PERSPECTIVE Management Paradigms for Diabetic Macular Edema

 
PERSPECTIVE
      Management Paradigms for Diabetic Macular Edema

  PAUL MITCHELL AND TIEN YIN WONG, FOR THE DIABETIC MACULAR EDEMA TREATMENT GUIDELINE
                                    WORKING GROUP

                                                                             D
 PURPOSE:    To provide evidence-based recommenda-                                     IABETES MELLITUS (DM) IS A GLOBAL EPIDEMIC
tions for diabetic macular edema (DME) management                                      with significant morbidity.1 Although diabetic
based on updated information from publications on                                      retinopathy (DR) affects 1 in 3 people with
DME treatment modalities.                                                    DM,1 the leading cause of vision loss in this population is
 DESIGN: Perspective.                                                       diabetic macular edema (DME),2 which affects approxi-
 METHODS: A literature search for ‘‘diabetic macular                        mately 6.8% of the diabetic population.3
edema’’ or ‘‘diabetic maculopathy’’ was performed using                         DME represents a spectrum of retinopathy signs charac-
the PubMed, Cochrane Library, and ClinicalTrials.gov                         terized by edema and thickening of the central macula and
databases to identify studies from January 1, 1985 to                        surrounding noncentral macula that are not explained by
July 31, 2013. Meta-analyses, systematic reviews, and                        the presence of an epiretinal membrane (ERM) at the mac-
randomized controlled trials with at least 1 year of                         ula. These symptoms are typically confirmed by slit-lamp
follow-up published in the past 5 years were preferred                       biomicroscopy and, increasingly, with the aid of optical
sources.                                                                     coherence tomography (OCT).
 RESULTS: Although laser photocoagulation has been the                         For nearly 30 years, focal/grid laser photocoagulation has
standard treatment for DME for nearly 3 decades, there is                    been the mainstay of treatment for clinically significant
increasing evidence that superior outcomes can be achieved                   DME (CSME).4 However, there have been substantial
with anti–vascular endothelial growth factor (anti-VEGF)                     advances in our understanding of DME since this method
therapy. Data providing the most robust evidence from large                  was first used. First, epidemiologic data indicate that
phase II and phase III clinical trials for ranibizumab demon-                DME, more than DR severity, is the most common cause
strated visual improvement and favorable safety profile for                  of vision loss for patients.5 Second, there is now better
up to 3 years. Average best-corrected visual acuity change                   understanding that risk factors for DME (eg, serum lipids) may
from baseline ranged from 6.1-10.6 Early Treatment Dia-                      be different from those for DR, highlighting the importance
betic Retinopathy Study (ETDRS) letters for ranibizumab,                     of systemic management being targeted at DME.6,7 Third,
compared to 1.4-5.9 ETDRS letters with laser. The propor-                    improved knowledge of the pathophysiology of DME has
tion of patients gaining ‡10 or ‡15 letters with ranibizumab                 enabled the development of alternative therapies.1,8
was at least 2 times higher than that of patients treated with               Fourth, the development of modern imaging techniques,
laser. Patients were also more likely to experience visual loss              such as OCT, has allowed assessment of early DME,
with laser than with ranibizumab treatment. Ranibizumab                      including subclinical DME.9 Last, the results from several
was generally well tolerated in all studies. Studies for beva-               large phase III randomized controlled trials (RCTs) for
cizumab, aflibercept, and pegaptanib in DME were limited                     alternative therapies, namely anti–vascular endothelial
but also in favor of anti-VEGF therapy over laser.                           growth factor (anti-VEGF) treatments, have now been
 CONCLUSIONS: Anti-VEGF therapy is superior to laser                        reported.10–14
photocoagulation for treatment of moderate to severe                            The treatment algorithm for the selection of patients,
visual impairment caused by DME. (Am J                                       the initiation of anti-VEGF therapy, and the assessment
Ophthalmol 2014;157:505–513. Ó 2014 by Elsevier                              and retreatment of DME using this group of therapies has
Inc. All rights reserved.)                                                   not yet been established. This Perspective article summa-
                                                                             rizes major studies and RCTs examining DME treatment
                                                                             modalities with the aim of providing an initial set of
             Supplemental Material available at AJO.com.
Accepted for publication Nov 12, 2013.
                                                                             evidence-based recommendations for DME management.
   From the Centre for Vision Research, Westmead Millennium Institute,
University of Sydney, Sydney, Australia (P.M.); and Singapore Eye
Research Institute, Singapore National Eye Centre, National University
of Singapore, Singapore (T.Y.W.).                                                                     METHODS
   Inquiries to Professor Tien Yin Wong, Singapore Eye Research Institute,
Singapore National Eye Centre, National University of Singapore, 1E
Kent Ridge Road, NUHS Tower Block, Level 7, Singapore 119228;                WE CONDUCTED A LITERATURE SEARCH USING THE
e-mail: ophwty@nus.edu.sg                                                    PubMed,      Cochrane     Library,   and   ClinicalTrials.gov

0002-9394/$36.00                                 Ó   2014 BY   ELSEVIER INC. ALL   RIGHTS RESERVED.                                   505
http://dx.doi.org/10.1016/j.ajo.2013.11.012
databases with the terms ‘‘diabetes macular edema’’ or ‘‘dia-    visual impairment, in addition to stabilizing and preventing
betic maculopathy’’ to identify studies published from           future vision loss.5–13 Four VEGF-binding drugs are
January 1, 1985 to July 31, 2013. This was followed by a         currently used for ophthalmic conditions: ranibizumab,
manual search of references cited in selected major papers.      bevacizumab (off-label), aflibercept, and pegaptanib. Evi-
Meta-analyses, systematic reviews, and RCTs with at least        dence for DME treatment with anti-VEGF therapies is
1 year of follow-up published in the past 5 years were           largely based on data from phase II and phase III RCTs
preferred sources. Recommendations for DME treatment             for ranibizumab, including Safety and Efficacy of Ranibizu-
were drafted by the Diabetic Macular Edema Treatment             mab in Diabetic Macular Edema (RESOLVE):17 Two-year
Guideline Working Group and graded for importance of             Outcomes of the Ranibizumab for Edema of the mAcula in
clinical outcome and strength of evidence.15                     Diabetes (READ-2);18,19 A 12 Month Core Study to Assess
                                                                 the Efficacy and Safety of Ranibizumab Intravitreal
                                                                 Injections (RESTORE);10 Diabetic Retinopathy Clinical
                                                                 Research Network (DRCR.net) Protocol I;11–13 and A
           SYSTEMIC MANAGEMENT                                   Study of Ranibizumab Injection in Subjects with CSDME
                                                                 with Center Involvement Secondary to Diabetes Mellitus
OPTIMAL MANAGEMENT OF SYSTEMIC RISK FACTORS IS A
                                                                 (RISE and RIDE).14,20
key component of the primary prevention of DR. Intensive
control of hyperglycemia, hypertension, and possibly                Ranibizumab. RESOLVE was a phase II, double-masked,
hyperlipidemia delay the onset and progression of DR.            sham-controlled RCT evaluating the efficacy and safety of
Whether the same is useful for DME is less clear, as there       ranibizumab compared with sham treatment over
are fewer studies focused on DME alone. Because DME              12 months.17 Patients (n ¼ 151) with visual acuity (VA)
develops in a subset of patients with DR and the likelihood
                                                                 20/40-20/160 and central retinal thickness (CRT)
of developing DME increases with DR severity, control of         >
                                                                 _300 mm were randomly assigned to ranibizumab 0.3 mg
systemic risk factors would be expected to have a major          or 0.5 mg, or to sham injections. Dose doubling and
effect on DME. An overview of studies evaluating the             rescue laser treatment were permitted according to
effects of improving blood glucose levels, blood pressure,       predefined criteria. At the end of the study, a mean
and lipid profile is available online (Supplemental Refer-       average change in best-corrected VA (BCVA) of þ7.8
ences, available at AJO.com).                                    letters from baseline was observed in the ranibizumab
                                                                 groups compared with -0.1 letters in the sham group (P <
                                                                 .0001). Mean CRT reduction was parallel to mean
           OCULAR MANAGEMENT                                     BVCA improvement. More than 3 times the proportion
                                                                 of patients who were treated with ranibizumab gained
 LASER PHOTOCOAGULATION:            The use of laser photoco-   >
                                                                 _10 and > _15 letters compared with those receiving sham
agulation has been the mainstay of treatment for CSME            injections.
since the landmark Early Treatment Diabetic Retinopathy             READ-2 was a phase II, multicenter, interventional
Study (ETDRS) in 1985.4 However, laser photocoagula-             RCT comparing ranibizumab with focal laser treatment
tion mostly does not improve vision, and a significant pro-      and a combination of both in DME among patients with
portion of patients experience progressive worsening of          type 1 or 2 DM. Patients (n ¼ 126) with VA 20/40-20/
vision despite laser photocoagulation (Supplemental              320 and CRT >     _250 mm were randomized to receive
Table 1, available at AJO.com). Furthermore, long-term           0.5 mg ranibizumab injections at baseline and at months
use of this treatment is limited by significant risks and        1, 3, and 5 (Group 1); laser treatment at baseline and
adverse effects, such as central and paracentral scotomata,      then at month 3 as needed (Group 2); or ranibizumab
loss of color vision, progressive enlargement of laser scars     injections and laser treatment at baseline and at month 3
(‘‘laser creep’’), and occasional secondary choroidal neovas-    (Group 3).18 This was followed by a maintenance regimen
cularization.16 The subthreshold micropulse diode laser          of 0.5 mg ranibizumab every 2 months and/or laser treat-
and the patterned scan laser are 2 innovations developed         ment every 3 months for residual edema. Mean BVCA
to minimize scar formation. However, long-term experi-           change from baseline to month 24 was þ7.7 letters for
ence is needed to define their precise roles in DME treat-       Group 1, þ5.1 letters for Group 2, and þ6.8 letters for
ment.                                                            Group 3, although the mean differences were not signifi-
                                                                 cantly different among all groups. Patients in Groups 2
 ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR                        and 3 who received ranibizumab injections on top of laser
AGENTS: VEGF is a potent factor in the pathogenesis of           treatment required less frequent injections without
DME that is upregulated in hypoxic and hyperglycemic             compromising visual outcomes at 2 years than those who
states. Elevated VEGF levels in the intraocular fluid corre-     received ranibizumab only in Group 1. More aggressive
late with vascular hyperpermeability and DME severity.           treatment with ranibizumab from year 2 to year 3 demon-
Current evidence shows that anti-VEGF therapies reverse          strated that mean BCVA could be further improved by

506                                         AMERICAN JOURNAL OF OPHTHALMOLOGY                                    MARCH 2014
3.1 letters (P ¼ .009) in Group 1.19 Resolution of edema         reduced risk of DR progression, and regression of DR was
was more frequent in Groups 2 and 3, in which laser treat-       observed in eyes with DME.20
ment was included as part of the treatment regimen.
   RESTORE was a double-masked, multicenter, laser-                 Bevacizumab. The Bevacizumab or Laser Therapy
controlled phase III study examining the efficacy of ranibi-     (BOLT) study was a single-center, 2-year, phase II RCT
zumab 0.5 mg as monotherapy or combined with laser ther-         comparing the effects of repeated intravitreal bevacizumab
apy over laser treatment alone.10 Patients (n ¼ 345) with        (ivB) and laser therapy in 80 patients with persistent
visual impairment 20/32-20/160 were enrolled in the study.       DME causing moderate visual impairment of >          _20/200 or
Significant improvement in BVCA was seen with ranibizu-          <
                                                                 _20/40 and whose CRT was >         _270 mm at baseline.21,22
mab alone (þ6.1 letters) and combined with laser (þ5.9           These patients were randomized to receive intravitreal
letters) compared with laser monotherapy (þ0.8 letters)          bevacizumab (ivB) 1.25 mg every 6 weeks or laser
at 12 months. The proportions of patients who gained             treatment every 4 months. Retreatment was based on CRT
>
_10 and > _15 letters were 2-3 times greater in the ranibizu-    stability. Results at 2 years showed that patients who were
mab groups compared within the laser group (37.4% vs             treated with ivB had þ8.6 mean letter gain compared with
15.5% and 22.6% vs 8.2%, respectively). Approximately            a mean loss of 0.5 letters with laser. The proportion of
9.2% more patients experienced >   _10 letters loss with laser   patients who gained >  _10 letters was significantly greater for
than with ranibizumab. Up to 8.2% of patients experienced        ivB than for laser (49% vs 7%, P ¼ .001). Approximately
loss of >
        _15 letters with laser only compared with 0.9% in        32% of patients in the ivB group gained >           _15 letters,
the ranibizumab-only group.                                      compared with 4% in the laser group (P ¼ .004). No
   DRCR.net protocol I was a 5-year, independent, multi-         patient lost >_15 letters with ivB but 14% of patients in the
center RCT involving 854 study eyes with center-                 laser group sustained > _15 letters loss (P ¼ .03).
involved DME causing vision impairment 20/32-20/320                 Soheilian and associates reported a phase III RCT exam-
and central subfield thickness > _250 mm.11 Patients were        ining the efficacy of ivB alone or in combination with
randomized to receive sham injection plus prompt laser,          intravitreal triamcinolone acetonide (IVTA) vs laser photo-
ranibizumab 0.5 mg plus prompt laser, ranibizumab                coagulation as primary treatment for DME.23 One hundred
0.5 mg plus deferred (> _24 weeks) laser, or triamcinolone       and fifty eyes of 129 treatment-naı̈ve patients with VA 20/
4 mg plus prompt laser. Results demonstrated that ranibizu-      50-20/300 were randomized to receive ivB, combined ivB
mab combined with prompt or deferred laser therapy was           and IVT, or laser treatment. The treatments were adminis-
more effective than laser alone for the treatment of             tered at 12-week intervals. After 3 loading doses, further
DME, with substantially more eyes gaining ETDRS letters          ivB injections were given if DME persisted and VA was not
and fewer eyes losing ETDRS letters (Supplemental                better than 20/40. Mean VA improvement for ivB was
Table 1, available at AJO.com). The mean change from             12.8% compared with 9.5% for ivB and IVTA and 10.9%
baseline VA at 1 year was þ9 letters in the ranibizumab          for laser, but the results were not statistically significant.
plus prompt or deferred laser groups, compared with þ3 let-      The superior effect of ivB over other treatments was signifi-
ters in the sham plus prompt laser group. VA continued to        cant at 6 months but diminished thereafter. The proportion
improve in the second year by a mean change of þ3.7 let-         of eyes with >
                                                                              _15 letter gain was 41.0% for ivB, 36.1% for com-
ters more with ranibizumab plus prompt laser and þ5.8            bined ivB and IVTA, and 23.7% for laser treatment.
letters more with ranibizumab plus deferred treatment,
compared with sham plus prompt laser treatment.12 At 3              Aflibercept. A key RCT of note is the phase II, double-
years, prompt laser treatment was related to fewer cumula-       masked, active-controlled DME and VEGF Trap-Eye:
tive ranibizumab injections than deferred, but patients who      INvestigation of Clinical Impact (DA VINCI) study,
received deferred laser experienced better visual outcomes       which was designed to examine the effects of intravitreal
(þ6.8 letters vs þ9.7 letters, respectively, P ¼ .02).13         aflibercept compared to those of standard laser
   RISE and RIDE were 2 parallel, phase III, double-             treatment.24,25 Patients (n ¼ 221) with CSME with
masked, sham-controlled RCTs comparing the efficacy              baseline BCVA 20/40-20/320 and CRT >        _250 mm were
and safety of ranibizumab 0.3 mg and 0.5 mg over                 randomized to receive VEGF Trap-Eye at different dosage
24 months.14 The overall study population involved 759           and schedules or laser treatment (Supplemental Table 1,
patients (1 eye per patient) with center-involved DME            available at AJO.com). Results at 52 weeks showed greater
who had VA 20/40-20/320 and central subfield thickness           VA gains for aflibercept (9.7-12.0 letters) than for laser
>
_275 mm. In both studies, the proportion of patients who         treatment (1.3 letters).25 Patients who were treated with
gained > _15 letters with ranibizumab was twice that of          VEGF Trap-Eye were more likely to experience gains of
patients receiving sham injections (Supplemental                 >
                                                                 _10 and >   _15 letters than those who received laser
Table 1, available at AJO.com), with an average gain of          treatment (45%-71% vs 30% and 23.8%-45.5% vs 11.4%,
8.5-9.9 letters from baseline at month 24 with ranibizumab       respectively). The following phase III studies are currently
compared with sham treatment (P < .0001). In addition,           underway: VEGF Trap-Eye in Vision Impairment due to
patients treated with ranibizumab were found to have a           DME (VIVID-DME; NCT01331681), VIVID EAST-DME

VOL. 157, NO. 3                             DIABETIC MACULAR EDEMA MANAGEMENT                                               507
(NCT01783886), Japanese Safety Study of VEGF Trap-Eye          well as aflibercept (NCT01627249), in DME are in progress
in DME (VIVID-Japan; NCT01512966), and Study of                and should provide additional insights on this issue. Systemic
Intravitreal Administration of VEGF Trap-Eye (BAY86-           adverse events in patients who received ranibizumab for DME
5321) in Patients with DME (VISTA; NCT01363440).               occurred at rates equal to those in patients who received laser
                                                               treatment or sham injection. The incidences of cardiovascu-
   Pegaptanib. A phase II/III, multicenter, double-masked,     lar events and arterial thromboembolism reported in these
sham-controlled, parallel-group study reported by Sultan       studies were low, possibly because high-risk patients were
and associates was performed to compare the effects of         excluded. A definitive conclusion regarding the safety of
pegaptanib 0.3 mg and sham injections in patients with type    bevacizumab could not be drawn from the BOLT study owing
1 and type 2 DM, center-involved DME (CRT >      _250 mm),     to its small sample size.21,22 The safety profile of aflibercept
and vision loss (BVCA 20/50-20/200).26 Efficacy results        reported in the DA VINCI study was consistent with those
were derived from 1-year (n ¼ 260) and 2-year (n ¼ 207)        seen with other intravitreal anti-VEGF agents.24,25 Data
intention-to-treat analyses. Treatment was administered at     from both the RESTORE and BOLT studies also showed
6-week intervals during the first year and as needed           that anti-VEGF treatment had no deleterious effect on capil-
subsequently. Rescue focal/grid photocoagulation was           lary perfusion at the macula.10,21,22
permitted after week 18. At 1 year, 36.8% of patients in the
pegaptanib group achieved >  _10-letter gains compared with     INTRAVITREAL            CORTICOSTEROIDS: Triamcinolone
19.7% in the sham group. These proportions increased to        Acetonide. In a 2-year, phase II/III, double-masked,
38.3% and 30.0%, respectively, in the second year. Mean        placebo-controlled RCT, 84 eyes in 54 patients with
BCVA change from baseline was 6.1 letters in the               diffuse or focal DME with VA 20/40-20/400 and CRT
pegaptanib group compared with 1.3 letters in the sham         >250 mm were randomized to receive IVTA 4 mg vs
group at 2 years (P < .01). Significantly fewer patients in    placebo 6 weeks before laser treatment.35 Although the
the pegaptanib group required laser treatment than in the      proportion of patients in the IVTA plus laser group who
sham group in the first (23.3% vs 41.7%, P ¼ .0023) and        experienced 10-letter improvement was double that in
second years (25.2% vs 45.0%, P ¼ .0032).                      the laser-only group, there was no difference in mean VA
                                                               or CRT change between the 2 groups. The need for
 ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR                      further treatment during the second year of the study was
SAFETY: Ranibizumab was generally well tolerated in all        no lower in the IVTA group than in the laser-only group
studies.10–14,17–20 The most commonly reported ocular-         (69% vs 45%, P ¼ .187).
related serious adverse events were endophthalmitis and           In another 2-year, prospective, double-masked RCT, 69
increased intraocular pressure (IOP). Because patients         eyes in 43 patients with advanced, refractory DME and
with DM have a higher risk of cardiovascular disease that      impaired vision (BCVA 20/30 or worse) were given 4 mg
is exacerbated in the presence of DME, the safety profile      IVTA or placebo.36 IVTA improved BCVA by >         _5 letters
of anti-VEGF agents should be carefully considered.24–31       in 19 of 34 eyes (56%) compared with in 9 of 35 eyes
For age-related macular degeneration (AMD), the 2-year         (26%) treated with placebo. Mean VA improvement was
Comparison of Age-related Macular Degeneration Treat-          5.7 letters more with IVTA than with placebo. The BVCA
ment Trial (CATT) demonstrated no significant difference       gains with IVTA were maintained after 5 years in 42% of
in arteriothromboembolic events or deaths between beva-        eyes.37 However, initial treatment with IVTA did not reduce
cizumab and ranibizumab.32 The incidence of systemic           the risk of recurrent edema and need for further injections.
serious adverse events was significantly higher in patients       The phase III DRCR.net study compared the effects of
who received bevacizumab, although it was uncertain if         1 mg and 4 mg IVTA against those of laser treatment in
these were drug related. In contrast to the CATT, interim      840 eyes of 693 patients with DME and visual impairment
analysis from the Alternative Treatments to Inhibit VEGF       20/40-20/320.38 Laser treatment was superior to IVTA at 2
in Age-related Choroidal Neovascularization (IVAN)             years, despite an initial greater response with IVTA. The
study demonstrated a more favorable safety profile for beva-   mean difference in VA change for laser vs 1 mg IVTA
cizumab over ranibizumab.33 Even if inferences were to be      was 3.5 (P ¼ .02) and 4.6 (P ¼ .002) for laser vs 4 mg
drawn from the CATT and IVAN studies, DME and AMD              IVTA. There was no significant difference between the 2
should be considered as separate disease entities.             IVTA groups (mean difference 1.1, P ¼ .49).
   If ranibizumab and bevacizumab were equally effective and      In the DRCR.net protocol I study evaluating patients
safe, bevacizumab would be considered more cost effective.34   receiving 0.5 mg ranibizumab combined with prompt or
The annual risk of cerebrovascular accident would have to be   deferred laser, 4 mg IVTA plus prompt laser, or laser
at least 1.5% higher with bevacizumab in order for ranibizu-   only, treatment with IVTA plus laser resulted in a mean
mab to be the preferred anti-VEGF treatment.34 Whether         loss of 1.5 letters from baseline compared with laser-only
one anti-VEGF drug is safer than the other for DME remains     treatment at 12 months.11 In an analysis limited to pseudo-
to be answered. Head-to-head studies comparing ranibizumab     phakic eyes, the mean change in VA was 1.6 letters greater
and bevacizumab (NCT00545870 and NCT01610557), as              in the IVTA plus prompt laser group compared within the

508                                       AMERICAN JOURNAL OF OPHTHALMOLOGY                                       MARCH 2014
laser-only group, and this was comparable to the improve-      well-designed RCTs with long-term follow-up is needed
ments achieved with ranibizumab plus prompt/deferred           to establish a role for this treatment approach in DME.
laser.

   Fluocinolone acetonide. The Fluocinolone Acetonide in
Diabetic Macular Edema (FAME) study, a 36-month,                          TREATMENT GUIDELINES
double-masked, sham-controlled, phase III study,
examined the efficacy and safety profile of fluocinolone       TREATMENT OF DME SHOULD BE PRECEDED BY ASSESSMENT
acetonide (FA) compared with that of sham injection in         of VA, a full ocular examination, and confirmation of
patients with persistent or recurrent DME.39,40 Patients       DME. Although the ETDRS definition of CSME has
(n ¼ 956) with BCVA 20/50-20/200 and CRT >        _250 mm      long been considered the ‘‘gold standard’’ for characterizing
were randomized to receive 0.2 mg or 0.5 mg FA                 DME severity, it remains difficult to use and does not help
intravitreal inserts or sham injection. Treatment efficacy     identify patients at risk of vision loss.49 Another definition
was similar for low- and high-dose FA but the benefit-to-      for DME is the International Clinical Classification Scale
risk profile was more favorable with the low dose. FA          (Supplemental Table 2, available at AJO.com).[C:III]49
provided no benefit in preventing vision loss compared            As outlined earlier, DME should be more simply defined
with nontreatment, as similar proportions of patients          as thickening of the central or noncentral macula,
progressed to blindness (BCVA 20/200 or worse). In             confirmed either at slit-lamp biomicroscopy or with
another phase II/III study evaluating the efficacy and         OCT, which is not explained by thickening from an
safety of FA 0.59 mg inserts against standard of care (ie,     ERM. Currently, qualitative assessment of thickening
laser treatment or observation), there was no significant      seen on OCT is used to define DME. Further research is
difference in the proportion of eyes gaining >  _15 letters    needed to clarify if specific features (eg, intraretinal cysts
between patients in both arms after 3 years post implant.41    or disruption of the inner segment/outer segment junction)
                                                               and quantitative measures (eg, volume of thickening) are
 INTRAVITREAL CORTICOSTEROID SAFETY:             The high     useful in assessing the need for anti-VEGF treatment or
incidence of premature cataract formation and increased        in predicting outcomes.
IOP with intravitreal corticosteroids compared to with
sham and laser treatments raises important concerns             INDICATIONS FOR ANTI–VASCULAR ENDOTHELIAL
in clinical practice.35–41 The risk for interventional         GROWTH FACTOR THERAPY: Findings from meta-
procedures, such as cataract surgery, laser trabeculoplasty,   analyses by Virgili and associates50 and Wang and associ-
and incisional glaucoma surgery, increases treatment           ates51 support the use of anti-VEGF agents, namely ranibi-
morbidity. There was no significant difference in the rate     zumab, as an alternative or adjunctive treatment to laser.
of adverse events when IVTA was extended to 5 years.37            Treatment with anti-VEGF should be considered if
A minority of patients in the IVTA study who underwent         center-involving DME is present and VA is 20/30 or worse,
steroid-induced cataract surgery became unresponsive to        as this was the basis for entry into both the RESTORE and
further IVTA treatments and experienced poorer visual          the DRCR.net Protocol I studies. Outcomes showed visual
prognosis than those who did not need surgery.3 Patients       benefit for subgroups with this level of VA.[A:I]10–14,17–20
who received FA were also more likely to report cardiovas-        Focal laser photocoagulation using ETDRS guidelines
cular adverse events than sham-treated patients, although      should still be considered for patients with DME without
the incidence seemed to be low (
TABLE. Summary of Diabetic Macular Edema Treatment
                                                                                       Recommendations

                                                                                         Key Points                           Evidence Levela

                                                                       Laser therapy remains the standard of care                  A:I4
                                                                          for patients with non-center-involving
                                                                          edema or early DME without decreased
                                                                          VA
                                                                       Commence anti-VEGF treatment in patients               A:I10–14,17–20
                                                                          with center-involving DME and VA of 20/
                                                                          30 or worse
                                                                       In patients who do not meet the threshold                  A:III4
                                                                          for anti-VEGF treatment, manage
                                                                          according to ETDRS guidelines using
                                                                          focal or grid laser treatment
                                                                       Ranibizumab injections should be                        A:I10–13,53
                                                                          administered on a monthly basis for at
FIGURE. Diabetic macular edema (DME) treatment flow dia-                  least 3 visits, then as needed depending
gram. Treatment should be given according to the Early Treat-             on VA (with or without OCT) stability
ment for Diabetic Retinopathy Study (ETDRS) guidelines in              Follow-up should be monthly for                         A:I10–14,53
patients without center involvement, and in patients with center          6-12 months; once visual stability
involvement but with vision better than 20/30. Anti–vascular              can be maintained for 3 consecutive
endothelial growth factor (anti-VEGF) treatment is recommended            visits, follow-up intervals can be
in patients with center involvement and vision 20/30 or worse.            prolonged to between 2 and 4 months
OCT [ optical coherence tomography; VA [ visual acuity.                Administer ETDRS laser treatment if                     A:I10–14,53
                                                                          response to anti-VEGF treatment is
                                                                          unsatisfactory, generally after at least
given for at least 3 consecutive months (‘‘loading’’ dose)                6 months
followed by monthly assessment visits.[A:I]10–13,53 The                Vitrectomy may be indicated when                         A:II56,57
decision to continue anti-VEGF injections may be guided                   vitreomacular traction is responsible for             C:III46–48
either by VA stability (RESTORE) or by VA and OCT sta-                    reduced VA, after confirming its presence
                                                                          using spectral-domain OCT; such cases
bility (DRCR.net Protocol I). The rationale for using VA
                                                                          may also respond to adjunctive
stability is that if VA is still improving, or if VA has fallen
                                                                          intravitreal anti-VEGF, corticosteroid,
and this reduction is considered attributable to DME, then                and/or laser therapy
injection should be continued. If VA is stable for at least 2          There may be a role for IVTA as an adjunct                B:I11,12
consecutive visits, then injections could be suspended and                to laser treatment in pseudophakic eyes
monthly follow-up continued. Stability of signs on OCT,                   of DME patients; further data are needed
particularly the presence of intraretinal or subretinal fluid,
could also guide either the continuation or the suspension                DME ¼ diabetic macular edema; ETDRS ¼ Early Treatment
                                                                       Diabetic Retinopathy Study; IVTA ¼ intravitreal triamcinolone
of injections.[C:III]53
                                                                       acetonide; OCT ¼ optical coherence tomography; VA ¼ visual
   The fixed monthly schedule used in RISE and RIDE
                                                                       acuity; VEGF ¼ vascular endothelial growth factor.
was designed to optimize treatment outcomes based on                      a
                                                                            Presented as importance of clinical outcome, strength of
the pharmacokinetic studies of ranibizumab,54 but this                 evidence. A indicates that the recommendation is considered
schedule leads to considerable burden in DME patients                  very important or crucial to a good clinical outcome; B, moder-
who frequently have multiple comorbidities, with regular               ately important to clinical outcome; C, may be relevant but cannot
visits needed to many other subspecialists. Fixed dosing               be definitely related to clinical outcome. I indicates data providing
also leads to greater exposure to treatment-related risks              strong evidence in support of clinical recommendation; II, sub-
and increased treatment costs.                                         stantial evidence in support of recommendation but the
   The treatment approach proposed was therefore based on              evidence lacks some qualities; III, insufficient evidence to provide
flexible dosing schedules used in both the RESTORE                     support for or against recommendation, or panel consensus.15
(Supplemental Figure 1, available at AJO.com) and
DRCR.net (Supplemental Figure 2, available at AJO.com)              follow-up visits, and the visual and quality-of-life outcomes
treatment protocols. The validity of a flexible dosing              between flexible and fixed dosing schedules.
schedule is supported by its ability to maintain visual stability      Doubling of follow-up intervals may be considered within
achieved early in the treatment initiation phase with less          the first 6 months if visual stability can be maintained for 3
than monthly injections.10–13,53 Future studies should              consecutive visits.[C:I]10–13,53 If DME continues to progress
quantify and compare costs associated with treatment,               and other causes of vision loss have been excluded,

510                                           AMERICAN JOURNAL OF OPHTHALMOLOGY                                                 MARCH 2014
laser treatment should be considered using ETDRS                                 to aid in patient selection. The appropriate dose for anti-
guidelines.[A:I]10–13,53 In patients with DME undergoing                         VEGF treatment remains to be defined, as existing
cataract surgery, efforts should be made to resolve the DME                      trials were not powered to compare different doses (eg,
before surgery.[A:I]55 The DRCR.net cautions against the                         ranibizumab 0.3 mg vs 0.5 mg). The clinical impact and
long-term use of IVTA owing to increased risk of glaucoma                        cost effectiveness of both flexible and fixed monthly dosing
and almost inevitable progression of cataract.[A:I]11,12,38                      regimens also require further exploration.
However, pseudophakic eyes may benefit from combined
IVTA and laser therapy, although similar outcomes were
achieved with ranibizumab plus laser without steroid
complications.[A:I]11–13 IVTA may provide an alternative
                                                                                                         CONCLUSIONS
to anti-VEGF therapy in patients who are either hypersensi-                      DME IS THE MAJOR CAUSE OF VISION LOSS IN PATIENTS
tive or nonresponsive to anti-VEGF therapy.[A:I]11–13 The                        with DM. Although laser treatment has long been the pri-
Table summarizes the recommendations discussed in this                           mary therapy for preventing blindness in patients with
section.                                                                         DME, treatment goals should now aim to restore impaired
                                                                                 vision, prevent further vision loss, and improve visual func-
                                                                                 tion. Recent RCTs suggest that these goals can be obtained
                         DISCUSSION                                              using intravitreal anti-VEGF therapy, with a well-
                                                                                 documented tolerable safety profile. As a result of these
RECOMMENDATIONS MADE IN THIS GUIDELINE WERE BASED                                recent data, we propose the use of anti-VEGF therapy as
on the best available data; results from ongoing and future                      the first line of treatment in place of laser photocoagulation
RCT studies may alter treatment recommendations. There                           in DME causing vision loss.
are certain limitations to our recommendations. As high-                            We note that the current evidence is largely based on
lighted, although there is value in using OCT to define                          studies with ranibizumab. Until additional data for the
DME, a standardized OCT-based DME classification has                             use of bevacizumab and aflibercept become available, this
yet to be developed, and the features that predict the                           guideline recommends ranibizumab as the treatment of
need or type of treatment and the treatment outcomes                             choice for patients with center-involving DME with mod-
remain unclear. Comparative evidence on the long-term                            erate visual impairment. This is recommended to be given
efficacy and safety of anti-VEGF agents in DME are absent.                       in a flexible dosing schedule, rather than continuously.
There is currently no evidence to support the use of anti-                       Patients who do not yet meet the treatment threshold
VEGF agents in eyes with VA better than 20/30. More                              should be managed with laser therapy according to ETDRS
data on predictors of treatment response are also needed                         guidelines or should continue to be closely observed.

BOTH AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTER-
est. Paul Mitchell has served on advisory boards for Abbott, Allergan, Bayer, Novartis, and Pfizer, and has received honoraria for travel, service on advisory
boards, and research support from these companies. Tien Yin Wong is on advisory boards for Abbott, Allergan, Bayer, Novartis, and Pfizer, and has received
honoraria for travel, service on advisory boards, and research support from these companies. Funding for Diabetic Macular Edema Treatment Guideline
Working Group member meetings and the medical writing service was provided by Novartis AG, Basel, Switzerland. Contributions of authors: concept and
outline (P.M., T.Y.W.); literature search (T.Y.W.); manuscript development (P.M., T.Y.W.); review and final approval (P.M., T.Y.W.). All content was
reviewed, discussed, and given final approval by the DME Treatment Guideline Working Group Members.
    The Diabetic Macular Edema Treatment Guideline Working Group consists of the following members from the Asia-Pacific region: Paul Mitchell
(Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Australia); David Liu (Chinese University of Hong Kong, China);
Taraprasad Das (L.V. Prasad Eye Institute, Bhubaneswar, India); Iwan Sovani (National Eye Center Cicendo Eye Hospital, Bandung, Indonesia);
Hakyoung Kim (Hallym University Medical Center, Seoul, South Korea); Hyung Chan Kim (Konkuk University School of Medicine, Seoul, South
Korea); Hyung Woo Kwak (Kyung Hee University Medical Center, Seoul, South Korea); Harvey Uy (Pacific Eye and Laser Institute, Makati City,
Manila, Philippines); Tien Yin Wong (Singapore Eye Research Institute, Singapore National Eye Centre, National University of Singapore, Singapore);
Shwu-Jiuan Sheu (Kaoshiung Veterans Hospital, Kaoshiung, Taiwan); Paisan Ruamviboonsuk (Rajavithi Hospital, Bangkok, Thailand).
    The authors thank Charity Yii Tien Jen of In Vivo Communications (Asia) Pte Ltd for medical writing support, which encompassed research, drafting,
and revisions of the manuscript, tables, and figures, all under the direction of the authors. Novartis AG did not influence any content of this paper. The
authors and the Diabetic Macular Edema Treatment Guideline Working Group did not receive any honorarium for their involvement in the development
of this manuscript.

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513.e1                                           AMERICAN JOURNAL OF OPHTHALMOLOGY                                              MARCH 2014
SUPPLEMENTAL FIGURE 1. Anti–vascular endothelial growth factor (anti-VEGF) treatment decision tree based on the treat-
ment and retreatment schedule from A 12 Month Core Study to Assess the Efficacy and Safety of Ranibizumab Intravitreal Injections
(RESTORE).10 Flow diagram showing anti-VEGF treatment for diabetic macular edema (DME) based on initial treatment with three
consecutive monthly injections and whether stable visual acuity (VA) is achieved.

VOL. 157, NO. 3                             DIABETIC MACULAR EDEMA MANAGEMENT                                            513.e2
SUPPLEMENTAL FIGURE 2. Anti–vascular endothelial growth factor (anti-VEGF) treatment decision tree based on the Diabetic
Retinopathy Clinical Research Network (DRCR.net) retreatment and follow-up schedule.53 Flow diagram showing anti-VEGF treat-
ment for diabetic macular edema (DME) based on assessment 1 month after initial injections and whether DME improves. Reprinted
from Ophthalmology, 118/12, Aiello LP, Beck RW, Bressler NM, et al., Rationale for the diabetic retinopathy clinical research
network treatment protocol for center-involved diabetic macular edema, e5–14, Copyright (2011), with permission from Elsevier.

513.e3                                     AMERICAN JOURNAL OF OPHTHALMOLOGY                                      MARCH 2014
VOL. 157, NO. 3

                                                                      SUPPLEMENTAL TABLE 1. Overview of Selected Randomized Controlled Trials for Treatment in Diabetic Macular Edema

                                                                                                           Mean 6 SD          Mean 6 SD
                                                                         Study                               (Where        (Where Available)                         Proportion of Patients With BCVA Change (%)                             Licensed
                                                       Randomized       Design                              Available)       ETDRS Letter                                                                                                  Indication for
                                                        Controlled        and           Treatment             VA at          Change From            >
                                                                                                                                                    _10 Letters              >
                                                                                                                                                                             _10 Letters             >
                                                                                                                                                                                                     _15 Letters          >
                                                                                                                                                                                                                          _15 Letters       Ophthalmic
                                      Treatment          Trial (n)      Duration         Arms (n)           Baseline           Baseline               Gained                    Lost                   Gained                Lost               Use

                                    Anti-VEGF agents
                                    RBZ            RESOLVE            Phase II,    Study treatment:                                                                                                                                       Yes
                                                       (151)17          12 months 0.3/0.6 mg RBZ (51) 60.2 6 9.9         RBZ pooled:            RBZ pooled: 60.8       RBZ pooled: 4.9        RBZ pooled: 32.4      RBZ pooled: 2.9
                                                                                   0.5/1.0 mg RBZ (51)                     7.8 6 7.7
                                                                                   Comparator:
                                                                                   Sham (49)               61.1 6 9.0    Sham: 0.1 6 9.8       Sham: 8.4              Sham: 24.5             Sham: 10.2            Sham: 20.4
                                                   READ-2             Phase II,    Study treatment:
                                                       (126)18          24 months 0.5 mg RBZ (33)          24.85         0.5 mg RBZ: 7.7        0.5 mg RBZ: 43         N/A                    0.5 mg RBZ: 25        N/A
DIABETIC MACULAR EDEMA MANAGEMENT

                                                                                   Comparator:
                                                                                   Laser (34)              23.83         Laser: 5.1             Laser: 23%                                    Laser: 9
                                                                                   0.5 mg RBZ              24.84         0.5 mg RBZ             0.5 mg RBZ þ                                  0.5 mg þ laser: 7
                                                                                     þ laser (34)                          þ laser: 6.8           laser: 38
                                                   READ-2             Phase II,    Study treatment:
                                                       (126)18          36 months 0.5 mg RBZ (28)          N/A           0.5 mg RBZ: 10.3       0.5 mg RBZ: 46         N/A                    0.5 mg RBZ: 32        N/A
                                                                                   Comparator:
                                                                                   Laser (22)                            Laser: 1.4             Laser: 23%                                    Laser: 9
                                                                                   0.5 mg RBZ                            0.5 mg RBZ             0.5 mg RBZ þ                                  0.5 mg RBZ þ laser:
                                                                                     þ laser (24)                          þ laser: 8.9           laser: 38                                     21
                                                   RESTORE            Phase III,   Study treatment:
                                                       (345)10          12 months 0.5 mg RBZ (116)         64.8 6 10.11 0.5 mg RBZ:             0.5 mg RBZ: 37.4       0.5 mg RBZ: 3.5        0.5 mg RBZ: 22.6      0.5 mg RBZ: 0.9
                                                                                   0.5 mg RBZ              63.4 6 9.99     6.1 6 6.43           0.5 mg RBZ þ laser: 0.5 mg RBZ þ              0.5 mg RBZ þ laser: 0.5 mg RBZ þ
                                                                                     þ laser (118)                       0.5 mg RBZ þ             43.2                   laser: 4.2             27.9                  laser: 3.4
                                                                                   Comparator:                             laser: 5.9 6 7.92
                                                                                   Laser (111)             62.4 6 11.11 Laser: 0.8 6 8.56       Laser: 15.5            Laser: 12.7            Laser: 8.2            Laser: 8.2
                                                   DRCR.net           Phase III,   Study treatment:a                     At 12 months:
                                                       Protocol I       60 months 0.5 mg RBZ þ             63 6 12       0.5 mg RBZ þ           0.5 mg RBZ þ           0.5 mg RBZ þ           0.5 mg RBZ þ          0.5 mg RBZ þ
                                                       (854 eyes)11                  prompt laser                          prompt laser: þ9       prompt laser: 30       prompt laser: 50       prompt laser: 4       prompt
                                                                                     (187 eyes)                            6 11                                                                                       laser: 2%
                                                                                   0.5 mg RBZ þ                          0.5 mg RBZ þ           0.5 mg RBZ þ           0.5 mg RBZ þ           0.5 mg RBZ þ          0.5 mg RBZ þ
                                                                                     deferred laser (188                   deferred laser: þ9     deferred laser: 28     deferred laser: 47     deferred laser: 3     deferred
                                                                                     eyes)                                 6 12                                                                                       laser: 2
                                                                                   Comparator:
                                                                                   4 mg TA þ prompt                      4 mg TA þ prompt       4 mg TA þ prompt 4 mg TA þ prompt             4 mg TA þ prompt      4 mg TA þ prompt
                                                                                     laser (186 eyes)                      laser: 4 6 13          laser: 21              laser: 33              laser: 14             laser: 8
  513.e4

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