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NLA Position Statement on the Useof Icosapent Ethyl in High- or
Very-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
www.lipid.org
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 ASCVD2 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 ofABI: ankle brachial indexCABG: Coronary artery bypass surgeryPCI: Percutaneous coronary interventionCKD: 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
www.lipid.org
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
www.lipid.org
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
www.lipid.org
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
www.lipid.org
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
1.00.5
CHD Death EventsTreatmentn = 1301 (3.3%)
Controln = 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 CohortPrimary 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
Majo
r coro
nary
events
(%
)
Hazard ratio: 0.81 (0.69–0.95)
p=0.011 ARR 0.7%
Years
Control
1
2
3
4
01 50 2 3 4
Years
0.5
1.0
1.5
2.0
01 50 2 3 4
4.0
8.0
01 50 2 3 4
Years
EPA*
Control
EPA*
Control
EPA*
*1.8 g/day
Coronary events:Sudden cardiac deathFatal and non-fatal MIUnstable anginaPCICABG
N=18,645Baseline LDL-C 182 mg/dLRandomized 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
Le
ve
l (m
g/d
l)
GISSI-P
1999
0
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
Pri
mary
En
dp
oin
t (%
)
GISSI-P
1999
0
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
1:1Randomization
withcontinuation of
stable statintherapy
(N=8179)
Lead-in
•
•
•
Key Inclusion Criteria
• Statin-treated menand women ≥45 yrs
Established CVD(~70% of patients) orDM + ≥1 risk factor
TG ≥150 mg/dL and<500 mg/dL*
LDL-C >40 mg/dL and≤100 mg/dL
•
•
•
IcosapentEthyl4 g/day
(n=4089)
Placebo(n=4090)
Lab values Screening Baseline
Visit 1 2 3 4 5 6 7 Final Visit8 9
Months -1 Month 0 4 Every 12 months12
Up to 6.2 years†Year 0
Primary Endpoint
Time fromrandomization to the
first occurrence ofcomposite of CV death,nonfatal MI, nonfatal
stroke, coronaryrevascularization,unstable angina
requiring hospitalization
4 months,12 months,
annually
End-of-studyfollow-up
visit
End-of-studyfollow-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).
Statinstabilization
Medicationwashout
Lipidqualification
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
Pa
tie
nts
wit
h a
n E
ve
nt
(%)
0 1 2 3 4 5
0
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
Pa
tie
nts
wit
h a
n E
ve
nt
(%)
0 1 2 3 4 5
0
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 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
<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 TestingRRR
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
Pati
en
ts w
ith
an
Ev
en
t (%
)
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
0 1 2 3 4 5
0
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
Pati
en
ts w
ith
an
Ev
en
t (%
)
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
0 1 2 3 4 5
0
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 andHDL-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
on 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]
Nu
mb
er
of
Pri
mary
Co
mp
os
ite
En
dp
oin
tE
ve
nts
3rd1st 2nd ≥4
1,076
Icosapent Ethyl
[N=4089]
7263
705
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
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
Reduced Dataset Event No.
-63
-71
-196
-140
-470
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.
1,600
1,200
800
400
0
600
1,000
1,400
200
Total (First and Subsequent) EventsPrimary: CV Death, MI, Stroke, Coronary Revasc, Unstable Angina
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
Primary Composite Endpoint
0 1
Years since Randomization
5
Cu
mu
lati
ve E
ven
ts p
er
Pati
en
t
2 3 40.0
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
0
Ris
k D
iffe
ren
ce
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 functionNitric oxide bioavailablity
EPA/AA ratio Fibrous cap thicknessLumen diameterPlaque stability
Decrease Cholesterol crystalline domainsOx-LDLRLP-CAdhesion of monocytesMacrophagesFoam cells
IL-6ICAM-1IL-10hs-CRPLp-PLA2
MMPs
Plaque volumeArterial stiffnessPlaque vulnerabilityThrombosisPlatelet activation
www.lipid.org
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
www.lipid.org
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
www.lipid.org
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 IcosapentEthyl in High and Very-high-risk Patients
• For patients 45 years of age or older with clinical ASCVD, or 50 years of 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)
or 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-
or Very-high-risk Statin-treated Patients Supported
by RCT Evidence
Moderate or High-intensity
Statin
Moderate or High-intensity
Statin
EzetimibeEzetimibe 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;380:11-22Sabatine MS et al. N Engl J Med 2017;376:1713-1722
Schwartz GG et al. N Engl J Med 2018; 379:2097-2107
