AHA 2018 – Chicago, IL, USA

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

Presented at the AHA congress 2018 by: Yasuyoshi Ouchi (Tokyo, Japan)

Introduction and methods

The number of patients aged 75 years with hypercholesterolemia has dramatically increased, as a consequence of an explosive increase in the population of older people aged 75 years in many countries including US, Europe, and Asian countries, especially Japan. However, prospective RCTs on the efficacy of LDL-c-lowering therapy in patients aged  75 years of age with elevated LDL-c have not been conducted.

The EWTOPIA75 study was a prospective, randomized, open-label, blinded-endpoint trial that tested the hypothesis that LDL-c lowering therapy in patients 75 years with elevated LDL-c levels (140 mg/dL) without a history of CAD can significantly prevent the occurrence of cerebrovascular and CV events. Ezetimibe, an inhibitor of cholesterol absorption in the intestine, was used to lower LDL-c. Eligible patients were randomized to receive either dietary counseling only (control group; n=1,716) or dietary counseling and ezetimibe 10 mg/day (ezetimibe group; n=1,695) (February 2009 to December 2014), and were followed for 3 years (February 2009 to March 2016).

The primary endpoint was a composite of the following atherosclerotic CV events: sudden cardiac death, fatal and non-fatal MI, coronary revascularization (PCI or CABG), and fatal and non-fatal stroke. Major secondary endpoints were all types of cardiac events, all types of stroke, revascularization, aortic diseases, all-cause mortality, and new onset of malignant tumors. Of 3796 patients enrolled, 74% were female.

Main results

• After 5 years, participants treated with ezetimibe showed significantly reduced LDL-c (120.1 vs. 131.4 mg/dL, P<0.001), TG (111.7 vs. 114.5, P=0.003) and non-HDL-c (144.8 vs. 156.5 mg/dL, P<0.001) levels, compared to the control group.
• HDL-c (57.9 vs. 56.6 mg/dL, P=0.119) levels did not significantly differ between the two groups after 5 years.
• The ezetimibe group showed an HR of 0.659 (95%CI: 0.504-0.862, P=0.002) for the composite of atherosclerotic CV events, compared to the control group.
• Individuals treated with ezetimibe had an HR of 0.602 (95%CI: 0.370-0.979, P=0.041) for cardiac events, compared to only dietary counseling, whereas the risk of cerebrovascular events and all-cause mortality did not significantly differ between the two groups.
• More adverse events were observed in the ezetimibe group, compared to the control group (185 [10.62%] vs. 166 [9.62%]). No statistical analyses of individual AEs were shown.

Conclusion

This was the first randomized trial showing prevention of atherosclerotic CV events with ezetimibe therapy in patients aged ≥75 years with elevated LDL-c levels without history of CAD, suggesting that the primary prevention of atherosclerotic CV events is possible by lipid-lowering therapy for eligible older patients aged ≥75 years. The presenter acknowledged that a limitation was that no placebo was used, but believed the endpoints to be objective enough and not open to the investigator’s subjective judgment

Discussion

During the press conference, Jennifer G. Robinson discussed the main results of Ouchi et al. and highlighted the reduction in LDL-c, which was accompanied by a proportional CVD risk reduction. Surprisingly, this reduction in CVD risk was greater compared to what was observed in other LDL-lowering trials. She wondered, however, whether this effect is limited to older Japanese individuals or not.

Robinson discussed several study limitations possibly underlying the greater CVD risk reduction observed in this trial. The outcomes might have been a result of chance, since the trial had an open-label design and it did not include a control group treated with placebo. Moreover, the Japanese participants might have responded differently to the treatment, concerning plaque regression and stabilization, due to genetic polymorphisms in NPC1L1. Also, it might be that older patients respond differently than younger patients. Robinson concluded: ‘Ongoing placebo-controlled trials, including the STAREE and USA NIH RFA-AG-19-020 trials, will tell us more about the effect of LDL-c lowering on CVD risk in older patients.’

- Our reporting is based on the information provided at the AHA congress -