Results from A Study of Cardiovascular Events in Diabetes (ASCEND): Taking a Closer Look at the Potential Benefit of Omega-3 Fatty Acids for Preventing Cardiac Death
By Kevin C Maki, PhD; Mary R Dicklin, PhD
Results from A Study of Cardiovascular Events in Diabetes (ASCEND) were recently presented at the European Society of Cardiology (ESC) Congress 2018 held in Munich, Germany, along with their simultaneous publication in the New England Journal of Medicine.1,2 ASCEND was designed to evaluate whether daily aspirin safely prevented cardiovascular disease (CVD) and cancer in patients with diabetes, but without known CVD.3 The study also assessed whether supplementation with 1 g/d omega-3 fatty acids prevented CVD. Persons with diabetes (n = 15,480) were randomly assigned to receive 100 mg/d aspirin or placebo and, in a factorial design, 1 g/d omega-3 fatty acid capsules, containing 460 mg eicosapentaenoic acid (EPA) and 380 mg docosahexaenoic acid (DHA), or placebo (olive oil). The primary outcome was a first serious vascular event, which was defined as a composite of nonfatal myocardial infarction or stroke (excluding confirmed intracranial hemorrhage), transient ischemic attack, or vascular death. The secondary outcome was a composite of any serious vascular event or any arterial revascularization procedure.
The results for the omega-3 fatty acid portion of the trial showed no benefit from omega-3 vs. placebo for the primary or secondary composite outcomes. During a mean follow-up of 7.4 years, a serious vascular event occurred in 8.9% and 9.2% of patients in the omega-3 and placebo groups, respectively, with a rate ratio of 0.97, 95% confidence interval (CI) 0.87 to 1.08, p = 0.55. The composite outcome of any serious vascular event or revascularization occurred in 11.4% and 11.5% of patients in the omega-3 and placebo groups, respectively, with a rate ratio of 1.00, 95% CI 0.91 to 1.09. The lack of a significant benefit of omega-3 fatty acids on the pre-specified primary outcome in ASCEND was consistent with results from recent meta-analyses of randomized controlled trials (RCTs) of long-chain omega-3 polyunsaturated fatty acids (compared to control or no treatment) on coronary heart disease (CHD) events.4 In a meta-analysis of 10 RCTs (n = 77,917) Aung et al. reported a risk ratio (95% CI) for a CHD event of 0.96 (0.90 to 1.01).5 Similarly, in a meta-analysis of 18 RCTs (n = 93,633) Alexander et al. reported a risk ratio of 0.94 (0.85 to 1.06).6 Abdelhamid et al. reported a risk ratio of 0.93 (0.88 to 0.97) in a meta-analysis of 28 RCTs (n = 84,301).7
Although the balance of the evidence from the RCTs conducted to date is supportive of the conclusion that omega-3 long-chain polyunsaturated fatty acid supplementation does not reduce risk for CHD events, there is promising evidence to suggest that omega-3 fatty acids may be beneficial for preventing fatal CHD or cardiac death.4,8 A meta-analysis of the effects of omega-3 fatty acids on cardiac death (defined as deaths from CHD, cardiac arrhythmia or heart failure) in 14 RCTs (n = 71,899) showed a risk ratio of 0.92 (0.86 to 0.98), p = 0.015.8 Aung et al. also reported a marginally significant reduction in CHD death 0.93 (0.85-1.00).5 In ASCEND, there was a near-significant difference in coronary deaths (incidence rate ratio = 0.79, 95% CI 0.61 to 1.02).1 In addition, there were significantly fewer vascular deaths (which represented 28% of all deaths) in the fatty acid group than in the placebo group (incidence rate ratio = 0.82, 95% CI 0.68 to 0.98). Vascular deaths included coronary, sudden, stroke, and pulmonary embolism mortality.
The ASCEND investigators suggested the possibility that if their results were to be combined with the studies reported in the meta-analysis by Aung et al., that a small benefit for fatal CHD might be detected.1,5 To assess this possibility, we have added the events reported in ASCEND to the events reported by Aung et al., and there was, in fact, a significant reduction in CHD/coronary death.
CHD deaths were as follows:
- Aung meta-analysis5: 1301 of 39017 participants for omega-3 and 1394 of 38900 participants for control
- ASCEND1: 100 of 7740 participants for omega-3 and 127 of 7740 participants for control
- When combined, this is 3.00% of 46757 participants for omega-3 and 3.26% of 46640 participants for control
- The relative risk is 0.919 (95% CI 0.855 to 0.987, p = 0.021)
Although it is important to not over-interpret findings from post-hoc subset analyses, these results show promise for the prevention of cardiac death with omega-3 fatty acid supplementation through mechanisms that we outlined in our recent editorial comment in Nutrients.4 Unfortunately, the dosages used in most RCTs of omega-3 fatty acids conducted to date have been small (most employed 1 g/d Omacor/Lovaza, which contains 840 mg of EPA + DHA). Pooled results from observational studies with omega-3 biomarker measurements suggest that each 1-standard deviation (SD) increase in omega-3 status is associated with a 12-16% reduction in risk for CHD death.9 Based on the same observational study dataset, Harris et al. estimated that a 1-SD increase in omega-3 index (erythrocyte fatty acid EPA + DHA content), or 2.1% from the 10 cohorts included in the analysis, was associated with a 15% (95% CI 9% to 20%) reduction in risk for fatal CHD.10
A subset of 152 of the ASCEND participants had omega-3 index measurements completed. There was no material change in the placebo group (6.6% at baseline and 6.5% at follow-up), whereas the index increased from 7.1% to 9.1% in the omega-3 fatty acid group, resulting in a net difference of 2.1% in the change from baseline, and a difference between groups of 2.6% at the end of the trial. If the Harris et al. estimate of a 15% reduction in fatal CHD risk per 2.1% (1-SD) omega-3 index difference is applied to the ASCEND data, the predicted risk reduction would be 15%, or 18% if the difference between groups during follow-up of 2.6% (1.24-SDs) is used.10 These estimates are close to the observed difference of 21% in coronary death.
At lower dosages, it is our opinion that there is no compelling evidence to suggest benefits regarding non-fatal myocardial infarction or stroke, but that there is promising evidence for prevention of cardiac death. Of the three large-scale trials that have been recently completed or are underway, including the Vitamin D and Omega-3 Trial (VITAL),11 the Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH)12 and the Reduction of Cardiovascular Events with EPA – Intervention Trial (REDUCE-IT),13 only the latter two trials are using a higher EPA+DHA dosage (≥3000 mg/d). Future investigation should focus on higher dosages than have generally been employed to date.
Our view is that the potential for omega-3 fatty acid supplementation to reduce cardiac death clearly deserves additional study. Further details about why we hold this view may be found in our recent commentary in Nutrients.4 Also, we agree with the recent recommendation from the American Heart Association that it is reasonable to consider an omega-3 fatty acid supplement for patients with atherosclerotic CVD or heart failure. The message to patients can be as follows:
- There is little or no risk associated with taking an omega-3 fatty acid (EPA + DHA) supplementation;
- The available evidence does not support a benefit of EPA + DHA supplements for reducing risk of heart attack or stroke;
- However, if a heart attack or heart failure should occur, those who take an omega-3 supplement might be less likely to die as a result.
- The ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018 [Epub ahead of print].
- The ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018 [Epub ahead of print].
- Bowman L, Mafham M, Stevens W, et al. ASCEND: A study of cardiovascular events in diabetes: characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes. Am Heart J. 2018;198:135-144.
- 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;10:864.
- 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 77,917 individuals. JAMA Cardiol. 2018;3:224-234.
- Alexander DD, Miller PE, Van Elswyk ME, et al. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin Proc. 2017;29:15-29.
- Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7:CD003177.
- 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. 2017;11:1152-1160.
- Del Gobbo LC, Imamura F, Aslibekyan S, et al. n-3 polyunsaturated fatty acid biomarkers and coronary heart disease: pooling project of 19 cohort studies. JAMA Intern Med. 2016;176:1155-1166.
- Harris WS, Del Gobbo L, Tintle NL. The omega-3 index and relative risk for coronary heart disease mortality: estimation from 10 cohort studies. Atherosclerosis. 2017;262:51-54.
- Manson JE, Bassuk SS, Lee IM, et al. The Vitamin D and Omega-3 Trial (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33:159-171.
- NIH. U.S. National Library of Medicine. ClinicalTrials.gov. Outcomes study to assess statin residual risk reduction with Epanova in high CV risk patients with hypertriglyceridemia (STRENGTH). NCT02104817. https://clinicaltrials.gov.ct2/show/NCT02104817.
- Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: Reduction of cardiovascular events with icosapent ethyl-intervention trial. Clin Cardiol. 2017;40:138-148.