Decreased Cardiovascular Risk Associated With Ezetimibe in Acute Coronary Syndrome

electrocardiogram, STEMI
Investigators sought to identify the cardiovascular effects of adding ezetimibe to statin therapy in patients with acute coronary syndrome and dyslipidemia.

In patients with acute coronary syndrome (ACS) and a low eicosapentaenoic acid (EPA) to arachidonic acid (AA) ratio (<0.34 μg/mL), adding ezetimibe to pitavastatin was associated with decreased cardiovascular risk compared with pitavastatin alone, according to a study published in Journal of the American Heart Association.

In the HIJ‐PROPER (Heart Institute of Japan Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome) study, 1721 participants were randomly assigned to either pitavastatin monotherapy or pitavastatin plus ezetimibe. Clinical outcomes of participants with ACS, dyslipidemia, and available baseline EPA/AA ratio measurements (n=1187) were examined. To examine the potential impact of EPA/AA ratio on cardiovascular events, the 1187 participants with those baseline measurements were divided into 2 groups based on EPA/AA baseline ratio, with 0.34 μg/mL as the median cutoff. Triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were collected at enrollment and at follow-up assessments at 3, 6, 12, 24, and 36 months. The primary end point was a combination of all‐cause death, nonfatal stroke, nonfatal myocardial infarction, ischemia‐driven revascularization, and unstable angina pectoris.

Individuals in the low baseline EPA/AA ratio group were found to have significantly higher LDL-C, lower HDL-C, and higher triglyceride levels compared with those in the high EPA/AA group. Percentage reduction in triglycerides and LDL-C from baseline to follow-ups was similar between groups. Despite the high and low EPA/AA ratio groups having a similar mean LDL-C level at follow-up (68.8±19.5 vs 67.2±18.7, P =.31 for pitavastatin plus ezetimibe; 87.2±18.0 vs 86.2±17.2, P =.53 for pitavastatin monotherapy), a significantly higher mean triglyceride level was seen in the low vs high EPA/AA ratio groups (134.3±67.1 vs 120.0±50.1, P=.004 for pitavastatin plus ezetimibe; 159.1±84.1 vs 143.4±77.8, P =.02 for pitavastatin monotherapy).

At 3-year follow-up, the cumulative incidence of cardiovascular events in participants with low EPA/AA was 27.2% in those receiving pitavastatin plus ezetimibe group compared with 36.6% in those receiving pitavastatin monotherapy (HR 0.69; 95% CI, 0.52-0.93; P =.015). Cumulative incidence of cardiovascular events in patients with high EPA/AA ratio was 33.0% in the pitavastatin plus ezetimibe group compared with 36.6% in those receiving pitavastatin monotherapy (HR, 0.92; 95% CI, 0.70–1.20; P =.52).

Based on these results, the study investigators concluded, “Among ACS patients who have dyslipidemia and a low EPA/AA ratio, adding ezetimibe to statin decreases the risk of cardiovascular events compared with statin monotherapy.”

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Study limitations include that the findings were from retrospective subgroup analyses of a prospective clinical trial, and differences in clinical characteristics were found between the low and high EPA/AA ratio groups, indicating that results should be interpreted with caution. Additional limitations include there being no established normal range for EPA/AA ratio in a clinical setting and that the only difference in the low EPA/AA ratio group treated with pitavastatin plus ezetimibe was ischemia-driven revascularization (37% reduction compared with pitavastatin monotherapy). Despite these limitations, the researchers state that findings indicate that, “Risk stratification of patients is possible by measuring EA/AA ratio on admission” to determine whether adding ezetimibe to statin treatment would be recommended.

Disclosure: This clinical trial was supported by the Japan Research Promotion Society for Cardiovascular Diseases, which is sponsored by Abbott Vascular Japan Co, Ltd, AstraZeneca KK, Bayer Yakuhin, Ltd, and other pharmaceutical companies. Please see the original reference for a full list of authors’ disclosures.


Arashi H, Yamaguchi J, Kawada-Watanabe E, et al. Polyunsaturated fatty acid impact on clinical outcomes in acute coronary syndrome patients with dyslipidemia: subanalysis of HIJ-PROPER [published online August 8, 2019]. J Am Heart Assoc. doi: 10.1161/JAHA.119.012953