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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ELEVATED TRIGLYCERIDES: RISK MARKER OR RISK FACTOR?

ICOSAPENT ETHYL FOR CV RISK REDUCTION: WHO AND WHEN?

Alan D. Bell, MD, CCFP, FCFP Robert Hegele, MD, FRCPC, FACP, FAHA, FCAHS, FCCS Milan Gupta, MD, FRCPC, FCCS, FACC, FAHA Shaun Goodman, MD, MSc, FRCPC, FACC, FAHA, FESC

Faculty

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

Faculty Disclosures

• Dr. Milan Gupta

Consultant:

• Amgen, HLS, Sanofi
• Dr. David Lau

Grant/Research Support

• AstraZeneca, Novo Nordisk

Consultant

• Abbott, Amgen, AstraZeneca,

Bausch Health, Boehringer- Ingelheim, CME at Sea, Gilead, HLS Therapeutics, Janssen, Eli 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

• Dr. Rick Ward

Advisory Board

• Amgen, Shire, Janssen

Grant/Research Support

• AstraZeneca, Boehringer-Ingelheim,

BMS, Janssen, Lilly, Lundback, Merck, Purdue, Pfizer, Shire, Servier, Takeda

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

Polling Question

• 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

Learning Objectives

Residual Risk beyond LDL-C: FOURIER and ODYSSEY OUTCOMES

CHD death, non-fatal MI, ischemic stroke,

• r UA requiring hospitalization (%)

Hazard Ratio 0.85 (95% CI 0.78, 0.93) P=0.0003

Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).

4 6 8 10 12 14 16 Evolocumab Placebo CV Death, MI, Stroke, Hosp for UA, or Cor Revasc (%) 2 6 12 18 24 30 36 Months from Randomization Hazard ratio 0.85 (95% CI 0.79, 0.92) P<0.0001

Sabatine MS et al. N Engl J Med. 2017;376:1713-1722

FOURIER ODYSSEY Outcomes

LDL-C-related risk reduction Statins

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.

Persistent risk

Cardiovascular Risk Goes Beyond LDL-C

Many factors beyond LDL-C play a role in the pathogenesis of CV disease, thus contributing to CV risk

• Triglycerides
• Oxidation
• Diabetes mellitus
• Hypertension
• Lp(a)
• Thrombosis
• Endothelial dysfunction
• Inflammation
• Membrane instability/cholesterol crystals
• Plaque instability

• Are serum triglycerides a risk factor?

Agenda

Non-Fasting Triglycerides (mmol/L) 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

5 4 3 2 1 Hazard Ratio (95% CI)

Myocardial Infarction Ischemic Heart Disease All-Cause Mortality Ischemic Stroke

N=98,515 (events = 14,547) N=97,442 (events = 2994)

Copenhagen City Heart Study and Copenhagen General Population Study

Observational Association Between Elevated TGs, CV Risk, and Mortality

Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635.

N=93,410 (events = 7183) N=96,394 (events = 3287)

Emerging Risk Factors Collaboration Ischemic Heart Disease N=302,430 (events = 12,785) Ischemic Stroke N=173,312 (events = 2534)

Observational Association Between Elevated TGs and Cardiovascular Risk

16

Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635.

20.3 13.5 5 10 15 20 25 ≥2.26 <2.26 2-Year Risk of Death, MI, or Recurrent ACS On-Treatment TG (mmol/L) n = 603 n = 2796

HR 0.64 (0.53, 0.78), P = .001

Miller M et al. J Am Coll Cardiol. 2008;51:724-30.

Elevated TGs Predict Persistent Risk Despite Achieving LDL-C <1.80 mmol/L With a High-Dose Statin

Higher TG levels are associated with a 41% increase in risks of coronary events P = .001

Elevated TGs Contribute to Persistent Risk After Statin Treatment: Results From PROVE IT-TIMI 22

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

Lawler PR et al. Eur Heart J. 2020;41:86-94.

TG Category (mmol/L) Increasing concentration of TG was associated with increased risk of CV events ˂1.0 1.0- 1.5 1.5- 2.0 2.0- 2.5 2.5- 3.0 3.0- 3.5 3.5- 4.0 ≥4.0 Adjusted HR (95% CI) Primary Composite CV Outcome

CANHEART ASCVD Study: Real-World Patient Data from Ontario

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.

Key trials Achieved primary MACE endpoint? Possible reasons for lack of benefit Fibrates

• ACCORD
• FIELD

Trials did not prospectively enroll patients with elevated TG levels despite statin therapy

(although subgroup analyses suggested possible CV benefits to TG lowering in patients with dyslipidemia)

Niacin

• AIM-HIGH
• HPS2-THRIVE

Prior TG Lowering Therapies: Failure of CV Benefit

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

Agenda

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.

Key trials Achieved primary MACE endpoint? Possible reasons for lack of benefit Fibrates

• ACCORD
• FIELD

Trials did not prospectively enroll patients with elevated TG levels despite statin therapy

(although subgroup analyses suggested possible CV benefits to TG lowering in patients with dyslipidemia)

Niacin

• AIM-HIGH
• HPS2-THRIVE

Rx & supplement, mixtures of omega-3 fatty acids (EPA + DHA)a as common fish oil (including carboxylic acids) and krill oil

• ASCEND
• OMEGA
• ORIGIN
• RISK & PREVENTION
• VITAL
• STRENGTH
• TRILOGY1

Trials evaluated people with TG <2.26 mmol/L (non-hypertriglyceridemic) treated with low omega-3 fatty acid doses Unknown Large placebo effect

Prior TG Lowering Therapies: Failure of CV Benefit

Number of events (%) Rate ratio (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 3040 (9.3) 3044 (9.3) 1.00 (0.93–1.07) Non-coronary 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 = 0.60 Any major vascular event 5930 (15.2) 6071 (15.6) 0.97 (0.93–1.01) P = .60 0.5 1 2

Favors Treatment Favors Control

Meta-analysis: Omega-3 Fatty Acids (EPA Plus DHA)

Aung T et al. JAMA Cardiol. 2018;3:225-234.

23

FDA guidance regarding fish oil supplements for ASCVD risk

2-9

Dietary Supplement Fish Oil:

FDA Product Classification1 Food Clinical Trials/FDA Not Required Pre-Approval1 Content & Purity

Often difficult to achieve high doses likely needed for efficacy Often have high saturated fat content Omega-3 content often overstated Tend to contain relatively high amounts of

• xidized lipids which may increase CV risk

Can contain PCBs and dioxins at harmful levels

Ability to reduce ASCVD Not demonstrated

• 1. US Food and Drug Administration. www.fda.gov/Food/DietarySupplements/default.htm. Updated April 4, 2016. Accessed Nov. 4, 2018. 2. Hilleman D and Smer A. Manag Care.

2016;25:46-52. 3. Mason RP and Sherratt SCR. Biochem Biophys Res Commun. 2017;483:425-9. 4. Albert BB et al. Sci Rep. 2015;5:7928. 5. Kleiner AC et al. J Sci Food Agric. 2015;95:1260-7. 6. Ritter JC et al. J Sci Food Agric. 2013:93:1935-9. 7. Jackowski SA et al. J Nutr Sci. 2015;4:e30. 8. Rundblad A et al. Br J Nutr. 2017;117:1291-8. 9. European Medicines Agency, 2018: 712678.

• Are serum triglycerides a risk factor?
• Do fish oils reduce CV risk?
• How does icosapent ethyl differ from fish oils?

Agenda

Background: Omega-3 Dietary Supplements

• Fish oil is among the most commonly used dietary supplement among US adults

– Global market is expected to reach $3.3 billion by 2020

• Based on the 2012 National Health Interview Survey, ~7.8% of adults (19 million)

had taken a fish oil supplement in the previous 30 days

• Although numerous dietary supplements containing omega-3s are widely available,

their integrity and efficacy remain unverified

• 1. Barnes PM et al. National Health Statistics Reports. 2008;12:1-24.
• 2. http://globenewswire.com/news-release/2014/10/28/677161/10104781/en/Global-Fish-Oil-Market-By-Application-

Aquaculture-Direct-Human-Consumption-Is-Expected-to-Reach-USD-3-300-0-Million-by-2020-New-Report-By- Grand-View-Research-Inc.html?parent=676724#sthash.GIGle3SR.dpuf

• 3. NIH NCCIH. Available at: https://nccih.nih.gov/health/omega3/introduction.htm
• 4. Mason RP et al. Poster presented at the AMCP 2015 Nexus. Orlando, FL.

Commercial fish oils Consist of mixtures of omega-3 and/or omega-6 fatty acids in variable concentrations and purity Omega-3 Comprises the active ingredients DHA and EPA

Ganda OP et al. J Am Coll Cardiol. 2018;72:330-343.

Fish oil and its constituents: Clarifying the terminology

Omega-6 vs. Omega-3 Fatty Acids: Pro vs. Anti-Inflammatory

Omega-3 fatty acids

Alpha-linoleic acid (LNA) Stearidonic acid Eicosatetraenoic acid

EPA

DHA PGE3

(anti-inflammatory)

LTB5

(anti-inflammatory)

delta-5-desaturase cyclooxygenase lipoxygenase delta-6-desaturase

Balogun KA, Cheema SK. Pathophysiology and Pharmacotherapy of Cardiovascular Disease. 2015:563-588. doi: 10.1007/978-3-319-15961-4_27.

Omega-6 fatty acids

Linoleic acid Gamma-linoleic acid (GLA) Dihomo-gamma-linoleic acid (DGLA)

delta-5-desaturase

Arachidonic acid

PGE1

(anti-inflammatory) delta-6-desaturase cyclooxygenase lipoxygenase

PGE2

(pro-inflammatory)

LTB4

(pro-inflammatory)

Fatty Acid Content of Leading Fish and Krill Oil Supplements

21% 34% 36% 30% 37% 9% 21% 12%

Leading Fish Oil Supplement Leading Krill Oil Supplement

EPA DHA Saturated Fats Unsaturated Fats

These chromatography findings have been noted by R. Preston Mason, PhD (unpublished data, 2015).

EPA and DHA have different effects on LDL-C

EPA

LOWERING

TG LDL-C

DHA

LOWERING

TG

LDL-C

• Both the amount and

type of omega-3 fatty acid are important for TG lowering

• No head-to-head

studies have been done to compare the effects of prescription

NEUTRAL RAISING

TG-lowering medicine

*Studies were conducted in subjects with varying baseline TG levels.

• 1. Miller M et al. Circulation. 2011;123(20):2292-2333; 2. Jacobson TA et al. J Clin Lipidol. 2012;6(1):5-18;
• 3. Wei MY, Jacobson TA. Curr Atheroscler Rep. 2011;13(6):474-483; 4. VASCEPA [package insert]. Bedminster, NJ: Amarin Pharma, Inc; 2017.

Purification of omega-3 to pure EPA

The Purification Process of IPE Removes DHA, Fatty Acids, and Toxins

˂3% Fatty acids

(saturated fatty acids, pro-inflammatory arachidonic acid)

≥96% EPA-ethyl esters

(DHA below detection limits) Mason RP, Sherratt SCR. Biochem Biophys Res Commun. 2017;483:425-429. Hilleman DE et al. Adv Ther. 2020;37:656-670. Amarin – Data on File.

Icosapent ethyl 36% saturated fat 21% EPA 34%

• ther fats

9% DHA

Manufacturing Purification Processes (Oxygen-Free Environment)

Common fish oil (mixtures of omega-3 fatty acids)

• Are serum triglycerides a risk factor?
• Do fish oils reduce CV risk?
• How does icosapent ethyl differ from fish oils?
• What are the main results of the REDUCE-IT study?

Agenda

Bhatt DL et al. N Engl J Med. 2019;380:11-22.

REDUCE-IT: A Multicenter, Randomized, Double-Blinded, Event-Driven, Placebo-Controlled Trial

Placebo N=4090 Completed study 3630 (88.8%) IPE (4 g/day) N=4089 Completed study 3684 (90.1%) Median follow up: 4.9 years Randomized N=8179 Known vital status 4083 (99.9%) Known vital status 4077 (99.7%)

Prevention cohorts Secondary ≥45 years with:

• Established CVD (documented

CAD, CVD, or PAD)

• Fasting TG level

≥1.52 mmol/L and ˂5.63 mmol/La

• LDL-C

>1.06 mmol/L and ≤2.59 mmol/L and on stable statin therapy (± ezetimibe) for ≥4 weeks prior to qualifying measurements for randomization Primary ≥50 years with:

• Diabetes
• ≥1 additional risk factor for

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. PAD=peripheral artery disease. Bhatt DL et al. N Engl J Med. 2019;380:11-22.

REDUCE-IT Key Inclusion Criteria

• 1. Diabetes mellitus requiring medication AND
• 2. ≥50 years of age AND
• 3. ≥1 additional risk factor for CVD
• Men ≥55 years and women ≥65 years
• Cigarette smoker or stopped smoking within 3 months
• Hypertension (≥140 mmHg systolic OR ≥90 mmHg diastolic) or on antihypertensive

medication

• HDL-C ≤1.03 mmol/L for men or ≤1.29 mmol/L for women
• hs-CRP >3.00 mg/L
• Renal dysfunction: creatinine clearance >30 and <60 mL/min
• Retinopathy
• Micro- or macroalbuminuria
• ABI <0.9 without symptoms of intermittent claudication

Bhatt DL et al. N Engl J Med. 2019;380:11-22.

REDUCE-IT Inclusion Criteria: Primary Prevention Cohort

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.

REDUCE-IT: Key Baseline Characteristics

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.

REDUCE-IT: Key Baseline Characteristics (continued)

28.3% 23.0% 17.2% 22.0%

HR (95% CI): 0.75 (0.68-0.83) ARR: 4.8% NNT = 21 P = .00000001

IPE PBO

REDUCE-IT: Primary Endpoint

Adapted from Bhatt DL et al. N Engl J Med. 2019;380:11-22.

20.0% 16.2% 14.8% 11.2%

HR (95% CI): 0.74 (0.65-0.83) ARR: 3.6% NNT=28 P = .0000006

IPE PBO

REDUCE-IT: Key Secondary Endpoint

Adapted from Bhatt DL et al. N Engl J Med. 2019;380:11-22.

REDUCE-IT: Individual Elements of Primary Endpoint

REDUCE-IT appendix. Bhatt, DL. NEJM epub Nov 10, 2018

HR Endpoint/subgroup (95% CI) IPE n/N (%) Placebo n/N (%) HR (95% CI) P Risk category Secondary prevention cohort Primary prevention cohort .41 361/2892 (12.5) 98/1197 (8.2) 0.72 (0.63-0.82) 0.81 (0.62-1.06) 489/2893 (16.9) 117/1197 (9.8)

REDUCE-IT: Key Secondary Endpoint in Subgroups

Adapted from Bhatt DL et al. N Engl J Med. 2019;380:11-22.

Treatment-Emergent AESI, Serious Bleeding IPE, % (N=4089) Placebo, % (N=4090) P Bleeding related disorders 2.7 2.1 .06 Gastrointestinal bleeding 1.5 1.1 .15 Central nervous system bleeding 0.3 0.2 .42 Other bleeding 1.0 0.7 .19

• No fatal bleeding events in either group
• Adjudicated hemorrhagic stroke – no significant difference between treatments

(13 IPE vs. 10 placebo; P = .55)

REDUCE-IT: Adverse Events (continued)

Adapted from Bhatt DL et al. N Engl J Med. 2019;380:11-22.

Most frequent treatment-emergent AEs ≥5% in either treatment group IPE, % (N=4089) Placebo, % (N=4090) P Diarrhea 9.0 11.1 .002 Peripheral edema 6.5 5.0 .002 Constipation 5.4 3.6 < .001 Atrial fibrillation 5.3 3.9 .003 Anemia 4.7 5.8 .03 Adjudicated events: hospitalization for atrial fibrillation or atrial flutter IPE, % (N=4089) Placebo, % (N=4090) P Positively adjudicated atrial fibrillation/fluttera 3.1 2.1 .004

REDUCE-IT: Adverse Events (continued)

Adapted from Bhatt DL et al. N Engl J Med. 2019;380:11-22.

First and total events analysis

Cumulative Events per Patient 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Placebo: Total Events Icosapent Ethyl: Total Events Placebo: First Events Icosapent Ethyl: First Events

RR, 0.70

(95% CI, 0.62–0.78)

P< 0.0001

HR, 0.75 (95% CI, 0.68–0.83) P< 0.0001

1 2 3 4 Years Since Randomization

Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019;73:2791-2802.

5

1 2 3 4 5 30 20 10 Patients with an Event (%)

Hazard Ratio, 0.66

(95% CI, 0.58–0.76)

ARR = 4.1% NNT = 24 P=0.0000000008

Years since Randomization

Icosapent Ethyl Placebo

11.4% 16.7%

Peterson BE, Bhatt DL, Steg PG, et al. SCAI 2020, Atlanta (virtual).

Time to Coronary Revascularization

Icosapent Ethyl Placebo HR (95% CI): 0.68 (0.57–0.82) P-value: 0.00003 ARR: 2.1%

Time to Elective Coronary Revascularization

Patients with an Event (%) 4 8 10 2 6 Years since Randomization 2 3 4 5 1 9.0% 5.7%

Time to Emergent Coronary Revascularization

Icosapent Ethyl Placebo HR (95% CI): 0.62 (0.42–0.92) P-value: 0.02 ARR: 0.6% Years since Randomization 2 3 4 5 1 2.0% 1.4% 4 8 10 2 6 Icosapent Ethyl Placebo HR (95% CI): 0.66 (0.54–0.79) P-value: 0.00001 ARR: 2.1%

Time to Urgent Coronary Revascularization

Years since Randomization 2 3 4 5 1 8.2% 5.9% 4 8 10 2 6

Time to Elective, Emergent, and Urgent Revascularization

Peterson BE, Bhatt DL, Steg PG, et al. SCAI 2020, Atlanta (virtual).

• Are serum triglycerides a risk factor?
• Do fish oils reduce CV risk?
• How does icosapent ethyl differ from fish oils?
• What are the main results of the REDUCE-IT study?
• What is the mechanism of benefit?

Agenda

Adapted from Bhatt DL et al. N Engl J Med. 2019;380:11-22.

HR Endpoint/subgroup (95% CI) IPE n/N (%) Placebo n/N (%) HR (95% CI) P Baseline TGs ≥1.69 vs. <1.69 mmol/L TGs ≥1.69 mmol/L TGs <1.69 mmol/L .68 421/3674 (11.5) 38/412 (9.2) 0.74 (0.65-0.84) 0.66 (0.44-0.99) 546/3660 (14.9) 60/429 (14.0)

REDUCE-IT: Key Secondary Endpoint in Subgroups

Patients with an Event (%) Patients with an Event (%)

Outcomes were independent of achieved TG levels

A Primary End Point by Achieved Triglyceride Level at 1 Year

Hazard Ratio (95% CI):

B Key Secondary End Point by Achieved Triglyceride Level at 1 Year

Hazard Ratio (95% CI): 100 90 80 70 60 50 40 30 20 10 Icosapent Ethyl Triglyceride <150 vs ≥150 mg/dL Icosapent Ethyl Triglyceride ≥150 mg/dL vs Placebo Icosapent Ethyl Triglyceride <150 mg/dL vs Placebo Placebo Icosapent Ethyl Triglyceride ≥150 mg/dL Icosapent Ethyl Triglyceride <150 mg/dL 1 2 3 4 5 Years since Randomization 0.99 (0.84–1.16) 0.71 (0.63–0.79) 0.70 (0.60–0.81) 100 90 80 70 60 50 40 30 20 10 Icosapent Ethyl Triglyceride <150 vs ≥150 mg/dL Icosapent Ethyl Triglyceride ≥150 mg/dL vs Placebo Icosapent Ethyl Triglyceride <150 mg/dL vs Placebo Placebo Icosapent Ethyl Triglyceride ≥150 mg/dL Icosapent Ethyl Triglyceride <150 mg/dL 1 2 3 4 5 Years since Randomization 1.00 (0.82–1.23) 0.67 (0.56–0.80) 0.66 (0.57–0.77)

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22.

On-treatment EPA level, and not TG level, explains the majority of observed benefit in REDUCE-IT

Patients with an Event (%) Hazard Ratio (95% CI): Icosapent Ethyl EPA ≤116.9 µg/mL vs Placebo Icosapent Ethyl EPA >116.9 to ≤190.6 µg/mL vs Placebo Icosapent Ethyl EPA >190.6 µg/mL vs Placebo 0.85 (073–0.99) 0.74 (0.63–0.86) 0.63 (0.54–0.74) 0.3 0.2 0.1 0.0 Placebo Icosapent Ethyl EPA ≤116.9 µg/mL Icosapent Ethyl EPA >116.9 to ≤190.6 µg/mL Icosapent Ethyl EPA >190.6 µg/mL 1 2 3 4 5 Years Since Randomization Bhatt DL. ACC/WCC 2020, Chicago (virtual).

• No. of

Primary Endpoint1-5 Key Secondary Endpoint1-5 Cardiovascular Death1,2,4-6 TotalMortality1,2,4-6 P*<0.001 for all

Note: Area under the curve (AUC)-derived daily average serum EPA (µg/mL) is the daily average of all available post baseline EPA measurements prior to the event. Dose-response hazard ratio (solid line) and 95% CI (dotted lines) are estimated from the Cox proportional hazard model with a spline term for EPA and adjustment for randomization factors and statin compliance1, age2, sex3, baseline diabetes4, hsCRP5, treatment compliance6. *P value is <0.001 for both non-linear trend and for regressionslope.

Bhatt DL. ACC/WCC 2020, Chicago (virtual).

On-treatment EPA level, and not TG level, explains the majority of observed benefit in REDUCE-IT

Potential effects of icosapent ethyl

• Are serum triglycerides a risk factor?
• Do fish oils reduce CV risk?
• How does icosapent ethyl differ from fish oils?
• What are the main results of the REDUCE-IT study?
• What is the mechanism of benefit?
• How should we use icosapent ethyl in our practices?

Agenda

Adapted from Vascepa (icosapent ethyl) Product Monograph. HLS Therapeutics. December 30, 2019.

IPE Is Now Available in Canada: Indications

Clinical recommendations following REDUCE-IT

1

• ADA Standards of Care : (Persons with diabetes) ASCVD or other cardiac risk

factors on statin with controlled LDL-C, elevated triglycerides (1.53-5.64 mmol/L)

• AHA Science Advisory : for “improving cardiovascular disease risk in

patients with hypertriglyceridemia”

• ESC/EAS Guidelines : “high-risk” patients with TGs 1.53-5.64 mmol/L despite

statin treatment

• High risk=prior ASCVD, diabetes with target organ damage, diabetes

with prolonged duration, CKD, high 10-year risk, FH, CKD

• NLA Scientific Statement : ASCVD ≥45 years or Type 2 diabetes ≥50 years requiring

medication + 1 risk factor + TGs 1.53-5.64 mmol/L on high intensity or max tolerated statin

• Therapy cost-effective (ICER)
• 1. American Diabetes Association. Diabetes Care 2019;42(Suppl. 1):S103–S123. Retrieved from https://hyp.is/JHhz_lCrEembFJ9LIVBZIw;
• 2. Skulas-Ray AC, Wilson PWF, Harris WS, et al; Circulation. 2019;140:e•••–e•••. doi: 10.1161/CIR.0000000000000709; 3. Mach F, et al.

2019 European Heart Journal (2019) 00, 1-78. doi:10.1093/eurheartj/ehz455; 4.Orringer CE et. al. Journal of Clinical Lipidology (2019), doi: https://doi.org/10.1016/j.jacl.2019.10.014; https://icer-review.org/wp- content/uploads/2019/02/ICER_CVD_Evidence_Report_09122019.pdf

In a patient with ASCVD on high intensity statin/ezetimibe with LDL-c 2.3 and TG 2.3, which therapy would you consider adding next (beyond lifestyle advice)?

• 1. PCKS9 inhibitor
• 2. Icosapent ethyl
• 3. Both simultaneously
• 4. Neither

Polling Question

• CV risk persists despite controlling LDL-C.
• Elevated TGs are associated with increased CV risk, but to date, trials have not shown CV benefit

attributable to TG lowering.

• Elevated TGs therefore may represent a risk marker rather than a risk factor.
• Fish oil (mixtures of omega-3 fatty acids) and Krill oil have not demonstrated CV benefit in clinical

trials and are not indicated for management of CV risk.

• Icosapent ethyl represents a highly purified form of EPA, with no detectable DHA.
• Icosapent ethyl, based on REDUCE-IT, demonstrates CV risk reduction in statin-treated patients with

elevated TGs:

• Established CV disease, or
• Diabetes, and at least one other CV risk factor

Summary

Discussion

Housekeeping

• A link to the evaluation form will be emailed to you following the

completion of the program.

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credits for your participation in this session.

• Slides from this presentation will be emailed to you and will also be

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• This session has been recorded and will be made available on

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CCRN Podcasts

ELEVATED TRIGLYCERIDES: RISK MARKER OR RISK FACTOR?

ICOSAPENT ETHYL FOR CV RISK REDUCTION: WHO AND WHEN?

Alan D. Bell, MD, CCFP, FCFP Robert Hegele, MD, FRCPC, FACP, FAHA, FCAHS, FCCS Milan Gupta, MD, FRCPC, FCCS, FACC, FAHA Shaun Goodman, MD, MSc, FRCPC, FACC, FAHA, FESC

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The Role of Icosapent Ethyl for CV Risk Reduction