More Recent Headlines from the Late-breaking Clinical Trial Presentations at the American Heart Association Scientific Sessions -
Less Pessimism Called for When Interpreting the Results from VITAL Regarding Cardiovascular Benefits with Omega-3
By Kevin C Maki, PhD and Mary R Dicklin, PhD
The primary results from the Vitamin D and Omega-3 Trial (VITAL) were recently presented at the late-breaking clinical trial sessions of the American Heart Association (AHA) meeting in Chicago, IL and simultaneously published in the New England Journal of Medicine.1 VITAL was a randomized, placebo-controlled trial of a 1 g/d fish oil capsule (Lovaza®/Omacor®) and 2000 IU/day vitamin D3 administered to 25,871 men ≥50 y of age and women ≥55 y of age. The primary endpoints were major cardiovascular events (a composite of myocardial infarction [MI], stroke or death from cardiovascular causes) and invasive cancer of any type. The key secondary endpoints were individual components of the composite cardiovascular endpoint, the composite endpoint plus coronary revascularization, site-specific cancers and death from cancer. Patients were followed for a median of 5.3 y. A discussion of the findings from the omega-3 and cardiovascular disease portion of the trial follows.
A major cardiovascular event occurred in 386 subjects in the omega-3 group and 419 in the placebo group (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.80 to 1.06, p = 0.24).1 The HR (95% CI) for the key secondary endpoints were 0.93 (0.82 to 1.04) for the composite plus coronary revascularization, 0.72 (0.59 to 0.90) for total MI, 1.04 (0.83 to 1.31) for total stroke, and 0.96 (0.76 to 1.21) for death from cardiovascular causes. There were no excess risks of bleeding or other serious adverse events with the interventions.
In our opinion, the response to the results from VITAL has been unnecessarily pessimistic.2 It is true that the 8% reduction in the primary composite endpoint was not statistically significant. However, as we have previously written, we believe that the failure of many of the omega-3 cardiovascular outcomes trials to show clear evidence of benefit can likely be attributed, in part, to the low dosages of omega-3 administered (most <1 g/d eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) and the groups in which the studies have been conducted (without elevated triglycerides [TG] and not limited to subjects with low omega-3 dietary intake).3 This was also the case in VITAL, where subjects at relatively low cardiovascular risk were administered a 1g/d fish oil concentrate capsule (providing 840 mg/d EPA + DHA) and the median fish intake in the study sample at baseline was well above the average intake in the US general population.1
Results from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), presented in the same late-breaking clinical trials session at AHA and published simultaneously in New England Journal of Medicine, demonstrated that Vascepa® at a higher dosage of 4 g/d (~3700 mg/d EPA as icosapent ethyl) administered to subjects at higher risk with elevated TG (median of 216 mg/dL) resulted in a significant 25% reduction in the primary endpoint, the composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina.4 Unfortunately, an editorial that accompanied VITAL did not acknowledge the findings from REDUCE-IT, and in fact stated “…in the absence of additional compelling data, it is prudent to conclude that the strategy of dietary supplementation with either n-3 fatty acids or vitamin D as protection against cardiovascular events or cancer suffers from deteriorating VITAL signs.”2 It would seem that we do have “additional compelling data” in REDUCE-IT and that we should not abandon the idea that omega-3 fatty acids, when administered at higher dosages and to higher risk populations, reduces cardiovascular risk. This adds to the biologic plausibility of the secondary outcomes for which benefits were observed.
In VITAL, endpoints that achieved nominal statistical significance included reductions in total MI (HR 0.72, 95% CI 0.59 to 0.90), total coronary heart disease (composite of MI, coronary revascularization and death from coronary heart disease; HR 0.83, 95% CI 0.71 to 0.97) and death from MI (HR 0.50, 95% CI 0.26 to 0.97) with omega-3 fatty acids vs. placebo.1 However, the editorial that accompanied VITAL emphasized the strong need for caution in interpreting “positive” results from secondary endpoints.2 While we agree that statistically significant secondary endpoints should not outweigh the null findings from the primary endpoint, it is also important that findings from secondary endpoints are not overlooked, particularly when they are in general agreement with results from prior studies.3,5-7 It is also notable that the subgroup with below-median fish intake at baseline showed statistically significant reductions of 19% and 40% in the primary outcome variable and total MI, respectively.1 This observation further supports the possibility that a relatively low dosage of EPA + DHA may have benefits in those with lower omega-3 fatty acid intakes.8
Our group published a meta-analysis of 14 randomized controlled trials that investigated the effects of omega-3 fatty acid supplementation on cardiac death, and reported that there was an 8% lower risk with omega-3 fatty acids vs. controls (and ~29% lower risk when dosages >1 g/d EPA + DHA were evaluated).7 Death from CHD in VITAL was not statistically significantly lower (HR 0.76, 95% CI 0.49 to 1.16).1 However, to further assess the potential for fatal CHD reduction with omega-3 fatty acid supplementation, we added the results from VITAL,1 along with other recently published trials,4,6 to a previous meta-analysis published by Aung and colleagues.5 This analysis demonstrated a statistically significant reduction in fatal CHD with omega-3 fatty acid interventions (relative risk 0.901, 95% CI 0.841 to 0.965, p = 0.003).9
Thus, it is our opinion that the null findings for the primary cardiovascular endpoint in VITAL need to be interpreted alongside the favorable findings from REDUCE-IT. These results suggest the need for additional studies with higher dosages of EPA + DHA administered to high-risk populations. We eagerly await the results from the last of the large-scale omega-3 fatty acid trials that is underway, The Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH), which enrolled subjects with elevated TG and below-average high-density lipoprotein cholesterol levels.10
- 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.
- Keaney JF, Jr., Rosen CJ. VITAL signs for dietary supplementation to prevent cancer and heart disease. N Engl J Med. 2018; Epub ahead of print.
- 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).
- 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.
- 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.
- 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.
- Rimm EB, Appel LJ, Chiuve SE, et al. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2018;138:e35-e47.
- Maki KC, Dicklin MR. 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. November 27, 2018. Available at https://mbclinicalacademy.com/headlines/.
- 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.