Statin therapy has long been thought to cut the risk for ischemic coronary events, in part by stabilizing atherosclerotic plaques that are vulnerable to rupture, which would trigger thrombosis, and in part by depleting lesions of lipid and other soft components.
But it might be that statins, with a certain amount of irony, also intensify the process of plaque calcification, a familiar marker of increased risk. Statin therapy might raise the density of lesion calcifications in a way that makes rupture less likely, suggests a study of plaque size and composition by serial coronary CT angiography (CTA).
Two CTA scans were obtained at least 2 years apart on more than 2500 coronary lesions in 857 patients in an international registry, 64% of whom had been on statin therapy continuously throughout that time. The remainder had not been on a statin at any time between scans.
Not unexpectedly, there were signs that plaques in statin-treated patients progressed in volume more slowly than those not exposed to the drugs. But CTA caught other changes over time based on the density of lesion components, as visualized and measured by within-lesion variation in gray-scale signal attenuation.
In general, coronary plaques in statin-treated patients transformed from containing calcium at low densities to showing predominantly higher-density calcifications. Meanwhile, plaques with the lowest calcium densities progressed in volume at the highest rate, and those containing the densest calcium showed the slowest progression.
In other words, the findings might partly account for the way statin therapy lowers atherothrombotic risk, in that they suggest statins make plaques progressively less vulnerable by “increased densification” of calcium and diminishing softer components, Alexander R. van Rosendael, MD, told theheart.org | Medscape Cardiology.
“We very nicely saw that the plaques that are considered the highest-risk, the low-attenuation plaques, actually decrease. And probably parts of them will become this very dense calcium,” said van Rosendael, New York–Presbyterian Hospital and Weill Cornell Medicine, New York City. “We believe that this partially explains why statins work.”
The analysis, based on the Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry, was published online August 18 in JAMA Cardiology, with van Rosendael as lead author.
In Context With IVUS Research
There is abundant evidence that coronary plaque burden tracks with risk for ischemic events, and that lipid-modifying drug therapy — especially with statins — shrinks coronary plaque volume and promotes their calcification. Such evidence on intravascular ultrasound (IVUS) goes back more than a decade, whereas the data from CTA have been accumulating more recently.
“Basically, the more plaque you have, the higher the risk for future heart attack,” van Rosendael said. “But this can be refined by looking at plaque composition.” It’s becoming increasingly clear that the very dense calcium on CTA is not a high-risk lesion component and actually may be “protective.”
So, he speculated, “the lower the plaque burden, the better. But if you have plaque, then it probably is best to have very dense calcium.” And that might have implications for the use and interpretation of coronary artery calcium (CAC) scores for risk stratification.
CAC scores comprise both volume and density of lesion calcification, so the greater the volume and, separately, the more dense the calcium, “the higher the calcium score will be,” van Rosendael observed. But the calcium density aspect of the score could potentially lead to wrong conclusions about risk.
For example, if the volume of plaque calcium stays the same at serial CAC assessments while the lesion shrinks in volume — increasing the calcification density — then “the calcium score goes up, but actually the risk is probably getting lower,” he said.
The “very interesting” results corroborate with CTA what has been repeatedly shown by IVUS in placebo-controlled trials, that statins don’t reduce plaque calcification even though plaque volume may regress, observed Steven E. Nissen, MD, Cleveland Clinic, who was involved in much of the IVUS research but isn’t part of the current study.
But IVUS in the earlier studies usually tracked plaque constituents in terms of percent atheroma volume, in contrast to density measured by signal attenuation on CTA.
Also, many of the IVUS studies were placebo-controlled, whereas the current study is observational and unlikely to have adjusted for all potential confounders. “It cannot be interpreted in the same way that you interpret a randomized controlled trial,” Nissen said.
Still the observations are important, he told theheart.org | Medscape Cardiology, because statin-mediated plaque changes can confuse the interpretation of serial CAC assessments, which some physicians order to monitor disease progression in their patients.
“I have patients coming to see me, sometimes from great distances, because they’re terribly concerned that their coronary calcium score went up,” Nissen said. “What I have told them, and what I believe we need to tell patients, is that you should get one coronary calcium score, and that repeating scores to track progression is unwise.”
Six Lesion Categories
As the report notes, the PARADIGM cohort consisted of 857 patients with suspected or recognized CAD enrolled at 13 institutions in seven countries from 2013 to 2016. They had 2458 coronary lesions tracked on CTA scans obtained at least 2 years apart. During that time, 548 patients were on statins and the remainder did not take statins at all. Women accounted for 37% of the cohort.
Coronary plaques were defined by composition, according to degree of signal attenuation on CTA, conventionally expressed in Hounsfield units (HU), with lower HU numbers corresponding to the lowest degree of signal attenuation, or radiodensity, and higher HU levels indicating greater radiodensity.
Six types of plaque composition were defined by varying radiodensity: three with and three without calcium. They ranged from the least-dense low-attenuation plaque (LAP), followed progressively by dense fibro-fatty, fibrous, low-density calcium, high-density calcium, and highest-density calcium plaque. The latter plaques were called 1K lesions because their radiodensity was more than 1000 HU.
In analyses adjusted for patient risk factors and time between the two CTA scans, increasing density of plaque calcification was inversely related (P ≤ .001) to quantity of LAP, fibro-fatty plaque, and fibrous plaque, the report notes.
Lesions in patients not treated with statins grew in volume for all six component types. By the second scan, their lesions contained a higher volume of LAP and lower volumes of all three types of calcific lesions.
Statins, compared with no statins, were associated with a greater increase in volume of high-density and 1K plaque, which in turn tracked inversely with overall plaque progression. All the interactions with statin therapy were significant at P ≤ .001.
The patterns suggest that statin therapy reconfigures the plaque components from predominantly lower attenuation to proportionally more in the highest-attenuation category; that is, from lower to higher calcium densities, van Rosendael said.
Serial CTA scans, with density measurements of the components of high-risk plaques, could potentially be used to evaluate the success of medical therapy for patients with coronary disease, van Rosendael speculated.
For example, if on the second scan the lesion has shown progression of LAP and no increase in very dense calcium on medical therapy, “maybe you would stent the lesion, because medical therapy didn’t work.”
But, Nissen said adamantly, “until there’s a randomized-controlled trial, we cannot recommend serial CTA as a means to track whether or not we’re effectively treating patients.”
van Rosendael reports receiving grants from the Leading Foreign Research Institute recruitment program through the National Research Foundation of Korea during the conduct of the study. Disclosures for the others are in the report. Nissen has reported that his center has received funding for clinical trials from AbbVie, AstraZeneca, Amgen, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Pfizer, The Medicines Company, Silence Therapeutics, Takeda, and Orexigen; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction.
JAMA Cardiology. Published online August 18, 2021. Abstract
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