Update on MIGS

Learning when and in whom to perform minimally invasive glaucoma surgery (MIGS) is key to unlocking its potency and efficacy, believes Keith Barton FRCS, Moorfields Eye Hospital, London.

In contrast to trabeculectomy, in which the surgeon will make a small hole in the sclera allowing fluid to drain from the aqueous humour through to a bleb under the surface of the eye, MIGS involves either the careful placement of a tiny device in the eye or the use of very small instruments. MIGS is appropriate in various groups of patients.

Patients with glaucoma that is manageable but who can’t (or won’t) adhere to eye drops in order to maintain intraocular pressure (IOP), and patients with glaucoma who are undergoing cataract surgery are candidates. Also, patients who need modest lowering may benefit from MIGS procedures that can reduce IOP in a way that is safer than traditional surgery. Furthermore, we now see more potent subconjunctival MIGS procedures that may compete with trabeculectomy in their ability to lower IOP substantially, but safer.

When dealing with patients who have cataract and glaucoma, Ike Ahmed MD explains it in the following words: “The good news is that cataract surgery can also potentially lower the pressure a little bit. While I’m in there I have the opportunity to do something that is very safe that provides an opportunity to eliminate more medications than if I didn’t do it, in a very safe manner that doesn’t really increase the risk of surgery in my experience.” It was Dr Ahmed, Assistant Professor, University of Toronto, Canada, who first coined the term MIGS back in the early 2000s.

“I can put a stent, the smallest stent in the world, to sit very quietly inside the drainage channels to provide a bypass from the blockage internally, draining naturally in your eye, so you don’t feel it, you don’t see it, it doesn’t impact the vision result, and the recovery is quite similar with the opportunity to lower medication,” he continues.

Philippe Denis MD, President of the French Glaucoma Society, sees MIGS as 
a midway point between medical treatment and “classical” surgery, such as trabeculectomy or non-penetrating deep sclerectomy.

“The interesting thing with MIGS using an ab interno approach is that when you do the surgery you don’t manipulate the conjunctiva a lot and the scleral dissection is very limited, so you can leave a space in the conjunctiva to do classical surgery in the future, if you need it.”

Million-dollar question
There is a range of different options when it comes to MIGS, with different devices entering different parts of the eye. Choosing a favoured device is “the one-million-dollar question”, according to Dr Denis.

“There are three ways of inserting MIGS within the eye: we can reduce intraocular pressure by using the trabecular pathway, the supraciliary space and also the conjunctival route. It’s difficult to say which MIGS is the best, because there is no head-to-head comparison between the implants, these studies are lacking.”

Instead, each device is brought to market following a range of trials, generally comparing the glaucoma surgery performed alongside removal of a cataract with removal of the cataract alone.

Dr Denis believes that we still need to establish uniformity of clinical trials evaluating MIGS (criteria of eligibility, safety and efficacy endpoints). The indications for each device may be defined by these considerations.

The iStent from Glaukos works by incising and then stenting Schlemm’s canal to increase trabecular outflow. It gained FDA approval in 2012, and at just 1mm, it is the smallest FDA-approved device ever implanted in the human body. A review of the literature regarding this device was carried out and published in 2016 (iStent® Trabecular Microbypass Stent: An Update, J Ophthalmol. 2016; 2016: 2731856). This review examined the results of a series of trials and case series involving implantation of the device. Primarily performed alongside phacoemulsification, use of the iStent led to a consistent lowering of IOP as well as a reduced dependence on medications.

“The stenting ones are obviously attractive because you’re slipping a very small device gently into the trabecular meshwork, and when you look across the data, it appears that the Hydrus is probably the best of the bunch in terms of efficacy,” says Dr Barton, a Consultant Ophthalmologist and Glaucoma Specialist at Moorfields Eye Hospital.

In the Horizon study (Ophthalmology. 2019 Jan;126(1):29-37), the Hydrus Microstent (Ivantis) demonstrated superior reduction in modified diurnal IOP and medication use among subjects with mild-to-moderate primary open-angle glaucoma who received a Microstent combined with phaco compared with phaco alone. The Microstent is an 8mm-long crescent-shaped scaffold that improves aqueous outflow by bypassing the trabecular meshwork.

The CyPass Micro-stent (Alcon), meanwhile, is a 6.5mm-long suprachoroidal shunt that can also be installed post-phaco. While results two years post-surgery showed little difference in endothelial cell loss between the CyPass and cataract surgery-only groups, at five years, the CyPass group experienced “statistically significant endothelial cell loss compared to the group who underwent cataract surgery alone”, according to an Alcon media release. “Out of an abundance of caution,” the CyPass was voluntarily withdrawn in August 2018.

“Specifically with the CyPass, it seems to be primarily a positioning-related issue,” says Dr Ahmed, “which doesn’t seem to be related or common with the other procedures we do in the trabecular meshwork. This device sits in a different position, so with some placements, the alignment and the rigidity of the device, the position of the device I think made it at increased risk.

Balancing act
“It does remind us that nothing is benign, nothing is ever completely risk free,” continues Dr Ahmed. “I think it’s always a balancing act, we know for example with other glaucoma surgeries like tube shunts, it’s well known that endothelial cell loss may occur; however, the risk-benefit is different in those patients, because those patients are typically more advanced.”

In a media release dated August 29, 2018, Dr Stephen Lane, Chief Medical Officer at Alcon, was quoted as saying: “We intend to partner with the FDA and other regulators to explore labelling changes that would support the reintroduction of the CyPass Micro-Stent in the future.”

In terms of bleb-forming devices, the XEN Gel Implant (Allergan) was approved in 2016. It is inserted into the anterior chamber, passed ab interno, and then tunnelled through sclera to deploy the device within the subconjunctival space.

A recently published study (‘A multi-centre interventional case series of 259 ab-interno Xen gel implants for glaucoma, with and without combined cataract surgery’, Eye (Lond). 2019 Mar;33(3):469-477) showed a reduction of both IOP and medication use at 18 months, with adverse events described as “uncommon”.

A previous study (‘Efficacy, Safety, and Risk Factors for Failure of Standalone Ab Interno Gelatin Microstent Implantation versus Standalone Trabeculectomy’, Ophthalmology. 2017 Nov;124(11):1579-1588) showed that there was no detectable difference in risk of failure and safety profiles between standalone ab interno microstent with mitomycin C [an anti-scarring agent] and trabeculectomy 
with mitomycin C.

A report from the XXXV Congress of the ESCRS in Lisbon, Portugal, suggested that the XEN worked best when implanted as part of a standalone procedure.

“Although XEN placement is a convenient operation to combine with cataract surgery, our data suggest that combining phaco with XEN is slightly less effective for IOP lowering than XEN alone,” said Jan Van der Hoek MD, FRCOphth, Scarborough General Hospital, Scarborough, UK.

Because of the position of where the bleb is formed, Dr Barton believes that the InnFocus MicroShunt (Santen) has a big efficacy advantage of other devices.

“You can ramp up the dose of mitomycin C quite high in order to get quite dramatic efficacy, without the bad side-effects,” says Dr Barton. Traditional trabeculectomy can lead to infection and discomfort, he adds, but the blebs formed with the MicroShunt are further back.

The MicroShunt is 8.5mm long and acts by allowing aqueous humour to drain from the anterior chamber into sub-Tenon’s space. It can be performed with or without cataract surgery. Trials are currently under way with a view toward gaining FDA approval. Moorfields Eye Hospital, where Dr Barton practises, was an investigative site for an FDA pivotal study, and it was provided with an endothelial cell counter, specifically for that study.
“The FDA is the one body that’s looking at [MIGS] more than anybody else.”

At present there are no guidelines in Europe regarding the use and practice of MIGS, but in the USA, the FDA published Premarket Studies of Implantable Minimally Invasive Glaucoma Surgical (MIGS) Devices in 2015.

Numbers add up
Cost is an important factor. In a public hospital, numbers add up.

“I could sell the MicroShunt and the XEN easily to the finance director,” says Dr Barton. “‘These are similar to trab and they take a third of the time so you can do three times as many cases in the operating theatre.’ Operating theatre space is a premium cost, therefore his eyes light up and he says ‘great, we’ll do them’.”

Dr Ahmed feels that the benefit of newer bleb-forming procedures like the Microshunt and Xen extend beyond the OR, and include less postoperative management, visits, interventions and complications as has been shown in recent studies (Schlenker et al, Ophthalmology Glaucoma 2018).

“Improved postoperative recovery and safety lead to a reduction of postoperative costs and can greatly enhance the patient’s quality of life,” says Dr Ahmed. “In the long run, we need proper cost-effectiveness studies, which I believe will show better visual recovery, less damage to the structure of the eye, better comfort and less complications leading to a better quality of life for our patients. This may lead to better cost-effectiveness (which is a balance of cost and quality of life).”

Things are harder to quantify with the iStent, which Dr Barton believes improves quality of life. “Obviously it’s very attractive to the greater NHS, to improve patients’ quality of life, but firstly we need to prove that there is a quality of life benefit in the longer term and secondly, they’re expensive.”

Because it remains a relatively young procedure, the long-term success (or failure) of MIGS is yet to be seen by those in charge of finance. The cost of the procedure must also be weighed up against long-term expenditure on drops and other medications. It is another balancing act.

“Anybody on a couple of glaucoma medications, if the device is free, [MIGS] wouldn’t be unreasonable. The question is how much you’re prepared to pay, and it’s as simple as that. There’s controlled glaucoma, where you’re not worried about the glaucoma, they’re on a bunch of medications, they’re having cataract surgery, that will bring the pressure down a bit, but can you improve on that with a MIGS? And if you’ve got a cheap and easy-to-implant device then it’s reasonable to put it in.”

The major benefit of MIGS is to address adherence issues with medications. “Studies have shown that most patients don’t take their medications regularly or properly, which has shown to risk progression,” says Dr Ahmed. So in the long-run, MIGS may provide a safe way to address adherence and thus reduce progression or need for more aggressive (and riskier) surgery.

What comes after MIGS? Something that always comes up when discussing glaucoma, be it MIGS or other approaches, is eye drops for IOP. Topical medications are effective, but only if they are administered correctly. This requires accurate placement of the drop on to the eye, an appropriate interval between doses and the correct number of administrations per day. For older patients especially, this is not always possible. What if there existed a slow-release system that could last for months at a time?

“The iDose Travoprost is filled with a special formulation of travoprost, a prostaglandin analogue used to reduce IOP, and designed to continuously elute therapeutic levels of the medication from within the eye for extended periods of time. When depleted, the iDose Travoprost can be removed and replaced in a similar, subsequent procedure.” This is from a Glaukos press release announcing sustained IOP reduction and a favourable safety profile after 12 months.

“The question is how long they’ll last and how many times you have to change,” says Keith Barton. “If they lasted a year that would be acceptable, but if they only last three months, this is a return to the operating room each time.”

Allergan, meanwhile, is developing the Bimatoprost SR (Sustained-Release) Implant, a biodegradable implant for the reduction of IOP. A phase III clinical study showed a 30% reduction of IOP over 12 weeks, meeting the predefined criteria for non-inferiority to the study comparator, timolol.

An Allergan press release said that this shows the potential for most patients to remain treatment-free for a year after the last implant was inserted – a Kaplan-Meier estimator showed figures above 80% requiring no retreatment after three cycles of implant – and the implant was well tolerated in most patients. Further trials are under way and more reports are due later this year.

Other new technologies include punctal plugs and contact lenses that live beneath the eyelid and release drugs over time.

What’s most exciting for Dr Ahmed is some of the durability effects seen with bioerodible intraocular implants, as well as the potential for a combination of effects from surgery and sustained-release systems.

“I can put a very safe MIGS device in, and get you to a certain point, and I can do a sustained-release implant and get you further and get you down where you need to go with a one-two punch, I think that synergy is potentially amazing.”