Unanswered COURAGE, BARI 2D Questions Tackled in Huge Trial

Reed Miller

August 04, 2011

August 3, 2011 (Bethesda, Maryland) — The National Heart, Lung, and Blood Institute is sponsoring an eight year trial in about 8000 patients to find the best management strategy for patients with stable ischemic heart disease and moderate to severe ischemia [1].

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches(ISCHEMIA), planned for at least 150 sites in more than 30 countries, will compare angiography and revascularization plus optimal medical therapy with the conservative strategy of optimal medical therapy only. ISCHEMIA's primary end point is time to cardiovascular death, MI, or hospitalization for unstable angina, resuscitated cardiac arrest, or heart failure. The secondary end points include angina-related quality of life and cost-effectiveness.

Trial chair Dr Judith Hochman (New York University, NY) told heartwire that ISCHEMIA is designed to answer questions raised by the seminal COURAGE and BARI 2D trials, which found no mortality benefit for revascularization over optimal medical management in patients with stable ischemic heart disease. "These trials have had an impact, but the medical community has had a very hard time accepting the results. Intuitively, it does not make a lot of sense that fixing the blockage does not improve clinical outcomes, even a short-term improvement in quality of life wasn't large or durable [in those trials]," Hochman said. "The community has been assessing what might be the shortfalls of those studies and what is the next question."

Based on those studies, some observers have hypothesized patients with the most severe ischemia, seen in the COURAGE nuclear substudy, might benefit from the early revascularization strategy. So the ISCHEMIA trial is focused on these patients.

Patients randomized to revascularization will undergo PCI or bypass surgery at the discretion of the local interventional cardiologist and cardiovascular surgeon based on protocol recommendations. Patients randomized to medical therapy only may cross over following acute coronary syndrome or other progressive symptoms. To minimize these crossovers, patients who have already failed treatment with maximal medical management are not eligible for the study.

Unlike past stable-ischemia trials, ISCHEMIA will randomize patients after they undergo a stress test but before angiography. Patients deemed to have moderate to severe ischemia on the stress test will also undergo a blinded coronary CT angiography to exclude left main disease and to confirm they have obstructive coronary disease.

Randomizing patients after a stress test "is supposed to address the criticism [of previous trials] that once you've defined the anatomy and seen these tight blockages, the most suitable patients for intervention or surgery never got into the randomized trials. So we're trying to get rid of that selection bias in terms of who is enrolled," Hochman said. Furthermore, to assess potential selection bias, the trial will include a dynamic registry that will ascertain baseline characteristics of those eligible for the trial but not randomized and whether there is a plan for catheterization.

Hochman said the patient enrollment will begin in about a year and take four to five years to accrue. Minimum follow-up will be two years and the whole study will take about eight years to complete.

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