Omega-3 fatty acids for CV risk reduction: The one that did not get away
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Despite significant medical advances in recent decades, CVD remains rampant, firmly positioned as the leading cause of morbidity and mortality worldwide. In the quest to reduce atherosclerotic CVD, statin therapy has emerged as the gold standard pharmacotherapy. Statins reduce LDL by 20% to 60%, corresponding to an approximately 30% reduction in ASCVD events, and have been studied among a myriad patient populations. Despite the success of statins and other CV therapies, significant residual risk remains. In addition to modulation of standard ASCVD risk factors such as diabetes and obesity to minimize residual risk, elevated triglyceride levels have recently been reinvigorated as a therapeutic target.
Several lines of epidemiological, genetic and biological data have implicated elevated triglyceride levels as an independent association with CVD risk. Historically, therapies targeting triglyceride reduction, such as niacin, fibrates, and omega-3 fatty acids — whose active ingredients consist of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) — have failed to demonstrate a consistent CV benefit (Tables 1 and 2).
Prior benefit observed
Older trials of omega-3 fatty acids hinted at a possible benefit, leading the American Heart Association to recommend treatment as reasonable for secondary prevention of CHD and sudden cardiac death in those with prevalent CHD (class IIa, level of evidence A), and secondary prevention of outcomes in patients with HF (class IIa, level of evidence B-R). However, more contemporary analyses of omega-3 fatty acids, most utilizing mixed DHA/EPA products and at lower dosages of 1 g or less per day, have failed to demonstrate a CV benefit. This was until publication of REDUCE-IT.
Before diving into the accolades of REDUCE-IT, it is important to consider prior EPA studies that give the magnitude of REDUCE-IT some clinical context. The first was JELIS, an open-label study of 18,645 Japanese patients (20% with CHD at baseline) with total cholesterol greater than 243 mg/dL and on predominately low-intensity statin therapy. EPA dosed at 1.8 g daily corresponded to a 19% RR reduction in major CHD events (2.8% vs. 3.5%) at 5 years. However, these results carried minimal clinical effect, largely due to three perceived biases: reduced generalizability due to an all-Japanese population, low-intensity statin use and an open-label trial design. A decade later, the CHERRY trial was published revealing greater coronary plaque regression (81% vs. 61%; P = .002) in 193 post-PCI Japanese patients randomly assigned to pitavastatin plus EPA 1.8 g daily compared with pitavastatin monotherapy over 6 to 8 months of follow-up. Finally, a third trial in 241 Japanese patients with ACS randomly assigned to pitavastatin 2 mg daily with or without EPA 1.8 g daily within 24 hours of PCI demonstrated a 58% risk reduction in CV death, nonfatal stroke, nonfatal MI and revascularization and a 78% risk reduction in CV death at 1 year. Thus, even before REDUCE-IT, there were several positive trials suggesting an ASCVD benefit with EPA.
REDUCE-IT
The REDUCE-IT study evaluated icosapent ethyl (Vascepa, Amarin), a purified ethyl ester of EPA, 2 g twice daily compared with mineral oil placebo on a background of statin therapy in patients with established ASCVD or diabetes plus one additional risk factor, with LDL 41 mg/dL to 100 mg/dL and triglycerides 135 mg/dL to 499 mg/dL. The trial enrolled 8,179 patients (approximately 71% with established ASCVD) and after a median follow-up of 4.9 years, icosapent ethyl displayed a striking reduction in first occurrence of the primary endpoint: CV death, MI, stroke, coronary revascularization or unstable angina (17.2% vs. 22%; HR = 0.75; 95% CI, 0.68-0.83; number needed to treat = 21). All individual endpoints were significantly reduced.
A post hoc analysis demonstrated a 30% reduction in total (initial and recurrent) events related to the primary endpoint. This magnitude of benefit with icosapent ethyl is on par with other blockbuster CV drugs such as statins, PCSK9 inhibitors and novel antidiabetic agents. However, improvements in lipoprotein and inflammation parameters, and even in sudden cardiac death, did not predict the full degree of benefit displayed, implying there are other factors involved. Overall and serious adverse events did not differ between treatment arms. However, icosapent ethyl was associated with a small increase in hospitalization for atrial fibrillation/flutter compared with placebo (3.1% vs. 2.1%; P = .004) and a trend toward increased serious bleeding (2.7% vs. 2.1%; P = .06).
Controversy surrounding the use of a mineral oil placebo arose out of concern for reduced statin absorption, elevating levels of atherogenic lipoproteins and inflammatory markers, and masking the difference in gastrointestinal adverse effects between treatment groups. In the placebo group, LDL rose by 10.9% and non-HDL by 10.4% at 1 year, and C-reactive protein increased by 32.3% at 2 years. However, a post hoc analysis suggested similar risk reduction regardless of LDL trends in the placebo group. Although the true magnitude of CV benefit experienced with icosapent ethyl may be less than that observed in REDUCE-IT, the small elevations in atherogenic lipoproteins and inflammatory markers in the placebo group are insufficient to explain the 25% to 30% lower risk for major adverse CV events.
After publication of REDUCE-IT, several international organizations provided recommendations in support of icosapent ethyl (Table 3). First, the American Diabetes Association updated its Standards of Medical Care to recommend icosapent ethyl with an A-level of evidence, followed by the European Society of Cardiology/European Atherosclerosis Society 2019 guidelines for the management of dyslipidaemias (class IIa, level of evidence B), and finally the National Lipid Association (class I, level of evidence B-R).
Questions remain
As with any novel advancements, questions remain:
- What is the mechanism for these benefits? Are pleiotropic effects (eg, antioxidant, antithrombotic, plaque stability, etc) at play?
- Is there a threshold dose?
- Should we be checking EPA levels?
- Are the CV benefits of omega-3 fatty acids solely the result of EPA? What about mixed DHA/EPA products?
- Is therapy cost-effective?
Future studies should help to clarify these questions. Notably, the EVAPORATE trial will investigate icosapent ethyl on low-attenuation plaque assessed by CT in patients with elevated triglycerides; interim 9-month data presented in November at the AHA Scientific Sessions were encouraging. STRENGTH examined the effect of omega-3-carboxylic acids (Epanova, AstraZeneca) on major adverse CV events as an add-on therapy to statins in patients at high CVD risk with hypertriglyceridemia and low HDL. As opposed to REDUCE-IT that used pure EPA ethyl esters, STRENGTH used a combination of EPA and DHA as free acids at 4 grams per day. In January, it was stopped for futility, and publication of the full results has yet to come.
For cost, the retail monthly expense of icosapent ethyl is approximately $350, significantly lower than other novel CV drugs on the market. Recently, a cost-effectiveness analysis conducted by the Institute for Clinical and Economic Review (ICER) concluded that icosapent ethyl provided clinical benefit in quality-adjusted survival and overall survival and provided “high long-term value.” In mid-November 2019, an FDA panel unanimously voted in favor of adding a CV risk reduction indication to the label for icosapent ethyl, and 1 month later, the FDA granted approval for icosapent ethyl as an adjunctive (secondary) therapy to reduce risk for CV events among adults with elevated triglyceride levels of at least 150 mg/dL. Nevertheless, REDUCE-IT was the fourth randomized trial of EPA to demonstrate significant benefit over statin monotherapy.
In an era plagued by devastating CVD, omega-3 fatty acids in the form of purified EPA has the potential to revolutionize how we approach CVD risk reduction and should be used as first-line add-on therapy in high-risk patients with hypertriglyceridemia and well-controlled LDL on maximal statin therapy.
References:
AIM-HIGH Investigators. N Engl J Med. 2011;doi:10. 1056/NEJMoa1107579.
American Diabetes Association. Diabetes Care. 2019;doi:10.2337/dc19-S010.
ASCEND Study Collaborative Group. N Engl J Med. 2018;doi:10.1056/NEJMoa1804989.
AstraZeneca. www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html. Accessed Jan. 17, 2020.
Baigent C, et al. Lancet. 2005;doi:10.1016/S0140-6736(05)67394-1.
Benjamin EJ, et al. Circulation. 2019;doi:10.1161/CIR.0000000000000659.
Bhatt DL, et al. J Am Coll Cardiol. 2019;doi:10. 1016/j.jacc.2019.02.032.
Bhatt DL, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1812792.
Budoff MJ, et al. Late Breaking Science VI: New Frontiers in Lipid Therapy. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
Ginsberg HN, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa1001282.
HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;doi:10.1056/NEJMoa1300955.
Mach F, et al. Eur Heart J. 2020;doi:10.1093/eurheartj/ehz455.
Nordestgaard BG. Circ Res. 2016;doi: 10.1161/CIRCRESAHA.115.306249.
Nosaka K, et al. Int J Cardiol. 2017;doi:10.1016/ j.ijcard.2016.11.105.
Ollendorf D, et al. Additive Therapies for Cardiovascular Disease: Effectiveness and Value. Institute for Clinical and Economic Review, Oct. 17. 2019. Available at: https://icer-review.org/material/cvd-final-evidence-report/.
Orringer CE, et al. J Clin Lipidol. 2019;doi:10.1016/ j.jacl.2019.10.014.
Siscovick DS, et al. Circulation. 2017;doi:10.1161/CIR.0000000000000482.
Watanabe T, et al. J Cardiol. 2017;doi:10.1016/ j.jjcc.2017.07.007.
Yokoyama M, et al. Lancet. 2007;doi:10.1016/S0140-6736(07)60527-3.
For more information:
Carol Heunisch, PharmD, BCPS, BCCP, is director of Inpatient Pharmacy Services at Glenbrook, Highland Park and Skokie Hospitals, NorthShore University HealthSystem, Skokie, Illinois.
Bruce A. Warden, PharmD, BCPS-AQ Cardiology, CLS, is clinical pharmacist in the Center for Preventive Cardiology at Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy practice in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. She can be reached at sspinler@ binghamton.edu.
Disclosures: The authors report no relevant financial disclosures.
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- AIM-HIGH Investigators.N Engl J Med. 2011;doi:10. 1056/NEJMoa1107579.
- American Diabetes Association.Diabetes Care. 2019;doi:10.2337/dc19-S010.
- ASCEND Study Collaborative Group.N Engl J Med. 2018;doi:10.1056/NEJMoa1804989.
- AstraZeneca. www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html. Accessed Jan. 17, 2020.
- Baigent C, et al.Lancet. 2005;doi:10.1016/S0140-6736(05)67394-1.
- Benjamin EJ, et al.Circulation. 2019;doi:10.1161/CIR.0000000000000659.
- Bhatt DL, et al.J Am Coll Cardiol. 2019;doi:10. 1016/j.jacc.2019.02.032.
- Bhatt DL, et al.N Engl J Med. 2019;doi:10.1056/NEJMoa1812792.
- Budoff MJ, et al. Late Breaking Science VI: New Frontiers in Lipid Therapy. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
- Ginsberg HN, et al.N Engl J Med. 2010;doi:10.1056/NEJMoa1001282.
- HPS2-THRIVE Collaborative Group.N Engl J Med. 2014;doi:10.1056/NEJMoa1300955.
- Mach F, et al.Eur Heart J. 2020;doi:10.1093/eurheartj/ehz455.
- Nordestgaard BG.Circ Res. 2016;doi: 10.1161/CIRCRESAHA.115.306249.
- Nosaka K, et al.Int J Cardiol. 2017;doi:10.1016/ j.ijcard.2016.11.105.
- Ollendorf D, et al. Additive Therapies for Cardiovascular Disease: Effectiveness and Value. Institute for Clinical and Economic Review, Oct. 17. 2019. Available at: https://icer-review.org/material/cvd-final-evidence-report/.
- Orringer CE, et al.J Clin Lipidol. 2019;doi:10.1016/ j.jacl.2019.10.014.
- Siscovick DS, et al.Circulation. 2017;doi:10.1161/CIR.0000000000000482.
- Watanabe T, et al.J Cardiol. 2017;doi:10.1016/ j.jjcc.2017.07.007.
- Yokoyama M, et al.Lancet. 2007;doi:10.1016/S0140-6736(07)60527-3.
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