Download Use of Corticosteroids in the Treatment of Patients With Diabetic

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C L I N I C A L
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Use of Corticosteroids in the Treatment of Patients With
Diabetic Macular Edema Who Have a Suboptimal Response
to Anti-VEGF: Recommendations of an Expert Panel
Carl D. Regillo, MD; David G. Callanan, MD; Diana V. Do, MD; Howard F. Fine, MD, MHSc;
Nancy M. Holekamp, MD; Baruch D. Kuppermann, MD, PhD; Michael A. Singer, MD; Rishi P. Singh, MD
EXPEDITED
REVIEW
BACKGROUND AND OBJECTIVE: Guidance on the use
of corticosteroids in the treatment of diabetic macular
edema (DME) is lacking. This study aimed to develop
a clinically recommended treatment paradigm for DME
with emphasis on the role of corticosteroids.
PATIENTS AND METHODS: An expert panel of nine retinal specialists in the United States developed consensus
recommendations for DME treatment through a modified Delphi process.
RESULTS: The panelists typically use intravitreal injections of vascular endothelial growth factor (VEGF) antagonists as first-line treatment of DME and switch patients
with an inadequate response to anti-VEGF therapy (failure of best-corrected visual acuity to improve to 20/40
or better because of edema after three to six monthly injections, or a less-than-50% reduction in excess macular
thickness after three to four monthly injections) to intravitreal corticosteroid treatment.
CONCLUSION: Intravitreal corticosteroids have a potentially useful role in the treatment of patients with DME
who have an inadequate response to intravitreal antiVEGF therapy.
[Ophthalmic Surg Lasers Imaging Retina. 2017;48:291-301.]
INTRODUCTION
Diabetic macular edema (DME) is characterized by accumulation of fluid and retinal thickening within the macula. The pathogenesis of DME is
multifactorial. Vascular endothelial growth factor
(VEGF) has a central role in the breakdown of the
blood-retinal barrier that leads to DME,1 but other
pro-inflammatory factors and processes also appear
to be involved.2,3 DME is the most common cause of
vision loss in patients with diabetes.4 It is estimated
to affect approximately one in 25 individuals with
diabetes older than age 40 in the United States,5
and the number of cases of DME can be expected to
increase because of the growing prevalence of diabetes and its complications.6
The American Academy of Ophthalmology Preferred Practice Patterns-recommended first-line
treatment for center-involved DME is intravitreal
anti-VEGF therapy, with or without adjunct focal
laser treatment.7 Ranibizumab 0.3 mg (Lucentis; Genentech, South San Francisco, CA) and aflibercept
2 mg (Eylea; Regeneron, Tarrytown, NY) are U.S.
Food and Drug Administration (FDA)-approved
anti-VEGF treatments for DME. Bevacizumab 1.25
mg (Avastin; Genentech, South San Francisco, CA)
From the Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia (CDR); Texas Retina Associates, Arlington, Texas (DGC); Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA (DVD); NJ Retina, New Brunswick, NJ (HFF); Rutgers UMDNJ Department of Ophthalmology, New Brunswick, NJ (HFF); Pepose
Vision Institute, Chesterfield, MO (NMH); Gavin Herbert Eye Institute, University of California, Irvine, CA (BDK); Medical Center Ophthalmology Associates, San Antonio, TX
(MAS); Cole Eye Institute, Cleveland (RPS).
© 2017 Regillo, Callanan, Do, et al.; licensee SLACK Incorporated. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (https://creativecommons.org/licenses/by/4.0). This license allows users to copy and distribute, to remix, transform, and build upon the article, for any purpose, even
commercially, provided the author is attributed and is not represented as endorsing the use made of the work.
Originally submitted February 7, 2017. Revision received March 15, 2017. Accepted for publication March 20, 2017.
This study was sponsored by Allergan plc, Dublin, and conducted by Endpoint Outcomes, Boston, MA. The study sponsor had the opportunity to review the manuscript but
could not make changes in the manuscript; the content of the manuscript was fully controlled by and approved by the authors.
The authors report no proprietary interests in the products described in the article. Dr. Regillo is a consultant for Alcon, Allergan, Bayer, Genentech, Iconic, and Novartis and has
received research grant support from Accucela, Alcon, Alimera, Allergan, Bayer, Genentech, GSK, Iconic, Novartis, Ophthotech, and Regeneron. Dr. Callanan is a consultant for
AbbVie, Alcon, Allergan, Allgenesis, Forsight, Graybug, Regeneron, pSivida, and Santen. Dr. Do is a consultant for Allergan, Genentech, and Santen and has received research
funding from Allergan, Genentech, Regeneron, and Santen. Dr. Fine is a consultant for Alimera, Allergan, Genentech, and Regeneron and has received research grant support
from Alcon, Alimera, Allergan, Genentech, GSK, and Regeneron. Dr. Holekamp is a consultant for Alimera Sciences, Allergan, Genentech, Katalyst, Novartis, and Regeneron and
has received research grant support from Alimera Sciences, Allergan, Genentech, and Opthotech. Dr. Kuppermann is a consultant for Acucela, Aerpio, Alcon, Alimera, Allegro,
Allergan, Ampio, Catalyst, Dose, Eleven Biotherapeutics, Genentech, Glaukos, Lumenis, Novartis, Ophthotech, Regeneron, and ThromboGenics and has received research
grant support from Alcon, Alimera, Allegro, Allergan, Apellis, Genentech, GSK, J-Cyte, Neurotech, Ohr, Ophthotech, Regeneron, and ThromboGenics. Dr. Singer is a consultant
for Aerpio, Alimera, Allergan, Ampio, Genentech, and Santen and has received research grant support from Acucela, Aerpio, Alcon, Alimera, Allergan, Ampio, Genentech,
Ophthotech, and Regeneron. Dr. Singh is a consultant for Alcon, Genentech, Optos, Regeneron, Shire, and Zeiss and has received research grant support from Alcon, Apellis,
Ophthotech, Regeneron, and Roche.
The authors thank Chris Evans, Nate Johnson, and Nicole Lyn of Endpoint Outcomes for their contributions to the study. Writing and editorial assistance was provided to the
authors by Kate Ivins, PhD, of Evidence Scientific Solutions, Philadelphia, and funded by Allergan plc. All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship.
Address correspondence to Carl D. Regillo, MD, Wills Eye Hospital, 840 Walnut Street, Suite 1020, Philadelphia, PA 19107; email: [email protected].
doi: 10.3928/23258160-20170329-03
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Figure. Recommended treatment paradigm for center-involved DME. BCVA = best-corrected visual acuity; DME = diabetic macular
edema; VEGF = vascular endothelial growth factor.
is commonly used via an intravitreal injection in
an off-label fashion for treatment of DME; a formulation approved for systemic cancer therapy is
repackaged in syringes by a compounding pharmacy
for off-label intravitreal ophthalmic use. Many studies
have demonstrated that intravitreal anti-VEGF treatment has a favorable tolerability profile and is effective
in reducing central retinal thickness and improving
best-corrected visual acuity (BCVA) in patients with
DME.8 Even with monthly administration of anti-VEGF,
however, the response to anti-VEGF therapy is suboptimal in a substantial proportion of patients.9-11 After 2
years of monthly ranibizumab 0.3 mg injections for the
treatment of DME in the RISE/RIDE registration trials,
central foveal thickness remained greater than 250 µm
on time-domain optical coherence tomography (OCT)
in 24.8% of patients, and BCVA was worse than 20/40
in 42.8% of patients.9
Corticosteroids are also available for the treatment
of DME. Although intraocular corticosteroid treatment
is commonly associated with adverse effects of cataract
and increases in intraocular pressure (IOP), intravitreal
corticosteroids have demonstrated efficacy in improving central retinal thickness and BCVA in DME and,
therefore, are viable treatment options.7,12,13 In the United States, dexamethasone intravitreal implant 0.7 mg
(DEX implant) (Ozurdex; Allergan plc, Dublin, Ireland)
is FDA-approved for treatment of DME, and intravitreal
fluocinolone acetonide insert (FAc) (Iluvien; Alimera
Sciences, Alpharetta, GA) is approved for treatment
of DME in patients who have been previously treated
with a course of corticosteroids and did not have a clinically significant rise in IOP. In addition, intravitreal triamcinolone acetonide (TA) has been used off-label for
many years and has demonstrated beneficial effects in
patients with DME.14
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TABLE 1
Delphi Panel Consensus on Issues in the Treatment of DME
Issue
Consensus Opinion/Recommendation
Classification of DME
Center-involved or non-center-involved
First-line treatment for center-involved DME
Intravitreal anti-VEGF injections
Ideal response to anti-VEGF treatment
1. Resolution of edema (primary)
2. Improvement in visual acuity (secondary)
Most important factor contributing to different levels
of patient response to anti-VEGF
The balance of VEGF versus other inflammatory cytokines
Second most important factor contributing to different The chronicity of the DME
levels of patient response to anti-VEGF
Long-term DME
Results in poorer outcomes
Treatment decision when early response to anti-VEGF
(after three or more injections) is suboptimal
Switch to a different anti-VEGF agent if initial anti-VEGF agent
was not the most efficacious available
Definition of inadequate response to anti-VEGF
therapy
BCVA worse than 20/40 after three to six monthly anti-VEGF
injections because of edema, or less-than-50% reduction in
excess macular thickness after three to four monthly antiVEGF injections
How long to tolerate persistent edema
4 to 6 months
Reasons to incorporate additional treatment modalities beyond anti-VEGF
1. Fluid still present on the retina
2. Lack of anatomical improvement (eg, CRT)
3. Lack of improvement in BCVA
4. Monthly injections are too burdensome (ie, poor compliance)
Reasons to potentially consider switching or stopping
anti-VEGF treatment
1. Fluid still present on the retina
2. Lack of anatomical improvement (eg, CRT)
3. Lack of improvement in BCVA
4. Monthly injections are too burdensome (ie, poor compliance)
5. Recent stroke or cardiovascular event
Importance of treating the inflammatory versus the
VEGF component of DME
More important to treat the inflammatory component after a
suboptimal response to anti-VEGF therapy
Treatment decision when patient has an inadequate
response to anti-VEGF therapy
Switch to a corticosteroid (consensus choice is DEX implant)
Choice of corticosteroid
FDA-approved corticosteroid is preferred
Use of macular laser in center-involved DME
Laser used as adjunct (not rescue) treatment
Frequency of monitoring
1. Monthly for patients on anti-VEGF
2. Every 1 to 2 months for patients on corticosteroid
3. Every 1 to 2 months for patients newly on combination of
anti-VEGF and corticosteroid
4. Every 2 months for patients established on combination of
anti-VEGF and corticosteroid
Management of IOP increases during corticosteroid
treatment
1. Treat elevated IOP of 30 mm Hg or less with topical IOP-lowering medication (single medication or fixed combination)
2. For patients with IOP higher than 30 mm Hg, treat with
fixed-combination IOP-lowering eye drop and/or refer the
patient to a glaucoma specialist
BCVA = best-corrected visual acuity; CRT = central retinal thickness; DEX implant = dexamethasone intravitreal implant; DME = diabetic macular edema; FDA = U.S.
Food and Drug Administration; IOP = intraocular pressure; VEGF = vascular endothelial growth factor
April 2017 · Vol. 48, No. 4
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TABLE 2
Delphi Panel Consensus on Candidates for Corticosteroid Treatment of DME
Patient Scenario
Definite or Likely
Candidate for
Corticosteroid
Treatment
Inadequate responder to anti-VEGF after three to six injections

Inadequate responder to anti-VEGF who is pseudophakic

Inadequate responder to anti-VEGF who is phakic and older than 60 years old

Inadequate responder to anti-VEGF who is phakic and younger than 60 years old

Patient in need of rescue

Patient who is scheduled to undergo cataract surgery

Patient with a history of vitrectomy

Patient with persistent DME

Patient with severe edema

Suboptimal response to anti-VEGF treatment after three injections

Patient who is resistant to laser photocoagulation

Patient who had successful filtration surgery to control IOP

Patient with POAG well controlled on one glaucoma drop

Patient with POAG well controlled on two glaucoma drops (status of optic
nerve not specified)
Patient with POAG well controlled on two glaucoma drops and a healthy
optic nerve
Unlikely
Candidate for
Corticosteroid
Treatment


DME = diabetic macular edema; IOP = intraocular pressure; POAG = primary open-angle glaucoma; VEGF = vascular endothelial growth factor
There is a need for guidelines on how DME should
be treated to provide patients with the best possible
outcomes when the response to anti-VEGF therapy
is inadequate. To address this need, a panel of clinical experts in retinal ophthalmology was brought
together to develop consensus recommendations
for DME treatment through a modified Delphi process. The objective was to develop a clinically recommended treatment paradigm for DME, with particular focus on how corticosteroids fit within the
treatment paradigm.
The Delphi technique is a widely used and accepted method for building consensus from experts
in a field through iterations of a survey and anonymous feedback; in each round of the survey, the participants review and assess the results and feedback
from the previous round, then respond to the survey
again, and the process is repeated until consensus is
reached.15 A modified Delphi approach incorporating a face-to-face meeting led by a moderator has
been used in previous studies to develop recom-
mendations for the assessment and management of
ophthalmic diseases16-21 and was used in this study
to develop a recommended treatment paradigm
for DME. A panel of nine retina specialists with
expertise in the treatment of diabetic retinopathy
and DME were invited and agreed to participate in
the development of the treatment guidelines. After
a literature review was conducted to identify current treatment patterns in DME, a survey including 22 multipart, multiple-choice, and open-ended
questions regarding treatment scenarios and clinical decision-making was developed by Endpoint
Outcomes and Allergan (Appendix A available at
www.Healio.com/OSLIRetina). The questions were
designed to elucidate key elements of the treatment
paradigm including assessment of the response to
anti-VEGF therapy, the role of corticosteroids in
the treatment paradigm, differentiation of available
corticosteroid treatment options, and corticosteroid
use and side effects.
The panel responded to the survey in two formal rounds of feedback. The first round of the survey was conducted on the SurveyMonkey online
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PATIENTS AND METHODS
survey platform (www.surveymonkey.com). Nine
panelists participated in the survey and provided
anonymous feedback. Following the first round,
the results were summarized and provided to the
panelists. Eight of the panelists then participated in the second round of the survey at a “realtime” Delphi panel meeting on June 4, 2016, in
Philadelphia, Pa. At the meeting, the anonymous
summary results of the first round were presented to
the panelists. Answers to open-ended questions in
the first round were used to frame multiple-choice
answers to survey questions for the second round
(Appendix B available at www.Healio.com/OSLIRetina). For each survey question, if consensus was
not reached in the first round, the results were discussed and debated by the panelists. The panelists
then voted for their chosen response. An electronic
audience response system (ResponseCards; Turning Technologies, Youngstown, OH) was used to
capture anonymous votes during the Delphi panel
discussion, and all panelists were required to vote
before results were displayed. Discussion was continued and voting was repeated until consensus
was reached, or it was clear that it was impossible
to achieve consensus. During this process, modification of survey questions and possible responses,
based on opinions expressed during the discussion, was allowed to facilitate the achievement of
consensus. Consensus was defined as agreement by
at least six of the nine panelists in the first round
(66.7%), or by at least six of eight panelists at the
Delphi panel meeting (75%).
RESULTS
The panelists reached consensus on many issues
in the treatment of DME (Table 1) and developed
a recommended treatment paradigm for centerinvolved DME in patients who have an incomplete
response to anti-VEGF treatment (Figure).
The key aspects of the treatment paradigm are
as follows.
Disease Classification
The majority of panelists (75%; six of eight)
agreed that clinical decision-making on whether
and how to treat DME begins with the classification of the DME as center-involved or non-centerinvolved.
First-line Treatment for Center-Involved DME: AntiVEGF Therapy
Members of the expert panel typically use intravitreal bevacizumab, ranibizumab, and aflibercept
as first-line treatment for center-involved DME. In
April 2017 · Vol. 48, No. 4
the first round (online) survey, there was consensus agreement (77.8%; seven of nine) that if there
was a suboptimal response to anti-VEGF injections
early in treatment (after three or fewer injections),
the patient is typically switched to another antiVEGF agent. In the discussion at the Delphi meeting, panelists clarified that insurance coverage and
reimbursement can affect the choice of anti-VEGF
agent initially used. When the early response to
anti-VEGF is poor, they may switch to a different
anti-VEGF agent that is believed to be more efficacious, but they generally limit the total time on
anti-VEGF-only therapy to 6 months for patients
who have an inadequate response.
The response to anti-VEGF treatment is variable among patients. All panelists agreed that the
relative roles of VEGF and other inflammatory cytokines in the edema is the most important factor
contributing to different levels of patient response
to anti-VEGF. The panelists also all agreed that the
chronicity of the edema is a second key factor contributing to different levels of patient response to
anti-VEGF.
There was unanimous agreement that long-term
DME results in poorer outcomes. Panelists stated
that chronic DME may be less responsive to antiVEGF therapy and is likely to involve inflammatory pathways and cytokines other than VEGF that
can cause tissue damage. Photoreceptor damage
and permanent loss of visual acuity can occur in
chronic DME. Prompt treatment of center-involved
DME with anti-VEGF is recommended for optimal
outcomes.
Evaluating the Response to Anti-VEGF Therapy
All panelists agreed that the most important determinant of an ideal response to anti-VEGF therapy
is the resolution of edema. Most of the panelists
(87.5%; seven of eight) further agreed that improvement in visual acuity is the second most important
determinant of an ideal response to anti-VEGF therapy. Improvement in visual acuity is important, but
it is a secondary factor in evaluation of the treatment
response because other factors beyond DME can affect vision.
A patient can be determined to be an inadequate
responder to anti-VEGF therapy based on anatomic
criteria, or a combination of BCVA and anatomic criteria. Almost all (87.5%; seven of eight) of the panelists agreed that a DME patient who after three to
four monthly anti-VEGF injections has a less than
50% reduction from baseline in the excess macular
thickness (defined as thickness over the upper limit
of normal) is an inadequate responder to anti-VEGF
295
therapy. In addition, the majority of panelists (75%;
six of eight) agreed that a DME patient whose BCVA
after three to six monthly anti-VEGF injections has
failed to improve to 20/40 or better because of edema
is an inadequate responder to anti-VEGF therapy.
The panel was unable to agree on a value for the
central subfield thickness on OCT that indicates an
inadequate response to anti-VEGF therapy. Although
the central subfield thickness measurement is valuable for evaluation of changes in retinal thickness
over time and after treatment, qualitative assessment
of the persistence of edema, which is associated with
visual acuity loss, may drive treatment decisions.
Almost all panelists (87.5%; seven of eight) agreed
that they are prepared to tolerate persistent edema for
4 to 6 months in patients who are receiving monthly
anti-VEGF injections. Panelists agreed that waiting
longer than 6 months to move on to other modalities
of treatment is potentially detrimental. It was noted
that DME may be present for months before patients
are seen by a clinician and initiate treatment, so
the persistence of edema through 6 months of treatment may indicate the development of chronic DME,
which involves inflammatory pathways and cytokines other than VEGF and potentially has reduced
responsiveness to anti-VEGF therapy. Panelists cited
clinical data (the EARLY Study) showing that the
BCVA outcomes of patients in the DRCR.net Protocol
I study after 3 years of ranibizumab 0.5 mg treatment
could be predicted by results at week 12.11 These results support a change in therapy when edema persists and BCVA does not improve after 3 months of
ranibizumab treatment, because most patients who
had less-than-five-letter BCVA gain from baseline after 3 months continued to have less-than-five-letter
BCVA gain from baseline after 3 years of ranibizumab
administration.
Reasons to Change Therapy
In the first round of the survey, all panelists reported that they were somewhat or very likely to use
treatment options in addition to anti-VEGF if monthly injections were too burdensome for the patient (ie,
there was poor compliance with frequent injections).
After discussion at the Delphi panel meeting, the majority of panelists (62.5%; five of eight) agreed that
they typically would be likely to consider switching
anti-VEGF treatment to other therapy if monthly injections are too burdensome. Panelists emphasized
that to facilitate compliance, it is important to discuss
with patients the importance of frequent injections to
preserve vision.
The panelists agreed that persistent edema and
lack of improvement in BCVA are important factors
296
driving decisions to change therapy. In the first round
of the survey, all panelists reported that they would
be somewhat or very likely to incorporate additional
treatment modalities beyond anti-VEGF if fluid was
still present on the retina, and all but one of the panelists responded that they would be somewhat or very
likely to consider switching or stopping anti-VEGF
treatment in this scenario. Similarly, all panelists reported that they would be somewhat or very likely to
incorporate additional treatment modalities beyond
anti-VEGF if there was lack of anatomical improvement (eg, in retinal thickness). In the second round,
consensus was reached regarding switching treatment, and 75% (six of eight) of panelists agreed that
they typically would be likely to consider switching
from anti-VEGF to another treatment modality if there
was a lack of anatomical improvement. Consensus
was reached in the first round of the survey with respect to the effect of lack of improvement in BCVA
on treatment decisions. Most panelists (77.8%; seven
of nine) reported that they would be very likely to incorporate additional treatment modalities in patients
who had no improvement in BCVA with anti-VEGF
therapy, and almost all panelists (88.9%; eight of
nine) reported that they would be somewhat or very
likely to switch or stop anti-VEGF treatment.
Most panelists (87.5%; seven of eight) also agreed
that they typically would be likely to consider switching from anti-VEGF to another treatment modality in
patients who have had a recent stroke or cardiovascular event.
The panelists were unable to reach consensus on
the relative importance of treating the VEGF component of DME compared with the inflammatory component of DME. However, all panelists agreed that it
is more important to treat the inflammatory component of DME than the VEGF component of DME after
it has been established that the response to anti-VEGF
therapy is suboptimal.
Treatment When the Response to Anti-VEGF Is
Inadequate
The panelists agreed unanimously that they
would be most likely to switch a patient who is an
inadequate responder after three to six monthly injections of anti-VEGF agents to corticosteroid treatment.
All panelists reported they are most likely to switch
an anti-VEGF inadequate responder to DEX implant
treatment, and their second most likely choice for
corticosteroid therapy is intravitreal TA (Triesence;
Alcon, Fort Worth, TX).
All panelists further agreed that laser photocoagulation should be used as an adjunct treatment in
patients with center-involved DME, but should not
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be considered a rescue treatment. Panelists agreed
that the rescue treatment for patients with suboptimal anti-VEGF response is a corticosteroid.
Role of Corticosteroids in the Treatment Paradigm
Consensus was reached that intravitreal corticosteroid treatment is appropriate in multiple scenarios
of DME (Table 2). Phakic as well as pseudophakic patients who have an inadequate response to anti-VEGF
therapy can be candidates for corticosteroid treatment,
and corticosteroid treatment can be used in patients
with severe edema and those who have undergone
vitrectomy. Corticosteroid treatment can also be considered in DME patients with co-existing glaucoma as
long as IOP is controlled on one or two medications
and the optic nerve is healthy. Several panelists indicated that patients who have had successful filtering
surgery can be candidates for corticosteroid therapy as
long as the cup-to-disc ratio does not exceed 0.8.
Patient Monitoring
Most panelists (77.8%; seven of nine) reported that
their patients who are on anti-VEGF therapy are monitored monthly. There was no consensus regarding the
frequency of monitoring for patients on corticosteroidonly therapy. Two panelists reported that they monitor patients monthly, four monitor patients at intervals
of 6 to 8 weeks, and two monitor 1 month after the
corticosteroid injection and 2 to 3 months afterward,
depending on the IOP. During subsequent discussion,
it was pointed out that these results indicate that the
panelists typically monitor patients on corticosteroidonly therapy every 1 to 2 months. Patients who receive
a sustained-release implant may be monitored at 4 to
6 weeks after their first corticosteroid injection, then
subsequently at extended intervals not exceeding 3
months.
For patients receiving a combination of anti-VEGF
and corticosteroid treatment, the frequency of monitoring is dependent on whether patients are new to
or established on the combination treatment. Most
panelists (75%; six of eight) agreed that patients who
are new to combination therapy should be monitored
every 1 to 2 months, and almost all panelists (87.5%;
seven of eight) agreed that patients who are established
on combination therapy should be monitored every 2
months.
Choosing Among Corticosteroid Options
All panelists agreed that they would prefer to use
a corticosteroid approved by the FDA for DME treatment (DEX implant or FAc) when considering efficacy,
safety, and duration of effect, and all panelists reported
that they use an FDA-approved corticosteroid in most
April 2017 · Vol. 48, No. 4
cases. In their comments on the first-round survey,
panelists indicated that they usually treat patients
with DEX implant and sometimes use the FAc implant
after DEX implant treatment in patients who are not
steroid responders, who have shown a good response
to multiple DEX implants, and who need long-term
treatment.
Some panelists reported that they occasionally use
a nonapproved corticosteroid (TA) when lack of insurance coverage or cost is an issue.
Management of the Side Effects of Corticosteroid
Treatment
All panelists agreed that side effects of corticosteroid treatment are monitored in conjunction with efficacy, and no additional office visits are scheduled to
monitor for side effects, unless a problem is detected
and requires follow-up. Panelists commented that side
effects of cataract are manageable and side effects of increases in IOP are generally manageable. The panelists
reached consensus on how they treat increased IOP in
patients on corticosteroid therapy. For patients who
have elevated IOP of 25 mm Hg or less, six panelists
(75%) agreed that they would prescribe a single topical
IOP-lowering medication, and for patients with IOP
between 26 mm Hg and 30 mm Hg, almost all panelists (87.5%; seven of eight) agreed that they would prescribe a fixed-combination IOP-lowering eye drop. For
patients with IOP higher than 30 mm Hg, all panelists
agreed that they would prescribe a fixed-combination
IOP-lowering eye drop or refer the patient to a glaucoma specialist, and most agreed that they would both
prescribe the fixed combination and make the referral.
DISCUSSION
The introduction of anti-VEGF treatment has greatly improved visual outcomes in patients with DME,
but a significant proportion of patients have an incomplete response to anti-VEGF treatment.9-11 Corticosteroids are a rational approach to the treatment of
DME because inflammatory mediators and pathways
in addition to VEGF appear to be involved in the development of DME. However, there has been limited
practical guidance on when and how to use corticosteroids in the treatment regimen. The consensus recommendation of this panel is that corticosteroids be used
in patients with an inadequate response to anti-VEGF
treatment, and guidance is provided on how to identify patients who are inadequate responders to antiVEGF, and when to progress to corticosteroid therapy.
The recommendation of the panel is that centerinvolved DME with some degree of decreased visual
acuity should be treated promptly with anti-VEGF
therapy. Most patients with DME respond well to
297
anti-VEGF treatment. Currently bevacizumab is
used more frequently than ranibizumab or aflibercept for treatment of ophthalmic disease in clinical
practice22 because of its lower cost. In the DRCR.net
Protocol T study comparing these anti-VEGF agents
in patients with DME, after 1 year of treatment,
aflibercept was more effective than ranibizumab
or bevacizumab in improving BCVA in patients
with baseline BCVA worse than 20/40, whereas
the anti-VEGF agents showed comparable efficacy
in patients with baseline BCVA of 20/32 to 20/40.23
After 2 years of treatment, aflibercept and ranibizumab provided similar improvement in BCVA,
and aflibercept continued to be more effective than
bevacizumab in improving BCVA in patients with
baseline BCVA worse than 20/40.24 Although the
efficacy of switching among anti-VEGF therapies
has not been well studied,25 favorable outcomes
have been reported after patients with suboptimal
response switched from bevacizumab to ranibizumab,26 or from bevacizumab or ranibizumab to
aflibercept.27 Therefore, if a patient has a poor early
response to anti-VEGF, and the initial anti-VEGF
agent used was not aflibercept because of considerations such as cost and reimbursement, the clinician may consider switching the patient to aflibercept. The consensus of the panel, however, is that
whether or not there is a switch among anti-VEGF
therapies, continued edema should be tolerated for
no longer than 6 months.
There are three fundamental reasons why a patient with an inadequate response to anti-VEGF
therapy typically should remain on anti-VEGF
treatment for no longer than 6 months before proceeding to a corticosteroid. First, there is evidence
that anti-VEGF treatment is most effective in early
disease.28-30 In the RISE/RIDE registration studies of
ranibizumab, patients in the initial sham group who
crossed over to ranibizumab treatment at year 2 had
less favorable outcomes after 12 months of ranibizumab treatment than patients in the initial ranibizumab groups,28 and patients with a longer duration
of DME at baseline required more as-needed ranibizumab injections during the open-label study extension after year 3,29 suggesting that prompt treatment of shorter-term DME with ranibizumab results
in better outcomes. Similarly, in the VIVID/VISTA
registration studies of aflibercept, patients in the
initial laser treatment group achieved a smaller gain
in BCVA after receiving rescue aflibercept treatment
compared with patients in the initial aflibercept
treatment groups, suggesting that delaying aflibercept treatment results in poorer outcomes and that
aflibercept treatment is more effective in shorter-
term DME.30 Second, continuing anti-VEGF treatment when the early response to treatment is poor
usually does not result in favorable outcomes. The
EARLY study analysis of results from the DRCR.
net Protocol I study showed that the majority of patients who had a less-than-five-letter gain in BCVA
from baseline at week 12 (after three monthly ranibizumab injections) continued to have less-thanfive-letter gains in BCVA from baseline at week 156
(after 3 years of monthly ranibizumab injections).11
Third, delaying effective treatment increases the
risk of permanent vision loss, because chronicity of
DME is associated with foveal atrophy and photoreceptor damage.31
Members of the panel agreed that the balance
of VEGF versus other inflammatory cytokines appears to be an important factor contributing to the
different levels of anti-VEGF response observed
in patients with DME. The importance of this balance goes hand-in-hand with the importance of the
chronicity of DME in the variability observed in patient response to anti-VEGF treatment, because it is
generally believed that DME is primarily mediated
by VEGF in its early phase, whereas the involvement of other cytokines and inflammatory mechanisms becomes more important in chronic disease.2
Low-grade inflammation has been postulated to be
responsible for the retinal damage that occurs in
chronic DME.2
It may be important to treat the inflammatory
component of DME in patients who do not respond
adequately to anti-VEGF treatment. Studies have
demonstrated the effectiveness of corticosteroid
treatment in long-standing and refractory DME. In
the MEAD registration studies for DEX implant, the
treatment effects of DEX implant relative to sham
were similar in subgroups defined by the duration
of DME at baseline: DEX implant had beneficial effects in longer-term (duration of more than 3 years)
as well as short-term (less than 1 year in duration)
DME.12,32 Furthermore, in the FAME registration
studies for FAc, the percentage of patients with
15-letter or greater gains in BCVA from baseline
was superior with FAc relative to sham only in the
subgroup of patients with long-standing DME (duration of 3 years or longer),33 consistent with an important role of inflammatory pathways amenable to
corticosteroid treatment in the pathophysiology of
persistent DME.
The panel recommends that a patient who has
a less than 50% reduction from baseline in the excess macular thickness after three to four monthly
anti-VEGF injections, or whose BCVA has not improved to 20/40 after three to six monthly injections
298
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because of edema, be switched to corticosteroid
treatment. The definitions of inadequate response
include a range in the number of anti-VEGF injections, because the decision of whether to change
treatment should take into account the trajectory
of the response. A patient with continual improvement in edema after three or four sequential injections typically would be re-treated with anti-VEGF,
whereas a patient with no improvement in edema
after three or four anti-VEGF injections typically
would be switched to a corticosteroid.
The panelists recommend that patients on antiVEGF therapy receive frequent (monthly) injections
and have monthly assessments to evaluate the trajectory of the response to treatment and identify
inadequate responders. However, they recognize
that some practitioners may see patients monthly
for anti-VEGF injections but wait until after three
to four injections before doing a full examination
and OCT, rather than doing full exams at every visit. With this approach, the decision of whether to
continue anti-VEGF treatment or switch to a corticosteroid is still made 3 to 4 months after the initial
anti-VEGF injection, consistent with the suggestion
from the EARLY study that this is an appropriate
timeframe for deciding whether to switch therapy,
since BCVA outcomes at week 12 in the Protocol I
study were predictive of long-term outcomes.11 Although this approach does not consider the trajectory of the treatment response, there are cost savings
associated with fewer examinations, and there is
little risk of overtreatment, since edema is unlikely
to resolve after one to three anti-VEGF injections.
The panelists also recognize that the frequency of
anti-VEGF injections required can be burdensome
for patients,34,35 but in the experience of the panelists, patients are likely to adhere to frequent injections if they are educated on the alternative of risk
of permanent loss of vision. The consensus opinion of the panel is that frequent monitoring is also
needed for patients who have switched to corticosteroid implant treatment, but the recommended interval between visits for these patients is longer (1
to 2 months) than that recommended for patients on
anti-VEGF therapy.
The panel’s consensus choice of corticosteroid
for treatment of DME in inadequate responders to
anti-VEGF is DEX implant, primarily because DEX
implant has a more favorable safety profile compared
with FAc and intravitreal TA. The increases in IOP
associated with intraocular corticosteroid use are
less frequent, less severe, and more easily managed
with DEX implant than with FAc or intravitreal
TA.12,13,36-38 Accordingly, the FDA-approved indica-
April 2017 · Vol. 48, No. 4
tion for FAc in DME is limited to patients who have
been demonstrated to have no clinically significant
IOP response to a corticosteroid. Disadvantages of
use of intravitreal TA include its lack of FDA approval for treatment of DME and the possible need
for more frequent injections. DEX implant has been
demonstrated to be effective in patients with previous vitrectomy,39 patients with previously treated
DME,40 and patients with DME that has been demonstrated to be resistant to anti-VEGF treatment.41-45
The primary role of corticosteroids in the treatment paradigm for DME is as alternative treatment
after a suboptimal anti-VEGF response, but corticosteroids may also be considered for treatment in patients who discontinue anti-VEGF therapy because
of systemic safety concerns. Although intravitreal
anti-VEGF treatment is generally believed to be
systemically safe, it has been difficult to determine
whether anti-VEGF might increase the risk of stroke,
arteriothrombotic events, or cardiovascular events
because studies have been underpowered and patients with DME may be at increased risk of these
events regardless of treatment.46 However, the majority of panelists agreed that they typically would
likely consider a change in therapy if a patient being treated with anti-VEGF had a recent stroke or
cardiovascular event. In a recent meta-analysis that
pooled systemic safety data from patients treated
with ranibizumab 0.5 mg or aflibercept in clinical
studies, the risk of cerebrovascular accidents and
vascular deaths was significantly higher in patients
treated monthly for 2 years with anti-VEGF injections than in patients treated with sham,47 suggesting that frequent anti-VEGF injections over the long
term may increase the risk of serious systemic adverse events.
There is a lack of evidence from clinical studies
concerning some aspects of care in DME, such as
the benefits of using combination therapy with an
anti-VEGF agent and a corticosteroid. In their discussion at the Delphi meeting, panelists indicated
that they generally use combination anti-VEGF and
corticosteroid therapy only for patients with severe
and persistent DME. Furthermore, based on their
clinical experience, the panelists believe that a patient with a suboptimal response to anti-VEGF has
better improvement in retinal drying if the patient
is switched to a corticosteroid than if the patient
is switched to a different anti-VEGF agent, but supporting data from clinical trials are lacking.
The clinically recommended treatment paradigm
for DME presented here includes recommendations
for the medical treatment of DME, and it was developed with the understanding that the recommen-
299
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13. Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery
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LP, et al. Randomized trial evaluating ranibizumab plus prompt
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macular edema. Ophthalmology. 2010;117(6):1064-1077.e5.
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17. Lee PP, Sultan MB, Grunden JW, Cioffi GA, IOP Consensus Panel.
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18. Ferris FL 3rd, Wilkinson CP, Bird A, et al. Clinical classification of age-related macular degeneration. Ophthalmology.
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19. Ohno-Matsui K, Kawasaki R, Jonas JB, et al. International photographic classification and grading system for myopic maculopathy.
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20. Bandello F, Midena E, Menchini U, Lanzetta P. Recommendations
for the appropriate management of diabetic macular edema: Light
on DME survey and consensus document by an expert panel. Eur
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21. Rodrigues IA, Sprinkhuizen SM, Barthelmes D, et al. Defining a
minimum set of standardized patient-centered outcome measures
for macular degeneration. Am J Ophthalmol. 2016;168:1-12.
22. Parikh R, Ross JS, Sangaralingham LR, Adelman RA, Shah ND,
Barkmeier AJ. Trends of anti-vascular endothelial growth factor
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23. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203.
24. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab,
or ranibizumab for diabetic macular edema: Two-year results from
a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-1359.
25. Do DV, Nguyen QD, Vitti R, et al. Intravitreal aflibercept injection
in diabetic macular edema patients with and without prior antivascular endothelial growth factor treatment: Outcomes from the
phase 3 program. Ophthalmology. 2016;123(4):850-857.
26. Fechter C, Frazier H, Marcus WB, Farooq A, Singh H, Marcus DM.
Ranibizumab 0.3 mg for persistent diabetic macular edema after
recent, frequent, and chronic bevacizumab: The ROTATE trial.
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27. Lim LS, Ng WY, Mathur R, et al. Conversion to aflibercept for diabetic macular edema unresponsive to ranibizumab or bevacizumab.
Clin Ophthalmol. 2015;9:1715-1718.
28. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes
of ranibizumab therapy for diabetic macular edema: The 36-month
results from two phase III trials: RISE and RIDE. Ophthalmology.
2013; 120(10):2013-2022.
29. Wykoff CC, Elman MJ, Regillo CD, Ding B, Lu N, Stoilov I.
Predictors of diabetic macular edema treatment frequency with ranibizumab during the open-label extension of the RIDE and RISE
Trials. Ophthalmology. 2016;123(8):1716-1721.
30. Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal aflibercept
for diabetic macular edema: 148-week results from the VISTA and
VIVID studies. Ophthalmology. 2016;123(11):2376-2385.
31. Channa R, Sophie R, Khwaja AA, et al. Factors affecting visual outcomes in patients with diabetic macular edema treated with ranibizumab. Eye (Lond). 2014;28(3):269-278.
32. Loewenstein A, MEAD Study Group. MEAD: Diabetic macular
edema trial subanalysis. Paper presented at: American Academy of
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34. Shea AM, Curtis LH, Hammill BG, et al. Resource use and costs
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dations should be general and applicable in 80%
of cases. The authors recognize that there are exceptions and that there is a need for individualized
patient care, as well as a need for surgery in cases
of epiretinal membrane or vitreomacular traction.
Some patients will lose vision irretrievably even
if the recommendations are followed. The recommendations are based on evidence from reported
studies and the clinical experience of the panelists, and they may be modified when more data become available. It is anticipated that results of the
ongoing DRCR.net Protocol U study (clinicaltrials.
gov identifier: NCT01945866), comparing ranibizumab monotherapy to combination therapy with
ranibizumab and DEX implant in patients with an
incomplete response to three monthly injections of
ranibizumab, may further help guide corticosteroid
use in the treatment of DME.
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301
APPENDIX A
Draft Questions for DME Round 1 Delphi Survey [via SurveyMonkey]
Instructions: Thank you for your participation in the diabetic macular edema (DME) Delphi panel. In this survey, we will be asking
you open and closed-ended questions about your experience with DME treatment scenarios. Your answers will remain anonymous,
however the results of this survey will be summarized along with other panelists’ answers in order to inform our discussion during the
Delphi meeting on [June 4th].
Section 1: Defining Treatment Response to Anti-VEGF Therapy
1.
Do you classify DME patients into types before deciding on treatment options?
a. Response options: Yes/No
b. If Yes, how do you classify DME patients?
i. [Open-ended]
2.
What would you consider to be an adequate response to anti-VEGF therapy? Please describe in a few brief sentences.
a. [Open-ended]
3.
When would you consider someone an inadequate responder to anti-VEGF treatment?
a. [Open-ended]
b. Please fill in the blanks:
i. After X injections failed to improve best-corrected visual acuity to 20/XX
ii. After X injections failed to improve best-corrected visual acuity by X lines
iii. After X injections, OCT-measured retinal thickness of is equal to or above X µm
iv. After X injections, OCT-measured retinal thickness has not improved by X% from baseline
4.
How long are you prepared to tolerate persistent edema despite treatment with multiple anti-VEGF injections? Please
explain.
a. [Open ended]
5.
What are the reason(s) for different levels of response to anti-VEGF therapy?
a. [Open ended]
6.
What do you consider an optimal response when treating DME with an anti-VEGF?
a. [Open ended]
7.
Does long-term presence of DME result in poorer outcomes? Please explain why.
a. [Open ended]
8.
Listed below are various scenarios for DME patients that are being considered for, or are on, anti-VEGF treatment. How
likely are you to consider incorporating additional treatment modalities (eg, introducing steroid) based on each scenario?
a. Monthly injection is too burdensome for patients (poor compliance by patients):
i. Response options for a-f:
1. Very likely to discontinue anti-VEGF treatment
a. [please explain open-ended question after each response option]
2. Somewhat likely to discontinue anti-VEGF treatment
3. Somewhat unlikely to discontinue anti-VEGF treatment
4. Very unlikely to discontinue anti-VEGF treatment
b. Systemic considerations (patients with increased risk of stroke/cardiovascular events)
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c. Lack of improvement in best corrected visual acuity
d. Lack of anatomical improvement (central retinal thickness)
e. Fluid still present on the retina
f. Other (please specify):
9.
Listed below are various scenarios for DME patients that are being considered for or are on anti-VEGF treatment. How
likely are you to consider switching or stopping treatment based on each scenario?
a. Monthly injection is too burdensome for patients (poor compliance by patients):
i. Response options for a-f:
1. Very likely to discontinue anti-VEGF treatment
a. [please explain open-ended question after each response option]
2. Somewhat likely to discontinue anti-VEGF treatment
3. Somewhat unlikely to discontinue anti-VEGF treatment
4. Very unlikely to discontinue anti-VEGF treatment
b. Systemic considerations (patients with increased risk of stroke/cardiovascular events)
c. Lack of improvement in best corrected visual acuity
d. Lack of anatomical improvement (central retinal thickness)
e. Fluid still present on the retina
f. Other (please specify):
10. How important is it to treat the inflammatory component of DME compared to the VEGF component? Please select
one answer below:
a. Response options:
i. Inflammation most important to treat
1. Please explain [open-ended] after each response option
ii. Inflammation somewhat more important to treat
iii. Inflammation and VEGF equally important to treat
iv. VEGF somewhat more important to treat
v. VEGF most important to treat
11. What would you typically do for a patient that does not respond optimally to anti-VEGF early in their treatment?
Please choose all that apply:
a. Continue anti-VEGF therapy with the same agent
i. For how many injections? [1, 2, 3, etc.]
b. Switch anti-VEGF therapy to a different agent within the anti-VEGF class
i. Which anti-VEGF treatment would you typically start with?
1. Intravitreal bevacizumab
2. Intravitreal ranibizumab
3. Intravitreal aflibercept
ii. Which anti-VEGF treatment would you typically switch to?
1. Intravitreal bevacizumab
2. Intravitreal ranibizumab
3. Intravitreal aflibercept
April 2017 · Vol. 48, No. 4
iii. For how many injections? [1, 2, 3, etc.]
c. Introduce a steroid
i. How would you introduce the steroid? Please choose one:
1. Monotherapy
2. In combination with anti-VEGF agent
ii. Which steroid would you typically introduce? Please rank in the order of steroid you would most likely
use, to steroid you would least likely use [ranking exercise 1-4]
1. Dexamethasone intravitreal implant (DEX)
2. Fluocinolone acetonide implant (FA)
3. Intravitreal triamcinolone acetonide
4. Other:
d. Incorporate laser treatment
i. How would you incorporate laser treatment? Please choose one.
1. In combination with anti-VEGF agent
2. In combination with steroid
3. In isolation
Section 2: Steroid Treatment Options
12. Listed below are various DME patient scenarios. Please indicate how likely you would be to recommend steroid treatment for each type of patient listed:
a. Persistent diabetic macular edema
i. Response options for a-k:
1. Definite candidate for steroid treatment
2. Likely candidate for steroid treatment
3. Unlikely candidate for steroid treatment
4. Not a candidate for steroid treatment
a. If 3 or 4 are chosen, please explain why [open ended]:
b. Cases with severe edema
c. Patients who do not respond optimally to anti-VEGF treatment after 3 injections
d. Patients who do not respond optimally to anti-VEGF treatment after 6 injections
e. Anti-VEGF suboptimal responders who are pseudophakic
f. Anti-VEGF suboptimal responders who are phakic and older than 60 years of age
g. Anti-VEGF suboptimal responders who are phakic and younger than 60 years of age
h. Patients scheduled to undergo cataract surgery
i. Patients resistant to laser photocoagulation
j. Patients with a history of vitrectomy
k. Patients with POAG well controlled on 1 glaucoma drop
l. Patients with POAG well controlled on 2 glaucoma drops
m. Patients who have had successful filtration surgery to control IOP
n. Patients that cannot afford branded anti-VEGF treatment?
o. Other (please specify):
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13. How frequently do you monitor subjects who are on anti-VEGF treatment?
a. Monthly
b. Every 2 months
c. Every 3 months
d. Other (please specify):
14. How frequently do you monitor subjects who are on combination anti-VEGF treatment and steroids?
a. Monthly
b. Every 2 months
c. Every 3 months
d. Other (please specify):
15. How frequently do you monitor subjects who are on steroid only treatment?
a. Monthly
b. Every 2 months
c. Every 3 months
d. Other (please specify):
16. What clinical observations occur after a DME patient has either switched treatments from anti-VEGF therapy to steroid
therapy, or steroid therapy has been incorporated in addition to anti-VEGF therapy?
a. [Open ended]
17. Considering your choice of steroids in the management of patients with DME:
a. When would you use a FDA approved steroid? [Open ended]
b. When would you use a non-approved steroid? [Open ended]
c. Which would you prefer when thinking about each of the following items:
i. Efficacy. Please choose from below:
1. Prefer FDA-approved steroid
2. Prefer non-approved steroid
ii. Safety. Please choose from below:
1. Prefer FDA-approved steroid
2. Prefer non-approved steroid
iii. Duration of effect. Please choose from below:
1. Prefer FDA-approved steroid
2. Prefer non-approved steroid
iv. Cost/cost effectiveness. Please choose from below:
1. Prefer FDA-approved steroid
2. Prefer non-approved steroid
18. Which type of implant do you prefer to use, and why? If you use both, please select both options and describe the
scenarios for using each type of implant:
a. Short acting implant [please explain]
b. Long acting implant [please explain]
April 2017 · Vol. 48, No. 4
Section 3: Steroid Use and Side Effects
19. Approximately how frequently do you monitor patients for possible side effects of steroid use?
a. At first follow-up only
b. Once every month
c. Every 2 to 3 months after the first month from an injection
d. Once every 6 months
e. Once a year
f. Other (please specify):
20. To what extent are the side effects of steroid use manageable?
a. [open ended]
21. How do you treat an increase in intraocular pressure following steroid use?
a. [open ended]
b. Is the treatment for increased IOP effective?
i. [open ended]
22. How do you treat glaucoma following steroid use?
a. [open ended]
b. Is the treatment for glaucoma following steroid use effective?
i. [open ended]
DME = diabetic macular edema; VEGF = vascular endothelial growth factor; IOP = intraocular pressure; POAG = primary open-angle glaucoma; FDA = U.S. Food and
Drug Administration
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APPENDIX B
Final Questions
1.
How do you classify DME patients?
a. Center-involved or non-center-involved
b. Focal areas of leakage, peripheral non-perfusion, or diffuse leakage
c. Focal versus diffuse (level of diabetic retinopathy matters)
d. Do not classify DME patients
e. Other
2.
Out of the following, which do you consider to be the most important factor determining an ideal response when
treating DME with an anti-VEGF?
a. Resolution of edema
b. Improvement in VA
c. Improvement in OCT thickness
d. Other
3.
Out of the following, which do you consider to be the second most important factor determining an ideal response
when treating DME with an anti-VEGF?
a. Resolution of edema
b. Improvement in VA
c. Improvement in OCT thickness
d. Other
4.
An inadequate responder to anti-VEGF treatment is determined when after monthly three to four injections, OCTmeasured retinal thickness has not improved by what percent of excess thickness from baseline?
a. 50%
b. 33%
5.
An inadequate responder to anti-VEGF treatment is determined after what number of injections failed to improve
BCVA to 20/x attributable to edema? (Value of “x” be defined in the next question.)
a. One to three
b. Three to six
c. Six to 10
d. Other
6.
An inadequate responder to anti-VEGF treatment is determined after three to six monthly injections failed to improve
BCVA to 20/x attributable to edema, with “x” = what value?
a. 40
b. 20
c. 30
7.
Do you use the number of lines of BCVA improvement in determining inadequate responders to anti-VEGF treatment?
a. Yes
b. No
8.
How long are you prepared to tolerate persistent edema despite treatment with monthly anti-VEGF injections (including any type of anti-VEGF used)?
a. 3 months
April 2017 · Vol. 48, No. 4
b. 4 to 6 months
c. As long as vision is stable or improving
d. Other
9.
Out of the following, what are two key factors that contribute to the different levels of anti-VEGF response? Choose
two answers from below:
a. Level of diabetic retinopathy
b. Balance of VEGF versus other inflammatory cytokines
c. Glycemic control (in diabetes)
d. Previous laser treatments
e. Chronicity of DME
f. Other
10. Out of the following, what is the most important factor that contributes to the different levels of anti-VEGF response?
a. Level of diabetic retinopathy
b. Balance of VEGF versus other inflammatory cytokines
c. Glycemic control (in diabetes)
d. Previous laser treatments
e. Chronicity of DME
f. Other
11. If monthly injection is too burdensome for patients (eg, poor compliance by patients), how would you typically proceed?
a. Likely to consider incorporating additional treatment modalities
b. Likely to consider switching treatment modalities
c. Likely to stop current treatment
d. Likely to continue current treatment
e. Provide better education to improve compliance
f. Other
12. Due to systemic considerations (eg, patients with recent stroke/cardiovascular events), how would you typically proceed?
a. Likely to consider incorporating additional treatment modalities
b. Likely to consider switching treatment
c. Likely to stop current treatment
d. Likely to continue current treatment
e. Other
13. If there is lack of improvement in best-corrected visual acuity, how would you typically proceed?
a. Likely to consider incorporating additional treatment modalities
b. Likely to consider switching treatment
c. Likely to stop current treatment
d. Likely to continue current treatment
e. Other
Ophthalmic Surgery, Lasers & Imaging Retina | Healio.com/OSLIRetina
14. If there is a lack of anatomical improvement (eg, central retinal thickness), how would you typically proceed?
a. Likely to consider incorporating additional treatment modalities
b. Likely to consider switching treatment
c. Likely to stop current treatment
d. Likely to continue current treatment
e. Other
15. When is it important to treat the inflammation component of DME compared to the VEGF component?
a. From the beginning
b. After a suboptimal response to anti-VEGF therapy
c. Never
d. Always
16. What would you most likely do for a patient that does not respond optimally to anti-VEGF agents early (three to six
monthly injections) in their treatment?
a. Continue anti-VEGF therapy
b. Switch anti-VEGF therapy to a different agent within the anti-VEGF class
c. Switch to a steroid
d. Add a steroid
e. Incorporate laser treatment
17. Which steroid would you most typically introduce?
a. Dexamethasone intravitreal implant
b. Fluocinolone acetonide implant
c. Intravitreal triamcinolone acetonide
d. Kenalog
e. Triescence
18. Which steroid would be your second most likely choice for initial steroid therapy?
a. Dexamethasone intravitreal implant
b. Fluocinolone acetonide implant
c. PFTA compounding therapy
d. Kenalog
e. Triescence
19. In a patient being treated for DME, do you use a steroid to help to protect against edema from cataract surgery?
a. Highly likely
b. Somewhat likely
c. Somewhat unlikely
d. Highly unlikely
20. Do you agree that steroid is the most preferred rescue modality?
a. Strongly agree
b. Somewhat agree
c. Somewhat disagree
April 2017 · Vol. 48, No. 4
d. Strongly disagree
21. How do you incorporate macular laser in center-involving DME treatment?
a. Adjunct
b. Rescue
c. First line
d. Never
22. Would you recommend steroid treatment for a patient with POAG and healthy nerve that is well controlled on two
glaucoma drops?
a. Potential candidate
b. Not potential candidate
23. How frequently do you monitor subjects after their first steroid injection?
a. Monthly
b. 6 to 8 weeks
c. Every 2 months
d. Every 3 months
e. 1 month after steroid and 2 to 3 months afterwards depending on IOP
f. Other
24. How frequently should you monitor subjects who are new to combination anti-VEGF treatment and steroids?
a. Monthly
b. 1 to 2 months
c. 2 to 3 months depending on IOP
d. Other
25. How frequently should you typically monitor subjects who are established on combination anti-VEGF treatment and
steroids?
a. Monthly
b. Every 2 months
c. Every 3 months
d. Other
26. After the first steroid injection, approximately how frequently do you monitor patients for possible side effects?
a. Every 2 two 3 months after the first month from an injection
b. Every 6 to 8 weeks
c. Every month for the first one to three injections, then just every 3 months
d. Other
27. Do you do any additional screening for side effects after steroid use beyond efficacy monitoring?
a. Yes
b. No
28. After a problem is detected, do you do any additional monitoring?
a. Yes
b. No
Ophthalmic Surgery, Lasers & Imaging Retina | Healio.com/OSLIRetina
29. How do you typically treat an increase in intraocular pressure (25 mm Hg or below)?
a. Single agent
b. Fixed combination
c. Refer to glaucoma specialist
d. Observe
30. How do you typically treat an increase in intraocular pressure (26 mm Hg to 30 mm Hg)?
a. Single agent
b. Fixed combination
c. Refer to glaucoma specialist
d. Observe
31. How do you typically treat an increase in intraocular pressure (above 30 mm Hg)?
a. Single agent
b. Fixed combination
c. Refer to glaucoma specialist
d. Fixed combination and refer to a glaucoma specialist
DME = diabetic macular edema; IOP = intraocular pressure; OCT = optical coherence tomography; PFTA = preservative-free triamcinolone acetonide; POAG = primary
open-angle glaucoma; VA = visual acuity; VEGF = vascular endothelial growth factor
April 2017 · Vol. 48, No. 4