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The Effects on Plaque of Statins & PCSK9 Inhibitors
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Download the PDF here
Download the PDF here
Question Does treatment with a PCSK9 inhibitor modify coronary atherosclerosis disease progression?
Findings In this clinical trial in which 968 patients with coronary disease were treated with the PCSK9 inhibitor evolocumab or placebo monthly for 76 weeks and underwent serial intravascular ultrasound determination of coronary atheroma volume, lower low-density lipoprotein cholesterol levels were observed in the evolocumab group (36.6 vs 93.0 mg/dL), which also was associated with a reduction in percent atheroma volume for evolocumab (−0.95%) but not placebo (+0.05%) and a greater percentage of patients demonstrating plaque regression (64.3% vs 47.3%).
Meaning Addition of the PCSK9 inhibitor evolocumab to statin therapy produced greater low-density lipoprotein cholesterol lowering and atheroma regression.
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The low-density lipoprotein-cholesterol (LDL-C) level of a 38-year-old man diagnosed with acute coronary syndrome was 257 mg/dL. The administration of a proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody in addition to rosuvastatin plus ezetimibe was initiated, reducing his LDL-C level to 37 mg/dL. A genetic analysis revealed both an LDL receptor (LDLR) mutation and a PCSK9 V4I mutation. Nine months after revascularization, intravascular ultrasound revealed plaque regression in the coronary arteries. LDLR/PCSK9 mutation carriers are prone to coronary artery disease. Intensive LDL-C lowering by including PCSK9 antibody was associated with coronary plaque regression, suggesting the expectation of prognosis improvement.
Introduction
Familial hypercholesterolemia (FH) is characterized by marked hypercholesterolemia since birth, and FH patients are known to develop early coronary artery diseases (CADs) (1). Therefore, the early diagnosis of this disease is important for the prognosis.
Evolocumab (AMG-145; Repatha™, Amgen, Thousand Oaks, USA) is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers the low-density lipoprotein cholesterol (LDL-C) levels (2). The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial recently revealed that the inhibition of PCSK9 with evolocumab combined with statin therapy lowered LDL-C levels and reduced the risk of cardiovascular events (3). Furthermore, the Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) Randomized Clinical Trial demonstrated that the addition of evolocumab to statin therapy produced greater LDL-C-lowering effects and atheroma regression than statin monotherapy (4).
The combination of an LDL receptor (LDLR) gene mutation and a PCSK9 V4I mutation in clinically diagnosed FH is a severe state and causes an individual to be prone to CAD (5). We herein report the first case of acute coronary syndrome in a double-heterozygous FH patient (LDLR/PCSK9) who received a PCSK9 antibody associated with coronary plaque regression.
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Perspectives
COMPETENCY IN MEDICAL KNOWLEDGE: Statins change the composition of intraplaque constituents by increasing calcification and reducing the noncalcified portion within plaques. Although statins do not have protective effect against the progression of coronary lesions to high-grade stenoses, statins reduce the risk of developing adverse plaque characteristics, including high-risk plaques and positive remodeling.
TRANSLATIONAL OUTLOOK: Prospective clinical trials targeting specific coronary atherosclerotic phenotypes based upon high-risk plaque features and plaque constituents are necessary to delineate the impact of statin-induced plaque calcification on clinical outcomes.
Discussion
In the analysis of this large, prospective observational cohort evaluating temporal changes in plaque characteristics by using quantitative assessment, statin therapy was associated with slower rates of progression of overall coronary atherosclerosis volumes with differential effects on different plaque types. Statins were also associated with the increase of calcified plaque components and reduced progression of noncalcified portions of atherosclerotic lesions. Moreover, although statins did not have a protective effect against the development of high-grade coronary stenoses, they successfully reduced the risk of positive remodeling and HRPs. Furthermore, we can generalize observations of the pro-calcific effects of statins, independent of their reduction in plaque progression, to a multiethnic, multinational, low-risk cohort outside of a clinical trial setting. Our study provides a context and data that have not been available previously for interpretation of serial coronary CTA and that provide insight into the natural history of both vulnerable and calcific plaque. Importantly, coronary CTA was able to effectively measure the impact of statin use on decreased progression of subclinical atherosclerosis.
Corresponding with early serial angiographic statin trials, we demonstrated slower coronary artery luminal narrowing, without affecting the binary development of obstructive CAD 25, 26. In line with both prior landmark studies of serial invasive imaging 7, 27 and more recent small coronary CTA studies 8, 9, we demonstrated that statins slow the progression of coronary atherosclerosis in whole-heart evaluations by coronary CTA, beyond the proximal arterial segments interrogated by intravascular ultrasonography. These prior studies preferentially used either invasive modalities focusing on a single culprit plaque or noninvasive modalities assessing the change in atherosclerosis on a per-patient level 4, 9.
However, neither approach can fully evaluate the impact of statin therapy on coronary atherosclerotic lesions, as evaluating only a single plaque will neglect the interactions between coexisting plaques, and per-patient analysis will aggregate the findings of individual plaques (28). Moreover, previous invasive studies have enrolled mainly patients undergoing clinically indicated invasive coronary angiography, meaning patients not indicated for invasive assessment, most of whom were at an earlier stage of CAD and possibly exhibited a different pattern of disease progression, and who accounted for much a greater portion of the population, were omitted. Therefore, the strengths of the current study include not only the large sample size and long follow-up duration but also the methodology of examining lesion-specific changes over time in a population with relatively lower risk, by quantitatively analyzing the entire coronary tree, using a noninvasive imaging modality.
Coronary artery calcium scoring is a robust tool for prognostication of future adverse cardiovascular events (29); and elevated coronary artery calcium score progression portends worse prognosis (5). However, a randomized controlled trial of statin therapy demonstrated no impact on slowing the progression of coronary artery calcium score 30, 31, 32. Given the present findings, it remains unknown whether an increasing calcium score in a patient who is being treated with statins represents a malignant or benign process, and uncertainty exists as to the utility of serial coronary calcium scoring for monitoring therapeutic efficacy in patients being treated with statins 5, 28.
Taken together, our results suggest that interpretation of calcium progression should be stratified by statin treatment, as increasing coronary calcification in statin-taking patients may represent stabilization of atherosclerotic lesions. Even furthermore, inducing calcification of plaques may be one of the mechanisms by which statins exert a positive effect in reducing the risk of major adverse cardiovascular events. This hypothesis, although attractive, remains to be proven; and future large-scale trials evaluating atherosclerosis treatment by targeting specific atherosclerotic characteristics based upon plaque composition and other high-risk plaque features now seem warranted.
Our results complement those of the ICONIC (Incident COroNary Syndromes Identified by Computed Tomography) trial, a nested case control study of atherosclerotic plaque precursors to acute coronary syndrome. In the ICONIC study, we observed that lesion characteristics and plaque burden by composition had predictive value for acute coronary syndrome, independent of clinical risk factors and total plaque burden. There was a continuum of risk of acute coronary syndromes by plaque composition, with greater weight for lower attenuation plaque burden. In the PARADIGM study, we observed that plaque composition and characteristics can be decoupled from plaque burden due to treatment effects. Increased calcification with statins, coherent with its known impact on reducing clinical events, support the concept of increased HU attenuation as evidence of plaque stabilization. Together, the results of these 2 studies demonstrate the applicability and insight of noninvasive plaque evaluation in the ranges of high and low risk.
Study limitations
First, our results did not attempt to distinguish between the impact of high- and low-intensity statins, and we cannot exclude confounding by indication or unmeasured and time-varying confounders. Among the statin-taking group, 303 patients began statin therapy during the interval (38.8%). However, the coherence of our study with findings in a large, pooled, high-risk intravascular ultrasonography cohort randomized to statins supports the validity of our finding. Second, although the HU thresholds for plaque composition were validated by using virtual histology-intravascular ultrasonography, the HU thresholds of low-attenuation and fibrous plaque demonstrate significant overlap relative to histopathology, and the spatial resolution of coronary CTA may result in partial volume effects within a pixel (17). Thus, the categories of plaque composition described should not be taken as discrete histopathological entities but rather as gradations of risk in plaques. Third, because of the observational design of the study, patients were not randomized, and there is a major difference in baseline characteristics between groups.
However, the main findings of this study remained consistent even after propensity score matching. Additionally, because only patients who had 2 coronary CTA scans were eligible, patients had a relatively low prevalence of obstructive CAD and event rate. Patients who progress more rapidly and, hence, who more likely to experience clinical events may not attend for a second coronary CTA. Thus, selection bias is inevitable, and the generalizability of our results to high-risk populations is not known, and our study was not powered to estimate the coronary event risk of plaque progression. To overcome these limitations, prediction models will require large, ideally, population-based prospective cohorts of serial coronary CTA or randomized study that may be economically feasible only with completely automated coronary CTA measurements. However, as there are no current professional society recommendations endorsing the routine use of serial coronary CTA for evaluation of CAD (18), an observational registry such as the present study provides a unique opportunity to assess the natural history of CAD.
Conclusions
Our findings suggest that, over a longer term and among lower-risk patients undergoing serial coronary CTA, statins are associated with slower progression of overall coronary atherosclerosis volume, with increased plaque calcification and reduction of high-risk plaque features.
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With statins, there is a shift toward denser, more-calcified plaque on CT, as well as less fibro-fatty and low-attenuation plaque
https://www.tctmd.com/news/statins-positively-alter-coronary-plaque-composition
Statin therapy in patients with atherosclerotic cardiovascular disease (ASCVD) is associated with positive changes in the phenotype of coronary lesions, with data from a new study showing there is a shift towards more-stable, calcified lesions and less higher-risk plaque.
In an analysis of patients undergoing serial coronary CT angiography (CTA), there were larger decreases in the amount of low-attenuation and fibro-fatty plaques, which are associated with adverse outcomes, with versus without statin use, as well as larger increases in dense and very dense calcified plaques.
What is evident in the statin-treated patients, said lead investigator Alexander van Rosendael, MD (Leiden University Medical Center, the Netherlands), is a "more-rapid transformation of soft plaque into the very dense calcium" and a lower progression of coronary plaque with increasing density.
Stephen Nicholls, MD, PhD (Monash University, Melbourne, Australia), who has studied the regression of coronary plaques on IVUS, praised the new analysis, stating that it clearly shows statins promote the stabilization of coronary plaque. "They do that not only by shrinking plaques, but by promoting an increase in calcification," said Nicholls. "They have nicely shown how that progresses from a density perspective. It extends the observations made with IVUS, but we never had the ability to look at calcium in the way that CT can and that is an important advance."
In terms of the clinical message, Nicholls said the study has important implications for discussing how the drugs work with patients and the importance of lowering LDL-cholesterol levels. "The ability to show someone their plaques and say, 'If we aggressively treat your lipids, we are going to cool down the plaques that will cause a heart attack,' can be motivating for many patients," Nicholls told TCTMD.
Burden of Atherosclerosis
Past studies have shown that the burden of atherosclerosis in the coronary tree is a strong predictor of future coronary events, said van Rosendael, but refining the risks associated with different components of coronary plaque is currently an important area of research. "We know that there are different compositions of the plaque," he said. "There is calcified and noncalcified plaque, and it looks like the calcified part of the plaque does have less prognostic value than the noncalcified plaque."
For example, studies have shown that low-attenuation plaque on CTA strongly predicts future events, such as MI. In SCOT-HEART, low-attenuation plaque was a better predictor of future events than other commonly used measures, such as a cardiovascular risk score, coronary artery calcium (CAC), Agatston units, and presence of obstructive coronary artery disease. On the flip side, van Rosendael previously showed that the presence of very dense coronary plaque, dubbed 1K plaque (> 1,000 Hounsfield units), was associated with a lower risk of ACS.
"As it becomes denser and denser, this type of plaque carries less risk," said van Rosendael. "We know that statins reduce the risk of heart attacks—that's been proven many, many times—so we wanted to know whether statins increase the good plaque, the very dense calcium, and decrease the very-high-risk plaque."
The new study, which was published last week in JAMA Cardiology, included 857 patients with known or suspected CAD participating in the CCTA PARADIGM study.
Within this observational registry, in which patients underwent serial coronary CTA at least 2 years apart (median 3.2 years), 548 were treated with statins and 309 were untreated. Those who were treated were older, more commonly male, and more likely to have diabetes and hypertension. In the statin-treated group, LDL-cholesterol levels were slightly lower than in the untreated group at baseline (107 vs 113 mg/dL; P = 0.03) but markedly lower in follow-up (88 vs 110 mg/dL; P < 0.001).
Statin treatment, which included a mix of moderate- and high-intensity statins, was associated with larger decreases in low-attenuation (β -0.02; P = 0.001) and fibro-fatty plaque volumes (β -0.03; P < 0.001) compared with no therapy. In contrast, statin therapy was associated with larger increases in high-density calcium volume and 1K plaque (both β 0.02; P < 0.001).
"If we look at the lesions not treated with statins, we see that all six components of the coronary plaque increase," he said, referring to low-attenuation, fibro-fatty, fibrous, and low-, high-, and very-high-density calcium (1K) plaque components. On the other hand, there was a bit of a "seesaw" effect seen in the statin-treated patients, whereby the decreases in low-attenuation and fibro-fatty plaque were offset by increases in high-density and 1K plaque.
That seesaw-like transformation isn't one to one, said van Rosendael, because the overall plaque progression is slower in the statin-treated patients. For patients treated with statins and those who were not, coronary lesions with a higher proportion of calcium showed less overall plaque progression (β -0.003; P < 0.001 for both groups).
"If the plaque is mainly composed of very dense calcium, then it'll progress less in total volume," said van Rosendael. "If it's 90% dense calcium, for example, it doesn't progress on the next CT scan. It's like a rock that doesn't grow."
For patients undergoing CAC screening, the new data can help refine how best to assess patient risk. While CAC scores are a strong predictor of future events, the score incorporates both calcified and noncalcified plaques. In patients treated with statin therapy, or other lipid-lowering agents, serially measuring CAC might reveal evidence of calcified plaque progression which does not reflect increased patient risk but rather a stabilization of the coronary plaque.
Nicholls said there is now evidence showing that a number of plaque characteristics on imaging, such as low-attenuation plaques on CTA, lipid burden on near-infrared spectroscopy (NIRS), and fibrous cap thickness and the presence of lipid-rich plaques on optical coherence tomography (OCT), are all associated with adverse outcomes. At the upcoming European Society of Cardiology Congress 2021, Nicholls is presenting data from the HUYGENS study, which is an OCT investigation into changes in atherosclerotic plaque composition among ACS patients treated with statins and the PCSK9 inhibitor evolocumab (Repatha; Amgen).
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