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REVIEW ARTICLe
Recommended Guidelines for Use of Intravitreal Aflibercept
With a Treat-and-Extend Regimen for the Management of
Neovascular Age-Related Macular Degeneration in the
Asia-Pacific Region: Report From a Consensus Panel
Adrian Koh, MMED, FRCS,*† Paolo Lanzetta, MD,‡§ Won Ki Lee, MD, PhD,¶
Chi-Chun Lai, MD,ǁ Wai-Man Chan, FRCOphth, FHKAM,** Chung-May Yang, MD,††
and Chui Ming Gemmy Cheung, FRCOphth†‡‡§§
Purpose: To summarize recommendations for the use of intravitreal aflibercept with a treat-and-extend regimen to manage neovascular age-related macular degeneration (nAMD) in the Asia-Pacific region. Although
anti–vascular endothelial growth factor therapies have improved the quality of life of patients with nAMD, a leading cause of blindness and visual
impairment, the high treatment frequency recommended by current guidelines places a significant burden on patients and healthcare providers.
Design: Recommended guidelines from a consensus panel.
Methods: An expert panel formed a consensus on recommendations for use
of intravitreal aflibercept as treatment of nAMD in the Asia-Pacific region.
Results: After 3 initial monthly doses, treatment interval could be extended by 4-week increments, to a maximum of 12 weeks, in patients with
inactive disease. Conversely, in active disease, treatment intervals should
be shortened, by 4 weeks, or to 4 weeks in cases of severe recurrence.
Treatment could be ceased in patients with stable disease activity after 12
months of treatment at 12-week intervals, as a means to prevent over treatment and lifelong injections.
Conclusions: These recommendations could potentially minimize the number of treatments while maintaining efficacy and improve compliance by reducing the number of clinic visits compared with existing recommendations.
Key Words: aflibercept, Asia, blindness, age-related macular
degeneration, vascular endothelial growth factor
(Asia-Pac J Ophthalmol 2017;0:0–0)
From the *Eye and Retina Surgeons, Singapore; †Singapore National Eye Centre,
Singapore; ‡Department of Medical and Biological Sciences – Ophthalmology,
University of Udine, Udine; §Istituto Europeo di Microchirurgia Oculare, Udine,
Italy; ¶Department of Ophthalmology, Seoul St. Mary’s Hospital, College of
Medicine, The Catholic University of Korea, Seoul, South Korea; ǁHong Kong
Sanatorium and Hospital, Hong Kong; **Department of Ophthalmology, National
Taiwan University Hospital, Taipei, Taiwan; ††Department of Ophthalmology,
Chang-Gung Memorial Hospital, Taoyuan, Taiwan; ‡‡Singapore Eye Research
Institute, Singapore; and §§Duke-NUS Graduate Medical School, Singapore.
Received for publication June 13, 2016; accepted December 19, 2016.
A.K. received honoraria from Bayer for consultancy fees, lecturing fees, and support
for travel to meetings/conferences. P.L. received honoraria from Allergan,
Bayer, and Novartis for consultancy and board membership; from Alimera,
Alcon, Genentech, Lupin, Lutronic, Teva, and Roche for consultancy fees; from
Bausch & Lomb for support for travel/accomodation to meetings/conferences.
W.K.L. received honoraria from Novartis, Bayer, Allergan, Alcon, and Santen
for consultancy and board membership; from Novartis, Bayer, Allergan, and
Alcon for lecture fees. C.C.L. received honoraria from Bayer for consultancy
and lecture fees. W.M.C. has no conflict of interest to disclose. C.M.Y. received
honoraria from Bayer for consultancy and lecture fees. C.M.G.C. received
honoraria from Bayer for consultancy fees, board membership, and provision of
writing assistance; from Novartis for consultancy fees and board membership;
from Bayer, Novartis, and Roche for grants and research support.
The authors have no other conflicts of interest to declare.
Reprints: Adrian Koh, #13-03 Camden Medical Centre, 1 Orchard Boulevard,
Singapore 248649. E‑mail: [email protected].
Copyright © 2017 by Asia Pacific Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.22608/APO.2016125
N
eovascular age-related macular degeneration (nAMD) is a
chronic, progressive disease of the central retina and a major
cause of irreversible blindness in the Western world and in AsiaPacific countries.1‒4
Recently, population-based studies have demonstrated that
the prevalence of nAMD is similar in Asian countries and in those
with white populations (pooled prevalence of 6.8% vs 8.8% in
people aged between 40 and 79 years).2,5‒7 The number of affected
individuals worldwide is likely to increase dramatically as a result of population aging. It has been estimated that by 2050, 25%
of Asians will be aged 60 years or older.8
Asian and white populations share key risk factors for
nAMD, including age, cigarette smoking, obesity, sunlight exposure, and cardiovascular disease.9,10 However, the manifestation
of the condition may be quite different. Thus, it is important to
consider the epidemiology, genetic factors, phenotypic presentation, and clinical subtypes of nAMD in the Asian population from
a unique perspective.
Moreover, social factors affect the determinants of successful treatment and must be considered in any management recommendations. Despite the clear burden of poorly managed nAMD,
the majority of patients living in the Asia-Pacific region are not
receiving the optimal evidence-based care needed to prevent
severe visual loss. This is mainly due to the following: (a) lack
of awareness about the importance of early diagnosis and treatment, (b) limited access to diagnostic screening and treatment,
(c) high financial costs of anti–vascular endothelial growth factor (anti-VEGF) treatments and relative lack of reimbursement,
(d) fragmented delivery-of-care systems, and (e) limited access to
continuing care (patient follow-up).
Pathophysiology of Neovascular AMD
The underlying etiology of nAMD is complex and its direct
cause is not fully understood. What is known is that overexpression of VEGF leads to choroidal neovascularization (CNV). The
new blood vessels tend to be disorganized and more permeable
than their normal counterparts; thus, blood and fluid leak into the
macula. Over time, this leakage results in the characteristic clinical features of nAMD: increased retinal thickness, subretinal fluid
accumulation, intra- or subretinal hemorrhage, retinal pigment
epithelial (RPE) detachment, and/or sub-RPE hemorrhage.
Other growth factors may contribute to CNV but their roles
are only just starting to be elucidated. Placental growth factor
(PlGF), a member of the VEGF family, is one such molecule.
Upregulation of PlGF has been observed in human nAMD and
mouse models of laser-induced CNV,11,12 suggesting that it might
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Asia-Pacific Journal of Ophthalmology • Volume 0, Number 0, Month 2017
be part of the pathological process. Further support for this hypothesis is provided by mouse studies that report prevention of
laser induced CNV in animals that do not express a functional
PlGF protein, either through gene knockout or inhibition by an
anti-PlGF antibody.13 Additionally, PlGF has been implicated in
the pathogenesis of diabetic retinopathy by modulating hyperpermeability of RPE cells, ultimately leading to subretinal fluid accumulation and edema.8 The potential role of PlGF on the pathogenesis of diabetic retinopathy is supported by the observation
that high levels of PlGF are found in the vitreous of patients with
diabetic retinopathy.14
Treatment Options for Neovascular AMD
The primary goals for the treatment of nAMD are improvement in visual acuity (VA), reduction of fluid and blood leakage,
and complete regression of choroidal neovascularization. Treatment options have included laser photocoagulation, photodynamic therapy, steroids, and anti-VEGF agents.
The introduction of intravitreal anti-VEGF agents within the
past decade has revolutionized the treatment of nAMD, offering
patients improvements in vision previously unachievable. A number of anti-VEGF agents are available to treat nAMD, with aflibercept, ranibizumab, and bevacizumab being most commonly
used. Aflibercept and ranibizumab are licensed for use in nAMD,
but bevacizumab, originally developed for use in an oncology setting, is not approved for ocular use. The decision of which agent
to use will be driven by physician choice and influenced by factors such as availability and access, along with reimbursement
considerations.
Ranibizumab, a humanized monoclonal antibody fragment,
was the first anti-VEGF agent shown to improve VA in patients with
nAMD.15‒17 Regulatory approval for the monthly 0.5 mg dose was
granted on the basis of the MARINA16,18,19 and ANCHOR15,20 study
data, which showed mean gains of 7–11 letters over 12 months.
The newest agent, aflibercept, is a fusion protein21,22 capable of
binding strongly to VEGF-A with 1:1 stoichiometry1,21 and also to
PlGF. The licence for intravitreal aflibercept injections (IVT-AFL)
was granted based on the VIEW 1 and VIEW 223 studies, which
demonstrated equivalent efficacy to ranibizumab, with a less frequent dosing schedule (8-weekly, after 3 initial monthly doses).23
The duration of the biological activity of individual anti
VEGF agents may be different and may influence their suitability for different treatment regimens. Studies demonstrate a mean
duration of intraocular VEGF suppression of 70.5 days with IVTAFL,24 offering the potential for extended treatment intervals.
Management of Neovascular AMD with AntiVEGF Agents: Reactive versus Proactive Regimens
Fixed proactive treatment regimens (eg, monthly injections)
have been shown to have great potential to improve and maintain VA.15,16,23,25‒27 However, adherence to monthly treatment regimens may be difficult to maintain, especially in self-pay markets
such as Asia-Pacific countries where the high costs of anti-VEGF
agents, such as IVT-AFL and ranibizumab, may be a significant
financial burden for patients. Moreover, monthly visits are unrealistic for most patients, who often rely on their family members to
bring them to the clinic. Additionally, any intraocular anti-VEGF
injection carries a potential risk of ocular (eg, inflammation, increased intraocular pressure, and endophthalmitis) and theoretical
systemic (eg, cardiovascular) side effects.28,29 For these reasons,
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2 alternative treatment strategies—pro re nata (PRN; as needed)
and treat-and-extend—have been trialled in an attempt to reduce
treatment burden.
PRN as a Reactive Approach
The PRN regimen has been extensively used in the clinic as
a means of minimizing injection frequency while aiming to maintain the best possible visual outcomes.25‒27,30,31 In principle, a PRN
regimen involves frequent (monthly) monitoring, with treatment
given only when patients show symptomatic disease.
In studies of ranibizumab for the treatment of nAMD, reducing injection frequency by using PRN treatment regimens
has led to variable outcomes, with mean VA gains of 2.3‒11.1
letters.25‒27,30,32‒34 In the HARBOR25,32 study, which evaluated the
efficacy of ranibizumab with a monthly or PRN regimen (with
strict monitoring criteria), visual outcomes of the PRN arms were
similar to the monthly arms of the study and to those seen in pivotal clinical trials (MARINA, ANCHOR)15,16,18‒20 that followed a
monthly treatment schedule.
Additionally, 1-year results from the CATT study26 show
that a ranibizumab PRN regimen, following strict monitoring and
retreatment criteria, was equivalent to a monthly regimen, with
patients gaining a mean of 8.5 and 6.8 letters, respectively. Similarly, the IVAN study demonstrated similar visual outcomes between a monthly and PRN dosing regimen (mean gains of 5.5 and
3.5 letters, respectively)35,36; however, the PRN regimen used was
atypical, in that patients requiring retreatment were given a new
initial cycle consisting of 3 monthly injections (overall average of
18 treatments in 2 years).35,36 In the SAILOR33 study, which used
a PRN regimen based on quarterly monitoring visits after 3 initial
doses, there was a mean gain of only 2.3 letters. Moreover, improvements in visual and anatomical outcomes achieved during
an initial monthly treatment period (typically 3 monthly doses)
often decline when patients transition to a PRN regimen.31,33,37
Taken together, the results from these studies suggest that only
PRN regimens with frequent monitoring and strict retreatment
criteria can achieve the visual outcomes similar to those seen with
monthly dosing.
As-needed regimens are even less likely to be effective in
normal clinical practice, where the monitoring requirements and
retreatment criteria used are nearly always less stringent than in
a clinical trial setting. Indeed, there is growing evidence that in
“real life” patients are typically not monitored monthly and correspondingly VA outcomes are poor, with a loss of 1–3.2 letters
after 4.3–5.1 injections at 12 months.38‒41
Several factors contribute to suboptimal PRN monitoring
frequency in the clinic. In the first instance, there is generalized
confusion and lack of clarity about the regimen itself and therefore some clinics do not mandate monthly visits. Furthermore, in
clinics that do schedule monthly visits, adherence can be problematic because patients do not see the value of visiting every
month when they only receive treatment on some occasions. Additionally, poor adherence to re treatment criteria and delays between treatment schedule and administration can also contribute
to the poor visual outcomes associated with PRN.
Treat-and-Extend as a Proactive Approach
Recently, the proactive treat-and-extend regimen has
emerged as a practical and effective alternative method of reducing the treatment burden without negatively affecting visual and
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Asia-Pacific Journal of Ophthalmology • Volume 0, Number 0, Month 2017
anatomical outcomes. With treat-and-extend, the patient receives
treatment at every visit; however, the interval between visits is
gradually increased once stabilization of the disease is achieved.
A nAMD retrospective study by Oubraham et al42 compared
the efficacy of anti-VEGF therapy (ranibizumab) administered via
either a treat-and-extend or PRN regimen. Visual acuity gains at
12 months were higher in the treat and extend arm compared with
the PRN arm (10.8 versus 2.3 letters, respectively), with patients
in the former receiving a mean of 7.8 versus 5.2 injections.42
Switching from a PRN to a treat-and-extend regimen has
also been shown to improve VA (by a mean of 3 letters) while
reducing the number of clinic visits, albeit with a greater number
of injections (0.76 vs. 0.47 per month).43 In addition, a comparative case series of treatment naive patients reinforced the idea
that a treat-and-extend regimen is often associated with improved
visual outcomes when compared with a PRN regimen.44 In this
study, patients switching from a PRN to a treat-and-extend regimen saw an increase in visual acuity from 0.49, during the PRN
maintenance phase (mean duration of 17 months), to 0.55 and
0.56 at 6 and 12 months, respectively.44
Results from the LUCAS45 study showed good outcomes (52
weeks) for treat-and-extend in the management of nAMD, with
patients gaining a mean of 8.2 letters over 8 treatments with ranibizumab.45 Similar visual gains (a 10–11 and 8–11 letter gain
from baseline at 12 and 24 months, respectively) were reported
in the ATLAS46 study, in which IVT-AFL was administered following a treat-and-extend regimen in patients with nAMD, with
a mean of 13.9 injections given over the course of 2 years (mean
of 8 injections at 12 months and an additional 5.9 by the end of
month 24).46 Other evaluations of the treat-and-extend approach
as an alternative to PRN and fixed regimens have reported variable outcomes, with mean 12-month gains in VA ranging from 3
to 16.2 letters,47‒52 with a mean number of 8–9 injections.47‒51 The
variability in outcomes seen in these studies could be attributed to
a number of factors, including differences in the anti VEGF drugs
used (ranibizumab, bevacizumab) and baseline VAs. Moreover,
different interpretations of the treat-and-extend regimen could
have influenced the results and highlight the need for guidance on
implementation of such an approach. Nevertheless, the results of
these studies confirm the potential for treat-and-extend to provide
the visual benefits achieved by fixed monthly dosing in pivotal
clinical trials. More recently, a study (n = 85) in patients with
nAMD treated with aflibercept according to the label (fixed bimonthly regimen for the first 12 months after 3 initial monthly
injections, followed by treat-and-extend), reported a gain of 7.2
and 8.7 at month 12 and month 18, respectively.53 These improvements were associated with a corresponding improvement in the
median near VA at 12 months—12 points at baseline to 5 points at
12 months—a result that was maintained at month 18.53
In the next section, we propose guidelines for the implementation of a treat-and-extend regimen using IVT-AFL in the AsiaPacific region to optimize visual outcomes and minimize burden
in nAMD. The scope of these guidelines is limited to the application of IVT-AFL in the treatment of nAMD and does not include
recommendations for other commonly used anti-VEGF agents.
Materials and Methods
An expert panel comprising the authors and 3 additional
international medical retina specialists met in Tokyo, Japan, to
Treat-and-Extend IVT-AFL for nAMD
discuss the application of IVT-AFL in the treatment of nAMD in
the Asia-Pacific region. The following regions and countries were
represented: Hong Kong, Indonesia, Korea, Malaysia, Singapore,
and Taiwan.
The main aim of the meeting was to evaluate current clinical
practice and consider how a treat-and-extend approach could be
implemented to facilitate optimal outcomes. A consensus algorithm for the use of IVT-AFL with a treat-and-extend approach
is presented below. It should be noted that the licensed posology
for IVT-AFL is stated in months. However, as most clinics are set
up using weekly rather than monthly schedules, the dosing guidelines provided in this manuscript are given in weeks rather than in
months. For example, “8-weekly” (q8) dosing is considered to be
equivalent to “every other month” dosing.
Results
Initiation of Treatment
Treatment should start with 3 mandatory 4-weekly (q4) injections followed by extension to a q8 interval.
This initial dose schedule is simple, predictable, and familiar
to both physicians and patients, as it is used routinely in the clinic.
As the initial response to anti VEGF is exponential, it is important
to prime patients with sufficient IVT-AFL to bring the disease under control as quickly as possible to optimize visual gains. Results
from clinical trials support the use of 3 initial doses. Currently,
there is no evidence that supports omitting the 3 initial doses and
adopting a treat-and-extend regimen from the outset.
Extension
After the initial period (3 monthly injections with IVT-AFL),
patients meeting the extension criteria can have their treatment interval extended by 4 weeks at a time, with a maximum treatment
interval of 12 weeks in patients with inactive disease.
The goal of the extension period is to find the optimal treatment interval at which there is maximum control of disease activity and stabilization of VA with minimum treatment burden.
Current treat-and-extend regimens extend the treatment interval by 2 weeks; however, as the VIEW studies showed that patients who received q8 treatment in year 1 (after 3 initial monthly
doses) had similar visual outcomes to those treated monthly, an
immediate extension to 8 weekly dosing seems reasonable.25 Although there are no data to support treat-and-extend per se, the
VIEW1 study provided robust data on a modified quarterly dosing (minimum dosing every 12 weeks with interim as needed
monthly injections) supporting extension to 12-week intervals in
year 2 (91–92% of patients maintained visual gains at the end
of year 2). Therefore, it may be possible to extend the treatment
interval up to this point on an individual basis. Additionally, studies of intraocular VEGF suppression show a mean duration of
VEGF suppression of 70.5 days with IVT-AFL,24 thus facilitating
extended treatment intervals.
Extending the treatment interval in 4-week increments has
advantages for patients (in terms of treatment costs) and the clinic
(in terms of scheduling visits) compared with the alternative 2
weekly increments used by existing treat-and-extend regimens.
For a patient responding well and having their treatment interval extended at the earliest opportunity, the recommended treatment approach would result in the following injection schedule
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Koh et al
Asia-Pacific Journal of Ophthalmology • Volume 0, Number 0, Month 2017
(weeks): 0–4–8–16–24–36–48, with 7 mandatory injections in
total given in the first year of treatment (Fig. 1). This number of
treatments is consistent with most PRN studies showing acceptable visual outcomes at year 1 and should not be deemed excessively high.
Assessment Criteria
Criteria for extending treatment should be easy to follow and
be based on the absence of disease activity, as indicated by stable
vision, a dry retina, or stable retinal thickness.
As a general rule, vision is considered stable in the absence
of a change of at least 5 letters between 2 consecutive visual acuity measurements. Additionally, retinal thickness is considered
stable if there is less than a 50 µm increase from the thinnest
macular measurement on optical coherence tomography.
Persistent subretinal or intraretinal fluid should not be tolerated. Existing treatment intervals should be maintained if persistent fluid is present.
Some level of physician discretion is required to differentiate
intraretinal cysts from other types of fluid, as intraretinal cysts
may not necessarily indicate activity but may result from cystoid
degenerative changes.
With regard to retinal pigment epithelium detachment, the
lesion may be considered stable if no change has been demonstrated on 2 consecutive visits.
Provided these criteria are met, the treatment interval may
be extended.
The presence of hard exudates and lipids, along with subjective symptoms such as visual distortion, should not be included as
assessment criteria because they are considered too variable and
subjective in the monitoring of nAMD patients.
Reduction of Treatment Interval
If criteria for extension of the treatment interval are not met,
the treatment interval should be reduced by 4 weeks. The treatment interval should be reduced by 4 weeks if there is new hemorrhage or loss of visual acuity (≥5 letter drop).
In practical terms, if a patient has stable disease with q8 but
not 12-weekly (q12) treatment, the treatment interval should be
initially reduced to q8. If the disease remains unstable, the treatment interval should be further reduced to q4.
In the case of a severe recurrence of disease activity, an instant
reduction to q4 intervals should be allowed as a rescue scenario,
even if the patient was previously being managed with q12 treatment. A severe recurrence is defined as a significant loss of VA (≥15
letters), a massive hemorrhage, or significant RPE detachment.
Stopping Treatment
Because nAMD is thought to be chronic and progressive,
treatment may be required indefinitely. However, it is reasonable to attempt to stop treatment in patients with inactive disease
who have completed at least 12 months of treatment given at 12
week intervals. The allowance to stop treatment in patients with
stable disease provides a mechanism by which over-treatment
and lifelong injections for the patient can be avoided. Once treatment is stopped, these patients should be monitored closely for
recurrences.
Stopping treatment after 72 weeks with appropriate followup (eg, quarterly monitoring) until the end of year 2 could be acceptable and would present minimal risk. The best-case scenario
in a patient with an optimal response would result in a total of 7
injections given in the first year of treatment and 4 injections in
the second year (Fig. 1).
Figure 1. Injection schedule for the recommended treatment approach in the first year of treatment.
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Asia-Pacific Journal of Ophthalmology • Volume 0, Number 0, Month 2017
Treat-and-Extend IVT-AFL for nAMD
Table 1. Comparison Between Treat-and-Extend and PRN Regimens
Treat-and-Extend
PRN
Proactive regimen
Guarantees minimum number of injections
Predictable injection schedule
Good long-term visual outcomes
Difficulty implementing treatment regimen in clinical practice
Confusion over scheduling
Limited evidence that supports the use of this regimen
Risk of under treatment if treat-and-extend is used without an initial
treatment period
Reactive regimen
Unpredictable injection schedule
Good long term visual outcomes only with strict monitoring and retreatment
criteria
Easy to implement in clinical practice (straightforward scheduling)
Monthly visits place a significant burden on patients and healthcare
professionals
Poor adherence to monitoring/retreatment criteria
Further Considerations
IVT-AFL treat-and-extend regimens in patients with nAMD.55,56
Further discussion and studies are necessary to assess the validity
of a treat-and-extend regimen for nAMD clinical subtypes that
respond differently to anti-VEGF agents.
Additional studies are necessary to address the validity of
treat-and-extend for the management of polypoidal choroidal
vasculopathy (PCV) and retinal angiomatous proliferation (RAP)
lesions. Treat-and-extend, with or without photodynamic therapy,
could be a useful regimen for managing sudden massive hemorrhages, which are a common feature in patients with PCV. However, the approach to the treatment of RAP lesions is challenging.
The high risk of recurrence in patients with RAP might suggest
that a proactive treatment strategy could be favored over a reactive
regimen. Nevertheless, a proactive strategy could be associated
with more frequent injections compared with a reactive regimen.
Additionally, it iis thought that more frequent injections could potentially increase the risk of development of geographic atrophy in
patients with RAP. Further analyses are required to clearly define
the appropriate treatment regimen for patients with RAP.
Acknowledgements
The authors take full responsibility for the scope, direction,
and content of the manuscript and have approved the submitted
manuscript. Medical writing assistance was provided by Porterhouse Medical Ltd and was funded by Bayer Pharmaceuticals.
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Discussion
These guidelines provide a suggested treat-and-extend protocol for use with IVT-AFL only. As previously indicated, other
anti-VEGF agents are in use in clinical practice across the AsiaPacific region; however, the specifics of a recommended treatment
protocol with these agents will be different to that outlined here.
Current anti-VEGF management of nAMD in the Asia-Pacific region relies on a fixed regimen in year 1, with the possibility of extending treatment in year 2. The majority of patients in
these self-pay markets are not receiving optimal eye care because
of poor treatment adherence and the high financial costs of antiVEGF treatment.54 A lack of disease understanding by the public
and policy makers, and limited access to diagnostic screening and
patient follow up, add to the problem.
Implementation of a proactive treat-and-extend regimen using IVT-AFL may help to address these issues by minimizing the
total number of clinic visits and injections per year, while preventing under-treatment by guaranteeing a minimum number of injections (Table 1). Therefore, we propose that such a regimen should
be considered as a suitable proactive treatment approach for the
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it relies on the ability of hospitals to schedule flexible appointments and to avoid confusion when scheduling visits (Table 1).
For this reason, we propose straightforward IVT-AFL treatand-extend guidelines that should be tested in a clinical setting.
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