No One Hit Wonder: High-Dose EPA Reduces Total Ischemic Events

Dr. Deepak Bhatt and colleagues released results of an interesting secondary analysis of the REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention) trial at ACC.19 in New Orleans on March 18. For background, REDUCE-IT was a randomized, placebo-controlled trial published in the New England Journal of Medicine in January 2019 in which 8,179 patients were randomized to either treatment with 2g twice a day of icosapent ethyl or mineral oil placebo.1 Icosapent ethyl is a highly purified form of EPA shown to reduce triglycerides, potentially stabilize membranes and reduce inflammation and oxidation.2

Patient selection was important in the design of the trial and is likely an important factor, in addition to the specific EPA product and dosing, in REDUCE-IT delivering a positive result amid a wasteland of negative omega-3 trials. In order to be included, patients had to meet the following three criteria: 1) established cardiovascular disease (secondary prevention cohort) or diabetes with at least one additional risk factor for CVD (primary prevention cohort); 2) fasting triglyceride levels between 135 and 500 mg/dL; and 3) LDL-C between 40 and 100 mg/dL on stable statin therapy for at least 4 weeks prior to randomization. Just over 70% of the randomized patients were in the secondary prevention cohort. The mean LDL-C was 75 mg/dL and the median triglyceride level was 216 mg/dL in both randomized groups. The primary endpoint was a composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization or hospitalization for unstable angina in a time-to-event analysis. The key secondary endpoint was a composite of CV death, nonfatal MI and nonfatal stroke in a time-to-event analysis. This secondary endpoint is important because it eliminates the relative subjectivity involved in determining who needs a revascularization procedure and in defining unstable angina.

Over a median follow-up of 4.9 years (maximum of 6.2 years), 23% of participants assigned to icosapent ethyl reached the primary endpoint compared to 28.3% assigned to placebo (HR 0.75, 95% CI 0.68-0.83) for a NNT of 21 to avoid one primary end-point event; 16.2% of participants assigned to icosapent ethyl met the key secondary endpoint (primary endpoint minus revascularization and unstable angina) and 20% of those assigned to placebo did (HR 0.74 95% CI 0.65-0.83) for a NNT of 28.

Upon prespecified hierarchical testing, participants assigned to icosapent ethyl experienced significantly fewer occurrences of each of the individual components composing the primary composite endpoint. Those in the intervention arm had a 13% relative risk reduction in total mortality, but this was not significant (HR 0.87, 95% CI 0.74-1.02).

At one year, triglycerides decreased by a median of 39 mg/dL in the intervention group and increased by 4.5 mg/dL in the placebo group. Interestingly, neither baseline triglyceride level nor magnitude of triglyceride lowering seemed to influence the efficacy of icosapent ethyl, suggesting that EPA may work via other mechanisms. Table 4 of the supplementary appendix accompanying the article showed that participants in the placebo group developed a significant increase in their non-HDL-C, LDL-C, apoB, and hsCRP. The placebo contained mineral oil in order to mimic the color and consistency of icosapent ethyl and was theorized to possibly interfere with statin absorption. However, the magnitude of the increase in LDL-C and other biomarkers seen in the placebo group is unlikely to explain more than a small fraction of the impressive 25% relative risk reduction seen.

The new analysis from Bhatt and colleagues presented at ACC.19 expands on their previous time-to-event analysis and informs us if icosapent ethyl prevents subsequent ischemic events. In the original report, the primary efficacy analysis was conducted from the time of randomization up to the point in time in which an occurrence of any event in the primary composite occurred. The follow-up presentation extended the time horizon to look at subsequent events following the index one.

A total of 2,909 events occurred throughout the length of the trial, including 1,606 first events (55%) and 1,303 subsequent events (45%). Specifically, 60% of subsequent events were coronary revascularization, 17% were fatal or nonfatal MI, 10% were cardiovascular death, 7% were hospitalization for unstable angina, and 6% were fatal or nonfatal stroke. In counting subsequent events, the investigators excluded nonfatal events that occurred on the same day as a CV death and only counted one nonfatal event per day. The percentage of participants assigned to the intervention group who were actually taking the study drug at the time they experienced each event declined in the following manner: 81% adherence at time of first event, 79% at time of second event, 68% at time of third event, and 68% at the time of the fourth or greater event.

Icosapent ethyl reduced events in the primary composite by the following amounts as compared to placebo:

  • First event: 25% (HR 0.75, 95% CI 0.68-0.83)
  • Second event: 32% (HR 0.68, 95% CI 0.60-0.78)
  • Third event: 31% (HR 0.69, 95% CI 0.59-0.82)
  • Fourth or greater events: 48% (RR 0.52, 95% CI 0.38-0.70)
  • Overall, icosapent ethyl reduced the number of total events by 30% (RR 0.70, 95% CI 0.62-0.78).

In regard to the key secondary endpoint, icosapent ethyl reduced the risk of the first event by 26% (HR 0.74, 95% CI 0.65-0.83) and the risk of all events (first event and then subsequent events) by 28% (RR 0.72, 95% CI 0.63-0.82).

Cost-effectiveness analyses are ongoing, and these findings in total event reduction are an important consideration in assessing the value of icosapent ethyl. From a clinical standpoint, it is our feeling that icosapent ethyl is a potentially valuable medication for reducing residual CV risk in patients with elevated triglycerides. It is known that even in patients on optimal medical therapy, a substantial risk of adverse events remains and triglyceride levels can serve as an independent marker of risk for future ischemic events.3-7 This study gives hope to clinicians that we can make a meaningful impact in reducing residual risk of not only first events, but also recurrent events. It remains to be determined whether patients with similar profiles to REDUCE-IT patients but lower levels of triglycerides could also benefit from icosapent ethyl. The trial results suggest that triglycerides were not a strong mediator of the outcome, but one challenge in interpreting this is that triglycerides levels are much more variable over time than, for instance, LDL-C. In any case, the mechanism of action warrants further study, as does the question of whether the effect is specific to icosapent ethyl or does it extend to other omega-3s such as the omega-3-carboxylic acid intervention being studied in the ongoing STRENGTH (Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia) trial.8 We look forward to seeing if the FDA gives a new indication for icosapent ethyl based on the impressive REDUCE-IT results.


  1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
  2. Bays HE, Ballantyne Cm, Braeckman RA, Stirtan WG, Soni PN. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs 2013;13:37-46.
  3. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.
  4. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2015;36:774-6.
  5. Klempfner R, Erez A, Sagit BZ, et al. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease: twenty-two-year follow-up of the bezafibrate infarction prevention study and registry. Circ Cardiovasc Qual Outcomes 2016;9:100-8.
  6. Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased cardiovascular risk in hypertiglyceridemic patients with statin-controlled LDL cholesterol. J Clin Endocrinol Metab 2018;103:3019-27.
  7. Toth PP, Granowitz C, Hull M, Liassau D, Anderson A, Philip S. High triglycerides are associated with increased cardiovascular events, medical costs, and resource use: a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J Am Heart Assoc 2018;7:e008740.
  8. Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH). Identifier: NCT02104817.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Heart Failure and Cardiac Biomarkers

Keywords: Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk Factors, Apolipoproteins B, Triglycerides, Secondary Prevention, Patient Selection, Cost-Benefit Analysis, Follow-Up Studies, Random Allocation, Hypertriglyceridemia, Eicosapentaenoic Acid, Angina, Unstable, Fatty Acids, Omega-3, Primary Prevention, Stroke, Diabetes Mellitus, Risk Reduction Behavior, Hospitalization, Inflammation, Biomarkers, Pharmacological, Carboxylic Acids

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