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Diabetic
macular edema (DME) is a vision-threatening disease that is estimated to affect
21 million individuals worldwide [1]. The etiology of DME is multifactorial,
involving vascular endothelial growth factor (VEGF) production as well as
inflammatory processes [2]. Asrecently as 2010, the only approved treatment for
DME was focal/grid laser photocoagulation of leaking microaneurysms and areas
of retinal thickening to decrease the risk of further vision loss. However,
laser photocoagulation is a destructive procedure, and potential
complications include the development of scotomas related to focal laser burns.
There was a need for new DME treatments thatwould restore lost vision, as well
as reduce the retinal fluid accumulation that causes vision loss.
Dexamethasone intravitreal implant 0.7 mg (DEX; Ozurdex, Allergan plc,
Dublin, Ireland) was developed to treat ocular posterior segment diseases that
have an inflammatory component. Thesustained-release implant contains 0.7 mg
dexamethasone embedded in a biodegradable polymer matrix of poly
d,llactide-co-glycolide. Dexamethasone is released slowly over a period of
months as the implant matrix is hydrolyzed to lactic acid and glycolic acid,
which are subsequentlymetabolized to carbon dioxide and water. A preloaded,
single-use 22-gauge applicator is used to insert the implant into the vitreous
through the pars plana.
DEX was evaluated for the treatment of DME in the 3-year MEAD global
registration study involving 1048 patients in 22 countries [3]. Adult patients
with DME, best-corrected visual acuity (BCVA) between 20/50 and 20/200, and
central retinal thickness (CRT)≥300 μm on optical coherence tomography were
enrolled and randomly assigned in a 1:1:1 ratio to treatment in the study eye
with DEX 0.7 mg, DEX 0.35 mg, or sham procedure. For the sham procedure, a
needleless applicator was pressed against the conjunctiva.Study treatment was
administered at baseline, and patients who met eligibility criteria could be
administered repeat treatment no more often than every 6 months, for a maximum
of 7 administrations over the 3-year period. Patients were followed for 3 years
(or 39 months for patients who were treated at month 36). Patients who required
rescue therapy were exited from the study before receiving the rescue
treatment.
In the total study population, DEX 0.7 mg and 0.35 mg were
significantly more effective than sham procedure in improving BCVA and
decreasing edema, as measured by a decrease in CRT. Both DEX 0.7 mg and DEX
0.35 mg met the primary endpoint: the percentage of patients with ≥15-letter
improvement in BCVA from baseline at study end (with missing values imputed
using the lastobservationcarriedforward) was 22.2% in the DEX 0.7mg group and
18.4% in the DEX 0.35mg group compared with 12.0% in the sham group (P≤0.018). The mean average improvement
in BCVA over the course of the study, measured with an area-under-the-curve
approach, was also greater in the DEX 0.7 mg group (+3.5 letters) and the DEX
0.35 mg group (+3.6 letters) compared with the sham group (+2.0 letters)(P≤0.023), and the mean average reduction
in CRT from baseline over the course of the studywas greater in the DEX 0.7mg
group (–111.6 μm) and the DEX 0.35 mg group (–107.9 μm) compared with the sham
group (–41.9 μm) (P<0.001).
The safety profile of DEX in the MEAD study was better than the
reported safety profile of other intraocular corticosteroidsustained-release
implants [4]. The most common adverse effects, as expected, were
steroid-related increases in IOP and cataract.
The
frequency of IOP increases did not increase with repeatedDEX treatment [5], and
the IOP increases were usually managed with topical medication. Only 1 (0.3%)
patient in each DEX group required glaucoma incisional surgery for a
corticosteroid-induced IOP increase [3]. Cataract-related adverse events were
reported in the majority of phakic eyes in the DEX treatment groups, and vision
loss occurred after these events. However, vision improved and treatment
benefit was restored after cataract surgery, which was performed in 59.2%,
52.3%, and 7.2% of study eyes that were phakic at baseline in the DEX 0.7 mg,
DEX 0.35 mg, and sham groups, respectively. In eyes with a cataract adverse
event that underwent cataract surgery, the mean average change in BCVA from
baseline, from the time of surgery to study end, was +4.3, +4.7, and +1.7
letters in the DEX 0.7 mg, DEX 0.35 mg, and sham groups, respectively. In eyes
that were pseudophakic at baseline, the mean average change in BCVA from
baseline during the study was +6.5, +5.9, and +1.7 letters, respectively.
The results of the MEAD study showed that in the total study
population, an average of only 4 or 5 injections of DEX implant 0.7 or 0.35mg
over 3 years provided long-term improvement in vision and macular edema in
patients withDME. These results led to regulatory agency approval of DEX 0.7 mg
for treatment of DME. Subsequently, subgroup analysis using MEAD study data
from patients in the DEX 0.7 mg group and the sham group was performed to
evaluate the effects of DEX 0.7 mg (marketed dose) treatment in patients with
DME that had been previously treated with laser or medical therapy [6].
Approximately 70% of patients in the DEX 0.7 mg group had been previously
treated for DME in the study eye. Among these patients, 231 (93.5%) had
received laser, 58 (23.5%) had received intravitreal steroid (triamcinolone
acetonide), and 25 (10.1%) had received intravitreal anti-VEGF therapy.
The primary efficacy and safety analyses that had been performed for
the total MEAD study population were repeated for previously treated patients
in the DEX 0.7 mg and sham groups. The efficacy results in previously treated
patients [6] were similar to those in the total study population. The
percentage of previously treated patients with ≥15-letter improvement in BCVA
from baseline at study endwas 21.5% in the DEX group compared with 11.1% in the
sham group (P=0.002), mean average
improvement in BCVA over the course of the study was +3.2 letters in the DEX
group compared with +1.5 letters in the sham group (P=0.024), and mean average reduction in CRT from baseline over the
course of the study was 126µm in the DEX group compared with 39 µm in the sham
group (P<0.001).In additional
subgroup analysis, DEX demonstrated benefit of treatment in patients previously
treated with laser, steroid, or anti-VEGF (Figure
1), as well as in in patients previously treated with at least two of these
modes of therapy.
The
safety profile of DEX was also similar in the total study population and the
subgroup of previously treated patients. Among previously treated patients,
cataract-related adverse events were reported in 70.3% of patients in the DEX
0.7 mg group who had phakic lens status at baseline. Cataract-related adverse
events led to vision loss in these patients, but vision gains were restored
after cataract surgery (Figure 2).
Intravitreal anti-VEGF therapy has becomethe standard first-line
treatment for center-involved DME. However, a significant number of patients
have a suboptimal response to anti-VEGF therapy even when monthly injections
are administered [7]. Additional treatment options are needed when anti-VEGF
therapy fails to normalize retinal thickness and improve vision. DEX
demonstrated efficacy in patients previously treated with anti-VEGF in the MEAD
study, but the sample size was small, because the study began in 2004, before
anti-VEGF was widely used for treatment of DME. Furthermore, in clinical
practice, DEX may be administrated more frequently than the minimum 6-month
interval used in the MEAD study, and this potentially may improve outcomes.
Following regulatory agency approval of DEX for treatment of DME, at least 12
studies have investigated DEX effectiveness in patients with DME refractory to
anti-VEGF therapy. A recent meta-analysis of results from these studies
reported robust (multiple-line) improvement in visual acuity after DEX
treatment in patients with DME resistant to anti-VEGF therapy [8]. Based on
evidence from the MEAD subgroup analysis, subsequent studies of DEX use in
patients previously treated with anti-VEGF,and their clinical experience, an
expert panel of retinal specialists recently developed guidelines for DME
management that recommend DEX treatment in patients with DME that responds
inadequately to anti-VEGF [9].
In summary, subgroup analysis of the MEAD study [6] showed that
patients with DME previously treatedwith laser, intravitreal anti-VEGF,
intravitreal triamcinolone acetonide, or a combination ofthese therapies had
significantly improved BCVA and CRT following DEX treatment. The safety profile
of DEX in previously treated patients was acceptable and similar to its safety
profile in the totalMEAD study population. Subsequent studies have confirmed
the benefit of DEX treatment in patients with DME refractory to anti-VEGF
therapy. DEX demonstrates efficacy and safety in patients with DME previously
treated with other therapy and isan excellent treatment option for patients
with a suboptimal response to anti-VEGF therapy.
ACKNOWLEDGMENTS
Financial disclosure: Albert J. Augustin has received research support
and speaker fees from Allergan.
Medical writing support, funded by Allergan, was provided by Kate
Ivins, PhD, Evidence Scientific Solutions, Philadelphia, PA, USA.
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Chin EK, Almeida DR (2017) Efficacy of the intravitreal sustained-release
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