Original Article

Visual Outcome Following Intra-vitreal

Bevacizumab Injection in Neovascular Agerelated Macular Degeneration
P. S. Mahar, Azfar N. Hanfi
Pak J Ophthalmol 2011, Vol. 27 No. 2
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See end of article for
Purpose: To assess the visual outcome after intravitreal Bevacizumab (Avastin)
authors affiliations
injection in eyes with choroidal neovascularization due to agerelated macular

degeneration (ARMD).
....
Correspondence to:
P.S. Mahar
Isra Postgraduate Institute of
Ophthalmology
Al-Ibrahim Eye Hospital, Malir
Karachi

Received for publication

March 2011
Acceptance for publication
May 2011
....

Material and Methods: This study was conducted in Isra Post-graduate Institute
of Ophthalmology / Al-Ibrahim Eye Hospital, Karachi from February 2007 to
January 2008. Forty two eyes of 30 patients with neovascular ARMD received
3 intravitreal injections of Bevacizumab (1.25 mg / 0.05 ml) at 4-weeks interval
and were followed up for 12 weeks after the initial treatment. Best corrected
visual acuity (BCVA), complete ophthalmic examination, and fluorescein
angiography were done at baseline and on follow up visits. Main outcome
measures were changes in Snellens acuity, and change in angiographic
characteristics of the lesions.
Results: The mean age SD of patients was 65.33 8.32 years. The mean
BCVA SD at baseline was 20/178 4.6 lines on Snellens quotations which
improved to 20/142 4.9 lines and 20/138 4.9 lines at 4 and 12 weeks,
respectively (p<0.001). Visual acuity (VA) improved or remained stable in thirtyseven (88%) eyes. Improvement of 1 or more lines was seen in 17 (40%) eyes.
In majority of the patients, fluorescein angiography showed decreased leakage
and regression of choroidal neovascularization (CNV). No patient had severe
vision loss or significant ocular or systemic side effects.
Conclusion: Intravitreal Bevacizumab injection is effective in improving and
stabilizing the visual acuity in patients with neovascular ARMD.

development of neovascularization. Not only does it

promote the growth and survival of vascular endothelial cells, but also causes conformational changes
of tight junctions of retinal vascular endothelial cells
leading to increased vascular permeability4.

ge related macular degeneration (ARMD) is

the leading cause of irreversible blindness in
patients over the age of 60 years in
developed nations1 and from a worldwide prospective,
it has been estimated to cause 8.7% of total blindness2.
The vast majority of severe vision loss occurs in
patients with the exudative (wet) form of the disease,
which is caused by the growth of abnormal blood
vessels under the central part of the retina3. Several
angiogenic factors have been identified as likely
stimuli for choroidal neovascularization (CNV).
Among them, vascular endothelial growth factor
(VEGF) has proven to be a major stimulus for the

A full length monoclonal antibody that binds all

isoforms of VEGF, Bevacizumab (Avastin, Genentech)
was developed for the treatment of colorectal cancer. It
has been used systemically as well as intravitreally for
the treatment of choroidal neovascularization
secondary to ARMD. Significant improvements in
visual acuity and decreased retinal thickness on

89

hydrochloride 1% ophthalmic drops (Alcaine, AlconBelgium). The site of the injection was measured with
the help of a caliper. Using a 30 gauge needle, 0.05ml
of Bevacizumab (Avastin; Roche Basel, CH;
Genentech, Inc, South San Francisco, California, USA)
was injected intravitreally through the pars plana 3.5
mm from the limbus. Intravitreal injection of
Bevacizumab was repeated in all eyes at four and
eight weeks of follow-up.

optical coherence tomography (OCT) were seen.

However, systemic administration of Bevacizumab
has a small but significant risk of thromboembolism in
patients with cancer6. Contrary, short-term effects of
intravitreal Bevacizumab has shown to be well
tolerated7.
The purpose of this study is to investigate the
short-term effect of intravitreal Bevacizumab on the
visual acuity of patients with neovascular ARMD.

After the injection, intraocular pressure was

measured along with the slit lamp examination of
anterior segment. Patients were instructed to use
topical ciprofloxacin 0.3% (Ciloxan, Alcon-Belgium)
four times a day for three days.

MATERIAL AND METHODS

This study was conducted in Isra Post-graduate
Institute of Ophthalmology/Al-Ibrahim Eye Hospital,
Karachi from February 2007 to January 2008. The
design of the study was Quasi experimental with
purposive sampling.

Patients were examined at one week and four

weeks after each injection. At each visit, BCVA was
measured along with the slit lamp examination of the
anterior segment, intraocular pressure measurement
and dilated fundus examination. Fluorescein fundus
angiography was repeated at 12th week follow-up.

Forty two eyes of 30 patients with neovascular

ARMD with clinical and angiographic evidence of
CNV, age 50 years or older, ability to comply with the
study protocol, and without any previous treatment
for neovascular ARMD were enrolled for the study.
Patients with a history of thromboembolic events
within the past 3 months, presence of ocular
conditions other than ARMD in the study eye that can
affect the vision and/or safety, previous intraocular
surgery within last 3 months and a history of
fluorescein allergy were excluded from the study.

The main outcome measures were changes in

Snellens acuity, and change in angiographic
characteristics of the lesions. Snellens acuities were
converted to the logarithm of the minimum angle of
resolution (log MAR) to facilitate statistical analysis.
The paired Student t-test was used to compare the
mean visual acuity at weeks four to 12 after treatment
with mean baseline measurements. The level of
statistical significance was set at P< 0.05 with a 95%
confidence interval. Statistical analysis was done
through statistical package for social sciences (SPSS)
10.0.

Patients were selected from Retina clinic at AlIbrahim eye hospital according to the inclusion and
exclusion criteria. The off-label use of the drug and its
potential risks and benefits were discussed extensively
with all patients. All patients signed a comprehensive
consent form before administration of bevacizumab.
Baseline assessment included: best corrected visual
acuity (BCVA) using Snellens chart; biomicroscopic
examination of anterior segment; intraocular pressure
measurement with Goldman applanation tonometer;
dilated fundus examination with +90 diopters lens and
indirect ophthalmoscope; and colored photograph of
the retina with the help of digital fundus camera.
Fluorescein angiography was performed to identify
the location and subtype of the lesions and to verify
the presence of active choroidal neovascular leakage.

RESULTS
Forty-two eyes of 30 patients with choroidal
neovascularization due to ARMD were treated with an
intravitreal injection of Bevacizumab. There were 19
men and 11 women. The average age was 65.3 years,
ranging between 54 to 83 years. Out of 30 patients, 12
(40%) patients of neovascular ARMD had active CNV
component in both eyes while the rest of the patients
had unilateral lesion.
Baseline characteristics of CNV lesions on
fluorescein angiography showed predominantly
classic lesion in 8(19%) eyes, minimally classic in
18(43%) eyes and occult in 16(38%) eyes (Fig. 1).

The Aga Khan University hospital pharmacy

prepared 1.25mg (0.05 ml) injections in a 30-guage
insulin syringe for each patient from commercially
available 4 ml vial of Bevacizumab (25mg/ml) under
aseptic techniques. The eyes to be treated were
prepared with 5% povidone-iodine solution. Topical
anesthesia was administered using proparacaine

Thirty-one (74%) eyes had subfoveal location of

CNV while the rest were juxtafoveal except for 2 (5%),
which were extrafoveal (Fig. 2).

90

The mean BCVA SD at baseline was 20/178 4.6

lines (LogMAR values= 0.950.46). Most significant
improvement was seen at 4th and 8th week with mean
BCVA SD of 20/142 4.9 lines (LogMAR values =
0.850.49) and 20/138 4.9 lines (LogMAR values=
0.840.49) [p < 0.0001], respectively (Tables 1, 2).

members of the family are usually overlooked.

Additionally, they have less access to any kind of
treatment and the least is spent on their health as
compared to males however it could not be stated
with certainty as the collection of socioeconomic status
and locality data of these patients was not carried out.

Overall, 20 eyes (47.6%) had stabilization of visual

acuity at the final follow-up. This was defined as no
gain or loss in visual acuity. Seventeen eyes (40.5%)
had improvement in visual acuity (Fig. 3).

The study found the baseline characteristics of

CNV lesions on fluorescein angiography as
predominantly classic lesion in 19%, minimally classic
in 43% and occult in 38% of the eyes which was similar
to a case series reported by Yoganathanet al15.

Mean IOP SD at baseline was 13.7 3.3.

Insignificant increase was seen in IOP after injecting
Bevacizumab (P-value = 0.096) (Table 3).

Laic R et al16 reported 74.8 years as mean age of

patients in his study. However, in our study the
average age of the patients was 65.4 years. The
discrepancy could be due to the fact that most of the
(74%) eyes had subfoveal location of CNV in the
current study and subfoveal CNV causes more severe
and more rapid loss of vision than juxtafoveal or
extrafoveal lesions, as fovea has the highest
concentration of photoreceptors which could get
damaged early due to the sub-retinal CNV. Therefore,
these patients presented at an earlier stage of the
disease.

After 12 weeks, 26 eyes (62%) showed regression

of CNV along with reduced leakage on fluorescein
angiogram while the rest had stabilization of CNV
after three injections of Bevacizumab (Fig. 4).
DISCUSSION
There is increasing evidence that medications
targeting vascular endothelial growth factor (VEGF)
are effective in the treatment of choroidal
neovascularization (CNV) associated with age-related
macular
degeneration
(ARMD).
Pegaptanib
(Macugen), and more recently, Ranibizumab
(Lucentis), have been subjected to large randomized
clinical trials and have been proven safe and effective810. Bevacizumab (Avastin) is also an anti-VEGF drug
which is Food and Drug Administration (FDA)
approved for intravenous use in patients with
colorectal cancer. In patients with ARMD, systemic
administration of the drug has been shown to improve
vision and decrease retinal thickness11. Preliminary
laboratory studies have demonstrated the drug to be
well tolerated as an intravitreal injection12. Avery et al
13reported a retrospective case series of 81 eyes that
had intravitreal Bevacizumab for CNV associated with
ARMD, showed promising results and supports the
continued exploration of Bevacizumab as a treatment
option.

Results of this study support the hypothesis that

there is significant improvement of visual acuity in
eyes with choroidal neovascularization due to agerelated macular degeneration after giving intravitreal
Bevacizumab injection. Mean Snellens acuity
improved from 20/178 to 20/145 at 3 months after
administrating 3 intravitreal Bevacizumab injections 1
month apart. Most significant improvement in mean
visual acuity, 20/142 and 20/ 138, was seen at 4 and 8
weeks respectively with a slight but significant decline
at 12th week follow-up. These results are less
impressive than those of Rich et al14 and Spade et al17
that described 3 lines of vision improvement in
38.3% to 44% of treated patients, respectively. This
may represent short-term variability of visual acuity
measurements or differences in baseline features of the
respective patient populations. More over Bari et al18
reported the vitreous half-life of 1.25 mg of intravitreal
Bevacizumab in a rabbit eye as 4.32 days. This also
explains the necessity for frequent intravitreal
injections of Bevacizumab in exudative ARMD to
persistently neutralize the VEGF in these patients.

In this study, 30 patients were included. The

gender distribution (63% males against 37% females)
shows a male preponderance. This was in contrast
with studies done in developed countries, where
either female preponderance13 or similar 14
distributions were seen. The difference in gender
distribution in our study could be attributed to our
rural social system where problems of female

Smith and his collegues19 combined the

photodynamic therapy with intravitreal injection of
Bevacizumab for the treatment of neovascular ARMD.

91

Table 1. Best corrected visual acuity pre and post bevacizumab injection, (n=42)
Best Corrected Visual Acuity (BCVA)

Mean SD

P-Value

Baseline

20/178 4.6 lines

First Week

20/158 4.6 lines

Fourth week

20/142 4.9 lines

Eighth week

20/138 4.9 lines

Twelfth week

20/145 4.9 lines

< 0.0001

Table 2. Comparison of baseline best corrected visual acuity (BCVA) with each post-injection follow-up, (n=42)
Factors

BCVA

Mean S.D

Comparisons

p-value

Baseline

20/178 4.6 lines

II

After 1 week

20/158 4.6 lines

I vs. II

0.058

III

After 4 weeks

20/142 4.9 lines

I vs. III

0.001

IV

After 8 weeks

20/138 4.9 lines

I vs. IV

0.003

After 12 weeks

20/145 4.9 lines

I vs. V

0.029

Table 3. Comparison of intra ocular pressure pre and post bevacizumab injection, (n=42)
Best Corrected Visual Acuity (BCVA)

Mean SD

Baseline

13.7 3.3

First Week

14.1 2.6

Fourth week

14.9 1.9

Eighth week

14.1 2

Twelfth week

14.45 2.3

P-Value

0.096

complete resolution of CNV component at 3 month. It

was a small, (< disc diameter) subfoveal and occult
type of CNV in a 54 year old male.

Seventy-three
percent
of
patients
showed
improvement in visual acuity. Mean improvement in
visual acuity of 1.73 lines in this study is similar to
findings of other studies13,20 in, which patients
received Bevacizumab injection as monotherapy.
However, they witnessed complete resolution of CNV
in 65% of eyes after a single combination treatment
while in this study 62% showed regression of CNV
along with reduced leakage on fluorescein angiogram
while the rest had stabilization of CNV after three
injections of Bevacizumab. Only one case showed

In the current study, overall post treatment visual

acuity improved in 40.5% of cases while it remained
stable in 47.6% of cases that was comparable with
other studies. Rich et al14 reported visual acuity
improvement in 44% of eyes at 3 month and Cleary et
al21 found improvement or stabilization of vision in
76.5% of cases at 6 months.

92

16 (38%)

not find any significant change in IOP pre and post

injection. Similar results were also reported by
Yoganathan and coworkers15. This could be due to the
short half-life of intravitreal Bevacizumab as shown by
Bari et al18, who obtained data from 40 eyes of 20
rabbits showing a peak concentration of 400 g/ml in
the vitreous humor 1 day after the intravitreal
injection of Bevacizumab. Vitreous concentrations of
Bevacizumab declined steadily with a half-life of 4.32
days maintaining the concentrations of 10 g/ ml for
30 days. Moreover, humans have a larger vitreous
cavity then rabbits (4.5 ml and 1.5 ml respectively). In
this study, after injecting intravitreal Bevacizumab, we
recorded the IOP at 1st week and then at 4, 8 and 12
weeks. There might have been a transient rise in IOP
during the first few days as shown by Fleckenstein et
al 22 and Hollands et al23 who reported a predictable
volume related rise in IOP after injecting intravitreal
Bevacizumab, which never occluded the central retinal
artery and which spontaneously fell below 30 mmHg
in all eyes within 15 minutes of injection.

8 (19%)

18 (43%)
Predominantly Classic

Minimally Classic

Occult

Fig. 1: Types of choroidal neovascular membrane on

fundus fluorescein angiography ( n = 42)
0%
2 (5%)

Subfoveal

9 (21%)

Juxtafoveal
Extrafoveal

31 (74%)

Fig. 2: Location of choriodal neovascular membrane

on fundus fluorescein angiography ( n = 42)
40

Fig. 4. Fluorescein angiographic changes in an eye

with subfoveal occult choroidal neovascularization
(CNV) due to age related macular degeneration
(ARMD) after three intravitreal injections of
bevacizumab. Late phase angiograms at baseline
(left) and at 12 weeks of follow-up (right), showing
considerable decrease in the leakage and size of the
CNV.

Number of Patients (%)

35
30
20 (47.6)

25
20

17 (40.5)

15
10

5 (11.9)

5
0
Improved

Decreased

The Bevacizumab preparation is unpreserved and

contains no ingredients that are known to be toxic to
the eye. Bevacizumab has been tested in rabbit eyes
and no evidence of toxicity was seen by electroretinogram (ERG) or visual evoked potential (VEP)
testing24. These findings were consistent with those by
Matura and associates25, who demonstrated that no
evidence of retinotoxocity noted in the short term use

Stable

Visual Acuity

Fig. 3: Overall post-treatment visual acuity, ( n = 42)

Theoretically, injecting any extra volume in the
closed vitreous cavity can cause an increase in
intraocular pressure. However, in this study we did

93

Authors affiliation

of intravitreal bevacizumab in patients with

neovascular ARMD. Adverse events observed during
intravenous use of Bevacizumab (5mg/kg) for treating
colorectal cancer include hypertension, impaired
wound healing, hemorrhage, thromboembolic events,
myocardial infarction, stroke and proteinuria26. Since,
the intravitreal dose of Bevacizumab is approximately
1/400th that of the intravenous dose therefore the
safety profile of intravitreal Bevacizumab appeared to
be more favorable. In a study of Avery and associates89
involving 79 patients, no significant systemic or ocular
complications were noted. This finding was consistent
with that of other investigators17,14,15,19. Similarly, in
the present study intravitreal Bevacizumab at a dose
of 1.25 mg (0.05 ml) appeared to be well tolerated by
all
patients.
Systemic
adverse
events
like
hypertension, stroke, or myocardial infarction and
ocular adverse events, like uveitis, raised IOP,
endophthalmitis, vitreous hemorrhage or retinal
detachment were not recorded. Few patients
experienced a reduction in visual acuity which could
be due to the disease progression rather than the drug
toxicity.

P.S Mahar
Isra Postgraduate Institute of Ophthalmology
Karachi
Azfar N. Hanfi
Isra Postgraduate Institute of Ophthalmology
Karachi
REFERENCE
1.

2.

3.

4.

5.

The weaknesses of this study include absence of

randomized controls, limited number of patients,
nonstandard visual evaluation and short term followup. Lesion size and chronicity were not evaluated.
Optical coherence tomography of these patients would
have provided us with a better visualization of the
retinal anatomy than fluorescein angiography.
However, the OCT was unavailable in our set up and
we could not subject our patients to an extra financial
burden of going to a private setup. Nevertheless OCT
is recognized as a superior tool to FFA in documenting
anatomical outcome.

6.

7.

8.

9.

Furthermore, randomized trials should also

compare intravitreal Bevacizumab with other available
anti-VEGF agents, such as pegaptanib sodium and
Ranibizumab because the much lower cost per dose of
intravitreal Bevacizumab compared with that of
pegaptanib and Ranibizumab, make it promising and
cost effective treatment option for those who may not
be able to afford the more expensive alternatives.

10.

11.

12.
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CONCLUSION

14.

Intravitreal Bevacizumab injection is effective in

improving and stabilizing the visual acuity in patients
with neovascular ARMD. Large, randomized,
controlled trial is warranted to evaluate the long term
efficacy and safety of this treatment.

15.

94

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Glaucoma

Considering the recent developments in imaging techniques and their applications to glaucoma, despite most of
these still being research tools, the OCT is somewhat better than HRT and GDx as diagnostic help and has the
most potential for long term detection of structural changes in glaucoma.

M Lateef Chaudhry
Editor-in-Chief

95