Age-related macular degeneration

Case Scenario

Kerry, 71 years, presents at the hospital emergency department with a 6-week history of sudden-onset right eye visual deterioration. The optometrist referral queries suspected right-eye retinal bleed. Kerry says vision in his right eye appears dark and blurry, but he denies any photopsia (flashes) and floaters, trauma, or pain at presentation. His medical history includes long standing hypertensive heart disease, type 2 diabetes, atrial fibrillation, and a previous pacemaker. While Kerry is compliant with his medication, his diabetes is poorly controlled (HbA1C = 11.1%). A smoker for >50 years, his diet comprises frozen pre-made meals.

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Introduction

Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss, estimated to affect around 200 million people worldwide.^1,2

The prevalence of AMD has increased significantly in recent years, with an estimated incidence of 1 in 7 Australians over the age of 50.³

The Macular Disease Foundation Australia (MDFA) has estimated a significant personal, social and economic health burden of AMD equating to $5.15 billion in 2010.³

AMD is a disease affecting the macula, a specialised area of the retina responsible for producing detailed colour images of central vision. Degeneration of the macula results in progressive central vision loss usually affecting both eyes, thereby impairing a patient’s ability to read, drive a car or recognise faces. The understanding of the pathophysiology of AMD is still evolving. Contemporary evidence supports a complex, multifactorial causality resulting from genetic, metabolic, functional and environmental factors.^1,4

Retinal angiography and optical coherence tomography (OCT) are the most common methods employed for the diagnosis of AMD. OCT is a non-invasive procedure used to visualise structures in the back of the eye.5 It allows for the detection and monitoring of intra- and sub-retinal fluid seen in the presence of newly grown blood vessels within the choroid layer of the eye (choroidal neovascularisation [CNV]) which is a major cause of central vision loss in AMD.⁵

Retinal angiography using fluorescein contrast was previously the gold standard when it came to diagnosis of CNV.^2,5 The invasive nature of this test, involving an intravenous injection of fluorescein dye, and rare but potentially serious adverse effects, have led to the test been largely replaced by OCT.^1,5

Early detection and treatment of AMD is crucial in preserving vision loss and maintaining the patient’s quality of life. Amsler grid eye test cards consist of a 10×10 cm square with a grid and a central spot for fixation in the centre of the grid. These cards are provided to patients by optometrists and ophthalmologists to use as a self-check test of worsening vision.² Patients are asked to fixate on the central dot from a distance (approximately 30 cm) and report any distortions, blurriness or missing lines on the grid.²

Pathogenesis

There are several different AMD classification systems.² More broadly, AMD can be classified into a non-exudative or dry AMD and an exudative neovascular or wet AMD. Dry AMD is the more common form and accounts for up to 85% of all presentations. It causes a slow central vision loss. Currently, no effective treatment exists for the dry AMD form.²

In wet or neovascular AMD (nvAMD), upregulation of vascular endothelial growth factor (VEGF) causes CNV, an outgrowth of abnormal blood vessels from the choroid into the sub-retinal space.⁴

Bleeding and subsequent macular scarring due to abnormal blood vessels may cause sudden loss of central vision and is considered the most aggressive form of AMD.⁴ Other commonly reported symptoms include blurred vision, metamorphopsia or image distortion, and scotoma or a “blind spot”.⁵

Risk factors

Due to structural and functional retinal changes over time, age represents the most significant risk factor for AMD. Patients older than 75 have a threefold higher risk of developing AMD (44%) compared to those aged 65–74 (24%).⁵ Data suggests that advancing age is associated more with progression to the dry form of AMD rather than to nvAMD.⁶ Similarly, family history of AMD is thought to increase risk in siblings by three- to sixfold compared to the general population.⁷ Prevalence of AMD differs between different ethnic groups and is highest in Caucasians (5.4%) followed by Chinese (4.6%), Hispanics (4.2%) and Africans (2.4%).⁶

Currently available data supports smoking as the only modifiable risk factor which significantly increases the risk of AMD.⁶ Long-term smoking (>40 years) has been shown to at least double the risk of developing AMD compared to non-smokers.¹

Diet, lifestyle and alcohol intake have all been reported to increase the risk of AMD; however, the evidence behind these risk factors is less robust.⁷ Similar conflicting evidence exists for comorbidities such as hypertension, diabetes, chronic kidney disease, hyperthyroidism, Alzheimer’s and Parkinson’s disease.⁸

Treatment

Upregulation of VEGFs, signal proteins, is one of the key contributing factors in the pathogenesis of nvAMD and an important therapeutic target to combat this otherwise blinding condition.⁸ VEGF family includes a number of different factors, with VEGF-A and placental growth factor (PIGF) thought to be major therapeutic targets in the treatment of angiogenic pathological conditions affecting the posterior segment of the eye.⁵ Introduction of anti-VEGF medications, administered via injection into the eye, has revolutionised nvAMD treatment and led to significantly improved patient outcomes, with a 30% chance of improvement in visual acuity observed in the first 2 years of treatment.⁶

Intravitreal anti-VEGF treatments for nvAMD include bevacizumab, ranibizumab, aflibercept and recently introduced brolucizumab (see Table 1).^6,9,10 Treatment protocol typically involves 4-weekly injections for 3 months followed by an ophthalmology review. Future treatment interval is then based on clinical presentation and OCT imaging results.¹¹

A Cochrane review evaluated data from 15 trials to investigate the efficacy between monthly and non-monthly intravitreal injections in people with newly diagnosed nvAMD. They concluded that visual outcomes favoured but were not statistically nor clinically significant for monthly injection interval compared with a PRN regimen, which included both standard and treat and extend (T&E) intervals. In the T&E strategy, the interval between intravitreal injections is slowly extended provided the retina remains stable. The rate of serious adverse effects, such as endophthalmitis, and costs were both higher in the monthly dosing regimen.¹²

Despite all efforts, real world data suggests that AMD patients are still undertreated.^7,13 Different factors including frequent injections, the need for regular follow-up review appointments, and repeated OCTs to monitor disease progression, all contribute to suboptimal treatment regimens regardless of the dosing schedule.^2,13 This further highlights the importance of an individualised patient plan where the treatment regimen is based on anatomical OCT assessments and extended whenever possible as a way of mitigating patient and healthcare treatment burden.¹³

Monthly injections impose a significant treatment burden and are associated with increased adverse effects risks and substantial costs, and therefore the focus of recent research has been on establishing an optimal dosing treatment that is effective but minimises the number of injections.¹³

The Port Delivery System (PDS) with ranibizumab, a novel drug delivery device, and faricimab are two novel agents that have the potential to significantly reduce AMD treatment burden while optimising patient outcomes. PDS with ranibizumab involves an intraocular surgical implantation of a permanent, refillable drug reservoir that will allow a controlled and continuous release of ranibizumab into the vitreous for up to 24 weeks. Faricimab is the first investigational, bispecific antibody for the eye targeting two pathways involved in pathogenesis of nvAMD.

Current data shows that visual acuity outcomes with intravitreal faricimab injections every 16 weeks were non-inferior to those receiving aflibercept at 8-weekly intervals.^14,15 The PBS listing of ranibizumab was considered at the March 2022 meeting of the Pharmaceutical Benefits Advisory Committee (PBAC) for Authority Required listing for the treatment of nvAMD responsive to prior anti-VEGF treatment and the decision was deferred. Faricimab was reviewed at the May 2022 PBAC meeting and received a positive recommendation.¹⁶

Antioxidant medicines

The Age-Related Eye Disease Study (AREDS) and AREDS2 are two large clinical studies which were designed to evaluate the effects of nutritional supplementation on progression of AMD.¹⁷ AREDS showed that supplement formulation containing zinc, copper and antioxidants (vitamins C, E and beta-carotene) helped reduce vision loss in some patients with moderate to severe vision loss resulting from neovascularisation or atrophy.^18,19

AREDS2 evaluated the effects of adding lutein/zeaxanthin instead of beta-carotene and/or omega-3 fatty acids to the original AREDS formulation. The authors concluded that lutein/zeaxanthin did not provide additional benefits in further reducing progression of AMD.¹⁹ However, the lutein/zeaxanthin combination was considered a suitable carotenoid substitute to beta-carotene, used in the AREDS formulation, which has been associated with an increased incidence of cancer in those at high risk of lung cancer.²⁰ It should therefore be avoided in all current and previous smokers.

Several non-prescription formulations, each containing various amounts of ingredients found in the original AREDS/AREDS2 formulation, are available. Many of these products contain zinc and antioxidants at significantly lower doses compared to those in AREDS/AREDS2, yet the manufacturers recommend once-a-day dosing for most. Pharmacists should emphasise to patients the recommended dosage of these supplements in line with the studied doses.

Table 1 – Intravitreal anti-VEGF medication

Adverse effects

AMD is a chronic disease requiring repeated, long-term intravitreal injections that can increase the incidence of ocular and systemic adverse effects of these agents.²¹

Adverse effects range in presentation from injection-related ocular irritation to very serious, sight-threatening infections.²² Minor, non-infectious adverse effects are found to occur within 48 hours following an injection and include irritation, floaters (intraocular air bubble), blurred vision, injection-site pain and subconjunctival haemorrhage.²²

Most physicians recommend the use of artificial tears on an as-needed basis after the injection, which may help ease irritation symptoms.²²

Flushing out the residual antiseptic agent used in preparation for the intravitreal injection has been shown to reduce post-injection-related irritation.²² Most of these minor complications are self-limiting within 24–48 hours post procedure and do not warrant repeat clinic appointments.²²

Evidence shows that physicians are able to resolve most of these problems over the phone and can identify patients requiring further follow-up.²⁰ Real-world data suggests that minor complications occur in 12.9% of all patients.²²

IOP, endophthalmitis, traumatic cataract, retinal artery occlusion, and retinal detachment are serious adverse effects related to the injection procedure of anti-VEGF agents.^10,23

The incidence rate of these adverse effects is less than 1%.^10,23

Systemic administration of anti-VEGF medicines is well known to cause decreased vascular permeability, increased systemic arterial blood pressure and to promote thromboembolic events.²⁴ A safety concern about intravitreal anti-VEGF agents is that some adverse effects can occur if these medicines are absorbed systemically at biologically active concentrations.²⁴ The observed incidence rate of thromboembolic events in patients receiving intravitreal injections was less than 4%, similar to those receiving placebo.

Evidence for the cardiovascular adverse effect associated with intravitreal administration of anti-VEGF agents is lacking, and large randomised controlled trials are required to answer this question. Until this time, treatment caution is recommended in high-risk patients, especially the elderly (>85 years), those with a history of recent stroke or thromboembolic event, and patients with diabetes or multiple comorbidities.²⁴

AMD is a chronic and complex disease, the pathogenesis of which we are still trying to understand. The development of intravitreal anti-VEGF agents has revolutionised the treatment of this disease, significantly reducing the incidence of severe visual impairment and blindness worldwide. However, intensive treatment with anti-VEGF agents poses a significant treatment burden and increases the risk of adverse effects. This, coupled with the lack of effective treatment for dry AMD, has made AMD a desirable target for gene therapy in numerous recent and ongoing studies. Data from large-scale gene therapy studies is hoped to shed more light on optimal treatment targets, administration routes as well as address any safety concerns. The potential of gene therapy in ameliorating the social and economic burdens of current AMD treatment is promising, and it is with cautious optimism that we await results.

Knowledge to practice

Pharmacists can provide support and education to patients on various aspects of AMD treatment, thereby positively impacting patient outcome. They can help with the management of risk factors and counselling about the different ocular and non-ocular adverse effects associated with anti-VEGF agents.

Being more readily accessible, it is important for pharmacists to be well aware of possible adverse effects and to advise patients of the following signs and symptoms that warrant prompt medical treatment:

• eye pain or increased discomfort
• worsening eye redness
• blurred or decreased vision
• increased sensitivity to light.

As smoking is the only known modifiable risk factor that significantly increases the risk of AMD,⁴ pharmacists should encourage smoking cessation and provide advice and support.

Key points

• Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss, with prevalence increasing significantly in recent years.
• Dry AMD, for which there is no effective treatment, is the more common form of AMD. Anti-VEGF medicines, administered via injection into the eye, have revolutionised the treatment of wet AMD and led to significantly improved patient outcomes.
• Smoking is the only modifiable risk factor that significantly increases the risk of AMD.
• Pharmacists should emphasise that the recommended dosage of nutritional supplements can have a positive effect in patients at certain stages of AMD.

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References

1. Al-Zamil WM, Yassin SA. Recent developments in age-related macular degeneration: a review. Clin Interv Aging 2017;12:1313–30.
2. Stahl A. The diagnosis and treatment of age-related macular degeneration. Dtsch Arztebl Int 2020;117(29–30):513–520.
3. Macular Disease Foundation Australia. About macular disease. 2022. At: www.mdfoundation.com.au/about-macular-disease/overview/
4. Nowak JZ. Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep 2006;58(3):353–63.
5. Sarwar S, Clearfield E, Soliman MK, et al. Aflibercept for neovascular age-related macular degeneration. Cochrane Database of Systemic Reviews 2016, Issue 2.
6. Ricci F, Bandello F, Navarra P, et al. Neovascular age-related macular degeneration: therapeutic management and new-upcoming approaches. Int J Mol Sci 2020;21(21):8242.
7. Lim LS, Mitchell P, Seddon JM, et al. Age-related macular degeneration. Lancet 2012;379(9827): 1728–38.
8. Heesterbeek TJ, Lores-Motta L, Hoyng CB, et al. Risk factors for progression of age-related macular degeneration. Ophthalmic Physiol Opt 2020;40(2):140–70.
9. García-Quintanilla L, Luaces-Rodríguez A, Gil-Martínez M, et al. Pharmacokinetics of intravitreal anti-VEGF drugs in age-related macular degeneration. Pharmaceutics 2019;11(8):365.
10. Cox JT, Eliott D, Sobrin L. Inflammatory complications of intravitreal anti-VEGF injections. J Clin Med 2021;10(5):981.
11. Royal Australian and New Zealand College of Opthalmologists. NZ National guidelines for management of neovascular AMD. 2021. At: ranzco.edu/wp-content/uploads/2018/11/National-Guidelines-for-management-of-neovascular-AMD-RANZCO-2-1.pdf
12. Li E, Donati S, Lindsley KB, et al. Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration. Cochrane Database Systematic Reviews 2020, Issue 5.
13. Khanna S, Komati R, Eichenbaum DA, et al. Current and upcoming anti-VEGF therapies and dosing strategies for the treatment of neovascular AMD: a comparative review. BMJ Open Ophthalmol 2019;4(1):e000398.
14. Heier JS, Khanani AM, Ruis CQ, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet 2022;399 (10326):729–740.
15. Holekamp NM, Campochiaro PA, Chang MA, et al. Archway randomized phase 3 trial of the port delivery system with ranibizumab for neovascular age-related macular degeneration. Opthalmology 2022;9(3)295–307.
16. Pharmaceuical Benefits Scheme. PBAC meeting agenda. 2022. At: www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/agenda
17. Aronow ME, Chew EY. AREDS2: perspectives, recommendations, and unanswered questions. Curr Opin Ophthalmol 2014;25(3):186–190.
18. American Otometetric Association. A summary of AREDS1 and AREDS2. 2013. At: www.optometrystudents.com/a-summary-of-areds-1-and-areds-2/?sfw=pass1650536612
19. Age-Related Eye disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10):1417–36.
20. Goralczyk R. Beta-carotene and lung cancer in smokers: review of hypotheses and status of research. Nutr Cancer 2009;61(6):767–74.
21. Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (Lond) 2013;27(7):787–94.
22. Ramos MS, Xu LT, Singuri S, et al. Patient-reported complications after intravitreal injection and their predictive factors. Ophthalmol Retina 2021;5(7):625–632.
23. Schargus M, Frings A. Issues with intravitreal administration of anti-VEGF drugs. Clin Ophthalmol 2020;14:897–904.
24. Fogli S, Del Re M, Rofi E, et al. Clinical pharmacology of intravitreal anti-VEGF drugs. Eye (Lond) 2019;32(6):1010–20.

LJUBICA BUKOROVIC BBioMedSc, BPharm, GradCertClinPharm is an Ophthalmology Clinical Pharmacist at Princess Alexandra Hospital, Brisbane, Queensland.

SCOTT MITCHELL BPharm BBioMedSc, GradCertClinPharm, AdvPP (II) is Assistant Deputy Director of Pharmacy (Clinical Support Services) at Princess Alexandra Hospital, Brisbane, Queensland.