Volume 8, Number 9
WELCOME to Review
of Ophthalmology's Retina
Online e-newsletter. Each month, Medical Editor Philip Rosenfeld,
MD, PhD, and our editors provide you with this timely and easily
accessible report to keep you up to date on important information
affecting the care of patients with vitreoretinal disease.
siRNA PF-04523655 vs. Ranibizumab for Neovascular AMD Treatment
To evaluate the efficacy of different dosing paradigms of PF-04523655 (PF) versus ranibizumab (comparator) in subjects
with neovascular age-related macular degeneration (AMD), this multicenter, open-label, prospective,
randomized, comparator-controlled exploratory study evaluated 151 patients with subfoveal choroidal neovascularization
(CNV) secondary to neovascular AMD who were naive to AMD therapy.
In this Phase II study, patients were randomized to one of five treatment groups with equal ratio. All groups received ranibizumab
0.5 mg at baseline and (a) PF 1 mg every four weeks (Q4W) from week 4 to week 12; (b) PF 3 mg Q4W from week 4 to week 12; (c)
PF 3 mg every two weeks (Q2W) from week 4 to week 12; (d) PF 1 mg + ranibizumab (combination) Q4W from baseline to week 12; and
(e) ranibizumab Q4W to week 12. All study treatments were given as intravitreal injections. The primary endpoint was the mean
change in best-corrected visual acuity (BCVA) from baseline at week 16; secondary end points included the percentage of patients
gaining ≥10 and ≥15 letters in BCVA and mean change in retinal central subfield thickness, lesion thickness and CNV area.
At week 16, the PF 1 mg + ranibizumab combination group achieved numerically greater improvement in mean BCVA from baseline
(9.5 letters) than the ranibizumab group (6.8 letters). The difference was not statistically significant. The BCVA improvement
in the PF monotherapy groups was less than in the ranibizumab group. Similar trends were observed in the percentage of patients
who gained ≥10 and ≥15 letters. It was reported that from baseline to week 16 (last observed carried forward), the combination
and ranibizumab groups had similar mean reductions in central subfield retinal thickness and total CNV area, which were greater
than in all PF monotherapy groups. There were no clinically meaningful differences in reduction of lesion thickness among
In this early, underpowered study evaluating treatments for neovascular AMD, the combination of PF with ranibizumab led to an
average gain in BCVA that was more than with ranibizumab monotherapy. No safety concerns were identified.
Source: Nguyen QD, Schacar RA, Nduaka CI, et al. Evaluation of the siRNA PF-04523655 versus ranibizumab for the
treatment of neovascular age-related macular degeneration (MONET Study). Ophthalmology. 2012;119(9):1867–1873.
Genetic Differences Between Advanced AMD Subtypes
The authors of the following sibling correlation study and genome-wide association study (GWAS) investigated whether the
two subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV) and geographic atrophy
(GA) segregate separately in families and sought to identify which genetic variants are associated with these two subtypes.
For the sibling correlation study, they included 209 sibling pairs with advanced AMD and for the GWAS, they included 2,594
participants with advanced AMD subtypes and 4,134 controls. Replication cohorts included 5,383 advanced AMD participants and
Participants had the AMD grade assigned based on fundus photography, examination or both and the authors performed a sibling
correlation study to determine heritability of advanced AMD subtypes. For the GWAS, they conducted genome-wide genotyping and
imputed 6,036,699 single nucleotide polymorphisms (SNPs). Then, they analyzed the SNPs with a generalized linear model controlling
for genotyping platform and genetic ancestry. They also evaluated the most significant associations in independent cohorts. Main
outcome measures were concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced
The study authors noted that the difference between the observed and expected proportion of siblings concordant for the same
subtype of advanced AMD was different to a statistically significant degree (p=4.2x10–5), meaning that in siblings of
probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV
to those with GA, they observed a statistically significant association at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR],
1.47; p=4.310–9), which was confirmed in the replication samples (OR, 1.38; p=7.4x10–14 for combined
discovery and replication analysis).
Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation, the authors found. In this large
GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but
imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced
AMD subtype. The authors detected other loci with suggestive associations that differ for advanced AMD subtypes and these
deserve follow-up in additional studies.
Source: Sobrin L, Ripke S, Yu Y, et al. Heritability and genome-wide association study to assess genetic
differences between advanced age-related macular degeneration subtypes. Ophthalmology. 2012;119(9):1874–1885.
ARMS2 Genotype and Bilateral Involvement of Exudative AMD
In Japan, researchers conducted a retrospective cohort study to investigate the association of ARMS2 A69S genotype
with the development of exudative age-related macular degeneration (AMD) in the unaffected fellow eye and to estimate
the duration until the development of AMD in the second eye.
They retrospectively reviewed 326 patients who had exudative AMD in at least one eye, genotyping of ARMS2 A69S, and a
minimum follow-up of two years. They used survival analysis and Cox proportional hazard regression analysis to examine the
association between candidate factors and the duration until the development of AMD in the second eye.
The study researchers reported that 119 patients (36.5%) had bilateral exudative AMD at the initial visit. They also noted
that a risk allele of ARMS2 A69S was more frequently seen in patients with bilateral AMD (p=.0270) than in those with
unilateral AMD. Of the 207 unilateral AMD patients, 23 (11.1%) had AMD in the fellow eye after a mean duration of 56.3 ±
40.4 months. Fellow-eye involvement was associated with ARMS2 A69S genotype (hazard ratio [HR], 2.673; p=.0013),
age (HR, 1.102; p=.0005) and smoking history (HR, 0.680; p=.3663). As HRs indicate, correlation of genotype (2.673)
was as high as that of 10-year aging (1.10210 = 2.641). According to the researchers, survival analysis revealed that patients with
risk homozygous (TT) genotype had second-eye involvement significantly earlier than those with other genotypes (p=.0028).
When the observation duration reached 120 months, second-eye involvement had developed in 50%, 6.6% and 11.2% of the
TT, GT and GG cohorts, respectively.
In conclusion, ARMS2 A69S genotype is associated with second-eye involvement of exudative AMD and with the
period between first- and second-eye involvements.
Source: Tamura H, Tsujikawa A, Yamashiro K, et al. Association of ARMS2 genotype with bilateral involvement
of exudative age-related macular degeneration. Am J Ophthalmol. 2012;154(3):542–548.
Comparison Between Intravitreal Ranibizumab and Bevacizumab for Treatment of Myopic CNV
A total of 55 patients fulfilling inclusion and exclusion criteria were randomized either to intravitreal bevacizumab (IVB) or
to intravitreal ranibizumab (IVR) in a study that sought to compare IVB and IVR in the treatment of subfoveal choroidal
neovascularization (CNV) associated with pathologic myopia.
After the first injection, re-treatments were performed on a pro re nata basis in monthly examinations over an 18-month
follow-up. Primary outcome measures were the change in mean best-corrected visual acuity (BCVA) and the proportion of eyes
improving in BCVA by >1 and >3 lines at the 18-month examination.
It was reported that 48 eyes received the treatment and were subsequently included in the analysis. At the 18-month examination,
a significant improvement of 1.7 lines and 1.8 lines compared with baseline were noticed in the IVR and IVB subgroups, respectively.
The difference in the final mean BCVA between the groups was not significant and a three-line gain or higher was noted in 30% of
eyes in the IVR subgroup and 44% of eyes in the IVB subgroup. Although both groups attained a significant improvement in
central macular thickness, the IVR subgroup achieved a faster central macular thickness reduction. Moreover, a significantly
lower number of injections were administered in the IVR subgroup (2.5) compared with the IVB subgroup (4.7; p<0.001).
To conclude, intravitreal ranibizumab and IVB are effective in the treatment of subfoveal myopic CNV. Intravitreal ranibizumab
achieved greater efficacy than IVB in terms of the mean number of injections administered.
Source: Iacono P, Parodi MB, Papayannis A, et al. Intravitreal ranibizumab versus bevacizumab for treatment of
myopic choroidal neovascularization. Retina. 2012;32(8):1539–1546.
Assessment of Efficacy and Safety of Verteporfin PDT Therapy With Ranibizumab or
Alone Versus Ranibizumab Monotherapy in Patients with Symptomatic Macular PCV
The authors of the following multicenter, double-masked, primarily indocyanine green angiography–guided trial sought to
assess the effects of verteporfin photodynamic therapy (PDT) combined with ranibizumab or alone versus ranibizumab monotherapy
in patients with symptomatic macular polypoidal choroidal vasculopathy (PCV).
They randomized 61 Asian patients to verteporfin PDT (standard fluence), ranibizumab 0.5 mg or the combination. They administered
patients with verteporfin PDT/placebo and initiated them with three consecutive monthly ranibizumab/sham injections starting Day 1,
and re-treated (Months 3–5) as per predefined criteria. The primary endpoint was the proportion of patients with indocyanine
green angiography–assessed complete regression of polyps at Month 6. Secondary endpoints included mean change in best-corrected
visual acuity (BCVA) at Month 6 and safety.
At Month 6, verteporfin combined with ranibizumab or alone was superior to ranibizumab monotherapy in achieving complete polyp
regression (77.8% and 71.4% vs. 28.6%; p<0.01); mean change ± standard deviation in BCVA (letters)
was 10.9 ± 10.9 (verteporfin PDT + ranibizumab), 7.5 ± 10.6 (verteporfin PDT), and 9.2 ± 12.4 (ranibizumab).
There were no new safety findings with either drug used alone or in combination, according to the authors.
They determined that verteporfin PDT combined with ranibizumab 0.5 mg or alone was superior to ranibizumab monotherapy in
achieving complete regression of polyps in this six-month study in patients with symptomatic macular PCV. All treatments
were well tolerated over six months.
Source: Koh A, Lee WK, Chen LJ, et al. EVEREST STUDY: Efficacy and safety of verteporfin photodynamic therapy in
combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal
choroidal vasculopathy. Retina. 2012;32(8):1453–1464.
PCV Development in Unaffected Fellow Eyes
Korean researchers assessed longitudinal changes and determined their angiographic risk factors in the fellow eyes of patients
with unilateral polypoidal choroidal vasculopathy (PCV). They found that the presence of late geographic hyperfluorescence
(LGH) on indocyanine green angiography (ICGA) in the fellow eye appears to be a significant risk factor for the development
of active PCV and may constitute the diagnosis of preclinical PCV.
The researchers reviewed the medical records of 47 patients with unilateral PCV, all of whom had completed at least 12 months
of follow-up. They evaluated the angiographic features including the development of active PCV over time, choroidal vessel
dilation, choroidal vascular hyperpermeability, the branching vascular network (BVN) and LGH, which was defined as a
well-demarcated geographic hyperfluorescent lesion on late-phase on ICGA.
The mean follow-up period was 30.3 ± 12.2 months. Among 47 fellow eyes, 24 (51.1%) had choroidal vascular dilation,
27 (57.4%) had choroidal vascular hyperpermeability, six (12.8%) had BVN and 23 (48.9%) had LGH. The study
researchers noted the development of active PCV in nine fellow eyes (19.1%), all of which had exhibited LGH at baseline.
However, they found that PCV did not develop in eyes without features of LGH at baseline (p&360;0.001). They did note
the development of PCV in three eyes with notification of BVN at baseline; however, PCV also developed in six eyes without
apparent features of BVN (p=0.08).
Source: Kim YT, Kang SW, Chung SE, et al. Development of polypoidal choroidal vasculopathy in unaffected
fellow eyes. Br J Ophthalmol. 2012;96(9):1217–1221.
Benefits of Bevacizumab for ME in CRVO
To evaluate the efficacy of intraocular injections with bevacizumab over 12 months in patients with macular edema (ME) secondary
to central retinal vein occlusion (CRVO), scientists performed this prospective study, which included a randomized six-month,
sham injection-controlled, double-masked clinical trial followed by a six-month open-label extension.
A total of 60 patients with ME secondary to CRVO participated. At baseline, the scientists randomized patients 1:1 to receive
intraocular injections of bevacizumab or sham injections every six weeks for six months. From month 6, all patients received
intraocular injections of bevacizumab every six weeks for six months. The primary outcome measure was the proportion of patients
gaining at least 15 letters at 12 months. Secondary outcome measures included mean change from baseline best-corrected visual
acuity (BCVA), change in foveal thickness and development of neovascular glaucoma.
The study investigators noted that at the end of follow-up, 18 of 30 patients (60.0%) in the bevacizumab/bevacizumab (bz/bz)
group had gained ≥15 letters compared with 10 of 30 patients (33.3%) in the sham/bevacizumab (sh/bz) group
(p<0.05). They reported that BCVA improved by 16.0 letters at 12 months in the bz/bz group compared with 4.6 letters
in the sh/bz group (p<0.05). In an unplanned retrospective analysis, patients aged >70 years had a significantly
worse outcome when receiving delayed treatment, losing 1.4 letters (95% confidence interval [CI], –9.7 to 8.4) in the
sh/bz group compared with a gain of 20.1 letters (95% CI, 13.9–26.3) in the bz/bz group in patients aged <70 years
(p<0.003). The mean decrease in central retinal thickness (CRT) was 435 µm in the bz/bz group compared with
404 µm in the sh/bz group (p= not significant). No patients developed iris rubeosis during the six-month open-label
extension period, the investigators indicated. Furthermore, they observed no events of endophthalmitis, retinal tear or retinal
detachment during the 12-month treatment period and no serious nonocular adverse events were reported.
Intraocular injections of bevacizumab given every six weeks for 12 months improve visual acuity (VA) and reduce ME significantly.
Patients receiving delayed treatment have a limited visual improvement.
Source: Epstein DL, Algvere PV, von Wendt G, et al. Benefit from bevacizumab for macular edema in central retinal
vein occlusion: twelve-month results of a prospective, randomized study. Ophthalmology. 2012; Aug 20.
[Epub ahead of print]. DOI: 10.1016/j.ophtha.2012.06.037.
Link Between Ocular Neovascularization and Central and Hemicentral RVO
Investigators studied the incidence of ocular neovascularization (NV) in central and hemicentral retinal vein occlusion (RVO).
Their study comprised consecutive 912 (673 nonischemic and 239 ischemic) central retinal vein occlusion (CRVO) and 190
(147 nonischemic, 43 ischemic) hemicentral RVO eyes. Ophthalmic evaluation at initial and follow-up visits included recording
visual acuity, visual fields and detailed anterior segment and fundus examinations as well as fluorescein fundus angiography.
In ischemic CRVO, within six months from time of onset, the investigators reported that cumulative probability of development
of iris NV was 49%, angle NV 37%, NV glaucoma 29%, retinal NV 9% and disk NV 6%. They also found that more
severe peripheral retinal hemorrhages were significantly associated with iris NV (p=0.005), angle NV (p=0.0004)
and NV glaucoma (p=0.012). Eyes that developed disk NV had more cotton wool spots (p=0.058) than those without.
Additionally, in ischemic hemicentral RVO, within 12 months of onset, the cumulative probability of development of retinal NV
was 29%, disk NV 12% and iris NV 12%; within six months of onset, angle NV was found in 10% and NV glaucoma in
5%. Anterior chamber flare was associated with anterior segment NV and may precede the development of NV. Patients who developed
NV were significantly younger, and there was a greater prevalence of NV glaucoma in patients with primary open-angle glaucoma.
The study investigators concluded that in ischemic CRVO, anterior segment NV is much more common than posterior segment NV, and
the cumulative chance of developing anterior segment NV is maximum during the first six months. In ischemic hemicentral RVO,
posterior segment NV is much more common than anterior segment NV.
Source: Hayreh SS, Zimmerman MB. Ocular neovascularization associated with central and hemicentral retinal
vein occlusion. Retina. 2012;32(8):1553–1565.
Implications of the CATT on Intravitreal Biologic Agents in Uveitis and Retinal Diseases
The following interpretative essay aimed at providing perspective on the implications of the Comparison of Age-Related
Macular Degeneration Treatments Trials (CATT) on intravitreal biologic agents in uveitis and retinal diseases in which ocular
inflammatory pathways are central to their pathogenesis.
Besides the clear importance of CATT from a patient treatment perspective in age-related macular degeneration (AMD), these data
highlight the critical relevance of highly specific protein immunotherapies offered with biologic agents. The CATT trial also
provides a reminder regarding the importance of rigorous efficacy and safety monitoring required when administering intravitreal
biologic therapy. Within the field of uveitis, systemic and local biologics have been used to effectively treat uveitis,
targeting pathways implicated in both angiogenesis and inflammation (e.g., tumor necrosis factor-α [TNF-α] and
interleukin-2 pathways), and research on intravitreal biologic therapy for uveitis and AMD will continue to expand. With more
than 25 ongoing clinical trials on intravitreal biologic therapy for AMD, enthusiasm for vanguard biologic therapies should be
tempered by judicious monitoring for adverse events.
The importance of the CATT trial encompasses day-to-day treatment decisions for AMD, as well as lessons on how biologics for
ocular disease should be implemented into clinical practice. Specifically, the introduction of intravitreal biologic therapies
into clinical practice for uveitis, AMD, and other ocular diseases in which inflammation is involved should be guided by a
clear understanding of the immunotherapeutic agent and its molecular target and with rigorous monitoring for both patient benefit
and patient safety.
Source: Yeh S, Albini TA, Moshfeghi AA, Nussenblatt RB. Uveitis, the Comparison of Age-related macular degeneration
Treatment Trials (CATT), and intravitreal biologics for ocular inflammation. Am J Ophthalmol. 2012;154(3):429–435.
Relationship Between Longer Axial Length, DR and ME
Investigators in the following cross-sectional, clinic-based study assessed the association of ocular biometric parameters
and refractive error with diabetic retinopathy (DR) and diabetic macular edema (DME) in persons with diabetes.
They included patients with diabetes aged 18 years or more from the Royal Victorian Eye and Ear Hospital in Victoria, Australia.
They assessed spherical equivalent (SE) refraction using objective autorefraction and measured axial length (AL), corneal curvature
(CC) and anterior chamber depth (ACD) using the IOLMaster (Carl Zeiss Meditec). The investigators also graded DR from two-field
retinal photographs using the modified Airlie House classification system. Finally, they defined DME as absent or present from
fundus photographs and confirmed this using optical coherence tomography (Stratus, Carl Zeiss Meditec). As for main outcome measures,
the investigators grouped severity of DR as no DR, mild DR (Early Treatment of Diabetic Retinopathy Study [ETDRS] = 20),
moderate DR (ETDRS = 31–43) and severe DR (ETDRS >43). They also classified DME severity as mild, moderate or severe.
They noted reported that a total of 208 of 630 eyes (33.0%) had DR. In multivariate models, eyes with longer AL were less
likely to have mild (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.41–0.83; p=0.006 per mm increase),
moderate (OR, 0.73; 95% CI, 0.60–0.88; p=0.002) and severe DR (OR, 0.67; 95% CI, 0.53–0.85; p=0.01),
and had a lesser risk of mild (OR, 0.70; 95% CI, 0.56–0.86; p<0.001) and moderate DME (OR, 0.72; 95% CI,
0.56–0.93; p=0.002) but not severe DME. No association was found for SE, ACD and CC with DR.
In conclusion, in persons with diabetes, eyes with longer ALs are less likely to have DR and DME.
Source: Kidd Man RE, Sasongko MB, Sanmugasundram S, et al. Longer axial length is protective of diabetic
retinopathy and macular edema. Ophthalmology. 2012;119(9):1754&3150;1759.
Factors Affecting Retinal Venular Diameter
The authors of this population-based cohort study described how retinal venular diameter changes over time for an individual
and examined differences in these changes among people with different risk profiles.
Participants included 4,600 persons aged 43 to 86 years from the Beaver Dam Eye Study (BDES) who participated in at least one
examination and had venular diameter measured in the right eye. The authors analyzed data from four examinations during a
15-year period. Retinal venular diameter was measured from photographs at each examination by computer-assisted methods and
summarized as the central retinal venular equivalent (CRVE). Associations of risk factors with concurrent CRVE measurements and
changes in CRVE over time were determined using multivariate analyses. Central retinal venular equivalent was the main outcome measure.
The CRVE tended to narrow with age, the study authors observed. They also found that mean CRVE was approximately 5 µm smaller
(225 µm vs. 230 µm) for the average 70-year-old compared with the average 50-year-old, and was approximately 13 µm
smaller (217 µm vs. 230 µm) for the average 85-year-old compared with the average 50-year-old. Male sex (beta estimate
[β] = 5.24; 95% confidence interval [CI], 3.58–6.90), history of current cigarette smoking (β = 9.38; 95% CI,
8.26–10.49) and higher white blood cell (WBC) count (per 1000/µL: β = 0.95; 95% CI, 0.74–1.16) were
independently associated with larger concurrent CRVE, whereas higher mean arterial blood pressure (per 5 mmHg: β = –0.36;
95% CI, –0.50 to –0.23) and higher serum high-density lipoprotein (HDL) cholesterol (per 10 mg/dl: β = 0.89;
95% CI, –1.15 to –0.63) were independently associated with smaller concurrent CRVE. The authors associated history
of cardiovascular disease (CVD) (β = –0.16; 95% CI, –0.26 to –0.06) and presence of chronic kidney disease
(CKD) (β = –0.20; 95% CI, –0.34 to –0.05) with a greater decrease in CRVE over time.
These data show that retinal venular diameter tends to narrow with age; concurrent venular diameter is independently associated with
sex, blood pressure, serum HDL cholesterol, WBC count, and history of current cigarette smoking; and change in CRVE is
independently associated with a history of CVD and presence of CKD. The different independent effects of these interrelated
factors on CRVE highlight the complex relationship between CRVE and systemic diseases and conditions and the difficulty in
determining specific causes of change in CRVE over time.
Source: Myers CE, Klein R, Knudtson MD, et al. Determinants of retinal venular diameter: the Beaver Dam Eye
Study. Ophthalmology. 2012;Aug 21. [Epub ahead of print]. DOI: 10.1016/j.ophtha.2012.06.038.