Intravitreal injections have become an increasingly familiar clinic-based treatment for exudative retinal and choroidal conditions. Despite their effectiveness, the intensified visit frequency related to intravitreal therapy is creating service pressures on clinics, as well as considerable burden on patients and their caregivers.
Doctors and pharmaceutical companies alike are working to overcome the resulting barriers to compliance that include patient anxiety, financial burden, time constraints and transportation issues.
The treatment of macular oedema has undergone a major paradigm shift over the past 13 years, from ceasing disease progression to focusing on improving visual outcomes. The identification of vascular endothelial growth factor (VEGF) and its role in the pathogenesis of macular oedema represents one of the most significant developments in the treatment of medical retina disorders,1 thus transforming the way macular oedema is treated. Anti-VEGF therapy has dominated the treatment of macular oedema over the past 13 years and is recognised with not only the preservation of vision, but also incomparable gains in vision not previously seen.2 Consequentially, it has become the gold standard of treatment for macula oedema. This has led to an increase in health resource allocation in the screening and treatment of macular oedema, resulting in a strain on health resources.
WIDE RANGING EFFECTS OF BLINDNESS
Pooled data from the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study, found that in any five year period, macular oedema becomes bilateral in 27–68% of unilateral late neovascular AMD patients.14 Significant decrements in vision related quality of life (VRQoL) are seen when nAMD and diabetic macular oedema (DMO) affects both eyes.15-17
LIMITATIONS OF CURRENT TREATMENT
While initially, anti-VEGF therapies improve vision by reducing leakage from neovascularisation in AMD, they do limit ability to cause regression of pathologic neovascularisation. Ultimately, submacular scarring occurs in as many as 50% of patients receiving anti-VEGF treatment over two years, further limiting visual benefits of treatment.4,8 Furthermore, up to 98% of those undergoing anti-VEGF therapy will develop macular atrophy as observed in the SEVEN-UP study.9 Atrophy and subretinal fibrosis were the main reasons for vision loss in the 10 year results of the Fight Retinal Blindness Project.10 After only one year of treatment, incidence of atrophy and subretinal fibrosis grew significantly from 9.7% to 17.2% and 13% to 37.8%, respectively in a Singaporean study.11 However, these are insignificant to the rates of atrophy seen in natural history.12,13
ADHERENCE TO TREATMENT AND COMPLIANCE FACTORS
It is clear from data of health behaviour patterns, and examinations of adherence to follow-up for chronic ocular conditions, that patients who appreciate the seriousness of their condition are more likely to follow treatment recommendations, more so if the patients understand that the existing treatment delivers favourable outcomes.19 Compliance and disease management have been key issues, particularly in diabetes. In the field of ophthalmology, numerous factors have been suggested for reduced compliance with demanding follow-up schedules, including expenses, age, degree of visual impairment, and increased distance between the home and clinic.20-22 People value vision greatly and are anxious about possible vision loss. In spite of this, if initial injection therapy does not restore vision loss, they would be more likely to suspend treatment. Addressing potential obstacles to therapy, such as cost, and patient education of the disease and ensuring realistic expectations, leads to increased adherence to therapy. In particular, patients with macular oedema due to AMD and diabetic retinopathy (DR), are more likely to have comorbidities that further influence their diminished adherence.15
A recent evaluation of prescription data of Australian patients undergoing injections for nAMD found that after only one year of treatment, 60% were lost to followup. 23 Another study by Jackson et al, on adherence and persistence rates of diabetic macular oedema (DMO) and nAMD Australian patients treated with anti-VEGF therapies, found that more than 30% of nAMD patients who were receiving bulkbilled treatment (with lower out of pocket costs) had not adhered to therapy only two years after initiating treatment.24 This increases to almost 50% non-compliance among those in ‘private’ clinics, where an out of pocket fee is charged. The numbers for DMO are even more significant, with only approximately half (54%) of bulk-billed DMO patients still in treatment after two years of therapy, and 36% of those from ‘private’ clinics. The analysis showed that adherence rates were significantly different among bulk-billing and private clinics, demonstrating lower out-of-pocket costs were associated with higher adherence rates to treatment.
A study by Habib et al found approximately 21% of patients were non-adherent to follow-up and injection during the course of treatment.25 They identified several factors that were associated with non-adherence to injection, including financial cost, perceived susceptibility, barriers, benefits, and whether the injections were unilateral or bilateral.
In a retrospective analysis of DMO and nAMD patients with similar numbers of visits and injections, Weiss et al, found a significant difference in the amount of missed appointments among those with AMD versus DMO (50% of nAMD had never been late versus only 35% of patients with DMO).26 Similarly, in a UK study of nAMD and DMO patients, 46% of DMO and 22% nAMD patients had at least one break in therapy over 30 months of observation.26 Both studies found that concurrent comorbidities was the most frequent reason for non-adherence.
An observational study of 1,264 nAMD and DMO patients in Austria, found that 28.8% of DMO and 2.9% of nAMD patients were lost to follow-up for at least six months.27 Regression analysis performed demonstrated that advancing age, lack of mobility, need for assisted transport, poor visual acuity despite treatment, and decrease in vision while under care were the leading risk factors for patients’ lack of adherence to treatment.
THE PATIENT EXPERIENCE
A cross-sectional study of 251 patients, conducted in Tasmania to evaluate the effect of intravitreal injections and blood pressure, demonstrated that 79% of patients were considered hypertensive (blood pressure ≥140/90mmHg) on the day of injection compared with 33% with baseline readings obtained from their primary care physician.28 They found that of those patients who were normotensive at baseline, 77% became hypertensive on the day of injection compared with 32% at baseline. Furthermore, an astonishing 22% were classified as experiencing a hypertensive urgency on the day of injection (≥180/120 mmHg) compared to 8% at random BP readings. The authors concluded these episodes of dangerously high BP are most likely related to the anxiety associated with the injection procedure.
An Australian study documented that the common reasons underlying patient anxiety encompassing treatment included the thought of having an injection, fear of losing vision, and fear of the unknown.29 A Scottish study found more patients experienced diminished expectations while receiving treatment; their reduced expectations were associated with higher expectations at the beginning of treatment, a more significant visual decline, and the patients’ perceived deterioration of vision after starting treatment.30 Among those patients, 32% disclosed they were planning to cease treatment and refuse further treatment. Their decline to continue with treatment was related to a loss in vision.
Patients also reported less pain and anxiety during intravitreal therapy when a friend or relative accompanied them to treatment. The authors concluded treatment is expensive and often prolonged, requiring repeated injections and patients’ expectations should be managed appropriately at the beginning of, and throughout, their course of treatment. Such targeted support aims to ensure they are less likely to become discouraged and cease their treatment, or become non-compliant when it doesn’t meet their initial expectations.30
Although ophthalmologists aim to ensure intravitreal injections are well tolerated, they can cause apprehension in most patients due to earlier hopes of intravitreal therapy, and previous incidents of pain and discomfort with the injection procedure. A qualitative study conducted by the authors, found that a concerning 95% of DME patients surveyed wished the injection experience improved.15 A relationship between pre-procedural anxiety and pain associated with intravitreal injections has been established.31 Managing anxiety and other aspects of poor patient experience is the responsibility of the clinician.
A recent Australian study highlighted that patient satisfaction with the educational information on their condition was low.32 In this study, many patients reported receiving inadequate information about their condition and treatment. Patient awareness and uptake of low vision services and support groups were low. They felt uninformed about their treatment and felt there was limited knowledge of available support services.
Various patient support programs have been initiated to improve emotional distress, foster education of disease processes, and to promote adherence to treatment among people with nAMD and DMO. SmartSight (Bayer/ Atlantis Healthcare) is a complementary evidence-based program for patients being treated with aflibercept for DMO and nAMD. It aims to support the patient through their treatment cycle, monitor vision, and provide support for carers. The program provides information on aspects of living with nAMD, treatment, as well as support services through trained call centre staff. A study on persistence rates by users of the SmartSight program, found those in the program had 18% higher adherence rates to treatment than those without over two years. Furthermore, patients on the SmartSight program have only one third of the drop-out rate compared to unsupported patients.33
The Macular Disease Foundation Australia (MDFA) provides support services to people living with macular disease, their family and carers, with access to relevant education, support and advice services, such as accessing low vision aids and technologies, social and/or mental health services.
Inservio Pty Ltd. (Australia), also works to provide patient education to support better outcomes by improving patient understanding of their condition and treatment. Inservio has patient educators that provide free seminars for patients to better understand their disease and how to better manage their condition, and why adherence to treatment is so critical.
BARRIERS AND BURDEN
The burden that comes with frequent treatment has been understood. The persistence of macular oedema imposes frequent and recurrent injections due to the restricted length of effect of anti- VEGF therapies, consequently further influencing treatment burden and inadequate treatment effect in some. The incidence of treatment resistance,3 fibrosis,4 and macular atrophy,5 together with the increasing risks of frequent injections such as endophthalmitis,6 further confines visual stability. Anti- VEGF therapy has demonstrated visual gains in a clinical trial setting. However, long-term outcomes have shown visual stability to be less reproducible, and often not replicated in real-world clinical practice.
Pooled analyses from the AURA study demonstrated that after initial visual acuity gains, there was a gradual decline in vision, and in some patients, further visual loss below baseline levels despite continued regular intravitreal injections.7 Furthermore, the insufficient treatment frequency seen in real-world clinical settings may reduce the definitive and potential visual gains.
LESS OBVIOUS FINANCIAL BURDEN
Limited financial and other resources can negatively affect adherence.15,16,24,29,34 Despite the PBS subsidising the cost of medical therapies and Medicare subsiding treatment costs in Australia, people undergoing intravitreal injections can expect to incur some out of pocket expenses associated with the treatment and monitoring of their condition.15,16,24 A survey performed by MDFA demonstrated that a majority of nAMD patients had out of pocket costs of >AU$100 per injection and that 13.5% of patients had considered ceasing therapy due to these expenses.36
A recent survey by the authors endeavoured to quantify the economic burden of patients with nAMD in a clinical setting.16 Private patients attended an average of 10 visits per year, resulting in lost productivity time due to travel and attendance for appointments. Direct and indirect medical costs associated with medical assessment and injections were over $300/month.
WHAT ABOUT CARERS?
We now understand that significant burden of therapy is imposed, not only by patients, but also their caregivers, which may subsequently lead to poor adherence. Patients report feelings of guilt from the sacrifice of caregivers looking after patients with nAMD and DMO.15,16,34 Inherently, the increasing prevalence of these conditions, together with considerable direct and indirect out of pocket costs that come with anti-VEGF treatment, represent substantial burdens for both patients and their caregivers.15,16
The role of caregivers includes supporting patients with tasks of daily living, transport and emotional care during appointments, as well as safeguarding their adherence to medical treatment.16,29,34,35 In a survey of Australian caregivers for people with nAMD, a majority of the respondents were self-sacrificing family caregivers who appreciated the importance of continuing treatment and providing emotional support.34 In addition, it was commonly seen that very few caregivers took time off from their caregiving,34 with many caregivers reporting loss of income due to their caregiving responsibilities.16 It has been shown that caregivers committed, on average, 6.2 hours per month to accompanying patients to appointments every four to six weeks, which equated to an average productivity loss equivalent of $260/month. Caregiver time assisting patients with their daily activities amounted to 4.3 hours per week.16
TREATMENT REGIMENS TO ADDRESS BURDEN
The fundamental objective of intravitreal therapy is to minimise vision loss while decreasing the burden of treatment. A treatand- extend (T&E) regimen may provide better outcomes, by reducing the number of clinic visits and potentially reducing the health care resource burden.37 Several studies have shown that similar results seen in clinical trials may be replicated with a pro-re-nata (PRN) treatment regimen.38 However, longer term follow-up has shown this approach to lead to greater clinic visits, and poorer visual outcomes.9,39 The aim to reduce injection frequency while maintaining efficacy has led to the adoption of proactive treatment regimens such as T&E.
The ALTAIR study was the first large, prospective randomised control trial (RCT) to compare two differing T&E protocols with aflibercept in nAMD.40 Patients received three initial monthly loading doses before increasing extension intervals in increments of two or four weeks if eligible. Good visual gains were observed in patients in both study arms, alongside significant reductions in treatment burden. The ARIES trial, another large, prospective aflibercept RCT, examined early vs. late T&E. It compared outcomes for patients maintained on a fixed dosing for one year prior to T&E, with patients eligible for T&E immediately following loading dose.41 Visual gains in both arms were good, with no statistical differences evident between early or late T&E.
NEW DRUGS AND DELIVERY DEVICES
Current research endeavours in pharmaceutical development seek to find the optimum treatment to prevent detrimental vision loss, while decreasing the burden of treatment. Areas of unmet need associated with intravitreal injections include the need for improved efficacy in the short term, increased durability of treatment, and the maintenance and improvement of long-term efficacy. Ophthalmologists have acknowledged the burden of treatment by modifying treatment regimens by administering less frequent injections. However, this under treatment may give rise to recurrent disease activity and further loss in vision. The ability to offset the regularity of injections with visual outcomes is vital in the management of macular oedema.
This desire to reduce the frequency of injections has also led to the development of longer-lasting, faster-acting drugs with increased potency, while still maintaining an acceptable safety profile. Of these, brolucizumab (Novartis) is the most recent biologic to have demonstrated both efficacy and durability in extended dosing late phase clinical trials.42 Brolucizumab has shown efficacy in Phase III trials with a 12-week schedule compared with eight weekly aflibercept, outperforming the latter agent on fluid resolution but with comparable vision gains.42 Of note, at 48-weeks, 57% of HAWK and 52% of HARRIER study patients in the 6mg brolucizumab arm, could be maintained at 12-weekly frequencies.42
Abicipar pegol, a 34-kDA designed Ankyrin repeat protein (DARPin) molecule (Allergan plc/Molecular Partners), has shown to be non-inferior to monthly ranibizumab, when dosed at both an eight and 12 weekly schedule in Phase III trials.43-46 Another emerging therapy is Faricimab (Roche, Basel, Switzerland), an antibody with dual action which blocks VEGF-A action and Angiopoietin 2.47 Phase II trials in DMO and phase III trials in AMD are currently underway to assess its efficacy and durability in extending treatment.48 Other unique anti-VEGF therapies under clinical trial include Conbercept (Chengdu Kanghong Biotech Co., Ltd.), a fusion protein of the VEGF receptor domains, and OPT-302 (Opthea), an inhibitor of VEGF-C/D.49
Furthermore, the ranibizumab delivered Port Delivery System (PDS, Genentech) is currently under phase III trial. The PDS is a refillable nanoparticle reservoir, that delivers continuous ranibizumab by passive diffusion. The Phase II study (LADDER), reported favourable functional outcomes and reduced burden on patients, with the median refilling time of the device being 15 months.50
IMPORTANCE OF CONTINUING MONITORING AND TREATMENT
Each patient has a variable response to anti-VEGF therapy. At present, there is no reliable means of determining, at initiation of therapy, whether a patient will respond well or poorly to therapy. Up to 30% of patients undergoing intravitreal injections require intensive injections schedules.3 Data from the CATT and VIEW studies have shown that patients who were maintained on strict monthly/bimonthly dosing, who were subsequently switched to variable dosing, lost vision51,52 with 23% of patients losing a line of vision on switch to PRN in the VIEW study.52 As demonstrated in the SEVEN-UP study, patients will continue to lose vison unless followed meticulously.53 Injection-intensive patients are those who are most vulnerable to burden and non-adherence and compliance issues. Therefore, it is important that this patient group is well supported by clinics to optimise the treatment benefit.
The treatment burden of repetitive injections posed to patients and the healthcare system is a significant issue. Ongoing research efforts have not only been centred around the development of novel anti-VEGF agents and modalities, but also refining treatment strategies with currently available therapies. The desire to reduce injection frequency while maintaining efficacy has led to the discovery of longerlasting, faster-acting drugs or drug-delivery devices with increased potency, while still maintaining an acceptable safety profile. As pharmaceutical development of longer-acting therapies continues, our patients hope to have a decreased burden of injections while still preserving vision. From a universal health perspective, this potentially has the benefit of minimising burden on patients, carers and healthcare providers by reducing the numbers of visits to hospital during each year of follow-up, while achieving similar visual outcomes.
Dr Kimberly Spooner is a researcher at Sydney Institute of Vision Science and a clinical research orthoptist at University of Sydney. She holds a PhD in Clinical Ophthalmology and a Bachelor of Applied Science (Orthoptics) from University of Sydney. At the time this work was completed, Dr Spooner was an employee of Sydney Retina. At the time of publication, she was an employee of Allergan, Australia. Allergan has no affiliation with this work.
Dr Thomas Hong is the Clinical Manager at Sydney Retina. In 2015, Dr Hong completed his PhD in Ophthalmic Science at University of Sydney. He had previously completed a Master’s Degree in Clinical Epidemiology at University of Sydney (2009) and a Bachelor’s Degree in Orthoptics (2001).
Associate Professor Andrew Chang MBBS(Hons), PhD (Syd), FRANZCO, FRACS, is a vitreoretinal surgeon and ophthalmologist. He is the Medical Director of Sydney Retina. He holds the academic appointment of Clinical Associate Professor at the University of Sydney and is Head of the Vitreoretinal Unit and Ophthalmology at the Sydney Eye Hospital.
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- Miere A, Semoun O, Cohen SY, et al. Optical coherence tomography angiography features of subretinal fibrosis in age-related macular degeneration. Retina (Philadelphia, Pa). 2015;35(11):2275-2284.
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- Tarrago R, Olea JL, Ramirez C, Escudero L. Endophthalmitis after intravitreal injections. Incidence, management and prognosis. Archivos de la Sociedad Espanola de Oftalmologia. 2017;92(3):107-111.
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- Bhisitkul RB, Mendes TS, Rofagha S, et al. Macular atrophy progression and 7-year vision outcomes in subjects from the ANCHOR, MARINA, and HORIZON studies: the SEVEN-UP study. American journal of ophthalmology. 2015;159(5):915-924.e912.
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- Gillies M, Arnold J, Bhandari S, et al. Ten-year treatment outcomes of neovascular age-related macular degeneration from two regions. American journal of ophthalmology. 2019.
- Cheung CMG, Grewal DS, Teo KYC, et al. The evolution of fibrosis and atrophy and their relationship with visual outcomes in Asian persons with neovascular age-related macular degeneration. Ophthalmology retina. 2019;3(12):1045-1055.
- Keenan TD, Agron E, Domalpally A, et al. Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16. Ophthalmology. 2018;125(12):1913-1928.
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- Spooner KL, Mhlanga CT, Hong TH, Broadhead GK, Chang AA. The burden of neovascular age-related macular degeneration: a patient’s perspective. Clinical ophthalmology (Auckland, NZ). 2018;12:2483-2491.
- Man RE, Fenwick EK, Sabanayagam C, et al. Differential impact of unilateral and bilateral classifications of diabetic retinopathy and diabetic macular edema on vision-related quality of life. Investigative ophthalmology & visual science. 2016;57(11):4655-4660.
- Chew JK, Zhu M, Broadhead GK, Luo K, Hong T, Chang AA. Bilateral neovascular age-related macular degeneration: comparisons between first and second eyes. Ophthalmologica Journal international d’ophtalmologie International journal of ophthalmology Zeitschrift fur Augenheilkunde. 2017;238(1-2):23-30.
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- Habib AE, Abdel-Kader AA, Eissa IM, Awadein A. Adherence to intravitreal anti-vascular endothelial growth factor (anti-vegf) drugs in diabetic macular edema in an Egyptian population: a health belief model. Current eye research. 2019;44(3):303-310.
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