The choice of what glaucoma surgery to utilize boils down to this constant tension between efficacy and safety. More aggressive IOP lowering improves the odds of preventing further progressive field loss; conversely, inadequate IOP lowering can result in slowed but continued progression.^1,2 But there is often a price to pay for more efficacy in IOP lowering, namely complications. Traditional glaucoma filtration surgeries such as trabeculectomy and glaucoma drainage implants (GDI) have well established efficacy in lowering IOP, but it comes at the cost of a very high rate of complications, some of which can be devastating.³

Microinvasive glaucoma surgery (MIGS), in contrast, dramatically reduces the risk for complications but is generally acknowledged to be inferior in IOP reduction.^4-6 The motivation for combining MIGS with different mechanisms of action is to try to achieve lower IOP than individual MIGS could accomplish alone, down to a level comparable to trabeculectomy and GDI to limit the risk of progression while keeping the coveted safety profile inherent to MIGS.

Here, I explore data on the effectiveness of combined MIGS outcomes, potential MIGS combinations and other considerations.

PUBLISHED DATA

No randomized prospective clinical trials have been performed to provide evidence that combining multiple MIGS techniques can produce better IOP lowering results than a single MIGS procedure alone.

Ferguson and colleagues retrospectively compared combined trabecular microbypass stent (iStent, Glaukos), cataract extraction and endoscopic cyclophotocoagulation (ECP, Endo Optiks) with those of iStent and cataract extraction without ECP. At 12 months postoperatively, the group that received both iStent and ECP (n=51) had greater mean IOP reduction (7.14 mm Hg vs. 4.48 mm Hg) than the group that only received iStent (n=50).⁷ Similarly, Izquierdo and colleagues in a retrospective study reported that phacoemulsification combined with ECP and ab interno trabeculotomy was superior to phacoemulsification combined with only ECP without ab interno trabeculotomy at 12 months both for IOP reduction and decreasing medication burden.⁸ Heersink and Dovich, in another retrospective study, reported that at 6 months, combined phacoemulsification, iStent and ab interno canaloplasty (AbIC) had a greater reduction in IOP and medication burden than phacoemulsification and iStent without AbIC. In this study the combined iStent/canaloplasty group had a higher baseline IOP, and final IOPs were similar between the groups.⁹

On the contrary, Scott and colleagues, looking retrospectively at phacoemulsification combined with both Kahook Dual Blade (KDB, New World Medical) and ECP found that it did not seem to further reduce IOP or medication use compared to phacoemulsification with KDB alone.¹⁰ But they noted that “these results may be confounded by differences in glaucoma severity between groups” as the group that received the combined KDB and ECP had worse glaucoma severity.

MY COMBINED MIGS OUTCOMES

I first started performing combinations of MIGS procedures in 2013 and presented the data at the American Glaucoma Society meeting in March 2019.¹¹ The types of outflow MIGS utilized in my patients were: two iStents, iStent Inject, Trabectome (MicroSurgical Technology), KDB, Hydrus microstent (Ivantis), Trab 360, Visco 360, Omni System (Sight Sciences), CyPass (Alcon), gonioscopy assisted transluminal trabeculotomy (GATT) and AbIC using a lighted microcatheter (Ellex iTrack). The cyclophotocoagulation (CPC) techniques utilized were Micropulse transscleral CPC (MP, Iridex) and ECP. As of December 2020, I have accumulated 104 combined MIGS cases. Average age was 69, 65% were African American and 29% were Caucasian. As a group, they had severe visual field loss with an average mean deviation of -14.5 dB, 37 had failed prior glaucoma filtration surgeries and 59 had their surgeries combined with phacoemulsification cataract surgery. The average pretreatment IOP was 33 +/- 9.0 mm Hg, and the average preoperative IOP was 23.4 +/- 7.0 mm Hg on 3.4 +/- 1.2 medications. The average postoperative IOP at last follow up (ranging from postoperative month 1 to year 5) was 13.1 +/- 2.3 mm Hg on 2.8 +/- 1.1 medications. Throughout the follow up of up to 6 years, the average IOP ranged from as low as 11.2 mm Hg to no higher than 13.4 mm Hg at all time points.

There were 17 failures (16%) who went on to require additional glaucoma surgery. Eight were managed with GDI, five with Xen 45 implants (Allergan), one with Cypass, one with MP, one with cataract surgery combined with synechialysis and ECP and one patient refused any additional surgical intervention. Those who failed had a significantly higher average preoperative IOP (27.9 +/- 8.8 mm Hg) than those who succeeded (22.7 +/- 5.7 mm Hg). Of note, three patients received selective laser trabeculoplasty at some point during their postoperative course but did not go on to require additional glaucoma surgical intervention and were not deemed failures. Twenty-four patients (23%) had complications: rebound iritis (six), stent occlusions (seven), cystoid macular edema (three) and serious complications including IOP elevations > 40 mm Hg (seven), retinal detachment (two) and hypotony maculopathy (one).

One specific sub-group that is of particular interest are the 37 eyes that had failed prior glaucoma surgeries: trabeculectomy and/or GDI. Their average preoperative IOP was 23.5 +/- 7.1 mm Hg on 3.7 +/-1.0 medications. Average postoperative IOP at last follow up (from postoperative month 1 to year 5) was 12.9 +/- 2.5 mm Hg on 3.5 +/- 1.1 medications. There were six failures (16%) in this group.

Combined MIGS may be a reasonable surgical alternative in patients who have proven refractory to prior trabeculectomy and/or GDI.

ISOLATING MIGS COMBINATIONS

There are many different potential combinations of MIGS procedures. I would break them down into three categories. The first combination is some manner of trabecular meshwork bypass (TMB) technique combined with some form of CPC (Figure 1). In my group, 54 eyes received this combination. TMB techniques included: two iStents, iStent Inject, Hydrus, Trabectome, KDB, GATT, AbIC, Visco 360, Trab 360 and Omni System. CPC techniques used included ECP and MP. Average preoperative IOP was 22.7 +/- 7.0 mm Hg on 3.4 +/- 1.2 medications, and the average postoperative IOP at last follow up (from postoperative month 1 to year 6) was 12.4 +/- 2.4 mm Hg on 2.6 +/- 1.4 medications. There were seven failures (13%). Similarly, Izquierdo and colleagues reported 27 eyes that received phacoemulsification and a combination of KDB and ECP. IOP was reduced from 17.0 ± 3.7 mm Hg on 1.9 +/- 1.4 medications to 11.4 +/- 1.8 mm Hg on 0.56 +/- 1.05 medications at 9 months with a 92.6% success rate.¹²

A second combination is supraciliary stenting combined with TMB. In my group, 32 eyes received this type of combination with CyPass and TMB (2 iStents, KDB, or Trab 360). Average preoperative IOP was 23.9 +/- 8.6 mm Hg on 3.6 +/- 1.0 medications, and average postoperative IOP at last follow up (from postoperative month 1 to year 2) was 13.3 +/- 2.2 mm Hg on 3.3 +/- 1.2 medications (Figure 2). There were 11 failures (34%). Cypass has since been recalled and is no longer available, and iStent Supra (Glaukos) is available outside the United States. The MIGS Study Group published a prospective study on a combination of two iStents and one iStent Supra with postoperative travoprost in 80 phakic open-angle glaucoma patients who had failed a prior trabeculectomy. Preoperative mean IOP was 22.0 +/- 3.1 mm Hg on 1.2 +/- 0.4 medications. Through 4 years of follow up, average postoperative IOP ranged from as low as 12.2 mm Hg to no higher than 13.7 mm Hg at all time points. An IOP of 15 mm Hg or less was achieved in 97% of eyes. There were no severe complications, and no eyes required additional glaucoma surgery.¹³

A final combination is AbIC with TMB. In my group, 17 eyes received this combination. AbIC was performed with either lighted microcatheter or Visco 360 or Omni System. TMB used included KDB, Trabectome, two iStents, iStent Inject and Hydrus (Figure 3). Preoperative IOP was 24.8 +/- 3.7 mm Hg on 3.0 +/- 1.2 medications, and average postoperative IOP at last follow up (from postoperative month 1 to year 4) was 14.5 +/- 2.7 mm Hg on 2.6 +/- 1.6 medications. There was one failure. Heersink and colleagues reported in their study of 86 eyes that received AbIC with iStent that IOP reduced from 16.6 mm Hg on 1.4 medications to 13.9 mm Hg on 0.5 medications at 6 months.⁹

SIGNIFICANCE AND APPLICATIONS

In general, MIGS procedures have been thought of as only applicable for those with mild to moderate disease with target IOP in the mid-to-high teens. Some even relegate MIGS to only be useful as a means to decrease medication burden in those with stable controlled disease. In general, those with uncontrolled and/or severe disease have often been relegated to trabeculectomy and GDI by default.

My experience with combined MIGS shows that the average postoperative IOP and standard deviation is actually quite low across all combinations and time points and is very comparable to published results of trabeculectomy and GDI.¹⁴ This suggests that combined MIGS procedures may be able to serve as a viable alternative even in patients with severe disease and advanced field loss with uncontrolled IOP who require a target IOP in the low teens. Combined MIGS can also be effective in those who have already failed trabeculectomy and GDI whose surgical options might otherwise be dwindling.

CONSIDERATIONS, DRAWBACKS AND HURDLES

Though the overall IOP lowering was satisfactory in my combined MIGS cases, postoperative medication burden remained in the two to three range, which is quite high. Combined MIGS gave, on average, a modest reduction in one medication from preoperative levels. Very few patients were able to stop all of their medications. This may have been due to the advanced nature of the disease for most patients in the study necessitating a very low target IOP. If the disease was milder and the goal IOP more modest, the postop medication burden could have been significantly lower.

Combining MIGS may not be ideal or necessary for every patient. The potential benefit has to outweigh the potential risk. TMB MIGS are very safe with very little risk aside from transient hyphema. However, MP and ECP, though safe, run the small added risk of inflammatory complications. Suprachoroidal devices have the disadvantage of occasionally causing transient cyclodialysis clefts and hypotony. None of these complications were persistent or insurmountable, but were unwelcome. Also, a few patients had very high acute IOP elevations postoperatively presumably due to steroid response, which could be problematic for patients with pre-existing advanced field loss with very little reserve.

Combining MIGS and the effect on reimbursement is another major consideration for some surgeons. In such cases, staging MIGS (doing one modality first and a second later if necessary) is certainly an alternative, with the disadvantage being that it requires a second trip to the operating room and another incision into the eye.

CONCLUSION

Combining MIGS procedures in an effort to achieve lower IOP comparable to trabeculectomy and GDI while keeping the coveted safety profile of MIGS is an exciting new frontier in glaucoma surgery. I believe it represents an important alternative in our surgical armamentarium that warrants greater consideration and study. OM

REFERENCES

1. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000;130(4):429-440.
2. Heijl A, Leske MC, Bengtsson B et al. Reduction of intraocular pressure and glaucoma progression; results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-1279.
3. Gedde SJ, Herndon LW, Brandt JD, et al. Postoperative complications in the Tube Versus Trabeculectomy (TVT) study during five years of follow-up. Am J Ophthalmol. 2012;153:804-814.
4. Richter GM, Coleman AL. Minimally invasive glaucoma surgery: current status and future prospects. Clin Ophthalmol. 2016;10: 189-206.
5. Chen DZ, Sng CCA. Safety and Efficacy of Microinvasive Glaucoma Surgery. J Ophthalmol. 2017;2017:1-13.
6. Agrawal P, Bradshaw SE. Systematic Literature Review of Clinical and Economic Outcomes of Micro-Invasive Glaucoma Surgery (MIGS) in Primary Open-Angle Glaucoma. Ophthalmol Ther. 2018;7(1):49-73.
7. Ferguson TJ, Swan R, Sudhagoni R, Berdahl JP. Microbypass stent implantation with cataract extraction and endocyclophotocoagulation versus microbypass stent with cataract extraction for glaucoma. J Cataract Refract Surg. 2017;43:377-382.
8. Izquierdo JC, Menzel CG, Arbealez NA, Ruiz-Montenegro Villa K, Canola L, Camargo G, Lastra BR, Lim M. Initial Outcomes of Combined Phacoemulsification with Endocyclophotocoagulation with and Without Ab Interno Trabeculotomy in Open-Angle Glaucoma. Poster presentation, American Glaucoma Society, Washington DC, March 2020.
9. Heersink M, Dovich J. Ab interno canaloplasty combined with trabecular bypass stenting in eyes with primary open-angle glaucoma. Clin Ophthalmol. 2019;13:1533-1542
10. Scott A, Sleck E, Young CC, Epstein R, Soohoo J, Pantcheva M, Patnaik J, Kahook M, Seibold L. Outcomes of Phacoemulsification Combined with Endocyclophotocoagulation and Kahook Dual Blade Goniotomy. Poster presentation, American Glaucoma Society, Washington DC, March 2020.
11. Oguntoye M, Chen K, Mudaliar S, Kim WI. Combining MIGS for the treatment of open angle glaucoma: a long term retrospective study. Poster presentation, American Glaucoma Society, San Francisco, CA, March 14, 2019.
12. Izquierdo JC, Mejías J, Cañola L, Agudelo N, Rubio B. Primary outcomes of combined cataract extraction technique with Ab-Interno trabeculectomy and endoscopic Cyclophotocoagulation in patients with primary open angle Glaucoma. BMC Ophthalmol. 2020;20:406.
13. Myers JS, Masood I, Hornbeak DM, et al. Prospective evaluation of two iStent trabecular stents, one iStent Supra suprachoroidal stent, and postoperative prostaglandin in refractory glaucoma: 4-year outcomes. Adv Ther. 2018;35(3):395-407.
14. Gedde SJ, Schiffman JC, Feuer WJ, et al. Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-up. Am J Ophthalmol. 2012;153(5):789-803 e2.

About the Author

Won I. Kim, MD, is an active duty Army ophthalmologist who did his residency at the San Antonio Uniformed Services Health Education Consortium and his glaucoma fellowship at Bascom Palmer Eye Institute. He currently serves as the program director for the Ophthalmology Residency Program at Walter Reed National Military Medical Center in Bethesda, Md. Email him at wonkim74@hotmail.com.

Dr. Kim reports no relevant disclosures.