By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: In those treated with statins vs. those who were not, statins decreased plaque volume in plaques with little or no calcium (plaque regression) and increased calcium density without changes in plaque volume in calcified plaques (plaque stabilization).
SOURCE: van Rosendael AR, van den Hoogen IJ, Gianni U, et al. Association of statin treatment with progression of coronary atherosclerotic plaque composition. JAMA Cardiol 2021; Aug 18:e213055. doi: 10.1001/jamacardio.2021.3055. [Online ahead of print].
Statin therapy has been associated with lower levels of lipid-rich coronary plaque and an increase in calcification, but high plaque burden is associated with a high future risk of coronary events. To explore whether higher calcium density associated with statin use results in a lower risk of coronary events, investigators from 13 sites in seven countries enrolled 2,252 consecutive patients with suspected or known coronary artery disease (CAD) from 2013 to 2016.
For this cohort study, the authors excluded those with uninterpretable studies, those without lesions, those who stopped or initiated statins after a baseline coronary CT angiography (CCTA), and those with no information on statin use. The remaining 857 patients formed the study cohort (63% men; mean age, 62 years). The baseline and follow-up CCTAs were read blinded in a core lab. Any plaques detected were categorized by plaque volume and composition based on fixed thresholds of Hounsfield Units (HU). The main outcome was progression of the composition of each individual plaque. The progression or regression of the plaques according to statin use was determined by changes in plaque volume.
To evaluate the association between statin therapy and coronary calcium density, van Rosendael et al excluded low-density and fibro-fatty plaques. Researchers analyzed 2,458 plaques in the baseline and follow-up CCTAs. Continuous statin use was present in 64% of the cohort. In the untreated group, plaque volume increased for all compositional types. Statin therapy was associated with decreased plaque volume in low attenuation plaques and fibro-fatty plaques, but not in the calcified plaques. Considering the calcium plaques alone, statin therapy was not associated with a change in plaque volume, but rather a transformation to denser calcium. Also, an interaction analysis of baseline plaque volume and calcium density showed denser plaques were associated with slower plaque progression. The authors concluded statin use was associated with greater rates of transformation to high-density calcified coronary plaque, and there was slower plaque progression with increasing calcium density levels.
The authors believe this study provides insight into the reduction in coronary events when statins are deployed as secondary prevention in patients with known or suspected CAD. However, coronary event outcomes were not assessed, so this is conjecture. On the other hand, this study expands on their previous publication from this cohort, an examination of patients who experienced an acute coronary event after their first CCTA vs. a matched group that had not. In that work, the authors showed acute coronary syndrome patients had significantly less highly calcified plaques (> 1,000 HU).1 In this most recent analysis, statin therapy seemed to reduce the size of fibro-fatty and low attenuation (very little calcium) plaques, but increased the calcium density of calcified plaques. These findings imply statins are shrinking the lipid core of plaques, shrinking the non-calcified plaques, and increasing the calcium density of calcified plaques, both of which should reduce coronary events.
There were limitations. This was an observational study. Statin use was not randomized but determined by the patient’s physician. Thus, it is not surprising the two groups were significantly different in several characteristics. The statin group was older, included more men, and included more patients with diabetes and hypertension. Although the authors adjusted for it in the multivariate analyses, unmeasured confounders could be present. Also, the decision to prescribe statins may have excluded both low-risk patients (no indication) and high-risk patients who were excluded from the study. In addition, the interval between CCTA exams was determined clinically, not by protocol. Finally, lesions that had coalesced or occluded between exams were not evaluated, which further limits the generalizability of the results.
Despite these limitations, the results do add to our knowledge about the effects of statins on coronary plaques and probably explain the paradox of increasing calcium scores on serial CCTAs in the face of fewer clinical events. This is of clinical importance because it supports the advice not to repeat CCTAs in patients with high calcium scores who were started on statins because they likely will be higher. This will cause anxiety in patients and does not inform therapy, as this likely is a good sign of plaque stabilization.
- van Rosendael AR, Narula J, Lin FY, et al. Association of high-density calcified 1K plaque with risk of acute coronary syndrome. JAMA Cardiol 2020;5:282-290.