Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration

Written by: Brian K. Do, MD

September 2019

Guymer RH, Wu Z, Hodgson LA, et al. Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial. Ophthalmology. 2019 Jun;126(6):829-838. doi: 10.1016/j.ophtha.2018.09.015. Epub 2018 Sep 20.

Rosenfeld PJ, Feuer WJ. Warning: Do not Treat Intermediate AMD with Laser Therapy. Ophthalmology. 2019 Jun;126(6):839-840. doi: 10.1016/j.ophtha.2018.12.016.

As retina specialists, we have the good fortune of having numerous treatment options at our disposal, within both the medical and surgical realms of vitreoretinal disease. We’ve seen the development and implementation of multiple different molecules for the treatment of various retinal vascular diseases, including exudative/neovascular AMD; unfortunately, little has been done to successfully combat the late atrophic complications of dry AMD.

A serendipitous discovery in 1971 demonstrated regression of drusen after thermal laser photocoagulation to the retina – subsequently, a number of thermal laser studies were conducted. Review of the results of these studies seemed to show that despite the fact that drusen were seen to regress, there was no reduction in the rates of progression to late AMD. More recently, the potential for short-pulse lasers to deliver subthreshold (nonvisible) energy to the RPE (theoretically, this could induce debris removal while minimizing collateral damage) has been investigated. In this particular randomized controlled trial, the LEAD study (Laser Intervention in Early Stages of Age-Related Macular Degeneration), the device used was the 2RT (Ellex Plt Ltd, Adelaide, Australia).

Across 6 sites (5 in Australia, 1 in Ireland), a total of 292 participants (out of 367 screened) were initially randomized to either a subthreshold nanosecond laser (SNL) arm, or to a sham arm. Individuals within the treatment arm had a total of 12 400 micron spots treated – 6 in an arc both just above the inferotemporal vascular arcade, as well as below the superotemporal vascular arcade. Individuals in the sham arm underwent the exact same procedure, except that short bursts of light from the illumination system on the laser device were used. Participants were then seen every 6 months following randomization/treatment, for up to 36 months. Ultimately, due to loss to follow-up and protocol deviations, a total of 119 (SNL) and 124 (sham) participants’ data were used in the final analyses.

Baseline characteristics were comparable between the two groups, except for a higher proportion of the sham group taking a supplement called Lutein-Vision (combination of: lutein, selonomethionine, zeaxanthin, omega-3 triglycerides fish oil) at the time of randomization. The average age of the study participants was 70 years; they were predominantly women (73.6%) and of white descent (89.7%), with 47.3% being past or current smokers.

A total of 45 randomized participants (15.4%) were found to have developed late AMD in the study eye at 36 months of follow-up: 20 from the SNL group (13.6%), and 25 from the sham group (17.2%). Of these, the breakdown was as follows: SNL – 7 neovascular AMD, 13 drusen-associated atrophy, sham – 5 neovascular AMD, 20 drusen-associated atrophy. None of these differences between groups were found to be statistically significant.

In a post-hoc analysis performed based on presence of coexisting reticular pseudodrusen (RPD), however, there appeared to be evidence of a strong treatment effect. Among the 222 participants without RPD at baseline, the rate of progression to late AMD was reduced in the treatment group, compared to that in the sham group. (adjusted HR 0.23; 95% CI, 0.09 – 0.59; P = 0.002). Conversely, among the 70 individuals with RPD in the study eye, there was an increased rate of progression to late AMD for the SNL group compared to the sham group (adjusted HR 2.56; 95% CI, 0.80 – 8.18; P = 0.112).

The authors go on to state that the direction of treatment effect was for a reduction in progression rate for individuals in the SNL group, but again, the differences in rates of progression (with the exception of in the post-hoc analysis based on presence of RPD) were not found to be statistically significant. They did caution readers to exercise caution when considering treating individuals with RPD until further studies are performed.

In their commentary on the LEAD trial, Rosenfeld & Feuer applaud Guymer et al for a well-formulated study that presented valuable natural history data and seemed to answer the bigger-picture question, but caution readers on the loss of baseline randomization that can be associated with retrospective subgroup analysis of a prospectively randomized trial (as was the case with the RPD post-hoc analysis).

Without any clear benefit, it’s difficult to recommend treatment of intermediate AMD with the 2RT’s Retinal Rejuvenation therapy. However, further trials should be considered to investigate prospectively the effect of RPD on response to subthreshold laser.