When I diagnose patients with glaucoma, I usually lay out 2 goals for them, both of which are aimed at preserving their vision-related quality of life. The first goal, of course, is preventing blindness. Fortunately, for the majority of patients, we are fairly optimistic at the time of diagnosis that this goal can be achieved. The second goal, which applies to far more patients, is avoiding traditional incisional glaucoma surgery. Traditional glaucoma surgery, while effective, carries significant risks, such as loss of visual acuity and the need for reoperation.¹

The Traditional Glaucoma Endpoint

The most classic glaucoma endpoint, from a research standpoint, has been the detection of visual field progression. However, detecting progression is laborious.² In the latanoprost for open-angle glaucoma study, 516 newly diagnosed open-angle glaucoma patients underwent 16 visual-field tests over 24 months to detect a difference in progression between latanoprost and observation.³ That would have amounted to more than 8,000 visual-field tests, had the study not been terminated early. The study was impeccably executed and is deserving of a separate focused article, but a take-home point is that the detection of visual-field progression requires a significant amount of visual field testing. While the detection of progression is critical, it is not 1 of the 2 major quality-of-life goals mentioned above, and more practical proxy outcomes have been developed to facilitate the evaluation of therapies.

New Endpoints for Glaucoma Trials

Thanks in part to the Tube Versus Trabeculectomy (TVT) study, the field of glaucoma has settled on several endpoints for minimally invasive glaucoma surgery (MIGS) outcomes.¹ The first standard outcome, which was also used in the TVT study, is the proportion of patients who achieve 20% intraocular pressure (IOP) reduction, and the second main outcome is the proportion of patients who are medication free. In the MIGS studies, we are able to see that cataract surgery with a MIGS device allows more patients to achieve a 20% IOP reduction than cataract surgery alone.⁴ In contrast, 2 recent studies have shown interesting results with a different outcome: the percentage of patients who went on to require incisional glaucoma surgery.

In the Laser in Glaucoma and Ocular Hypertension (LiGHT) trial, newly diagnosed glaucoma or ocular hypertension patients were randomized to medications or laser.⁵ At first glance, one might suspect that after 3 years, none of the patients in this population would go on to require incisional glaucoma surgery. However, it is important to remember that glaucoma is a progressive disease, and thus, mild glaucoma patients eventually become severe glaucoma patients. Therefore, every patient who has undergone incisional glaucoma surgery was once a patient with mild glaucoma. It is surprising therefore that in a 3-year study of newly diagnosed glaucoma patients, a proportion of patients would go on to require surgery, but the results of the LiGHT trial are extremely informative. In the medication group, 11 out of 362 patients went on to need surgery, whereas none of the 356 laser patients required surgery. The way I explain this to my patients is to inform them that if they choose medications over selective laser trabeculoplasty (SLT), they technically put themselves at a risk of needing surgery that is infinitely greater than that with SLT, according to the LiGHT study. Medication-treated, newly diagnosed patients had about a 3% risk of needing incisional surgery. For newly diagnosed patients and in a population including ocular hypertension, this number is high. I think it is fair to say that when we inform newly diagnosed glaucoma patients that we want to help them avoid glaucoma surgery, primary SLT laser should be part of that plan.

The next study to highlight the important outcomes of avoiding glaucoma surgery was the prospective, randomized HORIZON study, the 3-year outcomes of which were presented at the 2019 meeting of the American Society of Cataract and Refractive Surgery by Thomas Samuelson, MD.^6,7 In the HORIZON study, 369 mild and moderate open-angle glaucoma eyes were randomized after phacoemulsification to Hydrus Microstent (Ivantis), and 187 eyes underwent cataract surgery alone. The standard MIGS outcomes were reported at 24 months, with cataract extraction plus Hydrus patients achieving an unmedicated IOP reduction that was 20% more than achieved with cataract surgery alone (77.3% of Hydrus vs 57.8% of cataract-only eyes).

A common question is how much the difference between treatment groups (19.5%) really matters. At 3 years, that difference was significant to quite a few patients. In the cataract-surgery–only group, 3.9% of patients with mild-to-moderate glaucoma went on to require incisional glaucoma surgery, whereas 0.6% of patients receiving the Hydrus (P=.02) required incisional glaucoma surgery. It is remarkable that a number of patients with mild and moderate glaucoma went on to need traditional glaucoma surgery without Hydrus. In HORIZON, 53% of patients were on only one medication. Again, mild glaucoma progresses to more severe glaucoma that requires surgery. Also, the difference between the treatment groups became more apparent at 3 years, perhaps because that is when the IOP-lowering benefit of cataract surgery begins to wear off. Finally, it is notable that the Hydrus was the first MIGS device to demonstrate this effect with respect to the avoidance of glaucoma surgery.

The outcome of requiring incisional glaucoma surgery is an interesting endpoint. It is true that it is a difficult outcome to standardize, and in the 2 studies mentioned above, undoubtedly the decision for surgery was made after an informed consent discussion between patient and physician. However, in a randomized study, there should be appropriate balance to make a difference in this outcome meaningful. Furthermore, because most physicians are trying to help patients avoid incisional glaucoma surgery, it is hoped that this outcome represents a truly necessary intervention. There are 2 major lessons to take away from these differences. First, early and moderate glaucoma patients go on to require incisional glaucoma surgery more often than we might imagine. Second, safe interventions, including MIGS and laser, can have a significant impact on the likelihood of requiring vision-threatening incisional glaucoma surgery. We would do well to focus on this endpoint and to help our patients avoid traditional glaucoma surgery whenever possible. GP

References

1. Gedde SJ, Feuer WJ, Shi W, et al; Primary Tube Versus Trabeculectomy Study Group. Treatment outcomes in the primary tube versus trabeculectomy study after 1 year of follow-up. Ophthalmology. 2018;125(5):650-663.
2. Chauhan BC, Garway-Heath DF, Goñi FJ, et al. Practical recommendations for measuring rates of visual field change in glaucoma. Br J Ophthalmol. 2008;92(4):569-573.
3. Garway-Heath DF, Crabb DP, Bunce C, et al. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. Lancet. 2015;385(9975):1295-1304.
4. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus drops for newly diagnosed ocular hypertension and glaucoma: the LiGHT RCT. Health Technol Assess. 2019;23(31):1-102.
5. Samuelson TW, Sarkisian SR Jr, Lubeck DM, et al; iStent inject Study Group. Prospective, randomized, controlled pivotal trial of an ab interno implanted trabecular micro-bypass in primary open-angle glaucoma and cataract: two-year results. Ophthalmology. 2019;126(6):811-821.
6. Samuelson, T. Three year safety and efficacy outcomes from the multicenter randomized study of a Schlemm’s canal microstent (HORIZON trial). Paper presented at: American Society of Cataract and Refractive Surgery Annual Meeting; May 5, 2019; San Diego, CA.
7. Samuelson TW, Chang DF, Marquis R, et al; HORIZON Investigators. A Schlemm canal microstent for intraocular pressure reduction in primary open-angle glaucoma and cataract: the HORIZON study. Ophthalmology. 2019;126(1):29-37.

Nathan M. Radcliffe, MD, is a clinical assistant professor in the department of ophthalmology at the NYU Langone Medical Center and a surgeon at the New York Eye Surgery Center. Dr. Radcliffe reports consultancy to Glaukos, Alcon, Allergan, Ellex, Sight Sciences, New World Medical, and BVI. Reach him at drradcliffe@gmail.com.