Different Treatment Modalities in Diabetic Macular Edema Refractory to Intravitreal Bevacizumab: A Review Article
Shahin Faghihi, Fariba
Ghassemi, Fatemeh Abdi, Mandana Esfahani, Hooshang Faghihi*
Eye Research Center, Farabi Eye Hospital, Tehran University of
Medical Sciences, Tehran, Iran
*Corresponding author: Hooshang Faghihi, Eye Research Center, Farabi Eye Hospital,
Tehran University of Medical Sciences, Tehran, Iran. Tel: + (+98 21) 8897 0821;
Email: faghihih@hotmail.com
Background: Diabetic Macular Edema (DME) is a leading cause of vision loss
in diabetic population worldwide. Despite laser therapy had been standard
treatment in DME for years, nowadays Anti-VEGF agents have become first line
therapy. Although the use of Bevacizumab is still off-label, its low cost and
availability, consistent with its similar therapeutic effects to other
Anti-VEGF agents, make it first line therapy in DME in most countries.
Recently, refractory cases to multiple IVB injections have
emerged. In this study, we aimed to review the literature for other treatment
modalities in such patients.
Conclusions: Different treatment strategies have been suggested to be
beneficial in refractory cases; such as intravitreal triamcinolon, switch to
other Anti-VEGF agents, higher dose of Anti-VEGF agents, and combination of
triamcinolon and Anti-VEGFs. Each treatment modality can be beneficial in
selected patients. Despite favorable reports on the efficacy of these treatment
strategies, we still require the results of large, controlled trials to
elucidate the ideal therapeutic approach in each patient.
1. Introduction
The leading cause of visual disturbance in diabetic retinopathy
patients is Diabetic Macular Edema (DME) [1,2]. Although laser photocoagulation
is the standard treatment for DME [3-5], its side effects for the treatment of
severe retinopathy in the form of Pan Retinal Photocoagulation (PRP) are well
known [6-9]. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy has
recently gained credit as the first-line treatment for DME because numerous
trials have revealed its beneficial outcomes [10-14]. Despite these remarkable
effects, not all DME patients are responsive to anti-VEGF therapy. Bevacizumab
(Avastin, Genentech, San Francisco, California) is a humanized recombinant
antibody that binds all isoforms of VEGF [15]. The drug had received Food and
Drug Administration’s approval for the treatment of metastatic colorectal
cancer [16]. Although Bevacizumab is being used off label, its low cost and
availability, consistent with its similar therapeutic effects to other
Anti-VEGF agents, make it first line therapy for DME in most countries. Newer
treatment modalities are under investigation for DME refractory to anti-VEGFs.
Our ambition in this study is to review different therapeutic options in DME
patients, refractory to IVB treatment.
2. Materials and Methods
All studies who evaluated treatment options in refractory DME to
multiple IVB injections were included. We searched both Pub Med and Cochrane
database without time limit. The keywords we used were: Refractory DME, IVB
injections, DME refractory to IVB. We first searched the database in September
2016, and repeated it again in November 2016. We excluded all studies with
treatment modalities other than bevacizumab injection or combination of IVB
with other treatment strategies. Twenty-seven articles were reviewed and only
three of them met the inclusion criteria.
3. Results
Nourinia et al studied 15 eyes of 15 patients with the following
inclusion criteria: presence of type 2 diabetes mellitus and DME with no CMT
reduction or VA improvement after one or more IVB injections, BCVA ≤ 20/40 and
severe DME defined as CMT more than 320μm associated with large cystoids
changes and/or neuro sensory detachment [17]. Kim, et al. defined DME as
refractory to IVB if either of the following conditions were met
·
CST did not decrease by more than 30μm after ≥ 3 consecutive IVB
injections.
·
CST increased after 1 to 2 IVB injections [18].
Fasudil has improved understanding of the pathophysiology of
diabetic retinopathy and has facilitated the development of new drugs for
treatment of DME in cases refractory to current therapies. In addition to the
previously known high VEGF levels, increased activity of the Rho/Rock pathway
has recently been demonstrated in diabetic patients. This pathway promotes
leukocyte adhesion to the retinal vascular endothelium by increasing
Intercellular Adhesion Molecule 1 (ICAM-1) expression and stimulating Myosin
Regulatory Light Chain (MLC) phosphor relation [19]. Furthermore, increased
activity of the Rho/Rock pathway inactivates endothelial Nitric Oxide Syntheses
(eNOS), thereby reducing physiological levels of Nitric Oxide (NO), a potent
vasodilator and anti-apoptotic factor. Therefore, retinal endothelial cell
damage occurs as a result of leukocyte adhesion and decreased eNOS activity
[18]. Experimental studies have demonstrated that Fasudil (Asahi Kasei Pharma
Corporation, Tokyo, Japan) as a potent ROCK inhibitor can suppress leukocyte
adhesion and prevent neutrophil-induced retinal endothelial cell damage [20].
Exclusion criteria were active proliferative diabetic retinopathy, mono clarity
or VA of fellow eye < 20/40, other macular disorders, intravitreal
bevacizumab injection within the past 3 months, and ocular surgery over the
past6 months. All patients received IVB (1.25 mg/0.05 ml) and intravitreal
Fasudil injection (0.025 mg/0.05ml) using two separate syringes and at two
separate sites followed by anterior chamber paracentesis. Best-Corrected Visual
Acuity (BCVA) was measured and Optical Coherence Tomography (OCT) images were
obtained before and one month after the injections. Mean age of the patients
was 64.6 ± 7.3 (range, 49-79) years and the mean number of previous IVB
injections was 2.8. Mean BCVA was 0.84 ± 0.35logMAR before intervention
improving to0.49 ± 0.29 log MAR four weeks after treatment (P = 0.003). Mean
pre-injection CMT was 448 ± 123μm decreasing to 347 ± 76μm four weeks after
treatment (P = 0.001) (Table 1 and Figure 1). No adverse effects such as
intraocular inflammation, vascular accident, and IOP rise were observed
following intravitreal injection of Fasudil and bevacizumab.
The short-term results of this case series showed that in DME
refractory to IVB, combined intravitreal bevacizumab and Fasudil injection
resulted in structural (CMT reduction) and functional (BCVA) improvement. These
results are comparable or superior to other studies reporting intravitreal
injection of bevacizumab, triamcinolone and sustained release dexamethasone in
patients with refractory DME [1,3,4,10,11,15-18]. They used 0.025 mg Fasudil
intravitreally to achieve an intraocular concentration of 10μM/L [21]. Previous
animal studies have not shown any obvious electrophysiological or morphological
toxicity up to a maximum concentration of 100μM/L [22]. ERG findings in their
previous study [21] and comprehensive ocular examinations in the current study
did not show any toxic effect associated with intravitreal Fasudil injection.
The results of this study and their previous report on a smaller number of
cases [21] demonstrate a possible beneficial effect from intravitreal injection
of Fasudil in combination with IVB in patients with DME unresponsive to mono
therapy with IVB. This combination may reduce retinal vessel hyper-permeability
via simultaneous inhibition of VEGF activity and endothelial cell damage more
effectively than intravitreal injection of an anti-VEGF alone.
Yu¨ ksel Totan, et al. performed a prospective, non-randomized
study to evaluate a group of 30 patients unresponsive to regular intravitreal
bevacizumab injections for diabetic macular edema. Inclusion criteria were age
over18 years, a Best-Corrected Visual Acuity (BCVA) between 1.0 and 0.3 (log
MAR) and chronic resistant DME. They defined chronic DME as DME present for a
period of 6 months or more with Central Foveal Thickness (CFT) greater than 275
microns as measured by Optical Coherence Tomography (OCT). They also defined
chronic-resistant DME as chronic DME unresponsive (reduction of CFT less than
50 microns, or increase in CFT) to a minimum of three
2.5-mgintravitrealbevacizumab injections given 6 weeks apart before inclusion
into the study. The exclusion criteria were a history of glaucoma, severe
cataract, venous occlusions, epiretinal membrane visible by Optical Coherence
Tomography (OCT), age-related macular degeneration, uveitis, history of
cataract surgery (within the previous 6 months), YAG lasercapsulotomy (within 2
months prior to the trial), previous vitrectomy, pan retinal or grid laser
photocoagulation (within 3 months prior to investigation), and DME previously
treated with intravitreal or peri ocular corticosteroids injection.
Intravitreal dexamethasone implant (0.7-mgimplant of dexamethasone, Ozurdex;
Allergan, Inc, Irvine, CA) was administered intravitreally through the pars
plane using the original implanting device.
After the administration, IOP and light perception were
assessed. Complete ophthalmic examination, including IOP measurements was
performed at first week, 1, 3, and 6 months. BCVA, CFT, and MCV measurements
were performed at 1, 3, and 6 months. The main outcomes were the changes
between the initial and follow up visits in the mean BCVA, CFT, MCV (Mean cube
volume), and IOP measures [19]. A total of 30 eyes of 30 patients (12 males, 18
females; mean age 61.3 ± 7.3 years, range 47-76 years) with chronic resistant
DME were included in the analysis. The mean duration of DME was 29.7 ± 9.5
months (range 12-44 months), and the mean HbA1c value at baseline was 7.4%
(mean 7.4 ± 1.9). Of the 30 eyes, 12 had previous grid laser, 5 had scatter
laser treatment. The average interval between the last intravitreal bevacizumab
injection and dexamethasone implant application was 2 months (6 weeks to3
months). The mean number of the intravitreal bevacizumab injections was 6.0 ±
0.6. Preoperative and follow-up FFA showed no cases of macular or Para macular
retinal ischemia.
Statistically significant change from baseline was observed in
BCVA (at 1, 3 and 6 months), CFT (at 1, 3, and 6 months), MCV (at 1, 3, and 6
months), and IOP (at 1 week, 1 and 3 months). BCVA significantly (p = 0.04)
decreased at 6months (0.59 ± 0.39 log MAR) compared to the mean BCVA at 3
months (0.44 ± 0.28 log MAR) (Figure 1). At the 6 months visit, the mean CFT
(411 ± 126 mm, range 174-776 mm) (p < 0.001) was still significantly lower
compared to the baseline value (517 ± 136 mm, range 324-872 mm) (p = 0.01), but
significantly increased compared to the mean CFT at 3 months (314 ± 88 mm,
range 186-758 mm). At the last visit, the mean MCV was significantly lower than
baseline value (13.6 ± 1.9mm3) (p < 0.001). However, it was significantly increased to
12.1 ± 1.9mm3 (p = 0.01) compared to the mean MCV at 3 months (11.3
±1.5mm3). A recurrence of
macular edema at 6 months was observed in a total of 25 eyes with CFT ranged
from 321 mm to 800 mm and mean HbA1c value of6.8%. Three of 25 eyes showed a
CFT increase to a higher level than baseline (rebound effect) at the6-month
follow-up examination and were retreated with additional 2.5mg intravitreal
bevacizumab. These 3 patients had HbA1c values of 6.3%, 6.9%and 8.3%. Thirteen
of the remainder 22 eyes were retreated with 1.25mg of intravitreal
ranibizumab, and 9 eyes with additional 2.5mg intravitreal bevacizumab.
The BCVA was not significantly correlated with CFT and MCV at
6-month follow up (r = -0.10, p = 0.58; r = 0.29, p = 0.11, respectively). IOP
values were significantly higher at 1 week (p = 0.01), 1 month (p = 0.01) and 3
months (p = 0.04) compared to the baseline IOP. After 1 month, it was gradually
decreased to the baseline value at 6 months. During the follow-up period, they
found IOP higher than 21mmHg in 4 of 30 eyes (13.3%) (The maximum value was
32mmHg at 1 month). These eyes were treated and well-controlled with
topicality-glaucoma mono therapy. No inflammation, infection, thromboembolic
events, ocular toxicity, and cataract progression (based on the ‘‘Lens
Opacities Classification System’’ III) were observed in any of the patients.
Min Woo Kim, et al. conducted a retrospective, nonrandomized,
interventional study on patients who were diagnosed with DME between January
2011 and December 2012 at AS an Medical Center. Patients with DME involving the
fovea, a CST > 300μm, and who did not respond to IVB injection were
included. They defined DME as refractory to IVB if either of the following
conditions were met:
·
CST did not decrease by more than 30μm after ≥ 3 consecutive IVB
injections.
·
CST increased after1 to 2 IVB injections.
Exclusion criteria
were:
·
Age under 18 years.
·
History of retinal vein occlusion, retinal arterial occlusion,
uveitis, epi retinal membrane, or any chorioretinal disease other than diabetic
retinopathy.
·
Previous focal or grid laser treatment.
·
Pan retinal photocoagulation treatment less than 3 months before
the first IVB injection.
·
Previous IVTA or stTA (sub tenon triamcinolone acetonide)
treatment.
·
Suspected glaucoma (with a high cup to disc ratio, > 0.6) or
diagnosis of glaucoma by a glaucoma specialist.
·
Any kind of ocular surgery, including cataract surgery, within
the last 6 months.
Posterior subtenant injections of triamcinolone (20 mg/0.5mL)
were administered by a Single Retina Specialist (SGJ), all using the same
protocol.
Patients were examined every 2 months after injection. Each
patient’s Best-Corrected Visual Acuity (BCVA), IOP, and CST were evaluated on
the day of st TA injection and again at 2, 4, and 6 months. At each visit, lens
status was evaluated to determine if the posterior sub capsular cataract was
more advanced than PII (according to the Lens Opacities Classification System
III). BCVA was assessed using a Snellen visual acuity chart, and IOP was
measured using Gold man nap plantations tonometry. They prescribed Trusopt for
prophylactic IOP control. Other related factors, such as duration of diabetes,
glomerular filtration rate, and Hemoglobin A1c (HbA1c), were also assessed.CST
was measured using spectral-domain optical coherence tomography (Spectralis;
Heidelberg Engineering, Heidelberg, Germany). Macular edema patterns on OCT
were classified according to the criteria previously reported by [23,24],
including Sponge-Like Diffuse Retinal Thickening (SDRT), Cystoids Macular Edema
(CME), serous retinal detachment, and a combination of all three edema types
(FULL).
In total, 34 patients (40 eyes) met the inclusion criteria. Of
these, 33 patients (36 eyes) received 2 months of follow- up examinations.
Thirty-three patients received 4 months of follow-up examinations. One patient
did not receive a spectral-domain optical coherence tomography examination. At
6 months, 31 patients (37 eyes) received all examinations. The baseline
characteristics of the 34 patients are summarized here: the average patient age
was 61.7 ± 9.19 years, and 21 of these patients were male. The mean baseline
CST was 476 ± 153μm (range, 300 to988μm). Mean CST decreased to 368μm (p <
0.001, Wilcoxon signed-rank test) within 2 months of receiving stTA injection,
then increased slightly to 374μm. It sub sequently resumed its decreasing trend
from baseline at 4 months (p < 0.001, Wilcoxon signed rank test). CST
increased to 427μm by 6 months but was still lower than baseline (p = 0.046,
Wilcox on signed-rank test). Twenty-five eyes were diagnosed with SDRT, 12 eyes
were diagnosed with CME, and three eyes were diagnosed with FULL. No cases were
diagnosed as serous retinal detachment type. They did not identify any CST
differences between the classified forms of macular edema at any of the time
points. The effects of stTA, which were measured in terms of CST change at each
follow-up OCT examination, did not indicate any differences between groups.
The mean initial BCVA was 0.55 on the log MAR scale. The BCVA
improved to 0.50 at 2 months after stTA injection, remained at 0.50 after 4
months, and finally decreased to 0.48 by the 6months’ follow-up examination;
only the value at 2 months represented a statistically significant change (p =
0.023, p = 0.083, and p = 0.133, respectively; Wilcoxon signed-rank test). The
average IOP changed significantly from 15.50 mmHg at baseline to16.92 mmHg at 2
months (p = 0.040, paired t-test). However, IOP did not change significantly at
4 months (16.30mmHg, p = 0.103) or at 6 months (15.65 mmHg, p = 0.732, paired
t-test). Three eyes from 37 eyes were administered another IOP-lowering drug.
No eyes had an IOP > 21 mmHg during the entire follow-up period. Among all
40 eyes, 27 were phakic and 13 were pseudo phakic. They did not identify any
cases of advanced cataract during the follow-up period (i.e., no eyes were >
PII according to the Lens Opacities Classification System III classification).
No other stTA-related complications were noted during the study period [18].
4. Conclusion
Nourinia et.al pilot study, in summary, combined intravitreal
injection of bevacizumab and Fasudil seems to entail a beneficial effect in
terms of structural and functional outcomes in eyes with severe DME resistant
to current therapeutic modalities. Studies with larger sample size and longer
follow-up are required to establish the use of Fasudil for DME [17]. Study of
Yu¨ ksel Totan et al, suggested that dexamethasone intravitreal implant may
present a good alternative in the management of DME unresponsive to regular
intravitreal anti-VEGF injections. They also have observed that its efficacy
has remarkably been decreased between month 3 and 6 following administration
[19]. Min Woo Kim et.al, showed that stTA was associated with a lower rate of
adverse events than previous study, like cataract progression or elevated IOP
during the follow up period. In conclusion, stTA is an effective, safe, and
affordable treatment for reducing CST in DME refractory to IVB injection [18].
In summary, the study results suggest that continuation of anti-VEGF therapy
after 24 weeks in eyes that have persistent DME may lead to long-term visual
and anatomical improvement even in the setting of chronic persistent DME [20].
We excluded all studies on refractory DME with treatment modalities other than
Bevacizumab or combination of Bevacizumab with other treatments:
In the study by Edward H. Wood, et al. DME patients with
persistent retinal fluid despite regular (every 4 to 6 weeks) Intravitreal
Injection (IVI) with ranibizumab 0.3 mg, and/or bevacizumab 1.25 mg were
switched to IVI aflibercept 2 mg. A majority of patients with DME with
persistent fluid on SD-OCT despite regular ranibizumab 0.3 mg and/or
bevacizumab 1.25 mg IVI showed a positive anatomic response to IVI aflibercept2
mg [21]. Weiye Li, et al, studied intravitreal
injections of erythropoietin in eyes with severe, chronic diabetic macular
edema, 5 eyes of 5 patients underwent injections of rHuEPO alpha (EPO) intravitreally
every 6 weeks for three doses and followed for an additional 6 weeks. Visual
acuity of all patients was subjectively improved by 3 or more lines in 3 eyes
and 1 line in 2 eyes. Visual acuity improved to a larger extent than anatomic
improvement by OCT [22].
Khalil Ghasemi Falavarjani, et al, evaluate the efficacy of
intravitreal injection of 400μg Methotrexate (MTX) in patients with persistent
Diabetic Macular Edema (DME) nonresponsive to at least three consecutive
bevacizumab injections or two consecutive bevacizumab injections plus macular
photocoagulation. In this study, intravitreal injection of MTX resulted in
anatomical improvement in a significant proportion of eyes with persistent DME.
Significant visual improvement was found in 16.6 % of eyes [25]. Maria C.
Hernaez-Ortega, et al. investigated the effectiveness of a new prolonged
lanreotide formulation in patients with bad controlled diabetes and persistent
cystoid macular edema. Two patients treated with a subcutaneous injection of
lanreotide Autogel (Somatuline1 Autogel, Ipsen Pharma SA, Spain) of 90 mg every
4 weeks were monitored before (atbaseline) and after treatment (at 3, 6 and 12
months). This study revealed that monthly subcutaneous injections of lanreotide
Autogel offered an effective treatment alternative in patients with persistent
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