Download Individualizing Therapy For Patients With Neovascular AMD And DME

CME MONOGRAPH
Instant CME Certificate Available With
Online Testing and Course Evaluation
Individualizing Therapy
for Patients With
Neovascular AMD and DME:
Considerations for
Short- and Long-Term Management
Proceedings from an
Experts Roundtable Discussion
Allen C. Ho, MD (Chair and Moderator)
Robert L. Avery, MD
David M. Brown, MD
Jason S. Slakter, MD
Original Release Date: April 1, 2014
Most Recent Review Date: April 1, 2014
Expiration Date: April 30, 2015
Jointly sponsored by The University of Louisville
Department of Continuing Education and MedEdicus
This continuing education activity is supported through
an unrestricted educational grant from Regeneron Pharmaceuticals, Inc.
Distributed with
PURPOSE AND TARGET AUDIENCE
Experience of anti-VEGF treatment now well under way for neovascular agerelated macular degeneration (AMD) and attentions are directed at better
understanding how to individualize therapy for achieving long-term results.
Treatment of diabetic macular edema (DME) is undergoing a paradigm
shift as anti-VEGF therapy is becoming the treatment standard. Patients
with either of these diseases require lifelong treatment. Results from new
research is adding to the available evidence in helping inform management
approaches for short-term and for long-term treatment.
This educational activity is designed for retina specialists and other
physicians treating AMD and DME.
DESIGNATION STATEMENT
The University of Louisville Continuing Medical Education & Professional
Development designates this educational activity for a maximum of
2.0 AMA PRA Category 1 Credits™. Physicians should claim only the
credit commensurate with the extent of their paticipation in the activity.
ACCREDITATION
This activity has been planned and implemented in accordance with the
Essential Areas and Policies of the Accreditation Council for Continuing
Medical Education (ACCME) through the joint sponsorship of the University of
Louisville and MedEdicus LLC. The University of Louisville School of Medicine
is accredited by the ACCME to provide continuing medical education for
physicians.
INSTRUCTIONS & REGISTRATION
The course takes approximately 2 hours. Please read the monograph,
consult any additional references if needed. Once the materials have been
reviewed, you will go to http://bit.ly/neovascular14 to take a post test
followed by course evaluations, after which you will be able to generate
your CME certificate.
LEARNING OBJECTIVES
Upon completing this educational activity, participants should be able to:
• Describe results of recent studies evaluating anti-VEGF therapy in patients
with AMD and DME
• Apply information on therapeutic strategies to manage persistent fluid in
patients with neovascular AMD and DME who are receiving anti-VEGF
therapy
• Select appropriate anti-VEGF and other therapeutic strategies for long-term
management of patients with neovascular AMD and DME
HARDWARE & SOFTWARE REQUIREMENTS
High speed Internet connection (Broadband, Cable or DSL)
Windows 2000 or higher
256 MBs or more of RAM
Internet Explorer 6.0 higher
Windows Media Player 10.0 or higher
Adobe Acrobat 7.0 or higher
Course content compatible with Mac OS
DISCLOSURE
As a sponsor accredited by the ACCME, the University of Louisville School of
Medicine must ensure balance, independence, objectivity, and scientific rigor in
all its sponsored educational activities. All faculty participating in this CME activity
were asked to disclose the following:
1. Names of proprietary entities producing health care goods or services—with
the exemption of nonprofit or government organizations and non–healthrelated companies—with which they or their spouse/partner have, or have
had, a relevant financial relationship within the past 12 months. For this
purpose, we consider the relevant financial relationships of a spouse/partner
of which they are aware to be their financial relationships.
2. Describe what they or their spouse/partner received (eg, salary, honorarium).
3. Describe their role.
4. No relevant financial relationships.
2
DISCLOSURES
CME Reviewers: Shlomit Schaal, MD, PhD, has no relevant financial
relationships with any commercial interests. John Sorenson, MD, has no
relevant financial relationships with any commercial interests.
Faculty: Dr Robert L. Avery: Alcon, Inc (Consultant, Speaker); Allergan,
Inc (Consultant, Investigator); Bausch + Lomb Incorporated (Consultant);
Genentech, Inc (Consultant, Speaker, Investigator); Iridex Corporation
(Consultant); Notal Vision (Consultant); Novartis (Consultant, Ownership
Interest); Ophthotech Corporation (Consultant, Ownership Interest); QLT Inc
(Consultant); Regeneron Pharmaceuticals, Inc (Consultant, Ownership Interest);
Replenish Inc (Consultant, Advisory Board, Ownership Interest, Intellectual
Property Rights, Royalty); and SKS Ocular, LLC (Ownership Interest).
Dr David M. Brown: Allergan, Inc (Consultant, Independent Contractor);
Genentech/Roche (Consultant, Independent Contractor); Novartis (Consultant,
Independent Contractor); and Regeneron/Bayer (Consultant, Independent
Contractor).
Dr Allen C. Ho: Allergan, Inc (Consultant, Scientific Advisory Board); Genentech,
Inc (Consultant, Scientific Advisory Board); and Regeneron Pharmaceuticals, Inc
(Consultant, Scientific Advisory Board).
Dr Jason S. Slakter: Acucela Inc (Consultant, Contracted Research); Alimera
Sciences (Contracted Research); Bayer (Contracted Research); Genentech,
Inc (Contracted Research); Genzyme Corporation (Contracted Research);
Lpath Incorporated (Consultant, Contracted Research); Novagali Pharma SAS
(Contracted Research); OHR Pharmaceutical Inc (Consultant, Contracted
Research); Oraya Therapeutics, Inc (Consultant, Contracted Research);
Regeneron Pharmaceuticals, Inc (Consultant, Contracted Research); sanofiaventis U.S. LLC (Contracted Research); Santen Pharmaceutical Co, Ltd
(Contracted Research); and SKS Ocular, LLC (Ownership Interest).
MedEdicus: Cynthia Tornallyay, RD, MBA, CCMEP, and Barbara Lyon have no
relevant financial relationships with any commercial interests. Writer: Tony
Realini, MD, MPH: Alcon, Inc (Consultant, Contracted Research); Lumenis Ltd
(Honoraria, Contracted Research); and Sensimed AG (Contracted Research).
University of Louisville CME & PD: The CME & PD staff and Advisory Board
have nothing to disclose with the exception of Dr Douglas Coldwell: Sirtex, Inc
(Speaker) and DFine, Inc (Consultant).
Medium or Combination of Media Used: Online Enduring Material Activity
Method of Physician Participation: Printed and Online/Digital Monograph
Estimated Time to Complete the Educational Activity: 2.0 hours
COMMERCIAL SUPPORT
This activity is supported through an unrestricted educational grant from
Regeneron Pharmaceuticals, Inc.
SPECIAL SERVICES
If you need special accommodations due to a disability or for an alternative
form of course materials, please contact us at [email protected].
Continuing Medical Education & Professional Development fully complies with
the legal requirements of the ADA and the rules and regulations thereof.
PROVIDER CONTACT INFORMATION
For questions about the CME activity content, please contact University of
Louisville at [email protected].
PRIVACY POLICY
All information provided by course participants is confidential and will not be
shared with any other parties for any reason without permission.
COPYRIGHT
© 2014 MedEdicus LLC
FACULTY
Allen C. Ho, MD (Chair and Moderator)
Professor of Ophthalmology
Thomas Jefferson University School of Medicine
Attending Surgeon
Wills Eye Retina Service
Philadelphia, Pennsylvania
Robert L. Avery, MD
Founder
California Retina Consultants
and Research Foundation
Santa Barbara, California
David M. Brown, MD
Retina Consultants of Houston
Clinical Associate Professor
Weill Cornell Medical College, Methodist Hospital
Houston, Texas
Jason S. Slakter, MD
Clinical Professor of Ophthalmology
New York University School of Medicine
Partner
Vitreous Retina Macula Consultants of New York
INTRODUCTION
The clinical management of retinal diseases such
as age-related macular degeneration (AMD) and
diabetic macular edema (DME) continues to evolve
rapidly as novel therapies and new clinical trial
outcomes expand and refine our practice patterns.
In this educational activity, our primary goal is
to clarify optimal management of these common
retinal diseases in the context of existing and
emerging data from new and ongoing clinical trials.
We also will explore the therapeutic landscape and
provide pearls for selecting the appropriate therapy
for each patient on an individualized basis, as well
as examine the long-term management of these
chronic diseases. We hope that the discussion that
took place among our expert faculty panel provides
insight for the management of patients in your
clinical practice.
—Allen C. Ho, MD, Chair and Moderator
NEOVASCULAR AGE-RELATED MACULAR
DEGENERATION
Dr Ho: First-line therapy for neovascular AMD using
inhibitors of vascular endothelial growth factor ( VEGF) is a
paradigm shift that is now supported by a substantial volume
of Level I evidence. Equally importantly, we now have highquality data from randomized clinical trials demonstrating
the efficacy of not just 1 or 2, but multiple anti-VEGF agents.
The ability of retina specialists to improve significantly the
quality of life of the legions of older adults with neovascular
AMD has never been greater. These trials are, importantly,
not all industry sponsored, and many have been designed to
directly compare these agents, head to head. Driven by this
compelling body of evidence, we now have a high treatment
burden because many patients need frequent monitoring
and retreatment. It is neither practical nor necessary for all
patients to be seen and retreated monthly. However, once
we deviate from the frequent treatment schedule that has
been shown in many trials to provide the best visual acuity
( VA) outcomes, we find ourselves with less data to support
alternative treatment regimens.
3
Dr Avery: CATT was a 2-year noninferiority study
comparing bevacizumab and ranibizumab for the management
of neovascular AMD. There were 4 treatment groups,
with each drug being dosed either monthly or PRN, with
prespecified PRN retreatment criteria that indicated active
neovascularization and included fluid visualized with optical
coherence tomography (OCT), new or persistent hemorrhage,
decreased VA from the previous visit, or dye leakage or
increase in lesion size on fluorescein angiogram (FA). The
primary outcome measure was the mean change in VA at
1 year. Both 1-year1 and 2-year2 results have been reported in
the literature. These results demonstrated that the 2 drugs
were fairly similar in efficacy, particularly when dosed monthly
throughout the 24-month study (Figure 1). The mean change
in VA at 1 year in the monthly bevacizumab group (8.0 Early
Treatment Diabetic Retinopathy Study [ETDRS] letters)
was statistically noninferior to that shown in the monthly
ranibizumab group (8.5 ETDRS letters). In the PRN groups,
gains in the ranibizumab and bevacizumab groups were 6.5 and
5.9 letters, respectively, also noninferior. After the first year,
patients in the monthly treatment groups were rerandomized
to either continue monthly treatment or to switch to PRN
treatment using the same retreatment criteria.
At 2 years, the mean gains in VA in the monthly ranibizumab
and bevacizumab groups were 8.8 and 7.8 letters, respectively,
while the corresponding PRN groups gained 6.7 and 5.0 letters,
respectively, which were also noninferior with respect to drug
comparison, but the monthly outcomes were better than the
PRN outcomes (P=.046). Secondary outcomes also were
evaluated. Patients in the bevacizumab PRN group required
more frequent injections than those in the ranibizumab PRN
group (14.1 vs 12.6 over 24 months, respectively; P=.01).
Likewise, 45.5% of patients in the monthly ranibizumab group
were fluid-free on OCT at 24 months compared with only
4
Mean Change in Visual Acuity Score From
Baseline (no. of letters)
Herein we plan to shed some light on current practice
patterns in an evidence-based manner, and to provide some
clinical pearls for the management of patients with AMD
in your practices. These practice patterns are informed
by the lessons we have learned, and continue to learn,
from recent and ongoing clinical trials, including the CATT
(Comparison of AMD Treatments Trials), HARBOR (Study of
Ranibizumab Administered Monthly or an on As-Needed Basis
in Patients With Subfoveal Neovascular Age-Related Macular
Degeneration), and VIEW ( VEGF Trap-Eye Investigation of
Efficacy and Safety in Wet AMD) trials, among others around
the world, such as IVAN (Inhibit VEGF in Age-related Choroidal
Neovascularization), MANTA (Multicenter Anti-VEGF Trial in
Austria), and GEFAL (French Evaluation Group Avastin Versus
Lucentis). Dr Avery, please provide an overview of the CATT
study.
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Mean no. Inj:
R-M:
22
B-M:
23
R-PRN:
12.6
B-PRN:
14.1
Ranibizumab Monthly
Bevacizumab Monthly
Ranibizumab as Needed
Bevacizumab as Needed
+8.8
+7.8
+6.7
+5.0
Ranibizumab difference: 8.8-6.7=2.1 letters
Bevacizumab difference: 7.8-5.0=2.8 letters
0 4
12
N (146, 135, 287, 270)
24
36
52
64
(145, 135, 285, 270)
76
88
104
(134, 129, 264, 251)
Follow-Up Weeks
Figure 1. CATT results at 2 years.2
13.9% of those in the bevacizumab PRN group (P=.0003).
Also, mean retinal thickness was significantly lower at 24
months in the 2 monthly treatment groups compared with
their respective PRN treatment groups. The clinical importance
of the reduced retinal thickness is unclear. In general, thinner
is better; however, there is concern that in some patients, the
retina can be too thin, which can be associated with decreased
vision—for instance, if there is geographic atrophy.
Dr Ho: What is your practical take-home message from
CATT regarding drug efficacy?
Dr Avery: The take-home message is that these 2 drugs
and these 2 treatment regimens were fairly equivalent. When
given monthly, there was no significant difference in visual
outcome between bevacizumab and ranibizumab, despite
improved anatomic outcomes with ranibizumab. There
was a slight sacrifice of VA by using PRN instead of monthly
treatment. Also, there was a slight and statistically significant
increase in systemic serious adverse events with bevacizumab
vs ranibizumab. A similar trend has been observed in
3 other studies at the 1-year time point—IVAN,3 GEFAL4
and MANTA5—but not in LUCAS (Lucentis Compared to
Avastin Study).6 The clinical significance of an approximately
30% higher rate of systemic serious adverse events with
bevacizumab is not known.
Dr Ho: Panelists, are there any additional take-home
messages from CATT?
Dr Slakter: I have always had the clinical impression
that ranibizumab produced a better clinical outcome in
some selected patients. When dosed monthly, the drugs
are equivalent; however, with PRN dosing there is less of an
anatomic effect with bevacizumab than with ranibizumab. As
Dr Avery noted, the proportion of patients without fluid on
OCT was significantly greater in the ranibizumab PRN group
than in the bevacizumab PRN group. Therefore, when given
the choice, I prefer to use ranibizumab over bevacizumab.
The CATT data certainly demonstrate that I have not
been choosing the wrong agent. Interestingly, given that
both drugs were similar in efficacy when dosed monthly,
physicians who prefer bevacizumab also use the CATT data
to support their practice patterns. CATT did demonstrate
that bevacizumab dosed PRN may not be the best choice.
Dr Avery: I completely agree that CATT was taken as a
positive outcome for proponents of both bevacizumab and
ranibizumab. The difference in the number of injections is
also important and worth repeating. The PRN bevacizumab
group needed more injections per year than the PRN
ranibizumab group, and despite these extra injections, there
was a trend for VA outcomes in the bevacizumab PRN group
to be not quite as good as those in the ranibizumab PRN
group (5.0 vs 6.7 letters gained at 2 years).
Dr Ho: In CATT, the PRN groups received a single initial
injection, then were followed monthly for disease activity;
this protocol is different from many other studies with
less-than-monthly treatment arms in which there were 3
initial monthly injections, or a “loading dose”. Be aware of
this nuance when considering CATT in comparison to IVAN,
MANTA, and GEFAL. Efficacy is always a high consideration
in choosing a treatment agent and regimen, but safety
considerations are typically primary. How do the ocular and
systemic safety data from CATT affect your choice of antiVEGF agents?
Dr Brown: In terms of systemic safety, it is difficult to
make recommendations from the CATT data, as the actual
numbers of patients with systemic adverse events was very
small in each of the groups. First, I have difficulty believing
that any of these drugs, when injected in small quantities into
the vitreous cavity, achieve adequate systemic levels to cause
systemic adverse events. Such events—myocardial infarctions
and strokes, for example—happen naturally in people who
are in the age range of our AMD patients, and whether the
events seen in these trials were causally attributable to the
drugs has not been established. Second, the ocular safety
issues are more interesting, and among these, the risk for
endophthalmitis is one that concerns me.
In CATT, the doses of bevacizumab were prepared under a
strict protocol and provided in glass vials. This is significantly
different from the standard formulation of bevacizumab
I use in the clinic, in which the drug is formulated in
small batches under a variable degree of scrutiny and is
supplied in a plastic syringe in a plastic bag. In plastic
syringes, proteins aggregate,7 and the amount of active
drug available is variable. I was much more comfortable
using the strictly formulated bevacizumab in CATT than I
am using the formulation available in clinical practice. I am
unconvinced that the results of CATT can be generalized to
our routine clinical experience in terms of the true risk for
endophthalmitis due to drug formulation.
Dr Avery: I believe that there is a systemic effect of these
intravitreal injections of anti-VEGF agents. We have conducted
pharmacokinetic studies demonstrating that all 3 of the major
agents produce a transient but sometimes fairly pronounced
drop in the free VEGF levels as measured in plasma.8 This
drop in free VEGF levels is very transient with ranibizumab,
which has a very short systemic half-life, but it is prolonged
with bevacizumab and with aflibercept, lasting at least 7 days
and sometimes up to a month after the injection. I agree with
Dr Brown regarding causality. Whether this systemic VEGF
inhibition correlates with the systemic adverse events or not is
still unclear. But the pharmacokinetic data support a biologic
plausibility that some of these adverse events could be caused
by the systemic VEGF level changes.
Dr Ho: Many share some of the concerns regarding systemic
safety, although we recognize that all these AMD trials are
underpowered for the purpose of discerning statistically
meaningful differences in safety events. The body of evidence
from all 4 comparative clinical trials (CATT, IVAN, MANTA,
GEFAL) shows a potential disadvantage to bevacizumab with
respect to systemic adverse events supported by biologic
plausibility. Furthermore, any compounded preparation, by
definition, is prepared with less stringent safety conditions than
a commercially manufactured product.
On the other hand, likely every retina specialist around
the world has used intravitreal bevacizumab to the benefit
of his or her patients with great clinical and overall value.
Bevacizumab is used widely because it is significantly less
expensive than ranibizumab, or aflibercept, and when
dosed comparably, bevacizumab and ranbizumab produce
comparable VA outcomes. However, there may be some other
costs to consider. In addition to potential systemic adverse
effects just mentioned, these include the additional potential
risk for contamination from a compounded preparation
of bevacizumab for intraocular use, and also the potential
liability of using an off-label drug when 2 US Food and Drug
Administration (FDA)-approved drugs formulated specifically
for intraocular use are available. We are fortunate to have
treatment options. Let us consider the newest anti-VEGF
agent approved for the treatment of neovascular AMD,
aflibercept. Dr Slakter, please summarize the VIEW 1 and
VIEW 2 trials.
Dr Slakter: The VIEW studies were aflibercept’s registry
trials, of which the FDA requires 2. Patients with neovascular
AMD were randomized to 1 of 4 treatment groups: aflibercept
2 mg dosed monthly; aflibercept 2 mg dosed in 3 monthly
loading doses, and then every other month; aflibercept 0.5 mg
monthly; or ranibizumab 0.5 mg monthly. Aflibercept
5
The primary outcome was the proportion of patients
losing fewer than 15 ETDRS letters at the 52-week time
point, using a noninferiority statistical analysis of the
aflibercept groups in comparison to ranibizumab. Both
1-year9 and 2-year10 outcomes have been reported. At
1 year, the proportions of patients losing fewer than 15
letters in both aflibercept 2-mg groups were statistically
noninferior to those in the ranibizumab group in both
VIEW studies, with approximately 94% to 96% of patients
in all groups meeting this end point in both studies. In
the second year of the VIEW studies, all treatment groups
transitioned to a capped PRN dosing strategy that mirrored
traditional PRN therapy, with the exception that patients
were treated every 3 months even if retreatment criteria
were still not met. At 2 years, the mean change in VA from
baseline was 7.6 ETDRS letters in the aflibercept 2-mgevery-other-month group and 7.9 ETDRS letters in the
ranibizumab monthly group (Figure 2), a difference that
was not statistically significant. These similar outcomes
were accomplished with fewer injections in the aflibercept
group (average 11.2 injections over 2 years) compared
with the ranibizumab group (average 16.5 injections over
2 years).
The key take-home message from the VIEW studies is
that with aflibercept, every-other-month dosing after
3 monthly loading doses provides stability of VA
comparable to ranibizumab dosed every month. It is
important, however, to acknowledge that we do not
typically treat our ranibizumab patients every month. Most
of us use a treat-and-extend approach. The VIEW data
do not specifically tell us that aflibercept works longer
than ranibizumab. A patient who can extend to 8 weeks
using ranibizumab will not likely extend to 16 weeks using
aflibercept. But these data do suggest that aflibercept
may be more durable in some patients, although not
necessarily in every patient.
Dr Ho: The capped PRN treatment regimen in year 2 of
the VIEW trials mandated injections every 3 months and
may have undermined injection number differences in
the VIEW trials; that is, there was a requirement to inject
when clinical circumstances may not have called for an
injection. Naturally, that applies for both ranibizumab and
aflibercept. Is there anything else to add to this excellent
summary of the VIEW trials for aflibercept?
6
14
12
ETDRS Letters
2 mg was eventually approved by the FDA, so I will not talk
further about the 0.5-mg treatment arm: I will focus on the
2-mg groups dosed either monthly or every other month
following 3 monthly loading doses.
10
7.9
7.6
7.6
6.6
8
9.3
8.7
8.4
8.3
6
4
2q4
Rq4
2q8
0.5q4
Rq4
2q8
2q4
0.5q4
2
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
Week
Rq4
2q4
0.5q4
2q8
Rq4=ranibizumab every 4 weeks
2q4=aflibercept 2 mg every 4 weeks
0.5q4=aflibercept 0.5 mg every 4 weeks
2q8=aflibercept 2 mg every 8 weeks after 3 monthly loading doses
Figure 2. VIEW 2-year outcomes. Mean change in VA.10
Dr Brown: Dr Slakter correctly points out that VIEW does
not support that aflibercept lasts longer than ranibizumab
for the average patient. In VIEW, there was no arm in
which ranibizumab was dosed every 2 months. It is the
general consensus that for many patients aflibercept lasts
approximately a week or so longer than ranibizumab in a
treat-and-extend regimen. In my experience, when dosing
ranibizumab on a treat-and-extend regimen, I typically can
extend 1 to 2 weeks beyond the standard 4-week dosing
regimen for most patients. Being able to dose every 8 weeks
vs every 6 weeks means fewer injections and fewer visits to my
office per year.
Dr Avery: The second year of the VIEW studies utilized
a capped PRN arm. Everyone got injected at the 3-month
mark whether they needed it or not. Even with this regimen,
there was a slight difference between the ranibizumab and
the aflibercept PRN groups of approximately a half injection
less per year with aflibercept. This is further indirect evidence
that aflibercept has a little longer durability of effect than
does ranibizumab. My clinical impression is similar to that of
Dr Brown, that we get a slightly longer durability of effect—
perhaps a week longer on average—with aflibercept than with
ranibizumab.
Dr Ho: The study design of the VIEW studies—specifically
the capped PRN approach in year 2—limits our knowledge of
the true duration of action of aflibercept and of ranibizumab.
Might these patients have gone longer than 3 months if they
had not been required to receive a PRN treatment at month 3?
Dr Ho: That is an excellent point and it is clear that these
clinical trials answer specific questions, but provide only
guidelines for therapy. Individualized therapy is an important
concept for clinicians to practice because neovascular AMD
is a heterogeneous condition with a broad range of injection
requirements to control exudative disease. Dr Brown, please
summarize the HARBOR trial and provide us the key takehome points from that study.
Dr Brown: HARBOR was a 12-month prospective
randomized study in treatment-naïve patients with subfoveal
neovascular AMD assigned to treatment with ranibizumab
using 1 of 4 different treatment regimens: 0.5 mg or
2 mg, each dosed either monthly or PRN after 3 monthly
loading doses. PRN retreatment criteria were prespecified
and pertained to reductions in VA or evidence of active
neovascularization by spectral-domain (SD) OCT. The
primary end point was the mean change in best corrected
VA from baseline at month 12.
The 12-month results have been reported.11 To summarize
the results, there was no benefit to the increased dose of
ranibizumab (Figure 3). The mean VA gains were 10.1, 8.2,
9.2, and 8.6 ETDRS letters in the 0.5-mg monthly, 0.5-mg
PRN, 2-mg monthly, and 2-mg PRN groups, respectively, at
12 months (Table 1). Key secondary end points also were
evaluated. The proportions of patients gaining 15+ ETDRS
letters ranged from 30% to 36% across the groups, and
mean changes in central foveal thickness by SD-OCT ranged
from 161 to 172 microns. In the PRN groups, the 0.5-mg
group required 7.7 injections on average, compared with 6.9
injections in the 2-mg group. The key take-home message
from HARBOR is that the 0.5-mg dose of ranibizumab appears
to be at the top of the dose-response curve, with no benefit
from a higher dose in treatment-naïve patients.
Mean #Rx as needed Yr 1 & 2
0.5 mg: 7.7 & 5.6
2.0 mg: 6.9 & 4.3
12
Mean Change in BCVA (letters)
Dr Avery: This discussion very elegantly illustrates the
need to practice individualized medicine. Consider the
HARBOR trial. In the PRN arms of that study, there were
a few patients—approximately 6% or 7%—who required
monthly injections over 2 years. But there were also patients
who needed only 6, or 5, or 4, or even 3 injections over
the same time period. The need for retreatment is highly
individual, and it is difficult to predict up front who will need
more and who will need fewer injections.
10
8
6
0.5 mg monthly
0.5 mg as needed
2.0 mg monthly
2.0 mg as needed
4
2
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Evaluation Interval (Month)
Figure 3. Two-year VA outcomes in the HARBOR study
evaluating multiple doses of ranibizumab for AMD.11
Dr Ho: The HARBOR Study had a strict and low tolerance
for retreatment and is our only major neovascular AMD trial
to use all SD-OCT imaging. Many retina specialists thought
that the 2-mg dose of ranibizumab would achieve higher
efficacy, but this result was not realized. Are there any other
lessons to be learned from HARBOR?
Table 1. Mean change in BCVA (letters) in the Harbor Study11
Ranibizumab
0.5 mg monthly
0.5 mg PRN
2.0 mg monthly
2.0 mg PRN
Month 12
Month 24
Change Month 12
to Month 24
+10.1
+8.2
+9.2
+8.6
+9.1
+7.9
+8.0
+7.6
—1.0
—0.3
—0.3
—1.0
Dr Avery: The 2-mg dose appeared to have a slightly
longer half-life, as evidenced by the fewer number of
injections required by participants in the 2-mg PRN group
compared with those in the 0.5-mg PRN group. So the
higher dose provided a little more durability of effect.
Dr Brown: The safety profiles were similar in both
dosing groups as well. There was not an increase in adverse
events when the dose was increased 4-fold. This finding
is reassuring in light of the uncertainty surrounding the
systemic adverse event issues seen in the large clinical
trials. I am not very concerned about systemic adverse
events rates in AMD patients with our current dose of
ranibizumab.
7
Dr Ho: We have now discussed the key data for each of
our anti-VEGF agents. Let us set the premise for just this
next question. If cost and insurance coverage were not
issues, what would be your first choice for therapy for a
typical newly diagnosed neovascular patient with AMD?
Dr Slakter: I would choose aflibercept for 2 reasons.
First is its apparent increased durability. In a chronic
disease with the potential need for lifelong therapy, an
extra week or 2 between injections significantly reduces the
overall number of injections necessary, and thus reduces
the cumulative probability of developing a complication
related to the injection procedure, such as endophthalmitis.
Second is that aflibercept seems to be effective in eyes that
have suboptimal responses to ranibizumab or bevacizumab,
such as those with retinal pigment epithelial detachments,12
polypoidal choroidal vasculopathy,13 or, in my personal
experience, central serous chorioretinopathy. I want to
select the drug most likely to give the best response from
day 1. On the basis of the data and my personal experience
to date, that drug would be aflibercept.
Dr Brown: My first choice would be ranibizumab or
aflibercept. I would start with ranibizumab, and if the
macula is not dry after the first 3 injections, I would switch
to aflibercept. I recognize that ranibizumab may have
the shortest half-life of the available agents,8 but it is also
familiar and well established in clinical practice. Genentech
also has a more fully developed access program and sample
ranibizumab that allows me to treat patients who need it on
the spot without having to wait for insurance authorization.
Dr Avery: I, too,would start with ranibizumab or
aflibercept, given that cost would not be an issue. In a
patient with any issues that make me concerned about the
risk for systemic safety events—the extremely elderly, those
with a past stroke, or cardiovascular disease or diabetes, for
instance—I will usually err on the side of ranibizumab. In
the absence of potential safety issues, I often will start with
aflibercept because it seems to have a longer duration of
effect.
Dr Ho: My own practice pattern is in consensus with
those of my fellow panel members. Now that we have
discussed the agents, let us discuss the various dosing
regimens. Our typical choices are monthly—or every other
month with aflibercept—vs PRN vs treat-and-extend. Once
you have selected a drug, be it aflibercept, bevacizumab, or
ranibizumab, what is your preferred treatment regimen for
wet AMD?
8
Dr Avery: My preferred approach is treat-and-extend.
I give an initial injection and reevaluate in 4 weeks. If a
patient’s macula is flat and dry on OCT at 4 weeks, I will
extend by 2 weeks at a time. I do not routinely give 3
monthly loading doses before extending. In CATT, patients
essentially got 12 monthly loading doses in the first year
before going to PRN in year 2, and the outcomes were not
substantially different from those in the group who received
PRN therapy from the start. So it is not clear to me that 3
monthly loading doses are necessary. Exceptions include
high-risk patients, such as those blind in the fellow eye,
in whom I tend to stay on monthly therapy. If we achieve
stability and the disease involutes, I may transition to PRN
therapy.
Dr Brown: I start with 3 monthly loading doses of
my first-choice anti-VEGF drug. We have evidence that a
3-monthly-loading-dose regimen results in better VA than
does 1 dose.14,15 Then I reassess. If the macula is dry, I
extend. With ranibizumab, I will not extend past 10 weeks,
according to the pharmacokinetic data. For aflibercept, I do
not yet know the maximum time. There are a few patients—
perhaps 15% or 20%—who will not require any further
injections after the 3 loading doses. However, most will start
leaking again at 6 or 7 weeks post-injection.
The CATT data showed us that the patients in the PRN
arms progressively had loss of their initial VA gains. In light
of these data, in my opinion, PRN therapy for neovascular
AMD should be abandoned for standard care. Why would
you insist on recurrence of exudation before redosing an
efficacious medication?
Dr Slakter: I use the treat-and-extend regimen following
a 3-dose load. I use the initial response during those 3
months to inform my extension. If the macula is dry at
1 month vs 2 or 3 months, I am more confident about
extending. I typically will not extend beyond 10 to 12 weeks.
I use those 3 injections to give me an idea of how quickly I
can extend. If the macula is flat very quickly, then I feel more
comfortable extending more rapidly. If the patient still has
some fluid after 3 injections, then I will continue monthly
until the macula is dry, and extend very slowly.
Dr Ho: I also use the treat-and-extend approach, but I am
mindful that the literature supports that nothing provides
better VA outcomes than monthly or frequent therapy;
consider the decline in vision in the CATT trial in year 2
when monthly subjects were changed to a PRN regimen.
For this reason, I have a very low threshold for retreating,
and if I am undecided, I typically will retreat. My treat-andextend injection interval limit for ranibizumab or aflibercept
is typically 12 weeks, but not all patients require chronic
ongoing therapy and therefore, with involuted lesions, I may
treat PRN. Let us now discuss those difficult patients we all
have in our practices who have suboptimal responses to
our initial anti-VEGF intervention. What do we consider a
suboptimal response, and how do we handle these patients?
Dr Slakter: If after 3 monthly injections there is
absolutely no change in the retina, I will switch to a different
agent. If I get a partial response, I will continue through a
total of 4 to 5 injections. Before switching, however, I seek
to determine whether the agent is not working, or whether
it simply is not lasting long enough. One approach in these
patients is to bring them in 2 weeks after their injection,
rather than 4 weeks later, and see if their macula is dry. Some
patients respond well, but the effect wears off before 4 weeks.
If the macula is dry at 2 weeks but not at 4 weeks, I will use an
every-2-week treatment regimen. If they are not dry 2 weeks
after an injection, it is time to try something different.
Dr Brown: In my patients who require retreatment more
often than every 4 weeks, I also consider the presence of
lesion characteristics that might help guide my choice of
therapy. If I see evidence of polypoidal choroidal vasculopathy,
the EVEREST study supports photodynamic therapy in
combination with anti-VEGF therapy,16 for instance. The same
is true for presumed AMD that is actually undiagnosed central
serous chorioretinopathy, which occurs in patients who are
poor responders to anti-VEGF therapy—this can be treated
with photodynamic therapy alone without anti-VEGF therapy.
Likewise, an extrafoveal lesion may best be treated with
photocoagulation as in the Macular Photocoagulation Study
(MPS)17 rather than with anti-VEGF therapy.
Dr Ho: If you have determined the need to switch to
another therapy, to what do you switch?
Dr Avery: I typically progress from bevacizumab to
ranibizumab to aflibercept, in that order, except for the
high-risk patients I mentioned earlier in whom I start with
ranibizumab. If I cannot get the disease under control with
very frequent injections, photodynamic therapy is often my
next step.
Dr Ho: Related to the nonresponder patient is the patient
who was responding but has now stopped responding.
Consider a patient who responded very well to your therapy
and has a completely dry macula, but which then begins
leaking again. What is your next step for such a patient?
Dr Avery: Issues such as tolerance and tachyphylaxis
have been debated recently, but in most instances I think
these are simply cases of the disease getting worse. In
these situations, I either dose the drug more frequently
or switch to a different drug. Fortunately, these sorts of
relapses are uncommon. Typically, patients who are well
controlled on therapy remain well controlled, and often
can get by with less for long periods of time.
Dr Ho: Does changing to a different agent produce
better results in these patients?
Dr Brown: Interestingly, in the few studies that have
evaluated therapy changes, there are typically small
improvements in structure but not commensurate changes
in function.18,19 What I mean is that the OCT looks better,
but the vision does not improve. One important issue
is that of selection bias: we change therapy only in the
patients who had a poor response to initial therapy. These
may be the patients who will do poorly on any therapy.
Nevertheless, they are in our practices and we have to do
something. Switching therapy is reasonable, but may not
be very effective in most patients.
Dr Ho: In the patients who remain dry and stable with
good vision on therapy, is there an end to treatment or
should they receive therapy indefinitely?
Dr Avery: It is a challenge to know how to manage
the patient who has successfully extended to 12 weeks
for a long period of time. Should we stop abruptly, or
wean by treating every 3 months or PRN for a year first?
There are risks to continuing treatment as well as risks
to withdrawing treatment. I have the risk-benefit talk
with these patients and we make the decision together.
In the 1-eyed patient, I am much more inclined to
treat indefinitely. The risk of extending too long or of
discontinuing therapy is that the patient will return with
a subretinal hemorrhage in his or her only eye and never
regain vision. I have 1-eyed patients whom I have treated
monthly for up to 8 years who still have good vision.
Dr Brown: Once we extend to 10 weeks, I obtain
an FA, and in the absence of evidence of active
neovascularization, I give the patient the option of
reducing therapy.
Dr Slakter: I start managing the expectations
surrounding chronic therapy very early in the disease
process. I inform patients that we are going to start with
monthly therapy, and that they likely will need therapy for
the rest of their lives, but my goal is to get them stable so
we can see each other only every 3 months. If I can extend
them to 3 months, I will treat them quarterly forever or at
least until we have new forms of therapy.
9
Dr Ho: Is there a clinical pearl for the management of
available if prespecified criteria were met. The primary
outcome was the proportion of patients who gained a
minimum of 15 ETDRS letters from baseline at month
24. After month 24, subjects initially randomized to sham
therapy were treated with ranibizumab 0.5 mg monthly.
Two- and 3-year results have been reported.20,21 The
proportion of subjects meeting the primary outcome
threshold at 3 years was 19% to 22% in the sham/
ranibizumab 0-5-mg group, 37% to 51% in the ranibizumab
0.3-mg group, and 40% to 42% in the ranibizumab 0.5-mg
group. Both groups receiving initial ranibizumab did better
than the group receiving initial sham therapy (P≤.0026),
and the sham group did not catch up to the 2 active
groups after crossing over to ranibizumab therapy after
year 2 (Figure 4).
neovascular AMD?
Dr Slakter: In the past 8 years we have been fortunate
to see the introduction of anti-VEGF drugs that have
fundamentally altered the potential for visual outcomes in
people with exudative AMD. A thorough understanding of
the utility of each of these 3 drugs, as well as of the value
of the different treatment regimens, is critical in delivering
optimal care to our patients.
Dr Ho: We and our patients benefit from several
effective anti-VEGF therapies approved for neovascular
AMD. In general, our panel prefers on-label medication
(aflibercept or ranibizumab) as an initial agent and
generally employs a treat-and-extend approach. There is
some wariness regarding systemic safety concerns of offlabel use of bevacizumab, but all our panelists agree that
this is not proven; further, there is some inherent risk of a
compounded medication. Nevertheless, each panelist uses
off-label bevacizumab in his practice to varying degrees.
Unlike in AMD, the 0.3-mg dose of ranibizumab was at
the top of the dose-response curve and was approved
by the FDA for DME. The Diabetic Retinopathy Clinical
Research Network (DRCRnet) also has conducted a series
of studies evaluating anti-VEGF therapy for DME, of which
its Protocol I is of interest. This study assigned patients
to 4 treatment groups: sham injection plus prompt laser,
ranibizumab 0.5 mg plus prompt laser, ranibizumab 0.5
mg plus laser deferred for at least 24 weeks, triamcinolone
4 mg plus prompt laser. Retreatment was available if
prespecified criteria were met. The primary outcome was
the change from baseline in ETDRS VA at 12 months. The
1-year,22 2-year,23 and 3-year24 results have been reported
(Table 2).
There is general consensus that aflibercept may have
the greatest durability among our treatment options.
It is unclear whether switching agents in the setting of
unresponsive or previously responsive patients provides
meaningful visual benefit in our most challenging patients;
there is more evidence of anatomic benefit, although
these data are still evolving. There is no real consensus on
an end point for treatment with anti-VEGF therapy; some
clinicians treat indefinitely while others treat PRN.
Briefly, RISE and RIDE enrolled patients with diabetes
who had macular edema and VA of 20/40 or worse and
randomized them to receive either sham injections or
ranibizumab in a 0.3-mg or 0.5-mg dose. Rescue laser was
20
10
12.4
11.2
11.7
5
4.5
0
-5
2.5
Day 7
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36
Month
Subgroup of patients receiving ≥ 1 st
Figure 4. Three-year VA outcomes in the RISE and RIDE
20
studies
of diabetic macular edema.21
RIDE
Reprinted with permission from Elsevier.
13.9
15
13.0
12.8
13.1
10
7.5
5
4.5
0
50
n CFT, µm
12.0
15
-5
10
RIDE RISE Pooled
Mean change in CFT, µm
in that, for DME, there was an established effective
treatment—laser photocoagulation—before the advent
of anti-VEGF therapy. Thus, a higher threshold has been
established for a paradigm shift in DME: a new treatment
has to be better than the existing treatment in order
for a paradigm shift to occur. Numerous studies have
demonstrated that anti-VEGF therapy is, in fact, better than
laser therapy for the management of DME. Among these,
the RISE and RIDE trials were the registry trials that led to
ranibizumab’s approval for the management of DME.
Mean BCVA change, ETDRS letters
Dr Ho: Diabetic macular edema differs from AMD
Mean BCVA change from
baseline, letters
DIABETIC MACULAR EDEMA
RIDE and RIS
Day 7
0
RIDE
6
12
18
24
30
36
Month
0
-50
-100
-147.0
-1
Table 2. Mean ETDRS Letter Gains at 1, 2, and 3 Years
From Baseline in DRCRnet Protocol I Evaluating Ranibizumab
for DME.22-24
Year 1
Year 2
Year 3
Sham plus prompt laser
+3
+3
—
Raniibizumab 0.5 mg plus prompt laser
+9
+7
+6.8
Raniibizumab 0.5 mg plus deferred laser
+9
+9
Triamcinolone 4 mg plus prompt laser
+4
+2
+9.7
—
Additionally, 2 trials have evaluated the effect of aflibercept
on DME. Dr Brown, please summarize the aflibercept VIVID
and VISTA studies and provide some overall take-home
messages from these anti-VEGF trials for DME.
Dr Brown: VIVID and VISTA are the 2 ongoing registry
trials of aflibercept for DME. In these studies, patients with
DME received either aflibercept 2 mg monthly, aflibercept 2
mg every other month (after 5 monthly loading doses), or
laser. The primary outcome was the mean change in ETDRS
VA from baseline at 12 months. One-year results have been
reported25 (Table 3). The take-home message from these
studies is that aflibercept was superior to laser in restoring
VA in eyes with DME.
Table 3. Mean ETDRS Letter Gains at 1 Year From Baseline in
the VIVID and VISTA Trials of Aflibercept for DME.25
VIVID
VISTA
Aflibercept 2 mg monthly
+10.5
+12.5
Aflibercept 2 mg every other month
+10.7
+10.7
Laser
+1.2
+0.2
Dr Ho: We have no head-to-head data so far comparing
these anti-VEGF agents for DME. The ongoing DRCRnet
Protocol T study compares all 3 anti-VEGF agents head-tohead for DME and should be reported in approximately 1
year. In the meantime, how do we select first-line therapy
for DME?
Dr Brown: For those few patients who have small
circinate areas of DME with obvious microaneurysms, laser
is still my preferred approach. But most patients have more
diffuse DME and will require anti-VEGF therapy. These
eyes have large VEGF loads and require many injections to
achieve and maintain VA improvement.
Dr Slakter: Most of my patients have diffuse DME, and
so anti-VEGF therapy is my first-line approach. The edema
does not always resolve completely. After drying up most
of the macula with anti-VEGF therapy, an FA may reveal
a few focal microaneurysms that are amenable to laser
treatment. Another reason that edema does not always
resolve completely involves systemic disease control. I
often see patients for second opinions after they have
received 8 or 10 injections, and their HbA1c levels are 9,
which is much too high. If you can motivate patients to eat
better, lose weight, and control their blood glucose levels,
the macular edema also is often easier to manage—such
lifestyle changes make for a much better intervention than
serial intravitreal injections.
Dr Ho: That is an excellent point regarding our leverage
to inspire our patients with diabetes to optimize their
systemic and metabolic control in the battle against DME.
Patients with diabetes mellitus fear blindness even more
than premature death, and therefore we have unique
leverage and opportunity to effect change in not only their
ocular health but their systemic condition as well. Goals:
blood pressure of 130/80 or better, A1C level of 7, and
walking or equivalent cardio activity 30 minutes a day most
days of the week. They need to hear these goals from us.
A review of medications is important as well because some
oral hypoglycemic agents, such as the oral glitazone drugs,
can cause macular edema.26 Checking their medical status,
checking their medications, and encouraging them to
change behavior are all really important points.
Because we know that patients can go blind from DME, we
are in a powerful position to encourage self-care because
people often value their vision above most other senses.
Are there other thoughts on the selection of initial antiVEGF therapy for DME?
Dr Brown: People with diabetes have systemic
vascular disease and I am concerned that they may be at
increased risk for adverse events associated with systemic
VEGF suppression. For this reason, I typically start with
ranibizumab if the patient’s insurance coverage allows.
Dr Ho: Are there differences, in your clinical experience,
between anti-VEGF agents for DME, recognizing that
aflibercept is not commercially available at this time?
Dr Avery: It is my clinical impression that ranibizumab
works a little better than bevacizumab for DME. In addition
to the ongoing DRCRnet study, there was recently a small
prospective study comparing ranibizumab and bevacizumab
for DME.27 There were some small differences in VA
outcomes at various time points, but the 2 agents were
11
statistically equal in terms of efficacy at 12 months. The
ranibizumab group required fewer injections than the
bevacizumab group, however.
Dr Ho: My experience is similar; ranibizumab seems to be
a more effective agent than bevacizumab for DME and the
differences are greater than for AMD. How do we handle
suboptimal responders to anti-VEGF therapy for DME?
Dr Slakter: I tend to start with ranibizumab.
Suboptimal responders to anti-VEGF therapy are more
common in DME than in AMD, in my experience. This
occurrence may be due to the higher VEGF load in these
ischemic eyes. I am less quick in DME to declare a patient
a suboptimal responder. In AMD, there is an advantage to
quickly achieving and maintaining a dry macula. In DME,
these maculae are chronically edematous, and unless there
are large cysts in the foveal region, they tolerate edema
for a reasonable period of time. Therefore, I have a longer
period of time to assess the effectiveness of therapy before
feeling the need to switch to something different. When I
do decide to switch therapy, I typically start by changing to a
different anti-VEGF agent.
Laser also can be effective if the macula becomes partially
dry with VEGF inhibition. Steroids also can be useful, and to
spare the patients frequent injections, the sustained-release
dexamethasone implant can be useful in DME.28 Minimizing
the treatment burden is even more important in DME than
in AMD because unlike the older AMD patients who are
typically retired, DME patients are usually still working, so
there are added costs to the patient and to society from
frequent visits to my office.
Dr Avery: Along with reducing the treatment burden,
I have found it helpful to add micropulse laser therapy in
conjunction with anti-VEGF therapy in eyes with diffuse
edema. We are exploring the value of this adjunct in our
practice now, using systems that feature yellow and infrared
lasers. Some have advocated using the infrared laser in a sub
threshold fashion straight through the fovea.29 I am more
conservative and do not treat the fovea, but it is nice to
know that using certain sub threshold parameters, you may
not cause damage if you get too close to the fovea.
Dr Ho: Is there is a role for corticosteroids in eyes with
recalcitrant DME?
Dr Avery: The pathophysiology of DME is multifactorial
and involves VEGF and inflammation dually driving the
vascular permeability that results in edema. Steroids work
in a complementary fashion with anti-VEGF agents to
suppress the inflammatory component. There are, however,
downsides to steroids—namely, the possible development
of cataracts and glaucoma. Both of these situations can be
managed if they arise.
If anti-VEGF therapy alone cannot resolve DME, I frequently
will add steroids, particularly in pseudophakic patients. In the
previously mentioned DRCRnet Protocol I study, a subgroup
analysis revealed that triamcinolone was just as effective in
restoring vision as ranibizumab in pseudophakic patients.20
Dr Ho: There has been much publicity recently regarding
the potential risks of compounded steroids, albeit in
applications other than ocular disease. Given this issue,
what steroid do you use if a patient does not respond to
anti-VEGF therapy?
Dr Avery: I no longer use compounded triamcinolone.
I now use the branded triamcinolone product that is FDA
approved and specifically formulated for intraocular use
and is packaged in a single-use vial that all but eliminates
the risk of contamination. This branded formulation
of triamcinolone is not specifically approved for use in
DME, but I feel more comfortable with it than with a
compounded product.
Dr Brown: I wanted to believe that we could deliver
adequate levels of anti-VEGF agents into the eye to
suppress the VEGF associated with DME. The truth,
however, is that I have many patients in whom large
quantities of anti-VEGF drugs are inadequate, but they
respond very well to steroids. I have used triamcinolone
in some patients, but once we have elected to use steroid
therapy, I prefer to take advantage of a longer-acting steroid
formulation to reduce the treatment burden. I use more
of the dexamethasone implant. I wish the fluocinolone
acetonide implant had been approved by the FDA for use
in the United States; it is an approved indication in Europe.
We participated in those clinical trials and some patients
had long-term control with that device. However, the risk
for glaucoma with the device—often requiring filtering
surgery to control—was a safety issue that may have
impeded its approval.
Dr Ho: While anti-VEGF therapy is first-line treatment
in my hands for patients with fovea involving DME,
corticosteroids play an important role in eyes that respond
12
suboptimally; my preference is a noncompounded
corticosteroid such as triamcinolone acetonide or the
dexamethasone implant. Injecting corticosteroids is like
pressing a reset button for DME; it can, for example,
help an eye respond to anti-VEGF therapy.
Does surgery play a role in patients with DME?
Dr Avery: Vitrectomy certainly increases the
oxygenation of intraocular tissues, which is beneficial in
DME. But it also reduces the intravitreal half-life of any
subsequently injected therapeutic agents. Vitrectomy
is probably best suited for patients with vitreomacular
traction or epiretinal membranes, in whom flattening
the macula pharmacologically is very difficult.
Dr Ho: Are we treating DME patients who have
evidence of vitreomacular adhesions differently?
Dr Slakter: Vitreomacular adhesions do pose
an added component to the management of DME. I
will consider surgery in patients who have little or no
response to anti-VEGF therapy and in whom I believe
vitreomacular traction is playing a major role in their
disease process. I have to have a high suspicion that
traction is at play in order to make it worthwhile to give
up durability of anti-VEGF agents afterwards. I think
there may be value in releasing the adhesions while
removing as little vitreous as possible. This preserves
the vitreous to serve as a depot for the drug if I need to
continue injecting anti-VEGF therapy postoperatively.
to maintain control of the DME. Are there other
therapeutic options? Can we better control their
blood sugar or their hypertension? Can we encourage
our patients to lose weight? Are they on a glitazone
hypoglycemic medication that may be aggravating their
macular edema?
Dr Avery: I think the pathophysiology of DME is
different from that of AMD. In AMD, we are usually able
to get the macula bone-dry and flat with anti-VEGF
agents. Achieving that may not be as easy in some
patients with DME. This is not necessarily a treatment
failure if they maintain excellent vision. But given the
other pathways involved in DME, I foresee adjunctive
treatments playing a role as well. At present, though,
anti-VEGF therapy has the best proven outcome.
Dr Slakter: OCT is important in DME, but perhaps
not as important as in AMD. There is more to diabetic
eye disease than just macular edema, and there is more
to diabetes than just diabetic eye disease. We have to be
aware of proliferative neovascularization, and we have to
be aware that diabetes is a systemic disease. The central
subfield on the OCT does not tell the whole story in
eyes with DME the way it does with eyes in AMD.
Dr Ho: Before concluding this discussion, let us each
Dr Ho: We now practice in the era of anti-VEGF
therapy. Moreover, we have multiple agents from which
to choose, and there may be some relevant differences
between these agents that we are still teasing out
in head-to-head clinical trials. The approaches to
managing AMD and DME are quite similar in some
regards, yet quite different in others. In AMD, we have
fewer treatment options when anti-VEGF therapy
inadequately controls the disease, whereas in DME,
we have laser and steroids to help in suboptimally
responsive patients. In some patients with DME and
retinal interface abnormalities, surgery may play a role
to improve their course of treatment.
My pearl is to give your agent of choice longer time to
show a benefit in DME than you do in AMD and to be
more tolerant of DME.
As new and ongoing trials report their findings, our
ability to further individualize therapy for management
of both AMD and DME will continue to improve. We
should not forget that, particularly regarding those
with diabetes, we see our patients far more often than
do their primary care physicians, and so we have a
distinctive opportunity to help them effect the lifestyle
changes that can enhance their quality of life and our
ability to adequately treat their eye disease.
provide a clinical pearl for the management of DME
in clinical practice. Mine is to keep in mind that our
patients with DME are significantly younger than our
patients with wet AMD, and their diabetes likely will
be ongoing and lifelong because there is not yet a cure
for the fundamental disease. In DME, the response to
anti-VEGF therapy is more variable than in AMD. Visual
acuity does improve with anti-VEGF treatment in DME,
but more slowly than in AMD.
Dr Brown: I try to consider the whole patient,
particularly when he or she requires monthly injections
13
REFERENCES
1. CAT T Research Group, Mar tin DF, Maguire MG, Y ing
GS, Gr unwald JE, F ine SL, Jaffe GJ. R anibizumab and
be vacizumab for neovascular age-related macular degeneration.
N Engl J Med. 2011;364(20):1897-1908.
2. Comparison of Age-related Macular Degeneration
Treatments Trials (CAT T ) Research Group, Mar tin DF,
Maguire MG, F ine SL, et al. R anibizumab and be vacizumab
for treatment of neovascular age-related macular degeneration:
two-year results. Ophthalmolog y. 2012;119(17):1388-1398.
3. IVAN S tudy Investigators, Chakravar thy U, Harding SP,
Rogers CA, et al. Ranibizumab versus be vacizumab to treat
neovascular age-related macular degeneration: one-year
findings from the IVAN randomiz ed tr ial. Ophthalmolog y.
2012;119(7):1399-1411.
4. Kodjikian L. O ver vie w of the GEFAL S tudy. Presented at:
Annual Meeting of The Association for Research in V ision
and Ophthalmolog y ; May 5-9, 2013; S eattle, WA.
5. Krebs I, S chmetterer L, Boltz A, et al; MANTA Research
Group. A randomised double-masked tr ial compar ing
the visual outcome af ter treatment with ranibizumab or
be vacizumab in patients with neovascular age-related macular
degeneration. Br J Ophthalmol. 2013;97(3):266-271.
6. Berg K. Lucentis compared to Avastin study. Presented at:
Annual Meeting of the Amer ic an Ac ademy of Ophthalmolog y ;
November 16-19, 2013; Ne w O r leans, LA.
7. Kahook MY, Liu L, R uz yc ki P, et al. High-molecularweight aggregates in repac kaged be vacizumab. Retina.
2010;30(6):887-992.
8. Aver y RI, Castellar in A, S teinle N, et al. Compar ison
of systemic pharmacokinetics post anti-VEGF intravitreal
injections of ranibizumab, be vacizumab and aflibercept.
Presented at: Annual Meeting of the Amer ic an S ociet y of
Retina S pecialists; August 24-28, 2013; Toronto, Ontar io,
Canada.
9. Heler JS, Brown DM, Chong V, et al; VI EW 1 and VI EW 2
S tudy Groups. Intravitreal aflibercept ( VEGF trap-eye)
in wet age-related macular degeneration. Ophthalmolog y.
2012;119(12):2537-2548.
10. S chmidt-Erfur th U, K aiser P K, Korobelnik JF, et al.
Intravitreal aflibercept injection for neovascular age-related
macular degeneration: ninet y-six-week results of the VI EW
S tudies. Ophthalmolog y. 2014;121(1):193-201.
11. Busbee BG, Ho AC, Brown DM, et al; HARBOR S tudy
Group. Twel ve-month effic ac y and safet y of 0.5 mg or 2.0 mg
ranibizumab in patients with subfoveal neovascular age-related
macular degeneration. Ophthalmolog y. 2013;120(5):1046-1056.
12. Patel KH, Chow CC, R athod R , et al. R apid response
of retinal pigment epithelial detachments to intravitreal
aflibercept in neovascular age-related macular degeneration
refractor y to bevacizumab and ranibizumab. Eye (Lond).
2013;27(5):663-667.
13. Miura M, I wasaki T, Goto H. Intravitreal aflibercept for
pol ypoidal choroidal vasculopathy af ter de veloping ranibizumab
tachyphylaxis. Clin Ophthalmol. 2013;7: 1591-1595.
14. Brown DM, Heier JS, Ciulla T, et al; CLEAR-I T 2
Investigators. Primar y endpoint results of a phase I I study of
vascular endothelial grow th factor trap-eye in wet age-related
macular degeneration. Ophthalmolog y. 2011;118(6):1089-1097.
15. Heier JS, Boyer D, Nguyen QD, et al; CLEAR-I T 2
Investigators. The 1-year results of CLEAR-I T 2, a phase
2 study of vascular endothelial grow th factor trap-eye
dosed as-needed af ter 12-week fixed dosing. Ophthalmolog y.
2011;118(6):1098-1106.
14
16. Koh A, L ee WK, Chen LJ, et al. EVEREST study :
effic ac y and safet y of ver tepor fin photodynamic therapy in
combination with ranibizumab or alone versus ranibizumab
monotherapy in patients with symptomatic macular pol ypoidal
choroidal vasculopathy. Retina. 2012;32(8):1453-1464.
17. S ubfoveal neovascular lesions in age-related macular
degeneration. Guidelines for evaluation and treatment in the
macular photocoagulation study. Macular P hotocoagulation
S tudy Group. Arch Ophthalmol. 1991;109(9):1242-1257.
18. Bar baz etto IA, S orenson J, Gallego-Pinaz o R , Engelber t
M. Aflibercept for patients previousl y treated with antiVEGF therapy for age-related macular degeneration.
Presented at: Annual Meeting of the Amer ic an S ociet y of
Retina S pecialists; August 25-29, 2012; L as Vegas, NV.
19. S hah CP, Cho H, Br yant JS, et al. Aflibercept for
exudative AMD suboptimall y responsive to ranibizumab and
bevacizumab. Presented at: Annual Meeting of the Amer ic an
S ociet y of Retina S pecialists; August 25-29, 2012;
L as Vegas, NV.
20. Nguyen QD, Brown DM, Marcus DM, et al; RISE and
RIDE Research Groups. Ranibizumab for diabetic macular
edema: results from 2 phase III randomiz ed tr ials: RISE and
RIDE. Ophthalmolog y. 2012;119(4):789-801.
21. Brown DM, Nguyen QD, Marcus DM, et al; RIDE and
RISE Research Group. L ong-term outcomes of ranibizumab
therapy for diabetic macular edema: the 36-month results
from two phase III tr ials: RISE and RIDE. Ophthalmolog y.
2013;120(10):2013-2022.
22. Diabetic Retinopathy Clinic al Research Network, Elman
MJ, Aiello LP, Bec k RW, et al. Randomiz ed tr ial evaluating
ranibizumab plus prompt or deferred laser or tr iamcinolone
plus prompt laser for diabetic macular edema. Ophthalmolog y.
2010;117(6):1064-1077.e35.
23. Elman MJ, Bressler NM, Qin H, et al; Diabetic
Retinopathy Clinic al Research Network. Expanded 2-year
follow-up of ranibizumab plus prompt or deferred laser or
tr iamcinolone plus prompt laser for diabetic macular edema.
Ophthalmolog y. 2011;118(4):609-614.
24. Diabetic Retinopathy Clinic al Research Network, Elman
MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for
diabetic macular edema with prompt versus deferred laser
treatment: three-year randomiz ed tr ial results. Ophthalmolog y.
2012;119(11):2312-2318.
25. Regeneron and Bayer repor t positive one-year results
from two phase 3 tr ials of EYLEA® (aflibercept) injection
for the treatment of diabetic macular edema [press release].
Tarr ytown, NY: P RNewswire; August 6, 2013. http://
investor.regeneron.com/releasedetail.cfm?releaseid=782911.
Accessed December 13, 2013.
26. Fong DS, Contreras R . Glitaz one use associated
with diabetic macular edema. Am J Ophthalmol.
2009;147(4):583-586.e1.
27. Nepomuceno AB, Takaki E, Paes de Almeida FP, et al.
A prospective randomiz ed tr ial of intravitreal bevacizumab
versus ranibizumab for the management of diabetic macular
edema. Am J Ophthalmol. 2013;156(3):502-510.e2.
28. Haller JA, Bandello F, Belfor t R Jr, et al; OZURDEX
GENEVA S tudy Group. Randomiz ed, sham-controlled
tr ial of dexamethasone intravitreal implant in patients with
macular edema due to retinal vein occ lusion. Ophthalmolog y.
2010;117(6):1134-1146.e3.
29. L uttr ull JK, S inc lair SD. S afet y of transfoveal
subthreshold diode micropulse laser ( T F SDM) for intrafoveal diabetic macular edema (IF DME) in eyes with good
visual acuit y. Presented at: Annual Meeting of the Amer ic an
S ociet y of Retina S pecialists; August 24-28, 2013; Toronto,
Ontar io, Canada.
POST TEST WORKSHEET
Please go to http://bit.ly/neovascular14 to take the post test followed by course evaluations, after which you will be
able to generate your CME certificate. Below are the post test questions.
1. Which 2 anti-VEGF agents did CATT compare?
A. Bevacizumab and aflibercept
B. Bevacizumab and ranibizumab
C. Ranibizumab and aflibercept
D. Bevacizumab and aflibercept
2. A key take-home message from CATT is:
A. PRN dosing is superior to monthly dosing with
either agent
B. Aflibercept has more safety issues than does
bevacizumab
C. Bevacizumab and ranibizumab are equivalent in
efficacy when dosed monthly
D. Outcomes are the same when the drugs are dosed
either monthly or every other month
3. Which of the following drugs used to treat AMD has
the shortest systemic half-life in plasma?
A .Bevacizumab
B. Aflibercept
C. Ranibizumab
D. All 3 drugs have the same half-life
4. According to evidence provided by the VIEW studies,
which anti-VEGF drug has durability of action
that supports dosing every other month?
A. Bevacizumab
B. Aflibercept
C. Ranibizumab
D. Triamcinolone
5. A poor response to anti-VEGF therapy in an AMD
patient should prompt an evaluation to uncover
all the following potential conditions, except:
A. Retinal pigment epithelial detachment
B. Polypoidal choroidal vasculopathy
C. Juxtafoveal telangiectasis
D. Central serous chorioretinopathy
6. When a patient whose neovascular AMD was
previously controlled with anti-VEGF therapy begins
leaking again, a reasonable next step would be:
A. Dose the same anti-VEGF agent, but less often to
avoid tachyphylaxis
B. Extend the interval between injections to reduce
tolerance
C. Increase the dose of the current anti-VEGF agent
D. Increase the frequency of dosing of the current
anti-VEGF agent or switch to a different agent
7. The current standard of care for treating DME is:
A. Laser
B. Steroids
C. Anti-VEGF therapy
D. Vitrectomy
8. Which of the following statements is false regarding
the results of anti-VEGF trials in DME?
A. Ranibizumab has been proven to be effective in
clinical trials
B. Aflibercept has been proven to be effective in
clinical trials
C. Head-to-head comparisons of anti-VEGF agents
for DME have proven that they are equally effective
D. Anti-VEGF therapy is more effective than laser
therapy
9. A patient with DME responds suboptimally to initial
anti-VEGF therapy. Explanations for such a response
might include:
A. Well-controlled systemic diabetes
B. Use of glitazone hypoglycemic agents
C. Recent weight loss
D. Pseudophakia
10. Among the therapeutic options for a patient with DME
who responds suboptimally to anti-VEGF therapy are:
A. Laser
B. Steroids
C. Vitrectomy
D. All the above are reasonable options in select
patients
15
Individualizing Therapy
for Patients With
Neovascular AMD and DME:
Considerations for
Short- and Long-Term Management