Icosapent ethyl for CV risk reduction: who and when?
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This program was developed by the Canadian Collaborative Research Network and is supported by an unrestricted educational grant received from HLS Therapeutics Inc.
Discussants Milan Gupta, MD, FRCPC, FCCS, FACC, FAHA Shaun Goodman, MD, MSc, FRCPC, FACC, FAHA, FESC Associate Clinical Professor Associate Head, Cardiology, St. Michael's Hospital McMaster University Professor and Heart & Stroke Foundation of Ontario (Polo) Chair, Medical Director, Canadian Collaborative Research Department of Medicine, University of Toronto Network Consultant, Canadian Heart Research Centre Brampton, ON Adjunct Professor, Department of Medicine, Co-Director, Canadian VIGOUR Centre, University of Alberta Toronto, ON
Icosapent ethyl for CV risk reduction: who and when? Elevated triglycerides: risk marker or risk factor? - coming soon
Discussion topics 1. Do serum triglycerides predict risk? 2. Do fish oils reduce risk? 3. What are the key results from REDUCE-IT? 4. In which patients should we consider icosapent ethyl?
Discussion topics 1. Do serum triglycerides predict risk? 2. Do fish oils reduce risk? 3. What are the key results from REDUCE-IT? 4. In which patients should we consider icosapent ethyl?
Residual Risk beyond LDL-C: FOURIER and ODYSSEY OUTCOMES 16 CHD death, non-fatal MI, ischemic stroke, 14 or UA requiring hospitalization (%) CV Death, MI, Stroke, Hosp 12 for UA, or Cor Revasc (%) Placebo 10 8 Evolocumab 6 Hazard ratio 0.85 Hazard Ratio 0.85 (95% CI 0.79, 0.92) 4 (95% CI 0.78, 0.93) P<0.0001 P=0.0003 2 0 0 6 12 18 24 30 36 Months from Randomization Sabatine MS et al. N Engl J Med. 2017;376:1713-1722 Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).
Risk predictors beyond LDL-C LDL-C-related Statins risk reduction Many factors beyond LDL-C play a role in the pathogenesis of CV disease, thus contributing to CV risk • Triglycerides • Thrombosis Persistent • Oxidation • Endothelial dysfunction risk • Diabetes mellitus • Inflammation • Hypertension • Membrane instability/cholesterol crystals • Lp(a) • Plaque instability Ference BA et al. JAMA . 2019;321(4):364-373; Ganda OP et al. J Am Coll Cardiol . 2018;72:330-343; Libby P. Eur Heart J . 2015;36:774-776.
Association between TG and CV risk Emerging Risk Factors Collaboration Ischemic Heart Disease Ischemic Stroke N=302,430 (events = 12,785) N=173,312 (events = 2534) Nordestgaard BG, Varbo A. Lancet . 2014;384:626-635.
Canadian data CANHEART ASCVD: Cohort study of 196,717 patients with established ASCVD (secondary prevention) in Ontario investigating real-world associations between TG and risk of CV events over a median follow-up of 2.9 years Increasing concentration of TG was Adjusted HR (95% CI) Primary associated with increased risk of CV events Composite CV Outcome ˂1. 1.0- 1.5- 2.0- 2.5- 3.0- 3.5- ≥ 4.0 0 1.5 2.0 2.5 3.0 3.5 4.0 TG Category (mmol/L) Lawler PR et al. Eur Heart J . 2020;41:86-94.
Discussion topics 1. Do serum triglycerides predict risk? 2. Do fish oils reduce risk? 3. What are the key results from REDUCE-IT? 4. In which patients should we consider icosapent ethyl?
Fish oils: terminology Commercial Consist of mixtures of omega-3 and/or omega-6 fish oils fatty acids in variable concentrations and purity Comprises the active ingredients DHA and EPA Omega-3 Eicosopentaneoic acid EPA Icosapent ethyl: A new chemical entity, which IPE is a unique form of EPA used in the REDUCE-IT trial Ganda OP et al. J Am Coll Cardiol . 2018;72:330-343.
How icosapent ethyl and EPA differ from DHA PubChem Database: DHA, CID=445580; EPA, CID=446284; IPE, CID=9831415.
TG-lowering outcome trials Achieved primary Possible reasons for Key trials MACE endpoint? lack of benefit Fibrates • ACCORD Trials did not prospectively enroll patients • FIELD with elevated TG levels despite statin therapy Niacin • AIM-HIGH (although subgroup analyses suggested possible • HPS2-THRIVE CV benefits to TG lowering in patients with dyslipidemia) Rx & supplement, • ASCEND Trials evaluated people with mixtures of omega-3 • OMEGA TG <2.26 mmol/L fatty acids (EPA + DHA) a • ORIGIN (non-hypertriglyceridemic) as common fish oil • RISK & treated with low omega-3 fatty acid doses (including carboxylic PREVENTION acids) and krill oil • VITAL Unknown • STRENGTH Large placebo effect • TRILOGY1 Acasti Pharma Inc Press Release January 13, 2020: https://ca.proactiveinvestors.com/companies/news/910460/acasti-pharma-says-further-analysis-underway-after- trilogy-1-topline-results-show-unexpected-placebo-effect-910460.html. AstraZeneca Press release January 13, 2020: https://www.astrazeneca.com/media-centre/press- releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html. Anderson TJ et al. Can J Cardiol . 2016; 32:1263-1282. ASCEND Study Collaborative Group. N Engl J Med . 2018;379:1540-1550. Bhatt DL et al. Clin Cardiol . 2017;40:138-148. Ganda Om Pet al. J Am Coll Cardiol . 2018;72:330-343. Manson JE et al. N Engl J Med . 2019;380:23-32.
Meta-analysis of fish oil outcome trials 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) P =.12 Stroke 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) Unclassified/other 142 (0.4) 135 (0.3) 1.05 (0.77–1.43) Any 870 (2.2) 843 (2.2) 1.03 (0.93–1.13) P =.60 Revascularization Coronary 3044 (9.3) 3040 (9.3) 1.00 (0.93–1.07) 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 ǂ 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. [ ǂ https://creativecommons.org/licenses.org/by-nc/4.0/]
Discussion topics 1. Do serum triglycerides predict risk? 2. Do fish oils reduce risk? 3. What are the key results from REDUCE-IT? 4. In which patients should we consider icosapent ethyl?
REDUCE-IT inclusion criteria Prevention cohorts ≥45 years with: • Established CVD • Fasting TG level Secondary ≥1.52 mmol/L and ˂5.63 mmol/L a (documented CAD, CVD, or PAD) • LDL-C >1.06 mmol/L and ≤ 2.59 mmol/L ≥50 years with: and on stable statin therapy • Diabetes ( ± ezetimibe) for ≥4 weeks prior to Primary • ≥1 additional risk factor for qualifying measurements for randomization CVD a Due to the variability of TGs, a 10% allowance existed in the initial protocol, which permitted patients to be enrolled with qualifying TGs ≥ 1.52 mmol/L. In May 2013, the protocol was amended whereby the acceptable TG range was 1.69 mmol/L to 2.25 mmol/L, with no variability allowance. Bhatt DL et al. N Engl J Med . 2019;380:11-22.
Key baseline characteristics IPE (n=4089) Placebo (n=4090) Age (years), median (Q1-Q3) 64.0 (57.0-69.0) 64.0 (57.0-69.0) Female, % 28.4 29.2 Non-white, % 9.7 9.8 Westernized region, % 71.1 71.0 CV risk category, % Secondary prevention cohort 70.7 70.7 Primary prevention cohort 29.3 29.3 Ezetimibe use, % 6.4 6.4 Statin intensity, % Low 6.2 6.5 Moderate 61.9 63.0 High 31.5 30.0 Type 2 diabetes, % 57.9 57.8 Adapted from Bhatt DL et al. N Engl J Med . 2019;380:11-22.
Key baseline characteristics (2) IPE (n=4089) Placebo (n=4090) TGs (mmol/L), median (Q1-Q3) 2.44 (1.99-3.07) 2.44 (1.98-3.09) HDL-C (mmol/L), median (Q1-Q3) 1.03 (0.89-1.19) 1.03 (0.91-1.19) LDL-C (mmol/L), median (Q1-Q3) 1.91 (1.59-2.28) 1.97 (1.63-2.30) TG category, % <1.69 mmol/L 10.1 10.5 1.69 to <2.26 mmol/L 29.2 29.1 >2.26 mmol/L 60.7 60.4 Adapted from Bhatt DL et al. N Engl J Med . 2019;380:11-22.
Primary and key secondary endpoints Primary Composite Endpoint: Key Secondary Composite Endpoint: CV Death, MI, Stroke, Coronary Revasc, Unstable Angina CV Death, MI, Stroke 28.3% 30 30 Hazard Ratio, 0.75 Hazard Ratio, 0.74 (95% CI, 0.68–0.83) (95% CI, 0.65–0.83) Patients with an Event (%) Patients with an Event (%) 20.0% 20 23.0% 20 Icosapent Ethyl 16.2% 10 10 Icosapent Ethyl 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years since Randomization Years since Randomization ARR = 3.6% ARR = 4.8% NNT = 28 (95% CI, 20–47) NNT = 21 (95% CI, 15–33) P=0.0000006 P=0.00000001 Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22. Bhatt DL.AHA 2018, Chicago.
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