Add-on ezetimibe provides enhanced cardioprotection in high-risk ACS patients
Acute coronary syndrome (ACS) patients with diabetes mellitus (DM), as well as high-risk nondiabetic patients, appear to obtain significant cardioprotection from the addition of ezetimibe to simvastatin, and this benefit is achieved without compromising safety, according to an exploratory analysis of data from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).
“These findings support the 2017 American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease treatment goal of an LDL-C [low-density lipoprotein cholesterol],” researchers said.
IMPROVE-IT randomized 18,144 ACS patients with LDL-C levels of 50–125 mg/dL to receive either ezetimibe or placebo in combination with simvastatin 40 mg. The present analysis evaluated the effect of add-on ezetimibe in the subgroup of patients with DM (n=4,933; mean age 65.3 years; 28.5 percent female) vs their nondiabetic peers (n=13,202; mean age 63.7 years; 22.8 percent female).
Compared with nondiabetic patients, those with DM were more likely to be older and female, have had a prior myocardial infarction and revascularization, and present more frequently with non-ST segment elevation ACS (p<0.001 for each). Median LDL-C at admission was lower in patients with DM (89 vs 97 mg/dL; p<0.001).
Treatment with ezetimibe reduced the primary composite endpoint of cardiovascular death, major coronary events and stroke at 7 years in the DM subgroup (absolute difference, 5.5 percent; hazard ratio [HR], 0.85; 95 percent CI, 0.78–0.94) and in the no-DM subgroup (absolute difference, 0.7 percent; HR, 0.98; 0.91–1.04) relative to placebo. [Circulation 2018;137:1571-1582]
The difference in treatment benefit with add-on ezetimibe between the DM and no-DM subgroups was significant (p=0.02) and driven by reductions in myocardial infarction (24 percent) and ischaemic stroke (39 percent). Safety outcomes by treatment were similar, regardless of DM.
On further analysis, ezetimibe yielded greater benefits in patients with DM aged <75 years vs their nondiabetic counterparts (p=0.011 for interaction) and in nondiabetic patients with a high TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention vs similar patients with low or moderate TIMI risk score (p=0.034 for interaction).
Researchers noted that the enhanced benefit of ezetimibe plus simvastatin in patients with DM is consistent with the findings reported in other high-risk subgroups in IMPROVE-IT, including patients aged >75 years, with prior CABG and with prior stroke—all of which contribute to the TIMI risk score. [Circulation 2015;132:A16708; Eur Heart J 2016;37:3576-3584; Circulation 2015:A19694]
“Thus, [the current] observations in patients with DM are consistent with the hypothesis that patients at highest risk for cardiovascular events have the most to benefit from ezetimibe. This may reflect a greater proportion of ‘modifiable’ events with aggressive lipid-lowering in higher risk patients as compared to low-risk patients,” researchers said.
In an accompanying editorial, a team of experts from the University of Oxford in UK pointed out that while having important clinical implications, the new IMPROVE-IT results should be interpreted in light of the fact that subgroup analyses from clinical trials can be unreliable. [Circulation 2018;137:1583-1584]
“[However], because there is unlikely to ever be enough additional randomized data to definitively test these new hypotheses and given the various strands of compelling genetic and randomized trial evidence suggesting that relative cardiovascular benefit is likely to be similar in those with and without DM, it is reasonable to conclude that ezetimibe reduces atherosclerotic cardiovascular risk through lowering LDL-C irrespective of the presence or absence of DM,” they said.
According to the experts, one way to identify which patients might be expected to have a smaller or larger absolute benefit from ezetimibe (per unit reduction in LDL-C) is to classify their risk of atherosclerotic cardiovascular disease by using a relevant and reliable risk score and then applying the relative benefits estimated by the overall IMPROVE-IT result.