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

Many of the recent advances in retina have focused on getting to the root of the causes of visual degeneration in the major retinal diseases at the cellular level.

The Angiogenesis, Exudation, and Degeneration 2022 virtual conference sponsored by the Bascom Palmer Eye Institute, Miami, Florida, United States, was at the forefront of this movement.

Presenters at the conference, a two-day event spanning 11 and 12 February, provided new evidence about detecting geography atrophy and wet and dry age-related macular degeneration (AMD) early and predicting disease progression. Investigators are also focused on finding cures for inherited retinal diseases.

Here are just a few of the groundbreaking technologies discussed at the conference.

Disease detection/progression using optical coherence tomography

OCT is an important tool for detecting AMD, and both its limitations and benefits were evaluated in disease diagnosis, patient management, and progression. One example was the application of deep learning models for detecting AMD specific features and predicting progression to late-stage AMD. Dr Emily Chew reported that deep learning used to evaluate OCT images is highly accurate for predicting progression tothe late disease stage in either neovascular disease or geographic atrophy (GA).

Swept-source OCT angiography (OCTA), Dr Seung-Young Yu reported, is valuable for staging diabetic retinopathy based on an optimal combination of nonperfusion areas seen on OCTA and the macular ganglion cell/inner plexiform layer thickness, which she described as a novel strategy.

Researchers reviewed the results achieved with the currently available anti-vascular endothelial growth factor (VEGF) therapies, those that are in the pipeline, and those that have been approved recently.

A sampling of these included an emerging therapy for nonexudative AMD, as reported by Dr David Boyer. This drug, Xiflam (InflammX Therapeutics), works by inhibiting connexin43, thus stopping the initiation of the inflammatory cascade in its tracks in AMD and diabetic retinopathy.

A second treatment, an investigational subretinal implant, the California Project to Cure Blindness Retinal Pigment Epithelium (CPCB-RPE1, Regenerative Patch Technologies), to treat advanced dry AMD, was associated with some increases in vision, as reported by Dr Amir Kashani.

Dr Glenn Jaffe reported the results with avacincaptad pegol (Zimura, Iveric Bio) in the GATHER1 trial that indicated that the 2-mg dose of the drug slowed growth of GA lesions secondary to AMD in the central area that included the fovea, and in each quadrant surrounding the central area.

GA, also studied in the DERBY and OAKS Phase 3 trials, was shown to respond to pegcetacoplan (Empaveli, Apellis Pharmaceuticals) administered monthly and every other month in the OAKS study and the drug was more efficacious in patients with baseline extrafoveal lesions. In the DERBY trial, the drug did not meet its primary endpoint, according to Dr David Lally.

The Phase 2 part A results of the KALAHARI Study found that THR-149 (Oxurion), a plasma kallikrein inhibitor, was safe and well tolerated when up to 3 injections were administered to patients with diabetic macular oedema (DMO), according to Dr Arshad M. Khanani.

The Phase 3 KESTREL and KITE studies evaluated brolucizumab for treating DMO. The results showed that the drug was comparable to results achieved with aflibercept (Eylea, Regeneron) with fewer injections needed with the 6-mg dose along with robust anatomic improvements, Dr Carl Regillo reported.

The approval of the Port Delivery System (PDS) with ranibizumab (Susvimo, Roche/Genentech), caused excitement this year with its demonstrated positive results. Dr David Eichenbaum reported that device maintains the visual and anatomic outcomes over 3 years of treatment and beyond, and patients with neovascular AMD expressed a strong preference for implantation of the device over monthly anti-VEGF injections.

Another exciting advance was the approval of faricimab (Vabysmo, Genentech), reported by Dr Charles Wykoff. This treatment has the potential to have a three-pronged effect: inhibition of the disease processes of wet AMD and DMO, improvement of visual acuity (VA), and reduction of the patient treatment burden.

Dr Thomas Ciulla reported on the first drug approved for drug delivery into the suprachoroidal space. Xipere (triamcinolone acetonide injectable suspension 40 mg/ml, Clearside) was approved to treat macular oedema, the first therapy for macular oedema associated with uveitis.

Netherlands investigators led by Dr Carel Hoyng have gotten to the root cause of Stargardt disease with the development of an RNA therapy that can stop the progression of the disease. Antisense oligonucleotides

a new area of drug development, prevent the gradual decline in vision that characterizes Stargardt disease by binding to the targeted RNA. These synthetic RNA molecules work to restore the proteins that are affected by the disease.

Another drug for Stargardt disease is tinlarebant (LBS-008, Belite Bio), a retinal binding protein 4 antagonist, was reported by Dr Quan Dong Nguyen to be safe and well-toleratved in adolescent patients with Stargardt disease. In addition, patients for whom VA data were available had improvements ranging from 5 to 10 letters in at least one eye. The improvements were associated with reduced autofluorescence.

Angiogenesis, Exudation and Degeneration 2022: Spotlighting major advances in retinal diagnostics and therapies

Intravitreal injections (IVIs) have revolutionised ophthalmology. With ever-increasing numbers of injections and a shift from reusable to disposable instruments, waste production has also soared.

Initially, I accepted the disposable custom-pack with plastic bowls, speculum, cotton buds and drape. However, seeing the overflowing waste bins after an afternoon of injections, I became frustrated.

I critically reviewed the literature on IVI procedures and concluded that we could do without drapes and forceps. In consultation with the supplier, we omitted all plastic trays and bowls and replaced the polypropylene cover sheet with a crepe-paper wrap (see Figure 1). This allowed for a much smaller plastic package. In this way we reduced waste from 135.5 to 66.5 g per IVI and costs by 20%.

In combination with the recycling of paper and clean plastics, the carbon footprint of a single IVI decreased from 0.68 kg CO2 to 0.17 kg CO2. Performing 50 injections a day, the daily savings equate to 25.5 kg CO2, the equivalent of driving 116 km in a car.

This reduced IVI set has been adopted by the Dutch Ophthalmological Society and is being implemented in more and more hospitals. With over 400,000 annual injections nationwide,

 this small revision represents a large step forward in sustainable ophthalmology.

Last September, over 200 scientific medical journals simultaneously published a “Call for emergency action to limit global temperature increases, restore biodiversity and protect health.” Participating journals ranged from the 

. In this paper, editors call for governments and leaders to act on keeping the global temperature rise below 1.5°C and on restoring nature.

The science is unequivocal: a global increase of 1.5°C above the pre-industrial average and the continued loss of biodiversity risk catastrophic harm to health.

 Climate change is already impacting health in a myriad of ways, including death and illness from increasingly frequent extreme weather events such as heatwaves, storms and floods; the disruption of food systems; increases in zoonoses and food-, water- and vector-borne diseases; and mental health issues.

Furthermore, climate change is undermining many of the social determinants for good health, such as livelihoods, equality and access to healthcare and social support structures. Despite the world’s necessary preoccupation with COVID-19, we cannot wait for the pandemic to resolve before taking action and should act now to rapidly reduce greenhouse gas emissions.

What have ophthalmologists to do with this?

The healthcare sector is a major contributor to greenhouse gas emissions.

 It is estimated that healthcare’s climate footprint is equivalent to 4.4% of global net emissions (2 gigatons of CO2 equivalent). If the health sector were a country, it would be the fifth largest emitter on the planet. So, the healthcare system itself contributes to a decline in public health.

This message has been heard by leaders in the field. During the recent COP26 UN Climate Change Conference in Glasgow, a group of 50 countries, including the UK, the US, Germany and the Netherlands, committed to develop climate-resilient and low-carbon healthcare systems.

Previously, a target of net zero greenhouse gas emissions in the year 2030 was adopted by the UK National Health Service. In the Netherlands, all major players in the healthcare sector signed a Green Deal, committing to a 50% reduction in carbon footprint by the year 2030.

Important sources of healthcare carbon emissions are energy consumption, medication, disposables and patient travel (Figure 2).

 Although we are a small medical specialty, ophthalmology contributes significantly to all these components. We have the highest surgical volumes in medicine and use energy-consuming operating rooms (ORs); we increasingly use single-use products; we prescribe large amounts of (single-dose) eye drops; and we invite many patients to our clinics.

Are the highest ventilation standards really necessary for small-incision eye surgery? In the Netherlands, the recommendation for the OR air ventilation system for cataract surgery is an air change rate of at least six times per hour. We should turn off the air conditioning when the OR is not in use. This may seem obvious, but it is not common practice in many hospitals.

Research shows that shutting down OR ventilation during off-duty periods does not appear to result in an unacceptably high particle count or microbial contamination of OR air, 30 minutes after the system is restarted.

 Using an Eco-mode in OR air conditioning will save not only greenhouse gas emissions, but also money.

A critical factor is the source of electricity. The air conditioning accounts for more than 90% of the total energy use of the OR, so it is paramount to choose a renewable energy source instead of fossil-based energy. We should push our hospital management to buy 100% green energy.

One phaco procedure in the UK produces around 130 kg CO2, equivalent to a car ride of 500 km. More than 50% of this is due to procurement.

 More recent data are not available, but the use of disposables has grown, adding to clinical waste production. Disposable instruments can account for 10–20 times as much waste as reusable items.

 All clinically contaminated waste must be incinerated or burned, which produces large amounts of greenhouse gases.

It is feasible to lower the carbon footprint of cataract surgery. This has been shown by the Aravind Eye Care System in southern India. Aravind performs around 1,000 surgeries per day. They generate 250 g waste and nearly 6 kg CO2 equivalents in greenhouse gases per phacoemulsification (Figure 3).

This carbon footprint is approximately 5% of that in the United Kingdom, with comparable visual acuity outcomes. Many differences can account for this low carbon footprint, including efficient, high-volume logistics and the reuse of instruments, protective equipment and medicines.

These differences do not affect infection prevention. In fact, the endophthalmitis risk after a phaco in Aravind is 0.01%, which is lower than the 0.04% in the US.

 This fact can partly be explained by the standard use of intracameral moxifloxacin in Aravind. Ironically, this drug is not registered in the United States because of the lack of adequate randomised controlled trials.

Rigid adherence to single-use material creates an excessive amount of surgical waste at a high cost, with no proven benefit in postoperative endophthalmitis risk.

 Given the huge number of cataract operations worldwide, changes in the materials used will bring great environmental benefits.

In the past two decades, operating theatres have transformed into disposable theatres; in every surgical specialty the majority of what is used is disposable. The same holds for cataract surgery, where we have witnessed the transition to disposable I/A handpieces, disposable phaco-cartridges, disposable incision blades and preloaded IOLs.

Some colleagues argue that disposables are safer than reusables and should therefore be promoted.

 However, this claim has not been substantiated. The debate about disposable versus reusable surgical instruments should be settled by evidence. And the evidence shows that waste, greenhouse gas emissions and a shortage of commodities are a threat to future generations. As long as there is no evidence that disposable instruments are safer for our patients, their use should be discouraged, not promoted.

Recently, a large survey among more than 1,300 US cataract surgeons and nurses showed that 93% believe that operating room waste is excessive and should be reduced.

 More specifically, 78% believe that we should reuse more supplies and 87% want medical societies to advocate for reducing the surgical carbon footprint. Assuming comparable costs, 79% of surgeons preferred reusable over disposable instruments.

It is important to consider the “reduce-reuse-recycle” rationale for medication use in ophthalmology as well. Tauber 

 showed that in cataract surgery a lot of medication used pre- and intraoperatively is discarded.

 Discarded topical eye drops were the most costly, averaging 148 US dollars per case. Reasons for discarding these medications could be a lack of counselling for patients and lack of medication labelling, facility policies, and noncompliance with burdensome state requirements.

The largest component of pharmaceutical waste in the study of Tauber was antibiotic drops. As noted by the authors, given the lower rate of endophthalmitis after cataract surgery with the use of intracameral antibiotics, the use of antibiotic drops with cataract surgery is likely to decrease. One should consider whether postoperative antibiotic eyedrops are still necessary when perioperative intracameral antibiotics are used.

In many clinics it is policy to throw medication away after is has been opened for a single patient. But it is important to examine the justification of these policies.

Chambers showed that this justification is not scientifically based but rather a misinterpretation of the evidence.

 He explained that manufacturers of multiple-dose ophthalmic products are required (by the Federal Register) to use an antimicrobial preservative. This antimicrobial preservative minimises the chances of injury to the patient should a contamination event occur.

This additional protection also enables the drug product to be administered to multiple different patients until the bottle’s stated expiration date. Every ophthalmologist should consider whether it is possible to reuse multi-dose medication.

The COVID-19 pandemic has shown that remote care of patients via telemedicine is possible.

 Telephone calls and video visits can be used to review test results, check on medication adherence or triage patients, and can replace check-ups for oculoplastic, neuro or paediatrics. Remote care can save greenhouse gas emissions.

Another lesson from the COVID-19 pandemic is that online meetings and conferences are feasible. Online meetings have pros and cons, but they certainly cause less greenhouse gas emissions than long-distance travel.

 So, why not stick to virtual international meetings?

Social interactions are undeniably important, but a national gathering to watch lectures and discussions abroad may be a reasonable alternative for many attendants.

 Thousands of ophthalmologists flying abroad to attend a medical congress is not sustainable and not justifiable in these times.

Healthcare professionals are continuously trying to improve the quality of care as well as keeping the healthcare system affordable and accessible for future generations.If we do not lower the carbon footprint of our clinical practices, we will compromise the healthcare systems of our children and grandchildren.

We should evaluate our own actions, both private and professional, and take into account their carbon footprints. Only by doing so do we act according to the oath we swore: 

Dr van Leeuwen is an ophthalmologist and vitreoretinal surgeon at University Medical Center Utrecht. Dr Elferink is an ophthalmologist and cataract surgeon at Flevoziekenhuis/hospital Almere. They have worked together since 2019 to address the subject of sustainable ophthalmic healthcare in the Netherlands. They founded the Dutch Working Group on Sustainable Ophthalmology (see text box), which is currently an official counsel for the Dutch Ophthalmological Society and represent the ophthalmology sector in the National Network for Greening the OR. They have no financial disclosures.

2. Atwoli L, Baqui AH, Benfield T, et al. Call for emergency action to limit global temperature increases, restore biodiversity, and protect health. 

3. Eckelman MJ, Huang K, Lagasse R, et al. Health care pollution and public health damage in the United States: An update. 

4. Gupta strategists. Transition to a sustainable healthcare. https://gupta-strategists.nl/storage/files/1920_Studie_Duurzame_Gezondheidszorg_DIGITAL_DEF.pdf. May 2019 (Dutch).

5. Dettenkofer M, Scherrer M, Hoch V, et al. Shutting down operating theater ventilation when the theater is not in use: infection control and environmental aspects.

6. Morris DS, Wright T, Somner JEA, Connor A. The carbon footprint of cataract surgery.

7. Park EA, LaMattina K.C. Economic and environmental impact of single-use plastics at a large ophthalmology outpatient service. 

8. Chang DF. The ESCRS intracameral cefuroxime study: the debate continues.

9. Ambati B. Re: Schwartz et al: Intracameral antibiotics and cataract surgery: endophthalmitis rates, costs, and stewardship. 

10. Sauder G. Let’s throw everything away…except the patient and the surgeon. 

11. Chang DF, Thiel CL. Survey of cataract surgeons’ and nurses’ attitudes towards operating room waste. 

12. Tauber J, Chinwuba I, Kleyn D, et al. Quantification of the cost and potential environmental effects of unused pharmaceutical products in cataract surgery. 

13. Palmer DJ, Volpe NJ, Hackett NJ. Improving quality of care and reducing topical medication operating room waste. 

15. Saleem SM, Pasquale LR, Sidoti PA, Tsai JC. Virtual ophthalmology: telemedicine in a COVID-19 era. 

16. Neugebauer S, Bolz M, Mankaa R, Traverso M. How sustainable are sustainability conferences? – Comprehensive life cycle assessment of an international conference series in Europe. 

17. Bousema T, Selvaraj P, Djimde AA, et al. Reducing the carbon footprint of academic conferences: the example of the American Society of Tropical Medicine and Hygiene. 

The healthcare sector has high greenhouse gas emissions, to which ophthalmology is a significant contributor. Reducing waste, reusing instruments and medication and increasing our use of telemedicine can all contribute to reducing the carbon footprint of our specialty.

Ophthalmology Times Europe March 2022

Simplifying glaucoma medical therapy for patients in the United States

Angiogenesis, Exudation and Degeneration 2022: Spotlighting major advances in retinal diagnostics and therapies

Ophthalmology and the climate crisis: Time to take responsibility