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Residual cardiovascular risk persists despite statins, yet outcome studies of lipid‐targeted therapies beyond low‐density lipoprotein cholesterol (LDL‐C) have not demonstrated added benefit. Triglyceride elevation is an independent risk factor for cardiovascular events. High‐dose eicosapentaenoic acid (EPA) reduces triglyceride‐rich lipoproteins without raising LDL‐C. Omega‐3s have postulated pleiotropic cardioprotective benefits beyond triglyceride‐lowering. To date, no large, multinational, randomized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE‐IT; NCT01492361) is a phase 3b randomized, double‐blinded, placebo‐controlled trial of icosapent ethyl, a highly purified ethyl ester of EPA, vs placebo. The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in statin‐treated patients with high triglycerides at elevated cardiovascular risk. REDUCE‐IT enrolled men or women age ≥45years with established cardiovascular disease or age ≥50years with diabetes mellitus and 1 additional risk factor. Randomization required fasting triglycerides ≥150mg/dL and <500mg/dL and LDL‐C >40mg/dL and ≤100mg/dL with stable statin (± ezetimibe) ≥4weeks prior to qualifying measurements. The primary endpoint is a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Several secondary, tertiary, and exploratory endpoints will be assessed. Approximately 8000 patients have been randomized at approximately 470 centers worldwide. Follow‐up will continue in this event‐driven trial until approximately 1612 adjudicated primary‐efficacy endpoint events have occurred.
Statin therapy has been well established as a cornerstone of cardiovascular prevention, and yet despite potent therapies for lowering low‐density lipoprotein cholesterol (LDL‐C), substantial residual risk remains.1, 2, 3 Clinical and epidemiological studies have demonstrated that triglyceride (TG) elevation is an independent risk factor for increased cardiovascular (CV) events, and therefore may represent one contributive factor of residual CV risk beyond statin therapy.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 More recently, elegant Mendelian randomization studies have supported a causal role for TG in the pathogenesis of cardiovascular disease (CVD), showing that elevated TG are not merely a risk marker, but rather a risk factor and thus potentially modifiable.3 Despite the available data, an important question that remains is whether treatment of modest degrees of TG elevation would decrease CV events, in particular in patients already receiving LDL‐C–lowering therapy with statins. Prior CV outcome studies that administered therapies with TG‐lowering effects (niacin or fenofibrate) on top of statin therapy did not reach their primary endpoints. Nonetheless, these studies also did not prospectively enroll patients with elevated TG levels despite statin therapy,6, 12, 13, 14, 15 and subgroup analyses suggested possible benefits to TG lowering in patients with dyslipidemia.5, 6
Outcome studies of relatively low doses of prescription omega‐3 therapies in Japan (the Japan EPA Lipid Intervention Study [JELIS])16 and Italy (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico [GISSI])17, 18 have suggested that omega‐3 therapy may provide CV protection. However, these studies were performed in single countries prior to current treatment guidelines, and therefore provide supportive but not conclusive evidence of CV benefit. Other more recent omega‐3 therapy outcome studies conducted in the presence of statins have been less encouraging, but these studies were characterized by evaluating nonhypertriglyceridemic patient populations (eg, TG <200mg/dL) and administering low doses of long‐chain omega‐3 fatty acids (eg, eicosapentaenoic acid [EPA] and/or docosoahexaenoic acid [DHA]).19, 20, 21, 22, 23, 24
Omega‐3 therapies, including EPA, have been postulated to have cardioprotective effects such as beneficial changes to TG and other lipid and lipoprotein parameters (eg, non–high‐density lipoprotein cholesterol [non‐HDL‐C], apolipoprotein CIII), as well as other potential benefits beyond plasma lipid modification.19, 25, 26, 27, 28, 29, 30 Icosapent ethyl (Vascepa; Amarin Pharma Inc., Bedminster, NJ) is a highly purified ethyl ester of EPA, which has been reported to improve atherogenic dyslipidemia characterized by reductions in TG, TG‐rich lipoproteins, and factors involved in their metabolism, without raising LDL‐C.25, 26, 27, 28, 29 Based on trials with TG lowering as the primary endpoint, this prescription therapy is currently approved for use in the United States by the US Food and Drug Administration (FDA) as an adjunct to diet to reduce TG levels in adult patients with severe hypertriglyceridemia (≥500mg/dL).25, 26 In this range of very elevated TG levels, reduction is considered to be clinically necessary to decrease the risk of pancreatitis.
In addition to beneficial changes to TG‐rich lipoproteins and other plasma lipid markers, some clinical studies with higher‐dose EPA also suggest beneficial effects on markers of oxidation and inflammation, coronary plaque characteristics, and major CV events.16, 25, 26, 29, 31, 32, 33 For example, in contrast to the fenofibrate and niacin studies, JELIS found a 19% relative risk reduction in CV events in statin‐treated patients with relatively normal TG but a more pronounced 53% reduction in the subgroup with mixed dyslipidemia, specifically TG ≥150mg/dL and HDL‐C <40mg/dL.4, 16 Although confirmation of these results is needed in western populations, the reduction of CV events with EPA therapy in a patient population with relatively normal TG levels suggests that EPA may have pleiotropic effects beyond plasma‐lipid modification.
It is worth noting that the promising results from JELIS occurred with a high‐purity EPA preparation dosed at 1.8g/d in a Japanese population, for whom the baseline EPA levels are higher than in western populations due to greater dietary intake of marine omega‐3 fatty acids. Icosapent ethyl 12‐week dosing at 4g/d in a high‐risk population similar to that within the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE‐IT) who had persistent elevations of TG after treatment with statins resulted in significant reductions in TG and atherogenic lipoproteins,26, 27, 28 as well as comparable plasma EPA levels as the 1.8g/d dosing group in JELIS.34 Therefore, a dose of 4g/d was selected as the dose for further study. In this context, REDUCE‐IT was designed to determine if treatment with icosapent ethyl 4g/d vs placebo would reduce ischemic events in patients at increased CV risk already being treated with statins.
REDUCE‐IT (NCT01492361) is a phase 3b, international, multicenter, prospective, randomized, double‐blinded, placebo‐controlled, parallel‐group trial of icosapent ethyl 4g/d (2g twice daily with food) vs placebo (Figure). The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in patients at elevated CV risk concurrently treated with statins. Inclusion and exclusion criteria are listed in Table 1 and Table 2, respectively. Men or women age ≥45years with established CVD (CV risk stratum 1, Table 1) or age ≥50years with diabetes mellitus in combination with 1 additional risk factor for CVD (CV risk stratum 2, Table 1) were eligible for inclusion. Fasting TG levels ≥150mg/dL and <500mg/dL were required. A study amendment was made during the early part of the trial, increasing the lower end of the fasting TG level from ≥150mg/dL to ≥200mg/dL, to increase enrollment of patients with more significant TG elevations. LDL‐C levels needed to be >40mg/dL and ≤100mg/dL, with patients on stable statin therapy (± ezetimibe) for ≥4weeks prior to the LDL‐C and TG qualifying measurements for randomization.
Study design for REDUCE‐IT. During the screening period, patients were evaluated for inclusion/exclusion criteria. If patients met the inclusion criteria at Visit 1, they were asked to return for the randomization visit (Visit 2) and entered the ...
The primary endpoint is a composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of CV death, nonfatal MI, or nonfatal stroke. Several other secondary, tertiary, and exploratory endpoints are being assessed (Table 3), which were designed to provide additional insights into the potential effects of EPA therapy on various outcomes and in distinct high‐risk patient populations.
The sample‐size calculation was based on a hazard ratio assumption of 0.85. Therefore, 1612 events would be required to have approximately 90% power with a 1‐sided α‐level of 2.5% and with 2 interim analyses. This results in a total target sample size of 7990 patients. Approximately 70% of randomized patients were to be in CV risk stratum 1 (established CVD) and approximately 30% of randomized patients were to be in CV risk stratum 2 (high‐risk primary prevention defined by diabetes mellitus and other risk factors). Randomization was stratified by CV risk strata, ezetimibe use, and by geographical region.
The first patient was randomized on November 28, 2011. Protocol amendment 1 (May 2013) changed the lower limit of TG levels for entry into the trial from 150mg/dL to 200mg/dL, as a majority of the steering committee members felt that those were the patients most likely to benefit from TG lowering. Protocol amendment 2 (July 2016) designated the composite of hard major adverse cardiovascular events (CV death, nonfatal MI, nonfatal stroke) as the “key secondary endpoint” per suggestions from the FDA with steering committee concordance. The last patient was randomized on August 4, 2016. Approximately 8000 patients have been randomized at approximately 470 centers worldwide (see Supporting Information, Appendix, in the online version of this article). Follow up will continue in this event‐driven trial until approximately 1612 adjudicated primary efficacy endpoint events have occurred. This study is being conducted in accordance with a special protocol assessment agreement with the FDA.
Despite CV risk reduction through potent LDL‐C–lowering therapies such as statins, substantial residual CV risk remains. Epidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy.3, 4, 5, 6, 7, 8, 9, 10, 11 Finally, studies administering higher‐dose EPA suggest additional beneficial effects beyond lipid‐lowering that may be unique to EPA relative to other TG‐lowering therapies, such as beneficial changes in coronary plaque characteristics, which may lead to reductions in major CV events.4, 16, 25, 26, 27, 28, 29, 30, 31, 32, 33
However, randomized data from large outcome studies across broad populations regarding pharmacological TG lowering and effect on CV outcomes have been mixed (Table 4).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 Part of the reason may involve differences between the classes of drugs studied, such as fibrates, niacin, and omega‐3 fatty acids. Even among omega‐3 fatty acid studies, there are marked differences with respect to the relatively low doses of omega‐3 administered and the ratio of EPA to DHA.16, 17, 18, 19, 20, 21, 22, 23, 24 In addition, different TG‐lowering therapies may exert differential effects across lipid profiles. For example, fibrates and DHA‐containing omega‐3 fatty acid mixtures have been shown to increase LDL‐C, which in turn might adversely influence trial results. Among outcome studies administering TG‐lowering agents beyond statin therapy, only the JELIS trial using pure EPA demonstrated a significant reduction in CV events in patients with relatively normal TG levels.16 The subgroup data (Table 5) from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid,6 Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM‐HIGH),5 and JELIS4 trials further support a prospective study of EPA in a broader patient population with hypertriglyceridemia, as exemplified in REDUCE‐IT, as a potential add‐on to statin therapy to reduce residual CV risk. That the lipid changes in JELIS were relatively modest (ie, approximately a 5% TG reduction) raises the possibility that other pleiotropic effects beyond lipid lowering may have also contributed to the reduction in CV risk.4, 16 Finally, any benefits to TG‐lowering therapies may be most pronounced among statin‐treated patients in the higher range of TG elevation (ie, ≥200mg/dL),4, 5, 6 for whom randomized prospectively designed outcome studies have not been previously conducted prior to the REDUCE‐IT study.
CV outcome trials administering therapies that can be used for TG lowering
Subgroup analyses of patients with dyslipidemia from CV outcome trials administering TG‐lowering therapies added to statin therapy vs statin monotherapy
REDUCE‐IT is designed to evaluate whether treating at‐risk patients with high‐dose EPA will lower the rates of important ischemic events beyond statin therapy. However, this trial alone will not validate whether lowering TG specifically in patients with elevated TG levels will result in lower rates of important ischemic events, because the effects of EPA may be broader than TG reduction alone. Several trials, including REDUCE‐IT, are ongoing or planned to determine if different TG‐lowering therapies in patients with elevated TG levels lower the rate of important ischemic events.35, 36, 37, 38 The use of different therapeutic agents across these trials may in aggregate help us better understand the relative importance of TG lowering alone and may also help define which potential effects observed in REDUCE‐IT might be uniquely attributable to EPA therapy. Several lines of data, including comparison of the JELIS study results to those of fibrate and niacin outcome studies, suggest that EPA may be differentiated from other TG‐lowering agents as statin add‐on therapy, by potentially providing unique pleiotropic cardioprotective benefits in addition to TG lowering.
Other changes in the lipid‐lowering field may also affect the interpretation of the ongoing REDUCE‐IT trial. For example, the proprotein convertase subtilisin/kexin type 9 inhibitors are being tested in large CV outcome trials of patients for whom LDL‐C control from statin (± ezetimibe) therapy may be insufficient or poorly tolerated. If these LDL‐C–lowering agents are found to be beneficial, EPA therapy could potentially serve as a complementary approach to reduce residual CV risk even further, though this specific combination would not have been studied well in terms of incremental effects on CV events. Importantly, residual CV risk remains high in patients with LDL‐C well controlled by statins, and many of these patients will likely need to be treated from multiple angles. The growing body of TG‐related evidence suggests that TG‐rich lipoproteins may be a causal factor in such residual risk. Consequently, TG lowering represents a target of great interest to optimize further CV risk reduction beyond the LDL‐C–lowering benefits attained with statin use. EPA‐specific studies suggest that EPA may provide unique CV benefits through favorable effects on plasma lipid parameters, as well as on other pleiotropic pathways.
A major remaining question is how to achieve CV risk reduction beyond the benefits realized from effective management of LDL‐C. For patients with persistently high TG levels despite statin therapy, an agent that improves atherogenic dyslipidemia without raising LDL‐C and provides other potentially pleiotropic benefits may improve CV outcomes. The addition of EPA to statin therapy may thus provide additional CV benefit. The REDUCE‐IT trial with high‐dose EPA is designed to address this long‐standing scientific gap and to provide physicians with this much‐needed information to guide clinical care of patients at high CV risk.
The authors thank members of the Amarin team, including: Lisa Jiao, PhD, for statistical support; Katelyn Diffin, MBA, for operational support; Peggy Berry, BA, for regulatory support; and Craig Granowitz, MD, PhD, Joy Bronson, MA, CMPP, and Sephy Philip, RPh, PharmD, for editorial support.
Dr. Bhatt has served on advisory boards for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; has served on the board of directors for Boston VA Research Institute and Society of Cardiovascular Patient Care; has been chair of the American Heart Association Quality Oversight Committee; has served on data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and the Population Health Research Institute; has received honoraria from the American College of Cardiology (senior associate editor, clinical trials and news, for acc.org), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering committees); has served as deputy editor of Clinical Cardiology, as chair of the NCDR‐ACTION Registry Steering Committee, and as chair of the VA CART Research and Publications Committee; has received research funding from Amarin (for his role as chair of the steering committee and principal investigator of REDUCE‐IT), Amgen, AstraZeneca, Bristol‐Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi‐Aventis, and The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); has served as site co‐investigator for Biotronik, Boston Scientific, and St. Jude Medical; has served as a trustee of the American College of Cardiology; and reports unfunded research with FlowCo, PLx Pharma, and Takeda. Dr. Steg has received research grants from Merck, Sanofi, and Servier and has received speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, CSL‐Behring, Daiichi‐Sankyo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medicines Company. Dr. Brinton has received speaking and/or consulting honoraria from Alexion, Amarin, Amgen, Aralez, Arisaph, AstraZeneca, Janssen, Kastle, Kowa, Merck, PTS Diagnostics, Regeneron, and Sanofi‐Aventis and has received research funding from Amarin (for his role as steering committee member of REDUCE‐IT) and Kowa (for his role as steering committee member of PROMINENT). Dr. Jacobson has served as a consultant for Amarin, Amgen, AstraZeneca, Merck, Regeneron, and Sanofi and has done research for Amgen and Regeneron/Sanofi. Dr. Miller has served as a consultant for Amarin, Akcea, Gemphire, and Pfizer. Dr. Tardif has received research grants from Amarin, AstraZeneca, DalCor, Eli Lilly, Esperion, Merck, Pfizer, Sanofi, and Servier; has received honoraria from Amarin, AstraZeneca, DalCor, Sanofi, and Servier; and holds equity (modest position) in DalCor. Drs. Ketchum, Soni, Braeckman, and Juliano, and Mr. Doyle, are current or former Amarin employees and shareholders. Ms. Murphy has served as a consultant for Amarin and received honoraria from Merck. Dr. Ballantyne discloses grant/research support (all paid to the institution, not individual) from Amarin, Amgen, Eli Lilly, Esperion, Ionis, Novartis, Pfizer, Regeneron, Sanofi‐Synthelabo, the National Institutes of Health, the American Heart Association, and the American Diabetes Association, and has served as a consultant for Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, Ionis, Matinas BioPharma Inc, Merck, Novartis, Pfizer, Regeneron, and Sanofi‐Synthelabo.
Bhatt DL, Steg PG, Brinton EA, Jacobson TA, Miller M, Tardif J‐C, Ketchum SB, Doyle RT Jr, Murphy SA, Soni PN, Braeckman RA, Juliano RA, Ballantyne CM and 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. https://doi.org/10.1002/clc.22692
Funding information The trial is sponsored by Amarin Pharma Inc.