Monitoring the Response to Statin Therapy

One Scan at a Time

Corresponding Author

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• coronary artery atherosclerosis
• coronary artery disease
• coronary computed tomography angiography
• statins

Over the course of the last 3 decades, increasing use of statins to lower levels of atherogenic lipids has been consistently demonstrated to reduce cardiovascular event rates in large clinical outcome trials of high vascular risk patients. With technological advances in arterial wall imaging, a range of techniques have been used in both observational studies and the robust setting of the randomized controlled trial to evaluate the impact of statins on the natural history of coronary atherosclerosis. These studies have demonstrated that statin treatment exerts a favorable impact on disease progression, with a direct relationship observed between the degree of lipid lowering and change in plaque burden.

The importance of lipid lowering on atherosclerosis has been further evidenced by reported benefits of ezetimibe (1) and the proprotein convertase subtilisin kexin type 9 inhibitor, evolocumab (2). The finding that plaque regression is observed at low-density lipoprotein cholesterol levels <70 mg/dl provides further support for guidelines recommending intensive lipid lowering in patients with clinically manifest coronary artery disease. Independent observations of a direct relationship between the rate of disease progression and lowering levels of C-reactive protein suggest that statins may possess biologic properties, beyond lipid lowering, that may contribute to their clinical benefit (3). The introduction of imaging modalities that propose to characterize phenotypic elements within plaque has suggested that statins may also favorably modulate the composition of coronary atherosclerosis.

Major advances in computed tomography (CT) imaging now permit visualization of the coronary vasculature in most patients within increasing resolution. As a result, the information obtained from these scans has transitioned from calcium scores and rule out of obstructive disease to the quantitation of not only plaque burden, but further distinction of its calcified and noncalcified components. In addition to increasing evidence that these CT-derived parameters associate with prospective cardiovascular risk, the ability to image the coronary arteries with greater resolution and less radiation exposure, in most patients, enables noninvasive evaluation of the impact of medical therapies on coronary atherosclerosis. In theory, this will permit inclusion of asymptomatic patients and those at lower cardiovascular risk, given that they are typically not enrolled in studies that use invasive imaging techniques. With further technological advances and reduction in radiation exposure, it may also be possible to image patients on more than 2 occasions, providing the opportunity to determine whether disease progression and its response to medical interventions are linear over time.

In this issue of iJACC, Lee et al. (4) report observations from the PARADIGM study, in which serial CT coronary angiography enabled monitoring the effect of statin therapy. Their report described changes in a range of plaque parameters in a registry of 1,255 patients without a prior history of clinically manifest coronary disease, who had undergone serial CT coronary angiography at an interval of at least 2 years. Consistent with observations of invasive imaging studies, the authors report that statin-treated patients demonstrated less plaque progression, greater plaque calcification, and a lower likelihood of developing high-risk plaque features. These benefits were observed, despite no reduction in the prevalence of patients with obstructive stenoses >50%.

These findings from PARADIGM are important in that they confirm observations from invasive imaging–based clinical trials performed in higher risk, symptomatic patients to those whose atherosclerosis has yet to become clinically manifest. They distinguish reductions in vulnerable plaque components, while at the same time resulting in greater plaque calcium. This supports the notion that calcification in response to statin therapy may reflect an important process in plaque passivation (5) and further fuels criticism to the practice of use of serial calcium scores when patients are treated with a statin. They also provide a validation of findings from invasive imaging, in which calcium measurement is subject to inherent limitations regarding catheter position and acoustic shadowing. The observation of favorable effects of statins on plaque, but not the rate of stenosis >50% reflects, the disconnect between a lumen and vessel wall-based approach.

The findings continue to extend the potential for CT coronary angiography in the evaluation of cardiovascular risk in clinical practice. The proliferation of this technique in clinical practice has the potential to inform, yet the question remains: how can we best apply CT coronary angiography in a cost-effective manner? Who are the best patients, what is the best clinical setting, and is there use in monitoring responses to medical interventions? Would changes in medical therapy be implemented as a result of such serial scans? Considerable research effort has accompanied the technological development of CT coronary angiography. The need to perform large-scale clinical trials that will determine if CT coronary angiography cost effectively modifies clinical management and cardiovascular outcomes have the potential to justify the increasing number of scans performed in clinical practice. For now, the science continues to evolve 1 scan at a time.

• 2018 American College of Cardiology Foundation