Dr Inder Paul Singh

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Adherence with lifelong glaucoma therapy demands a great deal from our patients. They must be able to afford and acquire their medications, remember the daily dosing schedule, be able to tolerate the drops well enough not to skip doses and physically succeed in instilling the drops. This is a lot to ask of them, especially as they age and begin to have concomitant health problems or cognitive loss.

Numerous studies have shown that adherence declines with more complex regimens of more than one or two bottles. Various studies have shown that, when you add a second or third bottle with preservatives, such as benzalkonium chloride, the incidence of ocular surface disease (OSD) increases.

 Then, in a vicious cycle, patients with OSD become even less adherent.

More than ever, we are now beginning to appreciate the effect of compliance on long-term intraocular pressure (IOP) control in our glaucoma patients. Both the HORIZON study, looking at implantation of Hydrus Microstents (Ivantis) at the time of cataract surgery,

 and the LiGHT study, in which first-line selective laser trabeculoplasty (SLT) was compared with medical therapy,

 found that patients with the surgical/laser interventions were less likely to progress to incisional glaucoma filtration surgery.

Even though we have medications that nominally provide the same IOP-lowering effect as SLT or minimally invasive glaucoma surgery (MIGS), we are not getting the full benefit of these medications because patients simply are not using them consistently. More MIGS and SLT is part of the answer, but there will always be patients who need to continue topical therapy instead of, or in addition to, these options.

In my practice, I typically prescribe a branded, commercially available glaucoma drug first and I may make this choice for the second bottle as well. These drugs have gone through rigorous United States Food and Drug Administration (FDA) trials and are marketed accordingly. However, as the regimens get more complex with three to four medications, or if there are cost and adherence challenges with even two drops, I find that compounded fixed-combination glaucoma drops (Simple Drops, ImprimisRx) nicely address many of the factors that lead to poor adherence.

Although we have a few dual-drug combinations in the US, none of them include a beta-blocker with a prostaglandin analogue (PGA), and none include more than two agents. Using Simple Drops, as the name implies, allows me to simplify the regimen for the patient to a single bottle once a day or one bottle each for morning and evening.

These drugs are compounded in a Pharmacy Compounding Accreditation Board-accredited 503A patient-specific pharmacy that follows many of the same high manufacturing standards as its 503B facility. Every batch is tested for potency, sterility and endotoxins, so I can be confident that my patients get a high-quality product.

For many of our patients who are still progressing or have poorly controlled IOP on topical medications, the problem is not that the drops are not working; it is that their IOP is fluctuating with inconsistent use of the medication. The Advanced Glaucoma Intervention Study (AGIS) demonstrated that long-term IOP fluctuation of greater than 3.0 mm Hg is associated with visual field progression.

Among AGIS patients with low mean IOP—those patients whose pressure looks fine when we see them in the clinic—fluctuations increase the risk of progression more than three-fold.

 Simplifying the regimen for these patients can boost adherence enough to stabilise them.

In a study I conducted, switching my patients to a 3-in-1 or 4-in-1 drop resulted in lower IOP across most patient types, particularly among those who were poorly controlled on their prior regimen of three bottles or more.

 Four patients in the study were able to avoid planned surgery.

One of these patients was a 43-year-old African American woman with advanced glaucoma who was still progressing on brimonidine/timolol (Combigan, Allergan), brinzolamide (Azopt, Novartis), and travoprost (Travatan, Alcon Laboratories). Her eyes were always red, and she told me she could not keep taking so many drops.

We discussed trabeculectomy, and I decided to put her on Tim-Brim-Dor PF (timolol 0.5%, brimonidine 0.15%, dorzolamide 2.0%; ImprimisRx) and stop the PGA to improve her ocular surface symptoms before surgery. At the next follow-up, her IOP was down to our target of 12 mm Hg, her eyes were not red and she was happy with the reduced drop burden. Four years later, she is still on this regimen and has been able to avoid filtering surgery.

Another major reason for using compounded combination drops is that I know what to expect and what it will cost the patient. If I prescribe three separate medications to a patient, it is very hard for me to answer their very reasonable question, “How much is that going to cost?” in any sort of accurate or transparent way.

The cost to the patient could be $15 or $300, depending on their insurance coverage, co-pays and formulary requirements. Moreover, they are highly likely to get generic substitutions from the pharmacy.

The pH, viscosity and other aspects of the inactive vehicle ingredients can vary widely from one generic to another, greatly affecting the bioavailability and efficacy of the active ingredient and the tolerability and safety of the drop overall.

 There can even be considerable variability in the quality of the dropper bottle, causing drops to spill out too fast and the patient to run out of a 30-day supply in a much shorter period of time.

Finally, compounded drops also give me the ability to prescribe preservative-free formulations so the glaucoma medications are not contributing further to ocular surface toxicity. About half of our glaucoma patients have OSD,

 and those with concomitant OSD are more likely to experience adverse effects from topical glaucoma therapy, more likely to be non-adherent and more likely to progress.

 If we can minimise the effect on the ocular surface, we are also maximising the chances of success with later Xen implantation or filtration surgery if required.

If cost, compliance and generic substitution were not factors at all, I might prefer separate bottles of each branded medication. But we have to recognise that patients are not getting what we prescribe and are not consistently instilling what they do receive, with resulting IOP fluctuation and disease progression. A simplified regimen of compounded fixed-combination glaucoma therapy is a very welcome solution to these real-world problems.

Dr Singh is in practice at the Eye Centers of Racine and Kenosha, Wisconsin, US. He is a consultant for many glaucoma companies, including Glaukos, ImprimisRx and Ivantis.

1. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. 

2. Rossi GC, Pasinetti GM, Scudeller L, Raimondi M, Lanteri S, Bianchi PE. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. 

3. Baudouin C, Labbé A, Liang H, et al. Preservatives in eyedrops: the good, the bad and the ugly. 

4. Ahmed IIK, Rhee DJ, Jones J, et al; the HORIZON investigators. Three-year findings of the HORIZON Trial: a Schlemm canal microstent for pressure reduction in primary open-angle glaucoma and cataract. 

5. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. 

6. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al; Advanced Glaucoma Intervention Study. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. 

7. Caprioli J, Coleman AL. Intraocular pressure fluctuation: a risk factor for visual field progression at low intraocular pressures in the advanced glaucoma intervention study. 

8. Singh IP. Clinical outcomes after use of new combinations of topical antiocular hypertensive medications to maintain or lower IOP in patients with glaucoma. Poster presented at: 2018 American Society of Cataract and Refractive Surgery Annual Meeting; April 13-17, 2019; Washington, D.C., US. Accessed 18 January 2022. https://ascrs.org/meetings/post-meeting-resources/2018-ascrs-asoa-annual-meeting/films-and-posters

9. Kolko M, Koch Jensen P. The physical properties of generic latanoprost ophthalmic solutions are not identical. 

10. Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension. 

11. Diagourtas A, Kagelaris K, Oikonomakis K, et al. Prospective study comparing Xalatan eye drops and two similar generics as to the efficacy and safety profile. 

12. Tatham AJ. The use of generic medications for glaucoma. 

13. Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. 

14. Denis P, Lafuma A, Berdeaux G. Medical outcomes of glaucoma therapy from a nationwide representative survey. 

Articles

Compounded medications are playing a central role in the process.

Simplifying glaucoma medical therapy for patients in the United States

The marvel of minimally invasive glaucoma surgeries (MIGS)—and the reason we push them earlier in the disease course—is their safety and predictable postoperative recovery. In the past, we had fewer options, most of which were more invasive.

As a result, we had to delay surgery for years while patients suffered the discomfort, inconvenience and expense of multiple medications, until finally those medications were no longer enough and surgery was unavoidable. Now we can skip years of suffering and better manage glaucoma by making MIGS part of the treatment equation.

Nowhere is the divergence between traditional surgeries and more modern procedures more apparent than in subconjunctival surgery. Historically, we were hesitant to go into the subconjunctival pathway with trabeculectomy or tube shunt because of the often slow and variable nature of visual recovery and the complex postoperative management. Instead, we waited until glaucoma progressed and the target pressure was aggressively low, often near the 10–12 mm Hg range.

Thankfully, with the options available today, we no longer need to wait so long to perform subconjunctival surgery for patients who need it, and with this earlier intervention we have a better chance of achieving target IOPs because they are not so aggressively low.

Visual recovery and conventional pathway MIGS

With conventional pathway MIGS, such as stenting (iStent; Glaukos, Hydrus; Ivantis), viscodilating (iTrack; Nova Eye Medical, OMNI; Sight Sciences), stripping (Kahook Dual Blade goniotomy; New World Medical), cutting/GATT (OMNI) and others, visual recovery is generally not a major concern. Pressurising the eye intraoperatively usually prevents intraoperative and postoperative hyphaema, although if this does still occur, it usually clears up in a short period of time.

The mechanisms that make visual recovery so seamless for conventional pathway MIGS are also the reason they are not always the best option: the episcleral venous pressure is a floor we cannot cross, so it is hard to reach target pressures below the low to mid-teens. This floor, however, also means we do not get hypotony or flat chambers, which are often the cause of postoperative vision issues.

Unfortunately, some of our patients need those lower target pressures. We also do not know where the resistance to outflow is located in our glaucoma patients; in some, the distal channels are also collapsed or atrophied. In these cases, we are not able to achieve the IOP control we need through the conventional outflow system. Therefore, we need to turn to a subconjunctival procedure to bypass the conventional pathway.

Vision after trabeculectomy or tube shunt surgery

The most common causes of postoperative visual acuity changes are hypotony, choroidals, maculopathy and ocular surface problems. With trabeculectomy and tube shunt, all these problems are possible, so it is difficult to gauge how long visual recovery will take with each patient.

Depending on how flat the chamber becomes and the position of the iris lens diaphragm complex, a return to baseline vision may take 1 week to 1 month or even longer. A non-valve tube might open up in a month and a half or even earlier when the suture dissolves, and that sudden change in IOP can cause a sudden shift in chamber depth and thus a change in vision. In addition, postoperative drops can prolong recovery by destabilising the ocular surface.

Patients who endure weeks or months of recovery are generally not happy with their vision. IOP can be unstable, so they require multiple clinic visits, and they often call the clinic with questions about vision problems and irritation from eye drop medications. The recovery process may still be going on when it is time for the patient to schedule surgery on the fellow eye, which can make them reluctant to do so.

As an experienced glaucoma specialist, I still marvel at the high potential for variability of each step for a trabeculectomy. I use various techniques to manage outcomes by controlling the size, thickness and shape of the flap; titrating the flow by suture placement and tension; and trying to aggressively bring down the IOP yet prevent chambers from flattening postoperatively.

It takes time to build that comfort and skill set, and not all patients have access to surgeons who have completed 1,000-plus trabeculectomy procedures.

 For these and a variety of additional reasons, a less invasive and more predictable subconjunctival procedure is needed to allow access for more patients than traditional surgeries.

A postoperative look at a Xen eye at 1 day, 1 week and 1 month. (

When we want to reach a lower pressure, avoid being beholden to conventional pathways where levels and locations of resistance can be uncertain and follow a more predictable visual recovery than we achieve with traditional subconjunctival procedures, subconjunctival MIGS can deliver the benefits with few limitations. The Xen Gel Stent (Allergan) uses the same bypass mechanism as trabeculectomy, but the only outflow created is a 45-μm lumen, rather than a larger, less consistent hole in the sclera with a variable flap.

With less structural deformation of the sclera, there is less chance of flat chambers postoperatively. Even if numerical hypotony occurs, the chambers do not flatten quite as much because they retain greater structural integrity. There is less concern that deformation of the eye will shift the iris lens diaphragm and cause a myopic shift or, in a pseudophakic patient, move or de-centre a toric lens.

Based on the approval trial, Xen has demonstrated a high safety profile with rare complications.

 The less invasive nature of the device means that the eye remains stable, with less inflammation in the anterior chamber and conjunctiva, often because there is no peripheral iridotomy. In addition, if implanting from an external approach, intraoperative flattening of the anterior chamber is rare.

Since flow occurs through a single point around 5 mm posterior to the limbus, rather than in multiple directions closer to the limbus as in a trabeculectomy, the bleb forms more posteriorly and often with a lower profile, resulting in a quieter bleb and shorter-duration corticosteroid use after surgery. With fewer corticosteroids and thus fewer topical preservatives, the ocular surface tends to experience less disruption and resulting postoperative vision fluctuation. Xen has also been shown to cause less endothelial cell loss than trabeculectomy, which could be an issue as patients get older and have other corneal risk factors.

Although postoperative bleb needling is sometimes needed, my postoperative bleb needling rates have dropped significantly (now less than 10%) with changes in technique, intraoperative confirmation of a freely mobile stent and use of an intraoperative needling if resistance is found. If needling is required, it is a different type of intervention than a trabeculectomy needling. We do not see a sudden drop in IOP, so there is less change in chamber depth that could affect visual recovery.

In the end, Xen reaches similarly low pressures as traditional subconjunctival surgeries, with a predictable postoperative course, resulting in fewer visits (1 week and 1 month) and calls to my practice.

 In my experience, visual acuity is often similar to baseline on postoperative Day 1, and if not, it usually reaches baseline by the 1-week visit. Patients are happy and show no reluctance to undergo surgery on the second eye — all because their postoperative course is rather benign and visual acuity is maintained.

Owing to the high safety profile and rapid visual recovery, I have now offered this device to patients who are refractory to drops despite their level of glaucoma severity. For instance, a patient with mild or moderate open-angle glaucoma who is taking four classes of medication, has a history of a previous MIGS, has stable IOP and visual folds but is not compliant with drops would not typically have been a subconjunctival bypass candidate in the past, but this patient is now a perfect candidate for a Xen.

Welcome to the interventional glaucoma mindset.

Dr Singh is President of The Eye Centers of Racine and Kenosha, Wisconsin, United States. He is a consultant to Alcon, Allergan, Bausch + Lomb, Ellex, Glaukos, Iantech, New World Medical, Omeros, Shire and Zeiss.

1. Francis BA, Hong B, Winarko J, et al. Vision loss and recovery after trabeculectomy: risk and associated risk factors. 

2. Birchall W, Bedggood A, Wells AP. Do scleral flap dimensions influence reliability of intraocular pressure control in experimental trabeculectomy? Eye (Lond). 2007;21:402- 407.

Reitsamer H, Vera V, Ruben S, et al. Three-year effectiveness and safety of the Xen gel stent as a solo procedure or in combination with phacoemulsification in open-angle glaucoma: a multicentre study. 

Olgun A, Duzgun E, Yildiz AM, et al. Xen Gel Stent versus trabeculectomy: short-term effects on corneal endothelial cells. 

Marcos Parra MT, Salinas López JA, López Grau NS, et al. Xen implant device versus trabeculectomy, either alone or in combination with phacoemulsification, in open-angle glaucoma patients. 

A gel stent allows for less invasive subconjunctival procedures and an easier recovery course than traditional forms of minimally invasive glaucoma surgery.

Author | Dr Inder Paul Singh

Articles

Simplifying glaucoma medical therapy for patients in the United States

Achieving more predictable visual recovery following glaucoma surgery