As part of Macula Month this May, Insight explores why treatment adherence remains such a major challenge for some patients and how the sector is working to overcome it.
It was only a little over a decade ago that many patients with neovascular age-related macular degeneration (nAMD) resigned themselves to living the remainder of their years with blindness or severe vision loss.
Such a bleak prognosis swiftly eroded their quality of life, as well as those around them, while also impacting other measures such as productivity and the burden on the health system.
Today, thanks to the emergence of sight-saving anti-VEGF treatments, Australian Government reimbursement schemes and collaboration between researchers, healthcare professionals, the pharmaceutical industry and patient advocacy groups, Australia boasts some of the world’s best statistics in terms of nAMD patient outcomes.
While these results are increasingly being translated into positive real-world outcomes, for some patients the journey is not always so smooth.
In Australia, according to the Macular Disease Foundation Australia (MDFA), there is a 20-25% non-adherence rate for intravitreal injection treatment in the first 12 months.
The issue could become more pronounced this year, with clinics reporting that up to one third of patients are cancelling treatment due to confusion around whether they can attend appointments during COVID-19.
It also comes as new studies demonstrate just one missed ophthalmology appointment over a two-year period can lead to decreased visual acuity.
Insight examines what efforts are being made nationally to lift nAMD treatment adherence and how existing therapies are being utilised to ease the burden on patients.
Drop-out despite world-class care
MDFA CEO Ms Dee Hopkins and Professor Mark Gillies, director of research at the University of Sydney’s Save Sight Institute (SSI), agree that Australia is one of the top-ranking countries as far as treatment outcomes for nAMD patients are concerned.
“This is because of the ongoing collaboration of government, eye health professionals, industry, researchers and patient organisations like MDFA,” Hopkins says.
“15.5% of patients had either delayed receiving treatment or considered stopping treatment because of the cost of treatment and out-of-pocket expenses”
“In the past decade, together we have been able to increase national awareness of the condition, move swiftly to register and reimburse anti-VEGF treatments, and foster the skills required by the eye health profession to provide world-leading care for patients living with macular disease.”
Despite these successes, Hopkins and Gillies point to the adherence rate as a key area that still requires close attention, particularly for those that drop out after a year of intravitreal injection treatment, even in Australia.
Gillies has unique insight into the patterns of nAMD treatment in Australia. He is chief investigator of the Fight Retinal Blindness project, which captures data directly from clinicians worldwide on nAMD patients, as well as those with choroidal neovascularisation other than nAMD, diabetic macular oedema and retinal vein occlusion.
SSI established the project in 2009 and now has a cache of more than 10 years-worth of data.
“Australian clinicians have a ‘treat nAMD forever’ approach, whereas other countries try to stop the disease and discontinue treatment, but there is no clear set of criteria for that model. We get the best results because we treat indefinitely,” Gillies says.
“In uncommon patients in whom the injections are discontinued, we see high recurrence rates, with 40% of patients recurring within 12 months and 80% within five years. Undertreatment is a major problem. Observational studies over 15 years show there is a 10% drop-out per year.”
According to Gillies, a 10-year follow-up study of people who started injections soon after they were released in 2006 found a quarter of patients made it through treatment for 10 years, but three-quarters dropped out.
“Some drop-out can be explained by patients dying of unrelated illness, or moving to another doctor, but we estimate that at least half of the drop-outs were due to poor results,” he explains.
Further, the Pharmaceutical Benefits Advisory Committee’s Drug Utilisation Sub Committee May 2018 report found that 23-41% of patients using ranibizumab (Lucentis) or aflibercept (Eylea) – the two most commonly used Pharmaceutical Benefits Scheme (PBS) listed medications in intravitreal injection treatment for macular disease – discontinued treatment after the first year even while they kept taking their other medications.
“Australian clinicians have a ‘treat nAMD forever’ approach, whereas other countries try to stop the disease and discontinue treatment”
Hopkins adds: “This is a shared concern of peak bodies such as MDFA, as our purpose is to reduce the incidence and impact of macular disease and we therefore strive to avoid unnecessary vision loss for patients.”
She says the MDFA is now working with government and other stakeholders on behalf of the most vulnerable members of the macular disease community to improve access to affordable treatment. This will ensure that Australia can continue to be a global leader in treatment outcomes.
Addressing key challenges to adherence
It is generally accepted that the key challenges that lead to poor adherence among Australian patients include travel, access to public care and financial constraints associated with private care.
From her dealings with patients at MDFA, Hopkins identifies Australia’s predominantly private treatment model as a key challenge for patients, with only 18-23% being treated in public or bulk billing services.
Access to public care is also under further threat with the pending Medicare Benefits Schedule Taskforce Review into ophthalmology items, which, if the government adopts, would reduce the intravitreal injection MBS fee from $305.55 to $95.10. In turn, the patient benefit/rebate would drop 69% from $259.75 to $80.85.
The sector has warned this controversial proposal is well below the actual cost of providing the service, meaning bulk billers won’t be able to afford to provide the service.
As a result, many patients will likely be billed an out-of-pocket fee or have to find a public hospital that does injections. However, these are very few, advocates say, because state governments don’t fund it appropriately.
“The issue here unfortunately, is that public treatment is over-subscribed in most states and territories,” Hopkins explains.
“People just can’t get access or are put on a waiting list which can take months or years. This is why we are advocating for improved access to public or bulk-billed treatment which should be a joint responsibility of both the Commonwealth government and State and Territories.”
For many AMD patients who live on a government pension, Hopkins says affordability is one of the key factors for accessing sight saving treatment.
“MDFA surveyed more than 600 intravitreal injection patients in 2019. The results showed that of those who responded, 99.3% continued to adhere to treatment, although 15.5% of patients had either delayed receiving treatment or considered stopping treatment because of the cost of treatment and out-of-pocket expenses.”
She adds: “While the survey highlighted that anti-VEGF treatment is a high priority for patients, some sacrifices were necessary to remain on treatment. For many these sacrifices were essentials, including food and groceries, mortgage and rent, transportation, exercise and fitness, and other medical expenses, which was most disturbing.”
Hopkins says that while MDFA’s survey showed a strong result in terms of adherence rate, the people surveyed are already connected to MDFA, have undertaken its education program and the organisation is in regular contact to promote adherence and compliance.
“Our work promotes referral to MDFA for newly diagnosed patients so that we can work with them as soon as possible to improve health literacy and reduce modifiable risks,” she says.
To help further improve patient outcomes, the MDFA developed the National Strategic Action Plan for Macular Disease in collaboration with the wider eye health sector including consumers, which Health Minister Mr Greg Hunt launched last year.
Hopkins added: “His department has since announced $3 million to fund extended consumer education and a new health professional education program targeting GPs, optometrists, pharmacists and Aboriginal and Torres Strait Islander communities and providers.”
The implementation of this new program is likely to be delayed due to COVID-19.
The science of patient communication
According to Associate Professor Isabelle Jalbert, from the School of Optometry and Vision Science at the University of New South Wales, ‘cost of care’ and ‘patient not understanding what AMD is’ were the top two most cited barriers to treatment.
This was revealed in a qualitative study she co-authored, which received funding from the Blackmores Macular Disease Foundation Australia research grant to investigate AMD care from the perspectives of both practitioner and patient.
“There is a science to patient communications and in our research we can see that communication – depending how it is delivered – can lead to confusion”
Based on opinion sought from interviews and focus groups, ‘A qualitative exploration of Australian eyecare professional perspectives on Age-Related Macular Degeneration (AMD) care’ was published in Plos One in February.
“We spoke with 67 optometrists, 10 ophthalmologists and 56 AMD patients for our research. We’re continuing to analyse the patient’s perspective and aiming to publish those results by the end of this year,” Jalbert says.
“Anecdotally, we can see an interesting contrast between what messages optometrists and ophthalmologists think they are getting across to the patient, and what message the patients are taking away, keeping in mind that macular disease patients are typically elderly, and living with comorbidity.
“There is a science to patient communications and in our research we can see that communication – depending how it is delivered – can lead to confusion and misunderstanding on behalf of the patient.”
Jalbert says their “ground-up research” identified that eyecare professionals considered poor care pathways, poor patient understanding and denial of their disease, and cost of care and lack of funding, as the most significant barriers to AMD care.
Subsequently, their study yielded four recommendations, one of which is to assign a case manager for people diagnosed with AMD.
“Not an optometrist or an ophthalmologist but a third-party to help patients navigate their treatment. The MDFA does that to some extent through their hotline and printed material, which is beneficial, but we think something more substantial, akin to the diabetes model where the GP performs the role of case manager, could help reduce patients dropping out of treatment,” Jalbert explains.
The study concluded that “research into the potential benefits and costeffectiveness of public funding support of case managers for people with AMD is warranted”.
Jalbert and colleagues also recommend that affordable, accessible transportation services for people with AMD need to be broadly available.
The authors thought appropriately designed educational interventions directed at people with AMD, ophthalmologists, and optometrists could also be beneficial.
“Decision aids – a one-pager written in lay terms that explains what treatment research suggests, such as the kind used by ophthalmologists to explain cataract treatment – can help communication,” Jalbert says.
Clear, effective models of care should be developed collaboratively – not in silo – tested, and adequately incentivised, Jalbert’s study notes.
From the MDFA’s perspective, Hopkins says the organisation has a laser focus on achieving optimal outcomes for the macular disease community.
“In our prevention and early detection pillar, our impact goal is that Australians at risk self-identify and take early action to save sight,” she says.
“Our support pillar provides a range of holistic and practical resources, education and telecoaching to assist people throughout their journey and to live optimally with their macular condition.
“Importantly, this includes proactive engagement to promote treatment adherence by improving the understanding of macular disease treatment and the impact of vision loss resulting from treatment non-adherence.”
Individualised, nuanced treatment
Vitreoretinal ophthalmologist Associate Professor Andrew Chang is the medical director of the Sydney Retina Clinic, head of Ophthalmology at the Sydney Eye Hospital, and clinical Associate Professor at the University of Sydney.
He is familiar with the common reasons for missed appointments, pointing to a recent case concerning a nAMD patient requiring urgent treatment.
“We’re now individualising treatment, it’s more nuanced with drugs that can last longer, potentially reducing treatment for some patients to six-monthly injections”
“The patient had two injections of Lucentis but didn’t think it was working as he wasn’t seeing a significant improvement from his point of view,” he explains. As a result, Chang had to explain to the patient that his vision could become even worse if he ceased treatment or missed an injection.
Such cases, he says, highlight why managing patient expectations and education is crucial to ensuring patients return for their appointments – because the cost of missed visits and loss of vision could have serious ramifications for the patient and their quality of life.
For example, the true impact of missed anti-VEGF treatments was outlined in new clinical-based international research from the new Penn Medicine Study, published in February.
In that randomised clinical trial of 1,178 individuals, patients were expected to attend visits every four weeks. Each missed visit was associated with an average visual acuity letter score decline of 0.7. Compared with patients who were on time, those who averaged between 36 and 60 days and more than 60 days between visits lost 6.1 and 12.5 letters, respectively.
Chang believes anti-VEGF therapy has been sight-saving for patients with macular oedema due to nAMD, diabetic macular oedema, and retinal vein occlusion, but optimal visual outcomes of intravitreal therapy in the long-term depends on continuous monitoring and treatment, and optimising adherence and compliance.
“The evidence in clinical trials of regular fixed injections demonstrated up to 10 letters of improvement in visual acuity. However, real-world outcomes often were not as good as in the trials. In the real-world, this loss of vision may be due to patients being under-treated,” he says.
According to Chang, barriers to compliance include addressing the burden of treatment, patient education, and setting realistic expectations.
“The burden is due to multiple factors: financial, travel time, and loss of income are the main ones,” he says.
“To receive treatment, patients need to make a time-commitment that might include travel, clinical assessment, and then recovery-time after surgery. Patients can be incapacitated for one-to-two days, particularly if they’ve had bilateral injection treatment.
“The direct financial cost of treatment can be defined, but the indirect costs associated with travel and time off work which are often significant must also be accounted for.”
Chang says the ‘burden of treatment’ also affects the carer of the patient; the accompanying patient’s spouse, son or daughter who is also required to take time off work to accompany them to appointments.
“Surveys show carers are taking substantial time off work, and this alone can be a source of stress to the patient.”
Comorbidity – including hypertension, arthritis, and depression – is another factor that can affect a macular degeneration patient’s ability to attend surgical appointments for intravitreal injections. A younger patient with diabetic macular oedema has challenges of attending multiple medical appointments and clinics.
“Treatment adherence is a major public health challenge and a government funding issue of how to support ongoing treatment.”
Maximising exisiting treatments
For ophthalmologists like Chang who are looking at ways to overcome the treatment burden for his patients, proactive treatment regimes such as ‘treat-and-extend’ can maintain vision with fewer interventions.
He says there is a growing body of evidence that demonstrates a ‘treat-and-extend’ approach can reduce treatment burden without compromising patient’s vision.
“We are using different pharmaceutical drugs, and modifying the treatment regime, from fixed regular dosing to extending the time interval between injections based on an individual case approach, to help relieve the burden on patients.”
Anti-VEGF drugs such as Eylea (aflibercept) manufactured by Bayer, and Lucentis (ranibizumab) manufactured by Novartis, are now joined by newer drugs including Beovu (brolucizumab) also manufactured by Novartis, and Abicipar, manufactured by Allergan, which is on the horizon.
The Therapeutic Goods Administration registered Beovu for the treatment of nAMD as recently as January this year. Novartis is currently applying for the drug to be accessible on the PBS.
Clinical trials of an alternative delivery method known as the ‘port delivery system’ are also in the pipeline.
The system acts like a reservoir, a long-acting drug delivery system with the potential to reduce treatment burden, while maintaining optimal vision outcomes by enabling the continuous delivery of a customised formulation into the vitreous.
“Newer drugs like brolucizumab (Beovu), as demonstrated in the Hawk and Harrier trials, and Abicipar, used in the Sequoia and Cedar studies, and the near-future port delivery devices have the potential to extend to three monthly dosing,” Chang says.
“Eylea may be extended according to ’treat-and-extend’ regimes, as the Altair and Aries studies show.
“We’re now individualising treatment, it’s more nuanced with drugs that can last longer, potentially reducing treatment for some patients to six-monthly injections.”
Chang says clinicians need to assess the patient’s macular condition, but also understand their background, education, treatment affordability, and recommend a treatment plan accordingly. He cites the MDFA as a mainstay of patient support, but pharmaceutical companies also provide additional support.
“SmartSight is an evidence-based program for patients treated with aflibercept (Eylea) and is sponsored by Bayer Pharmaceuticals. It aims to support the patient through their treatment cycle, monitor vision, and provide support for carers,” he says.
Inservio, a company founded in 2007 to address an unmet need in the distribution of anti-VEGF in ophthalmology, also offers patient education.
Meanwhile, the SSI provides a patient care coordination service.
In addition to ophthalmologists, Chang says optometrists can play an important role in treatment adherence as well.
“Optometrists often make the initial diagnosis. They play an important role in supporting the need of patients to remain on therapy. These patients have other co-existent ocular conditions which also require monitoring and care.”
In reaching this point, Hopkins says it was only a little over a decade ago that people living with nAMD lost vision and often became legally blind.
“It has only been the collaboration between the Australian Government, eye healthcare professions, research agencies, the pharmaceutical industry and patient-focussed organisations such as MDFA that we have been able to advance the continuum of care and treatment in this country,” she says.
“As more treatment options come to light, we hope that this high level of healthcare continues to lead the world.”