Amarin 2017-07-19 03:45:25
Made possible through an unrestricted educational grant provided by Amarin EPA and Atherosclerotic Plaque: What Are the Potential Non-Statin Benefits? In patients with the complex condition of atherosclerosis, treatment with optimized statin therapy can still leave them at risk for cardiovascular (CV) events. Results from some recent studies, however, have suggested that eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, may help reduce CV risk in some patients when paired with optimal statin therapy. A new review by Nelson et al., published in Vascular Pharmacology, sought to summarize the current data on the relationship between EPA and atherosclerotic plaques. Summarizing results from a variety of clinical and preclinical trials from more than a decade’s worth of research, Nelson et al. noted in their review that “EPA has been shown to have a number of potential beneficial effects on atherosclerotic plaque factors, including antioxidant effects, anti-inflammatory effects, improved endothelial function, decreased adhesion of monocytes, decreased macrophage accumulation, decreased foam cell accumulation, increased fibrous cap thickness and an increase in a class of pro-resolving lipid mediators called resolvins.”1 “Low levels of EPA have been associated with the increased presence of lipid-rich atherosclerotic plaque, and patients on statin therapy with low levels of EPA have greater plaque involvement and more vulnerable plaque, and because of these facts, we decided to evaluate all of the published studies looking at the effects of EPA on plaque measured by a wide range of imaging modalities,” John R. Nelson, MD, of the California Cardiovascular Institute in Fresno, said in an interview. Imaging Studies Dr. Nelson and the review authors looked at data from a number of imaging studies in their review. The techniques were varied, and included coronary angiography, multi-detector computed tomography (MDCT), carotid artery ultrasound, intravascular ultrasound (IVUS) and back-scatter IVUS, and optical coherence tomography (OCT). In a 37-patient Japanese study, patients receiving EPA plus statins had a reduction in minimum luminal diameter on coronary angiography vs those taking statins alone (P=0.02),2 and in another 82-patient study using computed tomography angiography, was associated with the prevention of plaque progression (P=0.0061).3 Results from a study using MDCT showed that in 43 patients with suspected coronary artery disease, treatment with EPA was associated with significantly decreased plaque area (P=0.017), plaque volume (P=0.036), as well as significantly increased lumen area (P=0.004).4 Measuring carotid-artery intima-media thickness by carotid artery ultrasound, researchers looking at a small patient population (n=10) with hypertriglyceridemia reported that treatment with EPA was associated with a decrease in carotid-intima-media thickness after 11 months5, and annual decreases in both mean (P=0.029) and maximal (P=0.0008) carotid intima-media thickness in another study of patients with type 2 diabetes (n=60).6 Using IVUS to assess coronary artery wall thickness, results from another study of 34 patients with impaired glucose tolerance assigned to statin therapy suggested that the administration of EPA reduced coronary plaque volume at 8 months vs. controls (P<0.01).7 In another study using integrated backscatter IVUS to assess atherosclerotic plaques in patients with stable angina receiving either statin therapy alone (n=47) or statin plus EPA (n=48), EPA was associated with significantly reduced lipid volume at 6 months.8. Summarizing the cumulative weight of the imaging findings, Dr. Nelson said that “what we found was that EPA has shown consistent anti-atherosclerotic effects as demonstrated by a diverse array of imaging modalities. JELIS and CV Event Risk Among the large trials the authors cited was the Japan EPA Lipid Intervention Study (JELIS), which randomized 18,465 patients with hypercholesterolemia to receive a statin plus EPA 1.8g per day (n=9,326) or statin alone (n=9,319). The JELIS researchers reported a 19% relative reduction in risk for major coronary events (P=0.011) with no significant changes between treatment groups in low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol(HDL-c); there was a 5% greater reduction in triglycerides (Tg) in the EPA group(p<0.05).9 Results from another study of 241 Japanese patients (Nosaka et al.) with ACS treated within 24 hours of percutaneous coronary intervention (PCI) showed that the addition of EPA to a statin reduced the relative risk of CV events from 20.2% in the control group to 9.2% in the EPA plus statin group (absolute risk reduction of 11%; P=0.02).10 In this study there were no significant changes between treatment groups in LDL-C, HDL-C or Tg. A supplemental analysis of the JELIS results, which looked at 15,534 JELIS patients (n=7812 EPA + statin and n=7,722 on statin alone), higher plasma concentrations of EPA were associated with a lower risk for major coronary events (HR: 0.83; 95% CI, 0.68-0.99; P=0.049), and the group with the highest plasma EPA concentrations had a lower risk for major coronary events vs. those with the lowest plasma concentrations of EPA.11 Dr. Nelson said it was also important to note the significance of the ratio of EPA to arachidonic acid (EPA/AA). In the JELIS subanalysis, patients with EPA/AA ratios >0.75 and >1.00 had a significantly lower risk for major coronary events than patients with EPA/AA ratios <0.75 (HR=0.83; P=0.031 and HR=0.80; P=0.021, respectively).11 “EPA exerts beneficial effects through the entire pathophysiologic cascade of atherosclerosis from its onset to its resolution of inflammation,” Dr. Nelson said. “The JELIS and the Nosaka, “What we found was that EPA has shown consistent anti-atherosclerotic effects as demonstrated by a diverse array of imaging modalities.” John R. Nelson, MD et al studies both showed that significant event rate reduction occurred with the addition of EPA to statin therapy without any differences between groups in regard to LDL-C lowering. There were also no significant differences in the change in HDL-c between treatment arms in either study” Dr. Nelson went on to add that only in the JELIS trial (unlike the Nosaka et al study) was there a significant 5% decrease in triglyceride difference in the EPA group.” Dr. Nelson said it was unlikely that this 5% difference in triglyceride reduction in the EPA arm (from a baseline Tg of 153mg/dL) resulted in the 19% relative risk reduction seen in the JELIS trial. The results of these larger studies, Dr. Nelson said, are in line with the results from the imaging studies covered in the review. . “Why am I bringing all this up about the JELIS trial?” Dr. Nelson asked. “The JELIS trial published 10 years ago first brought to my attention the possibility of pleiotropic, that is mechanisms independent of cholesterol lowering, effects of EPA. We found the same phenomenon with these imaging trials. There’s a general pattern of little difference between the LDL-C changes, HDL-C changes, and even triglycerides between treatment arms and yet there is a significant reduction in plaque when adding EPA.” However, EPA levels and the EPA/AA ratio has correlated with plaque reduction. Viet Le and Dr. Nelson also recently published an article regarding some of the myriad of non-lipid beneficial pleiotropic effects of EPA.12 What’s Next While the results from JELIS and its sub-analyses suggest potential benefits from the administration of EPA in addition to statin therapy in a number of different patient groups, the authors also cautioned that many of the studies they highlighted in the review were conducted in Japanese populations, and may not be generalizable to a broader population. Part of the problem, Dr. Nelson noted, is that patients in the United States have markedly lower baseline serum EPA levels than those seen in Japan. “We basically have an epidemic of low-EPA serum levels in the United States due to the comparative, very low rate of fish consumption,” he added. Research in the United States is progressing, however. The review authors noted that the ANCHOR trial13, which was conducted in the United States, had patients whose baseline levels of EPA were lower than the baseline levels observed in the Japanese study population of JELIS (28.1 μg/mL vs. 97.0 μg/mL). However, with a treatment of the high-purity prescription form of EPA known as icosapent ethyl (Vascepa®, Amarin Pharma Inc.) at 4g/day, the ANCHOR patient population ended up achieving a serum on-treatment EPA plasma concentration similar to that observed in the Japanese study population of the JELIS trial (going from baseline 28.1 μg/mL to 182.6 μg/mL, compared with 170.0 μg/mL in the JELIS population).14 The authors also highlighted two further current studies looking at icosapent ethyl. The first is the EVAPORATE study (NCT02926027), being conducted at two US centers, and looking at the progression of rates of low-attenuation plaque with icosapent ethyl 4g/day vs. placebo (and evaluated using MDCT). EVAPORATE is currently enrolling statin-treated patients with triglyceride levels of 200-499 mg/dL. The other large, global phase-3 study currently looking at the effects of icosapent ethyl 4g/day on CV outcomes is the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT; NCT01492361), which they said would “provide more insight into the potential clinical benefits of icosapent ethyl in reducing CV risk in high-risk patients” who are on statin therapy.15 The REDUCE-IT study is set to conclude in 2018 REFERENCES 1.Nelson JR, Wani O, May HT, Budoff M. Vasc Pharma. 2017;91:1-9. 2.Domei T, Amemiya K, Enomoto S, et al. Eur Heart J. 2013;34(Suppl. 1):137. 3.Nagahara Y, Motoyama S, Sarai M, et al. Eur Heart J. 2016;37(Suppl. 1):1052, 4.Shintani Y, Kawasaki T. J Am Coll Cardiol. 2012;59:E1731. 5.Katoh A, Ikeda H. Ther Res. 2011;32:863-68. 6.Mita T, Watada H, Ogihara T, et al. Atherosclerosis. 2007;191:162-67. 7.Wakita Y, Wakida T, Itou T, Mizuno R. Circ J. 2013;77(Suppl. 1):I-2678. 8.Niki T, Wakatsuki T, Yamaguchi K, et al. Circ J. 2016;2016:450-460. 9.Yokoyama M, Origasa H, Matsuzaki M, et al. Lancet. 2007;369:1090-1098. 10.Nosaka K, Miyoshi T, Iwamoto M, et al. Int J Cardiol. 2017;228:173-179. 11.Itakura H, Yokoyama M, Matsuzaki M, et al. J Athreoscler Throm. 2011;99- 107. 12.Le V,Nelson JR. Lipid Spin. 2017;Issue 1:11-14,35. 13.Ballantyne CM, Brakeman RA, Bays HE, et al. J Clin Lipidol. 2015;9:377-383. 14.Bays HE, Ballantyne CM, Doyle RT, et al. Prostaglandins Other Lipid Mediat. 2016;125:57-64. 15.Bhatt DL, Steg GP, Brinton EA, et al. Clinical Cardiology. 2017;40:138-148. The other large, global phase-3 study currently looking at the effects of icosapent ethyl 4g/day on CV outcomes is the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT; NCT01492361), which they said would “provide more insight into the potential clinical benefits of icosapent ethyl in reducing CV risk in high-risk patients” who are on statin therapy.
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