MIGS: Possible Benefits Beyond IOP

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The use of minimally invasive glaucoma surgery (MIGS) combined with cataract surgery has increased over the past decade, accelerated by short surgical times, low complication rates, and faster healing and recovery compared to traditional glaucoma surgery such as trabeculecto­my and aqueous drainage implants. In addition, for patients with mild disease, MIGS may help overcome some of the limitations of treatment with eye drops: patient adherence, cost of medications, and possible ocular surface toxicity.

The rationale for the use of com­bined MIGS procedures over cataract surgery alone is based mainly on a body of surgical trials that used reduc­tion of IOP as a primary endpoint, said Ahmad A. Aref, MD, MBA, at Illinois Eye and Ear Infirmary in Chicago. However, the real goal of any glaucoma treatment is the prevention of visual loss, he said, and the latest research is highlighting alternative outcomes for measuring the impact of MIGS.

“Now that we know MIGS lowers eye pressure, we’re shifting our focus to a fundamental and perhaps unan­swered question: Can these devices ultimately help patients keep their vision?” said Dr. Aref. “And we now have evidence from new studies that’s helping us look beyond IOP to see how MIGS may not only preserve vision but also contribute to improved quality of life and cost-effectiveness.”

The Big Three

The first FDA approvals for MIGS devices were predicated on three mul­ticenter randomized controlled trials: HORIZON (Alcon Hydrus), iStent inject (Glaukos iStent), and COM­PASS (Alcon CyPass Micro-Stent).^1-3 Although the CyPass device was subsequently withdrawn from the market due to corneal safety concerns, the data from these two-year pivotal studies demonstrated the superiority of combined MIGS and cataract sur­gery versus cataract surgery alone for the reduction of both IOP and topical medication usage.

A unique aspect of the trials was the practice of medication washout, said Pradeep Y. Ramulu, MD, PhD, at Johns Hopkins University in Baltimore. “Patients who entered each study were washed out of all IOP-lowering drops at baseline and two years,” he said. “Although this process is more expen­sive and labor intensive for the research teams, it really allows for a very stan­dardized comparison of IOP before and after the procedures, eliminating any effects of medication.”

HYDRUS IN PLACE. The Hydrus Microstent, implanted in the Schlemm canal, is visible on gonioscopy. About 7 mm of the microstent lies in the canal, scaffolding and dilating it. A 1-mm segment of the device prolapses at the site of implantation through the trabecular meshwork back in the anterior chamber.

Alternative Outcomes

These three trials provided founda­tional results for MIGS efficacy and are considered the gold standard for MIGS research, said Ramya N. Swamy, MD, at the University of Maryland in Baltimore. And they are also serving as springboards for demonstrating alter­native measures of MIGS benefits.

Cost-effectiveness. As the volume of MIGS procedures continues to increase worldwide, researchers are now starting to consider the associated economic impact on larger health care systems, said Dr. Aref. For example, a recent cost-utility analysis using data from the Italian National Health Service and the original iStent inject pivotal trial com­pared the lifetime cost-effectiveness of combined iStent/cataract surgery versus cataract surgery alone in patients with primary open-angle glaucoma. The investigators estimated both the clinical benefits and the costs associated with each treatment arm and found that the MIGS device provided a measurable gain in quality-adjusted life-years with a “modest economic investment.”⁴

“Because glaucoma is a chronic, progressive disease with no cure, the lifetime burden of having to pay for medication isn’t small,” said Dr. Swamy. “And we’re talking about more than just the cost to the patient, but also the cost to the payer, to the health care system, and to society as well. So if MIGS can reduce the need for high-dosage medical regimens and subsequent surgical interventions, we’re likely to see significant downstream cost savings take effect.”

Quality of life. Glaucoma is not only a major economic burden for both pa­tients and health care systems, it’s also a burden on an individual’s quality of life and social functioning, said Dr. Aref. And recent research is taking a closer look at patient-reported outcomes in MIGS.

One such study used the Visual Function Questionnaire and Ocu­lar Surface Disease Index to assess quality-of-life measures in participants from the original iStent inject pivotal trial.⁵ At two years, a greater proportion of patients randomized to combined MIGS/cataract surgery experienced improvements in these measures than those who underwent cataract surgery alone.

Decreased medication burden. This benefit in quality of life is likely attrib­utable to the decreased dependence on topical IOP-lowering medication in the participants who received the iStent device, said Dr. Aref. “These results reinforce the value of decreasing topical medical burden,” he said. “Drops can result in multiple adverse effects to the ocular surface and can increase dry eye symptoms. Being able to free a patient from that experience and avoid a bur­densome dosing regimen can lead to a tangible increase in their quality of life.”

Preserving Vision

Although the pivotal MIGS trials re­ported data after two years of follow-up, the chronic nature of glaucoma necessitates follow-up of a longer dura­tion, said Dr. Aref. And an expansion of the original HORIZON trial is providing just that—not only five-year results but also evi­dence that MIGS devices can help patients retain their vision.

The five-year HORIZON trial compared the treatment benefits of combined Hy­drus/phacoemul­sification versus cataract surgery alone.⁶ The results showed that the addition of the Schlemm canal microstent was safe, lowered IOP and medication use, and reduced the need for post­op glaucoma filtration surgery.

“This study is important because we now have data that supports the long-term durability and sustained efficacy of microinvasive glaucoma surgery,” said Dr. Ramulu. “And it also set the stage for some groundbreaking re­search that has fundamentally changed the impact narrative of MIGS.”

Visual field progression. A recently published post hoc subanalysis of the five-year HORIZON trial compared visual field (VF) progression between glaucoma patients who underwent cataract surgery alone and patients who also received a Hydrus Micro­stent.⁷ Both treatment arms underwent automated perimetry at six months and every year following surgery. Over the five-year period, the mean rate of progression of VF damage was signifi­cantly slower in patients who had the combined procedure (Fig. 2).

“For the first time, we have evi­dence that MIGS is effective not only in reducing IOP but also in decreas­ing the risk of permanent visual field damage,” said Dr. Ramulu, coauthor of the study. “So while MIGS has typically been characterized as a drop-reduction procedure, we should be referring to it as a vision-preserving procedure, which is the real goal of any glaucoma treatment.”

Another important finding from the trial was the ability of MIGS to reduce the proportion of “fast progressors,” said Dr. Swamy. “This is the only MIGS study to date to demonstrate this,” she said, noting that the number of people whose VF progression worsened at a rapid rate—0.5 dB or more per year—was significantly reduced with the microstent (Fig. 3).

Possible mechanisms. It’s still un­clear exactly why the Hydrus is associ­ated with lower rates of VF decline, said Dr. Ramulu. “What’s interesting is that the rate or likelihood of VF worsening in the MIGS group was independent of the clinically measured IOP alto­gether,” he said. “So comparing the two treatment arms, you might expect one of the reasons why the Hydrus slowed progression was its ability to lower IOP. However, if you add or remove IOP to the multivariable model, the impact of the Hydrus on visual field doesn’t change.”

One theory on how MIGS works to slow VF decline involves the reduction of topical medication, said Dr. Aref. “With typical IOP-lowering drops, a patient’s pressure is more volatile over a 24-hour period, particularly at night­time,” he said. “And it’s likely that those fluctuations in eye pressure lead to further decline in visual fields. But with the implantation of a MIGS device, the effect on the eye’s outflow pathway is steady and always active.”

Caveats. Although these findings on VF and rate of progression are promising and exciting, said Dr. Aref, it’s important to remember that they come from a single study. Moreover, he added, post hoc analyses—while they can be valuable in revealing potential benefits or safety signals not prespecified as outcomes in the original clinical trial—should be considered with caution and are best confirmed in a prospective trial design.⁸

VF PROGRESSION. Average baseline sensitivity and rate of progression per location and cluster of the 24-2 grid, calculated as the average of the estimates from the models fitted on individual eyes. CS = cataract surgery, HMS = Hydrus Microstent.

PLOTS OF CHANGE. Bar plots representing the estimates for the baseline sensitivity and the rate of visual field progression (in decibels) for the cataract-only group (CS) and the CS plus Hydrus Microstent group (CS-HMS). The error bars represent the 95% credible intervals from the hierarchical linear mixed effect model.

Potential Paradigm Shift Ahead?

Nevertheless, these findings could prove to be a game-changer, said Dr. Ramulu. “The HORIZON trial not only shows us that the procedure is effective at preserving sight,” he said. “It also shifts our paradigm in terms of how we think about IOP as an outcome.” And it could also change the way that ophthalmologists think about MIGS moving forward, he added. “The question has always been whether or not we are truly doing anything meaningful with MIGS procedures and whether or not the expense is justified,” said Dr. Ramulu. “In the past, some have called these pro­cedures ‘MEGS’—or ‘minimally effective glaucoma surgery’—but the evidence indicates that these proce­dures may actu­ally be targeting the underlying disease process.”

The HORIZON results are changing the MIGS narra­tive in another important way as well, said Dr. Swamy. “For many years, we’ve treated glaucoma with medication first, then laser and surgery as a last resort,” she said. “But now the paradigm is switching toward prevention via inter­vention. For a patient with glaucoma in a steep downward decline, an early MIGS procedure can both delay more invasive surgeries and preserve vision longer, which is a twofold advantage.”

And because it’s been suggested that even a 10% reduction in the rate of visual field progression might prevent blindness in thousands of patients, it’s possible that MIGS could play an important role on a much larger scale, said Dr. Swamy.⁹ “Imagine if we’re able to take a patient in their 50s and keep them from losing vision for the remain­der of their life,” she said. “Extrapolate that to a global scale. The extension of benefits in terms of improving quality of life and reducing societal health care costs really highlights the impact that MIGS could make from a public health perspective.”

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Dr. Aref is Associate Professor of Ophthalmolo­gy at Illinois Eye and Ear Infirmary in Chicago. Relevant financial disclosures: AbbVie: C; Alcon: C; New World Medical: C; Nova Eye Medical: C; Oculus Surgical: C.

Dr. Ramulu is Professor of Ophthalmology and Chief of the Glaucoma Division at Johns Hopkins University in Baltimore. Relevant financial disclo­sures: Alcon: C.

Dr. Swamy is Associate Professor of Ophthalmol­ogy at the University of Maryland in Baltimore. Relevant financial disclosures: None.

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