Statin Therapy Alters Composition of Coronary Plaques, Virtual Histology-IVUS Study Shows

A study evaluating the effect of statin therapy in patients with functionally insignificant coronary stenoses suggests that treatment can result in changes in the composition of coronary plaques.

Using intravascular ultrasound (IVUS)-derived virtual histology to assess plaque morphology, researchers show that 1 year of rosuvastatin therapy reduced the volume of atheroma and the volume of the necrotic core in fibroatheroma-containing nonculprit target lesion segments. In addition, the use of rosuvastatin reduced the presence of virtual histology-identified thin-cap fibroatheroma, the type of plaque suspected of rupturing in some acute coronary events.

“The results indicate that the amount and composition of atherosclerotic plaques in deferred lesions can be changed with statin therapy,” Soo-Jin Kang, MD (University of Ulsan College of Medicine, Seoul, South Korea), one of the study’s lead researchers, told TCTMD in email. “The appropriate treatment of non-ischemia producing coronary artery lesions with unstable plaque morphology is still under debate. This study suggests the possibility that even unstable morphology undergoes dynamic changes and the natural course of vulnerable plaques can be modified by statin treatment.” 

Results of the STABLE (Statin and Atheroma Vulnerability Evaluation) trial were published online April 11, 2016, ahead of print in the Journal of the American College of Cardiology.

Assessing How Statins Affect the Natural Course of Atherosclerosis

Virtual histology-IVUS is designed to overcome the difficulties of differentiating and analyzing coronary plaque composition with conventional grayscale-IVUS. The images obtained with virtual histology are based on the spectral analysis of the primary raw backscattered radiofrequency signals and provide detailed tissue characterization, explained Kang. The “spectral signatures” of the tissues can be color-coded into four major components: the necrotic core, fibrotic tissue, fibrofatty tissue, and dense calcium.

STABLE included 312 patients with a coronary lesion identified as containing fibroatheroma on virtual histology-IVUS and evaluated changes in plaque composition following treatment with statin therapy. Patients were randomized to treatment with rosuvastatin 10 mg or 40 mg and followed for 1 year. Of the randomized patients, 225 individuals had grayscale- and virtual histology-IVUS completed at baseline and 12 months.

Overall, treatment with rosuvastatin resulted in decreases in the normalized total and percent atheroma volumes. Importantly, treatment significantly reduced the size of the necrotic core, regardless of statin dose. Within the identified lesions, the volume comprised of the necrotic core declined from a mean of 21.3% at baseline to a mean of 18.0% at 12 months (P < 0.001). In contrast, the percentage of fibrofatty tissue increased while the volume of fibrous tissue and dense calcium was unchanged with treatment.

Rosuvastatin therapy also reduced the number of individuals with a virtual histology-defined thin-cap fibroatheroma to 29.3% at 12 months. Prior to statin therapy, 54.7% of subjects had a thin-cap fibroatheroma (P < 0.001).

Independent predictors of changes in the necrotic core included high-sensitivity C-reactive protein (CRP) levels, body mass index (BMI), and the baseline percentage of necrotic core volume, suggesting those with higher CRP, BMI, and larger necrotic cores might be more responsive to statin therapy. The researchers observed a correlation between the reduction in the necrotic core and change in CRP—but not LDL cholesterol levels—which implies “that the anti-inflammatory effect of rosuvastatin may be an important mechanism of the compositional changes,” according to Kang.  

To TCTMD, Kang said that all plaques identified in the present study had fibroatheroma, with the cohort characterized by having a larger necrotic core and a higher rate of thin-cap fibroatheroma. This distinguishes their study from previous trials evaluating the effects of statins on plaque regression. 

No Support for Notion of ‘Vulnerable Plaque’

The vulnerable plaque hypothesis stems from previous autopsy studies suggesting that a majority of fatal acute events were not the result of coronary blockages but rather caused by rupture of the coronary plaque’s fibrous cap. These vulnerable plaques have been characterized as having a large, lipid-rich necrotic core capped by the thin fibroatheroma. Yet despite the promise of this hypothesis, and the development of imaging modalities designed to assess it, some experts have called for a “requiem”, stating the data simply don’t support it.   

For Steven Nissen (Cleveland Clinic, OH), who led a number of prominent IVUS studies showing that statin therapy could halt, possibly even reverse, the progression of atherosclerosis, the STABLE results are provocative in that they hint statins might exert their beneficial effect, at least to some degree, by altering plaque morphology. That said, he told TCTMD the present study doesn’t provide support for the vulnerable plaque hypothesis, despite the changes in plaque composition.

“To support the vulnerable plaque hypothesis, you have to show that these changes translate into clinical-outcome benefits, and they’re light-years away that,” said Nissen. “At least now we know that there may be changes associated with more effective therapies, but we don’t know what the clinical implications are yet.”

Nissen, who wrote an editorial accompanying the study, praised the investigators for conducting a randomized controlled trial with virtual histology-IVUS, something he said is clearly lacking in the evidence base for that imaging modality. However, he was highly critical of the trial design, saying the results are very difficult to interpret given the multiple limitations. For one, he noted that 28% of individuals in the trial did not have a final virtual histology-IVUS performed. While the high rate of noncompleters is not uncommon for an invasive modality like IVUS, 45 of the 87 withdrawals were for atypical reasons, including stopping statin therapy. These patients should have been included as part of the intention-to-treat analysis, he said.

In addition, the patients in STABLE were highly selected, Nissen said, noting enrollment required individuals to have an IVUS-defined fibroatheroma within an index lesion. If the goal was to understand how statins affect plaque composition, he said, selecting a broader patient population would have allowed for more generalizable results. Moreover, the trial was underpowered to detect differences between the two rosuvastatin dose arms. As it stands, it is impossible to understand the relationship between statin dose and the effect on plaque composition.

He told TCTMD that investigators should have followed the example of previous IVUS studies, including REVERSAL, ASTEROID, and SATURN, and randomized patients to two different therapies (for example, low- vs high-intensity statin therapy) to determine if the more effective therapy and more intense LDL lowering would improve plaque composition. “There’s a little bit of evidence from this study, but it’s far from reaching the level of quality of a really compelling story,” said Nissen. “What I’m saying is that it’s time to start doing serious trials.”

For Kang, the lack of difference in the IVUS endpoints between the 10-mg and 40-mg dose is explained by ethnicity. Patients enrolled were South Korean, and previous studies of Japanese and Korean subjects suggested that moderate-dose statins in these subjects were as effective as high-dose statins in Caucasians, he said.   

On the whole, Nissen said it’s an open question as to what exactly virtual histology-IVUS measures, noting there remain questions about its accuracy and external validity. Given the quality of evidence, he believes virtual histology is an unvalidated methodology of uncertain clinical significance. “We need better research into virtual histology before anybody uses it for any important purpose, including for studying drugs,” he said. “We need to have good prospective, randomized trials.”

Note: Study coauthor Gary Mintz, MD, is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

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