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Miura et al. Vessel Plus 2019;3:1 I http://dx.doi.org/10.20517/2574-1209.2018.69 Page 9 of 15

during CAS. In a recent meta-analysis of 8 studies that investigated effects of pre-CAS treatments with
statins on periprocedural adverse events, statin treatments statistically reduced periprocedural risks of
[74]
ischemic strokes (OR, 0.39) and death (OR, 0.30) in CA stenosis patients treated with CAS .

OTHER LIPID-LOWERING AGENTS [Figure 2]
Classical non-statin lipid-lowering agents including niacin acids, fibrates and omega-3 fatty acids can
improve lipid profiles. However, the benefit of these non-statin lipid-lowering agents has not been well
established for the primary and secondary prevention of strokes. A meta-analysis including 78 clinical trials
revealed that non-statin lipid-lowering agents such as fibrates, diet and other treatments did not reduce the
[75]
risks of strokes (fibrates: OR, 0.98; diet: OR, 0.92; other treatments: OR, 0.81) .
Niacin can reduce peripheral blood levels of TG by approximately 35%, decrease LDL-C levels by 10%-15%, and
[76]
increase HDL-C levels by up to 25% . Niacins may also enhance a beneficial effect such as vasoprotection
[77]
[76]
and anti-inflammatory actions independent of its lipid-modifying activities . Although Villines et al.
revealed the regression of CA IMT thickening induced by niacin, its beneficial effects on the reduction of
ischemic stroke risks remain uncertain. In a meta-analysis of 11 clinical studies including 9,959 patients, no
[78]
significant association was found between niacin therapy and the risks of strokes (OR, 0.88) .
Fibrate also lowers TG levels and increases HDL-C levels. Fibrate furthermore may exert pleiotropic effects
via regulating the interaction with peroxisome proliferator activated receptor (PPAR) alpha, which influences
vascular inflammation and thrombogenesis [79,80] . However, it is uncertain if fibrates can reduce risks of stroke
event. In the clinical trial consisting of 2,531 men with coronary artery diseases and low levels of HDL-C,
[79]
benzofibrate showed a 31% reduction in the risks of stroke . On the other hand, a meta-analysis including
[80]
18 clinical trials with 45,058 patients showed no preventive effects of fibrates on stroke development .
Recently, pemafibrate has been drawn attention to as a novel selective PPAR alpha modulator. In the phase
III clinical trial, pemafibrate significantly reduced TG levels from baseline by up to 45% with low incidence
[81]
rates of adverse drug reactions . In addition, the combination therapy of pemafibrate with pitavastatin
[81]
exerted a robust reduction in a fasting level of TG by about 50% compared with the statin-monotherapy .
Another trial is ongoing to investigate the efficacy of pemafibrate on cereberovascular outcomes in patients
with diabetes, and the results are awaited. It will be also necessary to verify whether pemafibrate has
beneficial effects on the primary and secondary prevention of strokes in patients with CA stenosis.

Omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acids (EPAs) and docosahexaenoic acids
[82]
(DHAs) are approved as an adjunct to diet for lowering plasma TG via multiple metabolic pathways . In a
previous randomized clinical trial, 114 patients awaiting CEA were randomized to 3 groups taking placebo,
fish oils (n-3 PUFA), and sunflower oils (n-6 PUFA): CA plaques in the n-3 PUFA treatment group had
higher proportions of EPAs and DHAs, reduced infiltration of monocyte and macrophage, and a thicker
[83]
fibrous cap compared with other groups . In another randomized clinical trial including 121 patients
awaiting CEA, the proportion of EPAs was higher in CA plaques treated with n-3 PUFAs compared to
[84]
placebo . The remarkable thing is that the EPA content in plaque phospholipids had inverse association
[84]
with plaque instability, plaque inflammation, and the number of T cells in the plaques . CA atherosclerotic
plaque in patients treated with n-3 PUFAs showed a lower level of messenger ribonucleic acids (mRNAs) for
[84]
MMPs-7, -9, -12, interleukin-6 and ICAM-1 . Thus, the stability of plaques by increased n-3 PUFAs intake
may induce the reductions in the risk of ischemic stroke.

Ezetimibe prevents the absorption of Cho from intestines, and therefore reduces a level of TC. In the clinical
trial including 18,144 patients hospitalized for acute coronary syndrome, the combination therapy of 10
[85]
mg/day ezetimibe with 40 mg/day simvastatin resulted in a significant reduction in stroke risks (HR, 0.936) .