Access and Savings

VASCEPA is affordable for most patients*

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  • Access
  • Savings Card
  • Electronic Health Records
  • Low Income Subsidy
  • Mail Order Rebate Form

VASCEPA has unrestricted access on most plans regardless of TG level†

Graphic icon reading >80% overall unrestricted access and >95% unrestricted access for Medicare Part D patients
  • Overall, patients have >80% unrestricted access‡
Graphic icon reading >80% overall unrestricted access and >95% unrestricted access for Medicare Part D patients
  • Medicare Part D patients have >95% unrestricted access‡
Formulary coverage access

†VASCEPA has been studied in patient populations with TG levels ranging from 200 to 2000 mg/dL.

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Commercially insured patients§ can pay as little as $9 for a 90-day supply with the VASCEPA Savings Card. Subject to eligibility. Restrictions apply.‡

VASCEPA Savings Card
  • Most eligible, insured patients will pay as little as $9 of their copay every 90 days while saving up to $240 per 90-day fill§
  • If your patients prefer to get the copay card on a mobile device, instruct them to text "VASCEPA" to 97337. Message and data rates may apply
Get the card

§Offer Restrictions: May not be used to obtain prescription drugs paid in part by Federal or State Programs including Medicare, Medicaid, Medicare Advantage, Medicare Part D, Tricare, VA. Most eligible, insured patients will pay as little as $9 of their copay for either each month or a 90 day fill, with a maximum savings of up to $80 per month or $240 on a 90 day fill. Not for use by residents of VT, nor medical professionals licensed in VT. This offer is not valid for those patients under 18 years of age or patients whose plans do not permit use of a copay card. Void where prohibited by law, taxed, or restricted. Eligible patients include those who participate in commercial insurance, through a healthcare exchange, or pay cash. Offer good through December 31, 2019.

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Prescribe VASCEPA electronically

Universal Pharmacy Card (UPC) may be applied for any eligible patient by entering all 4 codes into the notes section of an e-prescription.

BIN# 004682

PCN# CN

GRP# EC86001050

ID# 49‍0665‍079‍08

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Low income subsidy (LIS)–qualified beneficiaries receive subsidized benefits||

LIS Medicare beneficiaries have low out-of-pocket prescription expenses (ranging from $0 to $8.35) for drugs such as VASCEPA, with a fixed branded copay that is not subject to a deductible or the coverage gap/donut hole.‡

Patients may be paying more than you think for generic medications

Average cost to patients with COMMERCIAL insurance in Q3 2018*
PRODUCT AVERAGE OUT OF POCKET PAID NUMBER OF PRESCRIPTIONS
Fenofibrate $19.61 967,185
Generic Lovaza® $21.83 174,289
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Mail order rebate form

Give your patients this form to fill out if they obtain their VASCEPA prescription via a mail order program.

Download rebate form
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Discover VASCEPA resources

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VASCEPA reduced TG without raising LDL-C as compared to placebo

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*Data on file.

‡As of August 31, 2018.

||Premium, deductible, copay, and drug costs in the coverage gap are reduced or eliminated for LIS beneficiaries.

Source: Symphony Health Claims Data; November 2018.

FDA-Approved Indication and Limitations of Use for VASCEPA1

  • VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia
  • In patients with severe hypertriglyceridemia, the effect of VASCEPA on cardiovascular mortality or morbidity or on the risk of pancreatitis has not been determined

Please see full Important Safety Information for VASCEPA and Important New Information from the recently completed REDUCE-IT™ cardiovascular outcomes study.

FDA has not reviewed and opined on a supplemental new drug application related to REDUCE-IT. FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population.

Important Safety Information for VASCEPA from FDA-Approved Label

    Data from Two 12-Week Studies (MARINE and ANCHOR) of Patients with Triglycerides Values of 200 to 2000 mg/dL (n=622 on VASCEPA, n=309 on placebo)1

  • VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components
  • In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy
  • Use with caution in patients with known hypersensitivity to fish and/or shellfish
  • The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia (2.3% VASCEPA, 1.0% placebo)
  • Adverse events may be reported by calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088
  • Patients receiving treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically
  • Patients should be advised to swallow VASCEPA capsules whole; not to break open, crush, dissolve, or chew VASCEPA

Please see full Prescribing Information for more information on VASCEPA.

IMPORTANT INFORMATION FOR HCPs ABOUT VASCEPA® (ICOSAPENT ETHYL) CAPSULES

IMPORTANT NEW INFORMATION: REDUCE-IT™ CARDIOVASCULAR OUTCOMES STUDY OF VASCEPA®2*

The effects of VASCEPA on the prevention of cardiovascular events was evaluated in a multi-center, double-blind, randomized, placebo-controlled, event-driven trial (REDUCE-IT, NCT01492361) in 8,179 adult patients at low-density lipoprotein cholesterol (LDL-C) goal, with established cardiovascular disease (CVD) or at high risk for CVD, and hypertriglyceridemia (fasting triglycerides (TG) ≥135 and <500 mg/dL).

  • Patients were eligible to enter the trial if they were at least 45 years of age and on stable statin therapy with fasting LDL-C levels of >40 and ≤100 mg/dL and fasting TG levels of ≥135 and <500 mg/dL. Patients also needed to have either established CVD (secondary prevention cohort), defined as documented history of coronary artery disease, cerebrovascular or carotid disease, or peripheral artery disease, or be at least 50 years of age with diabetes and at least one additional risk factor (primary prevention cohort).
    • Key exclusion criteria included severe heart failure, active severe liver disease, hemoglobin A1c >10.0%, planned coronary intervention or surgery, history of acute or chronic pancreatitis, and known hypersensitivity to fish, shellfish, or ingredients of VASCEPA or placebo.
  • 70.7% of patients were enrolled based on having established CVD (secondary prevention cohort), 29.3% were enrolled based on being at high risk for CVD (primary prevention cohort).
  • Patients were randomly assigned 1:1 to receive either VASCEPA (4 grams daily) or placebo (4089 VASCEPA, 4090 placebo).
  • The median follow-up duration was 58 months (4.9 years).
  • Overall, 99.8% of patients were followed until the end of the trial or death.
  • The median age at baseline was 64 years (range: 44 years to 92 years), with 46% being at least 65 years old; 28.8% were women.
  • The trial population was 90.2% White, 1.9% Black, and 5.5% Asian; 4.2% identified as Hispanic ethnicity.
  • Regarding prior diagnoses of cardiovascular disease, 46.7% had prior myocardial infarction, 6.1% prior unknown stroke or transient ischemic attack (TIA), and 9.2% had symptomatic peripheral arterial disease.
  • Selected additional baseline risk factors included hypertension (86.6%), diabetes mellitus (0.7% type 1; 57.8% type 2), current daily cigarette smoking (15.2%), New York Heart Association class I or II congestive heart failure (17.7%), and eGFR < 60 mL/min per 1.73 m2 (22.2%).
  • Patients enrolled were treated with statin therapy at baseline with most (93.2%) on a high- (30.8%) or moderate-intensity (62.5%) statin therapy, and 6.4% were also taking ezetimibe at baseline.
  • Most patients at baseline were taking at least one other cardiovascular medication including anti-platelet agents (79.4%), beta blockers (70.7%), angiotensin converting enzyme (ACE) inhibitors (51.9%), or angiotensin receptor blockers (27.0%).
  • On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline was 75.0 [62.0, 89.0] mg/dL; the mean (SD) was 76.2 (20.3) mg/dL.
  • On stable background lipid-lowering therapy, the median [Q1, Q3] fasting TG was 216.0 [176.0,272.5] mg/dL; the mean (SD) was 233.2 (80.1) mg/dL.

The primary results from REDUCE-IT are shown in the Table below (see CONDUCT OF REDUCE-IT AND ANALYSIS AND REVIEW OF REDUCE-IT DATA).

Effect of VASCEPA on Cardiovascular Events in Patients with Established CVD or at High Risk for CVD with Statin-treated Triglycerides ≥135 and <500 mg/dL in REDUCE-IT

Effect of VASCEPA on Cardiovascular Events in Patients with Established CVD or at High Risk for CVD with Statin-treated Triglycerides ≥135 and <500 mg/dL in REDUCE-IT

VASCEPA significantly reduced the following:

  • the risk for the primary composite endpoint (5-point MACE: time to first occurrence of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; p<0.001), and
  • the key secondary composite endpoint (3-point MACE: time to first occurrence of cardiovascular death, myocardial infarction, or stroke; p<0.001).

Prespecified hierarchical testing of other secondary endpoints revealed significant reductions in the following:

  • cardiovascular death (p=0.03),
  • fatal or nonfatal myocardial infarction (p<0.001),
  • fatal or nonfatal stroke (p=0.01),
  • emergent or urgent coronary revascularization (p<0.001), and
  • hospitalization for unstable angina (p=0.002).

The benefits of VASCEPA were seen on a background of predominately (93.2%) moderate- to high-intensity statin use and median baseline LDL-C levels of 75.0 mg/dL.

The Kaplan-Meier estimates of the cumulative incidence of the primary and key secondary composite endpoints over time are shown in Figure 1 and Figure 2 below.

Figure 1. Estimated Cumulative Incidence of Primary Composite Endpoint Over 5 Years in REDUCE-IT

Estimated Cumulative Incidence of Primary Composite Endpoint Over 5 Years in REDUCE-IT

CI denotes confidence interval. Curves were visually truncated at 5.7 years due to a limited number of events beyond that point in time; all patient data were included in analyses.


Figure 2. Estimated Incidence of Key Secondary Composite Endpoint Over 5 Years in REDUCE-IT

Estimated Incidence of Key Secondary Composite Endpoint Over 5 Years in REDUCE-IT

CI denotes confidence interval. Curves were visually truncated at 5.7 years due to a limited number of events beyond that point in time; all patient data were included in analyses.

The difference between VASCEPA and placebo in median percent change in TG from baseline to Month 4 was -20.1 (p<0.001) and from baseline to Month 12 was -19.7 (p<0.001). At Month 12, the median [Q1, Q3] TG was 175.0 [132.0, 238.0] mg/dL in the VASCEPA group, with 35.9% of patients having TG <150 mg/dL and 61.3% having a TG <200 mg/dL. The difference between VASCEPA and placebo in median percent change in LDL-C from baseline to Month 12 was -6.6% (p<0.001). At Month 12, the median [Q1, Q3] LDL-C was 77.0 [63.0, 94.0] mg/dL in the VASCEPA group, with 35.5% of patients having LDL-C <70 mg/dL and 79.9% having LDL-C <100 mg/dL.

Important Safety Information for VASCEPA from REDUCE-IT (n=4089 on VASCEPA, n=4090 on placebo)

  • Patients were exposed to VASCEPA or placebo for a median of 58 months; 86.9% of patients were exposed for ≥ 12 months, 77.2% were exposed for ≥ 24 months, 64.6% were exposed for ≥ 36 months, 53.6% were exposed for ≥48 months, 29.5% were exposed for ≥ 60 months, and 0.1% were exposed for ≥72 months.
  • Overall adverse event rates were similar across treatment groups.
    • Adverse events and serious adverse events leading to study drug discontinuation were similar to placebo.
    • The one serious adverse event that occurred at a frequency of at least 2% was pneumonia (2.6% in the VASCEPA group and 2.9% in the placebo group, P=0.42)

Treatment-Emergent Adverse Events

Treatment-Emergent Adverse Events

  • Adverse events occurring in 5% of VASCEPA patients and statistically more frequently with VASCEPA than placebo (Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018, Supplementary Appendix):
    • Peripheral edema (6.5% VASCEPA patients versus 5.0% placebo patients)
      • There was no significant difference in the prespecified adjudicated tertiary endpoint of new congestive heart failure, which occurred in 4.1% of VASCEPA patients versus 4.3% of placebo patients.
    • Constipation (5.4% VASCEPA patients versus 3.6% placebo patients)
    • Atrial fibrillation (5.3% VASCEPA patients versus 3.9% placebo patients)
      • This adverse event finding is consistent with an increase in the prespecified adjudicated tertiary endpoint of atrial fibrillation or flutter requiring hospitalization, which occurred in 3.1% of VASCEPA patients versus 2.1% of placebo patients (P=0.004).
    • The rate of treatment-emergent serious adverse events for bleeding was 2.7% in the VASCEPA group versus 2.1% in the placebo group, with a nonsignificant, but trending p-value of 0.06
    • There were
      • No fatal bleeding events in either group,
      • No significant increases in adjudicated hemorrhagic stroke (0.3% in VASCEPA patients versus 0.2% in placebo patients; P=0.55),
      • No significant serious central nervous system bleeding (0.3% versus 0.2%; P=0.42), and
      • No significant gastrointestinal bleeding (1.5% versus 1.1%; P=0.15).

Mineral oil placebo consideration and analysis

In REDUCE-IT, a placebo containing mineral oil was used to mimic the color and consistency of the drug studied. No strong evidence for biological activity of the same mineral oil was identified in connection with FDA approval of VASCEPA in July 2012 based on the MARINE phase 3 clinical trial, in connection with FDA review of the ANCHOR phase 3 clinical trial, or after several years of quarterly review by the Data Monitoring Committee (DMC) for REDUCE-IT after FDA requested that the DMC periodically assess unblinded lipid data to monitor for signals that the placebo might not be inert. While the DMC noted variation in LDL-C measurements in both arms and that a small physiological effect of mineral oil might be possible, the DMC concluded that it was not possible to determine if the LDL-C increase in the placebo arm was a natural increase over time or due to the mineral oil, they found no apparent effect on outcomes and found that this small change was unlikely to explain the observed benefit of VASCEPA over placebo.

Each of the three VASCEPA clinical trials, MARINE, ANCHOR and REDUCE-IT, was conducted under a special protocol, or SPA, agreement with FDA in which mineral oil was agreed with FDA as an acceptable placebo.

As published within the main presentation of the REDUCE-IT results (Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.), at baseline, the median LDL-C was 75.0 mg/dL. The median change in LDL-C was 3.1% (+2.0 mg/dL) for VASCEPA and 10.2% (+7.0 mg/dL) for the mineral oil placebo arm; placebo-corrected median change from baseline of -6.6% (-5.0 mg/dL; p < 0.001). If mineral oil in the placebo might have affected statin absorption in some patients, this might have contributed to differences in outcomes between the groups. However, the relatively small differences in LDL-C levels between groups would not be likely to explain the 25% risk reduction observed with VASCEPA, and a post hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDL-C level among the patients in the placebo group. Although open label, Japan EPA Lipid Intervention Study (JELIS) previously demonstrated a 19% risk reduction without a mineral oil placebo.

CONDUCT OF REDUCE-IT AND ANALYSIS AND REVIEW OF REDUCE-IT DATA

FDA has not reviewed and opined on a supplemental new drug application related to REDUCE-IT. FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population.*

REDUCE-IT results were first presented at the 2018 Scientific Sessions of the American Heart Association (AHA) on November 10, 2018 in Chicago, Illinois and concurrently published online in The New England Journal of Medicine (NEJM).2

REDUCE-IT was sponsored by Amarin Pharma, Inc. and its affiliates and conducted under a special protocol assessment agreement with FDA.

  • The REDUCE-IT steering committee, consisting of academic physicians, and Amarin representatives developed the protocol (Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.) and were responsible for the conduct and oversight of the study, and data interpretation.
  • The primary, secondary, and tertiary adjudicated endpoint analyses were validated by the data monitoring committee independent statistician.

Further REDUCE-IT data assessment and data release could yield additional useful information to inform greater understanding of the trial outcome:

  • Further detailed data assessment by Amarin and regulatory authorities will continue and take several months to complete and record
  • The final evaluation of the totality of the efficacy and safety data from REDUCE-IT may include some or all of the following, as well as other considerations:
    • New information affecting the degree of treatment benefit on studied endpoints
    • Study conduct and data robustness, quality, integrity and consistency
    • Additional safety data considerations and risk/benefit considerations
    • Consideration of REDUCE-IT results in the context of other clinical studies

VASCEPA may not be eligible for reimbursement under government healthcare programs (such as Medicare and Medicaid) and certain commercial plans to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population. We encourage you to check that for yourself.

IMPORTANT INFORMATION FOR HCPs ABOUT CONTINUED UNCERTAINTY AROUND THE BENEFIT, IF ANY, OF LOWERING TG LEVELS AFTER STATIN THERAPY IN PATIENTS WITH HIGH (200-499 mg/dL) TG LEVELS

  • In REDUCE-IT, cardiovascular benefits appeared similar across baseline levels of triglycerides (less than 150 mg/dL, 150 to 199 mg/dL, and 200 mg/dL or greater).
    • Additionally, the reduction in major adverse cardiovascular events with VASCEPA appeared to occur irrespective of an achieved triglyceride level above or below 150 mg/dL at one year, suggesting that the cardiovascular risk reduction was not tied to achieving a more normal triglyceride level.
    • These observations suggest that at least some of the impact of VASCEPA on the reduction in ischemic events may be explained by metabolic effects other than triglyceride lowering.
  • VASCEPA is not FDA-approved to lower TG levels in statin-treated patients with mixed dyslipidemia and persistent high (≥200 mg/dL and <500 mg/dL) TG levels due to current uncertainty regarding the benefit, if any, of drug-induced changes in lipid/lipoprotein parameters beyond statin-lowered LDL-C on cardiovascular risk among statin-treated patients with residually high TG.
    • Other cardiovascular outcomes trials (ACCORD Lipid, AIM-HIGH, and HPS2-THRIVE), while not designed to test the effect of lowering TG levels in patients with high TG levels after statin therapy, each failed to demonstrate incremental cardiovascular benefit of adding a second lipid-altering drug (fenofibrate or formulations of niacin), despite raising HDL-C and reducing TG levels, among statin-treated patients with well-controlled LDL-C.

Other cardiovascular outcomes trials that studied fish oil or mixtures of omega-3 acids that include the omega-3 acid, DHA, have reported negligible impact on cardiovascular events.

No head-to head, randomized, well-controlled studies have been conducted to compare the effects of VASCEPA with other FDA-approved TG-lowering therapies.

POTENTIAL MECHANISMS OF ACTION

Mechanisms responsible for the benefit shown in REDUCE-IT were not the focus of REDUCE-IT, but the banked samples and array of biomarkers measured leave room for mechanistic insights through future analyses. Potential mechanisms discussed in Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018., include TG reduction, anti-thrombotic effects, antiplatelet or anticoagulant effects, membrane-stabilizing effects, effects on stabilization and/or regression of coronary plaque and inflammation reduction. More study is needed to determine to what extent, if any, these effects or others may be responsible for the CV risk reduction benefit demonstrated with use of VASCEPA in REDUCE-IT.

*This information is intended to ensure Amarin meets its continuing obligation to update healthcare professionals regarding off-label use of VASCEPA to assure that its communications remain truthful and non-misleading, consistent with the federal court approved settlement under Amarin Pharma, Inc. et al. v. United States Food and Drug Administration et al., 119 F.Supp.3d 196, 236 (S.D.N.Y. 2015).

Disclosure References: 1. VASCEPA [package insert]. Bedminster, NJ: Amarin Pharma, Inc.; 2017. 2. Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018. Bhatt DL, AHA 2018, Chicago.

FDA-Approved Indication and Limitations of Use for VASCEPA1

  • VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.
  • In patients with severe hypertriglyceridemia, the effect of VASCEPA on cardiovascular mortality or morbidity or on the risk of pancreatitis has not been determined.

Please see full Important Safety Information for VASCEPA and Important New Information from the recently completed REDUCE-IT™ cardiovascular outcomes study.
FDA has not reviewed and opined on a supplemental new drug application related to REDUCE-IT. FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population.

Important Safety Information for VASCEPA from FDA-Approved Label

  • VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components
  • Use with caution in patients with known hypersensitivity to fish and/or shellfish
  • In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy
  • The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia (2.3% VASCEPA, 1.0% placebo)
  • Adverse events may be reported by calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088
  • Patients receiving treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically
  • Patients should be advised to swallow VASCEPA capsules whole; not to break open, crush, dissolve, or chew VASCEPA

Please see full Prescribing Information for more information on VASCEPA.

IMPORTANT INFORMATION FOR HCPs ABOUT VASCEPA AS AN ADD-ON TO STATINS IN PATIENTS WITH HIGH (200-499 mg/dL) TG LEVELS

  • Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease. VASCEPA should not be taken in place of a healthy diet and lifestyle or statin therapy
  • The ANCHOR trial demonstrates that VASCEPA lowers TG levels in patients with high (≥200 mg/dL and <500 mg/dL) TG levels not controlled by diet and statin therapy
  • In the ANCHOR trial, VASCEPA 4 g/day significantly reduced TG, non-HDL-C, Apo B, VLDL-C, TC, and HDL-C levels from baseline relative to placebo in patients with high (≥200 mg/dL and <500 mg/dL) TG levels not controlled by diet and statin therapy
  • The reduction in TG observed with VASCEPA was not associated with elevations in LDL-C relative to placebo
  • VASCEPA is not FDA-approved for the treatment of statin-treated patients with mixed dyslipidemia and high (≥200 mg/dL and <500 mg/dL) TG levels due to current uncertainty regarding the benefit, if any, of drug-induced changes in lipid/lipoprotein parameters beyond statin-lowered LDL-C on cardiovascular risk among statin-treated patients with residually high TG. No prospective study has been conducted to test and support what, if any, benefit exists
  • Recent cardiovascular outcomes trials (ACCORD Lipid, AIM-HIGH, and HPS2-THRIVE), while not designed to test the effect of lowering TG levels in patients with high TG levels after statin therapy, each failed to demonstrate incremental cardiovascular benefit of adding a second lipid-altering drug (fenofibrate or formulations of niacin), despite raising HDL-C and reducing TG levels, among statin-treated patients with well-controlled LDL-C
  • VASCEPA is not FDA-approved to reduce the risk of coronary heart disease
  • The effect of VASCEPA on the risk of cardiovascular mortality and morbidity has not been determined
  • A cardiovascular outcomes study of VASCEPA designed to evaluate the efficacy of VASCEPA in reducing cardiovascular mortality and morbidity in a high-risk patient population on statin therapy is currently underway (REDUCE-IT)
  • VASCEPA may not be eligible for reimbursement under government healthcare programs (such as Medicare and Medicaid) to reduce the risk of coronary heart disease or for treatment of statin-treated patients with mixed dyslipidemia and high (≥200 mg/dL and <500 mg/dL) TG levels. We encourage you to check that for yourself
  • The ANCHOR trial was sponsored by Amarin Pharma, Inc. and its affiliates

Results from the ANCHOR study1,3

Co-administration therapy with statins for additional lipid management in mixed dyslipidemia

  • The effects of VASCEPA as add-on therapy to treatment with statins were evaluated in a randomized, placebo-controlled, double-blind, parallel-group study of 453 adult patients (226 receiving VASCEPA and 227 receiving placebo) with persistent high triglyceride levels (≥200 mg/dL and <500 mg/dL) despite statin therapy
  • All patients were receiving statin therapy (atorvastatin, rosuvastatin, or simvastatin) and were treated to LDL-C goal prior to randomization
  • Patients were randomized to either VASCEPA or placebo and treated for 12 weeks with statin co-therapy
  • The same statin at the same dose was continued throughout the study
  • The median baseline TG and LDL-C levels in these patients were 259 mg/dL and 83 mg/dL, respectively
  • The randomized population in this study was mostly Caucasian (96%) and male (61%)
  • The mean age was 61 years and the mean body mass index was 33 kg/m2
  • Seventy-three percent (73%) of patients had diabetes at baseline

Response to the addition of VASCEPA to ongoing statin therapy in patients with high triglyceride levels (≥200 mg/dL and <500 mg/dL)

The changes in the major lipoprotein lipid parameters for the groups receiving VASCEPA plus statin or placebo plus statin are shown in the table.

(Data reviewed and confirmed by the FDA—indication not approved by the FDA)

Parameter VASCEPA 4 g/day + statin
(n=226)		 Placebo + statin
(n=227)		 Difference (95% Confidence Interval) P value
Baseline % Change Baseline % Change
TG (mg/dL) 265 -18 259 6 -22 (-27, -16) <0.0001
LDL-C (mg/dL) 82 2 84 9 -6 (-11, -2) <0.01
Non–HDL-C (mg/dL) 128 -5 128 10 -14 (-17, -10) <0.0001
Apo B (mg/dL) 93 -2 91 7 -9 (-12, -6) <0.0001
VLDL-C (mg/dL) 44 -12 42 15 -24 (-32, -17) <0.0001
TC (mg/dL) 167 -3 168 9 -12 (-15, -9) <0.0001
HDL-C (mg/dL) 37 -1 39 5 -5 (-7, -2) <0.01

% change=median percent change from baseline.

Difference=median of (VASCEPA % change–placebo % change) (Hodges-Lehmann Estimate).

P values from Wilcoxon rank sum test.

VASCEPA significantly reduced TG, non–HDL-C, Apo B, VLDL-C, TC, and HDL-C levels from baseline relative to placebo. The reduction in TG observed with VASCEPA was not associated with elevations in LDL-C relative to placebo.

The effect of VASCEPA on cardiovascular mortality and morbidity in patients with mixed dyslipidemia has not been determined.

Important Information for Healthcare Professionals on Inflammatory Markers3,4

  • The effect of VASCEPA on inflammatory biomarkers
    • The ANCHOR and MARINE trials assessed the effect of VASCEPA 4 grams/day (g/d) on the pre-specified inflammatory markers Lp-PLA2, hsCRP, Ox-LDL, ICAM-1, and IL-6 (see tables below)
      • With the exception of Lp-PLA2, a secondary endpoint, all of the other inflammatory markers were exploratory endpoints
    • In the ANCHOR and MARINE trials, VASCEPA 4 g/d significantly reduced Lp-PLA2 and hsCRP levels from baseline relative to placebo in each of the respective groups of patients with hypertriglyceridemia studied. In the ANCHOR trial, VASCEPA 4 g/d significantly reduced Ox-LDL levels from baseline relative to placebo
      • In the ANCHOR trial,
        • Lp-PLA2 and hsCRP were measured in ≥93% of randomized patients
        • ICAM-1, Ox-LDL, and IL-6 were measured in the first 240 of 702 (34.2%) of randomized patients (or approximately 80 patients per each of the three treatment arms)
      • In the MARINE trial, inflammatory markers were measured in ≥183 of 229 (≥80%) of randomized patients (or ≥60 patients per each of the three treatment arms)
      • hsCRP is an acute-phase reactant and has high intra-individual variability
        • Therefore, a single test for hsCRP, as was performed at each timepoint of the ANCHOR and MARINE trials, may not accurately reflect an individual patient’s basal or on-treatment hsCRP levels
        • Repeat measurement may be required to firmly establish an individual’s basal hsCRP concentration, as well as to accurately understand treatment-induced changes in hsCRP

ANCHOR Inflammatory Markers: Response to the Addition of VASCEPA to Ongoing Statin Therapy in Patients with High Triglyceride Levels (≥200 mg/dL and <500 mg/dL)

Parameter VASCEPA 4 g/day + Statin Placebo + Statin Difference (95% Confidence Interval) P value
Baseline % Change Baseline % Change
Lp-PLA2 (ng/mL)
[n=217, 213] 		180 -13 185 7 -19 (-22, -16) <0.0001
hsCRP (mg/L)
[n=217, 219] 		2 -2 2 17 -22 (-34, -9) 0.0005
Ox-LDL (U/L)
[n=78, 84] 		54 -5 52 12 -13 (-19, -8) <0.0001
ICAM-1 (ng/mL)
[n=78, 83] 		273 1 269 4 -2 (-6, 1) 0.1888
IL-6 (pg/mL)
[n=78, 83] 		3 3 3 3 -1 (-16, 15) 0.9031

% change=median percent change from baseline.

Difference=median of (VASCEPA % change–placebo % change) (Hodges-Lehmann Estimate).

P values from Wilcoxon rank sum test.

Only subjects with non-missing baseline and week 12 values are included. P values for Lp-PLA2, a secondary endpoint, were adjusted for multiple comparisons; all other endpoints are exploratory. The n’s represent the number of subjects with marker samples tested in the VASCEPA 4 g/day + statin and placebo + statin treatment arms, respectively.

hsCRP=high-sensitivity C-reactive protein, ICAM-1=intercellular adhesion molecule-1, IL-6=interleukin-6, Lp-PLA2=lipoprotein-associated phospholipase A2, Ox-LDL=oxidized low-density lipoprotein

MARINE Inflammatory Markers: Response to the Addition of VASCEPA in Patients with Very High Triglyceride Levels (≥500 mg/dL and ≤2000 mg/dL)

Parameter VASCEPA 4 g/day Placebo Difference (95% Confidence Interval) P value
Baseline % Change Baseline % Change
Lp-PLA2 (ng/mL)
[n=73, 70] 		246 -17 253 -2 -14 (-20, -6) 0.0003
hsCRP (mg/L)
[n=75, 72] 		2 -3 2 33 -36 (-58, -15) 0.0012
Ox-LDL (U/L)
[n=74, 71] 		76 -7 77 3 -7 (-13, 0.1) 0.0548
ICAM-1 (ng/mL)
[n=75, 72] 		250 -1 248 3 -3 (-6, 0.6) 0.1188
IL-6 (pg/mL)
[n=60, 61] 		2 0.3 3 5 11 (-11, 32) 0.3629

% change=median percent change from baseline.

Difference=median of (VASCEPA % change–placebo % change) (Hodges-Lehmann Estimate).

P values from Wilcoxon rank sum test.

Only subjects with non-missing baseline and week 12 values are included. P values for Lp-PLA2, a secondary endpoint, were adjusted for multiple comparisons; all other endpoints are exploratory. The n’s represent the number of subjects with marker samples tested in the VASCEPA 4 g/day and placebo treatment arms, respectively.

hsCRP=high-sensitivity C-reactive protein, ICAM-1=intercellular adhesion molecule-1, IL-6=interleukin-6, Lp-PLA2=lipoprotein-associated phospholipase A2, Ox-LDL=oxidized low-density lipoprotein

This information on inflammatory markers cannot be used in isolation. Please see additional information on the ANCHOR study above and inflammatory markers below.

  • Supportive, but not conclusive, data show that reducing inflammatory biomarkers may also reduce CV events with agents other than VASCEPA, but further trials are needed [Ridker et al., NEJM 2008; Nidorf et al., JACC 2013; Martinez et al., JAHA 2015; Ridker et al., NEJM 2017; Harrington, NEJM 2017]
  • Limitations of featured data
    • VASCEPA is not FDA-approved to reduce the inflammatory biomarkers discussed in this document
    • The effects of VASCEPA on inflammatory biomarkers have not been approved for inclusion in FDA-approved labeling of VASCEPA
    • Additional trials are needed to evaluate the CV benefit, if any, of reducing inflammatory biomarkers with VASCEPA
      • Despite the putative cardio-protective effects reported in earlier literature for niacin on markers including C-reactive protein (CRP), Lp-PLA2, and other inflammatory biomarkers, a beneficial effect on major adverse cardiovascular events (MACE) was not observed for niacin in the AIM-HIGH and HPS2-THRIVE trials when studied in patients with well controlled LDL-C levels on statin therapy. Therefore, a non-statin lipid altering drug effect on such inflammatory biomarkers may not translate into a reduced risk for MACE when used in combination with statin therapy
      • Lp-PLA2 has been evaluated in two large CV outcome trials with an investigational agent that inhibits Lp-PLA2 activity. One study showed no impact on CV events in patients hospitalized for acute coronary syndrome [O’Donoghue et al., JAMA 2014]. The other study showed no impact on CV events in patients with chronic coronary disease (prior myocardial infarction, prior revascularization, or multivessel coronary disease) [STABILITY Investigators, NEJM 2014]. Additionally, a genetic study found that variants that reduce Lp-PLA2 activity to a degree similar to activity associated with darapladib, an Lp-PLA2 inhibitor, had no effect on the risk of coronary heart disease [Polfus et al., NEJM 2015]
      • hsCRP was evaluated in a CV outcomes trial that demonstrated that high-intensity statin therapy reduced CV risk in individuals with hsCRP ≥2.0 mg/L, LDL-C <130 mg/dL, and one additional CV risk factor, however, the study was not designed to evaluate whether statin therapy would still reduce atherosclerotic cardiovascular disease (ASCVD) risk in individuals with CRP <2.0 mg/L and the same 10-year cardiovascular risk [Ridker et al., NEJM 2008; Stone et al., Circulation 2014]. Additionally, this CV outcomes trial, called Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), was not designed to evaluate whether treatment guided by risk based on hsCRP levels would improve health outcomes [Stone et al., Circulation 2014]. Statins are likely to provide benefit without regard to elevated hsCRP levels [Yousuf et al., JACC 2013]
        • It is unclear to what degree hsCRP reduction contributed to the results from the JUPITER trial
        • It is unknown whether results similar to those from the JUPITER trial could be achieved with other statins or with adjuncts to statin therapy
        • JUPITER did not use any adjuncts to statin therapy to reduce lipids or inflammatory biomarkers
        • JUPITER was not a study of patients with high median triglyceride levels (≥200 mg/dL) at baseline
      • Both hsCRP and IL-6 were evaluated in the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial with the use of canakinumab, a monoclonal antibody that neutralizes IL-1β, as secondary prevention in patients (N=10,061) with a previous myocardial infarction and an elevated level of hsCRP [Ridker et al., NEJM 2017]. Over 90% of patients also received statin therapy. The effect of VASCEPA, if any, on IL-1β has not been studied
        • The CANTOS trial did show a CV relative risk reduction (15%) in patients with a prior myocardial infarction and an hsCRP level of 2 mg/L with the 150-mg dose, but not with the other doses studied
        • In CANTOS, at 48 months, there were no significant reductions from baseline in LDL-C or HDL-C and a 4%-5% median increase in TGs from baseline
      • CRP evaluation in animal data and human genetic data indicate a lack of causal relationship with coronary heart disease [Yousuf et al., JACC 2013]
      • Reductions in Ox-LDL, ICAM-1, and IL-6 have not been repeatedly studied to examine effects, if any, on cardiovascular event reduction in prospectively designed, large, randomized, placebo-controlled cardiovascular outcomes trials. Additional studies are needed

JELIS: Important Information for Healthcare Professionals Considering Co-administration Therapy with Statins for Additional Lipid Management in Mixed Dyslipidemia

The publications, the study and sub-analyses, and the study sponsor

  • Yokoyama et al. 2007: The primary publication presenting the results of a long-term cardiovascular outcomes study of a highly purified eicosapentaenoic acid (EPA) product coadministered with statin therapy in 18,645 Japanese patients, the Japan EPA lipid intervention study (JELIS). JELIS was a prospective, randomized, open-label trial with blinded endpoint evaluation (PROBE design)5
  • Saito et al. 2008: A prespecified JELIS primary prevention sub-analysis that assessed, among other things, the differences in coronary artery disease (CAD) incidences in patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels6
  • Matsuzaki et al. 2009: An additional JELIS sub-analysis that assessed the incidence of secondary major cardiovascular events in patients with established CAD7

JELIS was supported by grants from the manufacturer of the product, Mochida Pharmaceutical Co Ltd, Tokyo, Japan.

The product studied in JELIS and VASCEPA® (icosapent ethyl) capsules

The product studied in JELIS and VASCEPA, are highly similar based on a US Food and Drug Administration (FDA) review of both a comprehensive analytical comparison and published reports on each product’s content. Each product is highly purified EPA. The product studied in JELIS is not available in the United States.

The highly purified EPA studied in JELIS was administered at 1.8 grams/day (g/d). VASCEPA at 4 g/d is an FDA-approved product indicated for a different use than that investigated in JELIS (see VASCEPA (icosapent ethyl) Indication and Limitations of Use above). The effect of VASCEPA on cardiovascular mortality and morbidity has not been determined. VASCEPA 4 g/d is under clinical investigation to evaluate its potential in reducing cardiovascular mortality and morbidity in a combined primary and secondary prevention (high-risk) patient population receiving statin therapy (see Ongoing cardiovascular outcomes study of VASCEPA in statin-treated patients below).

Important Information for healthcare professionals about JELIS

  • JELIS provides supportive but not conclusive data that EPA drug therapy may reduce major coronary events
    • JELIS reached its primary endpoint in the combined primary and secondary prevention population showing a 19% relative risk reduction in major coronary events in statin-treated patients with hypercholesterolemia in Japan
      • Major coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, and other nonfatal events, including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting
    • The main component contributing to the primary endpoint results in JELIS summarized herein was unstable angina involving hospital treatment, which is a more subjective endpoint result than, for example, objective major adverse cardiovascular event endpoints (e.g., heart attack, stroke, or cardiovascular death)
      • A subjective endpoint, such as unstable angina, may be particularly unreliable in an open-label trial, such as JELIS, where patients and healthcare professionals are making decisions regarding hospitalizations
  • JELIS results cannot be generalized to other populations
    • Subjects in JELIS were limited to Japanese adults
      • The average dietary intake of fish in Japan is about 5 times higher than that in other countries
      • Baseline blood EPA levels in JELIS before pharmacotherapy with 1.8 g/d of EPA were higher than those recorded in the US population
    • Subjects in JELIS received a low dose of statin therapy based on then-current Japanese treatment guidelines that may be considered inadequate under current guidelines in the United States
  • FDA determined that JELIS results could not be used as support for or against the use of TG levels as a surrogate for cardiovascular risk reduction
    • In the primary endpoint analysis, median baseline TG levels were not high (153 mg/dL [1.73 mmol/L])
      • Assessment of the TG-lowering benefits of EPA therapy in JELIS is complicated by the small number of subjects with high median TG levels (≥200 mg/dL) at baseline prior to statin treatment
        • A statin run-in or stabilization period prior to randomization to EPA would have likely further reduced the baseline median TG level
    • Patients treated with EPA and statin in JELIS achieved TG levels that were only 5% lower, on average, than those achieved among patients treated with statin alone; however, the reduction in cardiovascular risk in the primary endpoint analysis was 19% [Yokoyama]
      • Likewise, within the primary and secondary prevention sub-analyses, TG levels were lowered only 5% on average in the EPA plus statin group compared with the statin alone group; however, the relative risk reduction was
        • 53% in the primary prevention population with elevated TG and low HDL-C levels [Saito]
        • 23% in the secondary prevention population with established CAD [Matsuzaki]
    • These large differences in magnitude between TG reduction and risk reduction in JELIS suggest that the effects of EPA on TG levels alone may not be responsible for, or predict, the observed differences in cardiovascular events between treatment groups in JELIS
    • A nonstatin lipid-altering drug’s effects on biomarkers may not translate into a reduced cardiovascular risk when used in combination with statin therapy (see Important Information for HCPs about VASCEPA as an add-on to statins in patients with high [200-499 mg/dL] TG levels)
  • It is possible that the putative cardioprotective effects of EPA observed in JELIS are due not to a single mode of action, such as TG lowering, but rather to multiple mechanisms working together
    • EPA may have beneficial effects on multiple atherosclerosis processes, including endothelial function, oxidative stress, foam cell formation, inflammation/cytokines, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture8
    • Further study is needed to determine the clinical benefit, if any, of EPA therapy in statin-treated patients with elevated TG levels (see Ongoing cardiovascular outcomes study of VASCEPA in statin-treated patients below)
  • Limitations of subpopulation analyses
    • JELIS reached its primary endpoint in the combined primary and secondary prevention population
    • JELIS was not powered to evaluate primary and secondary prevention populations individually or those explored in the Saito and Matsuzaki publications

Major coronary events: JELIS and sub-analyses

Adapted from Yokoyama et al, Figure 3: Estimated hazard ratios of clinical endpoints stratified by prevention stratum; Saito et al, Figure 3: Effects of EPA on the incidence of MCE for the high TG/low HDL-C group; Matsuzaki et al, Figure 2a: Kaplan-Meier estimates of the incidence of the primary endpoint of coronary events occurring in the group of all patients.

Major Coronary Events EPA + Statin Statin (Control) P value HR (95% Confidence Interval)
Yokoyama et al.
  • Total population
    (N=18,645)
2.8% 3.5% 0.011 0.81 (0.69-0.95)
  • Primary prevention
    (n=14,981)
1.4% 1.7% 0.132 0.82 (0.63-1.06)
  • Secondary prevention
    (n=3,664)
8.7% 10.7% 0.048 0.81 (0.66-1.00)
Saito et al.
High TG (≥150 mg/dL)/low HDL-C (<40 mg/dL)
(n=957)* 		3.3% for pooled treatment arms; event rates were not reported for each arm 0.043 0.47 (0.23-0.98)
Matsuzaki et al.
  • CAD (n=3,664)†
8.7% 10.7% 0.017 0.77 (0.63-0.96)

HR, hazard ratio.

*There was no suggestion of a difference in treatment effect between TG levels of ≥151 mg/dL (HR, 0.84; 95% Confidence Interval, 0.68-1.04) and TG levels of <151 mg/dL (HR, 0.79; 95% Confidence Interval, 0.61-1.02) when HDL-C is not considered (interaction P=0.75).

†When JELIS was conducted (over the period of 1996-2004), cholesterol management was not as aggressive as it is today for someone with established CAD. In addition, there was likely less use of antiplatelet/anticoagulant agents for someone with established CAD as there is in medical practice today.

  • Safety findings from JELIS
    • Gastrointestinal disturbances (3.8% on EPA + statin and 1.7% on statin alone; P<0.0001)
    • Skin abnormalities (1.7% on EPA + statin and 0.7% on statin alone; P<0.0001)
    • Hemorrhage (1.1% on EPA + statin and 0.6% on statin alone; P=0.0006)
      • No between-group differences in stroke, including cerebral and/or subarachnoid hemorrhage
    • Abnormal laboratory data (slight excess of aspartate aminotransferase (AST) elevations, 0.6% on EPA + statin and 0.4% on statin alone; P=0.03)
  • The rate of discontinuation due to treatment-related adverse effects was 11.7% in the EPA group and 7.2% in the control group

Other cardiovascular outcomes trials in the omega-3 class have reported negligible impact on cardiovascular events

JELIS is the only cardiovascular outcomes trial that has examined the effects of EPA (1.8 g/d) plus statin vs statin alone. The 12-week end-of-treatment blood levels after 4 g/d of EPA in an American population achieved approximately the same end-of-treatment blood levels of EPA observed in the Japanese population studied in JELIS.9 The clinical relevance of EPA blood levels on cardiovascular outcomes has not been determined.

Following JELIS and GISSI-P (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico-Prevenzione),10 randomized placebo-controlled trials have failed to confirm definitive cardiovascular benefit with similarly low (<2 g/d) doses of omega-3 fatty acid mixtures. GISSI-P is an open-label outcomes trial (1 g omega-3 fatty acid mixture), conducted in Italy, that supported the hypothesis that omega-3 fatty acids likely exert their cardioprotective effects through nonlipid-mediated mechanisms. But, in GISSI-P, only ≈5% of patients were receiving statins at baseline compared with >40%-50% in more recent, similarly low-dose omega-3 trials that failed to confirm benefit. GISSI-P did not suggest an effect on the incidence of nonfatal cardiovascular events and the effects of omega-3 fatty acids on lipids, including serum TGs, were negligible.

The omega-3 fatty acid mixtures studied in such other outcomes trials were primarily comprised of EPA and docosahexaenoic acid (DHA) (typically, approximately 900 mg total per 1 gram capsule) and also typically included a number of other omega-3 and omega-6 acids, as well as other constituents. No head-to-head cardiovascular outcomes study of EPA vs a mixture of omega-3 acids has been conducted. No cardiovascular outcomes trial has been completed with sufficient power to prospectively evaluate the effect of EPA or omega-3 fatty acid mixtures in statin-treated patients, either with high TG levels (≥200 mg/dL) or with both high TG and low HDL-C levels.

Ongoing cardiovascular outcomes study of VASCEPA in statin-treated patients

The encouraging results of JELIS contributed to the justification to investigate the potential of VASCEPA to reduce cardiovascular risk. A cardiovascular outcomes study of VASCEPA designed to evaluate the efficacy of 4 g/d of VASCEPA in reducing cardiovascular mortality and morbidity in a high-risk patient population on statin therapy is currently underway (REDUCE-IT). The sponsor of REDUCE-IT, Amarin Pharma, Inc., and the FDA are strongly aligned in recognizing the importance of continuing to collaborate to complete REDUCE-IT so that a definitive answer may be provided to answer the question of whether VASCEPA, in combination with a statin, results in reduction of cardiovascular risk over a statin alone.

Participants in the clinical investigation of VASCEPA currently underway (REDUCE-IT) should not be advised to use VASCEPA in place of participation in that study. VASCEPA should not be taken in place of a healthy diet and lifestyle or statin therapy.

VASCEPA may not be eligible for reimbursement under government healthcare programs (such as Medicare and Medicaid) to reduce the risk of coronary heart disease or for treatment of statin-treated patients with high (≥200 mg/dL and <500 mg/dL) TG levels. We encourage you to check that for yourself.

These publications are provided to you by Amarin Pharma, Inc., the manufacturer of VASCEPA.

IMPORTANT INFORMATION FOR HCPs ABOUT VASCEPA®

References: 1. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110(7):984-992. 2.VASCEPA [package insert]. Bedminster, NJ: Amarin Pharma, Inc.; 2017. 3. Amarin Pharma, Inc. et al v. United States Food and Drug Administration et al, 119 F. Supp. 3d. 196 (S.D.N.Y. 2015). 4. Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs. 2013;13(1):37-46. 5. Yokoyama M, Origasa H, Matsuzaki M, et al; for the Japan EPA Lipid Intervention Study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090-1098. 6. Saito Y, Yokoyama M, Origasa H, et al; for the JELIS Investigators, Japan. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis. 2008;200(1):135-140. 7. Matsuzaki M, Yokoyama M, Saito Y, et al; for the JELIS Investigators, Japan. Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease. Circ J. 2009;73(7):1283-1290. 8. Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis. 2015;242(1):357-366. 9. Weintraub HS. Overview of prescription omega-3 fatty acid products for hypertriglyceridemia. Postgrad Med. 2014;126(7):7-18. 10. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999;354(9177):447-455.