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PHILADELPHIA -- It's COURAGE all over again: the landmark ISCHEMIA trial failed to show an outcome benefit from adding early stenting or bypass surgery to optimal medication in patients with stable, moderate-to-severe ischemic heart disease in the contemporary era.

Compared with optimal medical therapy alone, an early invasive strategy didn't reduce the primary composite outcome of cardiovascular death, myocardial infarction (MI), hospitalization for unstable angina, hospitalization for heart failure or resuscitated out-of-hospital cardiac arrest (adjusted HR 0.93, 95% CI 0.80-1.08, P=0.34).

The curves crossed over at about 2 years, with an absolute 1.9% more events in the first 6 months and 2.2% fewer at 4 years compared with optimal medical therapy alone, reported Judith Hochman, MD, of NYU Langone Medical Center in New York City, at the American Heart Association (AHA) meeting.

Results were nearly identical for the key secondary endpoint of cardiovascular death or MI (adjusted HR 0.90, 95% CI 0.77-1.06, P=0.21), which was the original primary endpoint and sparked controversy when changed to preserve statistical power in the face of slow enrollment.

Additional Analyses

Results were also similar in the parallel, similarly-designed ISCHEMIA-CKD trial of 777 patients with estimated glomerular filtration (eGFR) rate <30 ml/min/1.73 m² and moderate or severe ischemia randomized to invasive or conservative strategies.

Early invasive management had an adjusted HR of 1.01 for the primary endpoint of death or MI and for the composite endpoint of the main trial (P=0.95 and P=0.93, respectively). Rates of procedural complications, including stroke and acute kidney injury were low, reported Sripal Bangalore, MD, also of NYU Langone.

Quality-of-life (QoL) data presented by John Spertus, MD, MPH, of the University of Missouri-Kansas City and St. Luke's Mid America Heart Institute there, showed that an invasive strategy held a consistent advantage for Seattle Angina Questionnaire scores in the main trial, except for the 34% of patients enrolled without any angina at baseline.

"In patients with angina, shared decision-making should occur to align treatment with patients' goals and preferences," Spertus concluded.

However, in the ISCHEMIA-CKD trial, the QoL findings were similar between arms, even in those with frequent angina. Spertus cited "very skewed enrollment towards less symptomatic patients" that may have precluded discerning a benefit in more symptomatic patients.

Still, for the CKD group, AHA discussant Glenn Levine, MD, of Baylor College of Medicine in Houston, speculated these will be influential for guidelines, given that guidelines haven't had almost any evidence to go on.

"I will generally not go searching for ischemia and CAD in most severe and end-stage CKD patients, absent marked or unacceptable angina, and will treat them with medical therapy alone," he concluded.

Divergent Implications?

The results, which were held close to the vest until the day of the presentation, and not even shared with a journal to prevent the kind of embargo break that plagued COURAGE in 2007, were met by applause at the session entirely reserved for the four-part presentation of the results.

"This was one of those trials that positive, negative, or neutral was going to tell us important outcomes," commented Donald Lloyd-Jones, MD, of Northwestern University in Chicago, in an interview with 麻豆传媒.

"There's a very clear and definitive answer. I think it's going to have a huge impact on the way we practice," Spertus told 麻豆传媒.

The only surprise would have been a negative outcome, commented Kirk Garratt, MD, past president of the Society for Cardiovascular Angiography and Interventions and chair of cardiology at ChristianaCare in Wilmington, Delaware.

"Of those five elements in the endpoint, only one has got a track record of being improved with an early trip to the cath lab," he noted in an interview monitored by media relations.

"Consistent with what was seen in the , the ISCHEMIA trial shows that the use of early invasive therapy is not required in order to keep people safe from the dangerous outcomes that are typically associated with ischemia. This isn't too surprising because we know that good medical therapy can indeed provide great safety for people."

Even a positive finding, though, probably wouldn't cause a lot of change in U.S. practice, Garratt suggested. People will probably still get a stress test if they come in with chest pain suspicious of cardiac origin and will probably still head for catheterization if it's abnormal, he noted.

"The ISCHEMIA trial confirms that way we've evolved our practice over the last several decades is in fact wise and sensible for patient care," Garratt said.

Despite the lack of superiority, the early invasive strategy "is more effective in reducing angina. This will have the potential to change clinical practice," Jacobs noted.

Lloyd-Jones predicted some impact on shared decision-making discussions and perhaps which patients are selected for one approach or the other.

"So patients perhaps at higher risk we might be more inclined to use the early invasive approach [than is now the case]," he said, "whereas patients at lower risk for outcomes because of their burden of disease or their burden of ischemia, I think it would be very acceptable based on this to inform them about the quality-of-life outcomes; what they can expect and that up to a third of them over the next 4 years might still require an invasive approach, but optimal medical therapy seems very appropriate."

"They can safely chose either one as long as we're following them closely," Lloyd-Jones concluded.

"The biggest thing is to not generalize to all stress tests," commented Ajay Kirtane, MD, of of New York-Presbyterian/Columbia University in New York City.

Design Issues

The trial included 5,179 patients stable with moderate or severe ischemia who were randomized if the coronary CT angiogram (CTA) ruled out left main disease and affirmed ≥50% stenosis in a major epicardial vessel, or at least 70% blockage in a proximal or mid-vessel.

CTA was performed in 73% of randomized participants. It was not required for patients with eGFR of 30 to <60 or coronary anatomy previously defined. The trial selected sites with high PCI and bypass surgery volume and good outcomes. Of revascularization, 74% was PCI.

A paper in Circulation: Cardiovascular Quality and Outcomes released shortly before the conference showed that optimal medical therapy and 75% to a systolic blood pressure <140 mm Hg at 1 year post-randomization.

At a mean of 3.3 years of follow-up for survivors, Hochman reported "no heterogeneity of treatment effect, including by type of stress test, severity of ischemia or extent of CAD."

Hochman cautioned that the findings do not apply to patients with recent heart attack or other acute coronary syndromes within 2 months, those who are highly symptomatic, those with left main disease, or low ejection fraction.

Although there was no blinding, the longer-term follow-up reduces concerns about placebo effect, commented AHA discussant Alice Jacobs, MD, of Boston University.

Still, these design elements eliminate some of the arguments made about the 2007 COURAGE trial, Garratt told 麻豆传媒.

"People pushed back on COURAGE because all the patients in that study had diagnostic coronary angiograms before enrollment. That was felt to be important because doctors will often respond to worrisome anatomy and make a judgment that more aggressive therapy is needed without certainty that that is actually required," he said.

"That bias in physician thinking may have led to patients with higher risk being excluded from participation in the COURAGE trial," Garratt continued. "If that turned out to be true, then it would not be a shock COURAGE showed no benefit from catheter-based therapy because the only patients enrolled were those felt to have little opportunity to receive benefit from that invasive care."

ISCHEMIA "is much more implementable," Spertus agreed. "The Twittersphere is already going nuts about this. ... Let them argue."