NLA Position Statement on the Use of f Ic Icosapent Ethyl in High- or or Very ry-high Risk Patients Carl E. Orringer, MD, FNLA Terry A. Jacobson, MD, FNLA Kevin C. Maki, PhD, FNLA www.lipid.org
Disclosures • Carl E. Orringer, MD: None • Terry A. Jacobson, MD: Steering Committee, REDUCE-IT Trial, No personal compensation. • Kevin C. Maki, PhD: research grant support and/or consulting fees from Acasti Pharma, Akcea Therapeutics, Amgen, AstraZeneca, Corvidia Therapeutics, Matinas BioPharma, Pharmavite, Sanofi/Regeneron www.lipid.org
Objectives • Define high and very high ASCVD risk categories • Review treatment recommendations for these patients based on 2018 Cholesterol Guideline • Review impact of hypertriglyceridemia on ASCVD risk • Review effects of non-prescription Ω -3 FA on ASCVD risk • Review results and limitations of REDUCE-IT • State NLA position on use of icosapent ethyl in selected patients at high or very high risk for ASCVD www.lipid.org
Very High Risk ASCVD 2 or More Major Events or 1 Major Event and ≥ 2 High Risk Conditions High Risk Conditions Major ASCVD Events • Age ≥65 y • Recent ACS (within the past 12 mo) • Heterozygous familial • H/o MI (other than recent ACS event hypercholesterolemia listed above) • H/o prior CABG or PCI outside of major • H/o ischemic stroke ASCVD event(s) • Symptomatic peripheral arterial disease • Diabetes mellitus (H/o claudication with ABI <0.85, or • Hypertension previous revascularization or amputation) • CKD (eGFR 15-59 mL/min/1.73 m 2 ) • Current smoking • LDL- C ≥100 despite maximally tolerated statin + ezetimibe H/o : history of ABI : ankle brachial index • H/o heart failure CABG : Coronary artery bypass surgery PCI: Percutaneous coronary intervention Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA CKD : Chronic kidney disease Guideline on the Management of Blood Cholesterol. https://doi.org/10.1016/j.jacc.2018.11.003
2018 Guideline: Treatment of Patients at High and Very High Risk for ASCVD • Heart healthy diet and regular aerobic exercise • Maximally tolerated statin with goal to ↓LDL - C by ≥ 50% • High risk on maximally tolerated statin – May be reasonable to add ezetimibe if LDL- C ≥ 70 mg/dL • Very high risk on maximally tolerated statin – Add ezetimibe if <50% ↓ in LDL -C and LDL- C ≥ 70 mg/dL – Reasonable to add PCSK9i if LDL- C ≥ 70 mg/dL on ezetimibe Grundy SM et al. Circulation. 2019;139:e1046 – e1081 www.lipid.org
Triglycerides and ASCVD Risk Nordestgaard, B. G., & Varbo, A. (2014). Triglycerides and cardiovascular disease. The Lancet , 384 (9943), 626 – 635. doi: 10.1016/s0140-6736(14)61177-6 www.lipid.org
Hypothesized Mechanisms for the Atherogenicity of TG-rich Lipoproteins Goldberg IJ, Eckel RH, McPherson R. Triglycerides and heart disease: still a hypothesis?. Arterioscler Thromb Vasc Biol . 2011;31(8):1716 – 1725. doi:10.1161/ATVBAHA.111.226100 . 7 www.lipid.org
Possible Mechanisms of TG Lowering Effects of Omega 3 Fatty Acids • Increased clearance or reduced synthesis of apo B lipoproteins • Enhanced hepatic degradation of fatty acids • Increased activity of lipoprotein lipase • Increased catabolism of omega-3 enriched VLDL particles to LDL particles Jacobson TA et al. J Clin Lipidol 2012;6:5-18 www.lipid.org
Long Chain Omega-3 Interventions and CV Events No. of Events (%) Favors Favors Source Treatment Control Rate Ratios (CI) Treatment Control Coronary heart disease Nonfatal myocardial infarction 1121 (2.9) 1155 (3.0) 0.97 (0.87 – 1.08) Coronary heart disease 1301 (3.3) 1394 (3.6) 0.93 (0.83 – 1.03) Any 3085 (7.9) 3188 (8.2) 0.96 (0.90 – 1.01) CHD Death Events P =.12 Treatment Stroke n = 1301 (3.3%) Ischemic 574 (1.9) 554 (1.8) 1.03 (0.88 – 1.21) Hemorrhagic 117 (0.4) 109 (0.4) 1.07 (0.76 – 1.51) Control Unclassified/other 142 (0.4) 135 (0.3) 1.05 (0.77 – 1.43) n = 1394 (3.6%) Any 870 (2.2) 843 (2.2) 1.03 (0.93 – 1.13) P =.60 RR (95% CI) Revascularization 0.93 (0.85-1.00) Coronary 3044 (9.3) 3040 (9.3) 1.00 (0.93 – 1.07) P = 0.05 Noncoronary 305 (2.7) 330 (2.9) 0.92 (0.75 – 1.13) Any 3290 (10.0) 3313 (10.2) 0.99 (0.94 – 1.04) P =.60 Any major vascular event 5930 (15.2) 6071 (15.6) 0.97 (0.93 – 1.01) P =.10 0.5 1.0 2.0 Rate Ratio Adapted with permission * from Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234. [ * https://creativecommons.org/licenses.org/by-nc/4.0/]
Long Chain Omega-3 Interventions and Cardiac Death (Death from CHD, Cardiac Arrhythmia, Heart Failure) Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. Journal of Clinical Lipidology 2017;11:1152 – 1160
JELIS: Low intensity statin alone versus low intensity statin + EPA 600 mg 3 times daily N=18,645 Kaplan-Meier Estimates of Incidence of Coronary Events Baseline LDL-C 182 mg/dL Randomized open label trial Coronary events: Total Population Primary Prevention Cohort Secondary Prevention Cohort Sudden cardiac death Fatal and non-fatal MI 4 2.0 Unstable angina PCI Major coronary events (%) CABG 3 1.5 Control Control Control 8.0 EPA* EPA* 2 1.0 EPA* 4.0 1 0.5 Hazard ratio: 0.81 (0.69 – 0.95) Hazard ratio: 0.82 (0.63 – 1.06) Hazard ratio: 0.81 (0.657 – 0.998) p=0.011 ARR 0.7% p=0.132 p=0.048 0 0 0 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Years Numbers at risk Control group 9319 8931 8671 8433 8192 7958 7478 7204 7103 6841 6678 6508 1841 1727 1658 1592 1514 1450 Treatment group 9326 8929 8658 8389 8153 7924 7503 7210 7020 6823 6649 6482 1823 1719 1638 1566 1504 1442 *1.8 g/day Adapted with permission from Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.
Key Trials Employing TG-lowering Drugs: Effects on TG and CV Outcomes Control Treatment A Control Icosapent ethyl 250 *** * *** *** *** *** TG Level (mg/dl) 200 150 100 50 0 VA-HIT FIELD ACCORD-Lipid AIM-HIGH HPS2-THRIVE GISSI-P JELIS REDUCE-IT 1999 2005 2010 2011 2014 1999 2007 2018 B RRR 22% HR 0.89 HR 0.92 HR 1.02 HR 0.96 HR 0.90 HR 0.81 HR 0.75 Primary Endpoint (%) 25 p=0.006 p=0.16 p=0.32 p=0.79 p=0.29 p=0.48 p=0.011 p<0.001 20 15 10 5 0 VA-HIT FIELD ACCORD-Lipid AIM-HIGH HPS2-THRIVE GISSI-P JELIS REDUCE-IT 1999 2005 2010 2011 2014 1999 2007 2018 Fibrate Niacin Omega-3 Fatty Acid Patel PN, Patel SM, Bhatt DL. Curr Opin Cardiol. 2019;34 (in press). *** P<0.001; * P<0.05
Trials Employing Triglyceride-lowering Drugs: Subgroups with Elevated TG and Low HDL-C SSRE = summary rate ratio estimate Maki KC, Guyton JR, Orringer CE, et al. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. Journal of Clinical Lipidology 2016;10:905-914
REDUCE-IT Design N=8179 Key Inclusion Criteria Icosapent Primary Endpoint 4 months, End-of-study • Statin-treated men Ethyl Time from Lead-in 12 months, follow-up 1:1 and women ≥45 yrs randomization to the 4 g/day • annually visit Statin Randomization • Established CVD first occurrence of (n=4089) stabilization with (~70% of patients) or composite of CV death, continuation of • Medication DM + ≥1 risk factor nonfatal MI, nonfatal stable statin washout • stroke, coronary TG ≥150 mg/dL and therapy • 4 months, End-of-study Lipid Placebo <500 mg/dL* revascularization, (N=8179) 12 months, follow-up qualification unstable angina • (n=4090) LDL-C >40 mg/dL and annually visit requiring hospitalization ≤100 mg/dL Screening Period Double-Blind Treatment/Follow-up Period Randomization End of Study Year 0 Up to 6.2 years † Months -1 Month 0 4 12 Every 12 months 2 3 Visit 1 4 5 6 7 8 9 Final Visit Lab values Screening Baseline * Due to the variability of triglycerides, a 10% allowance existed in the initial protocol, which permitted patients to be enrolled with qualifying triglycerides ≥135 mg/dL. Protocol amendment 1 (May 2013) changed the lower limit of acceptable triglycerides from 150 mg/dL to 200 mg/dL, with no variability allowance. Median trial follow-up duration was 4.9 years (minimum 0.0, maximum 6.2 years). † Adapted with permission ǂ from Bhatt DL, Steg PG, Brinton EA, et al; on behalf of the REDUCE-IT Investigators. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial. Clin Cardiol . 2017;40:138-148. REDUCE-IT ClinicalTrials.gov number, NCT01492361. [ ǂ https://creativecommons.org/licenses/by-nc/4.0/]
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