The Efficacy of Ranibizumab and Triamcinolone on Macular Edema Following Cataract Surgery in Diabetic Retinopathy Patients
Erhan Yumusak*, Kemal Ornek, Hatice Ayhan Guler, Nesrin
Buyutortop
Départment of Ophthalmology, School of Médicine, Kırıkkale
University, Kırıkkale, Turkey
*Corresponding author: Erhan Yumusak, Department of Ophthalmology, School of Médicine,
Kırıkkale
University, Kırıkkale, Turkey, Tel: +90 5323719210; Fax: +90 3182240796; Email: erhanyumusak@yahoo.com
Citation: Erhan Y, Kemal O, Hatice Ayhan G, Nesrin B (2017) The
Efficacy of Ranibizumab and Triamcinolone on Macular Edema Following Cataract
Surgery in Diabetic Retinopathy Patients. Ophthalmol Res Rep 2017: J111
Purpose: To compare the efficacy and safety of Intravitreal Triamcinolone
Acetonide (IVTA) and Intravitreal Ranibizumab (RAN) in Diabetic Macular Edema (DME)
patients Schedule for Cataracta surgery.
Methods: The study included 42 eyes of 42 patients. All patients had
advanced Cataract a with DME and underwent an uneventful phacoemulsification
and intraocular lens implantation. Patients were divided in to 3 groups. The
first group received Intravitreal RAN injection (n=12), second group received
IVTA (n=10) and the third group did not received any injections (n=20).
Follow-up examinations were performed at 1 week, 1 and 3 months
postoperatively. A complète ophthalmic examinations and SD-OCT Imaging were
performed at each visit.
Results: There were 27 (64.3%) female and 15 (35.7%) male patients. The
mean age was 64.82±8.0 years. Compared to control visual acuity significantly
improved only in group 1 at 1st and 3rd months. (p<0,05). There were no
significant differences for fovéal thickness and intraocular pressure between
the three groups. (All p>0.05) Visual acuity significantly improved at 1stmonths
visit in all groups. (All p<0.05) Fovéal thickness showed a réduction only
in group 2 at 1stmonth. It increased in group 1 and 3. (All
p<0.05) Intraocular pressure showed an insignificant elevation in group 2 at
1st and 3rd months. (p>0.05)
Conclusions: No significant differences were found between the injection
groups. Ranibizumab showed a transient increase in visual acuity and IVTA was
more effective in reducing foveal thickness.
Keywords: Cataract Surgery; Diabetic Macular Edema; Ranibizumab;
Triamcinolone
1. Introduction
Diabètesaccelerates the formation of visually significant
cataracts and patients
Benefit from cataract surgery [1,2]. However, studies have shown
that cataract surgery, the definitive treatment for this type of visual
impairment, may worsen the underlying diabetic retinopathy and macular edema
[3-7]. Thus, ophthalmologists have searched for methods to minimize
exacerbation of the retinopathy and to optimize the outcome following cataract
surgery. This goal has led to several studies on peri-operative injections of
steroids and anti Vascular Endothelial Growth Factor (VEGF) agents to prevent progression
of diabetic retinal disease.
Funatsu et al. [8] showed that in diabetic patients, aqueous
levels of Vascular Endothelial Growth Factor (VEGF) and interleukin-6 at the
time of cataract surgery were significantly correlated with worsening of macular
edema postoperatively. In a study by Patel et al. [9] concentrations of
angiogenic and antiangiogenic growth factors were altered after cataract
surgery and this alteration may cause progression of diabetic maculopathy. It
is possible that eyes of patients with diabetes have higher levels of growth
factors, which modulate vascular proliferation and permeability, and this may
compromise the ability of retinal vasculature to recover from the injury and
subsequent inflammation caused by cataract surgery [10].
Ranibizumab is a human monoclonal anti body which inhibits all
VEGF-A isoforms. A detailed analysis of phase 3 clinical trials has generated
évidence-based guidelines for using ranibizumab for the treatment of Diabetic
Macular Edema (DME) [11]. Optical Coherence Tomography (OCT) studies [12,13] found
intravitreal steroidal agents to be effective in reducing macular edema. The
mechanism of action in diabetic macular edema appears to include inhibition of
VEGF and its anti inflammatory effects [14,15]. Cataract surgery can be an
ideal setting to administer intravitreal medications becausesurgery is
performed in a surgically sterile field with full control of the globe and
excellent İntraOcular Pressure (IOP) management [16].
The purpose of this study was to compare the efficacy and safety
of Intravitreal Triamcinolone Acetonide(IVTA) and Intravitreal Ranibizumab
(RAN) in DME patients Schedule for Cataract surgery, to provide a Framework for
the future treatment of patients.
2. Methods
This prospective clinical study was conducted between 2014 and
2015 in accordance with the principles of the Declaration of Helsinki. The
trial protocol has been approved by the Medical Ethical Committee of the
University of Kırıkkale. The study included 42 eyes of 42 patients.
All patients had advanced Cataract with DME and underwent an
uneventful phacoemulsification and intraocular lens implantation at Kırıkkale
University Hospital. Patients were divided in to 3 groups. The first group
received RAN injection (n=12), second group received IVTA (n=10) and the third
group did not receive any injections (n=20).
Inclusion criteria were sight-limiting Cataract in DM patients
with poor fundus view precluding adéquate monitoring and/or macular laser
treatment and the presence of macular edemaas determined by flourescein
angiography and Spectral Domaine Optical Coherence Tomography (SD- OCT).
Patients with active intraocular inflammation, intractable
glaucome, Age-related macular degeneration, a history of ocular trauma or
intraocular surgery with in the previous 3 months, any kind of Intravitreal
drug injections with in the previous 3 months, retinal laser treatment of me
with in the previous 3 months and any known history of adverse reactions to
anti-VEGF drugs were excluded.
Initially ophthalmological examinations findings were included;
Best-Corrected Visual Acuity (BCVA) which was measured with the Snellen chart
and then converted to Logarithme of the Minimum Angle of Resolution (log MAR),
Intraocular Pressure (IOP) by Goldmann applanation tonometry and biomicroscopic
anterior-posterior segment findings, SD-OCT (OCT Advance Nidek RS-3000; Nidek
Co. Ltd., Gamagori, Japan) and Fluorescéine Angiography (FA). After Cataract
surgery, Follow-up examinations were performed at 1 week, 1 and 3 months
postoperatively. A complete ophthalmic examination and SD OCT imaging were
performed at each visit.
All Cataract surgeries were performed Under topical anesthesia
by the same surgeon. A clear corneal side incision was made using a 2.75 mm
incision technique. The anterior chamber was filled with an ophthalmic
viscosurgical device (hydroxypropyl methyl cellulose) and a continuous
curvilinear capsulorhexis was created. After phacoemulsification of the nucleus
and aspiration of epinucleus and cortical material, a foldable hidrophylic
intraocular lens was implanted in to the capsular bag. A 0.05 ml of a solution
containing 0.5 mg of ranibizumab (Lucentis, Novartis Pharma AG, Basel, Switzer
land.) or triamcinolone acetonide as a off-label drug (prapered from 4 mg/0.1
ml- Kenacort®-A 40; Bristol-Myers Squibb, New York, NY, USA) was
injected intravitreally in operating room conditionsat the end of surgery.
SPSS 18.0 statistical program was used for the analysis (SPSS,
Inc., Chicago, IL) Parametric differences between the groups were assessed
using a multivariate analysis. Paired t test was used to
compare the continuous variables. A p value below 0.05 was regarded as
statistically significant.
3. Results
42 eyes of 42 patients with DME and Cataract who underwent
phacoemulsification Cataract surgery with intravitreal injection of 0.5 mg of
RAN or 4 mg IVTA were included in the study. There were 27 (64.3%) female and
15 (34.7%) male patients. The mean age was 64.82±8.0 years (range, 51-84
years).
Twelve patients were included in group 1 (RAN). The median
hemoglobin value was 8.80 (8.84 ±1.31, range 6.77-11.70), including 9 women
(75.0%) and 3 men (75.0%), who had a median age of 65.0 years (mean=64.08±8.57,
range 51-83). Ten patients were included in group 2 (IVTA). The median
hemoglobin value was 8.71 (8.71±1.19, range 6.77-10.23) including 4 women
(40.0%) and 6 men (60.0%), who had a median age of 65 years (mean=63.22±8.16,
range 51-83). And 20 patients were included in group 3 (control). The median
hemoglobin value was 9.62 (8.23±2.3, range 7.20-12.74) including 14 women
(70.0%) and 6 men (30.0%), who had a median age of 65.0 years (mean=66.0±5.61,
range 55-76).
In all groups, there were no significant differences in
termes of age and HbA1c values. (All p>0.05) At baseline, none of the
patients received Prior treatment (either macular laser photocagulation or
intravitreal injection) for macular edema. (Table-1) lists the demographic and
clinical parameters in study groups.
HbA1C=Hemoglobin A1C, Va0=Best corrected visual acuity at
baseline, Va1=Best corrected visual acuity at1st month, Va3: Best corrected
visual acuity at 3thmonth, FT0=Foveal thickness at baseline, FT1=Foveal
thickness at 1st month, FT3=Foveal thickness at3th month, To0=Intraocular
pressure at baseline, To1=Intraocular pressure at1st month, To3=Intraocular
pressure at 3thmonth.
Compared to controls BCVA significantly improved only in group 1
at 1st and 3rd months. (p<0,05).There were
no significant differences for Foveal Thickness (FT) and IOP between the three
groups. (All p>0.05) (Table-2).
Va0=Best corrected visual acuity at baseline, Va1= Best
corrected visual acuity at1st month, Va3: Best corrected visual acuity at 3rd
month, FT0= Foveal thickness at baseline, FT1= Foveal thickness at 1st month,
FT3=Foveal thickness at 3rd month, To0= Intraocular pressure at baseline, To1=
Intraocular pressure at1st month, To3=Intraocular pressure at
3thmonth.
In all groups, BCVA significantly improved at 1stmonths
visit. (All p<0.05) At month 3, significant improvement continue in group 2
and 3. (p<0.05) Foveal thickness showed a reduction only in group 2 at 1st month.
It increased in group 1 and 3. Changes in FT did not reveal any significance in
the study groups. (All p<0.05) Intraocular pressure showed an insignificant
elevation in group 2 at 1st and 3rd months.
(p>0.05) (Table-3).
Va0= Best corrected visual acuity at baseline, Va1= Best
corrected visual acuity at1st month, Va3: Best corrected visual
acuity at 3rd month, FT0= Foveal thickness at baseline, FT1= Foveal thickness
at 1st month, FT3= Foveal thickness at 3rd month, To0= Intraocular pressure at
baseline, To1= Intraocular pressure at1st month, To3= Intraocular pressure at
3thmonth.
No intraoperative complications (posterior capsular rupture,
vitreous loss and dropped lens fragments) and postoperative complications
(endophthalmitis, retinal tears, and retinal détachement) were observed in the
groups.
4. Discussion
Eyes with DR have been associated with an increased incidence of
postoperative macular edema. The macular edema after Cataract surgery in
diabetic patients could be the consequence of Cataract surgery, diabetic
retinopathy or both, but it is not usually easy to differentiate between these
two entities.
Diabetic macular edema results from multiple biochemical and
cellular changes That eventually cause leakage and exudation. Increased
permeability factors, interleukin-6 and VEGF and impaired blood-retina barrier
may lead to the passage of intravascular fluid in to the intra retinal and sub
retinal space through the microaneurysms and abnormal capillaries [18].
Corticosteroids are very potent anti-inflammatory drugs. They
not only inhibit the release of VEGFs but also various cytokines as well [19].
Triamcinolone acetonide is almost the first intravitreal agent used in
ophthalmology. The effective concentration of TA in human vitreous humor has
not been studied yet, but a similar steroid, fluocinolone acetonide has been
reported to be effective at concentrations>0.1 μg/ml [20]. The therapeutic
dose of an IVTA injection in human eye is known to be 4 mg/ml. Beer at al
reported the pharmacokinetics occurring after direct injection of IVTA in to
the vitreous humor [21]. After a single intravitreal injection of triamcinolone
acetonide, the mean elimination half-life was 18.6 days in non-vitrectomized
patients. The half-life in a vitrectomized eye was shorter (3.2 days). In their
study, there was a considerable intra-individual variations among peak
concentration, concentration-time curve values and elimination half-lives.
After Intravitreal injection, mesurable concentrations of triamcinolone
acetonide would be expected to last for approximately 3 months (93 ± 28 days)
in the absence of vitrectomy.
In this study, BCVA improved and FT reduced in triamcinolone
acetonide injected eyes. The therapeutic effect decreased at 3 months, as
expected. Takata et al. [22] found significantly decreased FT and improved BCVA
in 12 diabetic patients with refractory diffuse macular edema during 24 week
follow up. They measured the lowest FT at 1 month. A gradual increase was
observed after 2 months and it reached to baseline level at 6 months. Lam et
al. Followed 17 DME patients after combined cataracta surgery and TA injection
for 6 months. They found significantly improved BCVA and reduced FT at 2
months. There were no significant differences at 6 months [23] In our study, no
significant IOP elevations were found, topical medications were needed only in
two patients.
Recent studies [24-26] have established a strong link between
alterations in angiogenic growth factors and pathogenesis of DR. Angiogenic
growth factors, such as VEGF, induce subclinical and clinical worsening of DR
[9,10] and are biochemical mediators of progression of DR and maculopathy after
uneventful cataract surgery. Vascular endothelial growth factor is a potent
endothelial cell mitogen angiogenic factor and a powerful mediator of vascular
permeability. It leads to breakdown of the blood retina barrier, resulting in
leakage of intravascular fluid from abnormal retinal capillaries.
Krohne et al. Measured RAN concentration in human aqueous
samples and reported the data on the intraocular pharmacokinetics of RAN [27].
They found an aqueous half-life of 7.19 days. Aqueous and vitreous values in
some animal models indicate that RAN half-life measurements derived from
aqueous samples are a good representation of the vitreous values [28-30].
Muether et al. Measured VEGF suppression in the aqueous humor and showed that
the therapeutic effect disappeared after 33.7 ± 5.1 days (31). Pate et al.
Measured VEGF levels in 7 diabetic patients after cataracta surgery [9]. There
was a Ten fold increase at first day and by the end of first month VEGF levels
showed a significant reduction (2.5 fold).
Anti-VEGF drugs may prevent postoperative ME in cataract
patients with DR. Chen et al. Reported significant visual improvement and FT
reduction after bevacizumab injection in 15 patients [32]. Akıncı et al.
Found similar results, but They added grid laser photo coagulation at first
month [33]. Cheema et al. Did not observe any significant improvement in FT and
visual acuity during the 6 months follow up [34].
The effect of ranibizumab on postoperative ME in DR patients has
been shown in a Small number of studies. Rauen et al. Used ranibizumab in 11
refractory DME patients undergoing cataract surgery [35]. There was no control
group in their study. The Authors reported that BCVA improved at 4, 8 and 12
weeks. Six patients received macular laser photocoagulation due to increased FT
at 4 weeks. They did not find any significant difference in FT postoperatively
and linked this to the refractory nature of ME. Chae et al. Investigated the
effect of ranibizumab following cataract surgery in 76 DR patients without ME
[36]. They had 39 patients in phacoemulsification group and 37 patients served
as controls. There was no significant differences for FT, BCVA at 6 months
follow up. Only total macular volume significantly differed in ranibizumab
patients. In our study, BCVA improved significantly in RAN patients compared to
baseline at month one. Nevertheless, it began to decrease at 3rd month.
Foveal thickness increased at 1st month and it continued up to 3rd month.
The change was statistically insignificant.
In conclusion, we compared the efficacy and safety of
ranibizumab and triamcinolone acetonide in macular edema following cataract
surgery in diabetic patients and we found no significant differences between
injection groups and non-injection control group. Ranibizumab group showed a
transient increase in BCVA and TA group was more effective in reducing foveal
thickness. Future studies are still needed to better understand the effect of
these drugs on diabetic macular edema following cataract surgery.
Group |
N |
Age |
HbA1C |
Va0 |
Va1 |
Va3 |
FT0 |
FT1 |
FT3 |
To0 |
To1 |
To3 |
1 |
12 |
64 |
8.8 |
0.85 |
0.63 |
0.67 |
374.1 |
392 |
443.4 |
17 |
15.5 |
15.7 |
2 |
10 |
63.2 |
8.71 |
0.76 |
0.43 |
0.43 |
412.6 |
376.2 |
440 |
17.7 |
18.3 |
19.1 |
3 |
20 |
66 |
9.63 |
0.74 |
0.39 |
0.39 |
357.6 |
429.9 |
373.8 |
15.5 |
16.1 |
16.3 |
total |
42 |
64.8 |
9.18 |
0.76 |
0.56 |
0.47 |
351.8 |
392.4 |
394 |
15.8 |
15.6 |
16.7 |
Table 1: Demographics and clinical parameters in study groups.
Groups |
Va0 |
Va1 |
Va3 |
FTo |
FT1 |
FT3 |
To0 |
to1 |
to3 |
1-2 |
0.96 |
0.744 |
0.573 |
0.711 |
0.405 |
1 |
0.961 |
0.405 |
0.158 |
1-3 |
0.69 |
0.001 |
0.001 |
0.254 |
0.993 |
0.077 |
0.054 |
0.467 |
0.517 |
2-3 |
0.997 |
0.425 |
0.382 |
0.083 |
0.95 |
0.207 |
0.121 |
0.198 |
0.228 |
Table 2: Results of statistical comparisons between the groups (p values).
Groups |
Va0-val |
va0-va3 |
va1-va3 |
FTo -FT1 |
FT0-FT3 |
FT1-FT3 |
to0-to1 |
To1-to3 |
To0-to3 |
1 |
0.027 |
0.177 |
0.503 |
0.27 |
0.051 |
0.151 |
0.059 |
0.27 |
0.072 |
2 |
0.019 |
0.019 |
0.952 |
0.225 |
0.337 |
0.074 |
0.627 |
0.457 |
0.259 |
3 |
0.015 |
0.017 |
0.845 |
0.013 |
0.092 |
0.062 |
1 |
0.854 |
0.837 |
Table 3: Comparisons between pre- and postoperative BCVA, FT and IOP changes in study groups.
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