The new england journal of medicine Original Article Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus The ASCEND Study Collaborative Group*​​ ABSTRACT BACKGROUND Increased intake of n−3 fatty acids has been associated with a reduced risk of car- The members of the writing committee diovascular disease in observational studies, but this finding has not been confirmed (Louise Bowman, M.D., Marion Mafham, M.D., Karl Wallendszus, M.Sc., Will Stevens, in randomized trials. It remains unclear whether n−3 (also called omega-3) fatty Ph.D., Georgina Buck, M.Sc., Jill Barton, acid supplementation has cardiovascular benefit in patients with diabetes mellitus. Kevin Murphy, Theingi Aung, M.D., Rich- ard Haynes, D.M., Jolyon Cox, D.Phil., METHODS Aleksandra Murawska, M.Sc., Allen Young, Ph.D., Michael Lay, D.Phil., Fang We randomly assigned 15,480 patients with diabetes but without evidence of ath- Chen, M.D., Ph.D., Emily Sammons, erosclerotic cardiovascular disease to receive 1-g capsules containing either n−3 fatty M.B., Ch.B., Emma Waters, M.B., B.S., acids (fatty acid group) or matching placebo (olive oil) daily. The primary outcome was Amanda Adler, M.D., Ph.D., Jonathan Bo- dansky, M.D., Andrew Farmer, D.M., a first serious vascular event (i.e., nonfatal myocardial infarction or stroke, transient Roger McPherson, B.M., F.R.C.Ophth., ischemic attack, or vascular death, excluding confirmed intracranial hemorrhage). Andrew Neil, D.Sc., F.R.C.P., David Simp- The secondary outcome was a first serious vascular event or any arterial revascu- son, Richard Peto, F.R.S., F.Med.Sci., Co- lin Baigent, F.F.P.H., F.R.C.P., Rory Collins, larization. F.R.S., F.Med.Sci., Sarah Parish, D.Phil., and Jane Armitage, F.R.C.P., F.F.P.H.) as- RESULTS sume responsibility for the overall con- During a mean follow-up of 7.4 years (adherence rate, 76%), a serious vascular event tent and integrity of this article. The affili- occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the ations of the members of the writing committee are listed in the Appendix. placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P = 0.55). Address reprint requests to Dr. Bowman The composite outcome of a serious vascular event or revascularization occurred in at the Medical Research Council, Popula- 882 patients (11.4%) and 887 patients (11.5%), respectively (rate ratio, 1.00; 95% CI, tion Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies 0.91 to 1.09). Death from any cause occurred in 752 patients (9.7%) in the fatty acid Unit, Nuffield Department of Population group and in 788 (10.2%) in the placebo group (rate ratio, 0.95; 95% CI, 0.86 to 1.05). Health, Richard Doll Bldg., Old Road There were no significant between-group differences in the rates of nonfatal seri- Campus, Roosevelt Dr., Oxford OX3 7LF, United Kingdom, or at ascend@ ndph . ox . ous adverse events. ac . uk or louise . bowman@ ndph . ox . ac . uk. CONCLUSIONS *A complete list of the members of the ASCEND Study Collaborative Group is Among patients with diabetes without evidence of cardiovascular disease, there was provided in Supplementary Appendix 1, no significant difference in the risk of serious vascular events between those who available at NEJM.org. were assigned to receive n−3 fatty acid supplementation and those who were as- This article was published on August 26, signed to receive placebo. (Funded by the British Heart Foundation and others; 2018, at NEJM.org. Current Controlled Trials number, ISRCTN60635500; ClinicalTrials.gov number, DOI: 10.1056/NEJMoa1804989 NCT00135226.) Copyright © 2018 Massachusetts Medical Society. n engl j med nejm.org 1 The New England Journal of Medicine Downloaded from nejm.org by JULES LEVIN on August 26, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. The new england journal of medicine bservational studies in different findings that are now reported elsewhere in the populations have suggested that fish con- Journal.17 sumption once or twice a week is associ- O 1,2 ated with a reduced risk of heart disease. In 2002, Methods a systematic review concluded that eating the equivalent of 40 to 60 g of fish daily (providing Trial Oversight about 0.2 to 1.0 g of n−3 fatty acids) was associ- ASCEND was designed and conducted by inde- ated with nearly a 50% reduction in cardiovascular pendent investigators in the Clinical Trial Service mortality.3 However, randomized trials of supple- Unit at the University of Oxford (the regulatory mentation with n−3 (also called omega-3) fatty trial sponsor). The trial methods, patient charac- acids have shown conflicting results regarding the teristics, and data analysis plan (including out- effects on fatal or nonfatal outcomes.4-8 Meta- come definitions) have been reported previous- analyses of these trials have generally not identi- ly.18,19 The protocol (available with the full text of fied significant beneficial effects of n−3 fatty acid this article at NEJM.org) was approved by the supplementation on major vascular events.9,10 North West Multicenter Research Ethics Commit- However, interest has persisted about possible tee. The trial was funded by the British Heart benefits with respect to particular types of vascu- Foundation. Capsules containing the n−3 fatty lar events (including arrhythmias, heart failure, acids and matching placebo (along with funding and death from coronary heart disease) on the for packaging) were provided by Mylan (and for- basis, at least in part, of selected results in open- merly by Solvay and Abbott), and Bayer provided label trials.4,11,12 A recent meta-analysis10 was con- the aspirin and placebo. Mylan, Solvay, and Abbott ducted of 10 long-term, randomized trials of n−3 had nonvoting representation at meetings of the fatty acids as either primary or secondary pre- steering committee and provided comments re- vention in a total of 78,000 participants, includ- garding the trial design and draft manuscript ing approximately one third with diabetes or dys- but otherwise had no role in data collection or glycemia who were enrolled mainly in two large analysis or in the decision to submit the manu- trials.8,13 During a mean follow-up of 4.4 years, script for publication. the meta-analysis did not show significantly lower The manuscript was prepared by the writing rates of coronary heart disease or major vascular committee and was reviewed and approved for events among the patients who had received n−3 submission by the steering committee. The first fatty acids than among those in the control groups. and last members of the writing committee vouch The American Heart Association guidelines for the completeness and accuracy of the data and currently recommend n−3 fatty acid supplements analyses, and for the fidelity of the trial to the for secondary prevention of coronary heart dis- study protocol and data analysis plan. Requests ease,14 and fish consumption for primary preven- for data sharing will be handled in line with the tion is recommended in cardiovascular disease data access and sharing policy of the Nuffield prevention guidelines.15 Since patients with dia- Department of Population Health, University of betes have two to three times the risk of cardio- Oxford (available at www . ndph . ox . ac . uk/ about/ vascular disease as the general population,16 a data - access - policy). safe dietary supplement with even a modest protec- tive effect could have a major public health benefit. Patients We performed the randomized ASCEND Men and women who were at least 40 years of (A Study of Cardiovascular Events in Diabetes) to age (without an upper age limit) were considered assess the efficacy and safety of daily supplemen- eligible if they had received a diagnosis of diabe- tation with n−3 fatty acids, as compared with tes mellitus (any type) but did not have evidence placebo, in patients with diabetes without evi- of cardiovascular disease. Key exclusion criteria dence of cardiovascular disease at trial entry. Us- were a clear indication or contraindication for the ing a factorial design in the same trial, we also receipt of n−3 fatty acids or (with respect to the randomly assigned the patients to receive a daily factorial design, reported separately) aspirin or regimen of either 100 mg of aspirin or placebo, other condition that might limit adherence to at 2 n engl j med nejm.org The New England Journal of Medicine Downloaded from nejm.org by JULES LEVIN on August 26, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. n−3 Fatty Acid Supplements in Diabetes Mellitus least 5 years of participation in the trial. Patients mean follow-up of 2.5 years, we requested blood who reported the over-the-counter receipt of fish and urine samples, along with measures of blood oil or n−3 fatty acid supplements were asked to pressure and weight, from 1800 randomly selected stop them wherever possible, but they remained patients. (Details are provided in the Methods sec- eligible to participate in the trial, provided that tion of Supplementary Appendix 1, available at the daily dose was less than 1 g. All the patients NEJM.org.) provided written informed consent. Outcomes Procedures While recruitment was still ongoing, we modified Using regional diabetes registers or general prac- the original primary outcome to include transient tice data from around the United Kingdom, we ischemic attack (TIA) in the definition of serious identified potential patients and mailed them a vascular events, a change that was made to in- screening questionnaire.