Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75)

Abstract

Background: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C–lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. Methods: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. Results: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50–0.86; P =0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37–0.98; P =0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18–0.79; P =0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. Conclusions: LDL-C–lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp . Unique identifier: UMIN000001988.

Comparative efficacy of pharmacological agents on reducing the risk of major adverse cardiovascular events in the hypertriglyceridemia population: a network meta-analysis

“…In terms of sample size, with the exception of one study that included only 59 patients [ 42 ], the studies included more than 300 patients. The average age of the population was approximately 60 years old, except in one article in which the average age was approximately 80 years old [ 29 ]. The shortest follow-up period among the included studies was 1 year [ 42 ] (Table 1 ).…”

LDL-C: lower is better for longer—even at low risk

“…This latter interpretation is supported by the observation that ezetimibe therapy, despite producing a relatively mild LDL-C lowering, also caused a significant reduction of CVD risk [13,45]. Finally, when LDL-C remains > 115 mg/dl (3.0 mmol/L), despite LSI, and eventually nutraceuticals, statin and/or ezetimibe [41,45] therapy should be considered. In the opinion of the authors, there is no need for a more intensive approach for low-risk patients, particularly as we do not have enough data on the effectiveness of such an approach in reducing CVOT.…”

“…Although the LDL-C reductions elicited by these agents are generally modest compared with high-intensity statins and PCSK9-inhibitors, nevertheless, the ‘lower is better for longer’ approach to cardiovascular risk-reduction implies that a small reduction of LDL-C sustained over a long period of time would be expected to accrue a substantial benefit in terms of CVD risk reduction. This latter interpretation is supported by the observation that ezetimibe therapy, despite producing a relatively mild LDL-C lowering, also caused a significant reduction of CVD risk [ 13 , 45 ]. Finally, when LDL-C remains > 115 mg/dl (3.0 mmol/L), despite LSI, and eventually nutraceuticals, statin and/or ezetimibe [ 41 , 45 ] therapy should be considered.…”

Recent advances in preventing recurrent stroke

“…In an RCT in Japan, patients with a mean age of 80.6 years at baseline were randomized to diet alone or diet plus ezetimibe. Over a median follow-up of 4.1 years, there was a 34% reduction of composite cardiovascular events and a 40% reduction of combined coronary events 56 .…”