EWTOPIA75: Ezetimibe Reduced First Cardiac Events in Seniors

Marlene Busko

November 23, 2018

CHICAGO — Ezetimibe reduced the rate of a first cardiac event — a composite of sudden cardiac death, myocardial infarction (MI), coronary revascularization, and stroke — more than diet alone in 75- to 104-year-old Japanese patients with elevated LDL-cholesterol (LDL-C) and a second risk factor, randomized trial results show.

Treatment with 10 mg/day ezetimibe, which works by decreasing absorption of cholesterol from the small intestine, plus dietary counseling led to a 34% lower rate of this composite cardiovascular outcome at 5 years compared with diet alone.  

The finding "is the first evidence suggesting that the primary prevention of atherosclerotic cardiovascular events is possible by lipid-lowering therapy for eligible older patients aged 75 or older," Yasuyoshi Ouchi, MD, PhD, Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital and Professor Emeritus, University of Tokyo, reported.

He presented results of the Ezetimibe in Prevention of Cerebro- and Cardiovascular Events in Middle- to High-risk, Elderly (75 Years Old or Over) Patients With Elevated LDL-Cholesterol: A Multicenter, Randomized, Controlled, Open-label Trial (EWTOPIA75) here at the American Heart Association Scientific Sessions 2018.

EWTOPIA75 "supports the use of ezetimibe for primary prevention in statin-intolerant patients," the assigned discussant, Jennifer G. Robinson, MD, MPH, professor, Departments of Epidemiology & Medicine, and director, Prevention Intervention Center, University of Iowa, Iowa City, told theheart.org | Medscape Cardiology in an email.

However, "whether patient populations outside of Japan will experience a similar magnitude of risk reduction is unclear," she added.

The modest 18 mg/dL lower LDL-C in the treated versus control groups at 1 year was associated with a greater risk reduction in the composite cardiovascular (CV) outcome than would be expected based on the Cholesterol Treatment Trialists' Collaboration meta-analysis (Lancet. 2012;380:581-590), she noted.

However, the PRECISE-IVUS trial in Japanese patients also found a "quite remarkable reduction" in CV disease with the addition of ezetimibe to statin therapy, greater than what might be expected from the modest additional LDL-C lowering, so Japanese people may have genetic differences that make them hyper-responsive to ezetimibe's mechanism of action, she speculated.

However, statins appear to be better for increasing survival in elderly patients with elevated LDL-C, Robinson added, noting that EWTOPIA did not find a benefit for reduced CV or total mortality. It was not powered for this, but there was no evidence that rates would diverge.

According to Robinson, "we really need the results" of other ongoing trials, such as STAREE in Australia, which is looking at the effect of LDL-C-lowering with atorvastatin on the duration of a disability-free life in adults 70 years and older, and which is expected to provide data in 2022.

Diet Advice With/Without Ezetimibe

"The efficacy of lipid-lowering therapy with statins for high-risk patients is well established," Ouchi and colleagues write. "However, there is no evidence about its clinical benefits in Japanese elderly (75 years and older) patients" with elevated LDL-C but no history of CAD.

The researchers hypothesized that ezetimibe would decrease LDL-C and prevent the onset of cerebral and cardiovascular events in such patients.

From 2009 to 2016, EWTOPIA75 enrolled and randomized 3796 eligible patients in 363 institutions to receive 10 mg/day of ezetimibe plus dietary counseling, in accordance with the 2007 Guideline for Prevention of ASCVD from the Japan Atherosclerosis Society, or dietary counseling alone.

The patients were 75 years or older with LDL-C of at least 140 mg/dL plus one or more of seven CV risk factors (type 2 diabetes, hypertension, smoking, low HDL-cholesterol, high triglycerides, peripheral artery disease, or documented history of cerebral infarction) and were followed for 3 to 5 years.

Mean age of the study cohort was 81 years. Most participants were 75 to 79 (55%) or 80 to 84 (31%), but some were 85 to 88 (11%), 90 to 94 (2%), or older than 95 (1%). About three quarters (74%) were women.

Baseline characteristics were similar in the two groups. The patients had a mean LDL-C of 162 mg/dL. Only 14% were current or former smokers and a quarter had type 2 diabetes. Most (88%) had hypertension, but blood pressure was generally well controlled (mean, 136/75 mm Hg)

LDL-C dropped from 162 mg/dL to 126 mg/dL in the intervention group and 144 mg/dL in the control group at 1 year, and then gradually dropped to 120 mg/dL and 131 mg/dL in the two groups, respectively, by 5 years (< .001).

There were no significant between-group differences in HDL-C or triglycerides during follow-up.

The incidence of the primary composite outcome (sudden cardiac death, MI, coronary revascularization, and stroke) was significantly lower in the group that received ezetimibe plus diet than in the diet-alone group (hazard ratio [HR], 0.56; 95% CI, 0.50 - 0.86; = .002).

Similarly, the incidence of sudden cardiac death and fatal or nonfatal MI was lower in the intervention than in the control group (HR, 0.60; 95% CI, 0.37 - 0.98; = .041).

However, there was no significant between-group difference for cerebrovascular events or all-cause mortality. About 10% of patients in both groups had adverse events.

EWTOPIA75 was funded by the Public Health Research Foundation. Ouchi has no relevant financial disclosures. Robinson receives research grants from Acasti, Amarin, Amgen, Astra-Zeneca, Esai, Esperion, Merck, Pfizer, Regeneron, Sanofi, and Takeda, and is a consultant or on the advisory board for Amgen, Pfizer, Regeneron, Sanofi, Eli Lilly, Merck, and Novo Nordisk.

American Heart Association (AHA) Scientific Sessions 2018: Abstract 17581. Presented November 10, 2018.

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