Paradigm Shift from Ischemia to Vulnerable Plaque Needed to Prevent Sudden Coronary Death

MIAMI BEACH, FLA.—When it comes to the treatment of patients with stable CAD, TCT Course Director Gregg W. Stone, MD, of New York-Presbyterian Hospital/Columbia University Medical Center, New York, said it is now time for a paradigm shift—to think of atherosclerosis as a continual risk, with less focus solely on ischemia.

During a scientific session at TCT 2012, Stone spoke about the details of the ISCHEMIA trial, which is now enrolling patients. In the trial, 8,600 patients with moderate-to-severe ischemia and stable CAD will be randomized to optimal medical therapy (OMT), with diagnostic catheterization reserved for refractory ischemia or a more invasive strategy of catheterization plus PCI or CABG. The primary endpoint of ISCHEMIA is CV death or MI, with a major secondary endpoint of quality of life improvement.

“This should be the definitive study to answer the question of how important it is to reduce ischemia, and does revascularization improve death and MI by eliminating or reducing it?” he said.

In his presentation, Stone cited previous results from the CASS, COURAGE, FAME and FAME 2 trials, which had influenced the prior thought that the key to reducing death and MI in stable CAD could be in the prevention of ischemia. The results of CASS led experts to question the efficacy of angiography and hypothesize that ischemia produces lesions that could represent the “missing link,” Stone said. The COURAGE nuclear substudy demonstrated that the amount of residual ischemia was linked with subsequent death or MI and that, most importantly, OMT did not reduce ischemia. Lastly, Stone noted, the most recent data from FAME 2 signaled that the presence of ischemia was associated with lack of OMT benefit by showing that patients without ischemia had a lower incidence of death and MI after OMT.

Hoping to determine the types of coronary lesions from which adverse CV events arise, Stone said that ISCHEMIA would further center on defining non-culprit lesions and plaque morphology. Citing the research of Renu Virmani, MD, of CVPath Institute, Inc., who also presented during the session, Stone noted three substrates most strongly linked with subsequent AMI and sudden coronary death: plaque rupture; plaque erosion; and calcified nodules.

Pathology of vulnerable plaque

Dr. Virmani presented her research on novel developments in the pathogenesis of vulnerable plaque, noting that plaque rupture is by far the most common cause of thrombosis in coronary arteries (65% to 70% of cases); followed by erosion (30% of cases); and the least-common cause, calcified nodules (4% to 7% of cases). Virmani stated that calcified nodules are more likely to occur in elderly men with high plaque burden, tortuous arteries, diabetes, metabolic syndrome, hypertension and smoking history.

Vulnerable plaque (thin cap fibroatheroma) is a likely precursor to rupture, Virmani said, adding that macrophage infiltration plays an important role in the modification of plaque vulnerability.

In closing, Stone said physicians need to consider making modifications in treatment when there is interaction between varying lesion types. “When you’ve got calcific nodules and proteoglycan-rich lesions and there is some interplay between these different lesion types, we can’t think it’s all about ischemia. It’s really this interplay between plaque volume, ischemia and vulnerable plaque,” Stone said.