are all omega-3 agents similarfor ascvd prevention? · 2019-11-18 · •estimated global market...

Eliot A. Brinton, MD, FAHA, FNLA, FACEPast-President, American Board of Clinical Lipidology

President, Utah Lipid CenterSalt Lake City, UT, USAeliot.brinton@utah.edu

11th Annual Orange County Symposium on Cardiovascular Disease Prevention

9 November 2019Orange, CA

Are All Omega-3 Agents

Similar for ASCVD Prevention?

Disclosures: Duality of Interest

Dr. Brinton has received:

• Research support from Amarin and Kowa

• Honoraria as consultant/advisor: Akcea, Amarin, Amgen, AstraZeneca, Esperion, Kowa, Regeneron and Sanofi-Aventis

• Honoraria as speaker: Amarin, Amgen, Kowa, Regeneron and Sanofi-Aventis

Omega-3 Talk Outline

• Dietary Supplement omega-3

• Omega-3 Acid Ethyl Esters (O3AEE, Lovaza)

• Icosapent Ethyl (pure EPA, Epadel & Vascepa) – JELIS

– REDUCE-IT

• Omega-3 Carboxylic Acid (O3CA, Epanova)– STRENGTH

• Summary and Conclusions

Purification of Omega-3: Dietary Supplements

Background: Omega-3 Dietary Supplements

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

adults1

– Global market is expected to reach $3.3 billion by 20202

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

million) had taken a fish oil supplement in the previous 30 days3

• Although numerous dietary supplements containing

Omega-3s are widely available, their integrity and efficacy remain unverified4

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.

Fish Oil Dietary Supplements Are Widely Used

• Not over-the-counter but unregulated dietary supplements

• Estimated global market for omega-3 products was $31 billion in 2015

• In a large UK prospective study, 31% of adults reported taking fish oils

• Estimates suggest 7.8% of US population (19 million people) take fish

oil supplements

• Benefits claimed on the heart, brain, weight, vision, inflammation, skin,

pregnancy and early life, liver fat, depression, childhood behavior,

mental decline, allergies, bones…

• Most common dietary supplements report 15-80% of their

contents as omega-3s– Most common is ~30%

• Assumption: each 1 gram capsule contains 300 mg of

EPA/DHA – In order to reach 4 g/day of ω-3s, a patient would need 3 to 7 times as

many capsulesHigh-potency

Rx ω-3 FA (4)1.0 g fill EPA + DHA

Dietary Supplement (13)

0.5 g fill EPA + DHA

Dietary Supplement (27)

Mason RP et al. Poster presented at the AMCP 2015 Nexus. Orlando, FL

0.3 g fill EPA + DHA

Krill Oil Dietary Supplement (44)

How Much EPA/DHA Is in a Dietary Supplement Omega-

37%30%

21% 12%21%

36%34%

Leading Fish Oil Supplement Leading Krill Oil Supplement

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

Saturated Fats

Unsaturated Fats

Fatty Acid Content of Leading Fish and Krill Oil

Supplements

Fish oil dietary supplement

forms solid mass

Rx ω-3 is a clear fluid

High Saturated Fat Content in Dietary Fish Oil

Supplement Leads to Solid Mass Following Hydrolysis

Courtesy of Preston Mason, PhD.

Capsules were sliced open, contents crushed, and placed into vials

1 gm of ω-3 from

fish oil supplement

can include up to

1/3 of saturated fat

minimum daily

requirement

Peroxide, Anisidine, and TOTOX Values Measured in Rx and

Leading Dietary Supplements (DS)

*Global Organization for EPA and DHA Omega-3s (GOED). Available at: http://www.goedomega3.com/index.php

Mason RP et al. Poster presented at the AMCP 2015 Nexus. Orlando, FL.

Dietary Supplements

DS 1 DS 2 DS 3 DS 4

(med/L

20Anis

Normalized to Rx ω-3 FA

GOED standard*

<5 mEq/kg

<20 mEq/kg

<26 mEq/kg

Peroxide value (PV) measures

current oxidation

Anisidine value (AV) is a

measurement of past oxidation

TOTOX is total oxidation value,

past and present

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.

FDA Product Classification1 Food

Clinical Trials/FDA

Pre-Approval1Not Required

Content & Purity2-9

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

oxidized lipids which may increase CV risk

Can contain PCBs and dioxins at harmful levels

Dietary Supplement Fish Oil:Not Useful for ASCVD Prevention in HTG Patients

Use for Treatment of Disease Not Recommended

Ability to reduce ASCVD Not demonstrated

Purification of Omega-3: O3AEE (Lovaza)

EPA+DHA and Lipid Levels in Patients

with TG >500 mg/dL

*P<0.0001. †P=0.0015. ‡P=0.0059. §P=0.0002 between groups. Pooled analysis (N=82).

Harris WS et al. J Cardiovasc Risk 1997;4:385-91. Pownall HJ et al. Atherosclerosis 1999;143:285-97.

Placebo EPA+DHA (4 g/day)

Baseline

(mg/dL)C

Levels

–4.8*

–45.0*

–3.6†

–13.8†

–9.7‡

–1.7‡

–42.0*

–0.9*

VLDL-C

–4.2‡

–1.9

Statin + EPA/DHA: COMBOS Trial

(TG 200-500 mg/dL)

TG HDL-C

Additional changes to baseline

simvastatin therapy

–1.2

–6.3

–29.5*

–7.2

–27.5*

Apo BNon-

–9.0*

–2.2

*P<0.0001. †P=0.0522. ‡P=0.0232 between groups. COMBOS=Combination of Prescription Omega-3 with Simvastatin.

Davidson MH et al. Clin Ther. 2007;29:1354-67.

Placebo + simvastatin 40 mg/d (n=133)

EPA+DHA 4 g/d + simvastatin 40 mg/d (n=123)

VLDL-C LDL-C

–2.8

0.7†

EVOLVE: DHA+EPA Free Fatty Acid Effects

on Lipid Endpoints, TG >500 mg/dL

*P<0.001. †P<0.01. ‡P<0.05. P-values reflect differences between DHA+EPA free fatty acid (FFA) vs statin+ olive oil.

LSGM=least-squares geometric mean. Kastelein JJP et al. J Clin Lipidol. 2014;8:94-106.

n=99, TG ≥500 but <2000 mg/dL

Baseline

(mg/dL)

DHA+EPA FFA 4 g/day DHA+EPA FFA 2 g/day

HDL-CTG HDL-C Apo BLDL-C

‡†

ESPRIT: DHA+EPA Free-Fatty-Acid Effects on Lipid

Endpoints, TG 200-500 mg/dL

*P<0.001. †P<0.05. P-values reflect differences between DHA+EPA free fatty acid (FFA) vs statin+ olive oil.

LSGM=least-squares geometric mean. Maki KC et al. Clin Ther 2013;35:1400-11.

n=207, TG ≥200 and <500 mg/dL

Baseline

(mg/dL)

3.31.3

2.64.6

DHA+EPA FFA 4 g/day

DHA+EPA FFA 2 g/day

HDL-C HDL-C LDL-C Apo B

Omega-3 CV Outcome Trial Meta-Analysis: No ↓CVD w/ Low-dose EPA+DHA Mix (Diet Sup or Rx)

How Do EPA and DHA Differ?

Omega-3

Molecular

Structures

Adapted from Mozaffarian

D, Wu JH. J Am Coll

Cardiol. 2011;58:2047-67.

Not effective

for ↓TG

Effective

for ↓TG

• Both the amount and

type of omega-3 fatty

acid are important for

TG lowering1

• No head-to-head

studies have been

done to compare the

effects of Prescription

TG-lowering medicine

EPA and DHA Have Different Effects

on LDL-C1-4

LOWERING

EPA DHA

NEUTRAL RAISING

LOWERING

LDL-CLDL-C

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

Arrows are not representative of actual effect on TG or LDL-C; individual effects may vary.

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: Pure EPA (IPE, Vascepa)

EPA: MARINE Trial Lipid Efficacy with

TG >500 mg/dL

*P<0.0001. †P<0.001. ‡P<0.01. §P<0.05. NS = P≥0.05. P-values reflect differences between EPA vs placebo. ITT=intention

to treat; Lp-PLA=Lp-associated phospholipase A; NS=not significant. Bays HE et al. Am J Cardiol. 2011;108:682-90.

ITT PopulationM

Baseline TG >500 mg/dL

-17.7-16.3

-3.6-2.3

* EPA 4 g/day

HDL-CTG TC

VLDL-C HDL-C

VLDL-TG

All Patients No StatinWith Statin

n=19†

n=57†-33.1

Statin + EPA

TG Lowering

ANCHOR Study: EPA and Lipid Endpoints

(TG 200-500 mg/dL)

*P<0.0001. †P<0.01. P-values reflect differences between EPA vs placebo.

12-week trial in high-risk statin-treated patients (N=702) with residually TG levels (≥200 and <500 mg/dL) despite LDL-C

control (≥40 and <100 mg/dL). ANCHOR=Effect of AMR101 (Ethyl Icosapentate) on Triglyceride (Tg) Levels in Patients on

Statins With High Tg Levels (≥200 and <500 mg/dL). Ballantyne CM et al. Am J Cardiol. 2012;110:984-92.

TG ≥200 and <500 mg/dL

Baseline

(mg/dL)

EPA 4 g/day

-25.1-30

Prescription Omega-3 Significantly Reduce

Apo C-III Concentration

EE=ethyl ester; FFA=free fatty acid.

1. Kastelein JJP et al. J Clin Lipidol. 2014;8:94-106. 2. Dunbar RL et al. Lipids Health Dis. 2015;14:98.

3. Ballantyne CM et al. J Clin Lipidol. 2016;Feb 22 [Epub ahead of print].

P value for each trial 0.001 0.001 0.0001 0.0001

compared to its placebo

Note: No head-to-head comparisons are represented or implied.

EPA/DHA FFA 4 g

EVOLVE1 ESPRIT2 ANCHOR3 MARINE3

Baseline TG (mg/dL) ≥500, <2000 ≥200, <500 ≥200, <500 ≥500, ≤2000

Apo C3 concentration change from baseline, vs placebo (%)

EPA EE 4 g

Effects of Rx Omega-3 (EPA) on Remnant Cholesterol:

MARINE and ANCHOR Studies

All patients†

*P<0.05. **P<0.01. †Median differences in percent changes vs placebo are Hodges-Lehmann medians.

EPA=eicosapentaenoic acid ethyl ester; RLP-C=remnant-like particle cholesterol.

Serum RLP-C was measured with an immunoseparation assay by Polymedco (Cortlandt Manor, NY, USA) on the Daytona

chemistry analyzer (Randox, Crumlin, United Kingdom).

Ballantyne CM et al. Presented at the National Lipid Association Scientific Sessions, June 11–14, 2015, Chicago, IL.

Available at: https://www.lipid.org/util/eposters/PDF/172.pdf

MARINE study only

(w & w/o non-randomized statins)†

-29.8-25.8

Baseline

MARINE

ANCHOR

-56.8-60

Baseline

No Statin

Statin

EPA 4 g/day

MARINE 4 g/day

ANCHOR 4 g/day

Effect of EPA on Inflammatory Markers TG 200-500 and

> 500 mg/dL (12 wks, ITT)

*P<0.01; †P<0.001; ‡P<0.0001 (vs placebo). P values for Lp-PLA2 were adjusted for multiple comparisons.

hsCRP=high-sensitivity C-reactive protein; ICAM-1=intercellular adhesion molecule-1; IL-6=interleukin-6; IPE=icosapent

ethyl; Lp-PLA2=lipoprotein-associated phospholipase A2; NS=not significant; Ox-LDL=oxidized low-density lipoprotein.

Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46.

ICAM-1 Ox-LDL Lp-PLA2 IL-6 hsCRP

EPA (IPE)

‡ †

MARINE studied 229 patients with very high TG levels ≥500 mg/dL. ANCHOR studied 702 patients with well-controlled LDL-C and residually high TG levels 200–500 mg/dL.

Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46.

EPA Treatment Lowers Levels of Inflammatory and Oxidative Markers

No Statin With Statin

Median placebo-adjusted change (%)

4 g/day

2 g/day

Additive hsCRP reduction with IPE + Statin

MARINE + ANCHOR Pooled (N=931)

hsCRP decrease with EPA is enhanced with intensive statin use

MARINE, icosapent ethyl 4 g/day

ANCHOR, icosapent ethyl 4 g/day

Markers of Inflammation

Lp-PLA2 hsCRP Ox-LDL

EPA (4 g)

Statins

Lipid Therapy

EPA/DHA (4 g)

hsCRP Levels

EPA (4 g) + Statin

Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46. Dunbar RL et al. Lipids Health Dis. 2015:14:98. Ridker PM et al. N Engl J Med. 2008;359:2195-207.

Bohula EA et al. Circulation. 2015;132:1224-33. Pradhan AD et al. Circulation. 2018;138:141-9.

Ezetimibe

Ezetimibe + Statin

Variability Among Lipid Therapies In hsCRP Effect

PCSK9i + Statin

EPA vs DHA Anti-inflammatory Effects

• Both are metabolized to:

– Anti-inflammatory cytokines

– Inflammation-resolving factors

– Fibrosis-resolving factors

• EPA alone

– Same length as arachidonic-acid (AA), so

– Blocks production of pro-inflammatory cytokines

from AA

Confidential. For Speaker Training only. Not to be used in Speaker Presentations or promotion.

EPA vs Other TG-lowering Agents Effects on Oxidation of Membrane Lipid Hyperglycemia

In Vitro Model

96 hours; **P<0.001 vs vehicle-treated control. ‡P<0.001 vs glucose-treated control. §§P<0.001 vs EPA. ¶P<0.001 vs oxEPA1

(Student-Newman-Keuls multiple comparisons test; overall ANOVA: P<0.0001, F=278.23). Values are mean ± SD (N = 6).

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

EPA vs EA & ETE: Unique Structure of EPA Has Antioxidant Activity vs Glucose-induced Membrane Lipid Peroxidation

Adapted from Mason RP and Jacob RF. Biochim Biophys Acta. 2015;1848:502-509.

Schematic Illustration of the Distinct Membrane Structural & Biochemical Effects of EPA vs Other TG-lowering Agents

Schematic Illustration of the Protective Effects of EPA on sdLDL Lipid Oxidation

Adapted from: Mason RP, Jacob RF. Diabetes. 2015;64,Suppl 1:A178-A179.

EPA Uniquely

Inhibits Lipoprotein

Oxidation:

The antioxidant properties of

EPA were not observed with

other TG-lowering agents.

Each agent was tested at 10 µM

Mason RP et al. J Cardiovasc Pharmacol. 2016;68:33-40.

Effects of a DS Omega-3 (Fatty Acid Extract) vs Non-Oxidized and Partially Oxidized Preparations of EPA + DHA on Human sdLDL Oxidation

Vehicle

§†*

*P<0.001 vs vehicle alone. †P<0.001 vs DS. §P<0.001 vs oxEPA + oxDHA (Student-Newman-Keuls

multiple comparisons test; overall ANOVA: P<0.0001, F=993.26). Values are mean ± SD (N=3).

Mason RP, Sherratt SCR. Biochem Biophys Res Commun. 2016;1-5.

EPA Uniquely

Maintains

Inhibition of

Lipoprotein

Oxidation:

EPA were sustained over time,

while those of DHA were lost.

Peroxide, Anisidine, and TOTOX Values Measured in Rx and Leading Dietary Supplements

Mason RP, Sherratt SCR. Biochem Biophys Res Commun. 2016;1-5.

EPA and Atorvastatin Metabolite Inhibited sdLDL Oxidation to a Greater Extent

• EPA and ATM

independently inhibit

oxidation of apoB-

containing lipoproteins

• EPA and ATM effects are at

a minimum additive and

may approach synergy in

LDL and sdLDL

EPA Uniquely

Maintains

Inhibition of

Lipoprotein

Oxidation:

EPA were sustained over time,

while those of DHA were lost.

Effects of EPA and/or Statin on

Endothelial Function

Nitric Oxide Is a Key Mediator of Renal/Vascular Protection

Vessel lumen

Vascular smooth muscle cells

GUANYLATE

CYCLASE

GTP cGMP

NO Platelet

inhibition

Relaxation

Cell growth/proliferation

Matrix formation

Leukocyte migration

Subendothelium

Behrendt and Ganz. Am J Cardiol. 2002;90(suppl):40L.

Vita. J Card Fail. 2003;9(suppl nitric oxide):S199.

+ + +EPA Atorv EPA

+Atorv

Vehicle oxLDL oxLDL oxLDL oxLDL0.0

Atorvastatin active metabolite was used in this study. Values are mean ± SD (N=3-6). *P<0.05 and ***P<0.001 vs ox LDL. †P<0.01 vs

ox LDL + EPA. §P<0.001 vs ox LDL + Atorv (Student-Newman-Keuls multiple comparison test; overall ANOVA: P<0.0001, F=25.827).

Mason RP et al. J Clin Lipidol. 2014;8:342-343.

Combined Effects of EPA and Atorvastatin on Human Endothelial Function in vitro after Treatment with Oxidized LDL

Exposed to 300 mg/dL Glucose

**P<0.001 versus Control; *P<0.01 versus Control; †P<0.001 versus vehicle; §P<0.05 versus EPA + ATM.

(Student-Newman-Keuls multiple comparisons test; overall ANOVA: P<0.0001, F=38.885). Values are mean ± SEM (N = 4-8)

Mason RP et al. J Am Coll Cardiol. 2016 (in press).

Effects of EPA and ATM on NO Released from Glomerular Endothelial Cells Under Hyperglycemic Conditions ex vivo

OM=omega.

Mason RP et al. J Clin Lipidol. 2014;8:342-343.

Potential Co-protective Effects of EPA & Atorvastatin on Human EC Function

EPA vs DHA Other Long-Chain

Fatty Acids and Other TG-Lowering Agents

on Membrane Fluidity,

and Cholesterol Domain Formation

in Model Membranes

Cholesterol Crystals Can Evolve from Excess Cholesterol Domain Formation and Associate w/ Cell Death Atherosclerosis and Plaque Rupture

Kellner-Weibel G, Mason RP, et al. Arterioscler Thromb Vasc Biol. 1999;19:1891-1898.

Dose-dependent effects of EPA and DHA on the apparent rotational correlation time (ARCT)

measured for diphenylhexatriene (DPH) in POPC membranes prepared at 50 mol% cholesterol

DHA Increases Membrane Fluidity Compared to EPA

Mason RP et al. Biochim Biophys Acta. 2016;1858:3131-3140.

Schematic Illustration of the Distinct Membrane Structural & Lipid Dynamic Effects of EPA vs DHA

Oxidative Damage to Membrane Lipids Leads to Cholesterol Crystalline Domains and Cell Injury

Adapted from: Mason RP, Jacob RF. Adv Exp Med Biol. 2015;842:231-245.

Cholesterol Domain-Reducing Effects of EPA Not Reproduced by Other Fatty Acids or TG-Lowering Agents

In vitro Effects of EPA: Overall Summary

• EPA inhibits changes in membrane organization

through a potent antioxidant mechanism1

• EPA has unique antioxidant benefits in

apoB-containing compared to other TG-lowering

agents and DHA2

• EPA may reduce CV risk through these novel effects

on cell membranes3

• EPA may reduce inflammation and improve

endothelial function due to its unique structure3

1. Mason RP et al. Biochim Biophys Acta. 2015;1848:502-509. 2. Mason RP et al. J Cardiovasc Pharmacol. 2016;68:33-40. 3.

Pros of EPA 1. Fits between PL legs (in lipoproteins & cells):• More stable in PL

mono/bilayer• Longer/better antiox. effect• No ↑chol crystals (vs ↑w/

DHA)2. Fits in AA-series enzymes:• ↓AA→pro-inflam cytok.• ↓hsCRP3. No inhibition of LDL-R → modest ↓LDL-C/apoBPros of DHA 1. Coils up between PL legs so↑Membr. fluidity (good vs bad?)2. Modest ↑HDL-C (vs ↓w/ EPA)

How May EPA and DHA DifferRe: Anti-Atherosclerotic Mechanisms?

Bottom Line:• EPA appears

better than DHA in vitro + in vivo, but this is not yet proven; more research needed!

EPA and DHA Appear to be Similar Re:• ↓TG• ↓LpPLA2

• Anti-platelet• Anti/pro-

arrhythmia

IPE vs O3AEE vs O3 Dietary Supplements

Yes (4%) Yes (16%)

EPA Reduces Plaque Volume Evaluated by

Backscatter Intravascular Ultrasound (IB-IVUS)

Wilcoxon signed-rank test. Ando K on behalf of the CHERRY Investigators at the AHA Scientific Sessions, November 8, 2015.

Baseline Follow up

Pitavastatin group Pitavastatin / EPA group

72.7(43.9, 121.2) 67.4

(43.4, 117.2)

74.5(45.6, 107.3)

61.4(40.3, 91.4)

P=0.108 P<0.001

241 patients who received primary percutaneous coronary intervention (PCI) using IB-

IVUS in 6 hospitals were randomized to pitavastatin 4 mg/day or pitavastatin 4 mg/day +

EPA 1800 mg/day and followed for 6–8 months

JELIS: EPA Reduced Major Adverse Coronary Events (MACE)*

in Hypercholesterolemic Patients on Statins

Yokoyama M et al. Lancet. 2007;369:1090-8.

No. at Risk

Control

0 1 4 5 Years

9319 8931 8671 8433 8192 7958

9326 8929 8658 8389 8153 7924

P=0.011

Statin + EPA 1.8g/day

Statin only3

HR (95% CI): 0.81 (0.69–0.95)

N=18,645 Japanese pts with TC ≥251 mg/dL prior to baseline statin Rx. Baseline TG=153 mg/dL.

Statin up-titrated to 20 mg pravastatin or 10 mg simvastatin for LDL-C control.

*Primary endpoint: sudden cardiac death, fatal and non-fatal MI, unstable angina pectoris,

angioplasty, stenting, or coronary artery bypass graft.

–19%

*Pre-specified analysis in primary prevention subjects. MACE=major adverse CV event.

Saito Y et al. Atherosclerosis. 2008;200:135-40.

JELIS: Larger Decrease in MACE in Subjects with

TG >150 mg/dL & HDL-C <40 mg/dL*

HR and P-value

adjusted for age,

gender, smoking,

diabetes, and HTN

No. of patients

Control 475 444 432 414 400 392

EPA 482 455 443 427 413 403

0 1 2 3 4 5 Years

EPA 1.8 gm/day group

Control group

–53%

HR: 0.47

95% CI: 0.23–0.98

P=0.043

Omega-3 CV Outcome Trial Meta-Analysis:

No ↓CVD w/ Low-dose EPA+DHA Mix; ↓CVD w/ Mid-dose Pure EPA

REDUCE-IT Design

1. Age ≥45 y with established CVD (2o Prevention)

or high risk 1o prevention: ≥50 y with diabetes +

≥1 additional CVD risk factor

2. Fasting TG levels 135-500 mg/dL

3. LDL-C 40-100 mg/dL and on stable statin Rx (±

ezetimibe) for ≥4 weeks prior to qualifying

measurements for randomization

Primary Endpoint Events: CV death, nonfatal MI, nonfatal stroke, coronary revasc, hospitalization for unstable angina

Key Secondary Endpoint Events: CV death, nonfatal MI, nonfatal stroke

Double-blind study; Events adjudicated by CEC that was blinded to treatment during adjudication

Screened

N=19,212

Randomized

N=8179

(43% of screened)

Icosapent Ethyl

4 grams/day

N=4089

Placebo

N=4090

Known vital status 4083 (99.9%) Known vital status 4077 (99.7%)

Median trial

follow up

4.9 yr

Bhatt, DL, Steg PG, Brinton, EA. Clinical Cardiology. 2017;40:138–148 and Bhatt DL, Steg PG, Miller M, et al. NEJM. 2019; 380:11-22.

REDUCE-IT Design

1. Age ≥45 y with established CVD (2o Prevention)

or high risk 1o prevention: ≥50 y with diabetes +

≥1 additional CVD risk factor

2. Fasting TG levels 135-500 mg/dL

3. LDL-C 40-100 mg/dL and on stable statin Rx (±

ezetimibe) for ≥4 weeks prior to qualifying

measurements for randomization

Primary Endpoint Events: CV death, nonfatal MI, nonfatal stroke, coronary revasc, hospitalization for unstable angina

Key Secondary Endpoint Events: CV death, nonfatal MI, nonfatal stroke

Double-blind study; Events adjudicated by CEC that was blinded to treatment during adjudication

Screened

N=19,212

Randomized

N=8179

(43% of screened)

Icosapent Ethyl

4 grams/day

N=4089

Placebo

N=4090

Known vital status 4083 (99.9%) Known vital status 4077 (99.7%)

Median trial

follow up

4.9 yr

Bhatt, DL, Steg PG, Brinton, EA. Clinical Cardiology. 2017;40:138–148 and Bhatt DL, Steg PG, Miller M, et al. NEJM. 2019; 380:11-22.

↑↑ASCVD risk despite LDL-C controlled on statin & TG >135

Key Baseline Characteristics

Icosapent Ethyl

(N=4089)

Placebo

(N=4090)

Age (years) 64 64

Female, % 28.4% 29.2%

CV Risk Category, %

Secondary Prevention Cohort 70.7% 70.7%

Primary Prevention Cohort 29.3% 29.3%

Prior Atherosclerotic Cardiovascular Disease, % 68.9% 69.3%

Prior Atherosclerotic Cerebrovascular Disease, % 15.7% 16.2%

Prior Atherosclerotic Peripheral Artery Disease, % 9.5% 9.5%

LDL-C (mg/dL), Median (Q1-Q3) 74.0 (61.5 - 88.0) 76.0 (63.0 - 89.0)

Triglycerides (mg/dL), Median (Q1-Q3) 216.5 (176.5 - 272.0) 216.0 (175.5 - 274.0)

Triglyceride Category (by Tertiles)*

≥81 to ≤190 mg/dL 1378 (33.7%) 1381 (33.8%)

>190 to ≤250 mg/dL 1370 (33.5%) 1326 (32.4%)

>250 to ≤1401 mg/dL 1338 (32.7%) 1382 (33.8%)

Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019. Bhatt DL. ACC 2019, New Orleans.

*Baseline TG calculated as average of final screening TG and subsequent TG value from date of randomization.

Key Background Medical Therapy

Icosapent Ethyl

(N=4089)

Placebo

(N=4090)

Antiplatelet 3257 (79.7%) 3236 (79.1%)

One Antiplatelet agent 2416 (59.1%) 2408 (58.9%)

> 2 Antiplatelets 841 (20.6%) 828 (20.2%)

Anticoagulant 385 (9.4%) 390 (9.5%)

ACEi or ARB 3164 (77.4%) 3176 (77.7%)

Beta Blocker 2902 (71.0%) 2880 (70.4%)

Statin 4077 (99.7%) 4068 (99.5%)

Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.

Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPoint

Primary End Point:CV Death, MI, Stroke, Coronary Revasc, Unstable Angina

Icosapent Ethyl

23.0%Placebo

Years since Randomization

0 1 2 3 4 5

P=0.00000001

RRR = 24.8%

ARR = 4.8%

NNT = 21 (95% CI, 15–33)

Hazard Ratio, 0.75(95% CI, 0.68–0.83)

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22. Bhatt DL. AHA 2018, Chicago.

Icosapent Ethyl

Placebo

Key Secondary End Point:CV Death, MI, Stroke

Hazard Ratio, 0.74(95% CI, 0.65–0.83)

RRR = 26.5%

ARR = 3.6%

NNT = 28 (95% CI, 20–47)

P=0.0000006

0 1 2 3 4 5

Omega-3 CV Outcome Trials:

No ↓CVD w/ Low-dose EPA+DHA Mix; Yes ↓CVD w/ Mid-dose Pure EPA

REDUCE-IT is 2nd of 2 CVOT’s w/ ↓CVD from EPA as Statin AdjunctTWO Best RRRs of All: JELIS ↓19% and REDUCE-IT ↓25%

Total Mortality 0.87 (0.74–1.02) 0.09

Endpoint

Primary Composite (ITT)

Key Secondary Composite (ITT)

Cardiovascular Death orNonfatal Myocardial Infarction

Fatal or Nonfatal Myocardial Infarction

Urgent or Emergent Revascularization

Cardiovascular Death

Hospitalization for Unstable Angina

Fatal or Nonfatal Stroke

Total Mortality, Nonfatal MyocardialInfarction, or Nonfatal Stroke

310/4090 (7.6%)

Placebo

n/N (%)

901/4090 (22.0%)

606/4090 (14.8%)

507/4090 (12.4%)

355/4090 (8.7%)

321/4090 (7.8%)

213/4090 (5.2%)

157/4090 (3.8%)

134/4090 (3.3%)

690/4090 (16.9%)

274/4089 (6.7%)

Icosapent Ethyl

n/N (%)

705/4089 (17.2%)

459/4089 (11.2%)

392/4089 (9.6%)

250/4089 (6.1%)

216/4089 (5.3%)

174/4089 (4.3%)

108/4089 (2.6%)

98/4089 (2.4%)

549/4089 (13.4%)

Hazard Ratio (95% CI)

0.75 (0.68–0.83)

0.74 (0.65–0.83)

0.75 (0.66–0.86)

0.69 (0.58–0.81)

0.65 (0.55–0.78)

0.80 (0.66–0.98)

0.68 (0.53–0.87)

0.72 (0.55–0.93)

0.77 (0.69–0.86)

P-value

<0.001

Hazard Ratio

(95% CI)

Icosapent Ethyl Better Placebo Better

0.4 1.0

Prespecified Hierarchical TestingRRR

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

REDUCE-IT: Individual Elements of Primary Endpoint (5-POINT MACE)

Placebo

[N=4090]

3rd1st 2nd ≥4

Icosapent Ethyl

[N=4089]

2362nd EventsHR 0.68

(95% CI, 0.60-0.78)

1st EventsHR 0.75

(95% CI, 0.68-0.83) P=0.000000016

≥4 EventsRR 0.52

(95% CI, 0.38-0.70)

3rd EventsHR 0.69

(95% CI, 0.59-0.82)

RR 0.70(95% CI, 0.62-0.78)

P=0.00000000036

Reduced Dataset Event No.

No. ofFewerCases

30% Reduction in Total Events

First and Subsequent Events

Note: WLW method for the 1st events, 2nd events, and 3rd events categories;

Negative binomial model for ≥4th events and overall treatment comparison.

Total (First and Subsequent) EventsPrimary: CV Death, MI, Stroke, Coronary Revasc, Unstable Angina

Primary Composite Endpoint

tive E

2 3 40.0

Placebo: Total Events

Icosapent Ethyl: Total Events

Placebo: First Events

Icosapent Ethyl: First Events

HR, 0.75

(95% CI, 0.68–0.83)

P=0.00000001

RR, 0.70(95% CI, 0.62–0.78)

P=0.00000000036

Primary

Composite

Endpoint

Cardiovascular

Fatal or

Nonfatal MI

-42 Fatal or

Nonfatal

Stroke

Coronary

Revascularization

Hospitalization

for Unstable

Angina

For Every 1000 Patients Treated with Icosapent Ethyl for 5 Years:

PowerPoint Presentation

Rx EPA (IPE) ↓ASCVD in patients with

baseline TG 135-200 ≈ TG 200-500!

#AHA18: Cholesterol Guidelines full update; omega-3s and CV

events; yoga and risk reduction - Message (HTML)

Rx EPA (IPE) ↓ASCVD in patients with

baseline TG 135-150 ≈ TG 150-500!!

TOTAL EVENTS – Primary Composite Endpoint/Subgroup Icosapent Ethyl Placebo RR (95% CI) P-value

Rate per 1000

Patient Years

Rate per 1000

Patient Years

Primary Composite Endpoint (ITT) 61.1 88.8 0.70 (0.62–0.78) <0.0001

Baseline Triglycerides by Tertiles*

≥81 to ≤190 mg/dL 56.4 74.5 0.74 (0.61–0.90) 0.0025

>190 to ≤250 mg/dL 63.2 86.8 0.77 (0.63–0.95) 0.0120

>250 to ≤1401 mg/dL 64.4 107.4 0.60 (0.50–0.73) <0.0001

Primary Composite Endpoint:Total Endpoint Events by Baseline TG Tertiles

Bhatt DL. ACC 2019, New Orleans.

Placebo

Better

Icosapent Ethyl

Better

1.00.2 1.40.6 1.8 *P (interaction) = 0.17

↓CVD w/ EPA Was

Comparable w/ On-Rx TG

> vs < 150 mg/dL

Similar results were seen with the key secondary endpoint

Bhatt DL, et al. N Engl J Med. 2019;380(1):11-22.

Did ASCVD↓ More in Subgroup with TG > 200 PLUS HDL-C < 35? Maybe NOT

Subgroup % Subjects w/ CVD Events P-heterogeneity

TG ≥200 mg/dL and HDL-C ≤35 mg/dL

Icosapent Ethyl

Placebo HR (95% CI)0.04

Yes 18.1 27.0 0.62 (0.51-0.77)

No 17.0 20.9 0.79 (0.71-0.88)

Above data are with 1o endpoint, 5-point MACE, but

P-value only 0.50 (NS) for stronger 2o endpoint (“Hard” 3-point MACE)

REDUCE-IT Surprise:

In Mild-Moderate HTG Patients

Baseline & On-Rx TG Levels Don’t Seem to Matter!!

(opposite of LDL-C)

PowerPoint Presentation

(No Difference in Overall TEAE)

EPA Effects on Arrhythmias and Their SequelaeIPE 4g/d Pbo HR (95%CI) P value

Atrial* % N % N

Total Atr. Fibrillation 5.3 215 3.9 159 Sig↑** 0.003

Hosp. for Atr. Fib. 3.1 127 2.1 86 Sig↑** 0.004

Ventricular(?)

Sudden Cardiac Death 1.5 61 2.1 87 .69 (.50-.96) Sig↓**

Cardiac Arrest 0.5 22 1.0 42 .52 (.31-.86) Sig↓**

Arrhyth. Req. Hosp. >24h 4.6 188 3.8 154 1.21 (.97-1.49) NS

*No increases in the worst AFib sequelae: TIA, CHF, dyspnea or fatigue. **Not given.

JELIS provided no information about arrhythmias. See Yokoyama M Lancet 2007;369;1090-98.

EPA+DHA trials/studies sugg: ↑atrial fibrillation (↓if post cardiac surg) vs ↓ventricular events. (see Kowey, PR. JAMA;2010;304:2363-72; Mozaffarian, D. JACC;2011;58:2047-67; von Schacky, C. Frontiers in

Physiol. 2012; 3; 88. Christou, GA. Int J Mol Sci 2015;16: 22870-87 Siscovick, DS. Circul. 2017;135;e867-84.)

Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPointTrend Towards ↑Total Serious Bleeding Events—Likely Real

Improving Outcomes in Severe Hyperchol Rockpointe CME Amgen 2018 1555 Lipid GR-FULL vEAB.3 - PowerPointNo Apparent ↑Intracranial or Fatal Bleeding Events

JELIS reported modestly ↑total bleeding events: 1.1% vs 0.6% p=0.006 (no ↑intracranial bleeding; 1.8 g/d IPE on high-fish diet)

EPA Safety and Tolerability in Long-Term CVOT (JELIS, N=18,645)

CPK=creatine phosphokinase; GOT=glutamic oxaloacetic transaminase *No between-group differences in stroke (incl cerebral or subarachnoid hemorrhage). Hazard ratio for hemorrhagic stroke 1.12 (0.91–1.39, P=0.272).• The rate of discontinuation due to treatment-related adverse effects was 11.7% in the EPA + statin group and 7.2% in the statin only group• Most adverse events attributed to EPA treatment were regarded as mild by the investigators

EPA Group Control P Value

Pain (joint, lumbar, muscle) 1.6% 2.0% 0.04

Gastrointestinal disturbance (nausea, diarrhea, epigastric

discomfort)3.8% 1.7% <0.0001

Skin abnormality (eruption, itching, exanthema, eczema) 1.7% 0.7% <0.0001

Hemorrhage (cerebral, fundal, epistaxis, subcutaneous)* 1.1% 0.6% 0.0006

Abnormal laboratory data

•Total

•CPK increased

•GOT increased

•Blood sugar level increased

Yokoyama M et al. Lancet. 2007;369(9567):1090-1098.

Plasma EPA w/ Epadel 1.8 g/d in Japanese

vs Vascepa 4 g/d in Non-Japanese

Institute for Clinical and Economic Review, 2019. Draft Evidence Report. Additive Therapies for Cardiovascular Disease: Effectiveness and Value. https://icer-review.org.

IPE is Very Cost-Effective: REDUCE-IT Data

A preliminary report from the Institute for Clinical and Economic Review (ICER) on the effectiveness and value of icosapent ethyl• Comparative Clinical Effectiveness

“For adults with established CVD or at high risk of cardiovascular events who are being treated with statins, we have high certainty that icosapent ethyl provides a small-to-substantial net health benefit (“B+”).

• Long-term Cost Effectiveness

Icosapent ethyl (in patients receiving statins) provides clinical benefit in terms of gains in quality-adjusted survival compared to optimal medical management alone in the adult with established CVD cohort and without known CVD but at high risk for CVD events.

This translated into incremental cost-effectiveness estimates that fell below commonly cited cost-effectiveness thresholds under the assumptions used for this analysis, which were willingness-to-pay thresholds of both $50,000 per QALY and $100,000 per QALY gained.

Icosapent ethyl vs. optimal medical management yields $18,000 per QALY gained at the current

wholesale acquisition cost of $303.65 per month.

CVD Outcome Trials of Full-Dose Prescription Omega-3:

Pure EPA vs EPA + DHA Mix

1. Bhatt, DL, NEJM. 2019; 380:11-22. 2. http://www.clinicaltrials.gov.

REDUCE-IT1

(Results November ‘18)STRENGTH2

(Ongoing—Results 2020?)

Omega-3 type

DoseEPA (O3AEE)

4 g/day

EPA+DHA (FFA)

4 g/day

Population International International

Subjects/ CVD events 8179/1612 Estimated 13,000/~1600

GenderMen and non-pregnant or sterile women

ages 45 or olderMen or women, ≥18 years of age

Risk ProfilePrior ASCVD (70%),

High CV risk (30%); DM ~50%

Prior ASCVD (50%),

High CV risk (50%)

Follow-up 4.9 years ~3 years (planned)

Statin Use100%

(LDL-C <100l)

(LDL-C <100 or max tol statin dose)

Primary End PointExpanded Major adverse

cardiac event (5-point)

Expanded Major adverse

cardiac event (5-point)

Statistical PowerPowered for 15% RRR

25% RRR Seen Powered for 15% RRR

Baseline TG/HDL-C 135-500 mg/dL/HDL is NA 180-500/<42 men & <47 women

Rx EPA O3AEE (25% RRR, ~$220/mo) vs DHA-Containing Alternatives:

• Rx EPA+DHA O3AEE (generic Lovaza) ~$40/mo, but– ↓CVD not proven yet (likely not ever?)– +DHA net differences might be adverse, but– OK if pt can’t afford Rx EPA?? (=payer won’t pay) if DHA ≈ EPA

(i.e. if STRENGTH ≈ REDUCE-IT)• Rx EPA+DHA FFA

– DHA net effects vs EPA: might have less ↓CVD (?)– ↑GI absorption benefit is small and assoc w/ ↑GI side effects– (Not yet clinically available)– May be shown ≈ pure EPA for ↓CVD (if STRENGTH ≈

REDUCE-IT), but if so, might default Rx be generic Lovaza?– Likely $$ similar to branded IPE (but low-dose would be ½ cost)– Advantages vs IPE: qd dosing, low dose ok (linear dose-resp.)?

In Vivo Human Trial ASCVD Results:

Pure EPA vs EPA + DHA Mix

Evidence Type Pure EPA EPA+DHA Mix

Coronary Athero

Trials

Beneficial No data

CVOT Results Beneficial:REDUCE-IT & JELIS

Low-dose Negative(STRENGTH ongoing)

Summary Beneficial As beneficial vs less??

Fibrates as “TG-Lowering for ASCVD Prevention”

Adjuncts to Statin Mono-Rx• Gemfibrozil—good mono-Rx CVD data but not practical

as statin adjunct• Fenofibrate—cheap, safe, good ↓TG but CVD data w/

statin not convincing (and confusing re: formulations)• Pemafibrate—not yet available but may be shown to

↓ASCVD in PROMINENT (results ~2022)

Bottom line: Evidence lacking for generic TG-loweringw/ fibrate (or niacin)—use only EPA (=IPE) for now

Conclusion: ↓ASCVD (etc.) in Mild-Moderate HTG (fasting TG 135-200)

• Rx EPA—best statin adjunct if TG >135 (& payer ok)• Rx EPA+DHA (generic Lovaza)??—if TG >135 & pt can’t

afford EPA, and if STRENGTH ≈ REDUCE-IT• Rx EPA+DHA FFA—not available yet, if STRENGTH

≈REDUCE-IT→O3AEE mix? (generic Lovaza vs. Epanova)• Fibrates: feno vs pemafib.? Not yet, wait for PROMINENT• Further LDL-C Lowering beyond statins if LDL-C > thresh.

– Ezetimibe (~$9/mo), if LDL-C ~70-130 and pill-count ok

– PCSK9i if LDL-C >100 and cost ok (~$450/mo)

• SGLT2i: if CHF, BP, CKD (ESRD) & A1c >~8 (payer ok?)

• GLP1-RA: if ↓Obesity, CKD, A1c >~8 (payer ok?)

are all omega-3 agents similarfor ascvd prevention? · 2019-11-18 · •estimated global market...

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