Subthreshold Nanosecond Laser in Age-Related Macular Degeneration: Observational Extension Study of the LEAD Clinical Trial

Published:February 28, 2021DOI:


      To evaluate the long-term effect of subthreshold nanosecond laser (SNL) treatment on progression to late age-related macular degeneration (AMD).


      Observational extension study of a randomized, sham-controlled trial.


      Two hundred twelve participants with bilateral large drusen.


      The Laser Intervention in the Early Stages of AMD (LEAD) study was a 36-month trial where participants were randomized to receive SNL or sham treatment in 1 eye at 6-monthly intervals up to 30 months. After the completion of the LEAD study, the 2 largest recruiting sites offered remaining participants an opportunity to enroll in a 24-month observational extension study. This study thus examined all participants from these 2 sites who were enrolled in the LEAD study at baseline, including the additional observational data.

      Main Outcome Measures

      Time to develop late AMD, defined on multimodal imaging, between those randomized the SNL or sham treatment.


      Overall, no significant difference was found in the rate of progression over a 60-month period in those randomized to the SNL compared with the sham group (adjusted hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.36–1.09; P = 0.098), similar to the findings at 36 months in the LEAD Study. However, evidence of treatment effect modification continued to emerge based on the coexistence of reticular pseudodrusen (RPD; P = 0.007, adjusted interaction). Namely, progression was slowed significantly with SNL treatment for those without coexistent RPD (adjusted HR, 0.34; 95% CI, 0.16–0.71; P = 0.004), but it was not significantly different for those with RPD (adjusted HR, 1.81; 95% CI, 0.67–4.88; P = 0.239).


      A 24-month observational extension study to the LEAD Study confirmed that SNL treatment did not significantly reduce the overall rate of progression to late AMD in a cohort with intermediate AMD. However, the persistence of a potential beneficial treatment effect in those without coexistent RPD over a longer follow-up duration of an additional 24 months without additional treatment is encouraging. These findings provide further justification for future trials to examine the potential value of SNL treatment for slowing progression in intermediate AMD.


      Abbreviations and Acronyms:

      AMD (age-related macular degeneration), BCVA (best-corrected visual acuity), GA (geographic atrophy), CI (confidence interval), HR (hazard ratio), LEAD (Laser Intervention in the Early Stages of AMD), RPD (reticular pseudodrusen), SNL (subthreshold nanosecond laser)
      To read this article in full you will need to make a payment
      Subscribe to Ophthalmology Retina
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Wong W.L.
        • Su X.
        • Li X.
        • et al.
        Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.
        Lancet Global Health. 2014; 2 (e106–e16)
        • Age-Related Eye Disease Study Research Group
        A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8.
        Arch Ophthalmol. 2001; 119: 1417-1436
        • The Age-Related Eye Disease Study 2 Research Group
        Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration.
        JAMA. 2013; 309: 2005-2015
        • Meyers K.J.
        • Liu Z.
        • Millen A.E.
        • et al.
        Joint associations of diet, lifestyle, and genes with age-related macular degeneration.
        Ophthalmology. 2015; 122: 2286-2294
        • Lek J.J.
        • Brassington K.H.
        • Luu C.D.
        • et al.
        Subthreshold nanosecond laser intervention in intermediate age-related macular degeneration: study design and baseline characteristics of the Laser in Early Stages of Age-Related Macular Degeneration Study (report number 1).
        Ophthalmol Retina. 2017; 1: 227-239
        • Zhang J.J.
        • Sun Y.
        • Hussain A.A.
        • Marshall J.
        Laser-mediated activation of human retinal pigment epithelial cells and concomitant release of matrix metalloproteinases.
        Invest Ophthalmol Vis Sci. 2012; 53: 2928-2937
        • Jobling A.
        • Guymer R.
        • Vessey K.
        • et al.
        Nanosecond laser therapy reverses pathologic and molecular changes in age-related macular degeneration without retinal damage.
        FASEB J. 2014; 29: 696-710
        • Guymer R.H.
        • Brassington K.H.
        • Dimitrov P.
        • et al.
        Nanosecond-laser application in intermediate AMD: 12-month results of fundus appearance and macular function.
        Clin Exp Ophthalmol. 2014; 42: 466-479
        • Guymer R.H.
        • Wu Z.
        • Hodgson L.A.B.
        • et al.
        Subthreshold nanosecond laser intervention in age-Related macular degeneration: the LEAD randomized controlled clinical trial.
        Ophthalmology. 2019; 126: 829-838
        • Wightman A.J.
        • Guymer R.H.
        Reticular pseudodrusen: current understanding.
        Clin Exp Optom. 2019; 102: 455-462
        • Spaide R.F.
        • Ooto S.
        • Curcio C.A.
        Subretinal drusenoid deposits AKA pseudodrusen.
        Surv Ophthalmol. 2018; 63: 782-815
        • Ferris III, F.L.
        • Wilkinson C.
        • Bird A.
        • et al.
        Clinical classification of age-related macular degeneration.
        Ophthalmology. 2013; 129: 844-851
        • Wu Z.
        • Luu C.D.
        • Ayton L.N.
        • et al.
        Optical coherence tomography defined changes preceding the development of drusen-associated atrophy in age-related macular degeneration.
        Ophthalmology. 2014; 121: 2415-2422
        • Wu Z.
        • Luu C.D.
        • Hodgson L.A.
        • et al.
        Prospective longitudinal evaluation of nascent geographic atrophy in age-related macular degeneration.
        Ophthalmol Retina. 2020; 4: 568-575
        • Friberg T.R.
        • Musch D.C.
        • Lim J.I.
        • et al.
        Prophylactic treatment of age-related macular degeneration report number 1: 810-nanometer laser to eyes with drusen. Unilaterally eligible patients.
        Ophthalmology. 2006; 113: 612-622. e1
        • Choroidal Neovascularization Prevention Trial Research Group
        Laser treatment in fellow eyes with large drusen: updated findings from a pilot randomized clinical trial.
        Ophthalmology. 2003; 110: 971-978
        • Owens S.L.
        • Bunce C.
        • Brannon A.J.
        • et al.
        Prophylactic laser treatment hastens choroidal neovascularization in unilateral age-related maculopathy: final results of the drusen laser study.
        Am J Ophthalmol. 2006; 141: 276-281
        • Virgili G.
        • Michelessi M.
        • Parodi M.B.
        • et al.
        Laser treatment of drusen to prevent progression to advanced age-related macular degeneration.
        Cochrane Database of Systematic Reviews. 2015; : CD006537
        • Wood J.P.
        • Plunkett M.
        • Previn V.
        • et al.
        Nanosecond pulse lasers for retinal applications.
        Lasers Surg Med. 2011; 43: 499-510
        • Greferath U.
        • Guymer R.H.
        • Vessey K.A.
        • et al.
        Correlation of histologic features with in vivo imaging of reticular pseudodrusen.
        Ophthalmology. 2016; 123: 1320-1331
        • Wu Z.
        • Luu C.D.
        • Hodgson L.A.B.
        • et al.
        Secondary and exploratory outcomes of the subthreshold nanosecond laser intervention randomized trial in age-related macular degeneration: a LEAD study report.
        Ophthalmol Retina. 2019; 3: 1026-1034