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Page 10 of 15 Miura et al. Vessel Plus 2019;3:1 I http://dx.doi.org/10.20517/2574-1209.2018.69

Furthermore, in patients stabilized after acute coronary syndrome, the addition of ezetimibe to simvastatin
reduced the incidence of ischemic strokes (HR, 0.52): the preventive effects on ischemic strokes were
[86]
remarkable in patients with prior strokes .
Cholesteryl ester transfer protein (CETP) inhibitors increase a level of HDL-C, and some of them decrease
[87]
levels of LDL-C and TG in addition to increasing HDL-C . However, the first clinical trial to investigate
the effects of torcetrapib on atherosclerotic events was halted because of statistically higher incidences of
death: hypertension due to activation of the renin-angiotensin-aldosterone system was considered to be a
[87]
cause of the adverse events . In the subsequent randomized clinical trials of CETP inhibitors including
[89]
[88]
dalcetrapib and evacetrapib , serious off-target adverse events did not occur, but no risk reduction for
[90]
cardiovascular events was revealed. In a more recent randomized clinical trial , ≥ 4 years anacetrapib
treatments significantly prevented the development of coronary artery events (HR, 0.91) associated with no
increased risks of death, cancer, and other serious adverse events. It is necessary to examine whether CETP
inhibitors are effective for preventing stroke.

Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a hepatic protease, which decreases receptors
for LDL in liver and causes an increase in the plasma concentration of LDL-C. A monoclonal antibody
inhibitor of PCSK9 is a novel lipid-lowering agent, which has been reported to suppress LDL-C levels by
60%-70% in patients taking a statin [91-93] . A meta-analysis of 24 randomized clinical trials including 10,159
patients reported that a PCSK9 inhibitor significantly reduced all-cause mortality (OR, 0.45) and myocardial
[91]
infarction (OR, 0.49) . In a randomized clinical trial including 4,465 patients, evolocumab decreased
[92]
LDL-C levels by 61% as well as the incidence of cardiovascular events (HR, 0.47) . However, evolocumab
treatment exhibited neurocognitive adverse events more frequently compared with the control group
[92]
regardless of LDL-C levels during the treatment . Another phase III randomized clinical trial including
2,341 patients with high risks for cardiovascular events revealed that alirocumab treatment induced a 62%
reduction in a level of LDL-C, which in turn reduced a major adverse cardiovascular event compared with
[93]
placebo treatment (HR, 0.52) . However, alirocumab treatment did not decrease risks of ischemic strokes,
and rather had higher rates of injection-site reactions, myalgia, and neurocognitive side effects including
[93]
memory impairments, confusional states and ophthalmologic events . The mechanisms of neurocognitive
changes associated with PCSK9 inhibitors are not certain and the future clarification is required.

Randomized clinical trials have not been conducted and are needed to test the safety and efficacy of non-
statin lipid-lowering agents as add-on treatments to a statin in patients with CA stenosis.

NON-DRUG THERAPIES
In addition to medications, lifestyle changes are a requisite component of lipid-lowering therapies, including
diet and exercise. According to the 2016 guidelines of the European Society of Cardiology and the European
Atherosclerosis Society for the management of dyslipidemia, diet should include a reducing intake of saturated
fats and increasing intake of polyunsaturated and monounsaturated fats, cereals, fruits, vegetables and fat
[94]
2
free dairy products . In addition, patients with a body mass index greater than 25 kg/m should follow low-
calorie diets. Moreover, at least 30 min a day of moderate-intensity aerobic activity for five days a week are
recommended. The intake of dietary fiber, monounsaturated and PUFAs has been reported to decrease stroke
[95]
risks by reducing LDL-C and postprandial lipids levels with some discrepancies . Habitual exercise has also
been revealed to have beneficial effects on risk factors of stroke, including hypertension, dyslipidemia, diabetes
and body weight: moderate or high exercise was associated with a significant reduction in the incidence
[96]
of stroke or its mortality . However, there is no evidence from published randomized controlled trials to
support the secondary stroke prevention associated with post-stroke diet and exercise.