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Ezetimibe effective in primary prevention of atherosclerotic CV events in elderly Japanese

Pearl Toh
16 Nov 2018
Dr Yasuyoshi Ouchi

Lipid-lowering with ezetimibe monotherapy was effective for the primary prevention of atherosclerotic cardiovascular (CV) events in middle- to high-risk elderly Japanese patients with hypercholesterolaemia, according to the EWTOPIA75* study presented at AHA 2018 Scientific Sessions.

With increasing population of older people aged 75 years, the number of elderly people with hypercholesterolaemia has dramatically increased, said Dr Yasuyoshi Ouchi, president of Toranomon Hospital in Tokyo, Japan. “However, there is no evidence about the clinical benefits [of LDL-C-lowering therapy in this group of patients].”  

EWTOPIA75 met its primary endpoint of preventing a composite of atherosclerotic CV events comprising sudden cardiac death, fatal and nonfatal myocardial infarction, PCI or CABG**, and/or stroke, with a significant 34 percent reduction in risk with ezetimibe compared with control in this elderly population (aged ≥75 years; hazard ratio [HR], 0.659; p=0.002). [AHA 2018, abstract LBS.01-17581]

The secondary endpoint of all cardiac events was also significantly lower (HR, 0.602; p=0.041) in the ezetimibe group than the control group.

“This study [provides] the first evidence suggesting that the primary prevention of atherosclerotic CV events is possible by lipid-lowering therapy for eligible older patients aged 75 years or older,” said Ouchi.

No utopia yet 

Participants in the EWTOPIA75 trial with a PROBE*** design were 3,796 Japanese patients aged 75 years (mean age 80.7 years, 74 percent female) with LDL-C levels 140 mg/dL who had 1 CV risk factors such as hypertension (78 percent), diabetes (22.8 percent), smoking, and high triglyceride levels, and who had no prior coronary artery disease. They were randomized 1:1 to ezetimibe 10 mg/day plus diet counselling or diet counselling alone as control and followed up for at least 3 years.

From a baseline mean LDL-C of 161.6 mg/dL, LDL-C dropped to 126.1 mg/dL in the ezetimibe group vs 144.1 mg/dL in the control group after 1 year, and the reduction continued during the course of the study over 5 years (120.1 vs 132.4 mg/dL), with significant differences between both groups (p<0.001).

Although the reduction in LDL-C with ezetimibe translates to significantly fewer occurrence of the primary endpoint than control, there was no significant mortality benefit with ezetimibe vs control (HR, 1.087; p=0.427).

There was also no significant reduction in cerebrovascular events with ezetimibe vs control (HR, 0.781; p=0.171).

“Frankly, I was very surprised to see the large effect size [in primary endpoint reduction] compared with other trials of LDL-lowering drugs,” said invited discussant Professor Jennifer Robinson of University of Iowa in Iowa City, Iowa, US.

The lack of mortality benefit with ezetimibe in the current study despite its large effect size was in contrast to a similar primary prevention study (MEGA) with low-dose pravastatin, which showed mortality benefit despite having a smaller effects size in CV events reduction (HR, 0.74).   

“Statins appear to be better for reducing total mortality. We really need more results from ongoing studies in older populations which will be reported in the next several years,” commented Robinson, referring to the ongoing STAREE and RFA-AG-19-020 trials.

She also cautioned against the generalizability of the current findings to other population, since different genetic polymorphisms in NPC1L1 among Japanese may lead to different biological response to LDL lowering.

Prof  Jennifer Robinson
Prof Jennifer Robinson
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