Meeting News

EWTOPIA75: Ezetimibe prevents CV events in elderly patients

CHICAGO — Lipid-lowering with ezetimibe prevented cardiac events in Japanese adults aged 75 years and older with elevated LDL levels, according to data from the EWTOPIA75 trial.

In many countries, there has been “an explosive increase” in the population of people aged older than 75 years, Yasuyoshi Ouchi, MD, professor emeritus at the University of Tokyo, said during a presentation at the American Heart Association Scientific Sessions. “Along with this population change, the number of patients aged older than 75 years with hypercholesterolemia has dramatically increased. However, prospective randomized controlled trials on the efficacy of LDL-lowering therapy in patients aged older than 75 years of age with elevated LDL cholesterol have not been conducted.”

Ezetimibe beneficial in elderly patients

The EWTOPIA75 trial was conducted in Japan. Ouchi and colleagues randomly assigned patients aged older than 75 years with an LDL level of at least 140 mg/dL to dietary counseling only (n = 1,695) or dietary counseling plus treatment with ezetimibe 10 mg daily (n = 1,716).

After 5 years of follow-up, risk for the primary endpoint — a composite of atherosclerotic CV events, including sudden cardiac death, MI, PCI or CABG and stroke — was significantly lower with ezetimibe vs. control (HR = 0.659; 95% CI, 0.504-0.862; P = .002), Ouchi noted.

Also, at 5 years, LDL was lower in the ezetimibe group compared with the control group (P for main effect < .001 and P for interaction < .001) and reduction in non-HDL was also greater with ezetimibe group compared with the control group (P for main effect < .001 and P for interaction < .001). Ezetimibe was also associated with a significant decrease in triglycerides, but the effect did not differ significantly from that seen in the control group (P for main effect = .003 and P for interaction = .778).

In terms of major secondary endpoints, there was a lower incidence of cardiac events, including sudden cardiac death, fatal/nonfatal MI and coronary revascularization, in the ezetimibe group, but there were no significant differences in the incidence of cerebrovascular events or all-cause mortality, Ouchi reported.

The mean age of patients in EWTOPIA75 was nearly 81 years; the majority were aged 75 to 79. Three-quarters were women. Patients had no history of CAD and needed to have diabetes, hypertension, low HDL, hypertriglyceridemia, a previous history of cerebral infarction, peripheral artery disease or be smokers to qualify for inclusion in the study.

Ouchi cited the use of PROBE design in which placebo was not used as a major study limitation. However, he said the endpoints were entirely objective and investigator judgments were precluded and, therefore, he and his colleagues believe the primary and secondary endpoints were adequately assessed.

“Lipid-lowering monotherapy with ezetimibe prevented the occurrence of a composite of atherosclerotic CV events in patients aged older than 75 years with elevated LDL cholesterol who had no history of CAD. This was true for cardiac events by secondary endpoint analysis,” Ouchi said during his presentation. “The result obtained in this study is the first evidence suggesting that the primary prevention of atherosclerotic CV events is possible by lipid-lowering therapy for eligible patients aged 75 years and older.”

Potential explanations

During a discussion of the results, Jennifer G. Robinson, MD, MPH, professor in the departments of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, said she was surprised to see the large effect size in this study when compared with other LDL-lowering trials. As a result, she questioned whether the effect is unique to the Japanese population.

Jennifer G. Robinson

“How should we interpret this trial? I think [LDL-lowering with ezetimibe] is very effective in older Japanese adults, but is this generalizable to non-Japanese populations is the question,” Robinson said, noting that it is possible, though unlikely, that the findings are due to chance. Its open-label design, the potential for bias and possible differences in biological responses in Japanese patients may also contribute to these findings.

“Could it be some biological effect or could it be that older adults are different? We really need results from ongoing trials, including STAREE, which will be reported in the next several years,” she said. – by Melissa Foster

Reference:

Ouchi Y, et al. LBS.01 – Late Breaking Clinical Trials: Answers to Critical Questions in Cardiovascular Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Disclosure: Ouchi reports no relevant financial disclosures.

CHICAGO — Lipid-lowering with ezetimibe prevented cardiac events in Japanese adults aged 75 years and older with elevated LDL levels, according to data from the EWTOPIA75 trial.

In many countries, there has been “an explosive increase” in the population of people aged older than 75 years, Yasuyoshi Ouchi, MD, professor emeritus at the University of Tokyo, said during a presentation at the American Heart Association Scientific Sessions. “Along with this population change, the number of patients aged older than 75 years with hypercholesterolemia has dramatically increased. However, prospective randomized controlled trials on the efficacy of LDL-lowering therapy in patients aged older than 75 years of age with elevated LDL cholesterol have not been conducted.”

Ezetimibe beneficial in elderly patients

The EWTOPIA75 trial was conducted in Japan. Ouchi and colleagues randomly assigned patients aged older than 75 years with an LDL level of at least 140 mg/dL to dietary counseling only (n = 1,695) or dietary counseling plus treatment with ezetimibe 10 mg daily (n = 1,716).

After 5 years of follow-up, risk for the primary endpoint — a composite of atherosclerotic CV events, including sudden cardiac death, MI, PCI or CABG and stroke — was significantly lower with ezetimibe vs. control (HR = 0.659; 95% CI, 0.504-0.862; P = .002), Ouchi noted.

Also, at 5 years, LDL was lower in the ezetimibe group compared with the control group (P for main effect < .001 and P for interaction < .001) and reduction in non-HDL was also greater with ezetimibe group compared with the control group (P for main effect < .001 and P for interaction < .001). Ezetimibe was also associated with a significant decrease in triglycerides, but the effect did not differ significantly from that seen in the control group (P for main effect = .003 and P for interaction = .778).

In terms of major secondary endpoints, there was a lower incidence of cardiac events, including sudden cardiac death, fatal/nonfatal MI and coronary revascularization, in the ezetimibe group, but there were no significant differences in the incidence of cerebrovascular events or all-cause mortality, Ouchi reported.

The mean age of patients in EWTOPIA75 was nearly 81 years; the majority were aged 75 to 79. Three-quarters were women. Patients had no history of CAD and needed to have diabetes, hypertension, low HDL, hypertriglyceridemia, a previous history of cerebral infarction, peripheral artery disease or be smokers to qualify for inclusion in the study.

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Ouchi cited the use of PROBE design in which placebo was not used as a major study limitation. However, he said the endpoints were entirely objective and investigator judgments were precluded and, therefore, he and his colleagues believe the primary and secondary endpoints were adequately assessed.

“Lipid-lowering monotherapy with ezetimibe prevented the occurrence of a composite of atherosclerotic CV events in patients aged older than 75 years with elevated LDL cholesterol who had no history of CAD. This was true for cardiac events by secondary endpoint analysis,” Ouchi said during his presentation. “The result obtained in this study is the first evidence suggesting that the primary prevention of atherosclerotic CV events is possible by lipid-lowering therapy for eligible patients aged 75 years and older.”

Potential explanations

During a discussion of the results, Jennifer G. Robinson, MD, MPH, professor in the departments of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, said she was surprised to see the large effect size in this study when compared with other LDL-lowering trials. As a result, she questioned whether the effect is unique to the Japanese population.

Jennifer G. Robinson

“How should we interpret this trial? I think [LDL-lowering with ezetimibe] is very effective in older Japanese adults, but is this generalizable to non-Japanese populations is the question,” Robinson said, noting that it is possible, though unlikely, that the findings are due to chance. Its open-label design, the potential for bias and possible differences in biological responses in Japanese patients may also contribute to these findings.

“Could it be some biological effect or could it be that older adults are different? We really need results from ongoing trials, including STAREE, which will be reported in the next several years,” she said. – by Melissa Foster

Reference:

Ouchi Y, et al. LBS.01 – Late Breaking Clinical Trials: Answers to Critical Questions in Cardiovascular Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Disclosure: Ouchi reports no relevant financial disclosures.

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