadly to patients with symptomatic disease worldwide.”

At 5 years, 70% of the patients attained designated LDL-C and BP targets, and 45% of those with diabetes achieved a glycated HbA_1c level of ≤ 7.0%.

“This is good medical care. People do very well on medical therapy.… Revascularization procedures, if needed, can wait,” said Dr Boden.

Defenders of PCI pointed out that it was never marketed as a strategy to reduce the risk of MI and death but rather as a way to relieve symptoms. They pointed out that nearly one third of patients assigned to medical therapy had switched over to PCI at some point during the study’s 5-year follow-up.

Dr Boden countered, “There was an implicit belief that PCI would reduce the chance of having an MI and dying.” He also preferred to focus on the 75% of patients assigned to medical therapy who did not require PCI during the study. Moreover, an additional revascularization was needed in 21.1% of the group randomized to PCI, he said.

Salim Yusuf, MD, director of cardiology at McMaster University in Hamilton, Ontario, Canada, added that PCI’s role in stable CAD is now clear: as a strategy to relieve angina when medical therapy fails. “We should call medical therapy ‘aggressive management’ and PCI ‘palliative management,’” he said. “PCI has very little value to offer in the setting of stable CAD.”

Despite these findings from the  COURAGE study, Dr Yusuf questioned the impact they would have on medical practice. He estimated that up to 80% of PCIs done in the United States are performed in patients with stable CAD who would have been eligible for COURAGE.

“PCI represents a $15 billion to $20 billion industry in North America. You have huge vested interests that will push you back and have already done so,” he said. “We’re going to have a hell of a time putting the genie back in the bottle.”

Analysis showed that a PCI as a first choice relative to optimal medical therapy had an incremental cost-effectiveness ratio of $217,000 per quality-adjusted life-year gained, reported William Weintraub, MD, chief of cardiology and director of the Christiana Center for Outcomes Research, Newark, Del.

Interventions that have an incremental cost-benefit ratio of $50,000 or less are generally considered cost-effective, he said. At times during the study, optimal medical therapy was a dominant strategy, offering better outcomes at a lower cost.

The results have since appeared in the New England Journal of Medicine (2007; 356:1503-1516).