Hindawi

Journal of Ophthalmology
Volume 2019, Article ID 9821509, 10 pages
https://doi.org/10.1155/2019/9821509

Research Article
Management of Wet Age-Related Macular Degeneration in Spain:
Challenges for Treat and Extend Implementation in Routine
Clinical Practice

A. Garcı́a-Layana ,1 J. Garcı́a-Arumı́ ,2 M. S. Figueroa,3 L. Arias Barquet ,4

J. M. Ruı́z-Moreno,5 L. Monclús-Arbona,6 and The Spanish AMD Multicenter Group7
1
Clı́nica Universidad de Navarra, Avenida de Pı́o XII 36, 31008 Pamplona, Spain
2
Hospital de la Vall d’Hebrón, Passeig de la Vall d’Hebrón 119-129, 08035 Barcelona, Spain
3
Vissum Madrid, Santa Hortensia 58, 28002 Madrid, Spain
4
Hospital de Bellvitge, C/ Feixa Llarga s/n, L’Hospitalet de Llobregat, 08907 Barcelona, Spain
5
Hospital Universitario Puerta de Hierro-Majadahonda, Joaquı́n Rodrigo, 2, 28222 Madrid, Spain
6
Bayer Hispania, S.L., Av. Baix Llobregat, 3-5, 08970 Sant Joan Despı́, Barcelona, Spain
7
IQVIA Information, Barcelona, Spain

Correspondence should be addressed to A. Garcı́a-Layana; aglayana@unav.es

Received 23 November 2018; Revised 6 March 2019; Accepted 19 May 2019; Published 30 September 2019

Academic Editor: Manuel S. Falcão

Copyright © 2019 A. Garcı́a-Layana et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Purpose. To ascertain wet AMD (wAMD) management patterns in Spain. Methods. A two-round Delphi study conducted through
a questionnaire-based survey designed from literature review and validated by an independent Steering Committee. Results.
Forty-nine retina specialists experienced in wAMD participated by answering the two-round study questionnaire. Retina
specialists are the main responsible for wAMD diagnosis and monitoring, including visits and associated procedures, with a
median time per visit of 15 minutes. Standard treatment strategies are based on anti-VEGF administration, including standard
loading dose administration followed by maintenance with aflibercept or ranibizumab (81% of patients). Although treat and
extend (T&E) dosing strategy is considered as optimal for wAMD management (78% of the panelists), the main routine healthcare
limitations (i.e., visits overload, reduced staff, short visit time, coordination issues, lack of facilities) conduct to self-defined
“flexible” strategies, based on T&E and pro-re-nata (PRN) protocols. Conclusion. Proactive treatment patterns (T&E) are the
preferred ones by the retina specialists in Spain. However, their proper implementation is difficult due to healthcare resource
limitations, as well as organisation and logistic issues. The use of anti-VEGF agents with longer duration of action could facilitate
the use of strict T&E approaches according to routine clinical practices.

1. Introduction Wet AMD (wAMD) has no cure even though an

appropriated treatment could delay disease progression,
Age-related macular degeneration (AMD) is a chronic, avoiding the negative impact of vision loss in the quality of
progressive, and severe disease of the central retina and is the life of these patients [5, 6]. According to the most recent
main cause of irreversible blindness in the Western world AMD guidelines [7, 8], the intravitreal administration of
and Asia-Pacific countries [1, 2]. Up to date, 8.7% of the antivascular endothelial growth factor agents (anti-VEGF)
worldwide population has AMD [3]. The wet form of the constitutes the standard of care for wAMD patients due to
disease is responsible for more than 90% of the severe central the promising results provided by these therapies during
visual acuity (VA) loss associated with AMD [4]. clinical development [9].
2 Journal of Ophthalmology

However, the success of anti-VEGF therapy is closely interested participants signed an agreement, committing to
linked to strict intravitreal treatment patterns [10] that seem answer both Delphi rounds (approximately 20 minutes each).
not to be properly addressed in routine clinical practice The access link to the questionnaire was emailed to each
[11, 12], conducting to poorer outcome results for wAMD participant, together with a personal access individually pro-
patients than the expected according to clinical trials vided in a separated email. All questions were designed to be
[13, 14]. During the first year of treatment, results in real answered considering the experience of each panelist according
world practice seem to be closer to those reported for each to their routine clinical practice. Questions focused on treat-
drug [11, 12]. However, during the second year, treatment ment strategy prioritization were rated by the panelists, and
dosing increases in “flexibility” due to the rise in the amount each rank level was converted into scoring punctuation,
of patients, stress of monthly assessments, and economic providing mean priority scores per option.
burden, having a negative impact on outcomes and be- In Spain, there are more than 300 hospitals with oph-
coming an especially relevant issue [11, 12]. thalmology service and more than 600 retina specialists ex-
Healthcare limitations are a reality in routine clinical perienced in the management of wAMD. Since the sample size
practice. However, strict management protocols should be for a Delphi panel depends on study objectives, available re-
considered mandatory to guarantee optimal results for sources, and panel nature (ranging from 10–15 for homoge-
wAMD patients, involving drug selection and dosing neous groups to several hundreds in heterogeneous groups
strategy [15]. In order to choose the most appropriate [19]), a sample of 50 retina specialists (a homogeneous group of
therapeutic approach, it is necessary to consider several healthcare professionals with different realities) was considered
factors including patient profile, disease characteristics, drug as enough for this study purpose, prioritizing those from the
access, healthcare resources available, management pro- biggest hospitals of the different Spanish regions. In addition,
tocols, and healthcare burden, among others [14, 16]. In this all participants had been previously involved in wAMD and
regard, a Delphi study was conducted to describe wAMD Delphi studies in Spain, being experienced not only in the
management in Spain based on anti-VEGF administration. disease, but in methodology [16].
Challenges, limitations, and preferences of the retina spe- The same study questionnaire was used in both rounds,
cialists were assessed to identify the most appropriate with minor adaptations, so that answers could be reviewed,
treatment and dosing strategies for these patients in routine rechecked, and confirmed, providing robustness to the final
clinical practice. study results. The first Delphi round was carried out in April
2017, and the second in June 2017. The results collected in
2. Methods the first round were discussed by the Steering Committee,
and some items were slightly reworded for clarification.
2.1. Study Design and Development. According to the study Aggregated results were provided to the panelists before the
objectives, a two-round Delphi methodology [16–18] was second Delphi round, where the empty questionnaire was
considered as the most appropriate due to its capability to resent to the participants to be responded (none of the
define answer consensus and ratification. An ad hoc study participants had access to their previous individual answers).
questionnaire was developed after an exhaustive literature Consensus was predefined as homogeneity or consistency of
search on wAMD management and anti-VEGF evidence, being opinions among experts and understood as a reduction of
analysed and validated by a Steering Committee conformed by answer dispersion between data provided in the first and
5 ophthalmologists with retina expertise, from 5 different second Delphi rounds.
Spanish centres. The questionnaire included a final set of 38
questions, comprising 4 main sections: (i) participant profile,
(ii) general management of wAMD, (iii) wAMD diagnosis, and 2.2. Result Analysis. A descriptive analysis was conducted
(iv) wAMD treatment. Treatment strategy options were cate- per outcome, providing number of responses (n) and per-
gorized as “strict” or “flexible” according to the agreement level centage (%), mean result, and standard deviation (SD). For
with the recommended patterns [7, 8] and product technical abnormal outcomes, median and confidence interval were
conditions [10]. Thus, strict pro-re-nata (PRN) would involve calculated. Results of the second round were used as the final
monthly monitoring and immediate on-demand treatment validated data of the study. Considering the nature of the
after loading dose, while strict treat and extend (T&E) would questions, as well as the different scoring systems used in the
involve regular preplanned treatment administration after study, consensus was reached with ≥60% of agreement per
loading dose administration, including progressive increase in item. Additionally, the dispersion in the answers was also
the injection periods. Flexible strategies were considered as considered, being considerably lower than in first-round
deviations of the standard strategies, mainly represented by an responses.
irregular monitoring and/or treatment of the patients and
attributable to routine clinical practice needs. 3. Results
The study questionnaire was designed to be filled online by
50 retina specialists selected according to the following criteria: 3.1. Participant Profile. A total of 49 retina specialists from
(i) ≥5 years in wAMD management in Spain and (ii) to be the all around Spain participated in both Delphi rounds. Mean
current responsible for wAMD management in the centre (SD) age of participants was 49 (7) years, and they accounted
(including treatment administration and follow-up). Main for a mean (SD) of 16 (6) years of experience in the wAMD
contact for study recruitment was conducted by email, and the patients’ management. Most participants (82%) were
Journal of Ophthalmology 3

frequently involved in ophthalmology clinical trials (mean initiation (three monthly injections), using as drug choice
(SD) 3.7 (2.7) trials per year). aflibercept in 40% of the patients, ranibizumab in 36%, and
bevacizumab in 23%.
According to the experience of the panelists, 94% (SD
3.2. Burden of wAMD Management in the Ophthalmology 5%) of patients would complete appropriately the loading
Services. wAMD management represents 25% (18) of the dose schedule.
ophthalmology visits in Spain, with a median time (P25–
P75) per visit of 15 minutes (10–15 minutes). This time
considers the average time per patient including treatment 3.4.2. Maintenance Therapy. Maintenance therapy was done
administration and other procedures, when needed, and with the same anti-VEGF agent used during the loading
excluding patient waiting time. phase period. During the first and second year, 81% of the
wAMD patients are usually referred to the retina spe- patients would be treated with aflibercept and ranibizumab
cialist by other medical doctors (40%), from the same centre (first year: 43% and 38; second year: 45% and 36%, re-
or related (i.e., ophthalmologists from primary care), as well spectively). The remaining proportion of patients was
as from the emergency units (32%). The retina specialist is treated with bevacizumab. No patients were treated with
the main responsible for disease diagnosis and patient sodium pegaptanib.
monitoring, being involved in all the procedures performed Overall, no major safety concerns were reported with
to the patient (except for microperimetry, taken by the anti-VEGF therapies, even when planned and used for a long
imaging technicians). Together with the retina specialist, the time. According to the experience of the participants, 15% of
specialty trainee is responsible for slit lamp fundus exami- the patients require to stop treatment (19% bevacizumab,
nation, fluorescein angiography, indocyanine green angi- 12% ranibizumab, and 10% aflibercept), mainly due to in-
ography (ICGA), optical coherence tomography (OCT), sufficient treatment response, other clinical criteria, and
angio-OCT, and fundus autofluorescence. According to the issues with patient follow-up (Figure 2(a)).
experience of the study participants, optometrists and nurses Moreover, around 23% of patients need to be switched to
usually provide support with Snellen and/or ETDRS (Early another agent (24% bevacizumab, 23% ranibizumab, and
Treatment Diabetic Retinopathy Study) tests even though 15% aflibercept), usually because of an insufficient response
they could, eventually, also provide support in other tasks to the initial treatment (Figure 2(b)). In these cases, the most
such as OCT, fluorescein angiography, angio-OCT, or frequent switch was to aflibercept or ranibizumab,
fundus autofluorescence. depending on the first drug used.
wAMD diagnosis is usually done by slit lamp fundus
examination (98%), OCT (94%), Snellen test (82%), and/or
3.4.3. Treatment Dosing Strategy. The most frequently re-
fluorescein angiography (85%) (Figure 1(a)). Except for
ported treatment regimens for wAMD patients were T&E
fluorescein angiography, these tests are frequently repeated
and PRN (Figure 3). During the first year, the planned
during follow-up visits, to check disease progression and to
maintenance dosing strategies were strict T&E and PRN,
assess treatment effectiveness, with a mean frequency of
whenever possible (Figure 3(a)). However, during the sec-
2 months (Figure 1(b)).
ond year, these strategies needed to be adapted to a defined
as “flexible” scheduling (Figure 3(b)).
3.3. Intravitreal Administration Procedure. Most of the According to the 39% and 37% of the panelists, the
panelists (63%) reported to have specific protocols for treatment strategies used during the first and second year,
wAMD management, being mandatory in 10% of cases. respectively, would not be considered as optimal. In the
National SERV (Sociedad Española de Retina y Vitreo) opinion of the 78% of participants, the most appropriate
guidelines [8] were considered as key reference documents treatment strategy for the whole wAMD treatment should be
for 55% of the participants, while EURETINA guidelines [7] strict T&E approach (Figures 3(c) and 3(d)), with in-
were mainly considered as supportive references for wAMD dependence of the patient profile or lesion type. The only
management (51% of the panelists). exception would be identified in case of adverse events risk,
Intravitreal administration by one-stop visit was possible where PRN would be considered the most appropriate
in 57% of participant centres. Main limitations to conduct approach (Table 1).
this practice were due to lack of staff (57%), short visit time
(52%), limited access to the drug during the visit (52%), and
3.5. Challenges and Limitations for wAMD Management on
facility issues (52%). Access to anti-VEFG drugs was not
Routine Clinical Practice. According to the experience of the
identified as issue, with the exception of sodium pegaptanib,
study participants, treatment choice would be conditioned
restricted in 71% of the participant centres.
by healthcare overload (understood as lack of agenda for an
appropriate patient monitoring according to the strict
3.4. wAMD Treatment Pathways dosing strategy selected), lack of staff, healthcare
coordination issues, and prolonged waiting time for
3.4.1. Loading Dose. With independence of the patient intravitreal injection administration (Figure 4). In addition,
profile or lesion type, most of the panelists (92%) referred the the main limitations for an optimal treatment strategy
use of a standard loading dose for anti-VEGF treatment achievement would be mainly related with organisational
4 Journal of Ophthalmology

98%
Slit lamp fundus examination
88%
Optical coherence 94%
tomography (OCT) 98%
82%
Snellen test
84%
65%
Fluorescein angiography
16%
57%
Fundus autofluorescence
29%
51%
Angio-OCT
41%
ETDRS (Early Treatment 47%
Diabetic Retinopathy Study) 39%
Indocyanine green 27%
angiography (ICGA) 16%
2%
Microperimetry
2%
0% 20% 40% 60% 80% 100%
Participant answers (%)

First visit
Follow-up
(a)
Optical coherence 7.95
tomography (OCT)

Snellen test 7.98

Slit lamp fundus examination 8.08

ETDRS (Early Treatment 8.14

Diabetic Retinopathy Study)

Fundus autofluorescence 12.25

Indocyanine green 13.50

angiography (ICGA)

Fluorescein angiography 18.88

Angio-OCT 24.00

Microperimetry 24.00

0 5 10 15 20 25 30 35 40
Time period from first visit (weeks)
(b)

Figure 1: Use of diagnosis tests in routine clinical practice of the participant centres (n � 49), in patients with wAMD in Spain (multiple-
choice question): (a) diagnosis tests; (b) time interval from wAMD diagnosis to first visit.

problems, confusion over scheduling, and healthcare re- However, as it was evidenced in previous studies [13, 14],
source availability (Figure 5). these good practices seem not to be reflected on outcomes,
achieving suboptimal results compared with the expected by
4. Discussion the anti-VEGF clinical trials [12, 20–22]. The main reason
for these different results could be the difference in the
According to the main clinical guidelines and wAMD management patterns among the strict injection protocols
management protocols [7, 8], anti-VEGF therapies are the used in clinical trials and the adapted injection patterns used
gold standard for wAMD treatment, and, actually, these are in routine clinical practice [16, 23–25] and identified as
the therapies used on routine clinical practice in Spain. “flexible” in our study.
Journal of Ophthalmology 5

5.4
Insufficient response 5.2
4.9
5.4
Other clinical criteria 4.5
4.7
3.6
Patient loss 4.3
4.1
3.9
Patient’s request 3.2
3.4
1.2
Systemic adverse event 1.5
1.5
1.0
Ocular adverse events 1.1
1.1
0.7
Centre protocol 0.6
0.7
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0
Prioritisation ranking (mean score)
Bevacizumab (Avastin®)
Ranibizumab (Lucentis®)
Aflibercept (Eylea®)
(a)

5.0
Insufficient response 3.1
3.4

1.6
Patient’s request 0.8
0.9

1.3
Sistemic adverse event 0.9
0.8

1.2
Ocular adverse events 0.7
0.7

0.9
Service needs 0.4
0.5
0.0 1.0 2.0 3.0 4.0 5.0
Prioritisation ranking (mean score)
Bevacizumab (Avastin®)
Ranibizumab (Lucentis®)
Aflibercept (Eylea®)
(b)

Figure 2: Prioritization made by the retina specialists regarding the main reasons for (a) anti-VEGF treatment dropout (7 points score) and
(b) anti-VEGF switch (5 points score).

In general terms, according to the information provided A common fact among healthcare centres is that the
by the study panelists, in Spain, wAMD management is main responsible for wAMD management is the retina
mainly done according to the national and international specialist, involved from diagnosis to long-term moni-
retina guidelines (SERV and EURETINA) [7, 8] even though toring, and including standard visits and associated
adapted to specific management protocols that could vary procedures. Retina specialist tasks are supported by
according to the healthcare resources and limitations of each specialist trainees and, when available, by other health-
centre and that could conduct to those “flexible” strategies. care staff such as nurse or optometrists. This complete
6 Journal of Ophthalmology

3.1 3.9
T&E strict 3.3 T&E flexible 3.8
3.2 3.7
3.3 3.0
T&E flexible 3.2 T&E strict 2.8
3.0 2.9
2.5 2.7
PRN flexible 2.5 PRN flexible 2.9
2.2 2.5
2.6 2.0
PRN strict 2.2 PRN strict 1.4
2.2 1.7
1.6 1.0
Fixed doses 1.7 Fixed doses 0.9
2.2 1.4
1.6 0.8
New loading dose 1.2 New loading dose 0.4
1.2 0.6
0.0 1.0 2.0 3.0 4.0 5.0 6.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0
Prioritisation ranking (mean score) Prioritisation ranking (mean score)

Bevacizumab (Avastin®) Bevacizumab (Avastin®)

Ranibizumab (Lucentis®) Ranibizumab (Lucentis®)
Aflibercept (Eylea®) Aflibercept (Eylea®)

(a) (b)
4.3 4.2
T&E strict 4.5 T&E strict 4.2
4.4 4.2
3.8 2.7
PRN strict 3.2 PRN strict 2.3
3.0 2.4
2.3 2.6
T&E flexible 2.0 T&E flexible 2.3
2.3 2.4
1.6 1.5
Fixed doses 1.5 PRN flexible 1.3
2.0 1.3
1.2 1.2
PRN flexible 1.0 Fixed doses 1.1
1.0 1.3
1.3 0.8
New loading dose 0.8 New loading dose 0.4
1.0 0.5
0.0 1.0 2.0 3.0 4.0 5.0 6.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0
Prioritisation ranking (mean score) Prioritisation ranking (mean score)

Bevacizumab (Avastin®) Bevacizumab (Avastin®)

Ranibizumab (Lucentis®) Ranibizumab (Lucentis®)
Aflibercept (Eylea®) Aflibercept (Eylea®)

(c) (d)

Figure 3: Treatment strategies prioritized by the retina experts (6 points score) (a) according to use during the first year of treatment,
(b) according to use during the second year of treatment, (c) when considered as optimal for the first year of treatment, and (d) when
considered as optimal for the second year of treatment.

Table 1: Panelists opinion (n � 49) regarding anti-VEGF treatment strategies considered as optimal for wAMD management according to
patient profile and lesion type in Spain.
PRN strict PRN flexible Fixed dose T&E strict T&E flexible No treatment
Patient characteristics; opinion, n (%)
Very low initial VA 12 (24%) 6 (12%) 3 (6%) 25 (51%) 7 (14%) 6 (12%)
Good initial VA 10 (20%) 1 (2%) 9 (18%) 34 (69%) 3 (6%) 0 (0%)
Aged patient 7 (14%) 2 (4%) 9 (18%) 24 (49%) 13 (27%) 1 (2%)
Single eye 14 (29%) 0 (0%) 11 (22%) 34 (69%) 1 (2%) 0 (0%)
Adverse events risk 16 (33%) 9 (18%) 1 (2%) 12 (24%) 10 (20%) 2 (4%)
Centre accessibility (distance) 4 (8%) 4 (8%) 7 (14%) 26 (53%) 10 (20%) 0 (0%)
Protocol/centre guidelines 12 (24%) 3 (6%) 8 (16%) 27 (55%) 10 (20%) 0 (0%)
Patient cost 13 (27%) 10 (20%) 4 (8%) 15 (31%) 11 (22%) 1 (2%)
Disease characteristics (type of lesion); opinion, n (%)
Neovascularisation type 1 10 (20%) 0 (0%) 8 (16%) 37 (76%) 5 (10%) 0 (0%)
Neovascularisation type 2 13 (27%) 0 (0%) 10 (20%) 37 (76%) 2 (4%) 0 (0%)
Neovascularisation type 3 15 (31%) 0 (0%) 13 (27%) 33 (67%) 3 (6%) 0 (0%)
VA: visual acuity.

involvement of the retina specialist in the patient management, In terms of treatment, the standard management of the
although an advantage in terms of healthcare assistance quality patients is anti-VEGF therapies, according to the recom-
for the patient, represents an important overload for the mended practices [7, 8]. The main drugs used in routine
specialist, that finally conduct to a limitation for an optimal clinical practice, considering all the treatment pathway, are
disease management and one-stop procedures. aflibercept and ranibizumab, for both, loading dose and
Journal of Ophthalmology 7

Healthcare overload 49% 35% 8% 4% 4%

Lack of general staff 22% 45% 14% 10% 8%

Healthcare coordination issues 24% 41% 14% 16% 4%

Prolonged waiting times from visit to
treatment administration 39% 22% 14% 14% 10%

Lack of time per visit 18% 43% 29% 6% 4%

Lack of supporting staff 24% 33% 20% 10% 12%

Lack of adequate equipment 18% 31% 16% 20% 14%

Inadequate facilities for intravitreal
administration 18% 29% 16% 14% 22%

Treatment cost 10% 33% 29% 24% 4%

Limited space for visit 6% 29% 29% 24% 12%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Participant answers (%)
Very high Low
High Very low
Medium
Figure 4: Impact of different healthcare factors on treatment choice, according to the routine clinical practice of the 49 retina specialists
participating in the Delphi study.

100%
11% 13% 13% 13%
90% 17% 18%

80%
9%
17% 28% 25% 25%
70% 31%
Participant answers (%)

60%
36%
50%

40% 50%

30% 61% 63% 63%

56%
20% 36%
10% 17%
0%
Year 1 Year ≥ 2 Year 1 Year ≥ 2 Year 1 Year ≥ 2
Bevacizumab (Avastin®) Ranibizumab (Lucentis®) Aflibercept (Eylea®)

Organisational problems Economic issues

Patient needs Centre protocol
Lack of staff
Figure 5: Main limitations for the establishment of the optimal therapeutic strategy in routine clinical practice, according to the opinion and
experience of the 49 retina specialists participating in the Delphi study.

treatment maintenance, and being considered as the most panelists, although no significant issues are evidenced for
appropriated for all patient’s management, with in- the loading dose (successful administration in more than
dependence of the patient profile or the type of lesion. 90% of the patients), important management issues for long-
According to the information provided by the study term schedules are identified, being mainly related with
8 Journal of Ophthalmology

healthcare resource limitations, as well as their own stop management models, and appropriate treatment in-
healthcare overload and staff restrictions. jection facilities, overall leading to long waiting periods from
As it was anticipated in 2014 [16] and aligned with the visit to injection administration (healthcare overload). Then,
available evidence [16, 24, 26, 27], most of the retina spe- conducting to “flexible” management strategies for wAMD
cialists participating in the study (78%) agreed in the aim for patients agreed as not effective enough.
using T&E strategies in their routine clinical practice. Although these are the main issues identified in the Spanish
However, healthcare reality and the limited resources context, they are not exclusive from Spain [25]. Other countries
available conduct to a need for self-defined “flexible” have also identified similar issues, agreeing in the need for
strategies that could be a critical issue for achieving optimal investment in wAMD management [11, 30], with focus on better
healthcare results in routine clinical practice. coordination among healthcare teams, workload reduction for
Traditionally, reactive regimens for wAMD management retina specialists by increasing the involvement of optometrists
were the standard procedures in Spain [8]. Strict PRN pattern or nurses in the management of wAMD patients, favouring one-
was the reference protocol used in most centres even though stop model and the regular patient follow-up, with the aim of
not to be realistically conducted [12, 16]. Strict PRN protocols improving healthcare results.
are linked to regular monthly visits, where disease monitoring Apart from the need for resources optimisation, treat-
is mandatory, and only in case of disease progression, the ment patterns could be supported by the use of drugs that
patient would be retreated, ideally in a one-stop visit [8]. favour timings adaptation and minimising the need for
Different studies have evidenced that this PRN model is dif- changing routine daily clinical practice and associated in-
ficult to achieve in routine clinical practice due to the limi- vestment. In this regard, the use of drugs with a VEGF
tations that the ophthalmology routine exercise have [12, 16]. suppression longer than one month could have the potential
Actually, with a quarter of the retina specialist workload fo- to better suit to a proactive T&E regimen with a minor
cused on wAMD and a median of 15 minutes for patient care impact on resources [24]. These therapeutic options could
(including injection time), it is really difficult to achieve a strict potentially facilitate the appropriate implementation of strict
PRN dosing strategy. In addition, considering that the most T&E regimens that could improve treatment outcomes in
frequently used monitoring tests in Spain (slit lamp fundus routine clinical practice [27], achieving similar responses to
examination, OCT, and Snellen test) would be conducted with those reported in the clinical trials [27, 29, 31] and agreeing
a mean frequency of 8 weeks, it seems clear that the strict PRN with the opinion and experience of the study panelists re-
protocol could not be appropriately conducted in routine garding anti-VEGF choice.
clinical practice, as was confirmed by the panelists. The results of the present study showed that the
Recent studies indicate that a decrease in monitoring and healthcare reality in Spain has evolved from previous studies
injection frequency could not necessarily be related to conducted in this country [12, 16], and it is similar to that
negative impact on wAMD outcomes [24]. Then, strict PRN observed in other countries despite the limitations of a
protocols could not be cornerstones for a successful wAMD Delphi study of these characteristics. Data provided in the
management. Depending on disease progression and study reflected the experience of 49 retina specialists rep-
treatment response, the interval between injections could be resenting their routine activity in the management of wAMD
progressively increased and even treatment could be com- patients in Spain. All data were collected based on an ac-
pletely stopped in case of disease stabilisation for more than curate literature search and reviewed by a Steering Com-
12 months [26]. In this regard, T&E strategies could be mittee formed by reference Spanish retina specialists that
identified as optimal for wAMD management, in agreement confirmed results coherence according to their own expe-
with the opinion of our panelists. rience and in agreement with data reported in the previous
T&E regimen could be defined as an individualized Delphi study performed in Spain [16], showing some im-
proactive dosing strategy, whose driver is the adaptation of provement in the patient’s management due to the adoption
the treatment regimen and visits interval according to disease of proactive treatment strategies such as T&E and the
activity, with the aim to achieve optimal outcomes [24, 26], authorisation of new therapeutic agents in the wAMD
similar to that provided with regular fixed dosing regimens market. In addition, data were also confirmed by Delphi
[28, 29], but usually with a lower need for healthcare re- participants that validated the results provided in the first
sources. However, the success of this strategy depends on the round by means of the answers of the second round.
ability to perform the preplanned visits and effective treat- Although data provided in this study should be con-
ment injection schedule, which is the main challenge in our firmed by clinical charts and visit registries from healthcare
current routine clinical practice and the main reason for centres, it seems clear that wAMD management is not
defining this strategy as “flexible” for most of the panelists. optimal in most healthcare centres even though, in most
Delphi results evidenced many limitations that need to cases, there exists the initiative to adopt proactive models for
be addressed regarding wAMD management in Spain. In wAMD management. The use of agents allowing longer
addition to the retina specialists overload and the lack of treatment intervals could help, but the results of this study
supporting staff that could be useful to optimise healthcare indicate that additional organisational changes and re-
professional resources, the management of wAMD patients sources reallocation beyond financial investment could be
is affected by structural and organisational issues of the necessary, in order to provide a real improvement in the
centres, making it difficult to schedule and conduct regular management of wet AMD patients, favouring the effective
preplanned administration of intravitreal injections, one- implementation of a T&E strategy.
Journal of Ophthalmology 9

5. Conclusions Hispania S.L. Logistics. Coordination and medical writing

have been conducted by IQVIA.
Anti-VEGF administration is the cornerstone for wAMD
treatment, based on a loading dose followed by a long-term
treatment until disease stabilization. Traditionally, reactive
References
treatment regimens were the standard procedure for wAMD [1] S. Resnikoff, D. Pascolini, D. Etya’ale et al., “Global data on
management, usually focused on PRN dosing strategies. visual impairment in the year 2002,” Bulletin of the World
However, PRN regimen was linked to strict management Health Organization, vol. 82, no. 11, pp. 844–851, 2004.
protocols difficult to address in routine clinical practice, where [2] R. Kawasaki, M. Yasuda, S. J. Song et al., “The prevalence of
healthcare resources are limited. Organisational healthcare age-related macular degeneration in asians,” Ophthalmology,
limitations together with staff workload are the main reasons vol. 117, no. 5, pp. 921–927, 2010.
why neither monthly visit nor one-stop visits for immediate [3] W. L. Wong, X. Su, X. Li et al., “Global prevalence of age-
related macular degeneration and disease burden projection
retreatment could be conducted. Then, evolution to proactive
for 2020 and 2040: a systematic review and meta-analysis,”
treatment models (T&E) became a priority in this situation, The Lancet Global Health, vol. 2, no. 2, pp. e106–e116, 2014.
especially considering the potential advantages in terms of [4] Y. Chen, M. Bedell, and K. Zhang, “Age-related macular
appointment scheduling, healthcare resource management, degeneration: genetic and environmental factors of disease,”
and increasing the interval period between visits. Molecular Interventions, vol. 10, no. 5, pp. 271–281, 2010.
In this regard, as healthcare outcomes are linked to a [5] J. Mitchell and C. Bradley, “Quality of life in age-related
regular administration of the intravitreal therapy, mostly on macular degeneration: a review of the literature,” Health Qual
a proactive regimen basis, such as T&E, the use of drugs Life Outcomes, vol. 4, no. 1, p. 96, 2006.
allowing long administration intervals could contribute to [6] M. Yuzawa, K. Fujita, E. Tanaka, and E. Wang, “Assessing
the wAMD management optimisation in routine clinical quality of life in the treatment of patients with age-related
practice. In addition, optimal and preplanned drug ad- macular degeneration: clinical research findings and recom-
mendations for clinical practice,” Clinical Ophthalmology,
ministration frequencies could contribute to an improve-
vol. 7, pp. 1325–1332, 2013.
ment of the workload for retina specialists and the possibility [7] U. Schmidt-Erfurth, V. Chong, A. Loewenstein et al.,
for a regular one-stop administration of these therapies with “Guidelines for the management of neovascular age-related
a minimum impact on the centre’s resources. macular degeneration by the European society of retina
specialists (EURETINA),” British Journal of Ophthalmology,
Data Availability vol. 98, no. 9, pp. 1144–1167, 2014.
[8] Guı́as de Práctica Clı́nica de la SERV: Tratamiento de la
According to Delphi methodology, the study data were Degeneración Macular Asociada a la Edad (DMAE) Exudativa
collected from panelists’ answers in a specific study database. y Atrófica, January 2014, https://serv.es/publicaciones/guias-
This database would not be publicly available even though ad practica-clinica/.
hoc data or analysis could be provided upon request to the [9] J. W. Miller, “Age-related macular degeneration revis-
corresponding author. ited—piecing the puzzle: the LXIX edward jackson memorial
lecture,” American Journal of Ophthalmology, vol. 155, no. 1,
Conflicts of Interest pp. 1–35, 2013.
[10] European Medicines Agency (EMA), European Public As-
Drs. A. Garcia-Layana, J. Garcı́a-Arumı́, M. S. Figueroa, L. Arias sessment Report (EPAR), European Medicines Agency (EMA),
Barquet, and J. M. Ruı́z-Moreno report financed collaboration Amsterdam, Netherlands, 2017, https://www.ema.europa.eu.
as advisors for Bayer and Novartis. Drs. A. Garcia-Layana, M. S. [11] S. Sivaprasad, P. Hykin, U. Chakravarthy, A. Lotery,
M. McKibbin, and J. Napier, “A retrospective study of the
Figueroa, L. Arias Barquet, and J. M. Ruı́z-Moreno are also
real-life utilization and effectiveness of ranibizumab therapy
collaborating with Allergan. Dr. J. Garcı́a Arumı́ declares to be for neovascular age-related macular degeneration in the UK,”
also an advisor for Alcon, and Dr. M. S. Figueroa for Roche. Dr. Clinical Ophthalmology, vol. 10, pp. 87–96, 2016.
L. Monclús-Arbona is a staff of Bayer, Spain. [12] R. Casaroli-Marano, R. Gallego-Pinazo, C. T. Fernández-
Blanco et al., “Age-related macular degeneration: clinical
Acknowledgments findings following treatment with antiangiogenic drugs,”
Journal of Ophthalmology, vol. 2014, Article ID 346360,
The authors want to acknowledge the participation of the 49 6 pages, 2014.
panelists that filled the two rounds of the Delphi ques- [13] T. Wecker, C. Ehlken, A. Bühler et al., “Five-year visual acuity
tionnaire (S Abengoechea, M Abraldes, MS Alforja, JJ Araiz, outcomes and injection patterns in patients with pro-re-nata
F Armada, J Ascaso, JJ Barbón, E Basauri, F Cabrera, J treatments for AMD, DME, RVO and myopic CNV,” British
Campos, J Cañal, C Cava, E Cervera, LM Cordovés, J Crespı́, Journal of Ophthalmology, vol. 101, no. 3, pp. 353–359, 2016.
[14] S. Androudi, A. Dastiridou, N. Pharmakakis et al., “Guidelines
A Expósito, C Fernández, M Fernández, G Fernández, G
for the management of wet age-related macular degeneration:
Fernández-Baca, A Fernández-Vega, P Gili, B Goldaracena,
recommendations from a panel of Greek experts,” Advances
E Gutiérrez, M Lafuente, J Lavid, MI López, JA López, in Therapy, vol. 33, no. 5, pp. 715–726, 2016.
L López, N Martı́nez, JJ Martı́nez, J Montero, R Navarro, A [15] I. Mantel, “Optimizing the anti-VEGF treatment strategy for
Navea, AI Oca, V Poposki, E Rodriguez, E Rodriguez, M neovascular age-related macular degeneration: from clinical
Ruı́z, O Ruı́z, L Sararols, R Torres, P Udaondo, MA Zapata, trials to real-life requirements,” Translational Vision Science &
and J Zarranz). The study has been sponsored by Bayer Technology, vol. 4, no. 3, p. 6, 2015.
10 Journal of Ophthalmology

[16] A. Garcı́a-Layana, L. Arias, M. S. Figueroa et al., “A Delphi in real life: findings from the AURA study,” British Journal of
study to detect deficiencies and propose actions in real life Ophthalmology, vol. 100, no. 12, pp. 1623–1628, 2016.
treatment of neovascular age-related macular degeneration,” [31] J. Suleman, D. Ting, P. S. Severn, and S. Pushpoth, “Real-
Journal of Ophthalmology, vol. 2014, Article ID 595132, world data on intravitreal Aflibercept (Eylea) injection in
10 pages, 2014. patients with wet age-related macular degeneration,” In-
[17] C. Okoli and S. D. Pawlowski, “The Delphi method as a re- vestigative Ophthalmology & Visual Science, vol. 56, no. 7,
search tool: an example, design considerations and applica- 2015.
tions,” Information & Management, vol. 42, no. 1, pp. 15–29,
2004.
[18] N. Dalkey and O. Helmer, “An experimental application of
the Delphi method to the use of experts,” Management Sci-
ence, vol. 9, no. 3, pp. 458–467, 1963.
[19] G. J. Skulmoski, F. T. Hartman, and J. Krahn, “The Delphi
method for graduate research,” Journal of Information
Technology Education: Research, vol. 6, pp. 1–21, 2007.
[20] V. Chong, “Ranibizumab for the treatment of wet AMD: a
summary of real-world studies,” Eye, vol. 30, no. 2,
pp. 270–286, 2016.
[21] F. G. Holz, R. Tadayoni, S. Beatty et al., “Multi-country real-
life experience of anti-vascular endothelial growth factor
therapy for wet age-related macular degeneration,” British
Journal of Ophthalmology, vol. 99, no. 2, pp. 220–226, 2015.
[22] A. Wolf and A. Kampik, “Efficacy of treatment with ranibi-
zumab in patients with wet age-related macular degeneration
in routine clinical care: data from the COMPASS health
services research,” Graefe’s Archive for Clinical and Experi-
mental Ophthalmology, vol. 252, no. 4, pp. 647–655, 2014.
[23] T. A. Ciulla, F. Huang, K. Westby, D. F. Williams, S. Zaveri,
and S. C. Patel, “Real-world outcomes of anti-vascular en-
dothelial growth factor therapy in neovascular age-related
macular degeneration in the United States,” Ophthalmology
Retina, vol. 2, no. 7, pp. 645–653, 2018.
[24] P. Lanzetta, The Vision Academy Steering Committee, and
A. Loewenstein, “Fundamental principles of an anti-VEGF
treatment regimen: optimal application of intravitreal anti-
vascular endothelial growth factor therapy of macular dis-
eases,” Graefe’s Archive for Clinical and Experimental Oph-
thalmology, vol. 255, no. 7, pp. 1259–1273, 2017.
[25] R. Casaroli-Marano and M. Roura, “Disponibilidad de
recursos para pacientes con degeneración macular asociada a
la edad de tipo húmedo—estudio optimal,” Archivos de la
Sociedad Española de Oftalmologı́a, vol. 88, no. 8, pp. 307–312,
2013.
[26] W. Amoaku, K. Balaskas, T. Cudrnak et al., “Initiation and
maintenance of a treat-and-extend regimen for ranibizumab
therapy in wet age-related macular degeneration: recom-
mendations from the UK retinal outcomes group,” Clinical
Ophthalmology, vol. 12, pp. 1731–1740, 2018.
[27] A. Koh, P. Lanzetta, W. K. Lee et al., “Recommended
guidelines for use of intravitreal aflibercept with a treat-and-
extend regimen for the management of neovascular age-re-
lated macular degeneration in the asia-pacific region: report
from a consensus panel,” Asia-Pacific Journal of Ophthal-
mology, vol. 6, no. 3, pp. 296–302, 2017.
[28] C. C. Wykoff, W. C. Ou, D. M. Brown et al., “Randomized trial
of treat-and-extend versus monthly dosing for neovascular
age-related macular degeneration,” Ophthalmology Retina,
vol. 1, no. 4, pp. 314–321, 2017.
[29] F. C. DeCroos, D. Reed, M. K. Adam et al., “Treat-and-Extend
therapy using aflibercept for neovascular age-related macular
degeneration: a prospective clinical trial,” American Journal of
Ophthalmology, vol. 180, pp. 142–150, 2017.
[30] F. G. Holz, R. Tadayoni, S. Beatty et al., “Key drivers of visual
acuity gains in neovascular age-related macular degeneration