Cardiovascular Risk with Elevated Triglycerides – Does Icosapent Ethyl REDUCE-IT?

Author(s)
Melissa C. Norton, PharmD
Elizabeth A. Cook, PharmD, AE-C, BCACP, CDE

Reviewed By
Dawn Fuke, PharmD, BCPS
Joseph Saseen, PharmD, BCPS, BCACP, CLS

Citation
Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019, 380: 11-22.

The Problem

Without question, statins are the cornerstone to cardiovascular (CV) risk reduction.¹ To lower CV risk even more, several medications aimed at reducing low-density lipoprotein cholesterol (LDL-C) have been used as add-on therapy to statins.¹ Although hypertriglyceridemia has consistently been associated with increased CV events, medications that lower triglycerides have failed to reel in a significant reduction in major CV events when combined with statin therapy.^2-5 Could purified fish oil derivatives be the answer? Or just another red herring?

What’s Known

In previous clinical trials, medications with TG-lowering properties, such as niacin and fibric acid derivatives, have failed to reduce CV event rates when added to statin therapy.^2,3 Fish oil supplements, composed of two major long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are a popular “natural” choice that can reduce triglycerides. However, meta-analyses evaluating the use of fish oil supplements for the prevention of coronary heart disease and major vascular events have shown very limited benefit.⁶ The Reduction of CV Events with Icosapent-Ethyl Intervention Trial (REDUCE-IT) sought to clarify the utility of icosapent ethyl, a highly purified EPA derivative.⁷

What’s New

REDUCE-IT was a phase 3b multicenter, randomized, double-blind, placebo-controlled trial that evaluated the benefits of icosapent ethyl for the primary and secondary prevention of CV events.⁷ From November 2011 to August 2016, more than 19,000 individuals were screened and 8,179 patients met the inclusion and exclusion criteria listed in Table 1.

Table 1. Major Inclusion and Exclusion Criteria*

Inclusion Criteria	Exclusion Criteria
Age ≥ 45 years with established CV disease OR ≥ 50 years with diabetes and ≥1 additional risk factor Fasting TG between 150** – 499 mg/dL*** LDL-C between 41 – 100 mg/dL Taking a stable statin dose (±ezetimibe) for ≥4 weeks	Severe HF (NYHA Class IV) Active severe liver disease A1c ≥10% Planned coronary intervention or surgery History of acute or chronic pancreatitis Known hypersensitivity to fish, shellfish, or ingredients in either icosapent ethyl or placebo

^{*Full list of inclusion and exclusion criteria are outlined in the Supplemental Appendix}

^{**Persons with TG as low as 135 mg/dL were eligible for inclusion due to 10% intraindividual variability}

^{***Protocol amended in May 2013 to increase the qualifying TG level from 150 mg/dL to 200 mg/dL.}

^{Abbreviations: CV = Cardiovascular; HbA1c = hemoglobin A1c; HF = Heart failure; LDL-C = Low-density lipoprotein cholesterol; NYHA = New York Heart Association; TG = Triglycerides}

Patients were randomly assigned in a 1:1 fashion to receive either icosapent ethyl 2g, administered twice daily with meals, or a placebo capsule containing mineral oil. Randomization was stratified according to cardiovascular risk (primary or secondary prevention), baseline ezetimibe use, and geographic location to limit confounding.

The primary efficacy endpoint of this trial was a time-to-event analysis for the composite outcome including CV death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina. In July 2016, a protocol amendment requested by the FDA was approved and the 3-point major adverse cardiovascular event (MACE: composite of CV death, nonfatal MI, or nonfatal stroke) was added as a key secondary endpoint. Key subgroup analyses were specified a priori. An intention-to-treat analysis was used.

The majority of patients studied were white males, diagnosed with type 2 diabetes mellitus, and prescribed either moderate- or high-intensity statin therapy at baseline. Approximately 70% had a history of clinical atherosclerotic CV disease (ASCVD). Baseline characteristics were generally well distributed amongst intervention and control groups, with the exception of LDL-C, which was statistically higher in the placebo arm (74 vs 76 mg/dL; p = 0.03). Additional baseline characteristics can be found in Table 2.

Table 2. Baseline Characteristics

Characteristic	Icosapent Ethyl (n = 4,089)	Placebo (n = 4,090)
Age in years – median	64.0	64.0
Male sex – %	71.6%	70.8%
White race – %	90.3%	90.2%
Geographic region – %
United States, Canada, Netherlands, Australia, New Zealand, South Africa	71.1%	71.0%
Eastern European	25.8%	25.7%
Asia – Pacific	3.2%	3.2%
CV risk stratum – %
Primary prevention	29.3%	29.3%
Secondary prevention	70.7%	70.7%
Statin intensity – %
Low	6.2%	6.5%
Moderate	61.9%	63%
High	31.5%	30%
Unknown	0.3%	0.5%
Ezetimibe use – %	6.4%	6.4%
Diabetes – %
Type 1	0.7%	0.7%
Type 2	57.9%	57.8%
No diabetes at baseline	41.5%	41.4%
LDL-C mg/dL – median*	74.0	76.0
HDL-C mg/dL – median	40.0	40.0
TG mg/dL – median	216.5	216.0
<150 mg/dL	10.1%	10.5%
≥150 to <200 mg/dL	29.2%	29.1%
≥200 mg/dL	60.7%	60.4%
EPA level mcg/mL  – median	26.1	26.1

^{*Statistically significant difference in median LDL-C between icosapent ethyl and placebo groups}

^{Abbreviations: CV = Cardiovascular; EPA = eicosapentaenoic acid; HDL-C = High-density lipoprotein cholesterol; IQR = Interquartile range; LDL-C = Low-density lipoprotein cholesterol; TG = Triglycerides}

When compared to baseline, after one year, the median change in TG was an 18.3% decrease in the icosapent ethyl group and a 2.2% increase in the placebo group. The median LDL-C increased in both groups: +3.1% in the icosapent ethyl arm and +10.2% in the placebo arm.

The primary composite endpoint occurred in 17.2% of patients in the icosapent ethyl group vs. 22% in the placebo group (HR 0.75 [0.68 to 0.83]; p<0.001; NNT = 21). The key secondary composite (MACE) endpoint occurred in 11.2% of the intervention group and 14.8% in the placebo group (HR 0.74 [0.65 to 0.83]; p<0.001; NNT = 28). To learn more about how to calculate the NNT, check out the iForumRx Evidence Based Medicine Tutorials here.

Our Critical Appraisal

This trial had several strengths including a very rigorous study design (randomized, blinded, intention-to-treat, MACE endpoint). The median LDL-C was approximately 75 mg/dL, indicating that the majority of individuals with either established ASCVD or at high CV risk were adequately treated to evidence-driven lipid targets.  Further, the majority of the study population was treated with either moderate- or high-intensity statin therapy.

However, REDUCE-IT also had some limitations. The initial protocol prior to amendment allowed for individuals with TG as low as 135mg/dL to meet the threshold for inclusion. This threshold is lower than when we’d typically consider add-on therapy in clinical practice.  Moreover, patients with TG > 500mg/dL were excluded from the study, limiting our ability to extrapolate the results to those with severe hypertriglyceridemia. Furthermore, there was a significant increase in the risk of atrial fibrillation / flutter (3.1% vs. 2.1%, p=0.004) and a trend towards increased bleeding (2.7% vs. 2.1%, p=0.06) in the icosapent ethyl group compared to placebo. However, data pertaining to the use of antiplatelet or anticoagulant therapy was not reported, making it difficult to determine if the increase in bleeding is related to icosapent ethyl use. One can also question the investigators’ choice to use mineral oil “placebos.” Mineral oil is not benign and potentially decreases the systemic absorption of concomitantly administered oral medications, such as statins, as well as increases the levels of atherogenic lipoproteins and inflammatory markers.^7,8

The strong benefit observed with icosapent ethyl in the REDUCE-IT trial appears to correlate with data published by the Japan EPA Lipid Intervention Study (JELIS) investigators.  The addition of EPA to low-intensity statin therapy in JELIS significantly reduced major coronary events in Japanese individuals with dyslipidemia, with or without coronary artery disease.⁹

While the primary and secondary composite outcomes of the REDUCE-IT trial favored icosapent ethyl over placebo, it is not clear if all subgroups benefitted. Groups who may not have benefitted included females, individuals in the primary prevention stratum, individuals enrolled from Eastern Europe and Asia-Pacific regions, those taking ezetimibe, and those prescribed low intensity statin therapy. It is important to note that data from subgroup analyses must be carefully interpreted because studies are not powered to detect differences in outcomes in sub-populations. Additional studies are needed to further explore the risks and benefits of icosapent ethyl in these subgroups.

The Bottom Line

Icosapent ethyl, combined with moderate- or high-intensity statins, significantly reduced CV risk in a population of mostly white men with established ASCVD and moderately elevated serum triglycerides. Additional studies are needed to determine the benefits of icosapent ethyl in women and for primary prevention. What are your thoughts? Does this study sound fishy or does icosapent ethyl REDUCE cardiovascular risk enough to be a big catch?

The Key Points

• Icosapent ethyl significantly reduced CV morbidity and mortality (NNT = 28) when used in combination with statin therapy.
• Icosapent ethyl conveyed cardiovascular benefit in individuals irrespective of their baseline triglyceride levels, suggesting that other effects (e.g. anti-inflammatory, plaque stabilization) might be part of its mechanism of action.
• The results are specific to icosapent ethyl, a highly purified formulation of EPA, and cannot be applied to over-the-counter fish oil supplements or other prescription products composed of both EPA and DHA.  Previous clinical trials using these EPA/DHA products failed to demonstrate a clear benefit.

NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit https://www.pharmacist.com/ambulatory-care-review-and-recertification-activities.