Recent Headlines from the Late-breaking Clinical Trial Presentations at the American Heart Association Scientific Sessions -
REDUCE-IT – a Landmark Cardiovascular Outcomes Study of an Omega-3 Fatty Acid
By Kevin C Maki, PhD and Mary R Dicklin, PhD
The primary results from the Reduction of Cardiovascular Events with Eicosapentaenoic Acid (EPA) – Intervention Trial (REDUCE-IT) were recently presented at the late-breaking clinical trial sessions of the American Heart Association meeting in Chicago, IL and simultaneously published in the New England Journal of Medicine.1,2 These results followed the topline result announced last month by Amarin, the maker of Vascepa® (icosapent ethyl), indicating an ~25% relative risk reduction in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization or unstable angina.3
REDUCE-IT was a multicenter, randomized, double-blind trial that examined the effects of a high dosage of 4 g/d Vascepa providing ~3700 mg EPA vs. placebo on cardiovascular outcomes in 8179 statin-treated adults at high cardiovascular risk, followed for a median of 4.9 y.1 At entry, participants had an elevated fasting triglyceride (TG) level (median 216 mg/dL) and well-controlled low-density lipoprotein cholesterol (LDL-C; median of 75 mg/dL). The primary endpoint occurred in 17.2% of patients on Vascepa vs. 22.0% of patients on placebo (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.68 to 0.83, p < 0.001). The key secondary endpoint, which was a composite of cardiovascular death, nonfatal MI or nonfatal stroke, occurred in 11.2% of patients on Vascepa vs. 14.8% of patients on placebo (HR 0.74, 95% CI 0.65 to 0.83, p < 0.001). The rates of all of the individual and composite endpoints (except for death from any cause) were all significantly lower with Vascepa than with placebo. The overall rates of adverse events during the trial, and the rates of serious adverse events leading to discontinuation, were not significantly different between Vascepa and placebo groups.
A notable finding in REDUCE-IT was a 20% lower rate of cardiovascular death (p = 0.03).1 Our group previously conducted a meta-analysis of 14 randomized controlled trials that investigated the effects of omega-3 fatty acids on cardiac death, and found an 8% lower risk with omega-3 supplementation vs. controls.4 The effect was much larger (~29%) in studies that tested dosages >1 g/d EPA + docosahexaenoic acid (DHA). Although REDUCE-IT did not include a coronary heart disease (CHD) death endpoint, the publication did include enough information to perform a rough calculation of it based on fatal MI, sudden cardiac death (SCD) and heart failure death.1 There were numerically lower incidence rates for both fatal MI and SCD in REDUCE-IT, but death from heart failure did not differ in the treatment arms, which suggests that the benefit to cardiovascular death was driven by fatal MI, SCD and fatal stroke, but not heart failure death. To assess the possibility for detecting a benefit for fatal CHD with omega-3 fatty acids, we added our estimate from REDUCE-IT, to the results from a recent meta-analysis conducted by Aung et al.,5 along with data from A Study of Cardiovascular Events in Diabetes (ASCEND),6 and the recently published Vitamin D and Omega-3 Trial (VITAL).7 Doing this demonstrated a statistically significant reduction in fatal CHD with omega-3 fatty acids (details are below).
- Aung meta-analysis5: 1301 of 39,017 participants for omega-3 and 1394 of 38,900 participants for control;
- ASCEND6: 100 of 7740 participants for omega-3 and 127 of 7740 participants for control;
- VITAL7: 37 of 12,933 participants for omega-3 and 49 of 12,938 participants for control;
- REDUCE-IT (fatal MI + SCD)1: 74 of 4089 participants for omega-3 and 110 of 4090 participants for control;
- When combined, this shows that CHD death occurred in 2.37% of 63,779 participants receiving omega-3 interventions and 2.64% of 63,668 participants in control conditions; the relative risk is 0.901 (95% CI 0.841 to 0.965, p = 0.003).
The result is also statistically significant without inclusion of the REDUCE-IT findings (relative risk 0.914, 95% CI 0.852 to 0.981, p = 0.013). The robust results from REDUCE-IT, which included reductions in stroke as well as fatal and non-fatal CHD, suggest that low dosage in many of the prior studies was the reason for failure to demonstrate clear differences between the omega-3 and control groups in cardiovascular event rates. Whether EPA is superior to DHA for risk reduction remains to be determined, and the results from the ongoing Outcomes Study to Assess Statin Residual Risk Reduction with Epanova® in High Risk Patients with Hypertriglyceridemia (STRENGTH), which are expected in 2019 or 2020, should provide information relevant to assessing this question.8 Epanova provides EPA + DHA in carboxylic acid (free fatty acid) form.
Some experts expressed surprise with the results from REDUCE-IT, because of the numerous unfavorable interpretations of results from other recently published trials and meta-analyses of the effects of omega-3 fatty acids on cardiovascular outcomes.5,6 While we agree that the magnitude of effect in REDUCE-IT, i.e., 25% reduction in risk, was somewhat larger than expected, as we previously expressed, in our opinion, the failure to show benefit in some of those previous studies was due to study design issues.9 Many of the prior studies tested low dosages (most administered just 1 g/d Omacor®/Lovaza® providing ~840 mg EPA + DHA), and they failed to examine the intervention in subjects with hypertriglyceridemia who would be expected to benefit most from a TG-lowering intervention.9 In another meta-analysis, our group found that medications that substantially lower TG (i.e., fibrates, niacin, omega-3 fatty acids) appeared to reduce cardiovascular disease risk in those with elevated TG, especially if accompanied by low high-density lipoprotein cholesterol (HDL-C) levels.10,11 The results from REDUCE-IT confirmed the larger benefit in those with elevated TG plus low HDL-C, with a reduction in the primary outcome of 38% in those with TG ≥200 mg/dL plus HDL-C ≤35 mg/dL, and 21% in those without this combination (p = 0.04 for interaction).
The REDUCE-IT authors suggested that at least some of the reduced risk of ischemic events may be explained by metabolic effects other than reduced TG levels. This possibility is supported by the finding that the effect of the drug on primary and key secondary outcomes did not differ among those with and without achieved TG <150 mg/dL at one year. There are several potential mechanisms through which EPA could lower risk beyond TG lowering, including, among others, reductions in inflammation, antiplatelet effects and plaque stabilization. There was a statistically significant (p < 0.001) difference in high-sensitivity C-reactive protein (hs-CRP) response of 0.4 to 0.9 mg/L (21-40% depending on how calculated and timepoint) between the treatment arms favoring the active treatment group.1 Thus, it is possible, and in our view likely, that anti-inflammatory effects may have contributed to the observed benefits.
There have been concerns raised regarding some of the laboratory results in the trial. For example, the use of the mineral oil placebo was problematic in that it was associated with increases in TG, LDL-C and non-HDL-C of 2.2%, 10.9%, and 10.4%, respectively at year 1, and apolipoprotein B and hs-CRP of 7.8% and 32.3%, respectively at 2 years.1,2 While not ideal, it is important to compare this to other clinical trials of prescription lipid-altering medications. For example, among subjects taking placebo in the ODYSSEY Outcomes trial, there was an increase of approximately 12% in LDL-C during the treatment period (92 mg/dL to 103 mg/dL).12 Thus, it appears very unlikely that an adverse effect of the mineral oil placebo can explain more than a small fraction of the observed benefit. In the Japan EPA Lipid Intervention Study (JELIS),13 a similar drug (1.8 g/d EPA from ethyl esters) reduced the primary cardiovascular endpoint by 19% compared with a no treatment control (not placebo). The concordance in results between the trials provides compelling evidence that the benefit in REDUCE-IT is not artifactual.
Overall, it is our opinion that the results from REDUCE-IT are an important answer to the question of whether omega-3 fatty acids (EPA alone as icosapent ethyl in this instance) reduce cardiovascular risk when administered at a sufficiently high dosage to subjects with elevated TG who are at high cardiovascular risk. This is unequivocally good news for patients and has been long-awaited given the large number of trials of low-dosage omega-3 fatty acids that had failed to produce clear evidence of cardiovascular benefit. Additional trials are warranted to determine whether higher dosages of omega-3 fatty acids will also produce cardiovascular benefits in other population subgroups.
- Bhatt DL, Steg G, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2018; Epub ahead of print.
- Kastelein JJP, Stroes ESG. FISHing for the miracle of eicosapentaenoic acid. N Engl J Med. 2018; Epub ahead of print.
- Amarin Corporation. REDUCE-IT™ cardiovascular outcomes study of VASCEPA® (icosapent ethyl) capsules met primary endpoint. September 24, 2018. Available at https://investor.amarincorp.com/news-releases/news-release-details/reduce-ittm-cardiovascular-outcomes-study-vascepar-icosapent.
- Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: an updated meta-analysis and review of research gaps. J Clin Lipidol. 2018;11:1152-1160.
- 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 77917 individuals. JAMA Cardiol. 2018;3:225-234.
- ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018; Epub ahead of print.
- Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2018; Epub ahead of print.
- Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol. 2018;41:1281-1288.
- Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10(7).
- Maki JC, Guyton JR, Orringer CE, et al. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10:905-914.
- Maki KC, Dicklin MR. Do triglyceride-lowering drugs decrease risk of cardiovascular disease? Curr Opin Lipidol. 2017;28:374-379.
- Schwarz GG, Steg G, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018; Epub ahead of print.
- Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.