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Author: Mallory Mouradjian, PharmD and Stormi Gale, PharmD, BCCP

Patients with dyslipidemia remain at increased risk of cardiovascular disease (CVD) despite treatment with maximally tolerated statin therapy. For high-risk patients with established CVD or multiple risk factors for CVD, it is often necessary to reach for additional therapies as a means of lowering this residual risk. It is well-described that hypertriglyceridemia is an independent risk factor for CVD; therefore, lowering triglyceride (TG) levels is a reasonable target for non-statin therapy.1 Omega-3 fatty acids have been associated with lowering TG; however, robust data for clinical outcomes have been lacking until the recent publication of the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT).2,3 This blog will give a brief review of historical evidence, detail differences in fish oil supplements, and provide considerations for the role of Vascepa® (icosapent ethyl) in high-risk patients with dyslipidemia.

Omega-3 (n-3) fatty acids or “fish oil” supplements contain differing amounts of two polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Eicosapentaenoic acid and DHA have long had a proposed benefit in preventing and treating CVD through mechanisms that include stabilization of atherosclerotic plaque, inflammation modulation, and inhibition of free radicals.4 Both EPA and DHA reduce TG plasma levels. However, DHA also increases LDL, leading some experts to postulate that EPA may be the more beneficial of the two.5 Patients can increase EPA and DHA intake either through diet or n-3 fatty acid supplementation. Over the counter supplements are unregulated and therefore contain a highly variable ratio of EPA to DHA. Until recently, the only FDA-approved n-3 fatty acid supplement for hypertriglyceridemia was Lovaza (omega-3-acid ethyl esters), which contains 465 mg of EPA and 375 mg of DHA per 1 g capsule.6 The most recently approved agent, Vascepa® (icosapent ethyl), contains purified (>96%) EPA ethyl esters without DHA.7

Did You Know?
In order to consume 1 g of EPA and DHA from diet, patients would need to eat serving sizes varying from 1.5 – 12 ounces of oily fish.

Despite a long history of proposed cardiovascular benefit, the majority of literature surrounding use of n-3 fatty acids for this purpose has been negative or of marginal benefit. One of the few positive n-3 fatty acid trials, Japan EPA Lipid Intervention Study (JELIS), found a significant reduction in major adverse cardiovascular events (MACE) in 18,645 Japanese patients randomized to purified EPA 1.8 g per day plus a low-intensity statin versus statin therapy alone (2.8% versus 3.5%, HR 0.81, 95% CI 0.69 to 0.95; p=0.011).8 Of note, this was a higher dose of EPA than other n-3 fatty acid trials, 80% of patients were enrolled for primary prevention, and the exclusive enrollment of Japanese patients make the results of this trial difficult to extrapolate to Western populations. Conversely, two large, recently published studies, A Study of Cardiovascular Events in Diabetes (ASCEND) and the Vitamin D and Omega-3 Trial (VITAL), utilized n-3 fatty acids 1 g daily (460 mg EPA, 380 mg DHA) for primary prevention and failed to reduce MACE at 7.4 and 5.3 years follow-up respectively.9,10 Moreover, a meta-analysis of 10 trials and a Cochrane review of 79 trials found no association between cardiovascular benefit and fatty acid supplementation at doses ranging from 500 mg to 5 g per day for either primary or secondary prevention.2,11

The recent REDUCE-IT study randomized over 8,000 adults ≥ 45 years of age with established CVD or adults ≥ 50 years of age with diabetes mellitus and at least one additional risk factor to 4 g per day of icosapent ethyl (purified EPA) or mineral oil placebo. Patients had to be on stable statin therapy with a low-density lipoprotein (LDL) cholesterol level of 41 to 100 mg/dL and a fasting TG level 150 – 499 mg/dL.3 At baseline, 30% of patients were enrolled for primary prevention, 30% of patients had TG level between 150 – 200 mg/dL, and most patients were on a moderate intensity statin with a median LDL of approximately 75 mg/dL. At a median follow-up of 4.9 years, the composite endpoint of cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization, or unstable angina occurred in 17.2% of the icosapent ethyl group versus 22.0% of the placebo group (HR, 0.75; 95% CI, 0.68 to 0.83; P<0.001). This benefit was consistently significant for each of the individual components of the composite endpoint with the exception of death from any cause. Based on the Kaplan-Meier curves, this benefit appears to have been most evident after 1 year of treatment. Additionally, subgroup analyses suggest the benefit is less clear in primary prevention patients and those on ezetimibe at baseline. There were no significant differences in serious adverse events, including bleeding outcomes.

The results from REDUCE-IT are promising as it appears that icoasapent ethyl is a viable non-statin option to reduce cardiovascular events in high-risk patients with elevated TG on maximally tolerated statin therapy. Despite the optimistic results from REDUCE-IT, several questions remain unanswered and may warrant future studies to clarify the role of icosapent ethyl for cardiovascular risk reduction:

  • The exact mechanism of benefit of icosapent ethyl remains unknown and is unlikely to be attributable to TG-lowering alone. Benefits in REDUCE-IT were observed irrespective of baseline TG level and whether or not patients achieved normalization of TG levels at 1 year post-randomization.
  • It is unclear whether the higher dose of n-3 fatty acid, the formulation of purified EPA, or a combination of the two is responsible for beneficial effect seen with icosapent ethyl. N-3 fatty acids containing both EPA and DHA at a dose of 1 g per day failed to show benefit in both ASCEND and VITAL, whereas purified EPA at a dose of 1.8 g and 4 g (in JELIS and REDUCE-IT, respectively) lowered MACE. At this time, it appears that a daily dose of 1 g of n-3 fatty acids containing EPA and DHA is not beneficial for reducing cardiac events.
  • The validity of using a mineral oil placebo in REDUCE-IT has been called into question as it could result in incomplete absorption of statins. LDL levels increased marginally in both groups at one year post-randomization, with a 6.6% (5.0 mg/dL) lower increase with icosapent ethyl than with placebo (P<0.001). However, it seems unlikely that an absolute increase in LDL of 5.0 mg/dL in the placebo group could fully explain the overall difference in outcomes between groups. It is also notable that the JELIS trial found a decrease in MACE without the use of a mineral oil placebo.
  • The clinical significance of increased rates of atrial fibrillation (AF) found in the icosapent ethyl group is not known. The rate of AF was significantly higher in the icosapent ethyl group than in the placebo group (5.3% vs. 3.9%, P=0.003) as was the rate of hospitalization for AF (3.1% vs. 2.1%, P=0.004). It is possible that there were differences in AF management between groups that may explain this incidental finding. Therefore, the presence of AF would not preclude use of icoasapent ethyl at this time (though further studies would be beneficial to determine whether this finding was due to chance alone).
  • The benefit of icosapent ethyl for use in primary prevention of CVD is unclear. A statistically significant benefit was not found in the primary prevention subgroup in REDUCE-IT. There are few trials to date that examine use of n-3 fatty acids solely for primary prevention and as mentioned previously, two recent primary prevention trials, ASCEND and VITAL, found no benefit. A study utilizing the n-3 fatty acid dosing strategy from REDUCE-IT in an exclusively primary prevention population would help to further clarify the role of icosapent ethyl in this group.
  • It is not known how icosapent ethyl would compare in efficacy to other non-statin agents or in addition to other non-statin agents. Few patients (6.4%) in REDUCE-IT were prescribed ezetimibe at baseline, and patients prescribed any other non-statin therapy were excluded. A statistically significant benefit with use of icosapent ethyl was not found in the subgroup taking ezetimibe at baseline. Though this was a small subgroup analysis, it calls into question whether a benefit would be seen with icosapent ethyl in addition to or when compared with other non-statin therapies. Current guidelines recommend that in high-risk patients with LDL ≥ 70 mg/dL despite maximally-tolerated statin, non-statin therapy be added to reduce residual risk with a preference for ezetimibe over proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors based on cost, ease of use, and the allowance of ezetimibe use in PCSK9 inhibitor outcome trials.12 Given the inclusion criteria of REDUCE-IT, as well as baseline LDL values of approximately 75 mg/dL, it is reasonable to add ezetimibe first if LDL lowering is needed. However, icosapent ethyl could be useful for patients whose lipid panel reveal LDL < 70 mg/dL but TG remains elevated (>150 mg/dL).

Bottom Line

Icosapent-ethyl (purified EPA) at a dose of 4 g daily appears to decrease cardiovascular events significantly in patients with hypertriglyceridemia with minimal adverse events. Given the previous consensus of data finding a lack of benefit with n-3 fatty acids, this may be due to the increased dose or the formulation of purified EPA used. Based on the potential for benefit with a number needed to treat of 21 and minimal adverse events, icosapent ethyl appears to be a useful medication for reducing cardiovascular events in high-risk patients with elevated TG (>150 mg/dL) despite adequate LDL reduction on a maximally tolerated statin.

Mallory Mouradjian, PharmD

At the time of this writing, Mallory Mouradjian was a postgraduate year 2 (PGY2) cardiology pharmacy resident at the University of Maryland in Baltimore, MD.

Stormi Gale, PharmD, BCCP

Dr. Gale is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist at the University of Maryland Medical Center in Baltimore, MD. Follow her on Twitter @stormigale.

References:

  1. Ganda OP, Bhatt DL, Mason RP, et al. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia. J Am Coll Cardiol. 2018; 72: 330-43.
  2. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews. 2018, Issue 11. Art. No.: CD003177.
  3. Bhatt DL, Steg G, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11-22.
  4. Weitz D, Weintraub H, Fisher E, et al. Fish oil for the treatment of cardiovascular disease. Cardiol Rev. 2010; 18(5):258-263.
  5. Chang CH, Tseng PT, Chen NY, et al. Safety and tolerability of prescription omega-3 fatty acids: a systematic review and meta-analysis of randomized con- trolled trials. Prostaglandins Leukot Es- sent Fatty Acids 2018;129:1-12.
  6. Lovaza (omega-3-acid ethyl esters). [Prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; Apr 2019.
  7. Vascepa (icosapent ethyl). [Prescribing information]. Bedminster, NJ: Amarin Pharma Inc.; Feb 2017.
  8. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.
  9. The ASCEND Study Collaborative Group. Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus. N Engl J Med. 2018;379:1540-50.
  10. Mason JE, Cook NR, Lee I, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380:23-32.
  11. Aung T, Halsey J, Kromhout D, et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol. 2018;1(3):225-234.
  12. Grundy SM, Stone NJ, Bailey AL, et al. 2018 ACC/AHA/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;Nov 10:[Epub ahead of print].
Icosapent Ethyl for Prevention of Cardiovascular Disease: Worth the Hype or Fishing for a Place in Therapy?

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