ASCEND-Eye: Rationale, design and baseline characteristics for a sub-study of the ASCEND randomised trial, exploring the effects of aspirin and omega-3 fatty acids on diabetic retinopathy and age-related macular degeneration

Emily Sammons, Louise Bowman, William Stevens, Georgina Buck, Karl Wallendszus, Imen Hammami, Sarah Parish, Jane Armitage, ASCEND Collaborative Group, Emily Sammons, Louise Bowman, William Stevens, Georgina Buck, Karl Wallendszus, Imen Hammami, Sarah Parish, Jane Armitage, ASCEND Collaborative Group

Abstract

Background: Aspirin and omega-3 fatty acids (FAs) have potential disease-modifying roles in diabetic retinopathy (DR) and age-related macular degeneration (AMD), but randomized evidence of these effects is limited. We present the rationale and baseline characteristics of ASCEND-Eye, a sub-study of the double-blind, 2x2 factorial design, randomized placebo-controlled ASCEND (A Study of Cardiovascular Events iN Diabetes) trial of 100 mg aspirin daily and, separately, 1g omega-3 FAs daily for the primary prevention of serious cardiovascular events, in 15,480 British adults, aged 40 years or older with diabetes.

Methods: Eye events will be derived from three sources: 1) participant follow-up questionnaires from ASCEND, 2) electronic NHS Diabetic Eye Screening Programme (DESP) data and 3) responses to the National Eye Institute's Visual Function Questionnaire-25 (NEI-VFQ-25) sent to a subset of participants after the main trial ended. Analytic cohorts and outcomes relevant to these data sources are described. The primary outcome is referable diabetic eye disease, a secondary outcome is incident AMD events.

Results: Participant-reported events were ascertained for the full cohort of randomized individuals who were followed up over 7.4 years in ASCEND (n = 15,480). Linked DESP data were available for 48% of those (n = 7360), and 57% completed the NEI-VFQ-25 (n = 8839). The baseline characteristics of these three cohorts are presented.

Discussion: Establishing the risks and benefits of drugs commonly taken by people with diabetes, the elderly, or both, and finding new treatments for DR and AMD is important. ASCEND-Eye provides the opportunity to evaluate the effect of aspirin and, separately, omega-3 FAs for both conditions.

Study registration: Eudract No. 2004-000991-15; Multicentre Research Ethics Committee Ref No. 03/8/087; ClinicalTrials.gov No. NCT00135226; ISRCTN No. ISRCTN60635500.

Keywords: Age-related macular degeneration; Aspirin; Diabetic retinopathy; Omega-3 fatty acids; Randomized trial.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

© 2023 The Authors.

Figures

Fig. 1
Fig. 1
Consort Diagram for the DESP-Linked Cohort (Aspirin Arm) FAs = Fatty acids.
Fig. 2
Fig. 2
Consort Diagram for the VFQ Cohort (Aspirin Arm) FAs = Fatty acids.

References

    1. World Health Organisation . 2019. World Report on Vision.
    1. Zhao Y., Singh R.P. The role of anti-vascular endothelial growth factor (anti-VEGF) in the management of proliferative diabetic retinopathy. Drugs Context (US) 2018;7
    1. Rosenfeld P.J., Brown D.M., Heier J.S., et al. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 2006;355(14):1419–1431.
    1. Pope C.H., Jr. Retinal capillary microaneurysms: a concept of pathogenesis. Diabetes. 1960;9:9–13.
    1. Boeri D., Maiello M., Lorenzi M. Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. Diabetes. 2001;50(6):1432–1439.
    1. Powell E.D., Field R.A. Diabetic retinopathy and rheumatoid arthritis. Lancet. 1964;2(7349):17–18.
    1. Sun W., Gerhardinger C., Dagher Z., Hoehn T., Lorenzi M. Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non–platelet-mediated effects. Diabetes. 2005;54(12):3418–3426.
    1. Wright W.S., Messina J.E., Harris N.R. Attenuation of diabetes-induced retinal vasoconstriction by a thromboxane receptor antagonist. Exp. Eye Res. 2009;88(1):106–112.
    1. Kern T.S., Engerman R.L. Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin. Diabetes. 2001;50(7):1636–1642.
    1. Bucolo C., Ward K.W., Mazzon E., Cuzzocrea S., Drago F. Protective effects of a coumarin derivative in diabetic rats. Investig. Ophthalmol. Vis. Sci. 2009;50(8):3846–3852.
    1. Joussen A.M., Poulaki V., Mitsiades N., et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB (Fed. Am. Soc. Exp. Biol.) J. 2002;16(3):438–440.
    1. Waitzman M.B., Kaplan H., Cornelius L., Evatt B., Hunt B. Aspirin and prostacyclin treatment of diabetic dogs. Metab. Pediatr. Syst. Ophthalmol. 1983;7(3):153–158.
    1. Early Treatment Diabetic Retinopathy Study Research Group Effects of aspirin treatment on diabetic retinopathy. ETDRS Report Number 8. Ophthalmology. 1991;98:757–765.
    1. Early Treatment Diabetic Retinopathy Study Research Group Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology. 1991;98(5 Suppl):741–756.
    1. The DAMAD Study Group Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. Diabetes. 1989;38(4):491–498.
    1. Baigent C., Blackwell L., Collins R., et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849–1860.
    1. SanGiovanni J.P., Chew E.Y. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog. Retin. Eye Res. 2005;24(1):87–138.
    1. Haritoglou C., Gerss J., Hammes H.P., Kampik A., Ulbig M.W. Alpha-lipoic acid for the prevention of diabetic macular edema. Ophthalmologica. 2011;226(3):127–137.
    1. 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 Cardiology. 2018;3(3):225–233.
    1. Snow K.K., Seddon J.M. Do age-related macular degeneration and cardiovascular disease share common antecedents? Ophthalmic Epidemiol. 1999;6(2):125–143.
    1. Nowak J.Z. Aspirin and age-related macular degeneration: positives versus negatives. Expet Opin. Drug Saf. 2014;13(6):687–690.
    1. Christen W.G., Chew E.Y. Does long-term aspirin use increase the risk of neovascular age-related macular degeneration? Expet Opin. Drug Saf. 2014;13(4):421–429.
    1. Chong E.W., Guymer R.H., Robman L.D. Does aspirin increase the risk of age-related macular degeneration? Expet Opin. Drug Saf. 2014;13(6):691–693.
    1. Seddon J.M., George S., Rosner B., Rifai N. Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch. Ophthalmol. 2005;123(6):774–782.
    1. Anderson D.H., Mullins R.F., Hageman G.S., Johnson L.V. A role for local inflammation in the formation of drusen in the aging eye. Am. J. Ophthalmol. 2002;134(3):411–431.
    1. Anderson D.H., Radeke M.J., Gallo N.B., et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog. Retin. Eye Res. 2010;29(2):95–112.
    1. Laine M., Jarva H., Seitsonen S., et al. Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein. J. Immunol. 2007;178(6):3831–3836.
    1. Christen W.G., Glynn R.J., Chew E.Y., Buring J.E. Low-dose aspirin and medical record confirmed age-related macular degeneration in a randomized trial of women. Ophthalmology. 2009;116(12):2386–2392.
    1. Robman L., Baird P.N., Dimitrov P.N., Richardson A.J., Guymer R.H. C-reactive protein levels and complement factor H polymorphism interaction in age-related macular degeneration and its progression. Ophthalmology. 2010;117(10):1982–1988.
    1. Klein B.E.K., Howard K.P., Gangnon R.E., Dreyer J.O., Lee K.E., Klein R. Long term use of aspirin and age-related macular degeneration. J. Am. Med. Assoc. 2012;308(23):2469–2478.
    1. Christen W.G. vol. 119. 2001. Age-Related Maculopathy in a Randomized Trial of Low-Dose Aspirin Among US Physicians Archives of Ophthalmology; pp. 1143–1149.
    1. Robman L., Guymer R., Woods R., et al. Age-related macular degeneration in a randomized controlled trial of low-dose aspirin: rationale and study design of the ASPREE-AMD study. Contemporary Clin. Trials Commun. 2017;6:105–114.
    1. Robman L.D., Phuong Thao L.T., Guymer R.H., et al. Baseline characteristics and age-related macular degeneration in participants of the "ASPirin in Reducing Events in the Elderly" (ASPREE)-AMD trial. Contemporary Clin. Trials Commun. 2020;20
    1. Souied E.H., Delcourt C., Querques G., et al. Oral docosahexaenoic acid in the prevention of exudative age-related macular degeneration: the Nutritional AMD Treatment 2 study. Ophthalmology. 2013;120(8):1619–1631.
    1. Age-Related Eye Disease Research Group Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. J. Am. Med. Assoc. 2013;309(19):2005–2015.
    1. Christen W.G., Cook N.R., Manson J.E., et al. Effect of vitamin D and ω-3 fatty acid supplementation on risk of age-related macular degeneration: an ancillary study of the VITAL randomized clinical trial. J. Am. Med. Ass. Ophthalmol. 2020;138(12):1280–1289.
    1. 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.
    1. Bowman L., Mafham M., Wallendszus K., et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N. Engl. J. Med. 2018;379(16):1529–1539.
    1. Bowman L., Mafham M., Wallendszus K., et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N. Engl. J. Med. 2018;379(16):1540–1550.
    1. Aung T., Haynes R., Barton J., et al. Cost-effective recruitment methods for a large randomised trial in people with diabetes: a Study of Cardiovascular Events iN Diabetes (ASCEND) Trials. 2016;17(1):286.
    1. Pocock S.J., Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31(1):103–115.
    1. Royal college of ophthalmologists . Vol. 7. 2012. pp. 1–147. (Diabetic Retinopathy Guidelines).
    1. Scanlon P.H. The English national screening Programme for diabetic retinopathy 2003-2016. Acta Diabetol. 2017;54(6):515–525.
    1. Public Health England . 2021. NHS Diabetic Eye Screening Programme: Grading Definitions for Referable Disease.
    1. Public Health England . 2017. NHS Diabetic Eye Screening Programme: Overview of Patient Pathway, Grading Pathway, Surveillance Pathways and Referral Pathways.
    1. Hippisley-Cox J. 2013. Validity and Completeness of the NHS Number in Primary and Secondary Care: Electronic Data in England 1991-2013.
    1. Mangione C.M., Lee P.P., Gutierrez P.R., et al. Development of the 25-list-item national eye Institute visual function questionnaire. Arch. Ophthalmol. 2001;119(7):1050–1058.
    1. Public Health England . Crown copyright; 2017. NHS Diabetic Eye Screening Programme: Grading Definitions for Referable Disease.
    1. Peto R., Pike M.C., Armitage P., et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br. J. Cancer. 1976;34(6):585–612.
    1. Peto R., Pike M.C., Armitage P., et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br. J. Cancer. 1977;35(1):1–39.
    1. Sapieha P., Stahl A., Chen J., et al. 5-lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids. Sci. Transl. Med. 2011;3(69) 69ra12-69ra12.
    1. Yusuf S., Peto R., Lewis J., Collins R., Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog. Cardiovasc. Dis. 1985;27(5):335–371.
    1. Lee Johnson L., Shih J.H. In: Principles and Practice of Clinical Research. third ed. Gallin J.I., Ognibene F.P., editors. Academic Press; Boston: 2012. Chapter 23 - an introduction to survival analysis; pp. 285–293.
    1. Rothwell P.M., Wilson M., Elwin C.-E., et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754):1741–1750.
    1. Clarke T.C., Black L.I., Stussman B.J., Barnes P.M., Nahin R.L. Trends in the use of complementary health approaches among adults: United States, 2002-2012. Natl Health Stat Report. 2015;(79):1–16.
    1. Inker L.A., Schmid C.H., Tighiouart H., et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N. Engl. J. Med. 2012;367(1):20–29.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj