R3i Editorials

January 2021
Omega-3 fatty acids for residual cardiovascular risk: more questions than answers
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Omega-3 fatty acids have long been considered for a potential role in reducing residual cardiovascular risk. Meta-analyses have evaluated this issue; among the most recent, omega-3 supplementation significantly reduced the risk of cardiovascular events, as well as death due to coronary heart disease (CHD) or cardiovascular disease 1. It is, however, pertinent that the dose range of these studies varied widely (from 376 mg to 4 g daily), and that most used doses below 1 g 1.
Past outcomes studies of omega-3 fatty acids have had variable results. JELIS (Japan EPA Lipid Intervention Study) demonstrated a 19% relative reduction in the cardiovascular endpoint of sudden cardiac death, myocardial infarction, unstable angina and coronary revascularization with eicosapentaenoic acid (EPA) 1800 mg daily, on top of statin, versus statin monotherapy in patients with hypercholesterolaemia 2. In contrast, in both VITAL (Vitamin D and Omega-3 Trial) and ASCEND (A Study of Cardiovascular Events in Diabetes) there was no reduction in the primary cardiovascular endpoint in patients without clinically manifest atherosclerotic cardiovascular disease (ASCVD), albeit with a lower dose (1 g, containing 840 mg EPA and docosahexaenoic acid [DHA]) 3,4.
REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) was a landmark study, which specifically targeted high-risk patients with hypertriglyceridaemia (with and without ASCVD) 5. Treatment with high dose (4 g/day) icosapent ethyl (a purified EPA ester) was associated with a 25% reduction in the primary composite endpoint (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization or unstable angina). This was achieved despite a modest reduction (by 18%) in TG 5. While there was no evidence that baseline TG influenced the magnitude of clinical benefit 6, there was an association between achieved plasma EPA levels and cardiovascular benefit 7.
After the euphoria of REDUCE-IT the final report of STRENGTH (Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia) 8 was a sombre affair. STRENGTH was terminated in January 2020 for reasons of futility, on the recommendation of the Independent Data Monitoring Committee. The results pose many questions about these agents in the setting of residual cardiovascular risk.

Why was REDUCE-IT positive but STRENGTH neutral?
Several reasons may explain the discrepant results of these two studies. First, the omega-3 fatty acid formulation used in each study differed. Whereas REDUCE-IT evaluated high-dose EPA, STRENGTH tested a carboxylic acid formulation containing both EPA and DHA (Epanova). Despite a lower EPA dose, this formulation does not require hepatic metabolism, enabling systemic and tissue EPA levels similar to those seen with icosapent ethyl. Indeed, at 12 months, the increase in serum EPA levels was 67% in STRENGTH versus 63% in REDUCE-IT 5,8.

Other factors that may be relevant are the characteristics of the study patient populations, treatment adherence, as well as the impact of the comparator. With respect to patient populations, REDUCE-IT did enrol a higher proportion of patients with coronary artery disease (71% versus 56% in STRENGTH). There were, however, no obvious differences in treatment adherence or study retention between REDUCE-IT and STRENGTH. The comparator is clearly an issue. REDUCE-IT used a mineral oil as a comparator. This had unfavourable effects on both low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP), which may have exaggerated the magnitude of clinical benefit with icosapent ethyl. In contrast, the corn oil comparator used in STRENGTH did not raise LDL-C, apolipoprotein B or hsCRP, implying that this was a neutral comparator. Finally, it has been suggested that DHA may neutralize the benefit from EPA, although there is no evidence to support this proposal.

Were there consistent effects between the studies?
Both studies were consistent in showing an adverse signal for risk for atrial fibrillation (AF). Notably STRENGTH showed a 69% increase in the risk for AF 8; REDUCE-IT also showed a significant increase in hospitalization for AF or atrial flutter (p=0.004) 5. The recent OMEMI trial (OMega-3 fatty acids in Elderly patients with Myocardial Infarction) showed a similar increased risk for AF 9. The findings are noteworthy given that omega-3 fatty acids were extensively studied in past trials for preventing AF, mostly in patients without heart failure or left ventricular dysfunction. Analyses from the GISSI-HF study, however, provided no evidence that omega-3 fatty acids 1 g daily reduced incident AF in patients with chronic heart failure 10.

Given that the prevalence of AF increases in older patients, the latest findings from REDUCE-IT, STRENGTH and OMEMI are clearly a concern for clinicians. Furthermore, these results underline the need for additional treatments that are effective in lowering TG and, potentially, reducing residual cardiovascular risk. The race is on for novel approaches to this question, and we anticipate the results of PROMINENT with pemafibrate to provide the first insights 11.

References

  1. Hu Y, Hu FB, Manson JE. Marine omega-3 supplementation and cardiovascular disease: an updated meta-analysis of 13 randomized controlled trials involving 127 477 participants. J Am Heart Assoc 2019;8:e013543.
    2. 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.
    3. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 2019; 380:23–32.
    4. Group ASC, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018; 379:1540–1550.
    5. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
    6. Bhatt DL, Steg PG, Miller M, et al. Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J Am Coll Cardiol 2019;74: 1159 – 61.
    7. https://www.acc.org/latest-in-cardiology/articles/2020/03/24/16/41/mon-1045-eicosapentaenoic-acid-levels-in-reduce-it-acc-2020. 2020. [Accessed December 3, 2020].
    8. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020; doi: 10.1001/jama.2020.22258
    9. Kalstad AA, Myhre PL, Laake K, et al, on behalf of the OMEMI Investigators. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized controlled trial. Circulation 2020; doi/10.1161/CIRCULATIONAHA.120.052209.
    10. Aleksova A, Masson S, Maggioni AP, et al. n-3 polyunsaturated fatty acids and atrial fibrillation in patients with chronic heart failure: the GISSI-HF trial. Eur J Heart Fail 2013;15:1289-95.
    11. Pradhan AD, Paynter NP, Everett BM et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93.