NLA Position Statement on the Use of f Ic Icosapent Ethyl in High- - - PowerPoint PPT Presentation

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NLA Position Statement on the Use

• f

f Ic Icosapent Ethyl in High- or

• r

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

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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

Very High Risk ASCVD

2 or More Major Events or 1 Major Event and ≥ 2 High Risk Conditions

Major ASCVD Events

• Recent ACS (within the past 12 mo)
• H/o MI (other than recent ACS event

listed above)

• H/o ischemic stroke
• Symptomatic peripheral arterial disease

(H/o claudication with ABI <0.85, or previous revascularization or amputation)

High Risk Conditions

• Age ≥65 y
• Heterozygous familial

hypercholesterolemia

• H/o prior CABG or PCI outside of major

ASCVD event(s)

• Diabetes mellitus
• Hypertension
• CKD (eGFR 15-59 mL/min/1.73 m2)
• Current smoking
• LDL-C ≥100 despite maximally tolerated

statin + ezetimibe

• H/o heart failure

H/o: history of ABI: ankle brachial index CABG: Coronary artery bypass surgery PCI: Percutaneous coronary intervention CKD: Chronic kidney disease Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. https://doi.org/10.1016/j.jacc.2018.11.003

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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

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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

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Hypothesized Mechanisms for the Atherogenicity of TG-rich Lipoproteins

7 .

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

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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

Long Chain Omega-3 Interventions and CV Events

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/]

Source Treatment Control Rate Ratios (CI)

• No. of Events (%)

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 Favors Treatment Favors Control

2.0

Rate Ratio

1.0 0.5

CHD Death Events Treatment n = 1301 (3.3%) Control n = 1394 (3.6%) RR (95% CI) 0.93 (0.85-1.00) P = 0.05

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

Long Chain Omega-3 Interventions and Cardiac Death (Death from CHD, Cardiac Arrhythmia, Heart Failure)

JELIS: Low intensity statin alone versus low intensity statin + EPA 600 mg 3 times daily

Total Population

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.

Kaplan-Meier Estimates of Incidence of Coronary Events Secondary Prevention Cohort Primary Prevention Cohort

7478 7204 7103 6841 6678 6508 7503 7210 7020 6823 6649 6482 1841 1727 1658 1592 1514 1450 1823 1719 1638 1566 1504 1442

Hazard ratio: 0.81 (0.657–0.998) p=0.048 Hazard ratio: 0.82 (0.63–1.06) p=0.132

9319 8931 8671 8433 8192 7958 9326 8929 8658 8389 8153 7924 Numbers at risk Control group Treatment group Major coronary events (%)

Hazard ratio: 0.81 (0.69–0.95) p=0.011 ARR 0.7%

Years Control 1 2 3 4 1 5 2 3 4 Years 0.5 1.0 1.5 2.0 1 5 2 3 4 4.0 8.0 1 5 2 3 4 Years EPA* Control EPA* Control EPA* *1.8 g/day Coronary events: Sudden cardiac death Fatal and non-fatal MI Unstable angina PCI CABG N=18,645 Baseline LDL-C 182 mg/dL Randomized open label trial

Patel PN, Patel SM, Bhatt DL. Curr Opin Cardiol. 2019;34 (in press). *** P<0.001; * P<0.05

VA-HIT 1999 HPS2-THRIVE 2014 FIELD 2005 ACCORD-Lipid 2010 AIM-HIGH 2011

TG Level (mg/dl)

GISSI-P 1999

50 100 150 200 250 Control

Treatment

A

***

JELIS 2007 REDUCE-IT 2018

* *** *** *** ***

VA-HIT 1999 HPS2-THRIVE 2014 FIELD 2005 ACCORD-Lipid 2010 AIM-HIGH 2011

Primary Endpoint (%)

GISSI-P 1999

5 10 15 20 25

B

JELIS 2007 REDUCE-IT 2018

Fibrate Niacin Omega-3 Fatty Acid

RRR 22% p=0.006 HR 0.96 p=0.29 HR 0.89 p=0.16 HR 0.92 p=0.32 HR 1.02 p=0.79 HR 0.90 p=0.48 HR 0.81 p=0.011 HR 0.75 p<0.001

Control

Icosapent ethyl

Key Trials Employing TG-lowering Drugs: Effects on TG and CV Outcomes

Trials Employing Triglyceride-lowering Drugs: Subgroups with Elevated TG and Low HDL-C

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

SSRE = summary rate ratio estimate

REDUCE-IT Design

Adapted with permissionǂ 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. [ǂhttps://creativecommons.org/licenses/by-nc/4.0/] 4 months, 12 months, annually

Randomization End of Study Screening Period Double-Blind Treatment/Follow-up Period

1:1 Randomization with continuation of stable statin therapy (N=8179) Lead-in

• Key Inclusion Criteria
• Statin-treated men

and women ≥45 yrs Established CVD (~70% of patients) or DM + ≥1 risk factor TG ≥150 mg/dL and <500 mg/dL* LDL-C >40 mg/dL and ≤100 mg/dL

• Icosapent

Ethyl

4 g/day (n=4089)

Placebo

(n=4090) Lab values Screening Baseline Visit 1 2 3 4 5 6 7 Final Visit 8 9 Months

• 1 Month

4 Every 12 months 12 Up to 6.2 years† Year Primary Endpoint Time from randomization to the first occurrence of composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, unstable angina requiring hospitalization 4 months, 12 months, annually End-of-study follow-up visit End-of-study follow-up visit *

†

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). Statin stabilization Medication washout Lipid qualification

N=8179

Biomarker* Icosapent Ethyl (n=4089) Median Placebo (n=4090) Median Median Between Group Difference at Year 1 Baseline Year 1 Baseline Year 1 Absolute Change from Baseline % Change from Baseline % Change P-value Triglycerides (mg/dL) 216.5 175.0 216.0 221.0

• 44.5
• 19.7

<0.0001 Non-HDL-C (mg/dL) 118.0 113.0 118.5 130.0

• 15.5
• 13.1

<0.0001 LDL-C (mg/dL) 74.0 77.0 76.0 84.0

• 5.0
• 6.6

<0.0001 HDL-C (mg/dL) 40.0 39.0 40.0 42.0

• 2.5
• 6.3

<0.0001 Apo B (mg/dL) 82.0 80.0 83.0 89.0

• 8.0
• 9.7

<0.0001 hsCRP (mg/L) 2.2 1.8 2.1 2.8

• 0.9
• 39.9

<0.0001 Log hsCRP (mg/L) 0.8 0.6 0.8 1.0

• 0.4
• 22.5

<0.0001 EPA (µg/mL) 26.1 144.0 26.1 23.3 +114.9 +358.8 <0.0001

Effects on Biomarkers from Baseline to Year 1

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

*Apo B and hsCRP were measured at Year 2.

Primary End Point:

CV Death, MI, Stroke, Coronary Revasc, Unstable Angina

Icosapent Ethyl

23.0%

Placebo

28.3%

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

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. Bhatt DL. AHA 2018, Chicago.

20.0% 16.2%

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

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

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019. Bhatt DL. AHA 2018, Chicago.

Total Mortality 0.87 (0.74–1.02) 0.09 Endpoint Primary Composite (ITT) Key Secondary Composite (ITT) Cardiovascular Death or Nonfatal Myocardial Infarction Fatal or Nonfatal Myocardial Infarction Urgent or Emergent Revascularization Cardiovascular Death Hospitalization for Unstable Angina Fatal or Nonfatal Stroke Total Mortality, Nonfatal Myocardial Infarction, 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 <0.001 <0.001 <0.001 <0.001 0.03 0.002 0.01 <0.001 Hazard Ratio (95% CI) 1.4 Icosapent Ethyl Better Placebo Better 0.4 1.0

Pre-specified Hierarchical Testing

RRR

RRR denotes relative risk reduction

23% 28% 32% 20% 35% 31% 25% 26% 25% 13%

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019. Bhatt DL. AHA 2018, Chicago.

Achieved Triglyceride Levels: <150 and ≥150 mg/dL

A Primary End Point by Achieved Triglyceride Level at 1 Year

0.70 (0.60–0.81) 0.71 (0.63–0.79) 0.99 (0.84–1.16) Hazard Ratio (95% CI): Years since Randomization Patients with an Event (%) Placebo Icosapent Ethyl Triglyceride ≥150 mg/dL Icosapent Ethyl Triglyceride <150 mg/dL Icosapent Ethyl Triglyceride <150 mg/dL vs Placebo Icosapent Ethyl Triglyceride ≥150 mg/dL vs Placebo Icosapent Ethyl Triglyceride <150 vs ≥150 mg/dL 1 2 3 4 5 20 40 60 80 90 70 50 30 10 100

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

0.66 (0.57–0.77) 0.67 (0.56–0.80) 1.00 (0.82–1.23) Hazard Ratio (95% CI): Years since Randomization Patients with an Event (%) Placebo Icosapent Ethyl Triglyceride ≥150 mg/dL Icosapent Ethyl Triglyceride <150 mg/dL Icosapent Ethyl Triglyceride <150 mg/dL vs Placebo Icosapent Ethyl Triglyceride ≥150 mg/dL vs Placebo Icosapent Ethyl Triglyceride <150 vs ≥150 mg/dL 1 2 3 4 5 20 40 60 80 90 70 50 30 10 100

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

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

REDUCE-IT - % with Primary Efficacy Composite Endpoint in those with High TG Plus Low HDL-C

Subgroup Icosapent Ethyl Placebo HR (95% CI) P-heterogeneity TG ≥200 mg/dL and HDL-C ≤35 mg/dL % (Subjects with Event/Subjects) % (Subjects with Event/Subjects) 0.04 Yes 18.1 (149/823) 27.0 (214/794) 0.62 (0.51-0.77) No 17.0 (554/3258) 20.9 (342/1620) 0.79 (0.71-0.88)

Most Frequent Treatment-Emergent Adverse Events: ≥5% in Either Treatment Group and Significantly Different

Preferred Term Icosapent Ethyl (n=4089) Placebo (n=4090) P-value Diarrhea 367 (9.0%) 453 (11.1%) 0.002 Peripheral edema 267 (6.5%) 203 (5.0%) 0.002 Constipation 221 (5.4%) 149 (3.6%) <0.001 Atrial fibrillation 215 (5.3%) 159 (3.9%) 0.003 Anemia 191 (4.7%) 236 (5.8%) 0.03

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

Adjudicated Events: Hospitalization for Atrial Fibrillation or Atrial Flutter

Primary System Organ Class Preferred Term Icosapent Ethyl (N=4089) Placebo (N=4090) P-value Positively Adjudicated Atrial Fibrillation/Flutter[1]

127 (3.1%) 84 (2.1%) 0.004

Note: Percentages are based on the number of subjects randomized to each treatment group in the Safety population (N). All adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA Version 20.1). [1] Includes positively adjudicated Atrial Fibrillation/Flutter clinical events by the Clinical Endpoint Committee (CEC). P value was based

• n stratified log-rank test.

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

Proportions of First and Subsequent Events

Total N=2,909 Adjudicated Events Full Dataset

Subsequent Events n=1,303 45% First Events n=1,606 55%

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

Coronary Revascularization n=415 26% Fatal or Nonfatal MI n=532 33% Hospitalization for Unstable Angina n=214 13% Fatal or Nonfatal Stroke n=184 12% Cardiovascular Death n=261 16%

First Events Subsequent Events

Coronary Revascularization n=789 60% Fatal or Nonfatal MI n=225 17% Hospitalization for Unstable Angina n=85 7% Fatal or Nonfatal Stroke n=78 6% Cardiovascular Death n=126 10%

143 126 1,546 901 376 Placebo [N=4090] Number of Primary Composite Endpoint Events 3rd 1st 2nd ≥4 1,076 Icosapent Ethyl [N=4089] 72 63 705 236 2nd Events HR 0.68 (95% CI, 0.60-0.78) 1stEvents HR 0.75 (95% CI, 0.68-0.83) P=0.000000016 ≥4 Events RR 0.52 (95% CI, 0.38-0.70) 3rd Events HR 0.69 (95% CI, 0.59-0.82)

RR 0.70

(95% CI, 0.62-0.78)

P=0.00000000036

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

Reduced Dataset Event No.

• 63
• 71
• 196
• 140
• 470
• No. of

Fewer Cases

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.

1,600 1,200 800 400 600 1,000 1,400 200

Total (First and Subsequent) Events

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

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

Primary Composite Endpoint 1 Years since Randomization 5 Cumulative Events per Patient 2 3 4 0.0 0.1 0.2 0.3 0.4 0.6 0.5 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

• 159

Cardiovascular Death

• 12

Fatal or Nonfatal MI

• 42

Fatal or Nonfatal Stroke

• 14

Coronary Revascularization

• 76

Hospitalization for Unstable Angina

• 16
• 100
• 150
• 200
• 50

Risk Difference

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

For Every 1000 Patients Treated with Icosapent Ethyl for 5 Years

Adapted with permission* from Ganda OP, Bhatt DL, Mason RP, Miller M, Boden WE. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol. 2018;72:330-343. [*https://creativecommons.org/licenses.org/by-nc/4.0/]

Potential Benefits of EPA

Effects of EPA on Plaque Progression

Endothelial Dysfunction/ Oxidative Stress Inflammation/ Plaque Growth Unstable Plaque

Increase Endothelial function Nitric oxide bioavailablity EPA/AA ratio Fibrous cap thickness Lumen diameter Plaque stability Decrease Cholesterol crystalline domains Ox-LDL RLP-C Adhesion of monocytes Macrophages Foam cells IL-6 ICAM-1 IL-10 hs-CRP Lp-PLA2 MMPs Plaque volume Arterial stiffness Plaque vulnerability Thrombosis Platelet activation

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Limitations

• First in class to show ASCVD risk ↓ in placebo-

controlled RCT

• Mineral oil placebo

– LDL-C increased by 7 mg/dL in the placebo group compared with 2 mg/dL in the icosapent ethyl group

• Only 6% on ezetimibe
• PCSK9 inhibitors prohibited

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Positions of Other Organizations on Icosapent Ethyl

• American Diabetes Association Standards of Care

– Should be considered for patients with DM and ASCVD or other cardiac risk factors on a statin with controlled LDL-C and triglycerides 135-499 mg/dL to reduce ASCVD risk (3/27/19)

• 2019 EAS/ESC Guidelines

Baigent C et al. European Heart Journal 2019; 00: 1-78

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Positions of Other Organizations on Icosapent Ethyl

• American Heart Association Science Advisory

– In the context of HTG (TG 200-499 mg/dL), 4 g/d prescription n-3 FA effectively lowers TG by 20-30% and does not significantly increase LDL-C. – The TG-lowering efficacy and generally excellent safety and tolerability of n-3 FAs make them valuable tools for healthcare providers. – The use of n-3 FAs (4 g/d) for improving ASCVD risk in patients with HTG is supported by a 25% reduction in MACE endpoints in REDUCE-IT, a RCT of EPA-only in high risk patients on statin therapy. – We conclude that prescription n-3 FAs, whether EPA+DHA or EPA-only, at a dose of 4 g/d, are clinically useful for reducing TG, after any underlying causes are addressed and diet and lifestyle strategies are implemented, either as monotherapy or as an adjunct to other TG-lowering therapies.

Skulas-Ray A et al. Circulation 2019;140: DOI 10.1161/CIR.0000000000000709

Proposed NLA Position on the Use of Icosapent Ethyl in High and Very-high-risk Patients

• For patients 45 years of age or older with clinical ASCVD, or 50 years
• f age or older with type 2 diabetes requiring medication and ≥1

additional risk factor*, and fasting triglycerides 135-499 mg/dL on maximally tolerated statin, with or without ezetimibe, treatment with icosapent ethyl is recommended for ASCVD risk reduction. (I B-R)

• Age: men ≥55 years and women ≥65 years
• Cigarette smoker or stopped smoking within 3 months
• Hypertension (≥140 mmHg systolic OR ≥90 mmHg diastolic)
• r on antihypertensive medication
• HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women
• hs-CRP >3.0 mg/L
• Renal dysfunction: Creatinine clearance >30 and <60 mL/min
• Retinopathy
• Micro- or macro-albuminuria
• ABI <0.9 without symptoms of intermittent claudication

*

Adjunctive Therapies for ASCVD Risk Reduction in High-

• r Very-high-risk Statin-treated Patients Supported

by RCT Evidence

Moderate or High-intensity Statin Moderate or High-intensity Statin

Ezetimibe Ezetimibe

PCSK9 Inhibitor PCSK9 Inhibitor Icosapent Ethyl Icosapent Ethyl

Acute coronary syndrome within 10 days (IMPROVE-IT) Stable ASCVD; or Diabetes + ≥1 additional risk factor + TG 135-499 mg/dL (REDUCE-IT) Stable ASCVD + additional risk factors; or ACS within 1-12 months (FOURIER, ODYSSEY-Outcomes)

Cannon, CP et al.. N Engl J Med 2015;372:2387-97 Bhatt, DL et al. N Engl J Med 2019;380:11-22 Sabatine MS et al. N Engl J Med 2017;376:1713-1722 Schwartz GG et al. N Engl J Med 2018; 379:2097-2107