Pooled analysis of plaque progression shows limitations of grayscale IVUS

Virtual intravascular ultrasound histology identifies various components of plaque. Source: GE Healthcare.

After conducting a pooled analysis of five randomized controlled studies in which patients underwent serial intravascular ultrasound evaluation, researchers from the Cleveland Clinic concluded that diabetic patients need new anti-atherosclerotic strategies to address pathology specific to them. But a commentary related to the study suggests that research with grayscale intravascular ultrasound has plateaued and that researchers should investigate plaque composition, not just progression, with newer technologies.

Stephen J. Nicholls, MBBS, and colleagues undertook a systematic analysis of more than 2,000 subjects to compare the pattern of arterial remodeling, extent of coronary atherosclerosis and disease progression in subjects with and without diabetes. They published their results in the July issue of Journal of the American College of Cardiology.

Researchers found an association between the presence of diabetes and greater atherosclerotic burden, as well as impaired arterial wall remodeling. They also documented that diabetics experience a more rapid atheroma progression than non-diabetics, despite the high use of established medical therapies.
The authors said that these findings confirm that diabetic patients have an accelerated form of atherosclerotic disease.

“If you intensely lower LDL cholesterol in diabetics, you do slow the progression of disease, but only to the level in nondiabetics that haven’t been treated,” Nicholls told Cardiovascular Business. “It’s imperative that we understand that even when we see a benefit in diabetics from statins and other therapies, there is still a considerable risk for cardiovascular events.”

Interestingly, researchers found that impaired arterial remodeling was more prominent in diabetic patients treated with insulin. They suggested that the “proliferation of smooth muscle and fibrous tissue in response to insulin might increase vascular stiffness and further impair the ability of the artery wall to expand in response to accumulation of plaque.”

In an accompanying commentary, Gary S. Mintz, MD, chief medical officer for the Cardiovascular Research Foundation in New York City, praised Nicholls et al for their study. “The amount of work involved is staggering,” Mintz said.

Nevertheless, he also wrote that the study’s findings are “modest and somewhat internally inconsistent” and suggested that the present analysis highlights the limitations of grayscale IVUS.

“Perhaps, after almost two decades of work and thousands of publications, the revelations of IVUS have reached a plateau,” he said.

Mintz goes on to say that researchers should be assessing changes in plaque composition and stability, rather than its mere progression.

“It is the instability of the disease, not just the increase in plaque mass, that is different in high-risk patient subsets,” he said.

He suggested analyzing plaque composition with such modalities as virtual histology or integrated backscatter IVUS, palpography, optical coherence imaging, and spectroscopy.

“While there is much ongoing work looking at progression/regression and plaque stability using these other modalities, none of it is mature,” Mintz told Cardiovascular Business.

Nicholls said that Mintz is right regarding the need to focus more attention on plaque composition. But Nicholls doesn’t want researchers to separate progression and composition.

“We have gained an enormous amount of information from looking at the extent of disease. The more disease you have, the more likely you have diseased walls and the more likely you will have a rupture,” Nicholls said.

Since the current state of imaging cannot determine which particular vulnerable plaques will rupture, plaque composition is a moot point, because patients with a lot of plaque progression will be put on aggressive medical therapy anyway, Nicholls said.

Nicholls highlighted that this study is one of the first to investigate coronary artery disease in a very large diabetic population, confirming results from smaller randomized trials as well as observational studies.

Atheroma Changes in Patients With and Without Diabetes

Parameter Non-diabetic Patients (1,821) Diabetic Patients (416) p Value Percent atheroma volume 0.3 +/- 3.3 0.8 +/- 3.4 0.003 Adjusted percent atheroma volume* 0.05 +/- 0.3 0.6 +/- 0.4 0.0001 Total atheroma volume (mm3) -54.0 +/- 21.8 -1.8 +/- 23.3 0.15 Adjusted total atheroma volume (mm3)* -2.7 +/- 2.4 -0.6 +/- 2.5 0.03 Atheroma volume most diseased segment (mm3) -3.5 +/- 10.6 -2.6 +/- 10.4 0.13 Atheroma volume least diseased segment (mm3) 0.1 +/- 7.9 0.5 +/- 8.3 0.42 Substantial regressors (%) 20 16 0.04 Substantial progressors (%) 23 30 0.002 External elastic membrane volume (mm3) -13.2 +/- 38.4 -13.0 +/- 39.5 0.97 Lumen volume (mm3) -9.2 +/- 30.2 -11.2 +/- 32.3 0.14

In one of the largest studies of diabetics with coronary artery disease, researchers found that diabetics have significantly more atheroma volume and that their disease progresses faster than non-diabetics. *Adjusted for differences in clinical characteristics and baseline atheroma burden, expressed as least squared mean +/- SEM.