Assignment: National Lipid Association Scientific Statement Articles

Assignment: National Lipid Association Scientific Statement Articles ORDER NOW FOR CUSTOMIZED AND ORIGINAL ESSAY PAPERS ON Assignment: National Lipid Association Scientific Statement Articles read the articles and answer the questions found in the attached images……… Assignment: National Lipid Association Scientific Statement Articles screen_shot_2020_03_30_at_6.35.56_pm.png screen_shot_2020_03_30_at_6.36.07_pm.png screen_shot_2020_03_30_at_6.36.12_pm.png screen_shot_2020_03_30_at_6.35.50_pm.png orringer_ce_et_al.nla_scientific_statement___use_of_ipe_in_statin_treated_patients_with_elevated_tgs_and_high_cvd_risk.jclinlipid.2019.pdf aha_scientific_statement.pdf Journal of Clinical Lipidology (2019) 13, 860–872 NLA Scientific Statement National Lipid Association Scientific Statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk Carl E. Orringer, MD, FNLA*, Terry A. Jacobson, MD, FNLA, Kevin C. Maki, PhD, FNLA Miller School of Medicine, Cardiovascular Division, University of Miami, Miami, FL, USA (Dr Orringer); Department of Medicine, Emory University, Atlanta, GA, USA (Dr Jacobson); School of Public Health, Department of Applied Health Science, Indiana University, Bloomington, IN, USA (Dr Maki); and Midwest Biomedical Research, Center for Metabolic and Cardiovascular Health, Addison, IL, USA (Dr Maki) KEYWORDS: Omega-3 fatty acids; Icosapent ethyl; Eicosapentaenoic acid; Cardiovascular disease; Triglycerides Abstract: Representatives from the National Lipid Association (NLA) participated in the development of the 2018 American Heart Association/American College of Cardiology/Multisociety Guideline on the Management of Blood Cholesterol, which reaffirmed that lifestyle changes and statin treatment are therapeutic cornerstones for atherosclerotic cardiovascular disease (ASCVD) risk reduction. It also updated prior recommendations to incorporate newer data demonstrating ASCVD risk reduction with ezetimibe and proprotein convertase subtilisin kexin type 9 inhibitors as adjuncts to statin therapy for patients at high and very-high ASCVD risk. The 2018 Guideline was finalized shortly before full results were available from a randomized, placebo-controlled cardiovascular outcomes trial [Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT)] that examined the effects of icosapent ethyl (IPE) 4 g/d on major adverse cardiovascular events in selected high- or very high-risk, statin-treated patients with elevated triglycerides. The primary outcome variable of first major adverse cardiovascular event (cardiovascular death, myocardial infarction, stroke, coronary revascularization and hospitalization for unstable angina) was reduced by 25% (95% confidence interval 17%–32%, P , .001). REDUCE-IT served as the primary basis for the NLA’s review of evidence for the use of IPE for ASCVD risk reduction. Based on this review, the NLA position is that for patients aged $45 years with clinical ASCVD, or aged $50 years with diabetes mellitus requiring medication plus $1 additional risk factor, with fasting triglycerides 135 to 499 mg/dL on high-intensity or maximally tolerated statin therapy (6ezetimibe), treatment with IPE is recommended for ASCVD risk reduction (evidence rating: class I; evidence level: B-R). Ó 2019 National Lipid Association. All rights reserved. * Corresponding author. Miller School of Medicine, Cardiovascular Diseases, University of Miami, Clinical Research Building, 1120 NW 14th Street, Suite 1111, Miami, FL 33136, USA. E-mail address: [email protected] Submitted October 21, 2019. Accepted for publication October 25, 2019. Introduction Results from observational studies have suggested lower risks for adverse cardiovascular outcomes associated with higher intakes, or higher biomarker levels of, long-chain omega-3 fatty acids, particularly eicosapentaenoic acid 1933-2874/Ó 2019 National Lipid Association. All rights reserved. https://doi.org/10.1016/j.jacl.2019.10.014 Downloaded for Anonymous User (n/a) at Idaho State University from ClinicalKey.com by Elsevier on January 13, 2020. For personal use only. No other uses without permission. Assignment: National Lipid Association Scientific Statement Articles Copyright ©2020. Elsevier Inc. All rights reserved. Orringer et al NLA statement on icosapent ethyl (EPA) and docosahexaenoic acid (DHA).1–4 However, results from randomized, controlled trials (RCTs) of omega-3 fatty acid interventions have shown mixed results, with some suggesting cardiovascular outcomes benefits,5,6 while others failed to support beneficial effects.7,8 Interpretation of results from the previously available RCTs was complicated by several design limitations, chief among these being the low dosages used in most trials (median 840 mg/d of EPA 1 DHA as ethyl esters),9 which is substantially lower than those doses recommended by the Food and Drug Administration (FDA) for prescription omega-3 products that lower triglycerides (TGs). For example, the daily dosage of omega-3 ethyl esters available as Lovaza and generic products is 3.36 g of EPA 1 DHA, that of icosapent ethyl (IPE or EPA ethyl esters, available as Vascepa) is 3.84 g, and that of omega-3 carboxylic acids, approved as Epanova, is 3.40 g of EPA 1 DHA. Benefits in RCTs were observed more consistently in non–placebo-controlled trials,5,6 and less frequently in placebocontrolled studies.7,8 Moreover, as of mid-2018, none of the larger RCTs of omega-3 fatty acids that assessed cardiovascular outcomes had specifically selected a sample with elevated TGs. There are several well-documented effects of long-chain omega-3 fatty acids to modify atherosclerotic cardiovascular disease (ASCVD) risk factors, including lowering the plasma TG concentration, in a dose-dependent manner.10 One RCT, the Japan EPA Lipid Intervention Study (JELIS), used a higher dosage (1.8 g/d) of EPA given as ethyl esters than had been used in most prior studies.5 The trial randomly assigned a group of 18,465 Japanese primary and secondary prevention patients with hypercholesterolemia to receive EPA 1 statin therapy, or statin therapy alone (no placebo). The results showed a 19% relative risk reduction in the primary outcome of major fatal and nonfatal coronary events: hazard ratio (HR): 0.81 (95% confidence interval [CI] 0.69–0.95, P 5 .011). Of note, there was a modest effect of EPA on the plasma TG concentration, with 5% more lowering of the TG level in the EPA arm (9% in the EPA group compared with 4% in the control group). There was a larger reduction in the primary outcome with EPA in the subset of primary prevention subjects with elevated TGs ($150 mg/dL) and low highdensity lipoprotein cholesterol (HDL-C; ,40 mg/dL), HR 0.47 (95% CI 0.23–0.98).11 Greater ASCVD risk reduction among subjects with the phenotype of elevated TGs plus low HDL-C has been reported previously from subgroup analyses of other agents that lower the plasma TG concentration, such as fibrates.12–14 Furthermore, an analysis of the relationship between on-treatment plasma EPA concentration and incidence of coronary events suggested a dose-response relationship.11 Although subgroup and exploratory analyses should be interpreted with caution, the results from JELIS are consistent with the hypotheses that use of lower dosages of omega-3 fatty acids and selection of groups without the high TG and low HDL-C phenotype may have been factors in the failure of some prior trials to provide evidence of benefit.9 It should also be noted that most prior large-scale 861 omega-3 RCTs used a mix of EPA and DHA (as well as other minor omega-3 fatty acids), whereas JELIS used a formulation of EPA ethyl esters that is essentially free of other omega-3 fatty acids. In late 2018, results from the Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) were published.15 This trial was designed in a manner that avoided many of the limitations of prior RCTs by (1) enrolling a study sample at high or very-high ASCVD risk with elevated TGs while on statin therapy; (2) using a comparatively high dosage of omega-3 fatty acids (3.84 g/d of EPA in the form of IPE); and (3) using a double-blind, placebo-controlled design. REDUCE-IT served as the primary basis for the National Lipid Association’s (NLA’s) review of evidence for the use of IPE for ASCVD risk reduction. Assignment: National Lipid Association Scientific Statement Articles The rationale for the NLA’s recommendation is outlined in this Scientific Statement. 2018 American Heart Association/American College of Cardiology/Multisociety Guidelines for treatment of high-risk and very-high-risk patients Representatives from the NLA participated in the development of the 2018 American Heart Association (AHA)/American College of Cardiology (ACC)/Multisociety Guideline on the management of blood cholesterol, which reaffirmed that lifestyle changes and statin treatment are the therapeutic cornerstones for ASCVD risk reduction.16 The 2018 Guideline also updated prior recommendations to incorporate the newer data demonstrating ASCVD risk reduction with ezetimibe and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors as adjuncts to statin therapy for patients at high and very-high ASCVD risk. Very-high-risk individuals were characterized as having a history of two major ASCVD events or one major ASCVD event and two or more high-risk conditions. Major ASCVD events and high-risk conditions are defined in Figure 1. High-risk ASCVD is defined as clinical ASCVD in patients who do not meet the criteria for veryhigh-risk categorization. Based on RCT data, patients with uncomplicated ASCVD are estimated to have a 20% to 29% 10-year risk of ASCVD events.17 Those with very-high risk have an estimated 10-year risk $30%, and some patients, such as those with clinical ASCVD and either ischemic stroke, peripheral arterial disease, or recurrent cardiovascular events, have a 10-year risk exceeding 40%.17 Hypertriglyceridemia, TG-lowering therapies, and ASCVD risk Epidemiological18–20 and Mendelian randomization studies21 have demonstrated that fasting or nonfasting TG elevation is associated with increased ASCVD risk. This Downloaded for Anonymous User (n/a) at Idaho State University from ClinicalKey.com by Elsevier on January 13, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. 862 Journal of Clinical Lipidology, Vol 13, No 6, December 2019 Figure 1 2018 American Heart Association/American College of Cardiology/Multisociety Guideline on Management of Cholesterol: Classification of very high risk atherosclerotic cardiovascular disease (ASCVD)*. *Note: the definitions of high and very high risk for atherosclerotic cardiovascular disease (ASCVD) outlined in the 2018 American Heart Association (AHA)/American College of Cardiology (ACC)/Multisociety Guideline differ from those used to qualify for entry into the Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial (REDUCE-IT). However, a large majority of subjects in REDUCE-IT had 10-year ASCVD event risk $20%, as indicated by a 14.8% incidence of the key secondary end point (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in the placebo group during median follow-up of 4.9 years, which projects to .30% 10-year risk. heightened risk is associated with increased circulating concentrations of cholesterol carried by partially delipidated TG-rich lipoprotein particles,22,23 and the often coexistent proinflammatory, prothrombotic, and oxidative milieu23–25 associated with insulin resistance.Assignment: National Lipid Association Scientific Statement Articles 26 The 2018 AHA/ACC/Multisociety Guideline identifies moderate hypertriglyceridemia (TG $ 175 mg/dL) as a ‘‘risk-enhancing factor’’ to be considered in the clinician-patient risk discussion, the presence of which favors the initiation or intensification of statin therapy, but does not otherwise make specific recommendations about using TG-lowering drugs to improve cardiovascular outcomes.16 NLA’s Recommendations for the Patient-Centered Management of Dyslipidemia, published in 2015, outlined the central role of elevated concentrations of cholesterol carried by atherogenic lipoprotein particles (ie, non–HDL-C) as a root cause of atherosclerosis and that reduction in the circulating levels of these lipoproteins would lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced.27,28 Non–HDL-C comprises cholesterol carried by all apolipoprotein B (apo B)–containing lipoproteins, including low-density lipoprotein (LDL), intermediate-density lipoprotein, lipoprotein (a), very-lowdensity lipoprotein (VLDL), chylomicrons, and chylomicron remnant particles. Throughout this article, the term VLDL-C will be used to denote cholesterol carried by all apo B–containing particles with density lower than LDL, which includes true VLDL-C, as well as chylomicrons and chylomicron remnant particles. Other terms have been used in the literature for this fraction, including remnant cholesterol and TG-rich lipoprotein cholesterol. Elevation in plasma TG is typically accompanied by an elevation in VLDL-C, although the relationship becomes nonlinear at higher levels of TG, particularly above 400 mg/dL, because severe TG elevation is associated with a higher molar ratio of TG to cholesterol in VLDL and other TG-rich lipoprotein particles.29 Nevertheless, changes in plasma TG concentration induced by pharmaceutical agents such as omega-3 fatty acids, fibrates, niacin, and statins generally correlate strongly with changes in the VLDL-C concentration.30 Because of the central role in TG catabolism played by lipoprotein lipase (LPL), identification of mutations in apolipoproteins that alter the activity of this enzyme has been an important focus of studies on the impact of TG and VLDL-C levels on ASCVD risk. apo C3, which resides on the surface of TG-rich lipoproteins, inhibits LPL-mediated lipolysis of these lipoproteins and raises circulating TG levels. Exome sequencing studies of individuals of European or African American descent who have mutations in the gene encoding apo C3 demonstrated that heterozygous carriers of one of four loss-of-function mutations of APOC3 had circulating TG concentrations that were 39% lower and coronary heart disease (CHD) risk that was 40% lower than noncarriers.31 Mutations in the APOA5, ANGPTL3, and ANGPTL4 genes, as well in the LPL gene itself, also result in the altered expression of proteins that affect LPL function, and add further support to the concept that elevated concentrations of TG and TG-rich lipoproteins contribute to ASCVD risk.32–37 A series of Mendelian randomization analyses has demonstrated that TG-lowering LPL variants and LDL-Clowering LDL receptor (LDLR) variants were associated with similar reductions in risk of CHD per unit difference in LDL-C and VLDL-C, which is estimated with the Friedewald equation as the TG concentration in mg/dL divided Downloaded for Anonymous User (n/a) at Idaho State University from ClinicalKey.com by Elsevier on January 13, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. Assignment: National Lipid Association Scientific Statement Articles Orringer et al NLA statement on icosapent ethyl by five when the TG level is not markedly elevated.38 LDLC and VLDL-C (or TG) each lose statistical significance after adjustment for apo B concentration. Thus, genetically mediated differences in both components of non–HDL-C (LDL-C and VLDL-C) are independently associated with ASCVD risk to a similar degree per mg/dL difference. Furthermore, this relationship may be mediated through the concentration of circulating lipoprotein particles with atherogenic potential because each particle of LDL and VLDL contains a single molecule of apo B. Several investigations have identified hypertriglyceridemia as a marker of increased residual ASCVD risk in statintreated patients.39–41 RCTs of TG-lowering treatments, including niacin42,43 and some fibrates,44 in which trial enrollment was not based on the presence of hypertriglyceridemia, did not achieve their primary end points of CHD or ASCVD risk reduction. However, among trials that included subgroup analyses for subjects with elevated baseline TG, particularly if accompanied by low HDL-C, pooled estimates suggest ASCVD risk reduction.12–14,45 For example, in a meta-analysis of 10 RCTs of TGlowering therapies, including fibrates, niacin and EPA ethyl esters, for which subgroup analyses were reported for subjects with TG elevation and/or TG elevation plus low HDLC, the pooled estimate for relative risk reduction was 12% (95% CI: 5%–18%) overall, 18% (95% CI: 9%–27%) for subgroups with elevated TG, and 29% (95% CI: 19%– 37%) for subgroups with elevated TG plus low HDL-C.12 Effects of long-chain omega-3 fatty acid interventions on ASCVD risk A 2017 Science Advisory from the AHA stated that available evidence did not support the use of low-dose omega-3 fatty acid supplementation (approximately 850– 1000 mg of EPA and DHA/d) to reduce ASCVD risk for individuals in the general population, including those with prediabetes or diabetes, who are not at high risk of ASCVD. However, it stated that low-dose omega-3 fatty acid supplementation was reasonable for secondary prevention of CHD in those with a recent CHD event and for heart failure patients with reduced ejection fraction.46 This recommendation was based on a meta-analysis that showed modest risk reduction (RR) for CHD death (RR 0.91, 95% CI: 0.85–0.98) in secondary prevention4 and a reduction in total mortality (RR: 0.91, 95% CI: 0.83–0.99) in heart failure patients with reduced ejection fraction.47 Results from a subsequent meta-analysis of 10 trials, using aggregated study-level data involving 77,917 individuals, 66% with a prior history of CHD, 28% with a prior stroke, and 37% with prior diabetes treated with daily dosages of EPA from 226 to 1800 mg and DHA from 0 to 1700 mg, suggested no significant effects on the risks of CHD, stroke, coronary, or noncoronary revascularization or major vascular events.48 However, the results were consistent with a possible benefit for CHD death that was of 863 marginal statistical significance (RR: 0.93, 95% CI: 0.85– 1.00, P 5 .05) but similar in magnitude to previously reported findings.4,49 Since the publication of that meta-analysis, results from three large-scale RCTs of omega-3 fatty acid interventions have been published: A Study of Cardiovascular Events in Diabetes,50 the Vitamin D and Omega-3 Trial,51 and REDUCE-IT15 When the results from the 2 trials (A Study of Cardiovascular Events in Diabetes and Vitamin D and Omega-3 Trial) using lower dosage interventions (840 mg/ d EPA 1 DHA as ethyl esters). Assignment: National Lipid Association Scientific Statement Articles in primary prevention populations were added to those of the meta-analysis discussed previously,48 a benefit of low-dosage omega-3 therapy for lowering risk of CHD death was further supported: 1405 events in 59,684 subjects for the omega-3 interventions compared with 1529 events in 59,560 subjects for the control conditions (RR: 0.92, 95% CI: 0.86–0.99, P 5 .014).52 Significantly lower risks were also observed for myocardial infarction, total CHD, CVD death, and total CVD with pooled relative risk reduction estimates ranging from 5 to 8%. REDUCE-IT: RCT of high-dose IPE on cardiovascular outcomes in statin-treated subjects with elevated TG REDUCE-IT was a multicenter, randomized, doubleblind, placebo-controlled trial of 8179 statin-treated subjects with established ASCVD, or with diabetes and at least one other risk factor. REDUCE-IT was undertaken to assess whether the addition of this highly purified and stable formulation of EPA ethyl esters (ie, IPE) could safely provide net ASCVD risk reduction benefit in patients already receiving evidence-based statin therapy who continued to have persistently elevated fasting TG.15 Study subjects were men and women with established clinical ASCVD $45 years of age (secondary prevention cohort, 70.7% of those enrolled) or with type 2 diabetes mellitus $50 years of age requiring medication for their diabetes, with at least one additional risk factor (primary prevention cohort, 29.3% of those enrolled). All subjects were on a stable regimen of statin 6 ezetimibe for at least 4 weeks before qualification, with fasting TG levels of 135 to 499 mg and a median baseline concentration of 216 mg/ dL. They were required to have LDL-C 41 to 100 mg/dL and had a median baseline concentration of 75 mg/dL. Approximately 93% of subjects were receiving moderateor high-intensity statin therapy, 6% were receiving … Get a 10 % discount on an order above $ 100 Use the following coupon code : NURSING10

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