BEST PRACTICES FORUM: The Role of Icosapent Ethyl for CV Risk - PowerPoint PPT Presentation

BEST PRACTICES FORUM: The Role of Icosapent Ethyl for CV Risk Reduction

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CCRN Podcasts ICOSAPENT ETHYL FOR CV RISK REDUCTION: WHO AND WHEN? Milan Gupta, MD, FRCPC, FCCS, FACC, FAHA Shaun Goodman, MD, MSc, FRCPC, FACC, FAHA, FESC ELEVATED TRIGLYCERIDES: RISK MARKER OR RISK FACTOR? Alan D. Bell, MD, CCFP, FCFP Robert Hegele, MD, FRCPC, FACP, FAHA, FCAHS, FCCS

Faculty Milan Gupta, MD, FRCPC, FCCS David C. W. Lau, MD, PhD, FRCPC Rick Ward, MD, CCFP, FCFP Program Chair Professor of Medicine, Clinical Associate Professor, Associate Clinical Professor of Medicine, Biochemistry & Molecular Biology University of Calgary McMaster University Julia McFarlane Diabetes Research Centre and Medical Director, Primary Care, Medical Director, Libin Cardiovascular Institute of Alberta Alberta Health Services Canadian Collaborative Research Network University of Calgary Cumming School of Medicine Calgary, AB Brampton, ON Calgary, AB

Faculty Disclosures Dr. Milan Gupta Dr. David Lau Dr. Rick Ward Consultant: Grant/Research Support Advisory Board Amgen, HLS, Sanofi AstraZeneca, Novo Nordisk - Amgen, Shire, Janssen • • Consultant • Abbott, Amgen, AstraZeneca, Grant/Research Support Bausch Health, Boehringer- - AstraZeneca, Boehringer-Ingelheim, Ingelheim, CME at Sea, Gilead, BMS, Janssen, Lilly, Lundback, Merck, HLS Therapeutics, Janssen, Eli Purdue, Pfizer, Shire, Servier, Takeda Lilly, Novo Nordisk, Sanofi Speaker’s Bureau • Abbott, Amgen, AstraZeneca, Bausch Health, Boehringer- Ingelheim, CME at Sea, Gilead, HLS Therapeutics, Janssen, Eli Lilly, Merck, Novo Nordisk

Polling Question In a patient with ASCVD or diabetes with LDL-c at target, at what triglyceride level do you consider add-on therapy? 1. >1.5 – 2.0 mmol/L 2. >2.0 – 3.0 mmol/L 3. >3.0 – 4.5 mmol/L 4. > 4.5 mmol/L 5. Rarely ever add therapy for triglycerides

Polling Question OTC (over-the-counter) fish oil supplements reduce CV risk in which patient populations? 1. ASCVD with elevated TG levels 2. Diabetes with elevated TG levels 3. ASCVD with normal TG levels 4. All of the above 5. None of the above

Learning Objectives • To review the role of serum triglycerides as a risk marker vs. a risk factor • To differentiate icosapent ethyl from standard fish oils • To best apply the findings from the REDUCE-IT study to clinical practice

Residual Risk beyond LDL-C: FOURIER and ODYSSEY OUTCOMES 16 FOURIER ODYSSEY Outcomes 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).

Cardiovascular Risk Goes 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.

Agenda • Are serum triglycerides a risk factor?

Observational Association Between Elevated TGs, CV Risk, and Mortality Copenhagen City Heart Study and Copenhagen General Population Study Myocardial Ischemic All-Cause Ischemic Infarction Heart Disease Mortality Stroke N=93,410 N=98,515 N=97,442 5 (events = 7183) (events = 14,547) (events = 2994) Hazard Ratio (95% CI) 4 3 2 N=96,394 (events = 3287) 1 0 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Non-Fasting Triglycerides (mmol/L) Nordestgaard BG, Varbo A. Lancet . 2014;384:626-635.

Observational Association Between Elevated TGs and Cardiovascular Risk Emerging Risk Factors Collaboration Ischemic Heart Disease Ischemic Stroke N=302,430 (events = 12,785) N=173,312 (events = 2534) 16 Nordestgaard BG, Varbo A. Lancet . 2014;384:626-635.

Elevated TGs Contribute to Persistent Risk After Statin Treatment: Results From PROVE IT-TIMI 22 Elevated TGs Predict Persistent Risk Despite Achieving LDL-C <1.80 mmol/L With a High-Dose Statin 25 20.3 Higher TG levels are 2-Year Risk of Death, MI, or Recurrent ACS 20 HR associated with a 41% 0.64 (0.53, increase in risks of coronary 0.78), 15 13.5 events P = .001 P = .001 10 5 n = 603 n = 2796 0 ≥2.26 <2.26 On-Treatment TG (mmol/L) Miller M et al . J Am Coll Cardiol . 2008;51:724-30.

CANHEART ASCVD Study: Real-World Patient Data from Ontario 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 ˂1.0 1.0 - 1.5 - 2.0 - 2.5 - 3.0 - 3.5 - ≥4.0 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.

Prior TG Lowering Therapies: Failure of CV Benefit 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 CV • HPS2-THRIVE benefits to TG lowering in patients with dyslipidemia) a Canadian Cardiovascular Society: Omega-3 fatty acid supplements are not recommended for the reduction of CV events. 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.

Agenda • Are serum triglycerides a risk factor? • Do fish oils reduce CV risk?

Prior TG Lowering Therapies: Failure of CV Benefit 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 CV HPS2-THRIVE • 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 & PREVENTION treated with low omega-3 fatty acid doses (including carboxylic • VITAL acids) and krill oil • STRENGTH Unknown TRILOGY1 Large placebo effect • a Canadian Cardiovascular Society: Omega-3 fatty acid supplements are not recommended for the reduction of CV events. DHA=docosahexaenoic acid; EPA=eicosapentaenoic acid. 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.