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Re: Guymer et al.: Subthreshold nanosecond laser intervention in age-related macular degeneration: The LEAD Randomized Controlled Clinical Trial (Ophthalmology. 2019;126:829-838)

      To the Editor:
      We appreciate that the article by Guymer et al attempts to find a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD).
      • Guymer R.H.
      • Hodgson L.A.B.
      • Caruso E.
      • et al.
      Laser Intervention in Early Stages of Age-Related Macular Degeneration Study Group. Subthreshold nanosecond laser intervention in age-related macular degeneration: the LEAD randomized controlled clinical trial.
      However, there are many items that raise concern in the report. Functional outcomes (such as visual acuity) are usually pertinent when designing interventional trials to prevent “vision-threatening late complications.” We have already learned from previous “laser to drusen” trials that anatomic outcomes often do not correlate with functional outcomes.
      Complications of Age-Related Macular Degeneration Prevention Trial Research Group
      Laser treatment in patients with bilateral large drusen: the complications of age-related macular degeneration prevention trial.
      • Virgili G.
      • Michelessi M.
      • Parodi M.B.
      • et al.
      Laser treatment of drusen to prevent progression to advanced age-related macular degeneration.
      The primary outcome of the study was defined as late AMD as determined by multimodal imaging. This outcome is described in Table 1 in the original article, but there is no historical validation of the outcome as it is proposed in the study. Late AMD has not historically been described as including “nascent geographic atrophy.” It seems that 80% of the event rates leading to the determination of late AMD in this study were due to drusen-associated atrophy and a considerable proportion of the outcome is related to this nonvalidated “nascent geographic atrophy” classification. We would recommend using a primary outcome measure with longitudinal data and validation to support its use especially when functional outcomes are not used.
      In addition, patients identified as having late AMD by the Image Reading Center were adjudicated by the endpoint adjudication committee, but the criteria used by this committee have not been described.
      Post hoc analyses were performed based on the assessment of reticular pseudodrusen (RPD). RPD are subjectively described in the literature; however, the observation of RPD can be variable between imaging modalities and clinical examination. There is no definition of the assessment of RPD in the methods section. This omission is important because there may be significant controversy in the definition of RPD and its ascertainment.
      The treatment of subthreshold nanosecond laser has been described; however, there is an absence of before and after treatment fundus photographs or multimodality images, including OCT. For a novel treatment, it would seem important to demonstrate the effects of this new subthreshold treatment with imaging presented in the article. Furthermore, the presence of deep retinal hemorrhage in 10 subjects raises concerns about whether the treatment is truly subthreshold.
      Although the primary outcome did not show any significant difference between subthreshold nanosecond laser and sham treatment in the progression rate for late AMD, there is significant and disproportionate discussion about a post hoc analysis involving RPD. Even the final paragraph of the article devotes more text to describing the implications of the likely less valid post hoc analysis results, instead of concentrating on the actual negative primary result of the study. It would be more appropriate to briefly discuss the post hoc analysis in this article and present this discussion via a separate venue.
      Finally, there are several examples in the manuscript of prognostication about the future benefits of subthreshold nanosecond laser, despite the negative primary outcome of this trial. A more conservative and measured approach would be indicated based on the actual negative findings of this trial.
      Before requesting another randomized clinical trial exposing subjects to an intervention that, as studied here, has no effect on progression to late AMD we would recommend the following:
      • 1.
        Further correlation of this study’s endpoint with a functional outcome such as visual acuity.
      • 2.
        Better validation of multimodal imaging “nascent geographic atrophy” in describing the natural history and progression of AMD.
      • 3.
        Scientific restraint when proposing a new intervention for altering the progression of AMD based on an overall negative study result with only a treatment effect in a post hoc analysis of an arguably difficult to describe subgroup using an outcome that has never been associated with a functional outcome such as visual acuity.

      References

        • Guymer R.H.
        • Hodgson L.A.B.
        • Caruso E.
        • et al.
        Laser Intervention in Early Stages of Age-Related Macular Degeneration Study Group. Subthreshold nanosecond laser intervention in age-related macular degeneration: the LEAD randomized controlled clinical trial.
        Ophthalmology. 2019; 126: 829-838
        • Complications of Age-Related Macular Degeneration Prevention Trial Research Group
        Laser treatment in patients with bilateral large drusen: the complications of age-related macular degeneration prevention trial.
        Ophthalmology. 2006; 113: 1974-1986
        • Virgili G.
        • Michelessi M.
        • Parodi M.B.
        • et al.
        Laser treatment of drusen to prevent progression to advanced age-related macular degeneration.
        Cochrane Database Syst Rev. 2015; 10: CD006537

      Linked Article

      • Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial
        OphthalmologyVol. 126Issue 6
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          There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD.
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        OphthalmologyVol. 126Issue 12
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          We thank Drs Bhavsar and Baker for their interest in our article,1 which described the primary efficacy and safety outcomes of the Laser Intervention in the Early Stages of Age-Related Macular Degeneration (LEAD) study, a trial of a subthreshold nanosecond laser (SNL) treatment in intermediate age-related macular degeneration (AMD). Several concerns have been expressed, which we address herein.
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