ASCEND-Eye: Effects of Omega-3 Fatty Acids on Diabetic Retinopathy.

PURPOSE: Preclinical studies support a protective role for omega-3 fatty acids (FAs) on diabetic retinopathy (DR), but these observations have not been confirmed in randomized trials. We present randomized evidence for the effects of omega-3 FAs on DR outcomes. DESIGN: A substudy of the A Study of Cardiovascular Events iN Diabetes (ASCEND) double-blind, randomized, placebo-controlled trial of 1 g omega-3 fatty acids (containing 460 mg eicosapentaenoic acid and 380 mg docosahexaenoic acid) daily for the primary prevention of serious cardiovascular events, in 15 480 UK adults at least 40 years of age, with diabetes. PARTICIPANTS: Fifteen thousand four hundred eighty adults at least 40 years of age from the United Kingdom with diabetes from the ASCEND cohort. METHODS: Linkage to electronic National Health Service Diabetic Eye Screening Programme records in England and Wales and confirmation of participant-reported eye events via medical record review. Log-rank and stratified log-rank methods were used for intention-to-treat analyses of time until the main outcomes of interest. MAIN OUTCOME MEASURES: The primary efficacy endpoint was time to the first postrandomization recording of referable disease, a composite of referable retinopathy (R2 or R3a/s) or referable maculopathy (M1) based on the grading criteria defined by the United Kingdom National Screening Committee. Secondary and tertiary outcomes included the referable disease outcome stratified by the severity of DR at baseline, any progression in retinopathy grade, and incident diabetic maculopathy. RESULTS: Linkage data were obtained for 7360 participants (48% of those who were randomized in ASCEND). During their mean follow-up of 6.5 years, 548 participants (14.8%) had a referable disease event in the omega-3 FAs group, compared with 513 participants (13.9%) in the placebo group (rate ratio, 1.07; 95% confidence interval, 0.95-1.20; P = 0.29). There were no statistically significant between-group differences in the proportion of events for either of the secondary or tertiary outcomes. CONCLUSIONS: Representing the largest prospective test of its kind to date, these data exclude any clinically meaningful benefits of 1 g daily omega-3 FAs on DR. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

ASCEND-Eye: Effects of Aspirin on Diabetic Retinopathy.

PURPOSE: Preclinical studies support a protective role for aspirin in early diabetic retinopathy (DR), but the findings from randomized trials are limited. We present randomized evidence for the efficacy and safety of aspirin on DR outcomes. DESIGN: A substudy of the A Study of Cardiovascular Events in Diabetes (ASCEND) double-masked, randomized, placebo-controlled trial of 100 mg aspirin daily for the primary prevention of serious cardiovascular events in people with diabetes. PARTICIPANTS: Fifteen thousand four hundred eighty United Kingdom adults at least 40 years of age with diabetes. METHODS: Linkage to electronic National Health Service Diabetic Eye Screening Programme records in England and Wales and confirmation of participant-reported eye events via medical record review were carried out. Log-rank methods were used for intention-to-treat analyses of time until the first primary efficacy and safety outcomes. MAIN OUTCOME MEASURES: The primary efficacy end point was the first record of referable disease after randomization, a composite of referable retinopathy or referable maculopathy based on the grading criteria defined by the United Kingdom National Screening Committee. The primary safety outcome was the first sight-threatening eye bleed, defined as clinically significant bleeding in the eye that resulted in unresolved visual loss or required an urgent intervention such as laser photocoagulation, vitreoretinal surgery, intraocular injection, or a combination thereof. RESULTS: Linkage data were obtained for 7360 participants (48% of those randomized in ASCEND). During the mean follow-up of 6.5 years, 539 participants (14.6%) experienced a referable disease event in the aspirin group, compared with 522 participants (14.2%) in the placebo group (rate ratio, 1.03; 95% confidence interval [CI], 0.91-1.16; P = 0.64). No statistically significant between-group difference was found in the proportions of sight-threatening eye bleed events (57 participants [0.7%] and 64 participants [0.8%], respectively; rate ratio, 0.89; 95% CI, 0.62-1.27). DISCUSSION: These data exclude any clinically meaningful benefits of aspirin for DR, but give reassurance regarding the ophthalmologic safety of aspirin. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Streamlined mail-based methods for large randomised trials: lessons learnt from the ASCEND study.

Reliable assessment of the effects of an intervention usually requires large randomised trials but such studies are becoming increasingly complex and costly to run. 'Streamlined' trials are needed in which every aspect of the trial design and conduct is simplified, retaining only those elements needed to answer the research question and ensure the safety of the individual participants. In this review we discuss how the trial 'A Study of Cardiovascular Events iN Diabetes' (ASCEND) was streamlined. The study included a two-by-two factorial design: it assessed the effects of low-dose aspirin and, separately, supplementation with n-3 fatty acids on serious vascular events in 15,480 people with diabetes but no overt cardiovascular disease. Other key streamlined design features, such as mail-based recruitment and follow-up, mainly by post, with no in-person visits and use of a run-in period, are also described. We go on to discuss the success of the study and other studies that have employed a similar mail-based approach, and the type of clinical trials that are suitable for mail-based design. Finally, we consider the limitations of the study, and how these could be circumvented in future studies. ASCEND randomised large numbers of eligible participants, achieved good adherence rates and almost complete follow-up at a fraction of the cost of traditional clinic-based trials. Such studies are necessary if researchers are to address the important clinical questions most relevant to improving health.