Aims Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients. Methods and results A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was changed in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053). Conclusions Icosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE.

Vagus nerve stimulation (VNS) is currently Food and Drug Administration-approved for treatment of both medically refractory partial-onset seizures and severe, recurrent refractory depression, which has failed to respond to medical interventions. Because of its ability to regulate mechanisms well-studied in neuroscience, such as norepinephrine and serotonin release, the vagus nerve may play an important role in regulating cerebral blood flow, edema, inflammation, glutamate excitotoxicity, and neurotrophic processes. There is strong evidence that these same processes are important in stroke pathophysiology. We reviewed the literature for the role of VNS in improving ischemic stroke outcomes by performing a systematic search for publications in Medline (1966–2014) with keywords “VNS AND stroke” in subject headings and key words with no language restrictions. Of the 73 publications retrieved, we identified 7 studies from 3 different research groups that met our final inclusion criteria of research studies addressing the role of VNS in ischemic stroke. Results from these studies suggest that VNS has promising efficacy in reducing stroke volume and attenuating neurological deficits in ischemic stroke models. Given the lack of success in Phase III trials for stroke neuroprotection, it is important to develop new therapies targeting different neuroprotective pathways. Further studies of the possible role of VNS, through normally physiologically active mechanisms, in ischemic stroke therapeutics should be conducted in both animal models and clinical studies. In addition, recent advent of a non-invasive, transcutaneous VNS could provide the potential for easier clinical translation.

Abstract Aims Though statin therapy is known to slow coronary atherosclerosis progression and reduce cardiovascular(CV) events, significant CV risk still remains. In the REDUCE-IT study, icosapent ethyl (IPE) added to statin therapy reduced initial CV events by 25% and total CV events by 30%, but its effects on coronary atherosclerosis progression have not yet been fully investigated. Therefore, this study is to determine whether IPE 4g/d will result in a greater change from baseline in plaque volume measured by serial multidetector computed tomography (MDCT) than placebo in statin-treated patients. Methods and Results EVAPORATE is a randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis by coronary computed tomographic angiography CCTA (≥1 angiographic stenoses with ≥20% narrowing), on stable statin therapy with low-density lipoprotein cholesterol levels 40 to 115 mg/dl, and persistently high triglyceride levels (135-499 mg/dL). Patients underwent an interim scan at 9 months and were followed for an additional 9 months with CCTA at 0, 9 and 18 months. Here we present the protocol-specified interim efficacy results. A total of 80 patients were enrolled, with 67 completing the 9-month visit and having interpretable CCTA at baseline and at 9-months (age=57±6 years, male=36, 63%). At the 9-month interim analysis, there was no significant change in low attenuation plaque (LAP) between active and placebo groups (74% vs 94%, p = 0.469). However, there was slowing of total non-calcified plaque (sum of LAP, fibrofatty, and fibrous plaque)(35% v. 43%,p=0.010), total plaque (non-calcified + calcified plaque)(15% v. 26%,p=0.0004), fibrous plaque (17% v. 40%,p=0.011) and calcified plaque (-1% v. 9%,p=0.001), after adjustment by baseline plaque, age, sex, diabetes, baseline triglyceride levels, and statin use. Conclusions EVAPORATE is the first study using CCTA to evaluate the effects of IPE as an adjunct to statin therapy on atherosclerotic plaque characteristics in a high-risk CV population with persistently high TG levels. It provides important mechanistic data in regards to the reduction in CV events in the REDUCE-IT clinical trial. Translational Potential Given the robust cardiovascular event reduction seen in clinical trials of Icosapent ethyl, this study demonstrates that one potential mechanism of benefit of this therapy is to slow atherosclerosis progression. This study shows that most coronary plaque types show slowed rates of progression under the influence of statin plus Icosapent ethyl. A translational use of this information would be to potentially use this therapy in addition to statin therapy in cases with presence of significant atherosclerosis.