A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High-Risk Patients With Hypertriglyceridemia and on Statin

Conditions

Cardiovascular Diseases

Keywords

Coronary Artery Disease, Myocardial Ischemia, Coronary Disease, Heart Diseases, Acute Coronary Syndrome, Cardiovascular Diseases, Arteriosclerosis, Arterial Occlusive Diseases, Vascular Diseases, Angina Pectoris, Chest Pain, Anticholesteremic Agents, Hypolipidemic Agents, Lipid Regulating Agents, Hypertriglyceridemia, Omega-3 Fatty Acids, Statin, Triglycerides, EPA, Docosahexaenoic Acid, Fish, Fatty acids, Fibrates, Niacin, Lipids, Lipoprotein, Atorvastatin, Lovaza, Simvastatin, Lovastatin, Pravastatin, Fluvastatin, Rosuvastatin, Trilipix, Vytorin, Simcor, Ezetimibe, Zetia, Ethyl-EPA, Ethyl Icosapentate, Crestor, Zocor, Lipitor, LDL, HDL, Cholesterol, Dyslipidemia, AMR101, Cardiovascular Disease, Unspecified, VASCEPA, Icosapent Ethyl

Brief summary

AMR101 (icosapent ethyl \[ethyl-EPA\]) is a highly purified ethyl ester of eicosapentaenoic acid (EPA) developed by Amarin Pharma Inc. for the treatment of cardiovascular disease in statin-treated patients with hypertriglyceridemia. The purpose of this study was to evaluate whether this drug, combined with a statin therapy, will be superior to the statin therapy alone, when used as a prevention in reducing long-term cardiovascular events in high-risk patients with mixed dyslipidemia.

Chen Gurevitz, Deepak L. Bhatt, Robert P. Giugliano, Philippe Gabríel Steg, Michael Miller et al. (17 authors)

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Cardiovascular Outcomes With Icosapent Ethyl by Baseline Low‐Density Lipoprotein Cholesterol: A Secondary Analysis of the REDUCE‐IT Randomized Trial

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Journal of the American Heart Association2025-02-198 citations

10.1161/jaha.124.038656

Cost‐Effectiveness of Icosapent Ethyl in REDUCE‐IT USA: Results From Patients Randomized in the United States

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Effectiveness of icosapent ethyl on first and total cardiovascular events in patients with metabolic syndrome, but without diabetes: REDUCE-IT MetSyn

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European Heart Journal Open2023-11-0110 citations

10.1093/ehjopen/oead114

Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials.

Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE, PROMINENT, REDUCE-IT, and STRENGTH Investigators.

2023-03-06374 citations

10.1016/s0140-6736(23)00215-5

Cardiovascular Benefits of Icosapent Ethyl in Patients With and Without Atrial Fibrillation in REDUCE‐IT

Brian Olshansky, Deepak L. Bhatt, Michael Miller, Philippe Gabríel Steg, Eliot A. Brinton et al. (16 authors)

Journal of the American Heart Association2023-02-2125 citations

10.1161/jaha.121.026756

Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy

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Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction

Prakriti Gaba, Deepak L. Bhatt, Philippe Gabríel Steg, Michael Miller, Eliot A. Brinton et al. (16 authors)

Journal of the American College of Cardiology2022-04-2556 citations

10.1016/j.jacc.2022.02.035

Impact of Icosapent Ethyl on Cardiovascular Risk Reduction in Patients With Heart Failure in REDUCE‐IT

Senthil Selvaraj, Deepak L. Bhatt, Ph. Gabriel Steg, Michael Miller, Eliot A. Brinton et al. (11 authors)

Journal of the American Heart Association2022-04-0423 citations

10.1161/jaha.121.024999

Treatment With Icosapent Ethyl to Reduce Ischemic Events in Patients With Prior Percutaneous Coronary Intervention: Insights From REDUCE‐IT PCI

Benjamin E. Peterson, Deepak L. Bhatt, Ph. Gabriel Steg, Michael Miller, Eliot A. Brinton et al. (19 authors)

Journal of the American Heart Association2022-03-0937 citations

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Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients With Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL

Arjun Majithia, Deepak L. Bhatt, Allon N. Friedman, Michael Miller, Ph. Gabriel Steg et al. (18 authors)

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Icosapent Ethyl Reduces Ischemic Events in Patients With a History of Previous Coronary Artery Bypass Grafting: REDUCE-IT CABG

Subodh Verma, Deepak L. Bhatt, Ph. Gabriel Steg, Michael Miller, Eliot A. Brinton et al. (100 authors)

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Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT

Prakriti Gaba, Deepak L. Bhatt, Robert P. Giugliano, Philippe Gabríel Steg, Michael Miller et al. (17 authors)

Journal of the American College of Cardiology2021-10-0134 citations

10.1016/j.jacc.2021.08.009

Reduction in Revascularization With Icosapent Ethyl

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Circulation2020-11-0555 citations

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REDUCE-IT USA

Deepak L. Bhatt, Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Philippe Gabríel Steg et al. (18 authors)

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10.1016/j.jacc.2019.02.032

Icosapent Ethyl Effects on Fatty Acid Profiles in Statin-Treated Patients With High Triglycerides: The Randomized, Placebo-controlled ANCHOR Study.

Ballantyne CM, Manku MS, Bays HE, Philip S, Granowitz C, Doyle RT, Juliano RA.

2019-02-2016 citations

10.1007/s40119-019-0131-8

Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia

Deepak L. Bhatt, Philippe Gabríel Steg, Michael Miller, Eliot A. Brinton, Terry A. Jacobson et al. (12 authors)

New England Journal of Medicine2018-11-103,077 citations

10.1056/nejmoa1812792

Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY DM-DYSLIPIDEMIA randomized trial.

Ray KK, Ray KK, Leiter LA, Müller-Wieland D, Cariou B, Colhoun HM, Henry RR, Tinahones FJ, Bujas-Bobanovic M, Domenger C, Letierce A, Samuel R, Del Prato S.

2018-03-2364 citations

10.1111/dom.13257

Rationale and design of <scp>REDUCE‐IT</scp>: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

Deepak L. Bhatt, Philippe Gabríel Steg, Eliot A. Brinton, Terry A. Jacobson, Michael Miller et al. (14 authors)

Clinical Cardiology2017-03-01178 citations

10.1002/clc.22692

Triglyceride and cardiovascular risk: A critical appraisal

Awadhesh Kumar Singh, Ritu Singh

Indian Journal of Endocrinology and Metabolism2016-01-0145 citations

10.4103/2230-8210.183460

Effects of omega-3 fatty acids on arterial stiffness in patients with hypertension: a randomized pilot study.

Krantz MJ, Havranek EP, Pereira RI, Beaty B, Mehler PS, Long CS.

2015-12-0217 citations

10.1186/s12952-015-0040-x

Interventions

DRUGAMR101

Parallel Assignment

DRUGPlacebo

Parallel Assignment

DRUGStatin therapy

Stable statin therapy (± ezetimibe) for at least 28 days before lipid qualification measurement (LDL-C \>40 mg/dL and ≤100 mg/dL)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

45 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Men and non-pregnant or sterile women ages 45 and older * Hypertriglyceridemia * On statin therapy for at least four weeks * Either having established cardiovascular disease or at high risk for cardiovascular disease

Exclusion criteria

* Severe heart failure * Any life-threatening disease other than cardiovascular disease * Active severe liver disease * Hemoglobin A1c \>10.0% * Poorly controlled hypertension * Planned coronary intervention (such as stent placement or heart bypass) or any non-cardiac major surgical procedure * Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III) * Known hypersensitivity to the study product, fish and/or shellfish, or placebo * History of acute or chronic pancreatitis * Patients are excluded if using the following medications: * PCSK9 inhibitors * niacin \>200 mg/day or fibrates; * any omega-3 fatty acid medications ; * dietary supplements containing omega-3 fatty acids (e.g., flaxseed oil, fish oil, krill oil, or algal oil); * bile acid sequestrants

Design outcomes

Primary

Measure	Time frame	Description
Composite of CV Death, Nonfatal MI (Including Silent MI), Nonfatal Stroke, Coronary Revascularization, or Unstable Angina Determined to be Caused by Myocardial Ischemia by Invasive / Non-invasive Testing and Requiring Emergent Hospitalization.	Total follow-up time of up to approximately 6 years.	The primary outcome measure was the number of patients with a first occurrence of any component of the composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined to be caused by myocardial ischemia by invasive / non-invasive testing and requiring emergent hospitalization during the follow-up period.

Secondary

Measure	Time frame	Description
Composite of CV Death or Nonfatal MI (Including Silent MI).	Total follow-up time of up to approximately 6 years.	Number of patients with a first occurrence of any component of the composite of CV death or nonfatal MI (including silent MI) during the follow-up period.
Fatal or Nonfatal MI (Including Silent MI).	Total follow-up time of up to approximately 6 years.	Number of patients with a first occurrence of fatal or nonfatal MI (including silent MI) during the follow-up period.
Non-elective Coronary Revascularization Represented as the Composite of Emergent or Urgent Classifications.	Total follow-up time of up to approximately 6 years.	Number of patients with a first occurrence of non-elective coronary revascularization represented as the composite of emergent or urgent classifications during the follow-up period.
CV Death.	Total follow-up time of up to approximately 6 years.	Number of patients with an occurrence of CV death during the follow-up period.
Composite of CV Death, Nonfatal MI (Including Silent MI), or Nonfatal Stroke.	Total follow-up time of up to approximately 6 years.	The key secondary outcome measure was the number of patients with a first occurrence of any component of the composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke during the follow-up period.
Fatal or Nonfatal Stroke.	Total follow-up time of up to approximately 6 years.	Number of patients with a first occurrence of fatal or nonfatal stroke during the follow-up period.
Total Mortality, Nonfatal MI (Including Silent MI), or Nonfatal Stroke.	Total follow-up time of up to approximately 6 years.	Number of patients with a first occurrence of any component of the composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke during the follow-up period.
Total Mortality.	Total follow-up time of up to approximately 6 years.	Number of patients with an occurrence of death from any cause during the follow-up period.
Unstable Angina Determined to be Caused by Myocardial Ischemia by Invasive / Non-invasive Testing and Requiring Emergent Hospitalization.	Total follow-up time of up to approximately 6 years.	Number of patients with a first occurrence of unstable angina determined to be caused by myocardial ischemia by invasive / non-invasive testing and requiring emergent hospitalization during the follow-up period.

Countries

Australia, Canada, India, Netherlands, New Zealand, Poland, Romania, Russia, South Africa, Ukraine, United States

Participant flow

Participants by arm

Arm	Count
AMR101 AMR101: Parallel Assignment	4,089
Placebo Placebo: Parallel Assignment	4,090
Total	8,179

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	6	13
Overall Study	Other than specified above	106	138
Overall Study	Physician Decision	12	12
Overall Study	Withdrawal by Subject	281	297

Baseline characteristics

Characteristic	AMR101	Placebo	Total
Age, Continuous	64.0 years	64.0 years	64.0 years
Cardiovascular Risk Stratum Primary-prevention cohort	1197 Participants	1197 Participants	2394 Participants
Cardiovascular Risk Stratum Secondary-prevention cohort	2892 Participants	2893 Participants	5785 Participants
Race/Ethnicity, Customized Race Missing	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Race Other than white	398 Participants	401 Participants	799 Participants
Race/Ethnicity, Customized Race White	3691 Participants	3688 Participants	7379 Participants
Region of Enrollment Australia	102 participants	87 participants	189 participants
Region of Enrollment Canada	123 participants	127 participants	250 participants
Region of Enrollment India	130 participants	132 participants	262 participants
Region of Enrollment Netherlands	847 participants	831 participants	1678 participants
Region of Enrollment New Zealand	73 participants	61 participants	134 participants
Region of Enrollment Poland	195 participants	164 participants	359 participants
Region of Enrollment Romania	109 participants	93 participants	202 participants
Region of Enrollment Russia	352 participants	357 participants	709 participants
Region of Enrollment South Africa	213 participants	201 participants	414 participants
Region of Enrollment Ukraine	397 participants	439 participants	836 participants
Region of Enrollment United States	1548 participants	1598 participants	3146 participants
Sex: Female, Male Female	1162 Participants	1195 Participants	2357 Participants
Sex: Female, Male Male	2927 Participants	2895 Participants	5822 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	274 / 4,089	310 / 4,090
other Total, other adverse events	3,268 / 4,089	3,248 / 4,090
serious Total, serious adverse events	1,252 / 4,089	1,254 / 4,090

Outcome results

Primary

Composite of CV Death, Nonfatal MI (Including Silent MI), Nonfatal Stroke, Coronary Revascularization, or Unstable Angina Determined to be Caused by Myocardial Ischemia by Invasive / Non-invasive Testing and Requiring Emergent Hospitalization.

The primary outcome measure was the number of patients with a first occurrence of any component of the composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined to be caused by myocardial ischemia by invasive / non-invasive testing and requiring emergent hospitalization during the follow-up period.