Key words
age-related macular degeneration - choroidal neovascularisation - intravitreal therapy
- health care system
Introduction
Age-related macular degeneration (AMD) is one of the main causes of visual impairment
and blindness in people over 60 years of age in developed countries. This chronic,
progressive retinal
disease can be divided into early and late forms [1]. The early form is characterised by drusen and pigment changes and has a prevalence
of 13.2% in the European
population over 70 years of age. The late form of AMD is further subdivided into
two classes: the dry form, characterised by geographic atrophy (GA), and the wet form,
also called exudative or
neovascular AMD (nAMD), characterised by choroidal neovascularisation (CNV). The
prevalence of both classes of the late form combined is 3.0% in the European population
over 70 years of age
[2]. Unlike dry AMD, for which no effective treatment options currently exist, nAMD
progression can now be largely prevented or at least delayed. This involves the
inhibition of VEGF (vascular endothelial growth factor), which stimulates angiogenesis
and vascular leakage from newly formed vascular networks in the choriocapillaris and
is thus responsible
for the progression of nAMD, by anti-VEGF agents. These are administered by means
of intravitreal injection (IVI), which enables visual acuity to be maintained in many
cases or even increased
([Fig. 1]) [3]. Anti-VEGF therapy has revolutionised the treatment of nAMD in the last two decades,
although rising life expectancy
and increasing numbers of treatments present health systems and patients[*] with new challenges. The regular evaluation of treatment outcomes is therefore
important both in order to make treatment efficient and to improve compliance
and adherence to treatment among patients [4], [5], [6].
Fig. 1 Case – A female patient (59 years) presented with a deterioration in vision (visual
acuity: 0.8) in her left eye and subretinal fluid on OCT (CRT [central retinal
thickness]: 423 µm). Based on the diagnosis of neovascular age-related macular
degeneration, injection therapy was initiated. The patient received eleven injections
with ranibizumab
according to a PRN regimen and was then switched to a treat-and-extend regimen
with aflibercept, in which she had received 27 injections at varying intervals to
date. Over 5 years and a
total of 38 injections, the visual acuity decreased to 0.63, and the patientʼs
eyesight was largely maintained despite recurrent oedema and fibrosis.
Active Substances for treating exudative AMD
Active Substances for treating exudative AMD
Although initial attempts were made to treat nAMD with laser photocoagulation, this
form of treatment was replaced with photodynamic therapy in the early 2000s. Treatment
with photodynamic
therapy showed a stable visual prognosis, but led to recurrences in the medium
and long term and thus to a deterioration in the morphological and clinical findings.
Use of photodynamic therapy
in combination with intravitreal triamcinolone resulted in stabilisation of disease
activity but a poorer visual prognosis than for treatment with intravitreal anti-VEGF
agents [3], [7]. The authorisation of pegaptanib (Macugen; OSI Pharmaceuticals, Melville, NY, USA,
and Pfizer, New York, NY, USA) ([Table 1]) in 2004 in the USA and 2006 in Europe revolutionised the treatment of nAMD: As
a result of the administration of 0.3 mg of the anti-VEGF agent at 6-week
intervals, 70% (control group 55%) of the patients lost fewer than three lines
of visual acuity after one year. Of the patients treated with pegaptanib for another
year, 93% (control group
86%) lost fewer than three lines of visual acuity after 2 years [8], [9]. Pegaptanib was relatively quickly superseded by the anti-VEGF
agent ranibizumab (Lucentis; Genentech, South San Francisco, California) which
was authorised shortly afterwards in 2006 in the USA and 2007 in Europe ([Table
1]). Ranibizumab, administered every 4 weeks in a dose of 0.5 mg, prevented vision
loss of more than three lines in 95 – 96% of study participants, and a visual gain
of 7.2 and 11.3
ETDRS (Early Treatment Diabetic Retinopathy Study) letters was also identifiable
after one year [10], [11]. Finally, another anti-VEGF
product, aflibercept (Eylea; Regeneron, Tarrytown, New York) was authorised in
2011 in the USA and 2012 in Europe. Clinical equivalence to ranibizumab was demonstrated
with administration of
2 mg aflibercept in the form of a loading dose of 3 injections at 1-month intervals,
followed by injections at 8-week intervals [12].
Table 1 Anti-VEGF products used worldwide for the treatment of nAMD.
|
INN
|
Authorisation in DE
|
Structure
|
Mass
|
Target molecule
|
|
DE = Germany; INN = International non-proprietary name; PlGF = Placental growth factor;
VEGF = Vascular endothelial growth factor
|
|
Pegaptanib
|
2006
|
RNA aptamer
|
50 kDa
|
VEGF-A
|
|
Ranibizumab
|
2007
|
Monoclonal antibody
|
48.4 kDa
|
VEGF-A
|
|
Aflibercept
|
2012
|
Recombinant fusion protein
|
115 kDa
|
VEGF-A/B, PlGF
|
|
Ziv-aflibercept
|
Not authorised
|
Recombinant fusion protein
|
115 kDa
|
VEGF-A/B, PlGF
|
|
Bevacizumab
|
Not authorised
|
Monoclonal antibody
|
149 kDa
|
VEGF-A
|
|
Brolucizumab
|
2020
|
Antibody fragment
|
26 kDa
|
VEGF-A
|
Besides ranibizumab and aflibercept, bevacizumab (Avastin; Roche, Basel, Switzerland)
([Table 1]) is one of the three most widely used anti-VEGF agents. Unlike
ranibizumab and aflibercept, treatment of nAMD with bevacizumab has not yet been
authorised for intravitreal therapy and must therefore be used as an off-label therapy.
The drug was developed
for the treatment of gastrointestinal, lung and breast cancer. Bevacizumab is
also demonstrably non-inferior to ranibizumab in terms of its action [13]. Whereas,
because ranibizumab and aflibercept are fully reimbursed, bevacizumab use in Switzerland
constitutes less than 0.5% of all injections, bevacizumab injections account for around
35% of all
injections administered in Germany and 20 – 60% in Austria, depending on the treatment
centre [14]. The cost factor in particular plays a major role in the
administration of the different anti-VEGF agents. Worldwide, one dose of ranibizumab
costs around $ 240 (India) – $ 1950 (USA), for example, and one dose of aflibercept
approximately $ 846
(India) – $ 1950 (USA), whereas one dose of bevacizumab comes to just $ 50 in
the USA [15]. Ziv-aflibercept (Zaltrap; Regeneron, Tarrytown, NY and Bayer Healthcare,
Leverkusen, Germany) ([Table 1]) is another active substance that is administered off-label. Like bevacizumab, it
is authorised for the treatment of metastatic
colorectal cancer, but has also shown reliable long-term outcomes in the treatment
of nAMD [16]. In addition, ziv-aflibercept is considerably less expensive that
the authorised products, with one dose costing approximately $ 30 (USA) [15].
Brolucizumab (Beovu, Novartis, Cambridge, Massachusetts, US) ([Table 1]) has only recently been authorised in the USA (end of 2019) and the EU (start of
2020).
The injection interval is 12 weeks, with the option of reducing this to 8 weeks
if disease activity increases. The longer interval should reduce the burden on both
patients and hospitals [17].
The development of new active substances for treating nAMD has become a real race:
Besides the multitude of products that are already authorised and used off-label,
numerous active substances
that target not only VEGF but also other pathways are currently being studied
and research is being carried out into other formulations. Anti-VEGF medications currently
in various trial phases
include abicipar pegol (Allergan), conbercept (Chengdu Kanghong biotech Co., Ltd.,
Sichuan, China), faricimab (Roche, Genentech, South San Francisco, California) and
KSI-301 (Kodiak Sciences)
These promise a longer duration of action than the products available at present
and thus reduce the number of injections needed. A new formulation currently being
researched is the Port
Delivery System. This surgically implanted drug reservoir is filled with anti-VEGF
medication at regular intervals, and this is delivered continuously into the eye.
Another strategy is offered
by gene therapy. This is administered surgically or by means of intravitreal injection
and should considerably reduce the number of injections of anti-VEGF medication needed.
Gene therapies
currently in clinical research include RGX-314 RegenexBio (Rockville, MA, USA)
and ADVM-022 (Adverum) [18].
Besides the active substances available at present and used off-label for the treatment
of nAMD, research is being carried out into a large number of active substances aimed
at prolonging
effectiveness and thus reducing the number of injections. The use of these active
substances could lead to a considerable reduction in the burden not only on hospitals
and physicians but also
patients.
Treatment Intervals
In the pivotal studies for the authorisation of ranibizumab in classic and occult
nAMD (ANCHOR and MARINA study), a monthly injection regimen was used ([Fig. 2]). Patients who received injections of 0.5 mg ranibizumab every 4 weeks over a period
of two years showed a visual gain of 11.3 and 7.2 ETDRS letters respectively after
just one
year [10], [11]. A regular injection regimen of 3 initial injections at 4-week intervals followed
by injections at 8-week intervals was
also used in the pivotal studies for the authorisation of aflibercept (VIEW 1
and VIEW 2) to rule out inferiority compared with ranibizumab [12]. Because the
effects of the injections within the patient population were very varied, a different
treatment regimen was sought in order to be able to provide patients with more individual
care and, if
possible, to reduce the number of injections while maintaining visual acuity [17]. The PRN (pro re nata) regimen was developed for this: After a loading dose of 3
injections at monthly intervals, monthly assessments take place to decide, on
the basis of established criteria, whether the patient will receive an injection at
this visit or not. Criteria
include, for example, loss of over five lines of visual acuity, identification
of sub- and intraretinal fluid on OCT (optical coherence tomography) or retinal bleeding
([Fig. 2]) [17], [19]. Despite very promising results from the first study, the results of regular 4-
or
8-weekly administration could not be achieved in the subsequent studies [17]. The T&E (treat-and-extend) protocol represents another treatment regimen: As with
the PRN regimen, 3 injections are administered at monthly intervals initially
(loading dose), followed by regular monitoring. In contrast to the PRN regimen, however,
an injection is
administered at each monitoring visit and the interval between the injection visits
adjusted. Disease activity is assessed using similar criteria to the PRN regimen,
and the treatment interval
is extended by two weeks in each case if this has decreased or stabilised, and
shortened if it has increased, but never adjusted below 4 weeks or above 12(–16) weeks
([Fig. 2]) [19]. Unlike with the PRN regimen, similar outcomes to the monthly administration regimen
were achieved with the T&E protocol [17]. The observe-and-plan regimen described by Mantel et al. represents a variation
on the T&E protocol. After three injections at monthly intervals (loading
dose), follow-up visits are carried out at monthly intervals which are used to
establish the interval for future injections. If disease activity recurs, the interval
between the last injection
and follow-up visits is decreased by two weeks and set as the new interval for
the next three injections. The intervals, which are between 4 and 12 weeks, are re-evaluated
after three
injections for the next three injections ([Fig. 2]). With a significant improvement in vision within the first year of treatment and
a number of injections
similar to the other regimens, it was possible to considerably reduce the number
of monitoring visits [20].
Fig. 2 Regimens for injection intervals for the treatment of nAMD. FIX = Fixed intervals;
OAP = Observe-and-plan regimen; PRN = Pro re nata regimen; T&E = Treat-and-extend
protocol; W = Weeks.
In most cases, it was not possible to replicate results achieved in randomised controlled
studies in routine clinical practice, regardless of the active substance used (ranibizumab,
aflibercept, bevacizumab) [21]. Numerous studies investigating anti-VEGF therapy in a real-world setting showed
considerably poorer visual outcomes than indicated
by the pivotal studies. While the result after one year was predominantly a visual
gain, this largely gave way to a decline in visual acuity over longer periods of time.
Although maintenance
of baseline visual acuity was demonstrated, there were also studies which showed
a loss of visual acuity to below the level at baseline [21], [22], [23].
But what is the reason for this “efficacy gap”? Besides stricter selection criteria
for patients who participate in pivotal studies, the injection regimen plays a particularly
important role:
In routine clinical practice, patients are usually treated according to a PRN
regimen and receive fewer injections on average than in controlled studies [17], [21]. Better outcomes have been observed in real-world studies using a T&E regimen [21], [23]. The
development or progression of existing macular atrophy and fibrosis also have
a negative impact on visual acuity. Changing the anti-VEGF product does not appear
to have a negative impact on
visual acuity [23].
Subtypes and Complications in the Treatment of nAMD
Subtypes and Complications in the Treatment of nAMD
Although most patients with nAMD respond to treatment, there are cases in which the
response to anti-VEGF therapy is poorer. This is often attributable to one of the
subtypes of nAMD, in
particular polypoidal choroidal vasculopathy (PCV) and retinal angiomatous proliferation
(RAP). In a study by Ozkaya et al., it was found that around 1% of patients had a
morphologically poor
response to treatment with ranibizumab. Of these, only 9.8% were diagnosed as
having true nAMD, while the remaining 90,2% had a subtype of nAMD or other macular
diseases. In these cases, the
correct diagnosis was made by means of indocyanine green angiography. The diagnosis
was thus revised to PCV in 56.1% of cases, to chronic central serous chorioretinopathy
(CSC) in 26,5% of
cases and to RAP and CNV secondary to CSC in 2.3% cases. Additional photodynamic
therapy could be given if required. In this study, PCV and RAP are described as subtypes
of nAMD, although it
is pointed out that other authors consider these two entities as macular diseases
to be differentiated from nAMD [24].
Apart from the issue of the response to injection therapy, the associated risks and
possible complications must not be overlooked. Minor complications reported by patients
in connection with
injection therapy include eye irritation, subconjunctival haemorrhage and visual
disturbance from the medication or air bubbles [25]. The main serious complications
that should be mentioned are increased intraocular pressure after injection, corneal
abrasion, retinal detachment, vitreous or retinal haemorrhage and endophthalmitis
[25], [26]. Retinal pigment epithelial tears are a complication that deserves special mention
in the treatment of nAMD. These can occur spontaneously or in
connection with intravitreal therapy. The risk factors for pigment epithelial
tears also include pre-existing pigment epithelial detachments, large diameter and
vertical height. Better
maintenance of visual acuity was achieved in patients who continued to be treated
with anti-VEGF medication after pigment epithelial tear [26]. In the case of
brolucizumab, in addition to the complications mentioned, the increased incidence
of intraocular inflammation, retinal vasculitis and retinal artery occlusion should
also be noted [27].
Endophthalmitis is the most feared complication of intravitreal injection therapy.
A distinction needs to be made here between infectious endophthalmitis and non-infectious
endophthalmitis
(also called sterile intraocular inflammation or non-infectious vitritis). The
incidence of infectious endophthalmitis is 0.008% to 0.092% per injection, compared
with 0.09% to 0.37% per
injection for non-infectious endophthalmitis [28]. However, it is important to consider not only the incidence per injection but also
per patient, because most
patients receive multiple injections. Daien et al. documented the cumulative rate
of endophthalmitis after 10, 20, 30, 40, 50 and 60 IVI s. Although an increase in
infectious endophthalmitis
from 0.055% after 10 injections to 0.843% after 60 injections was identified,
the risk of infectious endophthalmitis did not increase significantly with each consecutive
injection. The
cumulative rate of non-infectious endophthalmitis increased from 0.087% after
10 injections to 0,228% after 20 injections and remained at the same level until after
60 injections. The risk of
non-infectious endophthalmitis did not increase significantly with each additional
injection administered either [28]. In order to prevent serious complications of
endophthalmitis, patients should be advised to return to the treatment centre
immediately at the first signs of any acute deterioration in their vision or eye pain,
so treatment can be
initiated as soon as possible [26].
Importance of nAMD Treatment for Patients
Importance of nAMD Treatment for Patients
Although patients benefit greatly from nAMD treatment, they also often see it as a
burden. Compliance and adherence to treatment are also critical factors for the success
of anti-VEGF therapy
and thus for maintaining vision. Patients with nAMD usually show a high level
of adherence to treatment. Nevertheless, with an average number of 10 injections within
a period of two years, a
premature dropout rate of approximately 20% has been observed among patients.
The main reasons given for missing monitoring and injection appointments included
difficulties with transport and
getting to the treatment centre, comorbidities preventing attendance and loss
of motivation [29]. Most of the patients also showed good adherence to treatment in a
study conducted by Boyle et al. examining the experiences of patients during therapy:
The participants understood the need for therapy and saw it as a compromise to maintain
their visual
acuity, mainly out of fear of losing their eyesight, despite the associated inconveniences.
Most therefore said that they would continue with their treatment and continue to
recommend it to
other patients with newly diagnosed nAMD. Prioritising treatment was described
as an additional burden for patients, however, as social and work commitments had
to be sacrificed for monitoring
visits. Besides the fear of losing eyesight, fear of the injection procedure itself
was also noted. In most cases, however, this decreased with the increasing number
of injections, duration of
treatment and familiarity with the injection procedure [4]. Classical music before and during the treatment also reduced patient anxiety [30]. Besides the fears mentioned, patients stated that the frequency of the visits and
waiting time represented a burden for them [5], [29]. Visits at longer intervals and with less waiting time would therefore be preferred
and having the assessment at the same visit as the injection would be favoured
over separate visits [5].
Overall, the high level of patient compliance is maintained mainly through fear of
losing eyesight, although patients wish the treatment was less burdensome.
Role of Relatives
Although many patients rely on help from relatives or caregivers, there has been little
research into the impact this has. Because most patients need help in getting to and
from home and
hospital, it is often relatives or friends who accompany patients [4], [29]. Approximately three quarters of patients have been
accompanied on their visits, mainly by spouses or children. Their age was over
60 years on average. Because the hospital visits lasted between one and several hours,
working relatives, who
accounted for around 35 – 46% of those surveyed, had to take time off or stated
that they suffered a loss of productivity or income as a result of their caregiving.
In addition, the relatives
spent between one and several hours a day on average helping the patient with
everyday activities such as shopping or personal hygiene. Relatives also incurred
costs amounting to around € 400
per year for transport, household assistance and purchases or changes. Besides
the time and financial burden, relatives reported that caregiving was associated with
a subjective burden and
reduced quality of life [31], [32].
Impact on Health Systems
The possibility of treating nAMD successfully also has considerable implications for
physicians, hospitals and health systems. With approximately 4.1 million injections
performed in the USA
in 2013, an increase to 5.9 million injections was estimated in 2016 [33]. The number of prescriptions in Germany in 2018 was 294,200 for ranibizumab and
303,600
for aflibercept [34]. These data also include prescriptions of the active substances for other conditions
such as diabetic macular oedema, as there has been no
separate analysis of data relating to nAMD on its own. In order to incorporate
this increase into routine clinical practice and to ensure that the process runs quickly
and smoothly, dedicated
IVI centres have been set up in many hospitals. However, there is a lack of standardised
recommendations regarding assessment and injection frequency [6]. Physicians
also feel increasingly overburdened with regard to the management of patients
with nAMD. In a survey by Prenner et al., physicians stated that this accounts for
around 20% of their weekly
workload. On average, one assessment took 90 minutes and involved around 23 members
of staff, including receptionists, office managers, account managers, technicians
and physicians. More than
half of the physicians said that the frequency of assessments and injections as
well as billing represented a time and materials burden for personnel and patients.
Two thirds would like
monitoring visits to be reduced [35]. Besides hospitals and physicians, health systems are also faced with the challenge
of increasing costs. In 2015, the American
Medicare Part B system spent $ 3 billion on aflibercept and ranibizumab [36]. Aflibercept also proved to be the medicinal product on which the most budget was
spent. In England, around 400 thousand injections were administered in the 2014/15
reference period, and in 2015/16 the NHS budget for ranibizumab and aflibercept corresponded
to £ 447 million
[37]. The net costs of ranibizumab and aflibercept in Germany in 2018, according to the
2019 Drug Prescription Report, were € 349.5 million and € 312.9 million.
Together, this accounted for around 57% of the total net costs for ophthalmic
agents, which in 2018 were € 1162.5 million. The products were thus the 7th and 9th
top medicinal products in
Germany in 2018 based on net costs. These costs relate to all prescriptions, as
there has been no separate analysis of data relating to nAMD on its own. Unfortunately,
data from Austria are
not accessible.
Physicians and hospitals are thus increasingly being faced with an rising number of
patients in ophthalmology with the associated workload and burgeoning costs, which
are also a burden on the
health systems of the individual countries.
Telemedicine – the Digitalisation of Medicine
Telemedicine – the Digitalisation of Medicine
The increasing digitalisation of medicine is opening up new possibilities for early
detection, treatment and care outside of the hospital setting for patients with nAMD.
Communication and
consultation between retina specialists and community-based ophthalmologists using
various information technologies make it possible to reduce the burden on treatment
centres and retina
specialists and at the same time support community-based ophthalmologists in patient
care. Patients who travel long distances for injection therapy also benefit from this.
Starr et al.
described a system whereby community-based specialists cared for patients with
nAMD and performed the injections themselves. The assessment, visual acuity and OCT
records were then sent to
hospital-based retina specialists via eConsult. These specialists reviewed the
data submitted and then issued their recommendations for the patientʼs further care.
Patients were thus able to
be cared for by their community-based ophthalmologist at the same time as benefiting
from the communication between this person and the hospital-based retina specialist
[38].
Another study compared diagnostic and treatment decisions by retina specialist relating
to patients following a PRN regimen. These decisions were made either in the office
or using “remote
evaluation” via a server. For the latter, visual acuity, OCT and digital fundus
images were stored on a server and downloaded for evaluation. Telemedicine diagnoses
showed a sensitivity of 96%
and a specificity of 85%, and at 1 minute and 21 seconds on average, the amount
of time spent in the evaluation was a fraction of the time needed for office decision-making,
which was around
10 minutes. In this study, telemedicine evaluation also proved to be a useful
and time-saving alternative to office evaluation [39].
In addition, telemedicine is used in the everyday home setting. Researchers have developed
a device which patients can use to test their eyesight at home for around 3 minutes.
The results are
then sent to a medical facility and the patient is contacted for a monitoring
visit if there are any significant changes. The ForeseeHome device has been tested
in a controlled clinical trial,
corresponding to level 1 evidence, and has been cleared by the FDA in the USA
[40].
As a result of this technical advance, it is now possible to test patientsʼ state
of health regularly in their home and, if necessary, to assess them personally as
quickly as possible.
Communication between hospitals and community-based practices is also simplified
and strengthened by the electronic transmission of assessment data. This makes it
possible to provide the best
possible care for patients with nAMD even outside the hospital setting.
Big Data and artificial Intelligence
Big Data and artificial Intelligence
The inexorable march towards electronic patient documentation and the development
of registries makes it possible to collect and analyse data in large quantities. As
a result, it is becoming
possible not only to analyse very large patient populations but also to assess
wider relationships. For example, a link has also been established between active
and previous smoking and
development of neovascular AMD [41]. Evaluating data from direct patient care represents another advance. Unlike randomised
clinical trials, these real-world data
are particularly interesting because they are not limited to a specific patient
population. Rather, it is now possible to verify the results of any studies and their
application under real
conditions of care.
Besides the collection and evaluation of big data, artificial intelligence (AI) also
represents a ground-breaking development in ophthalmology. Algorithms are developed
which enable patterns
and relationships to be identified using datasets. After this automated learning
phase, these can also be applied to unknown data [42].
Grassmann et al. created an algorithm which automatically identifies the stage of
AMD based on the AREDS classification. Classification by algorithm was even superior
to human assessment in
terms of accuracy [43]. Another example is an algorithm developed by Schmidt-Erfurth et al. for automated
quantification of the fluid volumes in the retina in the
presence of nAMD. This capability makes it possible to determine disease activity
in a very precise manner and adjust the treatment regimen as a result [44].
Around 40% of US ophthalmologists already only perform OCT in cases of more prolonged
anti-VEGF therapy and no longer carry out a slit-lamp examination at every visit [45]. It is therefore all the more important to establish disease activity in a precise,
rapid and standardised manner in future, as would be possible with such an algorithm.
The use
of artificial intelligence has already gained a foothold in clinical practice
in the treatment of nAMD. An algorithm designed to predict the risk of early AMD conversion
to nAMD based on
imaging and clinical data is currently undergoing clinical testing (NCT04640649).
Another algorithm which serves as a decision-making tool for the individual treatment
of nAMD based on the
automated analysis of sub- and intraretinal fluid is also in clinical trials (Eudra-CT
2019-003133-42). In the future, the use of artificial intelligence in the context
of nAMD could lead to
rapid and reliable disease stage and activity identification in routine clinical
practice. This would make it possible to optimise treatment management and reduce
costs.
Discussion
The treatment of nAMD has undergone a transformation in the last two decades. Anti-VEGF
agents have made it possible to maintain and even improve visual acuity in the long
term. The
opportunity of preventing blindness in patients worldwide is also fraught with
difficulties, however. Systems needed to be implemented that enable large numbers
of patients to be treated every
day at the same time as ensuring that the process runs smoothly. Reliable active
substances, the setting up of IVI centres, optimised monitoring and injection processes
and good patient
compliance are important prerequisites for the competent and smooth routine treatment
of nAMD. Ever increasing patient numbers and capacity utilisation mean that continuous
improvements will
also be necessary in the future to avoid overburdening treatment centres, physicians
and, not least, patients and their relatives. In view of the high financial burden
on health systems,
cost-effectiveness studies have been conducted which highlight, inter alia, the
possibility of using bevacizumab as an inexpensive alternative to authorised products
such as ranibizumab and
aflibercept [46]. In 2018, in a lawsuit brought by two pharmaceutical companies in England against
several NHS clinical commissioning groups, the High Court ruled
in favour of the off-label use of bevacizumab in clinical practice [47]. Another important goal is to find an optimised administration regimen which – despite
longer intervals between individual monitoring and injection visits – shows outcomes
similar to those of the registration studies. The T&E regimen has asserted itself
here: Because
monitoring and injection visits are combined and the intervals can be increased
if disease activity is absent or decreasing, patients are treated according to their
individual needs, visual
acuity is kept stable and savings are made in terms of capacities and resources
[21], [23]. Attempts are also made to meet the wishes of
physicians and patients in the development and manufacture of new anti-VEGF agents.
The dosing interval for brolucizumab is already 12 weeks, for example, and only has
to be reduced to 8 weeks
if disease activity increases [17]. It is important to bear in mind the expanded risk profile for these products, however.
In the case of brolucizumab, for example,
an increased incidence of intraocular inflammation, retinal vasculitis and retinal
artery occlusion has been observed [27]. There are also some very promising
active substances and mechanisms in the research pipeline. The more prolonged
effectiveness of the products and functional mechanisms could considerably reduce
the burden of treatment. New
anti-VEGF agents show a longer duration of action than active substances used
previously, for example, and thus longer intervals between the administered injections.
Gene therapies that are
administered on a one-off basis may considerably reduce the number of injections
for treatment with anti-VEGF medication. Surgically implanted Port Delivery Systems
deliver the active
substance continuously and are refilled at regular intervals which are considerably
longer than those of the active substances administered at present [18]. Another
strategy for increasing capacity is to have intravitreal injections performed
by specially trained nurses. This model has already proven reliable, used in parts
of the United Kingdom, and also
showed high levels of acceptance among patients [48]. It would also be possible to have imaging studies evaluated by a reading centre.
In patients treated according
to a PRN regimen, the retinal fluid measurement obtained was consistent with the
treatment decisions of the treating ophthalmologists for most visits [49]. Imaging
could therefore also be assessed by a reading centre for patients treated according
to a T&E regimen and the treatment intervals established in a standardised manner
according to its
recommendation. Finally, the implementation of artificial intelligence could enable
disease activity and course to be assessed rapidly and accurately and thus probably
enable the burden for
patients and health systems to be reduced from both a personal and financial perspective
[42], [43], [44], [50]. Because the ultimate decision regarding the monitoring intervals and time of treatment
remains with treating physicians, this supports medical
competence without rendering it obsolete.
Conclusion
Anti-VEGF therapy has helped to make it possible to largely prevent severe loss of
vision as a result of nAMD. This achievement of modern medicine is associated with
problems, however.
Increasing numbers of patients and treatments result in rising costs for health
systems. Research into new active substances and administration mechanisms offers
one approach to reducing the
burden of treatment. In the future, automated algorithms based on artificial intelligence
might pave the way for precision medicine at a high level and result in a higher quality
of patient
care. Hospitals, physicians, patients and relatives are also required to change
habits and adapt, and thus make the processes for nAMD injection therapy as efficient
as possible. Besides many
measures that have already been implemented, it will also continue to be necessary
in the future to work on these processes in order to be able to guarantee the best
possible treatment for
each patient without placing too high a burden on the health system and personnel.
